DE2058237B - Process for the preparation of trans-4-amino-methylcyclohexanecarboxylic acid- (l) - Google Patents

Description

The invention relates to a process for the preparation of trans-4-aminomethylcyclohexanecarboxylic acid (1) the following formula

NH ₂ CH ₂ -,

COOH

(D

The compound prepared according to the present invention is characterized by hemostatic activity and by other beneficial pharmacological effects. The compound is used as a medicinal product, used in particular as a hemostatic agent.

In the production of 4-aminomethylcyclohexanecarboxylic acid (l) according to a known method (German Auslegeschrift 1 300 558) was not only started from a more difficult to access starting material, but until now it was only afterwards the cis isomer, the pharmacological activity of which is far inferior to that of the trans isomer, available as a mixture with the trans isomer. The cis-isomers thus incurred in substantial proportions therefore previously had to be complicated and expensive to convert into the trans-isomerc chemical processes are subjected, so that this known process is altogether unsatisfactory is.

The object of the present invention is accordingly to find a simple and satisfactory process for industrial production which alone or predominantly the trans-isomcre can be obtained in high yields.

Surprisingly, it has been found that the desired trans isomer can be obtained in extremely high yields if the trans-COOR ¹

(II)

COOR ²

where R ^{1 can be the} same or different from R ² and denotes hydrogen or a lower alkyl group. If at least one of the radicals R ¹ or R ^{2 is} a lower alkyl group, hydrolysis is carried out at the same time during the last process step. The decarboxylation according to the invention is carried out by methods known per se by heating the dicarboxylic acid in an acidic solvent, preferably an inorganic acid such as sulfuric acid, hydrobromic acid or hydrochloric acid, or by heating in a high-boiling solvent such as diethylene glycol or quinoline, optionally in the presence of a Catalyst. The temperature range that can be used for decarboxylation is 100 to 230 "C.

The most significant advantage of this method is that it is almost exclusively hemostatically effective trans isomers of 4-aminomethylcyclohexanecarboxylic acid (l) is reverberated while in the preparation of the connection by known methods exclusively or largely the pharmaceutically practically worthless cis-isomer is obtained. To according to the process according to the invention, the reaction product consists of up to about 90% of the trans isomer, this yield depends on the decarboxy conditions. Even under unfavorable Conditions, the proportion of the trans isomer in the reaction product is rarely less than 70%.

This astonishing and at first by no means expected result is especially with regard to a significant enrichment of the previously taken detour via the cis isomer Technology.

The starting material for the decarboxylation reaction, i.e. H. the connection of. general formula II, is new. It is obtained by reducing 4-Cyancyclohexen- (4) -dicarboxylic acid- (l, l) odei one of its esters of the general formula

NC-

COOR ¹

COOR ²

(III)

obtained, In which R ¹ and R * have the meaning given above. The esters formed can, if appropriate, be hydrolyzed in the customary manner to form the free cyclohexanedicarboxylic acid.

This reduction can be carried out with the aid of the most varied of known reducing agents, for example with hydrogen in the presence of catalysts such as nickel. Platinum or palladium with aluminum, zinc, iron or sodium in the presence of acids, bases or organic solvents, with tin dichloride, iron! II V sulfate, with sodium hydrogen sulfite, with sodium borohydride. Lithium aluminum hydride, with hydrogen sulfide or hydrogen iodide. Preferably, however, catalytic hydrogenation is used.

The catalytic hydrogenation is carried out in an anhydrous or aqueous organic solvent, wc methanol or ethanol, carried out as Catalyst in the presence of ammonia Raney nickel or in the presence of hydrochloric acid palladium-carbon can be used. The catalytic hydrogenation can be carried out under one of the following conditions be carried out: At room temperature or under warming, at normal pressure or under Overpressure, although it is already completely sufficient for the reduction in question, at room temperature and normal pressure to work.

The amount of secondary amine formed in this reduction is extremely small; the desired product of the general formula II. the primary amine. is obtained in very good yield. When H ¹ and R ^{2 are} alkyl groups, the ester is considered an oil. The ester forms salts with acids and can be converted into the corresponding dicarhonic acid without further purification by customary hydrolysis with acid or alkali. The diacid obtained in this way is amphoteric, so that after the reduction or hydrolysis has taken place, it is preferably passed through an ion exchanger for separation.

