CZ2005230A3 - Novel synthesis process of trans-4-methylcyclohexylamine base and derived salts of trans-4-methylcyclohexylamine hydrochloride or pivalate usable as intermediates in the preparation of glimepiride antidiabetic - Google Patents

Abstract

In the present invention, there is disclosed a process for preparing trans-4-methylcyclohexylamine of the general formula V, optionally a corresponding trans-4-methylcyclohexylamine hydrochloride of the general formula VIII or pivalate of the general formula VII exhibiting high content of trans-isomer, wherein the preparation process is characterized by the following steps: a) subjecting a Schiff's base of the general formula to isomerization by treating thereof with a strong base in a solvent being selected from the group consisting of aliphatic ethers, cyclic ethers, dialkylsulfoxides, or dialkyl sulfones to obtain an isomeric compound of the general formula X; b) subjecting the isomeric compound of the general formula to acid hydrolysis by treating thereof with a mineral acid to obtain a corresponding salt of trans-4-methylcyclohexylamine; c) optionally converting the obtained salt of trans-4-methylcyclohexylamine to a base of the general formula V or hydrochloride of the general formula VIII pivalate of the general formula VII. The compounds of the general formulae V, VII or VIII are used for preparing glimepiride.

Description

A novel process for the synthesis of fra / is-4-methylcyclohexylamine base and derived hydrochloride or pivalate salts thereof from 4-methylcyclohexylanine useful as intermediates for the manufacture of the antidiabetic agent glimepiride

Technical field

The present invention relates to a novel process for the preparation of / Razzs-4-methylcyclohexylamine and its hydrochloride and pivalate salts, which are directly useful as intermediates in the preparation of the antidiabetic agent glimepiride of formula I.

Said drug is an important representative of antidiabetic drugs of the sulfonamide family.

BACKGROUND OF THE INVENTION

Glimepiride is produced according to the original patent EP 031058 (US 4379785) either by reaction of 3-ethyl-4-methyl-2-oxo-2,5-dihydro-pyrrole-1-carbox- [2- (4-sulfamoyl-phenyl) -ethyl] -amide of formula II

or by reaction of an alkyl [4- (2 - {[(3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl) carbonyl] amino} ethyl) phenyl] sulfonylcarbamate of the formula IV, wherein R is C 1 -C 5 alkyl,

(IV) of

with Zr, 4'-4-methylcyclohexylamine of the formula V. The trans-4-methylcyclohexylisocyanate of the formula III is prepared from Zr-5-4-methylcyclohexylamine of the formula V (V)

For the production of glimepiride a key factor is the sufficient purity of trans-4i

- methylcyclohexylamine of formula V with the lowest possible content of the cis-isomer. The most common method used is the reduction of 4-methylcyclohexanone oxime of the formula VI - &gt; = N (VI) by sodium in alcohols, most often in ethanol. The amine thus obtained typically has a cis -pomer content in the range of 8 to 10% (TP Johnston, J. Med. Chem. 1971, 14, 600-614). Further purification of the amine to a higher Zrans-isomer content is not sufficiently documented. In our patent CZ 293789 we have solved this problem by crystallizing the corresponding salt with pivalic acid. The amine obtained in this way contains a very low content of all impurities, in particular the corresponding cis-isomer. Moreover, we have surprisingly found that this trans-4-methylcyclohexylamine pivalate of formula VII - <> · ' ₂

COOH (VII) having a high content of the β5-isomer can be advantageously used directly for the production of very pure glimepiride. However, the production of Zr / 4-methylcyclohexylamine of formula V by reduction of 4-methylcyclohexanone oxime of formula VI cannot be considered to be ideal by the methods described so far. The use of sodium metal always poses a certain safety risk and in the case of metal pdk reductions in Mu always ... Iž. ·, LozkyM Q pdz-3 with hydrogen in alcohols vigorously releases hydrogen, which forms an explosive mixture with air and therefore such production requires special ventilation .

