RU2544859C1 - Method of producing (s)-3-aminomethyl-5-methylhexanoic acid (pregabalin) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (S)-(+)-3-aminomethyl-5-methylhexanoic acid (pregabalin) of formula (I)

The method includes steps (a)-(g). Step (a) includes reacting alkyl ether of cyanoacetic acid CNCH₂COOR (A) and isobutyraldehyde to obtain alkyl ether of 2-cyano-4-methylpentanoic acid (B)

At step (b) the obtained ether (B) reacts with ethyl ether of alpha-haloacetic acid (Hal=Cl, Br, I) in the presence of a base at 10-90°C in a solvent, such as N,N-dimethyl formamide, tetrahydrofuran, 1,4-dioxane, diemthyl sulphoxide and dimethoxyethane, or without a sovent to form 4-ethyl-1-methyl-2-cyano-2-isobutylsuccinate (C)

Step (c) includes hydrolysis of compound (C) under the action of a base, such as an alkali metal hydroxide, at 20-80°C, to obtain 2-cyano-2-isobutylsuccinic acid. Step (d) includes decarboxylation of the obtained 2-cyano-2-isobutylsuccinic acid in the presence of a mineral acid, e.g. sulphuric or hydrochloric acid, in an organic solvent, e.g. ethyl acetate, at 70-80°C to obtain (RS)-3-cyano-5-methylhexanoic acid. Step (e) includes separating enantiomers of the obtained (RS)-3-cyano-5-methylhexanoic acid by forming a corresponding salt with cinchonidine in an organic solvent, such as ethanol, methanol, 1,4-dioxane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane and diethylene glycol dimethyl ether, at 20-80°C, separating the cinchonidine salt of (S)-3-cyano-5-methylhexanoic acid and additional purification thereof by repeated salt formation in ethyl acetate. At step (f) the cinchonidine salt of (S)-3-cyano-5-methylhexanoic acid is treated with a mixture of ethyl acetate and diluted hydrochloric acid (1:1) at room temperature and the (S)-3-cyano-5-methylhexanoic acid (II)

formed is separated from the organic layer. Step (g) includes hydrogenation of the separated optically pure (S)-3-cyano-5-methylhexanoic acid (II), which is catalysed by Raney nickel, to form (S)-(+)-3-aminomethyl-5-methylhexanoic acid (pregabalin) (I). The method is characterised by that at step (a) reaction of the alkyl ether of cyanoacetic acid CNCH₂COOR, where R=C₁-C₄-alkyl, with isobutyraldehyde is carried out under the action of carbon monoxide at pressure of 1-200 atm and temperature of 20-200°C in a polar solvent, such as methanol, ethanol, water, 1,4-dioxane, tetrahydrofuran, acetonitrile, dimethoxyethane and diethylene glycol dimethyl ether, and the catalyst used is a cobalt, nickel, ruthenium or rhodium compound; at step (b) the base used is sodium hydride.

EFFECT: method reduces the number of steps when producing an intermediate, reduces the amount of wastes and improves environmental safety.

5 ex

Description

The invention relates to the chemistry of drugs, in particular to the production of γ-amino acids and their derivatives, and in particular to a method for producing (S) -3- (aminomethyl) -5-methylhexanoic acid (pregabalin).

(S) -3-Aminomethyl-5-methylhexanoic acid (pregabalin) (I)

is the active substance of a drug sold under the trade name Lyrica ^® (Lyric ^® ) (Pfizer, Inc.), which has antiepileptic and anticonvulsant activity (The Art of Drug Synthesis. Edited by Douglas S. Johnson and Jie Jack Li, 2007, John Wiley & Sons, Inc. pp. 225-227).

The mechanism of action of the drug is based on its ability to bind to alpha-2-delta subunits of calcium channels of neurons (calcium channels of N- and P / O-type), as a result of which there is a decrease in calcium transport to neuron cells in response to the action potential. The drug is characterized by a high degree of affinity for the alpha-2-delta protein located in the tissues of the central nervous system. The use of the drug leads to a decrease in the release of pain neurotransmitters (including glutamate, norepinephrine and substance P) into the synaptic cleft upon excitation of neurons. As a result of such changes, impulse conduction is selectively suppressed under the influence of the drug; it should be noted that the Lyrica ^® preparation inhibits the excitability of the neuron network only in pathological conditions.