The compound of the general formula III is also new. It is obtained by 4-cyano-4-hydroxy-cyclohcxanedicarboxylic acid- (l, l) or their alkyl esters of the general formula

HO

COOR ¹

(IV)

where in the general formula R ¹ and R 'can have the same or different meanings and represent hydrogen or lower alkyl groups and furthermore the product obtained in the case of the alkyl ester can optionally be hydrolyzed in the customary manner and furthermore the monoester obtained or the free acid obtained can optionally be alkylated.
To carry out the dehydration according to

ίο the invention becomes the starting material of the general Formula IV in an anhydrous organic solvent, for example in benzene, pyridine or Dissolved dichloromethane, then adding thionyl chloride as a suitable dehydrating agent to this solution or phosphorus pentachloride is given. The reaction mixture can be left to stand at room temperature or heated to a predetermined temperature. If the obtained in this way Compound of the general formula III is an ester, it can optionally partially or completely hydrolyzed in the usual manner with a basic compound in a polar solvent. A dilute alcoholic solution VOH sodium hydroxide can preferably be used for this purpose. About it in addition, various alkyl esters or mixed esters can be obtained by treating the Reaction product of the general formula III are prepared with an alkylating agent. The transesterification can be carried out simultaneously with the hydrolysis described above.

The starting material of the general formula used for the reaction step described above IV is also a new compound. By reacting cyclohexanone- (4) -dicarboxylic acid- (l, l) or one of its esters with acetone cyanohydrin in the presence of an organic base or Alkali cyanide can be prepared in a manner known per se, where in the general formula the cyclohexanone- (4) -dicarboxylic acid- ( 1.1)

NC COOR ²

be dchydrated in a manner known per se.

COOR ¹

COOR ²

R ¹ and R ^{2 have} the meaning described above.
Sodium cyanide or potassium cyanide can be used as the alkali metal cyanide. When reacted with alkali metal cyanide, the starting material is suitably treated with sodium bisulfite to form an adduct.

The inventive method for the preparation of the hemostatically active trans-4-Aminomclhylcyclohcxancarbonsäure- (l) (1) can be summarized in the following scheme:

COOR ¹

COOR ²

Acctonic anhydrin or
Alkali cyanide

HO

NC

COOR ¹

COOR ²

(IV)

Dehydration, optionally with hydrolysis, and / or alkylation

NC

COOR '

COOR ²

(III)

Reduction, if necessary
under hydrolysis

NH, CH

COOR ¹

COOR ²

(H)

Decarboxylation, optionally with hydrolysis

COOH

R ¹ can be the same or different from R ² , where R ¹ and R ^{2 are} hydrogen or lower alkyl groups.

The invention is to be described in more detail with the aid of the following examples.

Example I.

A. 4-Cj an-4-hydroxy-cyclohexanedicarboxylic acid (1,1) diethyl ester (compound IV; R ¹ = R ² = C ₂ R ₅ )

(a) A mixture of cyclohexanone (4) dicarboxylic acid (l, l) diethyl ester (2.4 g) and acetone cyanohydrin (0.85 g) is mixed with triethylamine (0.5 ml) and mixed thoroughly. The batch is left to stand overnight and the next morning concentrated under reduced pressure, giving in quantity ^: vcr yield 4-cyano-4-hydroxy-cyclohexanedicarboxylic acid (l, l) diethyl ester as a viscous oily residue.

(b) Sodium hydrogen sulfite (10 g) is dissolved in 30 ml of water. 7.2 g of cyclohexanone- (4) -dicarboxylic acid- ( 1,1) diethyl ester given, which was then thoroughly stirred.

After 2 hours, potassium cyanide (6 g) is added with subsequent stirring. After further The oil layer that has formed is taken up in benzene for 2 hours and the extract over sodium sulfite dried. After the solvent has been stripped off, 7 g of 4-cyano-4-hydroxy-cyclohexanedicarbon * acid (I, I) diethyl ester obtained.