The present invention describes a novel process for the production of trans-4-methylcyclohexylamine-based intermediates which overcomes the above disadvantages.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Zrarcs-4-methylcyclohexylamine of formula V or its hydrochloride of formula VIII

H-Cl (VIII) or a pivalate of formula VII having a high Zrazw-isomer content and their direct use in the manufacture of glimepiride. The whole process is based on the surprising finding that Schiff's base of formula IX, readily obtainable by reaction of 4-methyl-cyclohexanone with benzylamine, under strong action bases over the isomeric compound of formula X, with the content of the corresponding Zrans derivative strongly exceeding the undesired ceryl . This material then acid hydrolyzes directly to the corresponding salt corresponding to the acid used in the hydrolysis, for example the hydrochloride of formula VIII, hydrobromide, hydrogen sulphate, dihydrogen phosphate, preferably the hydrochloride of formula VIII, which can be easily converted into a base of formula V or a pivalate of formula VII. Both of these are important intermediates useful in the preparation of glimepiride of formula I.

A more detailed description of the invention follows.

Only a few cases of isomerization of the N -benzyl imines of formula XI to the corresponding isomerism of compound XII are described in the scientific literature. There is a balance between the two

- 4isomery wherein preparatively useful results are described practically only in case of perfluorinated derivatives, wherein R ^{1 =} CF3, CF2Cl, CF2CF3, and R ² = methyl, phenyl, benzyl, ethoxycarbonyl (Soloshonok VA Gerus 1.1, YagupoVskii Yu. L., Kukhar VG: Zh Org Khim 1988, 24, 993, Soloshonok VA, Kirilenko AG, Kukhar VP, Resnati G .: Tetrahedron Leti., 1994, 35, 3119; Ono T., Kukhar VP, Soloshonok VA: J Org. Chem., 1996, 61, 6563; Ohkura H., Berbasov DO, Soloshonok VA: Tetrahedron 2003, 59, 1667). The reaction is carried out by treatment with organic bases such as triethylamine or diaza [5.4.0] bicycloundec-7-ene. For non-fluorinated derivatives, the isomerization of imines XI to the corresponding isomerism of compound XII for cyclic derivatives is described wherein R 1, R ² = (Clfy) 4 (CH ₂ ) 4 and (CH ₂ ) 5 using potassium tert -butoxide in DMSO (Richer J. -C., Perelman D .: Can. J. Chem. 1970, 48, 570).

N

R 2 R ² (XI)

We have surprisingly found that this reaction is also useful for the synthesis of tert-4-methylcyclohexylamine, a prominent intermediate of the synthesis of the anti-diabetic glimepiride, and bases other than potassium tert-butanolate and preferably solvents other than DMSO can also be used.

The starting material of formula IX can be easily prepared by reacting 4-methylcyclohexanone with benzylamine in various solvents under various conditions. The reaction can be carried out under the catalytic action of acid catalysts, preferably 4-toluenesulfonic acid, optionally by heating in the absence of catalyst. Advantageously, an arrangement with azeotropic distillation of the resulting water may be used, or the resulting water may be bound by adding suitable desiccants, preferably magnesium sulfate, to the reaction mixture. The compound of formula IX

OF . .

it may be isolated and purified by distillation, but may preferably be used directly for isomerization.

The reaction according to the invention can be carried out in a number of suitable solvents, in particular from the group of aliphatic ethers, cyclic ethers, dialkyl sulfoxides or dialkyl sulfones, preferably in particular tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane or dioxane. Alkali metal alcoholates of the formula XIII have proved to be suitable as bases

R-O-M

- 5 ~ (ΧΠΙ) where R is unbranched or optionally branched C1-C10 alkyl and M is Na, K or Li, potassium tert-butoxide, potassium tert-amyl alcoholate or potassium 3,7-dimethyl-3-octyl alcoholate can preferably be used . The process of the invention provides a reaction mixture comprising a compound of formula X together with a small amount of a starting material of formula IX. This mixture can be further separated by conventional methods to give the pure compound of formula X. However, according to the invention, this separation is not necessary, the crude reaction mixture is subjected to acid hydrolysis by treatment with a suitable acid, preferably hydrochloric acid. In addition to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and other acids can also be used for the hydrolysis. The corresponding salt of trans-4-methylcyclohexylamine is thus contaminated with a small amount of the benzylamine salt.