The drug has an analgesic effect for pains of neuropathic etiology and postoperative pain, including in conditions such as hyperalgesia and alodynia.

The drug in a therapeutic dose is well tolerated by patients, when using the drug in doses 2 times higher than therapeutic, there is a lack of teratogenic effects. It has also been shown that pregabalin does not have a carcinogenic and genotoxic effect.

A number of methods for producing pregabalin are known, for example, those described in the monograph (The Art of Drug Synthesis. Edited by Douglas S. Johnson and Jie Jack Li, 2007, John Wiley & Sons, Inc. pp. 225-227, 234-240). In some known methods, a racemic mixture of 3-aminomethyl-5-methylhexanoic acid is synthesized and then it is separated into R- and S-enantiomers. In such methods, an azide intermediate, malonate intermediate, or Hoffmann synthesis can be used (US Pat. No. 5,531,375, US Pat. No. 6,046,353, No. 5,840,956 and No. 5,663,767 and US Pat. No. 5,629,447 and No. 5,616,793, respectively). In each of these methods, the racemate is reacted with a chiral acid (resolving agent) to form a pair of diastereoisomeric salts, which are separated by known methods, such as fractional crystallization and chromatography.

Known methods for producing directly (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin), such methods use a chiral auxiliary, for example, (4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone (US patents No. 6359169, 6028214, 5847151, 5710304, 5684189, 5608090 and 5599973). These methods provide pregabalin with high enantiomeric purity, but they are less preferred for large-scale synthesis, since they use expensive reagents (for example, auxiliary chiral substance) and special cryogenic equipment necessary for operation at low temperatures (up to -78 ° C )

A known method of producing pregabalin by asymmetric hydrogenation of a cyano-substituted olefin, which leads to the formation of a chiral cyano-substituted precursor (S) -3-aminomethyl-5-methylhexanoic acid (application for US patent No. 2003/0212290A). The resulting precursor is then reduced to obtain pregabalin. When carrying out asymmetric hydrogenation, a chiral catalyst is used, which consists of a transition metal bound to a bisphosphine ligand, for example, (R, R) -Me-DUPHOS ((-) - 1,2-bis ((2R, 5R) -2.5 dimethylphospholano) benzene). This method makes it possible to obtain 3- (aminomethyl) -5-methylhexanoic acid with a substantial predominance of (S) -enantiomer- (S) - (3- (aminomethyl) -5-methylhexanoic acid (pregabalin).

Such an approach to the preparation of pregabalin, which uses asymmetric catalysis, is very convenient, but chiral phosphorus catalysts are notable for their high cost and low stability. Therefore, there is a need for methods that use cheaper reagents and do not require the use of special equipment.

In this regard, methods of obtaining pregabalin in racemic form and subsequent separation of enantiomers are still of interest. This approach makes it possible to use cheaper and more affordable reagents. A known method (WO 2012/059797 A1), in which pregabalin precursors are obtained as racemate by multi-stage synthesis from cyanoacetic acid ester NC-CH ₂ -COOR (A), where R = CH ₃ ; C ₂ H ₅ , and then the desired enantiomer is isolated (see Scheme 1).

Scheme 1

The above method of obtaining pregabalin (I) was chosen as a prototype, since it is closest in essential features to the claimed method.

The prototype method includes:

a) (i) condensation of isobutyraldehyde with a cyanoacetic acid alkyl ester (A) in the presence of a base such as piperidine acetate, cesium acetate, and (ii) subsequent hydrogenation catalyzed by platinum group metals (platinum oxide, palladium on carbon, palladium on carbon ) or Raney nickel, in a polar solvent (such as methanol, ethanol, water, 1,4-dioxane, tetrahydrofuran, dimethoxyethane and diglyme) at a hydrogen pressure of 1-5 atm, with the formation of the corresponding alkyl ester of 2-cyano-4-methylpentanoic acids (B);

