Production of heterocyclic ketones

FIELD: chemistry.

SUBSTANCE: invention relates to production of heterocyclic ketones of formula or or their mixes, wherein R1 and R2 are hydrogen, alkyl, C6-C10 aryl; or R1 and R2 together form cyclic ring system;R3 C1-C40 alkyl; X sulfur; by interaction of heterocyclic compound of the formula (II) with α, β-unsaturated carboxylic acid or with anhydride of an acid in a liquid reactionary medium which includes a strong organic acid selected from the group includingC1-C8 alkylsulfonic acid and a water absorber selected from the group including phosphorus pentoxide, a strong organic acid possessing higher acidity, compared to carbolyxic acid; the process is effected by adding simultaneously the compounds of formula (II), acids or anhydride to the reactionary medium specified above, at temperature from 50 to 110°C. Replaced heterocyclic ketones make the important initial compounds on receiving heterocyclic metallocene catalysts for polymerization of α-olefines.

EFFECT: new compounds possess useful biological properties.

5 cl, 2 tbl, 5 ex

 

The present invention relates to a method for producing heterocyclic ketones of the formula (I) and (Ia)

the interaction of heterocyclic compounds of the formula (II)

with α,βunsaturated carboxylic acid of the formula (III)

or anhydride of the formula (IV)

where R1means hydrogen or a group containing from 1 to 40 carbon atoms,

R2means hydrogen or a group containing from 1 to 40 carbon atoms, or

R1and R2together form a cyclic ring system,

R3means a group containing from 1 to 40 carbon atoms, and

X is an element of the 16th group of the periodic table or is a divalent group,containing nitrogen -(N-R4)-, where R4represents an electron-withdrawing radical, which is selected from the group consisting of perhalogenated radicals containing from 1 to 40 carbon atoms, and C1-C40sulfonylamides groups.

Substituted heterocyclic ketones are an important source connections when receiving heterocyclic metallocene catalysts for the polymerization of α-olefins J. Am. Chem. Soc., Vol. 123, No. 20, 4763-4773). Of the substituted heterocyclic ketones which are square-chiral heterocyclic ANSA-metallocene, which are of great importance as a component of highly active catalysts for stereospecific polymerization of olefins containing a transition metal (WO 98/22486).

Changing ligand systems,for example, substitution allows the directto influence the catalytic properties metallocenes. This allows you to change to the desired value of the output of polymerization, the distribution of molecular weight, the regularity of the molecular structure and the melting point of the polymeralso, as noted in the case of related ANSA-bicentenaries (Chem. Rev. 2000, No. 4).

The cyclopent[b]tiophene and cyclopent[b]pyrrole are important precursors of ligands for the synthesis of chiral heterocyclic ANSA-metallocenes. The cyclopent[b]tiophene and cyclopent[b]pyrrole receive, principally from the corresponding heterocyclic ketones. An example of the possibilities of constructing sulfacetamide cyclic ketoester is the interaction of polyphosphoric supercolony (J. Am. Chem. Soc., Vol. 123, No. 20, 4763-4773).

However, it was found that the interaction of methacrylic acid with 2-methylthiophenol or with a variety of 2,3-disubstituted-typename, which are bulky radicals, does not receive the corresponding heterocyclic ketones in the known reaction conditions in the presence of polyphosphoric super is islote, or desired heterocyclic ketones receive only unsatisfactory yields.

Also known synthesis of substituted cyclopent[b]benzothiopheneby adding benzothiophene to a mixture solution of phosphorous pentoxide in methanesulfonic acid and methacrylic acid at room temperature (Organometallics, Vol. 21, No. 14, 2002, 2842-2855).

The aim of the present invention is to offer simple, efficient and economical method of producing heterocyclic ketones, which is devoid of the disadvantages of the known methods, allows to obtain new heterocyclic ketones and provides an economical getting well-known representatives of heterocyclic ketones.

This goal is achieved by using a method of obtaining a heterocyclic ketones of the formula (I) or (Ia), noted at the beginning, comprising conducting the reaction in a liquid reaction medium, which includes at least one strong organic acid and at least one topolitical, where a strong organic acid has a higher acidity than the carboxylic acid of formula (III), by adding at the same time with a heterocyclic compound of the formula (II) α,βunsaturated carboxylic acids of the formula (III) or anhydride of the formula (IV) to the specified the liquid reaction medium.