According to the process according to the invention, the base can be freed from this mixture in a conventional manner and then purified by fractional distillation at a pressure of 0.001 to 104 kPa, preferably at a pressure of 1 to 101 kPa. The amine of formula V thus obtained contains only a small amount of both the cis-isomer and benzylamine and is suitable for the preparation of glimepiride.

Furthermore, the trans-4-methylcyclohexylamine salt obtained by the process according to the invention can be converted to the corresponding amine, which can be further purified by steam evaporation and collection into a dilute acid such as hydrochloric, hydrobromic, sulfuric, phosphoric acid to obtain the corresponding trans-4-methylcyclohexylamine salt. C 1 -C 5 alcohols, their esters with C 1 -C 5 acids or mixtures thereof, both anhydrous and with a water content of up to 50% by weight, preferably up to 5% by weight, have proved to be a suitable solvent for the crystallization of the crude salt, in particular the hydrochloride. Particular preference is given to ethyl acetate and in particular to ethyl acetate mixtures with the addition of ethanol up to 50% by weight, preferably up to 5% by weight.

A further preferred option is to convert the trans-d-methylcyclohexylamine salt to a pivalate and further crystallize to obtain the p-a-4-methylcyclohexylamine pivalate of formula VII having a high .alpha.-isomer content and a low benzylamine pivalate content suitable for glimepiride production.

Procedures for purifying glimepiride obtained by reacting a compound of formula IV with trans-4-methylcyclohexylamine pivalate of formula VII were previously described in patent CZ 293789.

It has now been found that the purification procedures described in patent CZ 293789 are also effective for the glimepiride obtained by the process described in the present invention and can provide pure glimepiride of formula I, containing no detectable amounts of impurity of formula XIV by conventional techniques.

(XIV).

The advantage of the process according to the invention is the easy availability of the starting materials and reagents and, in particular, the fact that the reaction conditions are readily obtainable, that reducing agents such as alkali metals or hydrides are not used, and that hydrogen is not released during the reaction. Another advantage is that the ratio of trans: cis isomers is already much more advantageous in the crude reaction mixture than in other processes.

The invention is illustrated by the following examples. These examples, which illustrate preferred alternatives according to the invention, are illustrative only and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

N- (4-Methylcyclohexylidene) henzylamine (IX)

A mixture of 4-methylcyclohenanone (33.6 g, 0.3 mol), benzylamine (35 g, 0.33 mol), 4-toluenesulfonic acid (0.5 g) and toluene (400 mL) was refluxed for 10 h with azeotropic distillation of water. The cloudy solution was filtered through diatomaceous earth, the filtrate was evaporated to dryness and subjected to fractional distillation. 29.9 g of a fraction of b.p. 80-87 ° C / 27 Pa (according to GC content 92% IX). and 12.9 g fraction of b.p. 87 - 92 ° C / 13 - 27 Pa (according to GC content 94% IX).

Example 2 trans-N-benzylidene-4-methylcyclohexylamine (X) - standard

A mixture of benzaldehyde (10.6 g, 0.1 mol), trans-4-methylcyclohexylamine (11.3 g, 0.1 mol), 4-toluenesulfonic acid (0.1 g) and toluene (160 ml) was refluxed 6. h with azeotropic distillation of water. The reaction mixture was washed with saturated sodium carbonate solution and dried over magnesium sulfate. The filtrate was evaporated to dryness and subjected to fractional distillation. 11.5 g of a fraction of b.p. 76-78 ° C / 27 Pa (97% X according to GC).

