Methods of producing heterocyclic compounds

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a heterocyclic compound, involving: reaction of a mixture of 1-methylpiperazine and 5-halogen-2-nitroaniline in a first solvent and at a first temperature ranging from approximately 90°C to approximately 110°C to obtain a compound of formula where the first solvent contains alcohol; cooling the mixture containing the compound of formula VIH to a second temperature ranging from approximately 85°C to approximately 95°C; adding a volume of a second solvent which is different from the first solvent to the mixture, where the second solvent contains water; and forming a suspension of the compound of formula VIH; where the second solvent is heated to the second temperature. The invention also relates to methods of producing a compound of formula VIH using other solvents such as heptane and HO-(CH2)q-OH or HO-CH2CH2OCH2CH2-OH, where q is selected from 2, 3 or 4.

EFFECT: novel method of producing a compound of formula VIH, which enables to obtain a highly pure product which does not require additional purification and is more suitable for use on a large scale owing to the solvents used.

74 cl, 6 ex

 

The technical field to which the invention relates.

The present invention in General relates to methods of preparing compounds of Hinayana. More specifically, the present invention relates to improved methods of producing compounds of aminoquinoline and to methods for producing compounds of aminoquinoline and to compositions which contain small amounts of lithium.

Background of the invention

It has been described many chemical compounds and compositions having activity against one or more vascular endothelial growth factor receptor tyrosine kinase (VEGF-RTK). Examples include quinoline derivatives such as described in WO 98/13350, derivatives aminonicotinamide (see, for example, WO 01/55114), antisense compounds (see, for example, WO 01/52904), peptidomimetics (see, for example, WO 01/52875), derivatives of hintline (see, for example, US-6, 258, 951), monoclonal antibodies (see, for example, EP 1086705 A1), various 5,10,15,20-tetraarylporphyrins and 5,10,15-teerikorpi (see, for example, WO 00/27379), derivatives of heterocyclic alkanesulphonic and alkenylboronic acid (see, for example, DE 19841985), derivatives of oxiandoliluksousna (see, for example, WO 99/10349), derivatives of 1,4-desantana (see, for example, US 5, 763, 441) and derivatives cinnoline (see, for example, WO 97/34876) and various compounds indazole (see, for example, WO 01/02369 and WO 01/53268).

The synthesis of roizvodnykh 4-hydroxyquinoline and 4-hydroxyquinoline solution described in several sources. For example, article Ukrainets and al. described the synthesis of 3-(benzimidazole-2-yl)-4-hydroxy-2-oxo-1,2-dihydroquinoline. Ukrainets, I. and others, Tetrahedron Lett., 1995, 42, SS-7748; Ukrainets, I. and others, Khimiya Geterotsiklicheskikh Soedinii, 1992, 2, s-241. Ukrainets also discloses the synthesis, anticonvulsant and anti-thyroid activity of other 4-hydroxyquinolone and thioanalogues, such as 1H-2-oxo-3-(2-benzimidazolyl)-4-hydroxyquinolin. Ukrainets, I. and others, Khimiya Geterotsiklicheskikh Soedinii, 1993, 1, s-108; Ukrainets, I. and others, Khimiya Geterotsiklicheskikh Soedinii, 1993, 8, s-1108; Ukrainets, I. and others, Chem. Heterocyclic Comp., 1997, 33, s-604.

The synthesis of various quinoline derivatives described in WO 97/48694. These compounds are able to bind to nuclear receptors of hormones and are useful for stimulating proliferation of osteoblasts and bone growth. Also described that the compounds are useful for the treatment or prevention of disorders associated with families of nuclear receptors of hormones.

Various quinoline derivatives in which the benzene ring is substituted quinoline group of sulfur, described in WO 92/18483. These compounds are described as useful for obtaining pharmaceutical compositions and in the quality of medicines.

Described that quinolone derivatives and coumarin derivatives are used in a number of areas, not related to medical and pharmaceutical compositions. References which disclose the preparation of derivatives of quinolone to apply for photopolymerizing is omposite or possessing fluorescent properties, include: US 5, 801, 212, Okamoto and others; JP 8-29973; JP 7-43896; JP 6-9952; JP 63-258903; EP 797376 and DE 2363459.

The plethora substituted compounds of Hinayana, including connection chinainternational and 4-aminotoluene connection chinainternational, such as 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]quinoline-2(1H)-it is disclosed in a recent sources, such as WO 02/22598 and WO 2004/043389. Such compounds, as described, inhibit VEGF-RTK. Such compounds are also described in published applications US 2002/0107392 and US 2003/0028018 and US patents 6, 605, 617, 6, 774, 237 and 6, 762, 194. Heterocyclic compounds, close to benzimidazolidinone, have recently been described in WO 02/18383, US 2002/0103230 and US 6, 756, 383. Other such compounds, with new applications such compounds for the inhibition of serine/trainingin and tyrosinekinase described in WO 2004/018419 and US 2004/0092535 filed 19.08.2003, and have priority in the following applications: US 60/405,729, filed 23.08.2002; US 60/426, 107, filed 13.11.2002; US 60/426, 226, filed 13.11.2002; US 60/426,282, filed 13.11.2002; US 60/428, 210, filed 21.11.2002; US 60/460, 327, filed 3.04.2003; US filed 3.04.2003; US 60/460 .493 filed 3.04.2003; US 60/478, 916, submitted 16.06.2003; and US 60/484, 048, filed 1.07.2003. Each of the links in this paragraph are given in full in the reference and in order, as if they were given here in full.

Different ways of obtaining compounds aminobenzenesulfonamide described in US 10/982, 757 filed 5.11.2004, which is incorporated fully herein by reference and in order, as if it was given here in full.

Although there have been described various methods for obtaining compounds of Hinayana, there is a need for new methods that optimize the yield of these compounds, due to their important applications to obtain pharmaceutical compositions and applications.

The invention

The present invention relates to methods for heterocyclic compounds useful for the synthesis of aminosilane compounds of benzimidazolidinone.

In one embodiment, the present invention relates to a method for obtaining compounds of formula VIH:

The method involves the reaction of 1-methylpiperazine 5-halogen-2-nitroaniline with an internal temperature sufficient to obtain the compounds of formula VIH. In such embodiments of the method, 1-methylpiperazine and 5-halogen-2-nitroaniline is subjected to reaction in a solvent that contains water. Water may be present in more than 50 vol.% in terms of the amount of solvent. In some embodiments, the implementation of the 5-halogen-2-nitroaniline represents 5-chloro-2-nitroaniline, and in other embodiments, the implementation represents 5-fluoro-2-nitroaniline.

In some embodiments, the implementation of the solution is tel contains water in an amount more than 80% vol. in terms of the amount of solvent. In some such embodiments, the implementation of the solvent contains water in an amount of more than 90 vol.% in terms of the amount of solvent. In some other such embodiments, the implementation of the solvent contains water in an amount of more than 98% in terms of the amount of solvent. In some other embodiments, the implementation of the solvent contains essentially only water or a water. In some other embodiments, the implementation of the solvent contains essentially only deionized or distilled water or a deionized or distilled water.

In some embodiments, the implementation of the solvent is an aqueous solution containing salt, such as NaCl. In some such embodiments, the implementation of the concentration of salt in the aqueous solution ranges from about 1 to about 5 M In some such embodiments, the implementation of the salt concentration ranges from about 2 to about 5 M, in other embodiments, the implementation varies from about 3 to about 4.5 M, and in other embodiments, the implementation varies from about 3.5 to about 4.2 Meters In some other embodiments, the implementation of an aqueous solution saturated with salt, such as NaCl.

In some embodiments, the implementation of methods for obtaining the compounds of formula VIH solvent contains salt and an inorganic base. As with the other is their ways described here, salt can be an NaCl, but is not limited to it. The salt concentration in aqueous solution can vary from about 1 to about 5 M, from about 2 to about 5 M, from about 3 to about 5 M, or as described above. Suitable inorganic bases for use in the methods include NaOH, KOH, CA(Oh)2, Mg(OH)2, Na2CO3To2CO3To3RHO4or a mixture of any two or more of these grounds. The amount of the inorganic base used in some embodiments, the implementation can vary from about 0.5 to about 4 equivalents, in terms of the number of 5-halogen-2-nitroaniline. In other embodiments, the implementation of a number of inorganic bases is from about 1 to about 4 equivalents, from about 1 to about 3 equivalents, from about 1.5 to about 2.5 equivalents, or about 2 equivalents.

In some embodiments, the implementation of the internal temperature of the support above about 95°C. In various such embodiments, the internal temperature ranges from about 99°C. to about 115°C., from about 100°to about 110°C., from about 105°to about 115°C., or from about 105°to about 110°C.

In some embodiments, the implementation of the 1-methylpiperazine and 5-halogen-2-nitroaniline is subjected to reaction at an internal temperature for a reaction time less than 20 hours. In some such embodiments, the OS is supervising the reaction time is less than 10 hours. In some such embodiments, the implementation of the response time is less than 8 hours.

In some embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 2:1 to about 10:1 in the beginning of the reaction. In some such embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 3:1 to about 4.5:1 in the beginning of the reaction. In other such embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 4:1 to about 4.3:1 in the beginning of the reaction. The advantage of these methods using salt and inorganic bases is that fewer 1-methylpiperazine to obtain high yields of product VIH than is required to obtain high outputs without the use of inorganic bases. For example, 1-methylpiperazine and 5-halogen-2-nitroaniline may be present in a molar ratio ranging from about 1.5:1 to about 3:1.

In some embodiments, the implementation of the output of the compounds of formula VIH in terms of the number of 5-halogen-2-nitroaniline is over 90%. In other embodiments, implementation of the output is more than 93%. In other embodiments, implementation of the output is more than 96%.

In another embodiment, the described methods of obtaining the heterocycle is an economic connection, comprising the reaction of a mixture of 1-methylpiperazine and 5-halogen-2-nitroaniline in the first solvent and the first temperature sufficient to obtain the compounds of formula VIH in the first solvent, the first solvent is an organic solvent; adding to the mixture a second solvent different from the first solvent; and the suspension of the compounds of formula VIH. The first solvent may contain alcohol. For example, the first solvent may include, consist essentially of or consist of only ethanol. In some embodiments, the first temperature sufficient to obtain the compounds of formula VIH, can vary from about 90°to about 110°C. In some embodiments, the implementation of the 1-methylpiperazine and 5-halogen-2-nitroaniline are present in a molar ratio of from about 2:1 to about 5:1. In some embodiments, the implementation of the 5-halogen-2-nitroaniline represents 5-chloro-2-nitroaniline, and in other embodiments, the implementation represents 5-fluoro-2-nitroaniline.

In some embodiments, the implementation of the methods of obtaining the heterocyclic compounds of the second solvent includes, consists essentially of or consists only of water. Such methods may also include cooling the mixture containing the compound of formula VIH, to a second temperature, amounting to at least 80% of the first ones is the temperature before adding water, and where the water is heated to about the second temperature before adding. For example, the second temperature may range from about 85°to about 95°C. In some embodiments, the implementation of a suspension formed upon cooling the reaction mixture to a third temperature (e.g., from about 15°to about 25°C.) to induce a suspension of the compound of formula VIH.

In other embodiments, implementation of the methods of obtaining the heterocyclic compounds of the second solvent is an organic solvent. The second solvent includes, consists essentially of or consists only of heptane. In some embodiments, the implementation of the methods also include cooling the mixture containing the compound of formula VIH, to a second temperature, amounting to at least 70% from the first temperature, for example from about 70°to about 85°C, before addition of the second solvent. As described above, a suspension is formed by cooling the reaction mixture to a third temperature, which is in the range from about 15°to about 25°C. to induce a suspension of the compound of formula VIH. The methods may also include the addition of a second volume of the second organic solvent while cooling to a third temperature to form crystals of the compound of formula VIH. Crystals connection VIH can be collected and rinsed with water.

In another embodiment, the invention relates to methods for heterocyclic compounds through more effective use of 1-methylpiperazine in the separation of the product from the reaction solution and reuse the remaining reaction solution. Thus, the methods include the reaction of 1-methylpiperazine 5-halogen-2-nitroaniline in a solvent containing water and salt, with the first reaction mixture at a temperature sufficient to obtain the compounds of formula VIH. The first reaction mixture may be cooled and filtered to obtain a first filtered solids containing the compound of formula VIH, and the first filtrate containing solvent. The reaction can be carried out for the second time, when added to the first filtrate 1-methylpiperazine, 5-halogen-2-nitroaniline and amount of base sufficient to neutralize any amount of HCl in the first filtrate, to obtain a second reaction mixture at a temperature sufficient to obtain the compounds of formula VIH. Again the second reaction mixture is cooled and filtered to obtain a second filtered solids containing the compound of formula VIH, and the second filtrate containing solvent. The methods may further include adding a second filtrate methylpiperazine, 5-halogen-2-nitroaniline and amount of base sufficient to neutralize any amount of HCl in the second filtrate, to obtain a third reaction mixture at a temperature sufficient to obtain the compounds of formula VIH. Third, the reaction mixture may be cooled and filtered to obtain a third filtered solids containing the compound of formula VIH, and the third filtrate containing solvent. In some embodiments, the implementation of the salt is NaCl. In other embodiments, the implementation of the base is an NaOH or KOH. The temperature of the reaction solution may vary, for example, from about 95°to about 120°C. In some embodiments, the implementation of the 5-halogen-2-nitroaniline represents 5-chloro-2-nitroaniline, and in other embodiments, the implementation represents 5-fluoro-2-nitroaniline.

In another embodiment, the present invention relates to a method for obtaining compounds of formula VIH, including the reaction of 1-methylpiperazine 5-halogen-2-nitroaniline with an internal temperature sufficient to obtain the compounds of formula VIH. 1-Methylpiperazine and 5-halogen-2-nitroaniline is subjected to reaction with the solvent, which contains a component of an organic solvent that has a boiling point over 100°C at atmospheric pressure. In kotoryj variants of implementation of the 5-halogen-2-nitroaniline represents 5-chloro-2-nitroaniline, in other embodiments, the implementation represents 5-fluoro-2-nitroaniline.

In some embodiments, the implementation of the solvent is a compound of the formula HO-(CH2)q-OH, or HO-CH2CH2OCH2CH2-OH, where q is selected from 2, 3 or 4. In some such embodiments, the implementation of the solvent contains propylene glycol or ethylene glycol. In other such embodiments, the implementation of the solvent consists essentially of or consists only of propylene glycol or ethylene glycol. In other such embodiments, the implementation of the solvent consists essentially of or consists only of ethylene glycol.

In some embodiments, the internal temperature is over 95°C. In various such embodiments, the internal temperature ranges from about 99°C. to about 130°C., from about 115°to about 130°C. or from about 120°to about 125°C.

In some embodiments, the implementation of the 1-methylpiperazine and 5-chloro-2-nitroaniline is subjected to reaction at an internal temperature within the reaction time less than 20 hours. In some such embodiments, the implementation of the response time is less than 10 hours. In some such embodiments, the implementation of the response time is less than 8 hours. In other embodiments, implementation of the reaction time varies from 3 to 6 hours, and in some embodiments, the implementation of warerooms is from 4 to 5 hours.

In some embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 2:1 to about 10:1 in the beginning of the reaction. In some such embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 3:1 to about 4.5:1 in the beginning of the reaction. In other such embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 4:1 to about 4.3:1 in the beginning of the reaction.

In some embodiments, the implementation of the output of the compounds of formula VIH in terms of the number of 5-halogen-2-nitroaniline is over 90%. In other embodiments, implementation of the output is more than 92%. In other embodiments, implementation of the output is more than 96%.

As is obvious to a person skilled in the technical field, the compound of formula VIH and methods of obtaining this compound can be included in any scheme described here synthesis. For example, in some embodiments, the implementation of the methods according to the invention also include:

the recovery of the compounds of formula VIH, obtaining the compounds of formula IVA:

In other embodiments, implementation methods include the reaction of compounds of formula IVA with a compound of formula V to obtain the compounds of formula IIC or IID, where

the compound of formula V has the following structure is round:

where each R9arepresents independently unsubstituted alkyl group containing from 1 to 8 carbon atoms, and X represents a halogen atom selected from F, Cl, Br or I, or represents a conjugate base of the acid; and

the compound of the formula IIC or IID has the following structure:

In some embodiments, the implementation of R9arepresents methyl or ethyl, and X represents Cl.

In some other embodiments, implementation methods include the reaction of compounds of formula I with a compound of the formula IIC or IID in a suitable solvent in the presence of sodium or potassium base to obtain a reaction product comprising a compound of benzimidazolidinone, where the compound of formula I has the following structure:

where

R1, R2, R3and R4may be the same or different and independently selected from H, Cl, Br, F, I, -OR10groups, -NR11R12groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted etkinlik groups, substituted or unsubstituted heterocyclyl the x groups, or substituted or unsubstituted geterotsiklicheskikh groups; and

further, where the connection benzimidazolyl is a compound of formula IIIC, is tautomer compounds of formula IIIC, is a salt of compounds of formula IIIC, or a salt tautomer the compounds of formula IIIC:

In some embodiments, implementation methods, R1selected from H, Cl, Br, F or I. In other embodiments, implementation of R1represents F. In other R2, R3and R4all represent H. In some embodiments, the implementation of the methods, the compound of formula I is a compound of formula IA having the following structure:

and the connection of benzimidazolidinone is a compound of formula IIIB is tautomer the compounds of formula IIIB, is a salt of compounds of formula IIIB or salt tautomer the compounds of formula IIIB:

Such methods may also include the reaction of the compound of benzimidazolidinone with lactic acid to obtain the salt of lactic acid compounds of benzimidazolidinone.

Other objects, features and advantages of the invention will become apparent from the following detailed description.

Detailed description of the invention/p>

The present invention relates to methods for aminosilane compounds of Hinayana. Such compounds act as antagonists of the receptor tyrosinekinase and more specifically as inhibitors of the function of PDGFRα and PDGFRβ, bFGF and/or VEGF-RTK. Such compounds have significant activity against other tyrosinekinase, as well as against a variety of serine/trionychinae. These compounds can be introduced into pharmaceutical compositions, which are useful, for example, for the treatment of patients in need of an inhibitor of VEGF-RTK, especially for use in compositions and methods for reducing capillary proliferation and to treat cancer. Methods of obtaining aminosilane compounds of Hinayana allow synthesis of the compounds and compounds which contain reduced amounts of lithium.