R1means hydrogen or a group containing the Yu from 1 to 40 carbon atoms, for example With1-C40is an alkyl radical, With1-C10-alkyl fluoride radical, With1-C12-CNS radical, With6-C40-aryl radical, With2-C40heteroaromatic radical, With6-C10-porarily radical, With6-C10-aryloxyalkyl radical, With3-C18-trialkylsilyl radical, With2-C20-alkanniny radical, With2-C20-alkynylaryl radical, With7-C40-arylalkyl radical or8-C40-killkenny radical. R1represents preferablyhydrogen, a cyclic, branched or unbranched1-C20-preferably With1-C8is an alkyl radical, With2-C12-preferably With4-C8-ω-alkene-1-ilen radical, With6-C22-preferably With6-C14-aryl radical or arylalkyl radical containing from 1 to 10, preferably from 1 to 4 carbon atoms in the alkyl portion of the radical and from 6 to 22, preferably from 6 to 10 carbon atoms in the aryl part of the radical. Examples of particularly preferred radicals R1are methyl, ethyl, n-sawn, ISO-propyl, n-boutigny, ISO-boutigny, second-boutigny, tert-boutigny, cyclopentyl, n-sexily, tsiklogeksilnogo, 5-HEXEN-1-ilen, 7-octene-1-ilen phenyl, 2-colliny, 3-colliny, 4-colliny, 2,3-dimethylaniline, 2,4-dimethylaniline, 2,5-dimethylaniline, 2,6-dimethylaniline, 3,4-dimethylaniline, 3,5-dimethylaniline, 3,5-di-tert-butylphenyl, 2,4,6-trimethylphenyl, 2,3,4-trimethylphenyl, 1-nattily, 2-nattily, phenantroline, p-isopropylaniline, p-tert-butylaniline, p-sec-butylaniline, p-cyclohexylphenol, p-trimethylsilylpropyne, benzyl or 2-phenylethynyl, in particular methyl, ISO-through 5-HEXEN-1-ilen, phenyl, nattily, 2-3,5-di-tert-butylaniline, p-tert-butylaniline or benzyl.

R2means hydrogen or a group containing from 1 to 40 carbon atoms, for example With1-C40is an alkyl radical, With1-C10-alkyl fluoride radical, With1-C12-CNS radical, With6-C40-aryl radical, With2-C40heteroaromatic radical, With6-C10-porarily radical, With6-C10-aryloxyalkyl radical, With3-C18-trialkylsilyl radical, With2-C20-alkanniny radical, With2-C20-alkynylaryl radical, With7-C40-arylalkyl radical or8-C40-killkenny radical. R2represents preferablyhydrogen, a cyclic, branched or unbranched1-C20-predpochtitel the o 1-C8is an alkyl radical, With6-C22-preferably With6-C14-aryl radical or arylalkyl radical containing from 1 to 10, preferably from 1 to 4 carbon atoms in the alkyl portion of the radical and from 6 to 22, preferably from 6 to 10 carbon atoms in the aryl part of the radical. Examples of particularly preferred radicals R2are hydrogen, methyl, ethyl, n-sawn, ISO-propyl, n-boutigny, ISO-boutigny, second-boutigny, tert-boutigny, n-pentelenyi, cyclopentyl, n-sexily, tsiklogeksilnogo, n-Gately, n-octillery, phenyl, 2-colliny, 3-colliny, 4-colliny, 2,3-dimethylaniline, 2,4-dimethylaniline, 2,5-dimethylaniline, 2,6-dimethylaniline, 3,4-dimethylaniline, 3,5-dimethylaniline, 3,5-di-tert-butylphenyl, 2,4,6-trimethylphenyl, 2,3,4-trimethylphenyl, 1-nattily, 2-nattily, phenantroline, p-isopropylaniline, p-tert-butylaniline, p-biphenylyl, p-sec-butylaniline, p-cyclohexylphenol, p-trimethylsilylpropyne, benzyl or 2-phenylethynyl, specifically hydrogen, methyl, ISO-sawn, phenyl, nattily, 2-methylphenyl, 2,5-dimethylphenyl, 3,5-di-tert-butylaniline, p-biphenylyl, p-tert-butylaniline or benzyl.

R1and R2together can form a cyclic ring system, which can be the t to be either monocyclic, or polycyclic and / or saturated or unsaturated. The radicals R1and R2together preferably represent a substituted or unsubstituted 1,3-butadiene-1,4-dialnow group. The radicals R1and R2together, more preferably,represent unsubstituted 1,3-butadiene-1,4-dialnow group, or 1,3-butadiene-1,4-dialnow group having one or two terminal substituent, where the terminal substituents can be selected from the same group, and R2. Preferred terminal radicals of 1,3-butadiene-1,4-deeley groups are methyl or phenyl.