The cyanohydrin compound obtained by the method (a) or (b) was identified in the IR spectrum and with the aid of thin-film chromatography. The CN band (2247 cm " ¹ ), the OH band (3450 cm" ¹ ) and the ester band (1730 cm " ¹ ) were observed in the IR spectrum. The cyunhydrin compound is unstable and easily decomposes on distillation with reformation of the cyclohexanone .

B. 4-Cyan-cyclohexen- (4) -dicarbonsäi; .re- (IJ) -diethylester (compound III; R ¹ = R ² = C ₂ H ₅ )

(A) 4 - cyano - 4 - hydroxy - cyclohexanedicarboxylic acid (1,1) diethyl ester (2.4g) are dissolved in pyridine (7 ml) solved. To this solution are stirred and

ίο Ice cooling added 2 g of thionyl chloride drop by drop. After stirring for 2 hours and standing overnight at room temperature, ice water is added, the excess thionyl chloride is destroyed and the reaction mixture is extracted with benzene. the

The extract is washed with acid or alkali and dried over sodium sulfate. After distilling off of the benzene, a pale oily product was obtained. Nüv.h of the distillation in vacuum 1.6 g of 4 - cyano - cyclohexene - (4) - dicarboxylic acid (l, l) diethyl ester as an oily reaction product with a boiling point of 140C at 6mm Hg receive.

(b) Phosphorus pentachloride (22 g) is suspended in benzene (100 ml). This suspension is under Stir dropwise a solution of 4-cyano-4-hydroxy - cyclohexanedicarboxylic acid - (1,1) - diethyl ester (20 g) in benzene (70 ml). When the addition is complete, the mixture is refluxed for 5 minutes heated, then cooled, poured onto ice, separated the benzene layer, washed with water and dried. After stripping off the benzene and distilling under reduced pressure: the reaction product (18 g) is obtained.

With the aid of IR spectra and thin-layer chromatography it is shown that the products obtained by processes (a) and (b) are identical. The structure of the reaction product is secured with the aid of NMR and elemental analysis.
IR: CN (2200 cm ¹ ), ester (1735 cm " ¹ ), C = C (1645 cm" ¹ ), OH (3450 cm "') no longer occurs.

Elemental analysis for C ₁₃ H ₁₇ O ₄ N:

Calculated ... C 62.14, H 6.82, N 5.57%;
found .... C 61.83, H 6.97, NC, 13th
C 61.65, H 7.15, N 5.96%.

4-cyano-cyclohexen- (4) -dicarboxylic acid- (1,1)
(Compound III; R ¹ = R ² = H)

(c) The 4-Cyancyclchexen- (4) -dicarboxylic acid- (l, l) -diethyl ester (2.5 g) obtained according to Example 1B (a) is dissolved in ethanol (10 ml). A 20% aqueous sodium hydroxide solution (5 ml) is added to this solution. J hour is then '/: .70 warmed to ⁰ C for. The reaction solution is concentrated to half its volume under reduced pressure, cooled and acidified with 10% hydrochloric acid. The oily reaction product is extracted with ether, the extract is dried over sodium sulfate and the solvent is stripped off. After the distillation, the crystalline crude product (2.0 g) is obtained, which is purified by recrystallization from acetone-benzene mixtures. Colorless crystals which decompose ^{at 155 to 157 °} C. are obtained in this way.

The reaction product thus obtained is done with the help of the elemental analysis, the IP spectrum and identified by NMR as 4-cyano-cyclohexene (4) -dicarboxylic acid- (1,1).

IR: -COOH (2570cm- ¹ , 1745cm- ¹ and 1715cm '), -CsN (2225cm- ¹ ) C = C (1640cm- ¹ ) ·

Elemental analysis for C ₉ H ₉ O ₄ N:

Calculated ... C 55.38. H 4.65, N 7.18%:

found .... C 54.84. H 4.89, N 6.89

C 55.38. H 4.87, N 7.18

C 55.25. H 5.03. N 6.80%.