The description uses the following abbreviations and definitions:

"bFGF" is an abbreviation that refers to the main growth factor of the fibroblast.

"bFGFR", also known as FGFR1, is an acronym that refers to tyrosinekinase, which interacts with growth factor FGF fibroblast.

"PDGF" is an abbreviation that refers to a growth factor derived from platelets. PDGF interacts with tyrosine kinases PDGFRα and PDGFRβ.

"RTK" isone abbreviation which belongs to the receptor tyrosine kinase.

"Suspension" as used here refers to a mixture containing insoluble particles in a liquid.

"VEGF" is an abbreviation that refers to vascular endothelial growth factor.

"VEGF-RTK" is an abbreviation that refers to the receptor tyrosine kinase vascular endothelial growth factor.

Typically a reference to a particular element, such as hydrogen or N, includes all isotopes of this element. For example, if the R group is a hydrogen or N, it also includes deuterium and tritium.

The phrase "unsubstituted alkyl" refers to alkyl groups that do not contain heteroatoms. Thus, the phrase refers to a linear alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also refers to branched isomers of linear alkyl groups, including, but not limited to, the following pieces, which are included as an example: -CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)2- (CH3)2- (CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2CH3), -CH2CH(CH2CH3)2, -CH2C(CH3) 3, -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2CH(CH3)2, -CH(CH3)CH(CH3)CH(CH3)2, -CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3), and others. The phrase also refers to cyclic alkyl groups, such as cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and such rings substituted linear and branched alkyl groups, as defined above. The phrase also refers to polycyclic alkyl groups such as, but not limited to, substituted, norbornyl and bicyclo[2.2.2]octyl, and such rings substituted linear and branched alkyl groups, as defined above.

Thus, the phrase unsubstituted alkyl group refers to a primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Unsubstituted alkyl groups can be associated with one or more carbon atoms, oxygen atoms, nitrogen atoms and/and the and sulfur atoms in the initial compound. Preferred unsubstituted alkyl groups include linear and branched alkyl groups and cyclic alkyl groups containing from 1 to 20 carbon atoms. More preferred are unsubstituted alkyl groups containing from 1 to 10 carbon atoms, even more preferred are such groups containing from 1 to 5 carbon atoms. The most preferred unsubstituted alkyl groups include linear and branched alkyl groups containing from 1 to 3 carbon atoms and include methyl, ethyl, propyl, and-CH(CH3)2.

The phrase "substituted alkyl" refers to unsubstituted alkyl group, as defined above in which one or more links to carbon atoms or hydrogen substituted communication with atoms other than hydrogen and carbon, such as, but not limited to, halogen atom in halides such as F, CL, Br and I; an oxygen atom in groups such as hydroxyl group, alkoxygroup, alloctype and ester groups; a sulfur atom in groups such as tirinya group, alkyl - and arylsulfonyl group, sulfonic group, sulfonylurea group and group sulfoxide; a nitrogen atom in groups such as amines, amides, alkylamines followed, diallylamine, arylamine, alkylsilane, diarylamino, N-oxides, imides, and enamines; a silicon atom in groups such as trialkyls Lillie group, dialkylacrylamide group, alkyldiphenylamine group and triarylamine groups; and other heteroatoms in various other groups. Substituted alkyl groups also include groups in which one or more links to carbon atoms or hydrogen substituted communication with a heteroatom such as oxygen in carbonyl, carboxyl and ester groups; a nitrogen in groups such as imine, oximes, hydrazones, and NITRILES. Preferred substituted alkyl groups include, among others, alkyl groups in which one or more links with the carbon atom or hydrogen substituted by one or more bonds with fluorine atoms. One example of a substituted alkyl group is triptorelin group, and other alkyl groups that contain triptorelin group. Other alkyl groups include groups in which one or more links to carbon atoms or hydrogen substituted communication with the oxygen atom so that the substituted alkyl group contains hydroxyl, alkoxy, alloctype or geterotsiklicheskikh. Other alkyl groups include alkyl groups that contain the group, amine, alkylamine, dialkylamino, arylamino, (alkyl)(aryl)amine, diarylamino, heterocyclisation, (alkyl)(heterocyclyl)amine, (aryl)(heterocyclyl)amine or diameterically.

The phrase "unsubstituted ar is l" denotes aryl group, which do not contain heteroatoms. So, for example, the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracene and naphthyl. Although the phrase "unsubstituted aryl" includes groups containing condensed rings, such as naftalin, they do not include aryl groups that contain other groups, such as alkyl or halogen groups associated with one of the ring atoms, and aryl groups such as tolyl, condensed with substituted aryl groups as described below. Preferred unsubstituted aryl group is phenyl. In some embodiments, the implementation of the unsubstituted aryl groups contain from 6 to 14 carbon atoms. Unsubstituted aryl group can be associated with one or more carbon atoms, oxygen atoms, nitrogen atoms and/or sulfur atoms in the source connection.

The phrase "substituted aryl group" has the same meaning in respect to unsubstituted aryl groups that substituted alkyl groups have to unsubstituted alkyl groups. However, the substituted aryl group also includes aryl groups in which one of the aromatic carbon atoms connected to one of the atoms other than carbon or hydrogen, as described above, and also includes aryl groups in which one or more of the aromatic carbon atoms of the arilje the Oh group linked to a substituted or unsubstituted alkyl, alkenylphenol or alkenylphenol group, as defined here. They include the location of communication in which two carbon atoms, aryl groups linked to two atoms of alkyl, alkenylphenol or alkenylphenol group with the formation of the condensed cyclic system (for example, dihydronaphtho or tetrahydronaphthyl). Thus, the phrase "substituted aryl" includes, but is not limited to, among others, groups such as tolyl and hydroxyphenyl.

The phrase "unsubstituted of alkenyl" refers to linear and branched, and cyclic groups such as the groups described in respect to unsubstituted alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Examples include, but are not limited to, among others, vinyl, -CH=C(H)(CH3), -CH=C(CH3)2- (CH3)=C(H)2- (CH3)=S(N)(SN3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl. In some embodiments, the implementation unsubstituted alkeneamine groups contain from 2 to 8 carbon atoms.

The phrase "substituted alkenyl" has the same meaning as in relation to the unsubstituted alkenyl groups, which are substituted by an alkyl group with respect to unsubstituted alkyl groups. Replaced alkene the other group includes alkeneamine group, in which the atom associated with an atom other than a carbon atom or hydrogen, is connected by a carbon atom with a double bond with another carbon atom, and groups in which one atom other than carbon atoms or hydrogen, is connected with the carbon atom which is not included in the double bond with another carbon atom.

The phrase "unsubstituted quinil" refers to linear and branched groups, such as groups specified in respect to unsubstituted alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to, among others, With≡C(H)- C≡C(CH3), -C≡C(CH2CH3), -C(H2)≡C(H)- C(H)2With≡C(CH3and-C(H)2With≡C(CH2CH3). In some embodiments, implementation, unsubstituted alkyline groups contain from 2 to 8 carbon atoms.

The phrase "substituted quinil" has the same meaning as in relation to the unsubstituted etkinlik groups, which are substituted by an alkyl group with respect to unsubstituted alkyl groups. Substituted Alchemilla group includes alkyline group, in which an atom other than carbon or hydrogen, is associated with carbon atom of the triple bond with another carbon atom, and groups in which an atom other than a carbon atom or hydrogen, tie the n with the carbon atom, not included in the triple bond with another carbon atom.

The phrase "unsubstituted heterocyclyl" refers to both aromatic and nonaromatic cyclic compounds including monocyclic, bicyclic, and polycyclic ring compounds such as, but not limited to, genocidal containing 3 or more atoms in the cycle, among which one or more atoms are heteroatoms, such as, but not limited to, N, O, and S. Although the phrase "unsubstituted heterocyclyl" includes condensed heterocyclic cycles, such as benzimidazolyl, it does not include heterocyclyl groups that contain other groups, such as alkyl or halogen groups associated with one of the atoms of the ring, when compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups. Examples heterocyclyl groups include, but are not limited to: unsaturated 3-8-membered cycles containing 1-4 nitrogen atom, such as, but not limited to, pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridinyl, dihydropyridines, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc), tetrazolyl, (for example 1H-tetrazolyl, 2H tetrazolyl etc.); saturated 3 to 8-membered cycles containing 1-4 nitrogen atom, such as, but not limited to the mi, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinil; unsaturated condensed heterocyclic group containing 1-4 nitrogen atom, such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, hinely, ethanolic, indazoles, benzotriazolyl; unsaturated 3-8-membered cycles containing 1 or 2 oxygen atoms and 1-3 nitrogen atom, such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl etc.); saturated 3 to 8-membered cycles containing 1 or 2 oxygen atoms and 1-3 nitrogen atom, such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic group containing 1 or 2 oxygen atoms and 1-3 nitrogen atom, for example benzoxazolyl, benzoxadiazole, benzoxazines (for example, 2H-1,4-benzoxazine etc.); unsaturated 3-8-membered cycles containing 1-3 sulfur atom and 1 to 3 nitrogen atom, such as, but not limited to, thiazolyl, isothiazolin, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc); saturated 3 to 8-membered cycles containing 1 or 2 sulfur atom and 1 to 3 nitrogen atom, such as, but not limited to, diazolidinyl; saturated and unsaturated 3-8-membered cycles containing 1 or 2 sulfur atom, such as, but not limited to, thienyl, digit aditional, dehydratation, tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed heterocyclic cycles containing 1 or 2 sulfur atom and 1 to 3 nitrogen atom, such as, but not limited to, benzothiazolyl, benzotriazolyl, benzothiazolyl (for example, 2H-1,4-benzothiazines, etc), dihydrobenzofuranyl (for example, 2H-3,4-dihydrobenzofuranyl, etc), unsaturated 3-8-membered cycles containing oxygen atoms, such as, but not limited to, furyl; unsaturated condensed heterocyclic cycles containing 1 or 2 oxygen atom, such as benzodioxolyl (for example, 1,3-benzodioxolyl, etc); unsaturated 3-8-membered cycles containing an oxygen atom and 1 or 2 sulfur atom, such as, but not limited to, dihydroartemisinin; saturated 3 to 8-membered ring containing 1 or 2 oxygen atoms and 1 or 2 sulfur atom, such as 1,4-Ossetian; unsaturated condensed cycles containing 1 or 2 sulfur atom, such as benzothiazyl, benzodithiol; and unsaturated condensed heterocyclic cycles containing an oxygen atom and 1 or 2 oxygen atom, such as benzoxadiazole. Heterocycla the group also includes groups described above in which one or more S atoms in the cycle contain a double bond with one or two atoms of oxygen (sulfoxidov and sulfones). For example, heterocyclyl group VK is ucaut tetrahydrothiophene and tetrahydrothiophene 1,1-dioxide. Preferred heterocyclyl groups contain 5 or 6 atoms in the cycle. More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiomorpholine, thiomorpholine, in which the S atom thiomorpholine associated with one or more atoms Of the pyrrole, homopiperazin, oxazolidin-2-it, pyrrolidin-2-it, oxazol, Hinkley, thiazole, isooctanol, furan and tetrahydrofuran.

The phrase "substituted heterocyclyl" denotes unsubstituted heterocyclyl group, as defined above in which one or more atoms of the cycle is associated with an atom other than hydrogen, such as described above with respect to substituted alkyl groups and substituted aryl groups. Examples include, but are not limited to, 2-methylbenzimidazole, 5-methylbenzimidazole, 5-chlorobenzothiazole, N-alkylpiperazine groups such as 1-methylpiperazine, piperazine-N-oxide, N-alkylpiperazine N-oxide, 2-phenoxathiin and 2-chloropyridinyl among others. In addition, substituted heterocyclyl groups also include heterocyclyl groups in which communication with an atom other than a hydrogen atom, a represents a bond with the carbon atom that is part of a substituted and unsubstituted aryl, substituted and unsubstituted aralkyl or unsubstituted heterocyclyl the Noah group. Examples include, but are not limited to, 1-benzylpiperidine, 3-phenylthiomethyl, 3-(pyrrolidin-1-yl)pyrrolidine and 4-(piperidine-1-yl)piperidinyl. Groups such as N-alkyl substituted piperazinovogo group, such as N-methylpiperazine, substituted morpholino group and piperazine N-oxide groups, such as piperazine N-oxide and N-alkylpiperazine N-oxides are examples of some substituted heterocyclyl groups. Groups such as substituted piperazinovogo group, such as N-alkyl substituted piperazinovogo group, such as N-methylpiperazine and the like, substituted morpholino group, piperazine N-oxide group, and N-alkylpiperazine N-oxide groups are examples of some substituted heterocyclyl groups, which are preferred as R6or R7groups.

The phrase "unsubstituted geterotsiklicheskikh" refers to unsubstituted alkyl groups as defined above, in which the connection with hydrogen or carbon unsubstituted alkyl group substituted communication with heterocyclyl group, as defined above. For example, methyl (-CH3) is an unsubstituted alkyl group. If a hydrogen atom of a methyl group substituted communication with heterocyclyl group, such as if the methyl carbon is linked to a carbon atom 2 of pyridine (one atom of carbon is connected with the N atom p is Regina) or carbon atoms of 3 or 4 of the pyridine, the connection represents an unsubstituted heterocyclisation group.

The phrase "substituted geterotsiklicheskikh" has the same meaning as in relation to the unsubstituted geterotsiklicheskikh groups, which are substituted kalkilya group unsubstituted Uralkalij groups. However, substituted heterocyclisation the group also includes groups in which the atom other than hydrogen, is associated with the heteroatom in heterocyclyl group heterocyclisation group, such as, but not limited to, the nitrogen atom in piperidinium cycle piperidinylidene group. In addition, substituted heterocyclisation the group also includes groups in which the connection of the carbon or hydrogen bond alkyl group substituted communication with substituted and unsubstituted aryl, or substituted and unsubstituted aranceles group. Examples include, but are not limited to, phenyl-(piperidine-1-yl)methyl and phenyl-(morpholine-4-yl)methyl.

The phrase "unsubstituted alkoxy" denotes a hydroxyl group (-OH), in which communication with the hydrogen atom replaced by communication with the carbon atom otherwise unsubstituted alkyl group, as defined above.

The phrase "substituted alkoxy" refers to a hydroxyl group (-OH), in which communication with the hydrogen atom replaced by communication with the carbon atom otherwise substituted alkyl groups is, as specified above.

The phrase "unsubstituted, heterocyclic" denotes a hydroxyl group (-OH), in which communication with the hydrogen atom is replaced by a bond with an atom in the cycle otherwise unsubstituted heterocyclyl group, as defined above.

The phrase "substituted heterocyclic" denotes a hydroxyl group (-OH), in which communication with the hydrogen atom is replaced by a bond with an atom in the cycle otherwise substituted heterocyclyl group, as defined above.

The phrase "unsubstituted aryloxyalkyl" refers to unsubstituted alkyl group, as defined above, in which communication with the carbon atom or bond with the hydrogen atom is replaced by a bond with an oxygen atom, which is associated with the unsubstituted aryl group, as defined above.

The phrase "substituted aryloxyalkyl" denotes unsubstituted aryloxyalkyl group, as defined above, in which the communication of the carbon or hydrogen alkyl group aryloxyalkyl group is associated with an atom other than a carbon atom and hydrogen, as described above with respect to substituted alkyl groups, or aryl group aryloxyalkyl group is substituted by an aryl group as defined above.

The phrase "unsubstituted geterotsiklicheskikh" refers to unsubstituted alkyl group, as defined above, in which communication with the carbon atom or the ligature with the hydrogen atom is replaced by a bond with an oxygen atom, associated with unsubstituted heterocyclyl group, as defined above.

The phrase "substituted geterotsiklicheskikh" denotes unsubstituted geterotsiklicheskikh group, as defined above, with which the connection to the group of the carbon or hydrogen alkyl group heterocalixarenes group is associated with an atom other than a carbon atom and hydrogen, as described above with respect to substituted alkyl groups, or in which heterocyclyl group heterocalixarenes group is a substituted heterocyclyl group, as defined above.

The phrase "unsubstituted, geterotsiklicheskikh" refers to unsubstituted alkyl group, as defined above, in which communication with the carbon atom or bond with the hydrogen atom is replaced by a bond with an oxygen atom, which is connected with a source connection, and in which another bond with a carbon atom or bond with the hydrogen atom of the unsubstituted alkyl group is associated with unsubstituted heterocyclyl group, as defined above.

The phrase "substituted geterotsiklicheskikh" means the unsubstituted geterotsiklicheskikh, as defined above, in which the communication of the carbon or hydrogen alkyl group geterotsiklicheskikh associated with an atom other than a carbon atom and hydrogen, as described above with respect to substituted alkyl is Rupp, or in which heterocyclyl group geterotsiklicheskikh represents a substituted heterocyclyl group, as defined above. In addition, substituted geterotsiklicheskikh also includes groups in which communication with the carbon atom or bond with the hydrogen atom from the alkyl portion of the group may be substituted by one or more of substituted and unsubstituted heterocycles. Examples include, but are not limited to, pyrid-2-Immortalis-4-ylmethyl and 2-pyrid-3-yl-2-morpholine-4-ileti.

The phrase "unsubstituted alkoxyalkyl" refers to unsubstituted alkyl group, as defined above, in which communication with the carbon atom or bond with the hydrogen atom is replaced by a bond with an oxygen atom, which is associated with an unsubstituted alkyl group as defined above.

The phrase "substituted alkoxyalkyl" denotes unsubstituted alkoxyalkyl group, as defined above, in which the communication of the carbon or hydrogen alkyl groups and/or alkoxygroup alkoxyalkyl group is associated with an atom other than a carbon atom and hydrogen, as described above with respect to substituted alkyl groups.

The term "protected" in respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functional groups, which are protected from undesirable reaction with casinograndbay, well-known specialist in the art, such as the groups described in the book " Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P.G.M., John Wiley & Sons, New York, NY, (3rd edition, 1999), which can be added or removed using the techniques described here. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers, such as esters obtained by reaction of hydroxyl group with a reagent such as, but not limited to, tert-butyldimethylchlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to, methoxymethyl ether, methylthiomethyl ether, benzyloxyethanol ether, tert-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ester, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters, such as, but not limited to benzoylformate, formate, acetate, trichloroacetate and triptorelin. Examples of protected amino groups include, but are not limited to, amides such as formamide, ndimethylacetamide, triptorelin and benzamid; imides, such as phthalimide and dytiscinae; and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers, such as S-benzyldimethyl and S-4-picoliter; substituted S-methylpropane, such as gemiti, di is IO and aminothiazole; and others.

