Method of producing 1-formamido-3,5-dimethyladamantane

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1-amino-3,5-dimethyladamantane, involving reaction of 1,3-dimethyladamantane with formamide in concentrated acids to obtain 1-formamido-3,5-dimethyladamantane, provided that neither SO3-containing sulphuric acid nor 100% nitric acid is used, wherein the concentrated acids are 30-70% nitric acid and 90-100% sulphuric acid and further conversion of 1-formamido-3,5-dimethyladamantane to 1-amino-3,5-dimethyladamantane through hydrolysis with aqueous hydrochloric acid.

EFFECT: high efficiency of the method.

3 cl, 2 ex

 

The present invention relates to a method for producing 1-formamido-3,5-dimethyladamantane, which is an important intermediate product for the preparation of 1-amino-3,5-dimethyladamantane, which is used for the treatment of Alzheimer's disease and who is known as the tool called memantine. It is sold in Europe (and in many non-European countries) under the trade names Axura®and Ebixa®and called Namenda®in the United States.

Getting 1 formamido-3,5-dimethyladamantane on the basis of 1-bromo-3,5-dimethyladamantane and formamide, already known as such.

1-Amino-3,5-dimethyladamantane as a substance already known from the patent DE 2 318 461 A1. Its use for the prevention and treatment of cerebral ischemia described in the patent EP 0 392 059 B1. Accordingly, the synthesis of 1-formamido-3,5-dimethyladamantane, which is used for its production, is still being held by halogenation of 1,3-dimethyladamantane and subsequent formamidine. After this 1-formamido-3,5-dimethyladamantane hydrolyzing to the amine using diluted hydrochloric acid.

However, based on 1,3-dimethyladamantane, this method of synthesis requires three stages of synthesis to get memantine: halogenation, formamidine and acid hydrolysis. Thus requires the use of toxic elemental chlorine or B. the Ohm in excess; this causes additional costs for the disposal of waste and may lead to formation of undesirable side products.

Thus, the object of the invention is to develop a method formamidine 1,3-dimethyladamantane, which is more simple and can be carried out using less toxic or expensive reagents.

In international patent application WO 2006/010362 A1 has been described a method of obtaining derivatives of 3,5-substituted 1-aminoadamantana, which is derived 1,3-disubstituted adamantane suspended in HNO3and H2SO4and which reacts with the nitrile after adding oleum. On the contrary, in the method according to the invention receive 1 formamido-3,5-dimethyladamantane takes place only in two reaction stages by direct formamidine 1,3-dimethyladamantane the formamide in concentrated acids.

Preferred are 30-70%, in particular 65%nitric acid, and 90-100%, but especially 95-98%sulfuric acid. However, it can also be used 85-100%phosphoric acid, Perlina acid, dicerna acid or chlorosulfonic acid. In General, the reaction proceeds at temperatures from -40°C to 50°C, but preferably at 0°C. In the method according to the invention are achieved outputs mainly 40-95%.

Named method is e only characterized with the exception of the use of halogen-free, but is also more predominant impurity profile, because it is implemented with high yields and with only a small amount of by-products, and thus is insensitive even to impurities in the raw materials. According to the method of gas chromatography-mass spectrometry (GC-MS) when formamidine as by-products can be detected only unreacted starting material, and 3.5-dimethyladamantane-1-ol.

Perhaps even obtaining source material in situ from cheap precursors, so that the desired end product can be obtained “one-pot” method (i.e. in one flask without the isolation of intermediate products). Thus 1,3-dimethyladamantane, which should react with formamide, can be obtained in situ from a hydrocarbon having the empirical formula C12H20by cationic rearrangement under comparable reaction conditions, which are also applicable to the reaction of formamidine. For example, receive predecessors by full hydrogenation of acenaphthene, acenaphthalene or dimer of methylcyclopentadiene. Then spend formamidine formed dimethyladamantane in acidic conditions in the same reaction vessel.

Processing is fully hydrogenated dimer of methylcyclopentadiene concentrated acid on the makes it possible to obtain the source material, that is, 1,3-dimethyladamantane, in situ before formamidine according to the following reaction scheme:

The method described in international application PCT/DE2005/001304, is based on the generation in concentrated acids of carbocations, which can easily interact with a nucleophile, such as nitrile, and which are converted into the corresponding derivatives of 1-aminoadamantane when processing water according to the following reaction scheme:

On the contrary, the method according to the invention to obtain 1-formamido-3,5-dimethyladamantane allows the use of milder reaction conditions, excluding the use of oleum or 100%nitric acid. Further, as the nucleophile used formamid, and thus as a reaction product obtained is 1-formamido-3,5-dimethyladamantane, which can be hydrolyzed under milder conditions compared to other inorganic salts. So, for example, 1-acetamido-3,5-dimethyladamantane cleaved by heating with NaOH for several hours in an aqueous or alcoholic medium or in concentrated hydrochloric acid (36-37%) free 1-amino-3,5-dimethyladamantane, whereas the decomposition of formamide has already been successfully conducted in dilute hydrochloric acid for two hours at 100°C.