(d) A 20% strength aqueous sodium hydroxide solution is added to 0.5 g of 4-cyano-cyclohexene- (4) -dicarboxylic acids 1.1 monomethyl ester. The mixture obtained in this way is _{heated to 70 ° C. for 2} hours, then cooled and acidified with 10% hydrochloric acid. The oily reaction product obtained is extracted with ether. After the ethereal extract has dried, the ether is stripped off and, after washing with benzene, the crystalline crude product (0.4 g) is obtained, the decomposition point of which is 152 to 154 C. The IR spectrum and thin-layer chromatography ensure that the product obtained in this way is identical to the 4-cyano-cyclohexene (4) -dicarboxylic acid (II) obtained by process (c).

(e) Using 4-cyano-4-hydroxy-cycl «- hexanedicarboxylic acid- (1.l) processes (a) and (b) from Example I B are carried out, likewise the free 4-cyano-cyclohexen- (4) -dicarboxylic acid- (1.l) is obtained.

(f) 4-cyano-cyclohexen- (4) -dicarboxylic acid- (Ll) -

monoethyl ester (compound III;
R ¹ = C ₂ H ₅ and R ² = H)

2.5 g of the 4-cyanocyclohexene (4) -dicarboxylic acid (l,!) Diethyl ester prepared according to Example 1 B (a) are dissolved in ethanol (10 ml). A 20% strength aqueous sodium hydroxide solution is added to this solution with stirring. After 2 minutes, the reaction mixture is acidified with 10% hydrochloric acid, the oily reaction product obtained is extracted with ether, the ethereal extract is dried over sodium sulfate and the ether is stripped off, 2.3 g of an oily residue being obtained. The quickly crystallized residue is purified by recrystallization from benzene to give the thus obtained 4-Cyancyclohexen- (4) -dicarbonsäure- <1.1) -monoäthyIester in the form of crystals is obtained whose melting point 108-110 ⁰ C Hegt. The structure of the reaction product obtained in this way is identified by means of elemental analysis, IR spectra and NMR.

Analysis for C _n H ₁₃ O ₄ N:

Calculated ... C 59.18, H 5.87, N 6.25%;

found .... C 59.08. H 6.17, N 6.20

C 59.56, H 6.30, N 6.30%.

(g) 4-cyano-cyclohexen- (4) -dicarboxylic acid- (1,1) -

monomethyl ester (compound III;
R ¹ = CH ₃ and R ² = H)

The 4 - cyano - cyclohexene - (4) - dicarboxylic acid (L1) diethyl ester and water are added to a 5% strength methanolic sodium hydroxide solution. The mixture obtained is heated on a water bath for 3 minutes and then treated as described in Example 1B (f) to carry out the transesterification and hydrolysis. The obtained after recrystallization from benzene pure 4-cyano-cyclohexen (4) -dicarbonsäure- (l, l) -monomethylester has a melting point of 105-107 ⁰ C.

Elemental analysis for C | "Hi, O ₄ N:

Calculated ... C 57.41. H 5.30, N 6.70%;
found .... C 57.48, H 5.57, N 6.64

C 57.31, H 5.57, N 6.70%.

C. (a) 4-Aminomethyl-cyclohexanedicarboiic acid- (l, l) -diethyl ester (compound II: R ¹ = R ² = C ₂ H ₅ )

4-cyano-cyclohexen- (4) -dicarboxylic acid- (1,1) -diethyl ester (15.0 g) is dissolved in methanol (15 ml). to

This solution is used for the catalytic reduction, by introducing hydrogen at room temperature until the theoretical amount of hydrogen is absorbed Raney nickel (15 ml) and concentrated aqueous ammonia (15 ml) are added. After the reaction has ended, the catalyst is separated off by filtration. The filtrate will concentrated at low temperatures under reduced pressure. The residue is diluted with hydrochloric acid purified, neutralized with sodium carbonate, extracted with ether and separated. The ether layer is washed with water, the aqueous washing fractions with the aqueous layer of the Ether separation combined and then concentrated at low temperatures under reduced pressure will. The concentrate obtained in this way is treated with ethyl acetate and the ethyl acetate appears then washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and then concentrated. The residue obtained in this way is determined by means of IR spectra and NMR 4 - aminomethyl - cyclohexanedicarboxylic acid - (1,1) - diethyl ester identified. The yield is 13.8 g, corresponding to 90% of theory.

Elemental analysis of the reaction product:

Mp. 203 to 205 ⁰ C (after recrystallization from Essigsäureäthylestcr).