"Pharmaceutically acceptable salt" includes salts with inorganic base, organic base, inorganic acid, organic acid, or a basic or acidic amino acids. As the salts with inorganic bases invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia. As salts with organic bases invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine and triethanolamine. As salts with inorganic acids present invention includes, for example, hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid. As salts with organic acids present invention includes, for example, formic acid, acetic acid, triperoxonane acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, lactic acid, citric acid, succinic acid, malic acid, methanesulfonate acid, benzosulfimide acid and p-toluensulfonate acid. As salts with basic amino acids present invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, TSA is aginova acid and glutamic acid.

Unless otherwise indicated, the terms "temperature," "internal temperature and the internal temperature of the reaction" refers to the temperature of the reaction mixture in the reaction vessel. The temperature of the reaction mixture does not necessarily coincides with the temperature of the reaction vessel containing the reaction mixture, or a heat source used to heat the reaction mixture.

As used here, the term "about" with respect to temperature, time, weight, polyarnosti or molar ratio refers to the value of 10% of this temperature, time, mass, polyarnosti or molar ratio. In some embodiments, the implementation of "about" in relation to a given temperature indicates the temperature, which is ±5°C. from this temperature or ±2°C from the temperature in other variants of implementation. In examples where the value is ±5°or ±2°C of the specified temperature is more than 10% from the specified temperature, it is understood that dominate large ranges.

Typically the invention relates to methods for producing compounds of benzimidazolidinone, such as aminosilane connection benzimidazolidinone. The invention also relates to aminosilane connections benzimidazolidinone and compositions that include a reduced amount of lithium, and sposobnostey such compounds and compositions.

In one embodiment, the present invention relates to a method for producing a substituted or unsubstituted compound 4-amino-3-benzimidazolidinone and to compositions that include such a connection. The method involves the reaction of the first compound of formula I with a second compound of formula II in a suitable solvent in the presence of a base salt of sodium or potassium. In some embodiments, the implementation of the method involves the reaction of the first compound with the second compound in a suitable solvent in the presence of a base salt of potassium. The reaction of the first compound with the second compound yields a substituted or unsubstituted compound 4-amino-3-benzimidazolidinone. Formula I and formula II have the following structure:

where:

R1, R2, R3and R4may be the same or different and independently selected from H, CL, Br, F, I, -OR10groups, -NR11R12groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted etkinlik groups, substituted or unsubstituted heterocyclyl groups or substituted or unsubstituted geterotsiklicheskikh groups;

R 5, R6, R7and R8may be the same or different and independently selected from H, CL, Br, F, I, -OR13groups, -NR14R15groups, -SR16groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted etkinlik groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted geterotsiklicheskikh groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups or substituted or unsubstituted geterotsiklicheskikh groups;

Z is selected from-OR9agroups, or-NR9bR9cgroups;

R9arepresents an unsubstituted alkyl group containing from 1 to 8 carbon atoms, and is absent when Z represents-NR9bR9cc group;

R9band R9cindependently selected from unsubstituted alkyl groups containing from 1 to 8 carbon atoms, or both are missing, if Z represents-OR9agroup;

R10and R13may be the same or different and independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl g the SCP, substituted or unsubstituted geterotsiklicheskikh groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups or substituted or unsubstituted geterotsiklicheskikh groups;

R11and R14may be the same or different and independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heterocyclyl groups;

R12and R15may be the same or different and independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heterocyclyl groups; and

R16selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heterocyclyl groups.

In some embodiments, the implementation of the substituted or unsubstituted compound 4-amino-3-benzimidazolidinone is a compound of formula III, is tautomer the compounds of formula III, is a salt of the compounds of formula III or a salt tautomer the compounds of formula III. Formula III has the following structure:

where R1-R8and R10-R16and EUT values, above.

In some embodiments, the method R1selected from H, Cl, Br, F or I. In some such embodiments, the implementation of R1represents F. In some specific embodiments, the implementation of R1represents F and each of R2, R3and R4represents H, so that the first compound is a compound of formula IA, which has the following structure:

.

In other embodiments, the implementation of at least one of R6or R7represents a substituted or unsubstituted heterocyclyl group. In some such embodiments implement one of R6or R7represents heterocyclyl group and the other R6or R7represents N. In some embodiments, the implementation of one of R6or R7represents heterocyclyl group selected from substituted or unsubstituted piperidinyl group, piperazinilnom group or morpholinyl group. In some such embodiments implement one of R6or R7is a N-alkylpiperazine group, such as N-methylpiperidino group, or the like, and in some such embodiments, the implementation of the other R6or R7represents N. In other such embodiments, the implementation of the population Z represents-OR 9agroup. Therefore, in some embodiments, the implementation of the second compound is a compound of formula IIA or IIB, and has one of the following structures, where R5, R8and R9ahave the meanings described above for compounds of formula II.

In some other embodiments, the implementation of the second compound is a compound of formula IIA or IIB, and both R5and R8represent H, so that the second compound is a compound of formula IIC or IID, and has one of the following structures:

In some embodiments, the method R9a, R9band R9crepresent a linear alkyl group selected from methyl, ethyl, propyl, butyl or pentile or branched alkyl group selected from isopropyl, sec-butyl or tert-butyl. In some embodiments, the implementation of R9a, R9bor R9crepresent methyl, ethyl or propyl, and in other embodiments, implementation of R9a, R9bor R9crepresent an ethyl group.

In some embodiments of the method the method involves the reaction of the first compound with the second compound in a solvent such as diakidoy ether, such as, but not exhaust anievas them diethyl ether or the like; a cyclic ether, such as, but not limited to, dioxane, tetrahydrofuran or the like; an aromatic solvent such as toluene, o-xylene, m-xylene, p-xylene, mixtures thereof or the like, or combinations of these solvents. Other suitable solvents include polar aprotic solvents such as DMF (N,N-dimethylformamide and the like. In some such embodiments, the implementation of the solvent represents tetrahydrofuran. In other embodiments, the implementation of the solvent represents toluene. In some embodiments, the implementation of the concentration of the first compound is more or about 0.10 M or more, or about 0.15 M, in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some such embodiments, the implementation of the concentration of the first compound ranges from about 0.10 M to about 0.30 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some such embodiments, the implementation of the concentration of the first compound ranges from about 0.15 M to about 0.25 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some such embodiments, the implementation of the concentration of the first compound in rirette from about 0.17 M to about 0.22 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some such embodiments, the implementation of the concentration of the first connection is about to 0.19 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some such embodiments, the implementation of the concentration of the first compound and/or the second compound ranges from about 0.15 M to about 0,50 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some such embodiments, the implementation of the concentration of the first compound and/or the second compound ranges from about 0.20 M to about 0.45 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some such embodiments, the implementation of the concentration of the first compound and/or the second compound ranges from about 0.25 M to about 0.45 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some embodiments, the implementation of the concentration of the second connection is more than 0.10 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In other such embodiments, the implementation of the concentration of the second compound is more than 0.15 M, while to the to in other variants of the implementation of the concentration of the second connection is more than 0.20 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some embodiments, the implementation of the concentration of the second compound ranges from about 0.15 M to about 0.30 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some embodiments, the implementation of the concentration of the second compound ranges from about 0.18 M to about 0.26 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some embodiments, the implementation of the concentration of the second compound ranges from about 0.20 M to about 0.24 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some embodiments, the implementation of the concentration of the second compound is about 0.22 M in terms of the amount of solvent, when the first connection and the second connection is subjected to the reaction. In some embodiments, the implementation of the solvent is dried before use in the reaction. In some such embodiments, the implementation of the reaction solvent contains less than 0.5% water, less than 0.25% of water, less than 0.1% water or less than 0.05% water by weight. In other such embodiments, the implementation of the solvent contains less than 0.01% water or less than 0.005% of the water in terms of weight. In some embodiments, the implementation of the solvent in sosialt before use in the reaction. In some embodiments, the implementation of a mixture of solvent and the second connection is dried before the addition of potassium or sodium. In some such embodiments, the implementation of a mixture of solvent and the second compound contains less than 0.5% water, less than 0.25% of water, less than 0.2% water, less than 0.1% water or less than 0.05% of water, which can be determined by analytical method Karl Fischer.

In some embodiments of the method the method involves the reaction of the first compound with the second compound in a suitable solvent using sodium or potassium hydroxide as the base, which can be used for the formation of the enolate anion, which in some embodiments may not represent a steric-shortness basis. As used here, the term "base" refers to a chemical compound that deprotonized another connection, when it reacts with it. In some such embodiments, the implementation of the sodium or potassium salt of the base, which can be used to obtain the enolate anion is a base, such as NaH, KH, Na2CO3To2CO3the alkoxides of sodium and potassium, such as, but not limited to, tert-piperonyl, propoxide, ISO-propoxide, ethoxide, sodium methoxide and potassium, and the like, sodium amide (NaNH2), potassium amide (KNH2and under the service. In some embodiments, the implementation of the Foundation represents a tert-piperonyl sodium or potassium, and in some such embodiments, the implementation, the base represents a tert-piperonyl potassium in a solvent such as THF. In some of these embodiments, the implementation of the Foundation represents a tert-piperonyl potassium (20% in THF). In some embodiments, the implementation of the steric-shortness base is an amide anion, and in some such embodiments, the implementation of the amide nitrogen atom is linked to two trialkylsilyl groups. In some such embodiments, the implementation of the sodium or potassium salt of a base selected from bis(trialkylsilyl)amide, sodium or potassium. In some such embodiments, the implementation of the bis(trialkylsilyl)amide, sodium or potassium is a bis(trimethylsilyl)amide (NaHMDS) or sodium bis(trimethylsilyl)amide and potassium (KHMDS). In some embodiments, the implementation of the method also includes adding sodium or potassium salt of the base to the mixture of the first compound and the second compound in a suitable solvent. In some embodiments, the implementation of the sodium or potassium salt of the base is present in an amount of from 2 to 4 equivalents, and in some such embodiments, the implementation in an amount of from 2.5 to 3 equivalents, in terms of the first connection. In other embodiments, the implementation of NAT is Ieva or potassium salt of the base is present in an amount of from 2 to 4 equivalents, and in some such embodiments, the implementation in an amount of from 2.5 to 3 equivalents, in terms of the second connection. In some embodiments, the implementation of the second compound is present in an amount of from 1 to 2 equivalents, calculated on the first connection. In some such embodiments, the implementation of the second compound is present in an amount of from 1 to 1.5 equivalents, calculated on the first connection.

In some embodiments, the method of obtaining the substituted or unsubstituted compound 4-amino-3-benzimidazolidinone and compositions that include such compounds, the method includes adding a potassium salt base to the mixture containing the first connection, a second connection and a suitable solvent, at a temperature from about 20°to about 50°C. In some such embodiments, the implementation of the potassium salt of the base is added to the mixture, and the temperature of the mixture is from about 25°to about 45°C., from about 35°to about 45°C or from about 38°C to about 42°C, when first added to the mixture of potassium salt of the base. In some embodiments, the internal temperature is 40°C. or about 40°C. to the mixture when you first add a potassium salt base. The internal reaction temperature usually rises, for example to about 62°C. or about 65°C. when the addition of the potassium salt of the base to the reaction mixture, However, in some embodiments, the implementation of the internal temperature of the support is from about 30°to about 52°C. from about 36°to about 52°C., or in some embodiments, the implementation of from about 38°to about 50°C. during the addition of the potassium salt of the base. In some such embodiments, the implementation of the potassium salt of the base is added to the mixture over a period of from about 2 to about 20 minutes. In some such embodiments, implementation, potassium salt of the base is added to the mixture over a period of from about 3 to about 10 minutes, and in some such embodiments, the implementation of the potassium salt of the base is added to the mixture over a period of from about 5 to about 10 minutes, or in some embodiments, during a period of about 5 minutes.

In some embodiments, the method of obtaining the substituted or unsubstituted compound 4-amino-3-benzimidazolidinone and compositions that include such compounds, the method comprises adding sodium or potassium salt of the base to a mixture containing a first connection, a second connection and a suitable solvent at a temperature from about 15°to about 50°C. In some such embodiments, the implementation of the potassium salt of the base is added to the mixture and the temperature of the mixture support from about 15°to about 25°C., from about 15°to about 20°C., or from about 17°C to about 20°C. to the mixture when you first add a potassium salt base. In some embodiments, the internal temperature of the pillar is t from about 17°to about 20°C, when the mixture first add a potassium salt base. In some embodiments, the implementation of the internal temperature of the support at a temperature less than or about 25°C. during the addition of the base. In some such embodiments, the implementation of the internal reaction temperature was raised to about 30°C and the reaction course is supervised according to HPLC.

In some embodiments, the implementation of the method also includes (a) adding to the reaction flask aromatic solvent such as toluene, to obtain the reaction mixture containing a first connection and a second connection; (b) Stripping at least part of the aromatic solvent from the reaction flask and (C) repeating steps (a) and (b) up until the water content becomes less than 0.1%, 0,05%, 0.04% or 0.03 per cent, which can be determined by Karl Fischer analysis. In some embodiments, the implementation of the distillation may be conducted under reduced pressure. In some embodiments, the implementation of the second connection is dried (a) mixing a second connection with a suitable organic solvent, such as THF, toluene, ethanol or the like, to obtain a solution, (b) the concentration of the second connection by removing at least part of the solvent and (C) optionally repeating steps (a) and (b) optionally, one or more times. In some such in which the options for the implementation of stage (a) and (b) repeat until while the water content of the solution will not be less than 0.5%, less than 0.4%, less than 0.3%, less than 0.25%, less than 0.20 per cent, below 0.10%, less than 0.05%, or less than 0.03%, which can be determined by Karl Fischer analysis. In some embodiments, the implementation stage (a) and (b) is repeated at least four times. In some embodiments, the implementation of the second connection can be dried in the reaction vessel, and upon reaching the desired degree of drying, so that the water content is less than 0.25% or less of 0.20%, in the reaction vessel add the first connection and potassium or sodium salt of the base. In such scenarios, the implementation for drying the second connection may be used solvents such as solvents suitable for use in the reaction of the first compound with the second compound. Such solvents include ethereal solvents such as diethyl ether, dioxane, THF and the like, and aromatic solvents such as toluene.

In some embodiments, the method of obtaining the substituted or unsubstituted compound 4-amino-3-benzimidazolidinone and compositions that include such a connection, the method includes drying the second connection to the level of water content less than 5.5% by weight before carrying out the reaction with the first connection, or adding it to the reaction vessel containing pervoezasedanie or suitable solvent. In some such embodiments, the implementation of the second connection is dried until a water content less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2.5% by weight, less than 2% by weight, less than 1% by weight or less than 0.5% by weight. In some such embodiments, the implementation of the second connection may be dried by mixing the humidified second connection with an organic solvent, such as THF, toluene or ethanol to obtain a solution, the concentration of a solution by removing the solvent and drying the resulting composition in a vacuum while heating. In some such embodiments, the implementation of the second connection dried: (a) mixing the humidified second connection with an organic solvent, such as THF, toluene or ethanol, to obtain the solution, (b) concentrating the second connection removing at least part of the solvent, (C) optionally repeating steps (a) and (b) optionally, one or more times, and then (d) drying the resulting composition in a vacuum while heating.

In some embodiments, the method of obtaining the substituted or unsubstituted compound 4-amino-3-benzimidazolidinone and compositions that include such a connection, the method includes the reaction of the first compound with the second compound in the presence of sodium or potassium salt of the base within about is about 30 minutes to about 360 minutes, from about 120 minutes to about 300 minutes, from about 180 to about 300 minutes, about 180 minutes to about 270 minutes, from about 210 minutes to about 270 minutes, or from about 210 minutes to about 240 minutes, at a suitable temperature to give the desired compounds of benzimidazolidinone. In some embodiments, the implementation of the mixture of the reaction product of a substituted or unsubstituted compound 4-amino-3-benzimidazolidinone get the reaction of the first compound with the second compound in the quench by pouring the mixture of the reaction product in water. In other embodiments, the implementation to the reaction mixture, water is added, which in some embodiments, the implementation cooled to a temperature of from about 20°to about 35°C., or from about 20°to about 35°C before adding water. In some embodiments, the implementation of the solvent may be removed under vacuum after addition of water, and then further added water before collecting the solid by filtration. The mixture of the reaction product of damping is usually filtered and washed with water, obtaining the compound 4-amino-3-benzimidazolidinone, and in some embodiments, the implementation of the reaction product of damping can be assembled at a temperature from about 5°to about 10°C. before filtering, although this is not necessary. In some embodiments, the implementation of the assembled product may be dried in vacuum to receive the output of more than 30%, more than 40%, 50%, 60%, 70% or more than 80% of the compound 4-amino-3-benzimidazolidinone. Some embodiments of the method may also include: (a) mixing the collected product with ethanol; (b) heating the ethanol mixture for from about 10 minutes to about 180 minutes, from about 30 minutes to about 120 minutes, or about 60 minutes, at a temperature from about 40°to about 78°C., from about 45°to about 78°C., from about 60°to about 78°C. or at the boiling point; (C) cooling the mixture to a temperature of less than about 40°C., less than 35°C, less than 30°C or less than 20°C; (g) and filtration of the cooled mixture. However, it is not necessary that the mixture was cooled to filtering. In some such embodiments, the implementation of the filtered product may be washed with a solvent, such as ethanol or water. The resulting product can be dried under vacuum by heating, for example in a vacuum oven, drying pistol at a rotary evaporator or the like.

In some embodiments, the method of obtaining the substituted or unsubstituted compound 4-amino-3-benzimidazolidinone and compositions that include such a connection, the method includes the reaction of the compound of formula IV with a compound of formula V to obtain a second compound, where the variables R5, R6, R7, R8and R9ahave the meanings specified above, in which Oseni second compounds of formula II, and X represents a halogen atom such as F, Cl, Br or I, or represents a conjugate base of the acid.