b) reacting compound (B) with alpha-haloacetic acid ethyl ester, where the halogen is chlorine, bromine or iodine, in the presence of a base, preferably cesium carbonate, which is carried out in a solvent selected from N, N-dimethylformamide (DMF), tetrahydrofuran , 1,4-dioxane, dimethyl sulfoxide (DMSO) and dimethoxyethane, or without solvent at a temperature of 10-90 ° C, which gives 4-ethyl-1-alkyl-2-cyano-2-isobutyl succinate (C)

c) Hydrolysis of compound (C) in the presence of a base, preferably lithium hydroxide, at a temperature of 20-80 ° C (preferably at 65-70 ° C) to form 2-cyano-2-isobutyl succinic acid

d) Decarboxylation of the obtained 2-cyano-2-isobutyl succinic acid under the action of a mineral acid, for example sulfuric acid, in an organic solvent (for example, ethyl acetate), at 70-80 ° C, which leads to the formation of 3-cyano-5-methylhexanoic racemate acids

f) Separation of the enantiomers of 3-cyano-5-methylhexanoic acid through the formation of its cichonidine salt (III) obtained by reaction with cichonidine in an organic solvent such as ethanol, methanol, 1,4-dioxane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane or diglyme, at a temperature of 20-80 ° C. The cinchonidine salt of (S) -3-cyano-5-methylhexanoic acid (III) is isolated by known methods and further purified;

(f) Treatment of the obtained salt (III) with a mixture of ethyl acetate and dilute hydrochloric acid (1: 1) at room temperature, which leads to the formation of (S) -3-cyano-5-methylhexanoic acid (II) in the organic layer. Cinchonidine is regenerated from the aqueous phase by alkalization.

(g) Hydrogenation of optically pure (S) -3-cyano-5-methylhexanoic acid (II) in the presence of Raney nickel to form the desired product - (S) - (3- (aminomethyl) -5-methylhexanoic acid (I) (pregabalin )

At each stage, the products are isolated and further purified by appropriate methods.

The prototype method has several advantages compared with other known methods for producing pregabalin, it uses simple syntheses and available starting compounds.

However, the prototype has several disadvantages. Firstly, stage (a) actually consists of two stages: a (i) condensation of isobutyraldehyde with cyanoacetic acid alkyl ester (A) in the presence of a base (piperidine acetate or cesium acetate) in methanol and a (ii) recovery of the condensation product. It is necessary to isolate the condensation product before recovery. Explosive hydrogen is used as a reducing agent, the high fluidity of which can create additional problems in terms of safe operation of the equipment (leaks in the installation are easily formed). The use of large quantities of piperidine and acetic acid in the condensation reaction increases the amount of waste. As catalysts for hydrogenation, it is necessary to use platinum group metal compounds in significant quantities. Thus, the implementation of the prototype method in industry requires high costs and solutions to emerging environmental problems.

There is another method for the preparation of intermediate (B) by the reaction of alkyl cyanoacetates with halogen derivatives (WO 2011141923 A2); this method is also not without drawbacks: in this case, a more thorough and time-consuming purification of the final product from the starting materials is necessary due to the high toxicity of the halogen derivatives. In addition, the formation of acids entering the effluent is unsafe for the environment.

Thus, there is a need for methods for producing pregabalin, which can be used in industry for the large-scale production of this drug.

The present invention is to develop a more technologically advanced and environmentally friendly method for producing pregabalin for use in industry.

The problem is solved by the claimed method of obtaining (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin) of the formula (I)

including

(a) the interaction of the alkyl ester of cyanoacetic acid CNCH ₂ COOR and isobutyraldehyde, resulting in the alkyl ester of 2-cyano-4-methylpentanoic acid (B)

(b) reacting the obtained ester (B) with alpha-haloacetic acid ethyl ester (Hal = Cl, Br, I) in the presence of a base at a temperature of 10-90 ° C., which is carried out either without a solvent or in a solvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide and dimethoxyethane to give 4-ethyl-1-methyl-2-cyano-2-isobutyl succinate (C)

(c) Hydrolysis of compound (C) under the influence of a base, such as an alkali metal hydroxide, at a temperature of 20-80 ° C, which gives 2-cyano-2-isobutyl succinic acid

(d) Decarboxylation of the obtained 2-cyano-2-isobutyl succinic acid in the presence of a mineral acid, for example sulfuric or hydrochloric acid, in an organic solvent, for example ethyl acetate, at 70-80 ° C. to form (RS) -3-cyano-5 methylhexanoic acid