R3means hydrogen or a group containing from 1 to 40 carbon atoms, for example With1-C40is an alkyl radical, With1-C10-alkyl fluoride radical, With6-C40-aryl radical, With2-C40-heteroaromatic radical, With6-C10-porarily radical, With7-C40-arylalkyl radical or3-C18-trialkylsilyl radical. R3represents, preferably,cyclic, branched or unbranched1-C20-preferably With1-C8is an alkyl radical, With6-C22-preferably With6-C14-aryl radical or arylalkyl radical containing from 1 to 10, preferably from 1 to 4 atoms of plastics technology : turning & the Yes in the alkyl portion of the radical and from 6 to 22, preferably from 6 to 10 carbon atoms in the aryl part of the radical, or With4-C24-heteroaromatic radical selected from the group consisting of substituted 2 - or 3-thienyl radicals, substituted 2 - or 3-fueling radicals or substituted pyrrol-2 - or 3-ilen radicals, where substituted five-membered heteroaromatic radicals do not contain a hydrogen atom in positions 2 and 5 and have the same or different substituents in positions 1, 3 and 4, or unsubstituted, and where the substituents in the five-membered heteroaromatic radicals are the same or different With1-C20-hydrocarbon radicals, for example With1-C20-preferably With1-C4-alkyl radicals, or a C6-C20-preferably With6-C10-aryl radicals, particularly methyl, ethyl or phenyl. Examples of particularly preferred radicals R3are methyl, ethyl, ISO-propyl, tert-boutigny, tsiklogeksilnogo and phenyl, and R3specifically, represents a methyl or phenyl.

X is an element of the 16th group in the periodic table,such as oxygen, sulfur, selenium or tellurium, preferably sulfur or selenium, specifically sulfur, or X is a divalent group,containing nitrogen, -(N-R4)-, where R4represents electronographic the hydrated radical, which is selected from the group consisting of perhalogenated radicals containing from 1 to 40 carbon atoms, for example perfluorinated1-C40is an alkyl radical or perfluorinated6-C22-aryl radical, or With1-C40-sulfonylamides groups, for example, With1-C20-alkylsulfonyl group or6-C14-arylsulfonyl group. Examples of preferred radicals R4include trifloromethyl, n-nonafluorobutyl, pentafluoroaniline, heptafluorobutyryl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, p-tolerantly or trifluromethanesulfonate. Particularly preferred X is sulfur.

Used in this context, the term "alkyl" includes, unless its value will not be further limited to, linear or once or optionally repeatedly branched saturated hydrocarbon radicals, which can also be cyclic. It is preferable1-C20-alkyl, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclopentyl, cyclohexyl, isopropyl, isobutyl, isopentyl, isohexyl, sec-butyl or tert-butyl.

Used in this context, the term "alkenyl covers, if only it meant the e will not be further limited to, linear or momentaryor, if desired, also repeatedly branched saturated hydrocarbon radicals having at least one, optionally, more than one C-C double bonds, which can be cumulated or paired. Preferred are2-C12-ω-alkene-1-ilen radicals, such as vinyl, allyl, 3-butene-1-ilen, 5-HEXEN-1-ilen, 7-octene-1-ilen and 9-mission-1-ilen.

Used in this context, the term "aryl" refers to, unless its value will not be further limited to, aromatic and optionallycondensed polyaromatic hydrocarbon radicals, which optionally can be mono - or polyamidine linear or branched C1-C18-alkyl, C1-C18-alkoxyl,2-C10-alkenyl or3-C15-alkylammonium. Preferred examples of substituted and unsubstituted aryl radicals are, in particular, phenyl, 2-were, 4-were, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 1-naphthyl, 9-antrel, 9-phenanthrol, 3, 5dimethylphenyl, 3,5-di-tert-butylphenyl or 4-trifloromethyl.

Used in this context, the term "heteroaromatic radical" refers to an aromatic hydrocarbon radicals, the cat is where one or more carbon atoms are replaced by nitrogen atoms, phosphorus, oxygen or sulfur or a combination thereof. They can be optionally mono - or polyamidine linear or branched C1-C18-alkyl, C2-C10-alkenyl or6-C10-aryl. Preferred examples include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidinyl, pyrazinyl and the like, and their substituted derivatives containing radicals: methyl, ethyl, propyl, isopropyl and tert-butyl.

In a preferred embodiment of the method according to the invention R3is a methyl group, X is sulfur, and R1and R2as specified above.

The method according to the inventioncharacterized in that the reaction is carried out in a liquid reaction medium, which includes at least one strong organic acid and at least one topolitical, where a strong organic acid has a higher acidity than the carboxylic acid of formula (III), by adding heterocyclic compounds of the formula (II) and α,βunsaturated carboxylic acid of the formula (III) or anhydride of the formula (IV) to the said liquid reaction medium.

Strong organic acid, which can be used in the process according to the invention, has a higher acidity than the carb is new acid of formula (III). Examples of preferred strong organic acids include perhalogenated carboxylic acids, such as trichloroacetic acid, triperoxonane acid or performatively acid, or With1-C18-alkylsulfonate acid, which can also be galogenirovannyie. In a preferred embodiment of the method according to the invention is used With1-C8-specifically, With1-C4-alkylsulfonate acid. Preferred examples are methansulfonate acid, triftormetilfullerenov acid and econsultancy acid, specifically methansulfonate acid.