C ₉ H ₂₆ N ₄ O _n :

Calculated ..
found ...

C 46.91, H 5.91, N 11.52%,
C 46.69, H 5.62, N 11.17
C 46.77, H 5.59, N »\ 46%.

(b) 4-Aminomet hylcyclohexanedicarbonsäure-f 1,1) (Compound II; R ¹ = R ² = H)

(a) 4 - Cyano - cyclohexene - (4) - dicarboxylic acid - (1.1) (2.0 g) is dissolved in methanol (20 ml). For catalytic Concentrated aqueous ammonia (2 ml) and Raney nickel (2 ml) are added to the reduction The reduction is effected by introducing hydrogen at room temperature theoretical amount of hydrogen, the reactor is interrupted. The catalyst is removed by filtration separated, the filtrate concentrated and the Rückstanc after the addition of water on an ion exchange acid given. The eluate is concentrated under reduced pressure and the residue is recirculated from water staUisiert, with 1.6 g of 4-aminomethylcyclohexanedi carboxylic acid- (I, i) were obtained. The Schrnete point is 225 ° C (decomposition). The identity of this reaction product with that after the j in the following Process (c) described hereof is assured of the product obtained.

209527/5

(c) To produce the free acid by hydrolysis of the diethyl ester obtained according to Example 1C (a) is proceeded as follows:

(d) 0.5 g of the 4-aminomethyl - cyclohexanedicarboxylic acid - (l.l) -diäthylcs'.srs prepared according to Example 1C (a) are dissolved in 10% aqueous hydrochloric acid solution and refluxed for 3.5 hours warmed up. The reaction solution obtained is concentrated and the residue is washed with ethanol, after which 0.3 g of 4-aminomethyl-cyclohexanedicarboxylic acid (l, l) hydrochloride with a melting point of 203 ° C (decomposition) can be obtained.

Elementary analysis of the hydrochloride (C ₉ H ₁₆ NO ₄ Cl):

Calculated ... C 45.48. H 6.79. N 5.89%;

found .... C 45.56. H 7.22. N 5.85%;

C 45.62. H 6.99, N 5.85%.

The hydrochloride is also identified by IR spectra and NMR.

(e) According to a further embodiment, 0.4 g of the 4-aminomethyl-cyclohexanedicarboxylic acid (1.1) diethyl ester prepared according to Example 1C (a) are added dissolved in aqueous ethanol to which 0.4 g of sodium hydroxide had been added. The resulting solution is 4 hours heated to reflux. The reaction solution is concentrated under reduced pressure and the aqueous solution of the residue on a weakly acidic ion exchange column ("Amberlite IRC-50") given. After the eluate has been concentrated, 0.31 g 4-aminomethylcyclohexanedicarboxylic acid - (1,1) obtained, which, after recrystallization from water, has a melting point of 225 ° C. (decomposition).

Elemental analysis for C ₈ H ₁₅ NO ₄ :

Calculated ... C 53.72. H 7.51, N 6.96%;

found .... C, 53.53. H 7.77, N 6.93%;

C 53.51. H 7.37, N 6.97%.

The dicarboxylic acid obtained in this way is identified with the aid of IR spectra and NMR.

D (a) 4-Amüiomethyl-cyclohexanecarboxylic acid- (H.
(Compound I; R ¹ = R ² = H)

4 - Aminomethyl - cyclohexanedicarboxylic acid - (1.1) (1.0 g) is dissolved in 60% sulfuric acid and then heated on the oil bath for 1 hour at a bath temperature of 150 to 160 ° C. The reaction solution is then placed on an ion exchange column. After concentrating the eluate 0.73 g of 4-aminomethyl-cyclohexanecarboxylic acid- (1) are obtained under reduced pressure. The reaction product begins to soften at 250 ° C and melts at over 300 ° C. The reaction product becomes

to converted into the hydrochloride and the trans isomer separated from the cis isomer by fractional recrystallization from alcohol. After the Ion exchange is 0.07 g of ice isomer and 0.63 g trans isomer of 4-aminomethyl-cyclohexanecarboxylic acid (Herhalten.