In some such embodiments, the implementation of the compound of formula IV has the formula IVA:

In some such embodiments, the implementation of the compound of formula V has the formula VA:

In some embodiments, the implementation of the compound of formula IV is subjected to reaction with the compound of the formula V in a solvent such as an alcohol, such as, but not limited to, ethanol when the internal temperature from about 30°to about 70°C., from about 35°to about 60°C. or from about 40°to about 50°C., for from about 45 minutes to about 240 minutes, from about 60 minutes to about 180 minutes, or from about 60 minutes to about 120 minutes. In some embodiments, the implementation of the reaction product from the reaction of compounds of formula IV with the compound of the formula V are cooled, for example, up to about 25°C or so, and filtered. In other embodiments, implementation of the reaction product additionally heated, when it is filtered through the filter medium, such as celite. In some embodiments, the implementation of the filtering medium may be washed with a solvent, such as ethanol, and the filtrate can be concentrated by removal of solvent. Konz is nirovany product can then be mixed with an aqueous solution of HCl, in some embodiments, the implementation from 0.37% HCl solution and in other embodiments, the implementation with 1M HCl solution. Base, such as NaOH, for example 30% NaOH solution, then can be added at once or gradually, so as to form a precipitate. In some embodiments, the implementation of the reaction product may be mixed or dissolved in water, in some embodiments, the implementation of deionized water, which is neutral on the pH value. In such scenarios, the implementation of the resulting mixture is usually cooled to about 0°C and then alkalinized by addition of a base, such as NaOH. In some such embodiments, the implementation of the pH value is brought to a value of about 9.2 by adding 20% NaOH. In some embodiments, the implementation of the resulting mixture is stirred for from about 1 to about 5 hours, for example about 4 hours or so, and then filtered off, washed with water and dried in a vacuum oven or the like

In some embodiments, the method of obtaining the substituted or unsubstituted compound 4-amino-3-benzimidazolidinone and compositions that include such a connection, the connection formulas VIA, VIB, or a mixture thereof restore, usually catalytically as described below, H2obtaining the compounds of formula IV, where the variables R5, R6, R7and R8have the meanings described above in respect of the second compounds of formula II.

In some such embodiments, the implementation of the compound of formula VIA is a compound of formula VIC or VID and/or the compound of formula VIB is a compound of formula VIE or VIF. In some such embodiments, the implementation of R6or R7represent a substituted or unsubstituted heterocyclyl group, which in some embodiments implementing selected from substituted or unsubstituted piperidinyl groups, piperazinilnom groups or morpholinyl groups. In some such embodiments implement one of R6or R7is a N-alkylpiperazine group, such as N-methylpiperidino group, so that the compounds of formula VIC, VID, VIE and VIF have the formula VIG VIH or:

In some embodiments, the implementation of the connection is restored H2is a compound of formula VIH. In other embodiments, implementation of the connection is restored H2is a compound of formula VIG. In some embodiments, the implementation of the compound of the formula VIA, VIB or mixtures thereof restore H2in alcohol dissolve the e, such as ethanol using a catalyst gidrogenizirovanii based on the transition metal, such as palladium on coal (Pd/C). In some embodiments, implementation, Pd/C represents a 5% Pd/C and in some embodiments, implementation, Pd/C represents a 5% Pd/C with 50% water by weight by weight basis. In some embodiments, the implementation of the reaction is carried out at an internal temperature from about 25°to about 70°C., from about 30°to about 60°C., or in some embodiments, the implementation of from about 40°to about 55°C. or from about 45°to about 55°C for from about 1 to about 12 hours, from about 3 to about 10 hours, from about 4 to about 8 hours or about 6 hours. In some embodiments, the implementation of the recovered compound of formula IV directly subjected to the reaction with the compound of the formula V in the same reaction vessel without further purification.

In some embodiments, the method of obtaining the substituted or unsubstituted compound 4-amino-3-benzimidazolidinone and compositions that include such a compound, the compound of formula VII is subjected to reaction with the compound of the formula HR7or its salt to obtain the compounds of formula VIA, where the variables R5, R6and R8have the meanings described above in relation to the second of the compounds of formula II, Y is selected from CL or F.

In some of these is the option of implementing compound of formula VII is a compound of formula VIIA or VIIB. In some such embodiments, the implementation of R7represents a substituted or unsubstituted heterocyclyl group, which in some embodiments implementing selected from substituted or unsubstituted piperidinyl groups, piperazinilnom groups or morpholinyl groups. In some such embodiments, the implementation of R7is a N-alkylpiperazine group, such as N-methylpiperidino group, so that HR7represents the formula HR7(a)as shown below.

In some embodiments, the implementation of the compound of formula VII is subjected to reaction with the compound of the formula HR7such as N-methylpiperazine, at a temperature of from about 70°to about 120°C. or from about 80°to about 110°C., from about 85°to about 105°C. or about 100°C., for from about 2 hours to about 24 hours, from about 4 hours to about 12 hours, or from about 6 hours to about 10 hours. Various suitable solvents, such as, but not limited to, water or ethanol, can be used in the reaction of compounds of formula HR7in the reaction with the compound of the formula VII. The addition of a solvent, such as ethanol, to the reaction to prevent solidification of the reaction mixture. In some embodiments, the implementation of any reaction JV is soba is controlled according to HPLC and flows over a period of time, sufficient to source materials were observed in small quantities.

Discovered improved methods for obtaining the compounds of formula VIH:

The methods can be used to obtain heterocyclic compounds other than VIH. For example, the compound 5-halogen-2-nitroaniline, such as 5-chloro-2-nitroaniline, can undergo reactions with N-containing heterocycle, such as substituted or unsubstituted pyrrolidine, substituted or unsubstituted piperazine such as N-alkylpiperazine, or substituted or unsubstituted piperidine to obtain the desired compounds of formula VIHa, where Het is an N-containing heterocycle, and N atom of the heterocycle is linked with the benzene ring cycle. In some embodiments, the implementation of the heterocycle is a saturated a heterocycle such as piperazine, piperidine or pyrrolidine.

In some embodiments, the implementation of the halogen group 5-halogen-2-nitroaniline compounds used in the synthesis represents a fluorine or chlorine, so that the connection represents 5-fluoro-2-nitroaniline or 5-chloro-2-nitroaniline. Thus, some methods include the reaction of a mixture of 1-methylpiperazine and 5-halogen-2-nitroaniline compounds such as 5-chloro-2-nitroaniline, when the internal temperature is re, sufficient to obtain the compounds of formula VIH. Excessive heterocycle can be used to increase the completeness of the reaction.

For example, the methods include the reaction of a mixture of 1-methylpiperazine and 5-halogen-2-nitroaniline in the first solvent and the first temperature sufficient to obtain the compounds of formula VIH in the first solvent, for example, from about 70° to about 140°C., from about 80° to about 120°C., from about 90° to about 110°C., usually from about 90° to about 100°C., or more often from about 95° to about 100°C. the First solvent is an organic solvent, for example an alcohol, such as ethanol. 1-Methylpiperazine and 5-halogen-2-nitroaniline may be present in a molar ratio in the range from about 0.5:1 to about 10:1. In some embodiments, the implementation of an excess of 1-methylpiperazine towards nitroaniline can be used to increase the completeness of the reaction. For example, 1-methylpiperazine and 5-halogen-2-nitroaniline may be present in a molar ratio in the range from about 2:1 to about 5:1, from about 3:1 to about 5:1 or from about 3.5:1 to about 4.5:1. To highlight the compounds of formula VIH from the reaction mixture to the reaction mixture add the amount of the second solvent different from the first solvent, with a suspension of the compound of formula VIH.

In some embodiments, domestic the second solvent contains water. In other embodiments of the second solvent is completely or essentially consists of water. In some embodiments, the implementation of a mixture containing the compound of formula VIH, cooled to a second temperature not less than 80% from the first temperature (for example, from about 85° to about 95°C) before adding water. In some other embodiments implement the mixture is cooled to a temperature of at least 90% from the first temperature. Before adding water to the mixture is heated to approximately the temperature of the mixture, for example, to the second temperature. The suspension is then formed upon cooling the reaction mixture to a third temperature, for example, from about 15° to about 25°C. After some time, the slurry thickens and get homogeneous crystals VIH.

In other embodiments of the second solvent is an organic solvent, such as heptane. The reaction mixture may be cooled to a second temperature, amounting to at least 70% of the initial temperature before adding the second solvent to the mixture (for example, from about 70°to about 85°C). The reaction mixture containing the second solvent is cooled to a third temperature (e.g., from about 15°to about 25°C.) suspension of the compound of formula VIH. The second volume of the second solvent can be added during the cooling process to facilitate the contraction in the Finance crystals of compounds of formula VIH. As indicated above, the reaction mixture is then cooled to a temperature of, for example, from about 15 to about 25°C. to obtain crystals VIH. Crystals connection VIH can be collected and rinsed with water, for example by filtration. Preferably, but not necessarily to the crystals essentially did not contain ethanol before washing with water to prevent the formation of fine particles, which form the difficulty Department. After water washing, the crystals may not necessarily be again washed with an organic solvent, such as heptane, and then dried. Drying can be carried out in vacuum with heating or without him above the ambient temperature. The compound of formula VIH has purity equal to or more than 90% in some embodiments, the implementation of equal to or more than 95%, in other embodiments, implementation, and equal to or more than 99% in some other variants of implementation.

In some embodiments, the implementation of improved methods for obtaining the compounds of formula VIH carried out in a solvent which contains water in an amount of more than about 50% by volume, calculated on the amount of solvent, and/or the reaction is carried out in a solvent that contains an organic solvent that has a boiling point over 100°C at atmospheric pressure. Although the compounds of formula VIH can be easily obtained by the reaction of 1-methylpiperazine C5-halogen-2-nitroaniline in ethanol, it was shown that the reaction time is significantly shortened and achieved excellent outputs, when these reactions are carried out in water or in a solvent that includes an organic solvent with a boiling point of about 100°C. or higher. For example, when the reaction is carried out in aqueous solution with a salt, such as NaCl (can use other salts such as KCl, as is obvious to a person skilled in the technical field) at a concentration in the range from about 0 to about 5 M, the reaction usually terminates (determined according to HPLC) for from about 5 to about 6 hours instead of 36-40 hours, when the reaction is performed in ethanol at 97°C. the Improved efficiency of the time characteristic of the reaction in water or in aqueous salt solution, provides a significant cost reduction in industrial production. When the reaction is performed in aqueous solution of NaCl at a temperature of from about 100°to about 110°C. the compound obtained allocate with the release of 94% and a purity of 99.4% according to HPLC. This provides a distinct advantage compared with output in the range of 90-100%, when the reaction is carried out in ethanol.

In addition to reducing the reaction time, the treatment of the reaction mixture is usually simpler when education VIH is carried out by using the methods according to the invention. For example, when the synthesis is carried out in aqueous salt solution when the tempo is the atur from about 100°to about 110°C, treatment usually involves adding water to the reaction mixture at a temperature of from about 90°to about 105°C, which causes crystallization of the product. At this stage it is usually observed the formation of granular crystals, which are desirable because they have a positive impact on the ease of filtration and drying time. After cooling to room temperature (from about 20°to about 25°C.) of the desired product (VIH) can be filtered, washed and dried in a vacuum oven. Shortened the reaction time is also achieved when the reaction of 1-methylpiperazine with 5-chloro-2-nitroaniline carried out in a solvent that includes an organic solvent, such as ethylene glycol, which has a boiling point of about 100°C. or higher. When the reaction is carried out in water at a temperature of from about 100°to about 108°C., the reaction is usually completed within from about 6 to about 7 hours. When the reaction is carried out in ethylene glycol at a temperature of from about 120°to about 125°C., the reaction is usually complete within 4-5 hours. In some embodiments, the implementation of the temperature range is from about 95 to about 120°C.

In one embodiment, the present invention relates to a method for obtaining compounds of formula VIH:

The method includes in a first reaction mixture, the reaction of 1-metile the Razin 5-halogen-2-nitroaniline when the internal temperature sufficient to obtain the compounds of formula VIH. In such embodiments, the method 1-methylpiperazine and 5-halogen-2-nitroaniline is subjected to reaction in a solvent that contains water. In some embodiments, the implementation of the 5-halogen-2-nitroaniline represents 5-chloro-2-nitroaniline, and in other embodiments, the implementation represents 5-fluoro-2-nitroaniline.

In some embodiments, the implementation of the solvent contains water in an amount of more than about 50% by volume, calculated on the quantity of solvent. In other such embodiments, the implementation of the solvent contains water in an amount more than 80% by volume, calculated on the quantity of solvent. In some such embodiments, the implementation of the solvent contains water in an amount more than 90% by volume, calculated on the quantity of solvent. In other such embodiments, the implementation of the solvent contains water in an amount of more than 98% by volume, calculated on the quantity of solvent. In other such embodiments, the implementation of the solvent consists essentially of or consists of water. In other such embodiments, the implementation of the solvent consists essentially of or consists entirely of deionized or distilled water.

In some embodiments, the implementation of the solvent is an aqueous solution containing salt, such as NaCl. In some of the s such scenarios, the implementation of the concentration of salt in the aqueous solution ranges from about 1 to about 5 M. In some such embodiments, the implementation of the salt concentration ranges from about 3 to about 4.5 M, and in other embodiments, the implementation varies from about 3.5 to about 4,2M.

In some embodiments, the internal temperature is over 95°C. In various such embodiments, the internal temperature ranges from about 99°C. to about 115°C., from about 100°to about 110°C. or from about 105°to about 110°C. In some embodiments, the implementation of the reaction is carried out at atmospheric pressure, while in other embodiments implement the reaction is carried out at a pressure of up to about 2 ATM.

In some embodiments, the implementation of the 1-methylpiperazine and 5-halogen-2-nitroaniline is subjected to reaction at an internal temperature within the reaction time less than 20 hours. In some such embodiments, the implementation of the response time is less than 10 hours. In some such embodiments, the implementation of the response time is less than 8 hours.

It was shown that the use of inorganic bases can reduce the amount of excess 1-methylpiperazine required for the reaction towards formation of the product. The use of inorganic bases in some embodiments, the implementation of the methods leads to high yields and high purity of the compounds of formula VIH in less time than the structure with the same reaction without inorganic bases. Thus, in some embodiments, the implementation methods include the reaction of a mixture of 1-methylpiperazine and 5-halogen-2-nitroaniline in a solvent at a temperature sufficient to obtain the compounds of formula VIH, the solvent is an aqueous solution containing a salt and an inorganic base. Suitable inorganic bases for use in the reaction include hydroxides, carbonates and phosphates of alkali and alkaline earth metals. Examples of bases include, but are not limited to, NaOH, KOH, CA(Oh)2, Mg(OH)2, PA2CO3To2CO3and K3RHO4.

The ways in which such inorganic bases carried out similarly to the above methods of applying water with salt (salts) separately, but with fewer 1-methylpiperazine used to achieve the same yields and purity of product. Thus, in some embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 1.5:1 to about 3:1, or from about 2:1 to about 3:1. In some embodiments, the implementation of the concentration of salt in the aqueous solution ranges from about 1 to about 5 M, from about 2 to about 5 M in other embodiments, implementation, and from about 3 to about 5 M in other variants of the implementation.

In other embodiments, implementation of the ways of gaining the compound of formula VIH include recycling the mother liquor. These methods include collection of mother liquor, as will be complete reaction, adding a base to the stock solution, the restart in the mother solution of 1-methylpiperazine and 5-halogen-2-nitroaniline and re-conducting the reaction at a temperature sufficient to obtain the compounds of formula VIH. This leads to a decrease in the total number of source materials and reducing the total amount of waste in the form of mother solutions. Recycling the mother liquor may be one, two, three, four, or more times, or until until you decrease the product yield. Thus, in some embodiments, the implementation of the described methods of obtaining heterocyclic compounds containing: reaction of 1-methylpiperazine 5-halogen-2-nitroaniline with an internal temperature sufficient to obtain the compounds of formula VIH, in a solvent that contains water, where the solvent is an aqueous solution containing salt, with the first reaction mixture. In some embodiments, the implementation of the methods also include cooling the first reaction mixture to a temperature sufficient for the deposition of the first portion of solids containing the compound of formula VIH, and filtering the first reaction mixture with a first portion of the filtered solids containing soy is inania formula VIH, and the first filtrate containing solvent. In other embodiments implement the methods also include adding to the first filtrate 1-methylpiperazine, 5-halogen-2-nitroaniline and amount of base sufficient to neutralize any amount of HCl in the first filtrate, to obtain a second reaction mixture at an internal temperature sufficient to obtain the compounds of formula VIH. In other embodiments implement the methods also include cooling the second reaction mixture to a temperature sufficient to precipitate the second portion of solids containing the compound of formula VIH, and filtering the second reaction mixture to obtain a second portion of the filtered solids containing the compound of formula VIH, and the second filtrate containing solvent. In other such embodiments, the implementation of the methods also include adding a second filtrate 1-methylpiperazine, 5-halogen-2-nitroaniline and amount of base sufficient to neutralize any amount of HCl in the second filtrate, to obtain a third reaction mixture at an internal temperature sufficient to obtain the compounds of formula VIH. In other embodiments implement the methods also include the third cooling the reaction mixture to a temperature sufficient to precipitate a third portion of the solids containing the compound of formula VIH, and the third filtering the reaction mixture to obtain a third portion of the filtered solids containing the compound of formula VIH, and the third filtrate containing solvent. In some embodiments, the implementation of the salt is NaCl. In some embodiments, the implementation of the solvent is a saturated solution of NaCl. In some embodiments, the implementation of the base is an NaOH or KOH. In some embodiments, the internal temperature ranges from about 95°to about 120°C. After separation of the compounds of formula VIH at each stage of filtration, the compound of formula VIH has purity equal to or greater than about 90%, in some embodiments, the implementation of equal to or greater than about 95%, in other embodiments, implementation, and equal to or greater than 99%, in other embodiments, implementation.

In some embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 2:1 to about 10:1 in the beginning of the reaction, or even from about 0.5:1 to about 10:1 or about 1:1 to about 10:1 in the beginning of the reaction. In some such embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 3:1 to about 4.5:1 in the beginning of the reaction. In other such embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroanilines from about 4:1 to about 4.3:1 in the beginning of the reaction.

In some embodiments, the implementation of the output of the compounds of formula VIH in terms of the number of 5-halogen-2-nitroaniline is over 90%. In other embodiments, implementation of the output is more than 93%. In some other embodiments, the implementation of the output is more than 96%.