Topolitical must bind water reaction in an acid reaction medium physically, for example in the case of molecular sieves, or chemically, for example, in the case of phosphorous pentoxide. In a preferred embodiment of the method according to the invention as wadepolicies use phosphorous pentoxide.

In addition to the strong organic acid and a drying agent - wadepolicies, the liquid reaction medium may also include inert solvents such as alkanes or halogenated alkanes. Examples of suitable alkanes include pentane, hexane, heptane and dodecane, and examples of suitable halogenated alkanes include methylene chloride and 1,2-dichloroethane.

the preferred embodiment of the method according to the invention the liquid reaction medium by more than 50 wt.% consists of a mixture of methanesulfonic acid and phosphorous pentoxide. In a particularlythe preferred embodiment, the liquid reaction medium by more than 90 wt.% consists of a mixture of methanesulfonic acid and phosphorous pentoxide. The initial compounds of the formula (II), (III) and (IV) shall not be considered as components of the liquid reaction medium described above.

In the process according to the invention the molar ratio of the heterocyclic compound of the formula (II)/α,βunsaturated carboxylic acid of the formula (III) is usually in the range from 5:1 to 1:100. In a preferred embodiment, the ratio ranges from 2:1 to 1:3, specifically in the range from 1.1:1 to 1:1,5. If the implementation of the method according to the invention, instead of α,βunsaturated carboxylic acids of the formula (III) is the anhydride of formula (IV), it should be noted that one mole of the anhydride of formula (IV) corresponds to two moles of a carboxylic acid of formula (III).

In the process according to the invention, the mass ratio of the heterocyclic compound of the formula (II)/liquid reaction medium is typically in the range from 1:2 to 1:1000, preferably in the range from 1:3 to 1:50, more preferably from 1:5 to 1:35.

In the process according to the invention, the mass ratio topolitical/strong organic acid is preferably in the range from 1:99 to 25:75. In the case of intoxicator and methanesulfonic acid mass ratio is specifically between 5:95 and 15:85.

The temperature of the reaction mixture in the process according to the invention is usually in the range from 20 to 200°C, preferably in the range from 50 to 110°specifically in the range from 60 to 90°C. When the temperature of the reaction mixture 20°there is a very low conversion, only at 60°S - satisfactory conversion and 110°With the maximum conversion to the desired product of the reaction.

The method according to the invention is usually carried out at atmospheric pressure. However, in principle it can also be carried out under reduced or increased pressure. It is only important that the reaction partners are simultaneously in a liquid reaction medium under the reaction conditions, allowing them to interact in an optimal way.

The initial compounds of the formula (II), (III) and (IV) are known and commercially available or can be obtained by methods described in the literature. For example, 2,3-disubstituted tifany can be obtained as described in J. Chem. Soc., Perkin 1, 22, (1976), 2344.

The method according to the invention is distinguished by good outputs, high yields of product in a single pass per unit of time and ease of processing and separation of reaction products from the reaction mixture.

The invention is illustrated in the following that are not intended to limit the,examples.

Examples

General the information:

Mass spectra were recorded using a device Hewlett Packard 6890, which was equipped with mass analyzer 5973 (EI, 70 eV).

Super-FC(apolipopro acid) received mostly complete dissolution at 140°164,3 g of phosphorous pentoxide in 975,7 g of commercially available polyphosphoric acid (Aldrich) with stirring.

Used a commercially available agent Eaton (Aldrich; 7.5 wt.% peroxide phosphorus in methanesulfonic acid).

Example 1

Synthesis of 2,5-dimethyl-4,5-dihydrocyclopenta[b]thiophene-6-she

A mixture of 150 g of 2-methylthiophene (1.5 mol) and 157,5 g of methacrylic acid (1.8 mol) was added within 30 minutes at about 80°With 1500 ml of agent Eton, and the temperature was maintained between 78°83°C. After complete addition, the reaction mixture was stirred for 5 minutes and then gradually poured to a vigorously stirred mixture of 3000 ml of water and 500 ml of dichloromethane. The organic phase was separated and dried over magnesium sulfate. The solvent is kept on a rotary evaporator and received 263,5 g of the crude product with a degree of pure 88,2% according to GC-MS. Part of the crude product (79 g) was subjected to distillation (92°With, of 0.02 Torr). of 56.5 g (76%) of product was obtained as a mixture of two isomers in a ratio of 9:1 (thiophene-6-he:thiophene-4-one).