(b) 4-aminomethyl-cyclohexanedicarboxylic acid (l, l) diet hy ester (1.0 g) are dissolved in concentrated hydrochloric acid (4 ml) and refluxed for 50 hours. The reaction solution thus obtained is concentrated under reduced pressure, the residue in a little Dissolved water and applied to an ion exchange column. After the eluate has been concentrated 0.55 g 4 - aminomethyl - cyclohexanecarboxylic acid - (1) receive. The resulting reaction product begins to soften at 230 "C and decomposes at 300" C.

After treating the crystals as described in Example 1 D (a), 0.16 g of cis isomer and 0.37 g are obtained trans isomer obtained.

(C) According to a further embodiment of the invention, 50.5 g of 4-aminomethyl-cyclohexanedicarboxylic acid ( 1.1) diethyl ester in concentrated hydrobromic acid (Density = 1.48; 300 ml) heated under reflux for about 25 hours. Then will the hydrochloric acid removed in vacuo (density = 1.40 (42%); 265 ml). The residue will taken up in water and filtered to remove insoluble residues (0.17 g). The filtrate will first on an OH ion exchange column ("\ mberlit IR-48") and then on a small one Ion exchange column ("Amberlit IRC-50") given. From the concentrated and well-dried solution who the 25 g of 4-aminomethyl-cyclohexanecarboxylic acids 1 receive. 17.1 g of trans are obtained from the reaction product according to the manner described in Example ID (a) Isomer and 6.9 g of cis isomer isolated.

2399

Claims (1)

Palent claim: Process for the preparation of trans-4-aminomethylcyclohexanecarboxylic acid - (1), characterized in that cyclohexanone- (4) -dicarboxylic acid- (l, i) or one of the esters obtainable therefrom in a manner known per se with acetone cyanohydrin reacted in the presence of an organic base or with alkali metal cyanide, the resulting 4 - cyano - 4 - hydroxycyclohexanedicarboxylic acid (1,1) or one of its esters known per se Way in the presence of thionyl chloride or phosphorus pentachloride, expediently in an anhydrous organic solvent, dehydrated and optionally hydrolyzed in the usual way and / or alkylated, the 4 - cyanocyclohexene - (4) - dicarboxylic acid - (1,1) or obtained thereby one of its esters in a manner known per se with hydrogen in the presence of catalysts, such as Nickel, platinum or palladium, in the presence of an aqueous or anhydrous organic Reduced solvent, the reduction product optionally in a conventional manner with acids or Alkali hydrolyzed and the resulting 4-aminomethylcyclohexanedicarboxylic acid- (l, l) or one of its esters in a manner known per se by heating in an acidic solvent or a high-boiling solvent, optionally in the presence of a catalyst, to 100 is decarboxylated up to 230 C. 4-Aminomethylcyclohex? N-dicarboxylic acid- (l, l) or one of its esters partially decarboxylated with hydrolysis will. According to the invention it is therefore proposed that cyclohexanone - ^ - dicarboxylic acid-f 1,1) or one of the esters obtainable therefrom is reacted in a manner known per se with acetone cyanohydrin in the presence of an organic base or with alkali metal cyanide, the 4-cyano-4-hydΓoxycyclohexanedicarboxylic acid thus obtained - (l, l) or one of its esters in a manner known per se in the presence of thionyl chloride or phosphorus pentachloride, expediently in an anhydrous organic solvent, dehydrated and optionally hydrolyzed and / or alkylated in the usual way, the 4-cyanocyclohexene obtained thereby - (4) -dicarboxylic acid- (U) or one of its esters is reduced in a manner known per se with hydrogen in the presence of catalysts such as nickel, platinum or palladium, in the presence of a water-containing or anhydrous organic solvent, the reduction product optionally with Acids or alkali hydrolyzed and the 4 - aminomethylcyclohexanedicarboxylic acid - (1.1 ) Or one of its ester is decarboxylated in a conventional manner by heating in an acidic solvent or a high boiling solvent, optionally in the presence of a catalyst at 100 to 23O ⁰ C. The last process step consists in the partial decarboxylation of the 4-aminomethylcycIohexanedicarboxylic acid (U) or one of their esters, optionally with hydrolysis, of the general formula