The invention concretes is regulated in the following examples.

Example 1 - Synthesis of 1-formamido-3,5-dimethyladamantane

To 6,572 g (40 mmol) of 1,3-dimethyladamantane at a temperature of 0°C. successively added 4 ml of 65%technical nitric acid and then three hours 50 ml of 98%technical sulfuric acid. The mixture is stirred over night at 0°C and then poured at a temperature of 0 ° C in 100 ml of formamide in a round-bottom flask, which is equipped with a potassium chloride tube for protection from moisture in the air. This mixture is stirred for 30 minutes at a temperature of 0°C. and for 90 minutes at room temperature and add 200 ml of dichloromethane and 200 ml of water. After phase separation the organic phase is washed with water and 2%solution of NaHCO3, dried over Na2SO4and evaporated on a rotary evaporator to remove the solvent. The oily residue purified by chromatography (SiO2, CHCl3/acetone (20:1), Rf=0,39). Get 7,41 g (89.3 per cent) of formamide in the form of almost colorless solid.

1H-NMR (CDCl3, tetramethylsilane was, 400,13 MHz):δ=0.87 for h/mn, s, 6 H; 1,15 h/mn, s, 2H; 1,2-1,35 h/mn, m, 4 H; 1,35-1.55V hours/million m, 4 H; 1,65-1,78 hours/million m, 2 H; 2,10-2,27 hours/million m, 1 H; 5,90 7,21 and h/m; each ush. C, 1 H; 8,02, 8,20 and 8,27 h/m; each s, 1 H.

13C-NMR (CDCl3, tetramethylsilane was, 100,61 MHz):δ=29,46, 30,01, 32,00, 40,21, 41,85, 47,63, 49,94, 51,83, 160,15/162,24 hours/million

The mass spectrum; m/d=207 (M+), 192, 15, 136, 106, 91, 79.

Example 2 Hydrolysis of 1-formamido-3,5-dimethyladamantane to the hydrochloride of 1-amino-3,5-dimethyladamantane (Memantine)

A mixture of 0.02 mmol of 1-formamido-3,5-dimethyladamantane (4,14 g) and 100 ml of 15%hydrochloric acid is refluxed for 24 hours. After cooling, the precipitate is filtered off, dissolve it in methanol and precipitated by adding ethyl acetate (yield 80%).

1. The method of obtaining 1 formamido-3,5-dimethyladamantane direct formamidine 1,3-dimethyladamantane, characterized in that the aforementioned 1,3-dimethyladamantane react with formamide in concentrated acids, provided that there are no SO3-containing sulfuric acid or 100% nitric acid, and concentrated acids are 30-70% nitric acid and 90-100% sulfuric acid.

2. The way to obtain 1-amino-3,5-dimethyladamantane, which includes stages (i) and (ii):
(i) the interaction of 1,3-dimethyladamantane with formamide in concentrated acids to produce 1 formamido-3,5-dimethyladamantane provided that there are no SO3-containing sulfuric acid or 100% nitric acid, and concentrated acids are 30-70% nitric acid and 90-100% sulfuric acid;
(ii) the conversion of 1-formamido-3,5-dimethyladamantane 1-amino-3,5-dimethyladamantane via hydrolysis.

3. The method according to claim 2, featuring the the action scene, the hydrolysis is carried out using aqueous hydrochloric acid.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to amide of δ-amino-γ-hydroxy-ω-arylalcane acid of formula and its pharmaceutically acceptable salts. Also described are pharmaceutical compositions, which include said compounds, and application of said compounds for preparation of medication, intended for treatment of pathological states, associated with renin activity, in particular for treatment of hypertension.

EFFECT: obtaining pharmaceutically acceptable salts, which possess rennin-inhibiting ability.

21 cl, 161 ex

FIELD: chemistry.

SUBSTANCE: formula compound is described, where X is oxygen; R1 is a linear or branched C1-C8-alkyl chain, substituted with phenyl, optionally substituted with halogen atoms; R2, R3 independently represent hydrogen, C1-C3-alkyl chain, halogen, methoxy; R4, R5, R6, R7 independently represent hydrogen, as well as a method of obtaining formula (I) compound, and a pharmaceutical composition.