1H NMR of the main isomer (CDCl3):δ to 6.8(s, 1H), 3,2(l is, 1H), 2.95 and(m, 1H), 2,5(s, 3H), 2,4(m, 1H), 1,25(d, 3H), EIMS:m/z(%) 165 ([M+], 72), 151(100), 123(23), 97(11), 69(15).

Comparative example a

Synthesis of 2,5-dimethyl-4,5-dihydrocyclopenta[b]thiophene-6-she

A solution of 100 g of 2-methylthiophene (of 1.02 mol) and 104 ml of methacrylic acid (1,22 mol) in 200 ml dichloromethane was added dropwise within 30 minutes at 80°C to 1000 g super-FC. Then the reaction mixture was stirred at 80°C for 3 hours. Dark red mixture was added to 1000 g of crushed ice and stirred until complete dissolution of polyphosphoric acid. The aqueous phase was extracted twice, each time with 400 ml of a mixture of solvents dichloromethane/hexane (30 volume parts/70 parts by volume). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvents on a rotary evaporator received 136 g of the crude product. Distillation of the crude product (90°C, 0.1 Torr) received 76 g (46%) of product.

Example 2

Synthesis of 2,5-dimethyl-3-naphthalen-1-yl-4,5-dihydrocyclopenta[b]thiophene-6-it (2)

A mixture of 5 g of 2-methyl-3-naphthalen-intifada (0,022 mol) and 2.1 ml of methacrylic acid (0,025 mol) was added within 15 minutes at 80°C to 125 ml agent Eton. After 5 minutes the reaction mixture is poured into ice water and the precipitated product was dissolved by adding 300 ml of dichloromethane. Organic is ABC separated, washed with a saturated aqueous solution of sodium bicarbonate and dried over magnesium sulfate. After removal of solvent received 5 g of the product (2), which, according to GC, was a single isomer with purity of 99%.

1H NMR (CDCl3):δ 7,8-8,0(t, 2H), 7.3 to about 7.6(m, 5H), of 2.8-3.0(m, 2H), 2,2-2,4(m, 1H), 2,3(s, 3H), of 1.25(d, 3H), EIMS:m/z(%) 292 ([M+], 100), 277(62), 263(15), 249(16), 235(15), 215(8), 202(9), 189(6), 165(9).

Comparative example

Attempted synthesis of 2,5-dimethyl-3-naphthalen-1-yl-4,5-dihydrocyclopenta[b]thiophene-6-it (2)

A solution of 5 g of 2-methyl-3-naphthalen-1-intifada (0,022 mol) and 2.5 ml of methacrylic acid (0.03 mol) in 60 ml dichloromethane was added at 70°C to 300 g super-FC and was stirred for 20 hours Analysis of the reaction mixture GC-MS showed the presence of only the originalconnection and the complete lack of product (2).

Example 3

Synthesis of 5-methyl-2-phenyl-3-about-tolyl-4,5-dihydrocyclopenta[b]thiophene-6-she (3)

A mixture of 31.8 g of 2-phenyl-3-about-tolyl-thiophene (to 0.127 mol) and 13.3 ml of methacrylic acid (of) 0.157 mol) was added within 30 minutes at about 80°With 500 ml of agent Eton. After complete addition, the reaction mixture was stirred for 5 minutes and then slowly added to crushed ice. For dissolving the reaction product was added 300 ml of dichloromethane. The organic phase was separated, washed with saturated water is a sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent there was obtained 39 g of product (3), which according to GC-MS consisted of a single isomer and had a purity of 95%.

1H NMR (CDCl3):δ 7,0-to 7.3(m, 4H), 2,8-3,1(m, 2H), 2,2-2,4(m, 1H), and 1.9(s, 3H), 1,25(DD, 3H), EIMS:m/z(%) 318 ([M+], 100), 303(39), 275(16), 261(11), 247(6), 228(8), 215(13), 202(6), 189(6), 165(6).

Comparative example

Attempted synthesis of 5-methyl-2-phenyl-3-about-tolyl-4,5-dihydrocyclopenta[b]thiophene-6-she (3)

A mixture of 5 g of 2-phenyl-3-o-tolylthiourea (0.02 mol) and 2.5 ml of methacrylic acid (0.03 mol) was added to 75 g of super-FC at 90°and was stirred for 5 hours. In addition to the parent compound analysis of the reaction mixture GC-MS showed the presence of less than 5% of the product (3).

Example 4

Synthesis of 2-methyl-1,2-dihydrobenzo[b]cyclopenta[d]thiophene-3-one

A mixture of 13.4 g of benzo[b]thiophene (0.10 mol) and 9,04 g of methacrylic acid (0,105 mol) was added at 65°to 134 g agent Eton. The reaction mixture was stirred at 65°C for one hour and then was added to 150 ml of water. The aqueous phase was extracted using the solvent mixture dichloromethane/hexane (30 volume parts/70 parts by volume). The combined organic phases were washed with water and dried over magnesium sulfate. After removal of the solvent under reduced pressure was obtained of 14.7 g (72,8%) of product, which according to GC contained two isomers in which the ratio of approx. 3:1 (thiophene-3-one:thiophene-1-he).