Example 3

5-Methylcyclohexylamine hydrochloride (VIII)

A mixture of 4-methylcyclohenanone (10.2 g, 0.1 mol), benzylamine (lig, 0.1 mol) and toluene (200 mL) was refluxed for 10 h with azeotropic distillation of water. The reaction mixture was distilled to dryness, dry toluene (50 mL) was added and the mixture was again evaporated to dryness, which was repeated twice. The residue was dissolved in tetrahydrofuran (500 mL), potassium tert -butoxide (15 g) was added, and the mixture was stirred under nitrogen at 60 ° C for 14 hours.

Concentrated hydrochloric acid (200 mL) was added to the cold reaction mixture with cooling and the mixture was refluxed for 5 hours. The evaporation residue to dryness was diluted with water (200 mL) and extracted with ether. The aqueous portion was boiled for 1 hour with carboraffin, the carboraffin was hot filtered through diatomaceous earth and the filtrate was evaporated to dryness. The residue was dissolved several times in ethanol and evaporated to dryness and the residue thus obtained was boiled with ethyl acetate, cooled and the insoluble material was filtered off with suction. 14.1 g of white crystals of 4-methylcyclohexylamine hydrochloride (GC content of 92% 4-methylcyclohexylamine, 5.5% benzylamine,

4-methylcyclohexylamine trans-cis = 96.2: 3.8).

Example 4

Ripened 4-Methylcyclohexylamine hydrochloride (VIII)

A mixture of 4-methylcyclohexanone (10.2 g, 0.1 mol), benzylamine (11 g, 0.1 mol) and toluene (200 mL) was heated to boiling. After azeotropic removal of water, toluene was distilled off, the residue was subsequently dissolved in tetrahydrofuran at 50 ° C under nitrogen and after addition of 50% solution.

Potassium 3,7-dimethyl-3-octyl alcoholate in hexane (25 mL) was stirred at this α

After cooling, concentrated hydrochloric acid (200 mL) was added and the mixture was refluxed for an additional 5 hours. Subsequently, it was distilled from tetrahydrofuran / heptane and the reaction mixture was basified with 50% sodium hydroxide solution. The liberated amine was passed through steam and the distillate was collected into concentrated hydrochloric acid. The acidified distillate was evaporated to dryness, the residue was dissolved in ethyl acetate (100 ml) and pure white crystals were precipitated upon heating and cooling. 8.9 g of white crystals were obtained. The GC content (after conversion on the basis) was 97.7% 4-methylcyclohexylamine, 1.4% benzylamine, 4-methylcyclohexylamine trcins-cis = 99.9: 0.1).

Example 5

Sud-4-Methylcyclohexylamine hydrochloride (VIII)

A mixture of 4-methylcyclohexanone (51.5 g, 0.46 mol) and benzylamine (56 g, 0.52 mol) in toluene (900 mL) was heated to reflux. After azeotropic removal of water, toluene was distilled off, the residue was subsequently dissolved in tetrahydrofuran at 60 ° C under nitrogen, and after addition of potassium phosphate butanolate (75 g) was stirred at this temperature overnight. The next day was added from

concentrated hydrochloric acid (800 mL) and the mixture was refluxed for an additional 5 hours. Subsequently, it was distilled off from the tetrahydrofuran mixture (the last residues azeotropically after the addition of a small amount of water) and the reaction mixture was basified with 50% sodium hydroxide solution (440 ml). The liberated amine was passed through steam and the distillate was collected into concentrated hydrochloric acid. The acidified distillate was evaporated to dryness, the residue was dissolved in ethyl acetate (100 ml) and pure white crystals were precipitated upon heating and cooling. 28 g of white crystals were obtained. The GC content (after conversion on base) was 96% 4-methylcyclohexylamine, 3.8% benzylamine, 4-methylcyclohexylamine trcms-cis = 99.9: 0.1).