EFFECT: use of the compound to make a medicinal agent which is effective as a modulator of the sodium and/or calcium channel and, consequently, suitable for preventing, relieving and treating a wide range of pathologies which include neurological, psychiatric, cardiovascular, phlogistic, eye, urological, metabolic and intestinal diseases, where the above mentioned mechanisms are described as playing a pathological role.

6 cl, 11 ex

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method for synthesis of N,N-dimethylacetamide, which is widely used as a solvent in different fields, involving reaction of ethyl acetate (EA) and N,N-dimethylamine (DMA) in the presence of polyethylene polyamines (PEPA), having formula NH2[(CH2CH2)NH]n-1CH2CH2NH2, where n = 2-4, as a catalyst, where separate compounds of this group or their mixtures can be used.

EFFECT: high output of the end product (dimethylacetamide) of high quality (more than 99,9% content of basic substance) due to a simpler step for separating the catalyst from the reaction products.

3 cl, 16 ex, 1 tbl

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: industrial organic synthesis.

SUBSTANCE: process involves formic acid-methylamine reaction via intermediate methylammonium formate salt, which is dehydrated in presence of molybdenum trioxide catalyst dissolved in aqueous methylamine and added to formic acid in amount 2.0-4.0 wt % based on the latter. Reaction is carried out for 1-2 h in reactor filled with inert packing material having developed surface without cooling of reaction mixture, whereupon volatile products are distilled away at bottom temperature up to 190°C for 60-90 min. Bottom residue containing catalyst, after isolation of desired product, is returned to reactor.

EFFECT: reduced reaction time, reduced power consumption, improved quality of product obtained at increased yield, and diminished production waste.

5 cl, 8 ex

The invention relates to methods for metachlorophenylpiperazine, which can be used as an intermediate product in the preparation of biologically active compounds, particularly in the industrial development of the production of original domestic anticonvulsant galadima (meta-chlorobenzhydryl)

FIELD: chemistry.

SUBSTANCE: invention relates to a method of synthesis of N-substiuted salicylamide, involving reaction of a carsalam derivative with a chloro-substituted compound of formula (III) in the presence of a catalytic amount of a source of bromine ions, where n is an integer from 1 to 8, Q denotes a protected carboxylic group, and R5 and R6 are independently selected from a group containing hydrogen, -OH, NR3R4, halogen, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, where R3 and R4 are each independently selected from a group containing hydrogen, -OH, C1-C4 alkyl, C1-C4 halogenalkyl, C1-C4 alkoxy and C2-C4 alkenyl. The invention also discloses a method for synthesis of a compound of general formula IV.

EFFECT: improved method for synthesis of N-substituted salicylamide enables to obtain large amounts of high-quality product.

54 cl, 3 ex

The invention relates to the field of organic chemistry, in particular to a method for producing N-aminomethyl-(meth)acrylamido General formula given in the description

The invention relates to derivatives of Taxol, which have better solubility compared with Taxol and show good anticancer activity

FIELD: chemistry.

SUBSTANCE: invention relates to an ester derivative of 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid of formula (II) or the corresponding pharmaceutical salt, having group II metabotropic glutamate receptor antagonist properties. In formula X denotes fluorine, Y denotes 3,4-di-chlorobenzyloxy, R2 denotes hydrogen and R1 denotes an alkyl group selected from n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, 3-methylbutyl, 4-methylpenyl, 5-methylhexyl and 6-methylheptyl. The invention also relates to a medicinal agent and to use of formula (II) compounds as a medicinal agent for treating depression symptoms.

EFFECT: high yield.

14 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of bicyclo[3.1.0]hexane derivatives, used as mGIuR agonists having formulae ,

, where R1 and R2 represent hydrogen, X is a halogen, R3 is -O-Ra , Ra is C1-10alkyl, and R4 is (1) hydrogen or (2) Si-(R9)(R10)(R11), where each of R9, R10 and R11 is C1-10alkyl, as well as intermediate compounds obtained when realising the said methods.

EFFECT: design of an efficient method for synthesis of bicyclo[3,1,0]hexane derivatives.