EIMS M+ for C12H10OS: 202,0 (observed), 202,27 (calculated).

Comparative example D

Synthesis of 2-methyl-1,2-dihydrobenzo[b]cyclopenta[d]thiophene-3-one

The solution of 66.9 g of benzo[b]thiophene (0.5 mol) and 46.3 g of methacrylic acid (0,537 mol) in 60 ml dichloromethane was added drop by drop, starting at 70°C for 20 min to 1000 g super-FC. While adding maintained a temperature of 65-70°C. methylene chloride drove away. After 2 hours from the start of thereaction, the reaction mixture was added to crushed ice and stirred until complete dissolution of phosphoric acid. The aqueous phase was extracted using the solvent mixture dichloromethane/hexane (30 volume parts/70 parts by volume). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution and water and dried over magnesium sulfate. After removal of the solvent under reduced pressure was obtained for 79.8 g of a dark orange oil (71%).

1H NMR, 2 isomer (CD2Cl2):δ 7,2-8,2(m, 4H), 2,6-3,4(m, 3H)and 1.3(m, 3H).

Example 5

Synthesis of 2-methyl-8-phenyl-1,2-dihydrobenzo[b]cyclopent[d]thiophene-3-one

A mixture of 10 g of 4-phenylbenzo[b]thiophene (47,6 mol) and 4.8 ml of methacrylic acid (56,6 mol) was added within 30 minutes to 100 ml of the agent Eton when the temperature of the reaction mixture during the addition of 80°C. R. the action mixture was cooled to 60° With and gradually mix up in 400 ml of water with vigorous stirring. The precipitated product was completely dissolved by adding 250 ml of dichloromethane. After separation of the phases the organic phase was washed with a saturated aqueous solution of sodium bicarbonate and water and dried over magnesium sulfate. The solvent was removed and received 12 g of the product. According to GC, the product had a purity of 90% and consisted of two isomers, which were presented in a ratio of about 7:3 (thiophene-3-one:thiophene-1-he).

1H NMR of the main isomer (CDCl3):δ 7,8(d, 1H), 7,2-7,5(m, 7H), 2,85(m, 1H), 2,7(d, 1H), 2.05 is(d, 1H), 1,1(d, 3H), EIMS:m/z(%) 278 ([M+], 100), 263(65), 249(13), 234(21), 221(47), 202(16), 189(9), 176(6), 163(8), 151(3), 139(3).

Comparative example E

Attempted synthesis of 2-methyl-8-phenyl-1,2-dihydrobenzo[b]cyclopent[d]thiophene-3-one

The solution 76,2 g of 4-phenylbenzo[b]thiophene (0.36 mol) and 37.5 ml of methacrylic acid (0.44 mol) in 50 ml dichloromethane was added drop by drop to 1000 g super-FC heated to 80°C and stirred at 80°C for 5 hours. Dark red mixture was added to 1000 g of crushed ice and stirred until complete dissolution of polyphosphoric acid. The aqueous phase was extracted twice, each time with 400 ml of a solvent mixture of dichloromethane/hexane (30/70 parts by volume). GC-MS of the organic phase showed the presence of only the originalconnections and the absence of the ice of the desired product.

Table 1 presents the comparison of examples 1 to 5 and comparative examples a to E.

Table 1
Reactiona)Time< / br>
reaction< / br>
[h]
Outlet< / br>
[%]
Example 1

Comparative example a
0,25

3,0
76

46
Example 2

Comparative example
0,25

20
81

no
Example 3

Comparative example
0,25

4,5
86

<5
Example 4

Comparative example D
1,0

2,0
73

71
Example 5

Comparative example E
0,5

5,0
90

no
(a) shows only the major isomer

Example 6

Attempted synthesis of 2,5-dimethyl-4,5-dihydrocyclopenta[b]thiophene-6-she

Table 2 shows the various experiments that were carrying the s as well as the experiment of example 1, the implementation of which varied the weight ratio of 2-methylthiophene and agent Eton and the temperature of the reaction mixture.