In some embodiments, the implementation of the method also includes the restoration of the nitro group of compounds of formula VIH ~ obtaining the compounds of formula IVA. Some such embodiments of also include the reaction of compounds of formula IVA with a compound of formula V or VA with obtaining the compounds of formula IIC, the compounds of formula IID, or a mixture thereof, where R9Amatter described above. In some embodiments, the implementation of R9Arepresents an ethyl group. In some embodiments, the implementation of the compound of formula IIC, IID, or their mixture is subjected to reaction with a compound of formula IA with obtaining the compounds of formula IIIB or tautomer. Some such embodiments of also include the reaction of the compound of formula IIIB or tautomer with acid to obtain the salt of the compounds of formula IIIB or tautomer. In some such embodiments, the implementation of the acid is a lactic acid and salt is a salt of lactic acid compounds or tautomer.

In another embodiment, the present invention is tositsa to the method of obtaining the compounds of formula VIH:

.

The method involves the reaction of 1-methylpiperazine 5-halogen-2-nitroaniline with an internal temperature sufficient to obtain the compounds of formula VIH. 1-methylpiperazine and 5-halogen-2-nitroaniline is subjected to reaction in a solvent that contains an organic solvent that has a boiling point over 100°C at atmospheric pressure. In some embodiments, the implementation of the 5-halogen-2-nitroaniline represents 5-chloro-2-nitroaniline, and in other embodiments, the implementation represents 5-fluoro-2-nitroaniline.

In some embodiments, the implementation of the solvent is a compound of the formula HO-(CH2)q-OH, or BUT-CH2CH2Och2CH2Is HE, where q is selected from 2, 3 or 4. In some such embodiments, the implementation of the solvent contains propylene glycol or ethylene glycol. In other such embodiments, the implementation of the solvent consists essentially of or consists only of propylene glycol or ethylene glycol. In other such embodiments, the implementation of the solvent consists essentially of or consists only of ethylene glycol.

In some embodiments, the internal temperature is over 95°C. In various such embodiments, the internal temperature ranges from about 99°C. to about 130°C., from about 115°to about 130°C. or from about 120°to about 125°C. In some embodiments, the implementation of the reaction is carried out at atmospheric pressure, while in other embodiments implement the reaction is carried out at a pressure of up to about 2 ATM.

In some embodiments, the implementation of the 1-methylpiperazine and 5-halogen-2-nitroaniline is subjected to reaction at an internal temperature within the reaction time less than 20 hours. In some such embodiments, the implementation of the response time is less than 10 hours. In some such embodiments, the implementation of the response time is less than 8 hours. In other embodiments, implementation of the reaction time varies from 3 to 6 hours, and in some embodiments, the implementation varies from 4 to 5 hours.

In some embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 0.5:1 to about 10:1, from about 1:1 to about 10:1 or from about 2:1 to about 10:1 in the beginning of the reaction. In some such embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 3:1 to about 4.5:1 in the beginning of the reaction. In other such embodiments, the implementation of the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline ranges from about 4:1 to about 4.3:1 in the beginning of the reaction.

In some embodiments, the implementation of the output of the compounds of formula VIH in terms of the number of 5-halogen-2-nitroaniline is bol is e 90%. In other embodiments, implementation of the output is more than 92%. In other such embodiments, the implementation of the output is more than 96%.

In some embodiments, the implementation of the method also includes the restoration of the nitro group of compounds of formula VIH ~ obtaining the compounds of formula IVA. Some such embodiments of also include the reaction of compounds of formula IVA with a compound of formula V or VA with obtaining the compounds of formula IIC, the compounds of formula IID, or a mixture thereof, where R9Amatter described above. In some embodiments, the implementation of R9Arepresents an ethyl group. In some embodiments, the implementation, the compound of formula IIC, IID, or their mixture is subjected to reaction with a compound of formula IA with obtaining the compounds of formula IIIB or tautomer. Some such embodiments of also include the reaction of the compound of formula IIIB or tautomer with acid to obtain the salt of the compounds of formula IIIB or tautomer. In some such embodiments, the implementation of the acid is a lactic acid, and salt is a salt of lactic acid compounds or tautomer.

In some embodiments, the implementation of the substituted or unsubstituted compound 4-amino-3-benzimidazolidinone is a compound of formula IIIA is tautomer connection is ormula IIIA, is a salt of the compounds of formula IIIA or a salt tautomer the compounds of formula IIIA, and R7represents a substituted or unsubstituted heterocyclyl group:

In some such embodiments, the implementation of R7represents a substituted or unsubstituted heterocyclyl group that is selected from substituted or unsubstituted piperidinyl group, piperazinilnom group or morpholinyl group. In some such embodiments, implementation, R7represents a substituted or unsubstituted N-alkylpiperazine group, such as N-methylpiperazine group, N-ethylpiperidine group or N-propylpiperidine group.

In some embodiments, the implementation of the substituted or unsubstituted compound 4-amino-3-benzimidazolidinone is a compound of formula IIIB is tautomer the compounds of formula IIIB, is a salt of compounds of formula IIIB or a salt tautomer the compounds of formula IIIB:

In some embodiments, the implementation of the method involves the reaction of a substituted or unsubstituted compound 4-amino-3-benzimidazolidinone or tautomer connection with lactic acid where to get the salt of lactic acid compounds the Oia 4-amino-3-benzimidazolidinone or tautomer. In some such embodiments, the implementation of the compound of formula IIIB or tautomer subjected to reaction with lactic acid to obtain the salt of lactic acid compounds or tautomer. In some such embodiments, the implementation of the connection or tautomer subjected to reaction with D,L-lactic acid in water and ethanol, and is formed monolectic in the form of a crystalline solid.

The use of sodium or potassium salt of the base, such as, but not limited to, NaHMDS, KHMDS, tert-butoxide or sodium tert-butoxide potassium, and not a lithium salt, such as LiHMDS, in the reaction of the first compound with the second compound provides a method of producing compositions that include reduced amounts of lithium, and in some embodiments, the implementation may not contain lithium. In addition, the use of a base, such as tert-piperonyl potassium, leads to lower outputs connection of benzimidazolidinone. Therefore, in some embodiments implementing the invention relates to a composition that includes a compound of benzimidazolidinone formula III, tautomer connection benzimidazolidinone, salt compound of benzimidazolidinone, salt tautomer connection benzimidazolyl or mixtures thereof, where the compound of benzimidazolidinone is a compound of formula III:

where:

R1, R2, R3and R4may be the same or different and independently selected from H, Cl, Br, F, I, -OR10groups, -NR11R12groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted etkinlik groups, substituted or unsubstituted heterocyclyl groups or substituted or unsubstituted geterotsiklicheskikh groups;

R5, R6, R7and R9may be the same or different and independently selected from H, Cl, Br, F, I, -OR13groups, -NR14R15groups, -SR16groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted etkinlik groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted geterotsiklicheskikh groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups or substituted or unsubstituted geterotsiklicheskikh groups;

R10and R13may be the same or different and independently selected from substituted or unsubstituted alkyl which groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted geterotsiklicheskikh groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups or substituted or unsubstituted geterotsiklicheskikh groups;

R11and R14may be the same or different and independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heterocyclyl groups;

R12and R15may be the same or different and independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heterocyclyl groups;

R16selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heterocyclyl groups; and further, where

the quantity of lithium in the composition is less than 1% by weight, calculated on the weight of the connection benzimidazolidinone in composition.

In some embodiments, the implementation described here, the compositions of the quantity of lithium in the composition is less than 0.5%, less than 0.1%, less than 0.05%, less than 0.01%, less than 0,005% or less than 0.001 by weight in terms of n is the weight of connection of benzimidazolidinone, tautomer connection benzimidazolidinone, salts of compounds of benzimidazolidinone, salt tautomer connection benzimidazolyl or mixtures thereof in the composition. In some such embodiments, the implementation described here, the compositions of lithium is completely absent in the composition. In some embodiments, the implementation of the composition contains less than 1%, less than 0.05%, or less than 0.01% nellysimonova intermediate compounds shown in scheme 1, in terms of the weight of connection of benzimidazolidinone.

In some embodiments, the implementation described here, the compositions of the connection of benzimidazolidinone formula III is a compound of formula IIIB:

In different groups, which include heterocyclyl group, heterocyclyl group can join in a variety of ways. For example,- OCH2(CH2)q(heterocyclyl)group, where q is selected from 0, 1, 2, 3 or 4, heterocyclyl group may be linked to the methylene carbon atom-OCH2(CH2)qgroup-och2(CH2)q(heterocyclyl) through the various atoms of the cycle. As a non-limiting example, where q represents 1 and heterocyclyl group represents tetrahydrofuran, the group may be represented by the formula-och2CH2(tetrahydrofuranyl), the which corresponds to the following two structures:

where the structure VIII is a group that can be classified as-och2CH2(2-tetrahydropyranyloxy) group, and the structure IX is a group that can be classified as-och2CH2(3-tetrahydrofuranyl) group. When heterocyclyl group is a N-containing heterocycle, such as, but not limited to, piperidine, piperazine, morpholine or pyrrolidine, heterocycle may be associated with the methylene carbon atom through a carbon atom of the cycle or via the nitrogen atom of the cycle N-containing heterocycle. Both of these options are preferred. When heterocyclyl group represents piperidine and q has a value of 2 for-OCH2(CH2)q(heterocyclyl) group, possible and preferred the following structure:

Structure X is an example of a-O(CH2)3(N-piperidinyl) or-O(CH2)3(1-piperidinyl) group. Structure XI is an example of a-O(CH2)3-(2-piperidinyl) group. Structure XII is an example of a-O(CH2)3(3-piperidinyl) group. Structure XIII represents when the er-O(CH 2)3(4-piperidinyloxy) group. When heterocyclyl group is a piperazine and q has a value of 1 for-OCH2(CH2)q(heterocyclyl) group, the following structures are possible and preferred:

Structure XIV is an example of a-O(CH2)2(2-piperazinilnom) group, and the structure of XV is an example of a-O(CH2)2(1-piperazinilnom) or-O(CH2)2(N-piperazinilnom) group. When heterocyclyl group represents morpholine and q has a value of 1 for-OCH2(CH2)q(heterocyclyl) group, the following structures are possible and preferred:

Structure XVI is an example of a-O(CH2)2(3-morpholinyl) group structure XVII is an example of a-O(CH2)2(4-morpholinyl) or-O(CH2)2(N-morpholinyl) group, and the structure XVIII is an example of a-O(CH2)2(2-morpholinyl) group. Will be described the cases in which the group is pyrrolidin and q has a value of 1, the possible patterns include-O(CH2)2(1-pyrrolidinyl) or-O(CH2)2(N-pyrrolidinyl), -O(The N 2)2(2-pyrrolidinyl) and-O(CH2)2(3-pyrrolidinyl).

Scheme 1 shows one exemplary way of synthesis of compounds of benzimidazolidinone, and the scheme should not be interpreted as limiting the invention in any way. As shown below, it is believed that the reaction of the first compound with the second compound flows through the acyclic intermediate connection. However, it should be understood that this in no way limits the invention. It was found that the potassium salt of the compounds of the formula III is obtained by cyclization of an intermediate compound has a low solubility, resulting in precipitation of the product from the reaction mass. It was surprising and unexpected that the deposition was not observed when using a lithium salt, such as LiHMDS, not potassium salt, such as KHMDS. The use of potassium salt, and not lithium salts, leads to a significant increase in the yield of compounds of formula III, such as the compounds of formula IIIB, as shown in figure 1, especially when using a base such as potassium alkoxide, such as tert-piperonyl potassium. Discovered that the reaction of the first compound with the second compound also leads to substantially higher outputs compounds of formula III, when the reaction is carried out in solvents and reagents with low water content. N the example, it was found that the yield is significantly improved when a second connection is dried, as described here, for example azeotropic evaporation of absolute ethanol or in the reaction vessel by repeated addition of THF, followed by distillation. The output of the compounds of formula VI, such as the compound of formula VIH, obtained by the reaction of N-alkylpiperazine, such as N-methylpiperazine, with a compound of formula VII, increases when the temperature is reduced, and the amount of compounds of formula HR7increase in relation to the compound of formula VI. The reaction temperature is reduced and the reaction is diluted with ethanol in the process of scaling reactions. For example, a good outputs were obtained when the reaction was carried out at a temperature from 90°C to 100°C, and the compound of the formula HR, such as N-methylpiperazine, was attended by more than 2.5 equivalents relative to the amount of the compounds of formula VI, such as 5-chloro-2-nitroaniline. In some such embodiments, the implementation of the compound of the formula HR is present in the amount of more than 2.8, more than 2.9, more than 3.0 or 2.5 to 5 equivalents relative to the amount of the compounds of formula VI.

Scheme 1

Figure 2 shows the method of obtaining the compounds of formula VA and shows the General application of the method according to the invention. Specialist in the art it is clear that the choice samisen the th or the unsubstituted diaminobenzene and substituted or unsubstituted anthranilamide allows the synthesis of a wide number of compounds of the formula III. Specialists in this field of technology is also clear that some groups may require protection using standard protective group for the final cyclization reaction. Extremely a variety of synthesis methods allow you to easily access many of the compounds of formula III are highly convergent and efficient method of synthesis.

Scheme 2

The present invention, as described in General will become more clear with reference to the following examples which are given for illustration and are not intended to limit the present invention. The following documents, including the examples in the documents listed here as references in order, as if they were given here in full: US 6, 605, 617; application US 2004/0092535 filed 19.08.2003; application US 60/405, 729, filed 23.08.2002; application US 60/426, 107, filed 13.11.2002; application US 60/426, 226, filed 13.11.2002; application US 60/426, 282, filed 13.11.2002; application US 60/428, 210, filed 21.11.2002; application US 60/460, 327, filed 3.04.2003; application US No., submitted 3.04.2003; application US 60/460, 493, filed 3.04.2003; application US 60/478, 916, filed 16.06.2003; US 60/484, 048, filed 1.07.2003 and claim US 60/517, 915, filed 7.11.2003.

Examples

The following abbreviations are used in the examples:

Examples:

tO:ethanol
IPA: isopropanol; 2-propanol
H2O:water
HCl:hydrochloric acid
HPLC:high performance liquid chromatography
NMR:nuclear magnetic resonance
KHMDS:bis(trimethylsilyl)amide and potassium
LiHMDS:bis(trimethylsilyl)amide lithium
NaHMDS:bis(trimethylsilyl)amide sodium
NaOH:sodium hydroxide
N2:nitrogen
TWO:tert-butyl methyl ether
THF:tetrahydrofuran

Nomenclature for the compounds in the examples are using the software ACD Name version 5,07 (14.11.2001)available from Advanced Chemistry Development, Inc., Chemlnnovation NamExpert + software Nomenclator™, available from ChemInnovation Software, Inc., and AutoNom version 2.2, available in the software package ChemOffice® Ultra version 7.0, available on the CambridgeSoft Corporation (Cambridge, MA). Some compounds and starting materials are named according to standard IUPAC nomenclature.

Different source materials can be obtained from commercial sources and obtained by methods known to the person skilled in the technical field.

Example 1

Synthesis of 5-(4-methylpiperazin-1-yl)-2-nitroaniline

Method And

5-Chloro-2-nitroaniline (500 g, 2,898 mol) and 1-methylpiperazine (871 g 8,693 mol) were loaded into a flask with a volume of 2000 ml equipped with a fridge and a flush of N2. The flask was placed in an oil bath at a temperature of 100°C and was heated up until 5-chloro-2-nitroaniline fully react (usually during the night)that define the data HPLC. After HPLC confirms depletion of 5-chloro-2-nitroaniline, the reaction mixture was poured directly (still warm) in 2500 ml of water with room temperature with mechanical stirring. The resulting mixture was stirred until then, until it reaches room temperature, and then filtered. To the thus obtained yellow solid substance was added to 1000 ml of water and was stirred for 30 minutes. The resulting mixture was filtered and the resulting solid washed TWO (500 ml, 2 times) and then dried under vacuum for one hour, using a rubber press. Polucen the e solid was transferred into a dry pan and dried in a vacuum oven at 50°C until constant weight to obtain 670 g (97.8 per cent) indicated in the title compound as a yellow powder.

Method B

5-chloro-2-nitroaniline (308,2 g, 1,79 mole) were placed in a 4-necked round bottom flask with a volume of 5000 ml, equipped with a stirrer with a top drive, a refrigerator, a nozzle for gas inlet, addition funnel and a control thermometer. The flask was then purged with N2. Under stirring the reaction flask was added 1-methylpiperazine (758,1 g, 840 ml, EUR 7.57 mol) and ethanol fortress 200 proof (508 ml). The flask was again washed with N2and the reaction mixture was left in an atmosphere of N2. The flask was heated in a mantle until the internal temperature of 97°C (+/-5°C) and maintained at this temperature until the reaction is completed (usually within 40 hours), which was determined according to the HPLC. After the reaction, the heating was stopped and the reaction mixture was cooled to an internal temperature from about 20°C to 25°C under stirring, and the reaction mixture was stirred for 2 to 3 hours. To the reaction mixture were added seed crystals (0.20 g, of 0.85 mmole) 5-(4-methylpiperazin-1-yl)-2-nitroaniline until then, until he started sedimentation. To stir the reaction mixture was added water (2,450 ml) over a period of about 1 hour while the internal temperature was maintained in the range from about 20°C. to 30°C. After addition of water the mixture was stirred for about 1 hour at a temperature from 20°C to 30°C. the resulting mixture was then about filytrovali, and flask and the layer on the filter was washed with water (3×2,56 l). Golden solid product was dried to constant weight 416 g (yield 98,6%) in vacuum at approximately 50°C in a vacuum oven.