26 cl, 17 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new ester derivatives of 2-amino-bicyclo[3,1,0]hexane-2,6-dicarboxylic acid, with formula [I] or [II] and their pharmaceutical salts, with antagonistic properties towards II group metabotropic glutamate receptors. In general formulae [I] or [II] R1 and R2 are identical or different, and each stands for a C1-10alkyl group, or one of R1 or R2 is a hydrogen atom, and the other is a C1-10alkyl group, C2-10alkenyl group, C2-10alkynyl group, C1-10alkyl group, substituted with a phenyl group, possibly substituted with halogen atoms, C1-4alkyl group, C1-4 alkoxyl group; hydroxyC2-10alkyl group, halogenC1-10alkyl group, azidoC1-10alkyl, aminoC2-10alkyl, C1-10alkoxycarbonylC1-10alkyl group, farnesyl group, 4-morpholinyl-C1-10alkyl group, C1-10alkyl group, substituted with a group with formula -C(O)NRaRb (where Ra and Rb are identical or different and each represents a hydrogen atom or a C1-10alkyl group), or with a group with formula -CHRcOC(O)ZRd (where Z is an oxygen atom or a single bond; Rc represents a hydrogen atom, C1-10alkyl group or aryl group, chosen from phenyl and naphthyl, which can be substituted with a C1-4alkyl group or C1-4alkoxyl group), or substituted with a group with formula [i] [ii], (where Rd denotes the same as described above), or by a group with formula [ii]; X is a fluorine atom; and Y represents -OCHR3R4, -SR3, -S(O)nR5, -SCHR3R4, -NHCHR3R4, -N(CHR3R4)(CHR3'R4'), -NHCOR3 or -OCOR5 (where R3, R3', R4 and R4' are identical or different, and each represents a hydrogen atom, C1-10alkyl group, phenyl group, naphthyl group, phenyl group substituted with one-five substitutes, chosen from a group, consisting of a halogen atom, R5 represents a phenyl group, or a phenyl group substituted with one-five substitutes, chosen from a group, consisting of a halogen atom, and n is 1 or 2).

EFFECT: invented compounds can be used in treating and preventing mental illnesses, such as schizophrenia, anxiety and anxiety related diseases, depression, bipolar disorders and epilepsy, invention also pertains to a medicinal preparation.

30 cl, 5 tbl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-amino-3-alkoxy-6-fluorobicyclo[3.10]-hexan-2,6-dicarboxylic acid and a pharmaceutical composition based on thereof possessing antagonistic effect on the group of II metabotropic glutamate receptors. Also, invention relates to a medicinal agent possessing antagonistic effect on the group II metabotropic glutamate receptors and using derivatives of 2-amino-3-alkoxy-6-fluorobicyclo[3.1.0]-hexan-2,6-dicarboxylic acid used for treatment of depressive syndromes. Invention provides enhancing effectiveness of treatment.

EFFECT: improved and valuable properties of compounds, drug and pharmaceutical composition.

19 cl, 2 dwg, 1 tbl, 15 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new method for synthesis of substituted aryl-condensed azapolycyclic compounds of formulas (II) and (VIII) , novel intermediates compounds and methods for their synthesis. Substituted aryl-condensed azapolycyclic compound of the formula (II) show the binding capacity with neurone nicotine/acetylcholine specific receptor sites and can be used for modulation of cholinergic function in treatment of different diseases. Method for synthesis of compound of the formula (II) wherein R represents hydrogen atom; R2 and R3 are chosen independently from hydrogen, halogen atom, (C1-C6)-alkyl optionally substituted with 1-3 fluorine atoms and (C1-C6)-alkoxy-group optionally substituted with 1-3 fluorine atom involves the hydrogenation reaction of compound of the formula: (1a'): synthesized from compound of the formula (III): to yield intermediate compounds of formulas (IX): and (VII): . Compound of the formula (VII) is cyclized in treatment with a base to yield compound of the formula (VIII) that is reduced. Compound of the formula (III) can be prepared by interaction of compound of the formula (IV): with compound of the formula (V): .

EFFECT: improved methods of synthesis.

14 cl, 12 sch, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing hydrochlorides of amine-derivatives of adamantane of general formula:

,

where R=H, CH3; n=0, 1. According to the disclosed method, biologically active compounds such as, for example, hydrochlorides of 1-aminoadamantane (R=H, n=0) (amantadine) and 1-amino-3,5-dimethyl-adamantane (R=CH3, n=0) (memantine) are obtained, which are used in the chemical and pharmaceutical industry to prepare medicinal agents for treating Parkinson's disease, Alzheimer's diseases, neurodegenerative diseases, glaucoma etc. The method involves reaction of adamantane carboxylic acid with thionyl chloride at its boiling point for 1.5 hours in molar ratio 1:1.1 respectively, to form an acyl chloride of adamantane carboxylic acid, which reacts with sodium azide in anhydrous toluene at its boiling point in molar ratio 1:1:15-20 respectively for 1.5-2 hours, followed by addition of concentrated hydrochloric acid and holding the reaction mass for 1 hour and extracting the end product.

EFFECT: method is more technologically effective and ecologically clean and enables to obtain a large number of homologues of hydrochlorides of amine-derivatives of adamantane with quantitative output of 92-95%.

4 ex

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

Up!