Table 2
The weight ratio< / br>
agent Eaton/< / br>
2-methylthiophene
The reaction temperature< / br>
[°C]
Exit*< / br>
[%]
Example 6A2820<5
Example 6b288088
Example 6c287091
Example 6d286067
Example 6e148097
Example 6f680a)53
(a) during the addition the temperature rose to 110°C due to the exothermic effect of the reaction and the high concentration of the reaction partners
*) the outputs were identified by means of GC

1. A method of obtaining a heterocyclic ketones of the formula (I) or (Ia) or their mixtures

in which R1and R2means hydrogen, alkyl, C6-C10aryl; or R1and R2together form a cyclic ring system;

R3means1-C40alkyl;

X is sulfur;

the interaction of heterocyclic compounds of the formula (II)

with α, βunsaturated carboxylic acid of the formula (III)

or anhydride of the formula (IV)

in which the reaction is carried out in a liquid reaction medium, which includes a strong organic acid selected from the group comprising From1-C8alkylsulfonate acid, and topolitical selected from the group comprising phosphorous pentoxide, and a strong organic acid has a higher acidity than the carboxylic acid of formula (III), the process is carried out by simultaneously adding the compounds of formula (II), the acid of formula (III) or anhydride of the formula (IV) in the above reaction medium, at a temperature of from 50 to 110°C.

2. The method according to claim 1, where at least 50 wt.% the liquid reaction medium consists of a mixture of methanesulfonic acid and phosphorous pentoxide.

3. The method according to claim 1, where the molar ratio of the heterocyclic joint is of the formula (II):α that βunsaturated carboxylic acid of the formula (III) is in the range 5:1 to 1:100.

4. The method according to claim 1, where the mass ratio of the heterocyclic compound of the formula (II):liquid reaction medium is in the range 1:2 to 1:1000.

5. The method according to claim 1, where the mass ratio topolitical:strong organic acid is in the range of 1:99 to 25:75.



 

Same patents:

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to orthotamine compounds of the formula I or their pharmaceutically acceptable salts, are inhibitors of prostaglandin H synthase

Ethynylbenzoate // 2079495
The invention relates to light-sensitive pesticides, specifically to some ethynylbenzoate

The invention relates to heteroalicyclic alkanoyl derivatives, which have a biocidal effect, and more particularly to aminoalcohols derived molecules containing heteroalicyclic ring system, to methods of their synthesis, their new intermediates, containing pharmaceutical compositions and to their use as biocidal agents, in particular anticancer agents

The invention relates to heteroalicyclic alkanols derived, and in particular to methods of obtaining new polycyclic biocidal compounds of General formula I

ArCH2Other where Ar is 2-benzo/b/oil/2,1-d/thiophene-5-yl; 2-benzo/db/oil/2,3-d/furan-6-yl; 2-benzo/b/oil/1,2-d/furan-5-yl; 2-/7-methyl, 7H-benzo/with/carbazole-10-yl/methyl, 2-/benzo/b/oil/2,1-d/furan-5-yl; R= -H3or their salts, which can be used as anticancer agents

The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of heterocyclic ketones of formula or or their mixes, wherein R1 and R2 are hydrogen, alkyl, C6-C10 aryl; or R1 and R2 together form cyclic ring system;R3 C1-C40 alkyl; X sulfur; by interaction of heterocyclic compound of the formula (II) with α, β-unsaturated carboxylic acid or with anhydride of an acid in a liquid reactionary medium which includes a strong organic acid selected from the group includingC1-C8 alkylsulfonic acid and a water absorber selected from the group including phosphorus pentoxide, a strong organic acid possessing higher acidity, compared to carbolyxic acid; the process is effected by adding simultaneously the compounds of formula (II), acids or anhydride to the reactionary medium specified above, at temperature from 50 to 110°C. Replaced heterocyclic ketones make the important initial compounds on receiving heterocyclic metallocene catalysts for polymerization of α-olefines.

EFFECT: new compounds possess useful biological properties.

5 cl, 2 tbl, 5 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to sulfamate derivatives of benzothiophene, obtained by method including stages: 1) conversion of 6-methoxybenzothiophene (3); , where R3 represents monobromine-derivative using N-bromosuccinimide and APTS in standard conditions; 2) conversion of said monobromine-derivative by interaction with Mg in Et2O in argon atmosphere into magnesium-organic bromide and its further condensation with ketone or aldehyde selected from group, consisting of cyclopentanone, cyclohexanone, cycldecanone, 4-methylcyclohexanone, 2-methylcyclohexanone, 2,2-dimethylcyclopentanone, 2-adamantanone, propanal, hexanal, cyclohexane carboxaldehyde, cycloheptancarboxaldehyde in Et2O obtaining corresponding hydroxyl-substituted methoxybenzothiophene in standard conditions; 3) processing said hydroxy-substituted methoxybenzothiophene with triethylsilane in argon atmosphere in dichlomethane obtaining corresponding substituted methoxybenzothiophene; 4) optional alkylating of corresponding substituted methoxybenzothiophene using standard conditions obtaining corresponding substituted methoxybenzothiophene, carrying (C1-C6)alkyl or (C3-C12)cycloalkyl; removal of protective group from substituted methoxybenzothiophene, obtained at stage 3) or stage 4) in presence of tribromborane in standard conditions; conversion of obtained hydroxy-compound into corresponding sulfamate by processing with sodium hydrate and amidochlorsulfonic acid, or interaction with sulfamoylchloride in dimethylacetamide; 7) optional oxidation of obtained compound with hydrogen peroxide in trifluoracetic acid in standard conditions. Compounds can be used as inhibitors of steroid sulfatase enzyme in production of medication for treatment or prevention of estrogen-depending disorders. Also described are pharmaceutical composition based on compounds I and application of the latter.