9Example 6

Zra-4-methylcyclohexylamine pivalate (VII)

The crystals obtained according to the procedure described in the previous example were dissolved in a minimum amount of water and the solution was made basic with sodium hydroxide. After separation of the upper phase with liberated trans-4-methylcyclohexylamine (VIII), the lower phase was shaken with dichloromethane. Dichloromethane was distilled off and the distillation residue was added to the first separate phase. These combined trans-5-4-methylcyclohexylamine were dissolved in methanol (50 mL) and 8.5 g of pivalic acid were added to the resulting solution. Approximately 8 g of the crude product was obtained, which was dissolved in hexane (80 mL) at boiling point. After 1 hour the mixture was cooled and the precipitated white crystals were aspirated. 16.3 g of frazo- 4-methylcyclohexylamine pivalate (VII), m.p.168-173, were obtained. Deň: 32 ° C. Content according to GC 97% 4-methylcyclohexylamine, 2.2% benzylamine, 4-methylcyclohexylamine trans-cis = 99.5: 0.5.

Example 7

4-Methylcyclohexylamine pivalate (VII)

To a solution of sodium hydroxide (9.3 g) in water (24 mL) was added to the separatory funnel 5 ', 5'-4-methylcyclohexylamine hydrochloride (22.5 g, 0.15 mol) obtained as described in Example 5, and the mixture was shaken. After separation, the upper phase was poured into a flask, the lower layer was returned to a separatory funnel, water (5 mL) was added and the mixture was shaken. The combined upper layers of the liberated amine were stirred with methanol (32 mL). Pivalic acid (15.3 g, 0.15 mol) was added with stirring. The resulting clear solution was allowed to stir for 10 min at 65 ° C. Methanol was distilled from the solution under vacuum at a bath temperature of up to 50 ° C.

To the crude pivalate was added cyclohexane (10 mL) warm and the mixture was heated to 65-70 ° C and the last methanol residue was distilled off. Additional cyclohexane (90 mL) was added to the thick reaction mixture, and the mixture was heated to 75 ° C, where it was stirred for 0.5 h. Subsequently, the mixture was cooled to 15 ° C over 1.5 h. The resulting crystals were aspirated and washed with cyclohexane cooled to 7-10 ° C (20 mL). 26.7 g (83% yield) of white crystals of trans-4-methyl-cyclohexylamine pivalate were obtained. Content according to GC 98.3% 4-methylcyclohexylamine, 1.4% benzylamine, 4-methylcyclohexylamine trans-cis - 99.92: 0.08.

EXAMPLE 8 5-Methyl-4-methylcyclohexylamine (V)

X

A mixture of 4-methylcyclohexanone (102 g, 1 mol), benzylamine (110 g, 1 mol) and toluene (21 ml) was refluxed for 10 h with azeotropic distillation of water. The reaction mixture was distilled to dryness, dry toluene (250 ml) was added and the mixture was again evaporated to dryness, which was repeated twice. The residue was dissolved in 2-methyltetrahydrofuran (41), c

potassium Zeylamyl alcoholate (150 g) was added and the mixture was stirred under nitrogen at 50 ° C for hours. Concentrated hydrochloric acid (2 L mL) was added to the cold reaction mixture with cooling and the mixture was refluxed for 5 hours. The evaporation residue to dryness was diluted with water (2 L) and extracted with ether. The aqueous portion was evaporated to dryness, the residue was dissolved in a minimum amount of water and the solution basified with sodium hydroxide. After separating the upper phase with the released trans-4-methylcyclohexylamine (V), the lower phase was shaken out with dichloromethane. The dichloromethane extract was combined with the first separated organic phase and the resulting solution was dried with sodium sulfate. The filtrate was evaporated to dryness and subjected to fractional distillation. 75.5 g of a fraction of b.p. 150-153 ° C (98.5% 4k methylcy / lohexylamine, 1.3% benzylamine, 4-methylcyclohexylamine trans-cis = 98.3: 1.7 according to GC).