Method In

5-Chloro-2-nitroaniline (401 g, 2,32 mole) were placed in a 4-necked round bottom flask with a volume of 12 liters, equipped with a stirrer with a top drive, a refrigerator, a nozzle for gas inlet, addition funnel and a control thermometer. The flask was then purged with N2. Into the reaction flask with stirring was added 1-methylpiperazine (977 g, 1.08 l, 9,75 mole) and 100% ethanol (650 ml). The flask was again purged with N2and the reaction mixture was left in an atmosphere of N2. The flask was heated in a mantle until the internal temperature of 97°C (+/-5°C) and kept at this temperature until the completion of the reaction (usually 40 hours), which was determined according to the HPLC. After the reaction, the heating was stopped and the reaction mixture was cooled to an internal temperature of about 80°C. with stirring, and to the mixture was added water (3.15 l) using a dropping funnel over a period of 1 hour while the internal temperature was maintained at 82°C (+/-3°C). After adding water heating was stopped and the reaction mixture was left to cool for a period of not less than 4 hours until the internal temperature of 20-25°C. the Reaction mixture then was stirred for more the tion 1 hour at an internal temperature of 20-30°C. The mixture then was filtered and the flask, and a layer on the filter was washed with water (1×1 l), 50% ethanol (1×1 l) and 95% ethanol (1×1 l). Golden solid product was placed on a drying tray and dried to constant weight 546 g (yield 99%) in a vacuum at approximately 50°C in a vacuum oven.

Method G

5-Chloro-2-nitroaniline (200,0 g, of 1.16 mol) were placed in a 3-necked round bottom flask with a volume of 3000 ml, equipped with a stirrer with a top drive, a refrigerator, a nozzle for gas inlet, addition funnel and a control thermometer. A round bottom flask was then purged with N2. In the Erlenmeyer flask 1000 ml) was added 1-methylpiperazine (550 g, 552 ml, to 4.98 mol) and deionized water (330 ml). An aqueous solution of 1-methylpiperazine (~880 ml) was added in a steady stream in a round bottom flask over a period of about 5 minutes. The flask is then blew N2and the reaction mixture was left in an atmosphere of N2. The mixture was stirred at approximately 800 rpm and heated in a mantle until the internal temperature of 110°C (+/-5°C) and held at this temperature until completion of the reaction (usually around 7 hours), which was determined according to the HPLC. In the Erlenmeyer flask was added deionized water (170 ml) and isopropanol (500 ml). Heating of the reaction mixture was stopped and then to the reaction mixture in a steady stream added water-isopropanol the mixture. This caused the temperature drop of the reaction mixture to an internal temperature of about 66.5°C. the Mixture was led and kept overnight under stirring at a temperature of 40-50°C. the mixture then was filtered and the flask, and a layer on the filter was washed twice with water-isopropanol solution (water:isopropanol 3:1; 2×400 ml) at a temperature of about 15-20°C. the Orange solid product was dried to constant weight 267,3 g (yield of 97.6%) in vacuum at approximately 50°C in a vacuum oven.

Method D

5-Chloro-2-nitroaniline (150,0 g of 0.87 mole) were placed in a 4-necked round bottom flask with a volume of 3000 ml, equipped with a stirrer with a top drive, a refrigerator, a nozzle for gas inlet, addition funnel and a control thermometer. A round bottom flask was then purged with N2. In an Erlenmeyer flask of 500 ml was placed sodium chloride (57,87 g) and deionized water (250 ml). Obtained 4M solution of sodium chloride was added in a steady stream in a round bottom flask. In a round bottom flask in a steady stream was added 1-methylpiperazine (348 g, 386 ml of 3.48 mol) over a period of time of about 20 seconds. The flask is then blew N2and the reaction mixture was left in an atmosphere of N2. The flask was heated in a mantle until the internal temperature of 110°C (+/-5°C) and kept at this temperature until the completion of the reaction (usually OK the lo 5-6 hours), what was determined according to the HPLC. Deionized water (500 ml) was added dropwise to the reaction mixture, while the internal temperature was maintained at 108-110°C. the Obtained suspension was stirred for about 30 minutes. Heating of the reaction mixture was stopped, was added to the reaction mixture, 500 ml of water over a period of about 1 minute and the reaction mixture was cooled to a temperature of about 22°C. the resulting mixture was then filtered and the flask, and a layer on the filter was washed with water (750 ml) and an aqueous solution of ethanol (water: ethanol 1:1; 750 ml). The solid product was dried to constant weight 192,8 g (yield 93.9 per cent) in vacuum at a temperature of about 50°C in a vacuum oven.

Method E

5-Chloro-2-nitroaniline (100.0 g, of 0.58 mol) were placed in a 4-necked round bottom flask of 1 l equipped with a stirrer with a top drive, a refrigerator, a nozzle for gas inlet, addition funnel and a control thermometer. A round bottom flask was then purged with N2. In a round bottom flask was added ethylene glycol (100 ml) and the mixture was stirred in an atmosphere of N2. Then in a round bottom flask was added 1-methylpiperazine (232 g, 257 ml, 2,32 mol). The flask was again purged with N2and the reaction mixture was stirred in an atmosphere of N2. The flask was heated in a mantle until the internal temperature of 122°C (+/-5°C) and held at this temperature until completion of the reaction (usually the eye is about 4-5 hours), what was determined according to the HPLC. Heating of the reaction mixture was stopped and the reaction mixture was added water (800 ml) over a period of about 6 minutes. The obtained suspension was heated to an internal temperature of about 103°C and was stirred for 30 minutes. The suspension was then cooled to an internal temperature of 20-25°C with stirring overnight (~14 hours). The mixture then was filtered and the flask, and a layer on the filter was washed twice with water (2×500 ml) and once with an aqueous solution of ethanol (1:1 water: ethanol; 500 ml). The obtained solid product was dried to constant weight 126,9 g (yield of 92.7%) in vacuum at a temperature of about 50°C in a vacuum oven.

Methodology W

4-Necked round bottom flask of 1 l equipped with a mantle, stirrer with a top drive, a refrigerator, a nozzle for input of nitrogen and thermocouple. Into the flask was loaded 5-Chloro-2-nitroaniline (150 g, 869 mmole, 1 equiv.), 1-methylpiperazine (348 ml, 386 g of 3.48 mol, 4 equiv.) and 4M aqueous solution of NaCl (247 ml). The contents of the flask were stirred and blew N2for at least 15 minutes the Reactor was then heated to achieve an internal temperature 110-112°C. the Contents were stirred for 7-8 hours before the end of the reaction according to HPLC. After the reaction mixture was cooled to 20°C for 2 h before deposition of the product in the form of suspension and stirring was continued for an additional who's 16 PM The solid was filtered under vacuum, and the mother liquor is collected in the first reaction vessel. The solids were washed on the filter with N2About (2×250 ml), then was dispersible in heptane (200 ml) for 0.5 hours the Suspension was again filtered under vacuum and dried under vacuum (50°C, 30 inches Hg) to give 5-(4-methylpiperazin-1-yl)-2-nitroaniline (197,8 g, yield 96,3%). The remainder of the N-methylpiperazine was not determined according to the1H NMR.

The mother liquor of the reaction was brought back to working condition by the addition of NaOH pellets (34,9 g, 869 mmole, 1 equiv.) to the stock solution, and then stirred until complete dissolution of NaOH. The vessel was loaded 1-methylpiperazine (96,5 ml, 869 mmole, 1 equiv.) and 5-chloro-2-nitroaniline (150 g, 869 mmole). Blew, then heated until the end of the reaction, cooled, filtered and repeated washing with heptane as described above to obtain 5-(4-methylpiperazin-1-yl)-2-nitroaniline (of 203.2 g, yield 98.9 per cent). The remainder of the N-methylpiperazine was not determined according to the1H NMR.

The mother liquor was brought back to a working state for the second time in accordance with the above described method of obtaining 5-(4-methylpiperazin-1-yl)-2-nitroaniline (203,43 g, yield rate of 99.0%). Less than 1% of the residue N-methylpiperazine was determined according to the1H NMR.

Method 3

4-Necked round bottom flask with a volume of 5 l in the mantle was equipped with a stirrer with top results in the om, a refrigerator, a nozzle for N2and thermocouple. Into the flask was loaded 5-chloro-2-nitroaniline (365,3 g, 2,11 mol) and 1-methylpiperazine (848,6 g, 8,46 mol, 4 equiv.) in EtOH 200-proof (595 ml). This mixture was stirred and blew N2for at least 15 minutes, the Reaction mixture was then heated with stirring until reaching an internal temperature of 97°C.±5°C. Stirring is continued, maintaining the temperature 97°C±5°C until the end of the reaction (about 41 h), which was determined according to the HPLC. Deionized H2(1900 ml) was pre-heated to about 90°C. in a separate vessel. The reaction mixture was cooled to 90°C. and preheated H2(1900 ml) was transferred into the reaction vessel within 2-3 minutes of a Single reaction mixture then was cooled to 25°C for 4 h When the temperature reached about 80°C., the product was precipitated in the form of a fine mist, which continued to precipitate when cooled suspension. The crude product was then collected by vacuum filtration in a Buchner funnel. The mother liquor was brought back to a working state from the reaction vessel transfer the remaining solids on the filter. The crude product was washed with fresh deionized H2About (2×900 ml). The product was dried under vacuum (80°C, 28 to 30 inches Hg) until reaching a constant weight (about 21 hours). The product was collected with the release 94,1% (471 g). The remainder of the N-methylpiperazine not determined and according to 1H NMR.

Method And

4-Necked round bottom flask with a volume of 5 l in the mantle was equipped with a stirrer with a top drive, a refrigerator, the combination of nozzles for gas injection/thermocouple (via adapter Claisen) and addition funnel. The reactor was loaded 5-chloro-2-nitroaniline (500 g, 2,90 mol) and blew N2then the reactor was added 1-methylpiperazine (1160, 1,28 l, 11,58 mol) and EtOH 200 proof (811 ml). The mixture was stirred and blowing N2continued for at least 15 minutes, the Reaction mixture was heated to 97°C.±5°C. Stirring is continued and the temperature maintained at 97°C±5°C until the end of the reaction according to HPLC (about 40 hours).

The reaction mixture then was cooled to 75-80°C and was added heptane (375 ml) for 5-10 minutes After the addition of heptane, the reaction mixture was cooled to 65°C±3°C until precipitation of the product. (If precipitation did not occur, the solution can be added seed crystals of 5-(4-methylpiperazin-1-yl)-2-nitroaniline and the solution is maintained for 20-30 minutes Additional heptane (125 ml) can be added to precipitate). After cooling the reaction mixture to 65°C. to the suspension was added heptane (1,63 l) for 30-45 min, keeping the temperature at 65°C±3°C. After the addition of heptane suspension was cooled to 17-22°C for 1 h and kept at this temperature for at least 1 h the Product was filtered with the aid of the d vacuum funnel of coarse glass 3 HP The mother liquor was brought back to a working state from the reaction vessel transfer the remaining solids. In the funnel was added deionized H2On (2.00 l) and kept in the vortex for at least 5 minutes. The water was then removed by vacuum filtration. The solid is washed with fresh deionized H2About (2×1.1 l) on the filter. In the funnel was added heptane (1.5 l) layer and allowed to soak for at least 30 minutes, then used a vacuum to remove the heptane. The product was dried in vacuum (75-80°C, 28 to 30 inches Hg) until reaching a constant weight. 5-(4-Methylpiperazin-1-yl)-2-nitroaniline was obtained with the yield of 92.9% (636 g). The remainder of the N-methylpiperazine not determined according to the1H NMR.

Methods To

In a 4-necked vessel was added 5-chloro-2-nitroaniline (0.5 g, 2,90 mmole, 1 equiv.), NaOH (0,229 g, 5,71 mmole, 1,98 equiv.), 4 M NaCl (of 0.82 ml, aq.) 1-methylpiperazine (0,643 g of 0.71 ml, 5,79 mmole, 2 equiv.). The mixture was heated on a hot basis at 105°C for 22 h To the mixture was added deionized H2O (6 ml)which was cooled to room temperature and the precipitate was collected on a Buechner funnel. The precipitate is then washed with deionized H2O (5 ml) and heptane (5 ml). After drying in a vacuum oven (80°C, 30 inches Hg) during the night, the product (0,624 g, to 91.1%) was collected. According to HPLC analysis, the sample had a purity of 99.6 percent.

5-(4-Methylpiperazin-1-yl)-2-neither rosanilin 1H NMR (400 MHz, DMSO-d6) δ: 7,80 ppm (d, J=7.7 Hz, 1H), to 7.25 ppm (s, 2H), 6,38 ppm (dd, J=5,0 Hz, J=5.0 Hz, 4H), 2,39 ppm (dd, J=5,0 Hz, J=5.0 Hz, 4H), measuring 2.20 ppm (s, 3H).

Example 2

Synthesis of ethyl ether [6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]acetic acid

Method And

4-Necked flask with a volume of 5000 ml was equipped with a stirrer, a thermometer, a refrigerator and a nozzle for I/o gas. The air flask was loaded 265,7 g (1,12 mol. 1.0 equiv.) 5-(4-methylpiperazin-1-yl)-2-nitroaniline and 2125 ml tO 200 proof. The resulting solution was purged with N2within 15 minutes. Then added to 20.0 g of 5% Pd/C (50% H2About the weight.). The reaction mixture was intensively stirred at 40-50°C (internal temperature)until the mixture stood out H2. Over the course of the reaction was observed every hour on the subject of the disappearance of 5-(4-methylpiperazin-1-yl)-2-nitroaniline according to HPLC. Typically, the reaction time was 6 hours.

After the disappearance of all 5-(4-methylpiperazin-1-yl)-2-nitroaniline from the reaction mixture solution was purged with N2within 15 minutes. Then added 440,0 g (of 2.25 mol) of the hydrochloride of ethyl 3-ethoxy-3-aminopropanoic in the form of solids. The reaction mixture was stirred at 40-50°C (internal temperature) until the end of the reaction. Over the course of the reaction was observed by the disappearance of diaminobenzidine according to HPLC. Typically, the reaction time was 1-2 hours. After reacts and the mixture was cooled to room temperature and was filtered through a layer of celite (filter material). The filter material celite was washed with absolute tO (2×250 ml) and the filtrate was concentrated under reduced pressure, obtaining a thin brown/orange oil. The oil obtained was transferred into 850 ml of 0.37% HCl solution. Solid NaOH (25 g) was then added in one portion, and the formed precipitate. The resulting mixture was stirred for 1 hour and then filtered. The solid is washed with N2About (2×400 ml) and dried at 50°C in a vacuum furnace, receiving 251,7 g (74.1 per cent) ethyl ether [6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]acetic acid as pale yellow powder.

Method B

4-Necked flask with a shirt with a volume of 5000 ml was equipped with a mechanical stirrer, a refrigerator, a thermometer, a nozzle for gas and oil bubbler. The air flask was loaded with 300 g (1,27 mole) of 5-(4-methylpiperazin-1-yl)-2-nitroaniline and 2400 ml tO 200 proof (the reaction can be conducted and carried out with 95% ethanol, and use ethanol 200 proof for this reaction is optional). The resulting solution was stirred and purged with N2within 15 minutes. Then the reaction flask was added 22.7 g of 5% Pd/C (50% H2About the weight.). The reaction vessel was purged with N2within 15 minutes. After blowing N2the reaction vessel was purged H2maintaining a slow but steady stream of H2through the flask. The reaction mixture was stirred at 45-55°C (inside the inner temperature), while N2was passed through the mixture until complete disappearance of 5-(4-methylpiperazin-1-yl)-2-nitroaniline, which was determined according to the HPLC. The usual reaction time was 6 hours.

After the disappearance of all 5-(4-methylpiperazin-1-yl)-2-nitroaniline from the reaction mixture solution was purged with N2within 15 minutes. Diamino intermediate compound is sensitive to air, so it was carefully concealed from exposure to air. In the reaction mixture was added 500 g (2,56 mole) of the hydrochloride of ethyl 3-ethoxy-3-aminopropanoic over a period of about 30 minutes. The reaction mixture was stirred at 45-55°C (internal temperature) in an atmosphere of N2until complete consumption of the diamine, which is determined according to the HPLC. Usually the reaction time is about 2 hours. After the reaction is still warm reaction mixture was filtered through a layer of celite. The reaction flask celite and then washed tO 200 proof (3×285 ml). The filtrates were combined in a flask with a volume of 5000 ml and about 3300 ml ethanol was removed in vacuum, obtaining an orange oil. To the resulting oil was then added water (530 ml) and 1M HCl (350 ml) and the resulting mixture was stirred. The resulting solution was intensively stirred while adding 30% NaOH (200 ml) over a period of about 20 minutes, maintaining an internal temperature of about 25-30°C until the pH value reaches 9-10. The resulting suspension is eremetical for about 4 hours, maintaining an internal temperature of about 20-25°C. the resulting mixture was filtered, and the layer on the filter is washed with N2About (3×300 ml). The collected solid was dried to constant weight at 50°C under vacuum in a vacuum furnace, receiving 345,9 g (90,1%) ethyl ether [6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]acetic acid as pale yellow powder. In an alternative method of processing the filtrates were combined and the ethanol was removed in vacuum to remove about 90%. To the resulting oil was then added to water at a neutral pH value and the solution was cooled to about 0°C. and Then slowly added aqueous 20% NaOH solution with rapid stirring until a pH value of 9.2 (defined using the pH-meter). The mixture then was filtered and dried as described above. Alternative methods of processing yields a light yellow product with a yield of 97%.

Example 3

A method of reducing the water content in ethyl ether [6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]acetic acid

Ethyl ester [6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]acetic acid (120,7 g), which had previously been processed and dried to a water content of about 8-9% N2Oh, was placed in a round bottom flask with a volume of 2000 ml and dissolved in absolute ethanol (500 ml). The amber solution was concentrated to obtain a thin oil with ro is ornago evaporator when heated to completely remove all solvent. The methodology was repeated two more times. Thus obtained thin oil was left in the flask and placed in a vacuum oven and heated at 50°C during the night. The result of the analysis, Karl Fischer showed the water content of 5.25%. Low water content is achieved in this way, provides higher outputs in the method of example 4. Other solvents, such as toluene and THF may be used in place of ethanol in the drying process.

Example 4

Synthesis of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-it

Method And

Ethyl ester [6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]acetic acid (250 g, 820 mmol) (dried with ethanol as described above) was dissolved in THF (3800 ml) in a flask with a volume of 5000 ml, equipped with a fridge, a mechanical stirrer, thermometer, and was purged with argon. To the solution was added 2-amino-6-fluoro-benzonitrile (95,3 g, 700 mmol) and the internal temperature was raised to 40°C. When all solids had dissolved and the solution temperature reached 40°C, was added solid KHMDS (376,2 g, 1890 mmol) for 5 minutes. After adding potassium Foundation received a heterogeneous yellow solution and the internal temperature was raised to 62°C. After 60 minutes the internal temperature was reduced back to 40°C, and the end of the reaction was recorded according to the HPLC data (the absence of towel source material or acyclic intermediate connection). Thin the reaction mixture was then extinguished, pouring in N2On (6000 ml), and stirred the mixture to reach room temperature. The mixture then was filtered, and the layer on the filter was washed with water (1000 ml 2X). The bright yellow solid was placed on a drying tray and dried in a vacuum oven at 50°C during the night, getting was 155.3 g (47,9%) of the desired 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-it.