EFFECT: obtaining compounds which can be used as inhibitors of steroid sulfatase enzyme in production of medication for treatment or prevention of estrogen-depending disorders.

43 cl, 1 dwg, 10 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of a therapeutic agent which is an α-amino-amide compound of formula (I):

, in which R is a phenyl ring which is optionally substituted with one or two substitutes independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl; R1 is hydrogen or C1-C6-alkyl; R2 and R3 are independently selected from hydrogen, C1-C4-alkyl; R4 and R5 independently denote hydrogen, C1-C6-alkyl; X is O or S; Y and Z, taken together with X and a phenyl ring bonded to Y and X, form a 5-7-member saturated heterocycle containing O or S atoms, or Y and Z denote hydrogen; or its isomers, mixtures and pharmaceutically acceptable salts for preparing a medicinal agent for treating lower urinary tract disorders.

EFFECT: obtaining a pharmaceutical composition based on the said compounds.

8 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts which involves the use as a parent compound, (phenylthio)acetic acid derivative or its salts presented by general formula: where X1 represents halogen atom, and is applicable as a safe method of volume production of 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts effective as an agent in disorders of the central nervous system and peripheral nervous system.

EFFECT: there is provided high yield, safety for human body, low environment loads.

36 cl, 1 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a heterocyclic compound or salt thereof, having formula (1): where R2 is hydrogen or a lower alkyl group; A is a lower alkylene group or a lower alkenylene group and R1 is a cyclo(C3-C8)alkyl group, an aromatic group or a heterocyclic group selected from a group consisting of groups (I)-(IV), defined in the formula of invention. The invention also relates to a pharmaceutical composition, having activity as a partial agonist of dopamine D2 receptors and/or a serotonin 5-HT2A receptor antagonist and/or an adrenalin α1 receptor antagonist and/or a serotonin absorption inhibitor and/or serotonin reuptake inhibitor based on said compounds, a method of preparing a pharmaceutical composition, use of said compounds as a partial agonist of dopamine D2 receptors and/or a serotonin 5-HT2A receptor antagonist and/or an adrenalin α1 receptor antagonist and/or a serotonin absorption inhibitor and/or serotonin reuptake inhibitor, as well as a method of producing formula I compounds.

EFFECT: novel compounds are obtained and described, which have a wide range of curative effect on mental disorders, including central nervous system disorders, without side effects and with high degree of safety.

22 cl, 3110 ex, 314 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to sulphamate derivatives of benzothiophene of formula or

,

where R1, R2, R3, m and n assume values given in the claim.

EFFECT: possibility of use in treating oestrogen-dependent diseases.

38 cl, 63 ex, 10 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a compound of general formula VIII of enantiomeric purity min. 80% by a reaction of the compound according to general formula IV with enantiomeric pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid to produce a compound of general formula II to be reduced to prepare a compound for general formula I to be oxidated to form an aldehyde which then reacts with an aromatic amine of formula H2N-Ar to produce a respective imine which is then reduced to prepare a compound described by formula VIII in the enantiomeric pure form. Also, it refers to methods for preparing the compound of formula I, as well as to the compounds of formula I. In general formulas

, ,

, , X1, X2, X3 is specified in fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, trifluoromethyl, amino whereas the other groups X1, X2, X3 represent a hydrogen atom.

EFFECT: preparing the non-steroid anti-inflammatory drugs.

12 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of structural formula

,

which can be applied for treatment, prevention or carrying out treatment of neurological disorder. In formula (Iva) m is equal 0; n is equal 1; R1 and R2 are, each independently, hydrogen, C1-C4alkyl or C3-C6cycloalkyl; R3 and R4 are, each independently, hydrogen or C1-C4alkyl; R5 is hydrogen and R6 and R7 are, each independently hydrogen, halogen, C1-C4alkyl, C6-C10aryl, 5-10-membered heteroaryl, which contains one O atom, one S atom and/or 1-4 N atom(s), 3-8-membered heterocyclyl, containing 1-2 heteroatoms, selected from O, S and N, C1-C4alcoxyl or aminoC1-C4alkyl.

EFFECT: invention relates to pharmaceutical industry, which contains claimed compound, and to method of treatment, prevention or carrying out of treatment of neurological disorder such as psychosis or schizophrenia.

54 cl, 2 tbl

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