Claims (19)

PATENT CLAIMS 1. A process for the preparation of a &lt; 5 &gt; -4-methylcyclohexylamine of the formula V (V) or the corresponding hydrochloride of the formula VIII. NH, H-Cl (VIII) or β-4-methylcyclohexylamine pivalate of formula VII COOH (VII) characterized in that: a) The Schiff base of formula IX is isomerized by treatment with a strong base in a solvent from the group of aliphatic ethers, a. cyclic ethers, dialkylsulfoxides or dialkylsulfones to give a compound of formula X b) subjecting the compound of formula X to acid hydrolysis with a mineral acid to give the corresponding salt of trans-5 ^, 4-methylcyclohexylamine; A process for the preparation of a 6-methyl-4-methylcyclohexyl amine of formula V according to claim 1, characterized in that the strong base is an alkali metal alcoholate of the formula XIII R-O-M (ΧΠΙ) wherein R is unbranched or optionally branched C 1 -C 10 alkyl and M is Na, K or Li. A process for the preparation of Zran5-4-methylcyclohexylamine of formula V according to claim 1, characterized in that potassium tert-butanolate is used as the strong base. Process for the preparation of the trans-4-methylcyclohexylamine of formula V according to claim 1, characterized in that potassium tera-amyl alcoholate is used as the strong base. A process for the preparation of the trans-4-methylcyclohexylamine of formula V according to claim 1, characterized in that potassium 3,7-dimethyl-3-octyl alcoholate is used as the strong base. 6. A process for the preparation of the trans-4-methylcyclohexylamine of formula (V) according to claim 1, wherein the solvent is tetrahydrofuran. A process for the preparation of the trans-4-methylcyclohexylamine of formula V according to claim 1, characterized in that 2-methyltetrahydrofuran is used as the solvent. A process for the preparation of the trans-4-methylcyclohexylamine of the formula V according to claim 1, characterized in that the resulting amine of the formula V is further purified by fractional distillation at a pressure of 0.001 to 104 kPa, preferably at a pressure of 1.33 to 101. kPa. 9 9 9 9 999 »· • •... • · ······ < 4444 444 44 «44 444 Process for the preparation of trans-4-methylcyclohexylamine hydrochloride of the formula VIII according to claim 1, characterized in that the hydrochloride of the formula VIII obtained is further purified by crystallization from a solvent of the group C1-C5 alcohols, their esters with C1-C5 acids or 13 mixtures of both, both anhydrous and with a water content of up to 50% by weight, preferably up to 5% by weight. A process for the preparation of η 5 -4-methylcyclohexylamine hydrochloride of formula VIII according to claim 9, characterized in that the hydrochloride of formula VIII is purified by crystallization from ethyl acetate. Process according to claim 9, characterized in that the solvent used is a mixture of ethyl acetate with addition of ethanol up to 50% by weight, preferably up to 5% by weight. %, &gt; * 9 · 9 9 9 12 - c) converting the obtained trans-4-methylcyclohexylamine salt into a base of formula V or a hydrochloride of formula VIII or a pivalate of formula VII. The method of claim 12, wherein the application of the coating composition comprises spraying, pouring, rolling or squeegeing. The method of claim 11, wherein providing the glass surface with a layer comprises applying the coating composition in the solid state of the layer. The method of claim 14, wherein applying the coating composition comprises adhering a self-supporting film of the coating composition to the glass surface. The method of claim 14, wherein applying the coating composition comprises adhering the whole formed from the coating composition and the carrier film to the glass surface. The method of claim 16, wherein the carrier film is peeled off from the glass surface after irradiation. Method for producing a coating composition according to one of the preceding claims, comprising the steps of: - preparing a mixture from a first solution of at least one silver compound in an aqueous and / or organic solvent and from a second solution of at least one binder in an aqueous and / or organic solvent, providing the support surface with a mixture layer, and - removal of solvent. The method of claim 18, wherein providing the layer comprises depositing on a glass surface to be processed or deposited on a carrier film.