Method B

4-Necked flask with a shirt with a volume of 5000 ml was equipped with a nozzle for distillation, a thermometer, a nozzle for N2, addition funnel and mechanical stirrer. The reactor was loaded ethyl ester [6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]acetic acid (173, 0mm g, 570 mmol) and the reactor was purged with N2within 15 minutes. Into the flask was then loaded dry THF (2600 ml) under stirring. After dissolution of all solids the solvent was removed by distillation (vacuum or atmospheric (higher temperature facilitates the removal of water), optionally using heat. Then deleted the 1000 ml of the solvent, the distillation was stopped and the reaction mixture was purged with N2. In the reaction vessel was then added to 1000 ml of dry THF, and when all the solid had dissolved, the distillation (vacuum or atmospheric) again conducted to remove another 1000 ml of solvent. is the process of adding dry THF and solvent removal were repeated at least 4 times (4th distillation removed 60% of the solvent instead of 40% in the first 3 distillations), then 1 ml of sample was collected for analysis by Karl Fischer for water determination. If the analysis showed that the sample contains less than 0.20% of water, the reaction continued as described in the next paragraph. However, if the analysis showed the water content is more than 0.20%, the drying process described above is continued until the water content is less than 0.20 per cent.

After the water content has reached less than or about 0.20 per cent, using the methodology described in the previous paragraph, the nozzle for distillation was replaced with a reflux condenser and the reaction mixture was loaded 2-amino-6-perbenzoate (66,2 g, 470 mmol) in some techniques used 0.95 equivalent). The reaction mixture is then heated until the internal temperature of 38-42°C. When the internal temperature reached 38-42°C, the reaction mixture was added a solution of KHMDS (1313 g of 1.32 mol, 20% KHMDS in THF) via addition funnel over 5 minutes, maintaining an internal temperature of about 38-50°C during the addition. After adding a potassium base, the reaction mixture was stirred for 3.5 to 4.5 hours (in some instances it was stirred for 30-60 minutes, and the reaction may not be completed during this time), maintaining an internal temperature of about 38-42°C. and Then separated the sample of the reaction mixture and analyzed by HPLC. If the response has not ended, to the BU was added advanced solution of KHMDS in for 5 minutes and the reaction mixture was stirred at a temperature of 38-42°C for 45-60 minutes (the number of added a solution of KHMDS was determined as follows. If the ratio of IPC was <3,50, there was added 125 ml; if 10,0≥ IPC ratio≥3,50, then added 56 ml; if 20,0≥ IPC ratio≥10, then added 30 ml of the IPC Ratio is equal to the area corresponding 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-ONU divided by the area corresponding acyclic intermediate connection). Once the reaction was complete (IPC ratio>20), the reactor was cooled to an internal temperature of 25-30°C, and the reactor was loaded water (350 ml) over 15 minutes, maintaining the internal temperature at 25-35°C (in one alternative embodiment, the reaction was conducted at 40°C. and added water for 5 minutes. More rapid damping of the reduced amount of impurities, which are formed over time). The reflux condenser was then replaced with a nozzle for distillation and the solvent was removed by distillation (vacuum or atmospheric), using, if necessary, heating. After removal of 1500 ml of solvent distillation was stopped and the reaction mixture was purged with N2. In the reaction flask was then added water (1660 ml)while maintaining the internal temperature at 20-30°C. the Reaction mixture was then stirred at 20-30°C for 30 minutes before cooling it to an internal temperature of 5-10°C. and then was stirred for 1 hour. The resulting suspension was filtered, and to the BU, and a layer on the filter was washed with water (3×650 ml). The thus obtained solid residue was dried to constant weight in vacuum at 50°C in a vacuum furnace with getting to 103.9 g (yield of 42.6%) 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-it is in the form of a yellow powder.

Method In

Ethyl ester [6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]acetic acid (608 g a 2.01 mol) (dried) and 2-amino-6-perbenzoate (274 g, a 2.01 mol) were loaded into a 4-necked flask with a volume of 12 liters, placed in a heating mantle and equipped with a refrigerator, a mechanical stirrer, a nozzle for a gas inlet and a control thermometer. The reaction vessel was purged with N2and the reaction mixture was loaded toluene (7.7 l) under stirring. The reaction vessel was again purged with N2and left in an atmosphere of N2. The internal temperature of the mixture was raised to a temperature of 63°C (+/-3°C). The internal temperature of the mixture was maintained at 63°C (+/-3°C) up until from the bulb distills over approximately 2.6 l of toluene under reduced pressure (380+/-10 Torr, the temperature of the distillation head t=40°C (+/-10°C) (Karl Fischer analysis was used to test the water content in the mixture. If the water content was more than 0.03%, the newly added 2.6 liters of toluene and repeated distillation. This process was repeated until then, until he reached sod is neigh water less than 0.03%). After it was reached the water content is less than 0.03%, the heating was stopped and the reaction mixture was cooled in an atmosphere of N2until the internal temperature of 17-19°C. Then the reaction mixture was added tert-piperonyl potassium in THF (20% in THF; 3,39 kg, 6,04 mole of tert-butoxide potassium) in the atmosphere N2with such a rate that the internal reaction temperature was kept below 20°C. After adding tert-butoxide potassium, the reaction mixture was stirred at an internal temperature less than 20°C for 30 minutes. The temperature was then raised to 25°C and the reaction mixture was stirred for at least 1 hour. The temperature was then raised to 30°C and the reaction mixture was stirred for at least 30 minutes. The reaction mixture is then checked for completeness flow by HPLC to verify the complete consumption of starting materials (usually within 2-3 hours both original material was used (less than 0.5%% HPLC peak area)). If the reaction was not completed after 2 hours, was added 0.05 equivalent of tert-butoxide potassium, and the process was completed until HPLC shows that the reaction has ended. After the reaction to stir the reaction mixture was added 650 ml of water. The reaction mixture was then heated to an internal temperature of 50°C and drove THF (about 3 l in volume) from the reaction mixture under reduced Yes the tion. Then to the reaction mixture was added dropwise water (2.6 liters)using an addition funnel. The mixture was then cooled to room temperature and was stirred for at least 1 hour. The mixture then was filtered and the layer on the filter was washed with water (1.2 l), 70% ethanol (1.2 l) and 95% ethanol (1.2 l). The bright yellow solid was placed on a drying tray and dried in a vacuum oven at 50°C until constant weight, getting 674 g (85,4%) of the desired 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-it.

Example 5

Purification of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-it

3000 ml 4-necked flask equipped with a fridge, a control thermometer, a nozzle for N2and mechanical stirrer, were placed in a heating mantle. Into the flask was then loaded 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-he (101.0 g, of 0.26 mol) and the yellow solid is suspended in 95% ethanol (1000 ml) and stirred. In some cases, the ratio of solvent to 8:1. The suspension is then heated to a gentle boil (temperature of about 76°C.) with stirring over a period of about 1 hour. The reaction mixture was then stirred at boiling for 45-75 minutes. After it stopped heating the flask and the suspension was cooled to a temperature of 25-30°C. the Suspension is then otherthrow the Ali and the layer on the filter was washed with water (2×500 ml). The yellow solid was then placed on a drying tray and dried in a vacuum oven at 50°C until reaching constant weight (typically 16 hours) to obtain 97,2 g (96,2%) of the pure product as a yellow powder.

Example 6

Obtaining a salt of lactic acid 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-it

4-Necked flask with a shirt with a volume of 3000 ml was equipped with a fridge, a control thermometer, a nozzle for N3and a mechanical stirrer. The reaction vessel was then purged with N2at least for 15 minutes and then loaded 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-he (484 g of 1.23 mol). Preparing a solution of D,L-lactic acid (243,3 g, 1,72 mole of monomer - see the following paragraph) in water (339 ml) and ethanol (1211 ml) and then loaded him into the reaction flask. Stirring was started at a moderate speed and the reaction mixture was heated until the internal temperature 68-72°C. Internal temperature of the reaction was maintained at a level 68-72°C for 15-45 minutes and then heating was stopped. The resulting mixture was filtered through a filter with a porosity of 10-20 microns and collect the filtrate in a flask with a volume of 12 l Flask with a volume of 12 l equip internal control thermometer, reflux condenser, addition funnel, nozzle for Wadi gas outlet and a stirrer with a top drive. The filtrate is then stirred at a moderate speed and heated to boiling (internal temperature of about 78°C). Maintaining a low boil in a flask was loaded ethanol (3596 ml) over a period of about 20 minutes. The reaction flask was then cooled to an internal temperature in the range from about 64 to 70°C for 15-25 minutes, and this temperature was kept for a period of about 30 minutes. The reactor was checked for the presence of crystals. If no crystals were not found in the flask was added the salt crystals lactic acid 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-she (484 mg, 0.1 mole %), and the reaction mixture was stirred at 64-70°C for 30 minutes before re-checking in the flask crystals.

Once the crystals were found, the stirring, the stirring speed was reduced to minimum and the reaction mixture was stirred at 64-70°C for an additional 90 minutes. The reaction mixture then was cooled to about 0°C for a period of about 2 hours and the resulting mixture was filtered through a filter with a porosity of 25 to 50 microns. The reactor was rinsed with ethanol (484 ml) and stirred until reaching an internal temperature of about 0°C. Cold ethanol used for washing layer on the filter and this technique was repeated 2 more times. The collected solid was dried to constant weight PR is 50°C in vacuum in a vacuum furnace, obtaining 510,7 g (85,7%) of yellow crystalline salt of lactic acid 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-it. Usually used rubber press or inert conditions in the filtering process. Although the dried solid substance, apparently, is not very hygroscopic, but the damp layer on the filter tends to capture the water and become sticky. Must be taken precautions against long stay wet layer on the filter in the atmosphere.

Commercially available lactic acid usually contains about 8-12 wt.% water and contains in addition to the Monomeric lactic acid dimers and trimers. The molar ratio of dimer of lactic acid to the monomer is usually about 1.0:4,7. Commercially available lactic acid can be used in the process described in the previous paragraph, because of the reaction mixture predominantly deposited monopolowa salt.

It should be understood that organic compounds in accordance with the invention can exhibit the phenomenon of tautomerism. Since the chemical structure in the present description can represent only one of the possible tautomeric forms, it should be understood that the present invention encompasses any tautomeric form of the depicted structure. For example, the compound of formula IIIB are presented below in the form od the CSOs from the tautomers, tautomer VA:

Other tautomers of the compounds of formula IIIB, tautomer IIIBb and tautomer S shown below:

The contents of each of the patents, patent applications and journal articles, above, shown here as a reference and for all purposes, as if they were given here in full.

It is clear that the present invention is not limited to the variants of the implementation shown here for illustration, but applies here at all such forms are included within the scope of the following claims.

Specialist in the art can understand that all described variants can describe and really describe all the flavors for all purposes, and all such modifications are also part and group of the present invention. Any presents can be easily recognized as sufficiently described and feasible the same variant, which is divided at least into two equal halves, thirds, quarters, fifths, tenths parts, etc. as a non-limiting example, each variant described here can be easily divided into minor third, middle third, and most third etc.

All publications, patent applications, op is blokowanie patents and other documents which have links in the description given here as reference, as if each specified individual publication, patent, published patent application or other document was specifically and individually incorporated fully herein by reference. Definitions contained in the text as references, are excluded to the extent that they are inconsistent with the definitions in the present description.

1. The method of obtaining heterocyclic compounds, comprising: a reaction mixture of 1-methylpiperazine and 5-halogen-2-nitroaniline in the first solvent and the first temperature in the range from about 90°to about 110°C To produce the compounds of formula VIH:

where the first solvent includes alcohol;
cooling the mixture containing the compound of formula VIH, to a second temperature in the range from about 85°to about 95°C;
adding to the mixture volume of the second solvent different from the first
solvent, where the second solvent contains water; and
the suspension of the compounds of formula VIH;
where the second solvent is heated to the second temperature.

2. The method according to claim 1, where the first solvent consists essentially of ethanol.

3. The method according to claim 1, where the second solvent consists essentially of water.

4. The method according to claim 1, where a suspension is formed by cooling the reaction of smashedo third temperature in the range from about 15°to about 25°C. to initiate suspension of the compound of formula VIH.

5. The method according to claim 1, where 1-methylpiperazine and 5-halogen-2-nitroaniline are present in a molar ratio in the range from about 2:1 to about 5:1.

6. The method of obtaining heterocyclic compounds, including:
the reaction mixture of 1-methylpiperazine and 5-halogen-2-nitroaniline in the first solvent and the first temperature in the range from about 90°to about 110°C., to obtain compounds of formula VIH:

where the first solvent includes alcohol;
adding to the mixture volume of the second solvent different from the first solvent; where the second solvent contains heptane; and the suspension of the compounds of formula VIH.

7. The method according to claim 6, where the second solvent essentially consists of heptane.

8. The method according to claim 7, also comprising cooling the mixture containing the compound of formula VIH, to a second temperature, amounting to at least 70% from the first temperature, before adding a volume of the second solvent.

9. The method of claim 8, where the second temperature is in the range from about 70°to about 85°C.

10. The method according to claim 9, where a suspension is formed by cooling the reaction mixture to a third temperature in the range from about 15°to about 25°C. to initiate suspension of the compound of formula VIH.

11. The method according to claim 10, also comprising adding a second amount of the second organic solvent in the process is e cooling to a third temperature to form crystals of the compound of formula VIH.

12. The method according to claim 11, also including the collection of crystals of compounds of formula VIH and washing the crystals with water.

13. The method according to item 12, where the compound of formula VIH has purity equal to or greater than 90%.

14. The method according to item 13, where the compound of formula VIH has purity equal to or greater than 95%.

15. The method according to 14, where the compound of formula VIH has purity equal to or greater than 99%.

16. The method of obtaining heterocyclic compounds, including:
in the first reaction mixture, the reaction of 1-methylpiperazine 5-halogen-2-nitroaniline in a solvent which contains water, and when
temperature greater than 95°C., to obtain compounds of formula VIH:

and cooling the first reaction mixture, sufficient for the deposition of the first portion of solids containing the compound of formula VIH, and filtering the first reaction mixture to obtain a first filtered solids containing the compound of formula VIH and the first filtrate containing solvent.

17. The method according to clause 16, where the solvent contains water in an amount more than 50% by volume, calculated on the quantity of solvent.

18. The method according to 17, where the solvent contains water in an amount more than 80% by volume, calculated on the quantity of solvent.

19. The method according to p, where the solvent contains water in an amount more than 90% by volume in terms of the number is the proportion of solvent.

20. The method according to claim 19, where the solvent contains water in an amount of more than 98% by volume, calculated on the quantity of solvent.

21. The method according to clause 16, where the solvent consists essentially of water.

22. The method according to clause 16, where the solvent consists essentially of deionized or distilled water.

23. The method according to clause 16, where the solvent is an aqueous solution containing inorganic salt.

24. The method according to item 23, where the concentration of salt in the aqueous solution ranges from about 1 to about 5 Meters

25. The method according to paragraph 24, where the concentration of salt in the aqueous solution ranges from about 3 to about 4.5 Meters

26. The method according A.25 where the concentration of salt in the aqueous solution ranges from about 3.5 to about 4.2 M

27. The method according to clause 16, where the internal temperature is over 95°C.

28. The method according to item 27, where the internal temperature is in the range from about 99°C. to about 115°C.

29. The method according to p, where the internal temperature is in the range from about 100°to about 110°C.

30. The method according to clause 29, where the internal temperature is in the range from about 105°to about 110°C.

31. The method according to clause 16, where 1-methylpiperazine and 5-halogen-2-nitroaniline is subjected to reaction at an internal temperature within the reaction time less than 20 hours

32. The method according to p, where the reaction time is less than 10 hours

33. The method according to p, where reaction time is m is it 8 o'clock

34. The method according to clause 16, where the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline is in the range from about 2:1 to about 10:1 in the beginning of the reaction.

35. The method according to clause 34, where the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline is in the range from about 3:1 to 4.5:1 in the beginning of the reaction.

36. The method according to p, where the molar ratio of 1-methylpiperazine to 5-halogen-2-nitroaniline is in the range from 4:1 to 4.3:1 in the beginning of the reaction.

37. The method according to clause 16, where the output of the compounds of formula VIH in terms of the number of 5-halogen-2-nitroaniline is over 90%.

38. The method according to clause 37, where the output of the compounds of formula VIH in terms of the number of 5-halogen-2-nitroaniline is more than 93%.

39. The method according to § 38, where the output of the compounds of formula VIH in terms of the number of 5-halogen-2-nitroaniline is more than 96%.

40. The method according to item 23, where the solvent also contains inorganic base.

41. The method according to p, where the salt is NaCl, and the inorganic base is selected from the group consisting of NaOH, KOH, CA(Oh)2, Mg(OH)2, Na2CO3To2CO3and K3RHO4.

42. The method according to p where the concentration of salt in the aqueous solution is in the range from about 1 to about 5 Meters

43. The method according to § 42, where the concentration of salt in the aqueous solution is in the range from about 3 to about 5 Meters

44. The way is about p, where the amount of inorganic base is in the range from 0.5 to 4 equivalents, calculated on the number of 5-halogen-2-nitroaniline.

45. The method according to p, where 1-methylpiperazine and 5-halogen-2-nitroaniline are present in a molar ratio in the range from about 1.5:1 to about 3:1.

46. The method according to item 23, where the compound of formula VIH has purity equal to or greater than 90%.

47. The method according to item 46, where the compound of formula VIH has purity equal to or greater than 95%.

48. The method according to p, where the compound of formula VIH has purity equal to or greater than 99%.

49. The method according to item 23, also comprising adding to the first filtrate 1-methylpiperazine, 5-halogen-2-nitroaniline and amount of base sufficient to neutralize any amount of Hcl in the first filtrate, to obtain a second reaction mixture at an internal temperature sufficient to obtain the compounds of formula VIH.

50. The method according to § 49, where the compound of formula VIH has purity equal to or greater than 90%.

51. The method according to item 50, where the compound of formula VIH has purity equal to or greater than 95%.

52. The method according to § 51, where the compound of formula VIH has purity equal to or greater than 99%.

53. The method according to § 49, also includes adding the second filtrate 1-methylpiperazine, 5-halogen-2-nitroaniline and amount of base sufficient to neutralize any amount of HCl in the second filtrate with what rucenim third reaction mixture, when the internal temperature sufficient to obtain the compounds of formula VIH.

54. The method according to item 53, where the salt is NaCl.

55. The method according to item 54, where the solvent is a saturated aqueous NaCl solution.

56. The method according to § 49, where the base is selected from NaOH or KOH.

57. The method according to § 49, where the internal temperature is in the range from about 95°to about 120°C.

58. The method according to item 53, where the compound of formula VIH has purity equal to or greater than 90%.

59. The method according to § 58, where the compound of formula VIH has purity equal to or greater than 95%.

60. The method according to p, where the compound of formula VIH has purity equal to or greater than 99%.

61. The method according to any one of claims 1 to 60, where 5-halogen-2-nitroaniline represents 5-chloro-2-nitroaniline.

62. The method according to any one of claims 1 to 60, where 5-halogen-2-nitroaniline represents 5-fluoro-2-nitroaniline.

63. The method according to any one of claims 1 to 60, where the compound of formula VIH can then be recovered by obtaining the compounds of formula IVA:

64. The method according to p, where the compound of formula IVA then interacts with the compound of the formula V to obtain the compounds of formula IIC or IID, where the compound of formula V has the following structure:

where each R9arepresents independently unsubstituted alkyl group containing from 1 to 8 carbon atoms, and
X PR is dstanley a halogen atom, selected from F, Cl, Br or I, or represents a conjugate base of the acid; and compounds of formula IIC or IID have the following structure:

65. The method according to p, where R9arepresents methyl or ethyl and X represents Cl.

66. The method according to p, where the compound of the formula IIC or IID further interacts with the compound of the formula I in a suitable solvent in the presence of sodium or potassium salt of the base with obtaining the reaction product containing the compound of benzimidazolidinone, where the compound of formula I has the following structure:

where R1, R2, R3and R4may be the same or different and independently selected from H, Cl, Br, F, I, -OR10groups, -NR11R12groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted etkinlik groups, substituted or unsubstituted heterocyclyl groups or substituted or unsubstituted geterotsiklicheskikh groups;
R10selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or n is replaced geterotsiklicheskikh groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups or substituted or unsubstituted geterotsiklicheskikh groups;
R11selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heterocyclyl groups;
R12selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heterocyclyl groups; and
where the connection of benzimidazolidinone is a compound of formula S, tautomer the compounds of formula S, salt of the compounds of formula X or salt tautomer the compounds of formula C:
.

67. The method according to p, where R1selected from H, Cl, Br, F or I.

68. The method according to p, where R1is a F.

69. The method according to p, where R2, R3and R4all represent N.

70. The method according to p, where the compound of formula I is a compound of formula IA having the following structure:

and where the connection of benzimidazolidinone is a compound of formula V, tautomer the compounds of formula V, salt of the compounds of formula V or salt tautomer the compounds of formula V:

71. The way pop, where the connection of benzimidazolidinone further interacts with lactic acid to obtain the salt of lactic acid compounds of benzimidazolidinone.

72. The method of obtaining the compounds of formula VIH, including the reaction of 1-methylpiperazine 5-halogen-2-nitroaniline in a solvent, which contains a component of an organic solvent having a boiling point over 100°C at atmospheric pressure, to obtain the compounds of formula VIH:

where an organic solvent is a compound of the formula HO-(CH2)q-OH, or BUT-CH2CH2Och2CH2Is HE, where q is selected from 2, 3 or 4.

73. The method according to item 72, where the solvent contains propylene glycol or ethylene glycol.

74. The method according to item 72, where 5-halogen-2-nitroaniline 5-chloro-2-nitroaniline or 5-fluoro-2-nitroaniline.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 1H-quinazoline-2,4-diones of formula and to their pharmaceutically acceptable salts where R1 and R2 have the values specified in cl. 1 of the patent claim. The specified compounds exhibit antagonistic activity with respect to the AMPA receptor.

EFFECT: reception of a pharmaceutical composition for preparing a preparation used for treating a condition mediated by the AMPA receptor and first of all for treating epilepsy or schizophrenia.

8 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel derivatives of quinolone or one pharmaceutically acceptable salts thereof, solvates thereof or solvates of salts thereof, having general formula I , in which R1 denotes fluorine, R3 denotes halogen, a hydroxy group or a C1-C4-alkoxy group, R4 denotes C1-C6-alkyl or C3-C8-cycloalkyl, where the alkyl can contain 1-3 substitutes, and the substitutes are independently selected from a group comprising halogen or trifluoromethyl, and where the cycloalkyl can contain 1-3 halogen atoms as substitutes, or R3 and R4 together with atoms to which they are bonded form a ring with a group of formula , in which * indicates a site for bonding with a carbon atom, and # indicates a site for bonding with a nitrogen atom, R7 and R8 independently denote halogen, trifluoromethyl, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, C1-C3-alkyl or C1-C3-alkoxy group, and R9 denotes hydrogen, halogen or C1-C3-alkyl, or R8 denotes a trifluoromethoxy group, and R7 and R9 denote hydrogen, R10 denotes a group of formula or , in which * indicates a site for bonding with a carbon atom, R2 is bonded in position 3 or 4 and denotes a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C3-C6-cycloalkylcarbonyl or optionally hydroxy-substituted C1-C6-alkylaminocarbonyl, where the alkyl is substituted with one substitute and the substitute is selected from a group comprising a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxycarbonyl and 2-oxopyrrolidin-1-yl, R5 and R6 are independently bonded in positions 3, 4 or 5 and independently denote hydrogen, hydroxy group, methyl or ethyl, and Y denotes a methylene group or an oxygen atom. The invention also relates to methods of producing a compound of formula I, a medicinal agent based on the compound of formula I, use of the compound of formula I and a method of fighting viral infections.

EFFECT: novel substituted quinolone derivatives which are useful in treating viral diseases are obtained.

11 cl, 1 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), where A1, A2, A3, A4, A5 ad A6 are independently selected from a group comprising CR3 and N; provided that the biggest one of A1, A2, A , A4, A5 and A6 denotes N; B1, B2 and B3 are independently selected from a group comprising CR2 and N; each R3 independently denotes H or C1-C6 alkyl; and R1, R2, R4, R5, W and n are as given in the description, or salts thereof which are suitable for use in agriculture. The invention also relates to compositions containing compounds of formula (1), and insect-pest control methods which involve contact between the pest or habitat thereof with a biologically effective amount of the compound or composition according to the present invention, as well as to methods of protecting seeds and animals from insects-pests.

EFFECT: high effectiveness of the obtained compounds in insect-pest control.

29 cl, 12 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of general formula 1

by reacting a substituted indole derivative I'

with a heteroarylzinc halide of formula: or a diheteroarylzinc of formula:

where: L denotes Br, Cl; R denotes (C1-C8)alkyl; X denotes (C3-C8)cycloalkyl; Y denotes a 6-member heteroaryl with one or two N atoms; Z denotes HO2C-, (C1-C8)alkyl-O2C-, (C1-C6)alkyl-HNC(O)-, or in the presence of a Pd metal catalyst, a ligand selected from Ph3P, n-Tol3P, Cy3P, tpet-Bu3P, Cy2P(Ph-Ph), dppfh and dppb, in a solvent selected from tetrahydrofuran, dimethylformamide, N-methylpyrrolidone or any other combination thereof, at temperature between ambient temperature and 100°C. The invention also describes intermediate compounds.

EFFECT: high efficiency of the method.

12 cl, 3 dwg, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a heterocycle, L1 and L2 are different linker groups, and Q is a 6-member heterocycle, and use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds of compositions.

EFFECT: high effectiveness of the compounds.

17 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof , where D denotes phenyl; n equals 0; A, B and Q denote hydrogen; Z is selected from a group comprising a bond, straight C1-3alkylene; R1 is selected from a group comprising hydrogen, C1-10alkyl, C3-8cycloalkyl, benzyl, a 6-member monocyclic, 9-10-member bicyclic aromatic carbon-containing ring system and a spiro-ring system of formula (V): where X1 and X3 denote O; and where the said alkyl, cycloalkyl or benzyl from the R1 group is optionally substituted with 1-3 substitutes selected from a group comprising C1-3alkyl, cyano, phenyl, wherein the said phenyl is optionally substituted with 1-3 substitutes selected from halogen. The invention also relates to compounds of formulae .

Values of radicals of the said compounds are given in the claim. The invention also relates to a pharmaceutical composition having ORL1 receptor or µ opioid receptor inhibiting properties, containing an effective amount of the disclosed compound, a method of curing pain and a method of modulating pharmacological response from the opioid receptor, including the ORL1 or µ opioid receptor.

EFFECT: improved method.

41 cl, 5 tbl, 16 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I) or to their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity, and to a based pharmaceutical composition. (I) where P represents phenyl optionally substituted by 1 or 2 substitutes independently selected from halogen, C1-4alkyl, cyano, trifluoromethyl, C1-4alkoxy and trifluormethylthio, and R2 has the values specified in the patent claim.

EFFECT: preparation of new compounds of general formula (I) or their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity.

16 cl, 340 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula to its salt or hydrate where R1 represents hydrogen atom, alkyl group containing 1-6 carbon atoms or cycloalkyl group containing 3-6 carbon atoms; and alkyl group is optionally substituted by halogen atom; R2 represents hydrogen atom or alkyl group containing 1-6 carbon atoms; R3 represents alkyl group containing 1-6 carbon atoms or cycloalkyl group containing 3-6 carbon atoms; and alkyl group is optionally substituted by halogen atom; R4 and R5 independently represent hydrogen atom, halogen atom, alkyl group containing 1-6 carbon atoms, alkoxygroup containing 1-6 carbon atoms or alkenyl group containing 2-6 carbon atoms; and alkyl group is optionally substituted by halogen atom; and provided R4 and R5 are not hydrogen atoms simultaneously; or substitutes R4 and R5 together represent (a) 3-6-members cyclic compound including carbon atom, common for R4 and R5, with formation of a spirocyclic compound with a pyrrolidine ring; or (b) exomethylene group bound with the pyrrolidine ring by a double bond; R6 and R7 independently represent hydrogen atom or alkyl group containing 1-6 carbon atoms; R8 represents halogen-substituted alkyl group containing 1-6 carbon atoms or cycloalkyl group containing 3-6 carbon atoms; and cycloalkyl group can be substituted by halogen atom; R9 represents hydrogen atom; X1 represents hydrogen atom or halogen atom; and A represents nitrogen atom or a fragment presented by formula , where X2 represents hydrogen atom, alkyl group containing 1-6 carbon atoms or alkoxygroup containing 1-6 carbon atoms; or X2 together with R8 represents a cyclic compound containing a portion of a nucleus, and the ring formed thereby optionally contains oxygen atom and is substituted by alkyl group containing 1-6 carbon atoms. Besides, the invention refers to an antibacterial agent based on the compound of formula I, to a therapeutic agent for infections, to a method of treating an infectious disease and an application of said compounds for preparing an antibacterial drug.

EFFECT: there are produced and described new compounds showing strong antibacterial activity in relation to gram-positive and gram-negative bacteria.

30 cl, 112 ex, 10 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing cycloalkylamines of general formula Alk-R, where

, , , , , , , , , . The method is realised by reacting a cyclic ketone with an amine derivative and formic acid in the presence of a catalyst. The cyclic ketones used include cyclopentanone, cyclohexanone and 2-adamantanone, and the amine derivative used is formamide, cyclohexylamine, piperidine, morpholine, piperazine, 2-aminoethanol, 1,2-ethylenediamine, and the catalyst used is copper nanoparticles. The process is carried out in molar ratio ketone: amine derivative: HCOOH equal to 1:3-4:5-10, at temperature 100°C for 3-9 hours. The copper nanoparticles can be obtained in situ, as well as beforehand.

EFFECT: high output of cycloalkylamines under milder conditions for carrying out the process.

3 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of 1-aminomethyl-2-phenylacetylenes of formula (1), where is characterised by that, phenylacetylene (Ph-C≡CH) is reacted with gem-diamines R2NCH2NR2, where R2N is as defined above, in the presence of a Sm(NO3)2*6H2O catalyst in molar ratio phenylacetylene: gem-diamine: Sm(NO3)2*6H2O=10:(8-12):(0.2-0.6) at 80°C and atmospheric pressure for 3-5 hours.

EFFECT: new method is designed for synthesis of 1-aminomethyl-2-phenylacetylenes, which can be used in fine organic synthesis, particularly for synthesis of scarce polycyclic compounds.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining substituted aminobenzhydrols, which can be used as semi-products in synthesis of medications of general formula , where: R1=R3=H, R2=NH2, R4=Cl (1); R1=R3=H, R2=NH2, R4=Br (2); R1=R3=H, R2=NH2, R4=OCH3 (3); R1=R4=H, R2=NH2, R3=Cl (4); R1=H, R2=NH2, R3=Cl, R4=Cl (5); R1=NH2, R2=Cl, R3=R4=H (6); R1=NH2, , R3=R4=H (7); R1=NH2, R2=Cl, R3=H, R4=Cl (8); R1=NH2, , R3=H, R4=Cl (9); R1=NH2, R3=Cl, R2=R4=H (10); R1=NH2, , R2=R4=H (11); R1=NH2, R2=H, R3=Cl, R4=Cl (12); R1=NH2, R2=H, , R4=Cl (13), whish lies in simultaneous reduction of nitro- and carbonyl groups of respective nitrobenzphenones of general formula , where: R1=R3=H, R2=NO2, R4=Cl; R1=R3=H, R2=NO2, R4=Br; R1=R3=H, R2=NO2, R4=OCH3; R1=R4=H, R2=NO2, R3=Cl; R1=H, R2=NO2, R3=Cl, R4=Cl; R,=NO2, R2=Cl, R3=R4=H; R1=NO2, , R3=R4=H; R1=NO2, R2=Cl, R3=H, R4=Cl; R1=NO2, , R3=H, R4=Cl; R1=NO2, R3=Cl, R2=R4=H; R1=NO2, , R2=R4=H; R1=NO2, R2=H, R3=Cl, R4=Cl; R1=NO2, R2=H, , R4=Cl, reducing system Zn-NaBH4 in alcohol with molar ratio of substratum : zinc: sodium tetrahydroborate equal 1 : 3.5 : 0.25.

EFFECT: reduction of synthesis cost, reduction of time and temperature for process carrying out, increase of target products output.

1 cl, 2 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: inventive subject matter is compouns and their pharmaceutically acceptable salts which can be applied in prevention and treatment of diseases caused by HCV infection. Structural formulae of the compounds are presented in the claim.

EFFECT: obtaining anti-HCV medicine including the claimed compound or its pharmaceutically acceptable salt as active component.

2 cl, 100 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new method for production of compounds of general formula

R=-NH2, -NHCH2CH2OH, -NHCH2C6H5, -NHNHC6H3(NO2)2, -NHNH2, -NHNHC6H5, -NHCH2СН2NH2.

, , .

Claimed method includes interaction of 2-hydroxy-2-cyanoadamantane with ammonia or derivatives thereof such as piperidine, piperazine, 1,2-diaminoethane, etc, in ethanol medium, at 20-80°C for 8-72 h.

EFFECT: enhanced assortment of adamantine derivatives useful as synthetic intermediates for bioactive compounds, method of increased yield.

1 cl, 10 ex

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining amino adamantane General formula AdR, where R=NH2, NHBu-t,

< / BR>
< / BR>
< / BR>
which are biologically active substances and can find application in pharmacology and adamant-1-ylamine is the basis of the drug midantana"

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula I where A represents an optionally substituted aryl or heteroaryl, B - a benzene or thiophene cycle, C - a benzene or aliphatic hydrocarbon cycle, while values of other radicals are disclosed in the description. The compound according to the present invention, and the based pharmaceutical compositions exhibit a strong antagonistic effect in relation to GnRH receptor that makes them applicable for treatment of GnRH-related diseases, particularly prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid tumour.

EFFECT: improved clinical effectiveness.

11 cl, 70 tbl, 765 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I , where X is N or CH; R1 is -C(O)-NR8R9 or -C(O)-OR10, and R2 is hydrogen; or alternatively R2 is and R1 is hydrogen or halogen; Y is N or CH; R3, R4, R5 and R6 are independently selected from a group consisting of hydrogen, halogen, (lower)alkoxy, (lower)fluoroalkyl, (lower)fluoroalkoxy and (lower)fluoroalkylsulfanyl; or R3 and R4 together with carbon atoms with which they are bonded form a 6-member unsaturated ring which can contain one nitrogen heteroatom; R7 is hydrogen or (lower)alkyl; R8 is hydrogen or NH2; R9 is selected from a group consisting of (lower)alkyl, (lower)alkenyl, (lower)alkoxyalkyl, -(CH2)m-(C3-C7)cycloalkyl, -(CH2)m-piperidinyl, -(CH2)m-phenyl, where the phenyl ring is unsubstituted or substituted with one or two groups selected from halogen, (lower)alkoxy, (lower)fluoroalkyl and (lower)fluoroalkoxy, -(CH2)m-naphthyl and pyridylamino; R10 is (lower)alkenyl; R11 is selected from a group consisting of -C(O)-R12, -SO2-R13 and -SO2-NR14R15; R12 is selected from a group consisting of (lower)alkyl, (lower)alkoxyalkyl, -(CH2)n-(C3-C7)-cycloalkyl, -(CH2)n-phenyl and -(CH2)n-pyridyl, where phenyl or pyridyl are unsubstituted or substituted with one (lower)alkyl; R13 is selected from (lower)alkyl or -(CH2)n-phenyl, where phenyl is unsubstituted or substituted with one (lower)alkyl; R14 is (lower)alkyl; R15 is (lower)alkyl; m equals 0, 1 or 2; n equals 0 or 1; and all their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: novel indole and benzimidazole derivatives which have modulating effect on the CB1 receptor are obtained.

26 cl, 3 tbl, 148 ex

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