(e) Separation of the enantiomers of the obtained (RS) -3-cyano-5-methylhexanoic acid through the formation of the corresponding salt with cichonidine in an organic solvent such as ethanol, methanol, 1,4-dioxane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane and diglyme, at a temperature of from 20 to 80 ° C, the isolation of the cinchonidine salt of (S) -3-cyano-5-methylhexanoic acid and its further purification by repeated salt formation in ethyl acetate;

(f) Treatment of the obtained (S) -3-cyano-5-methylhexanoic acid (III) cichonidine salt with a mixture of ethyl acetate and dilute hydrochloric acid (1: 1) at room temperature and isolating the resulting (S) -3-cyano-5-methylhexanoic acid (II) from the organic layer and the regeneration of cichonidine from the aqueous phase

(g) Hydrogenation of the isolated optically pure (S) -3-cyano-5-methylhexanoic acid (II) catalyzed by Raney nickel to produce the desired product - (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin) (I) ,

moreover, at the stage (a) the interaction of the alkyl ester of cyanoacetic acid CNCH ₂ COOR, where R = C ₁ -C ₄ -alkyl, with isobutyraldehyde, resulting in the production of 2-cyano-4-methyl-pentanoic acid alkyl ester (B), is carried out under the action of carbon monoxide at a pressure of from 1 to 200 atm and a temperature of from 20 to 200 ° C, in a polar solvent such as methanol, ethanol, water, 1,4-dioxane, tetrahydrofuran, acetonitrile, dimethoxyethane and diglyme, and as a catalyst use compounds of cobalt, nickel, ruthenium or rhodium;

in step (b), sodium hydride is used as the base.

The inventive method is presented below in scheme 2.

Scheme 2

At the stage (a), the formation of the main intermediate, the 2-cyano-4-methylpentanoic acid alkyl ester (B), occurs as a result of the interaction of isobutyraldehyde, ether (A) and carbon monoxide.

The reaction is carried out at a pressure of carbon monoxide of 1-100 atm in the temperature range from 20-200 ° C or without solvent, or in a polar solvent such as methanol, ethanol, isopropanol, THF, dioxane, acetonitrile, etc., under the action of catalysts containing rhodium, ruthenium, cobalt, nickel derivatives as an active component. Obtaining ether In is carried out in one stage when using the catalyst in small quantities (up to 1 mol.%).

It is known that carbon monoxide is a potential reducing agent, but the scope of this reducing agent has so far been limited mainly to inorganic chemistry, in particular metallurgy, where it is used to reduce metal oxides. In organic chemistry, carbon monoxide is used only for the reduction of aromatic nitro groups. Other examples of the use of CO as a reducing agent in organic synthesis have not yet been known. Surprisingly, CO turned out to be an effective reducing agent in the reaction for the production of 2-cyano-4-methylpentanoic acid alkyl esters (B) from isobutyraldehyde in a single step in high yield (80-95%).

The invention is illustrated by the following examples.

¹ H NMR spectra were recorded on a Bruker Avance 300 and a Bruker Avance 400 NMR spectrometer. Chemical shifts are given in ppm. relative to tetramethylsilane, calibrated to the appropriate peak solvent. To study the enantiomeric purity of the product, a Perkin-Elmer chromatograph with a 4 × 100 mm IB-3 chiral column with a particle size of 3 μm was used.

EXAMPLES

Example 1. Obtaining (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)

(a) Reaction of cyanoacetic acid methyl ester (A, R = CH ₃ ), isobutyraldehyde and carbon monoxide when catalyzed by rhodium diacetate dimer

23 mg (44.2 μmol) of rhodium diacetate, 2.1 ml of methanol, 400 μl (4.42 mmol) of isobutyraldehyde, 380 μl (4.42 mmol) of cyanoacetic acid methyl ester are placed in a glass ampoule. The ampoule is placed in an autoclave. The autoclave is closed, purged with carbon monoxide and heated at 110 ° C for 24 hours. The reaction mass is filtered through a thin layer of silica gel. The yield of 2-cyano-4-methylpentanoic acid methyl ester (B, R = CH ₃ ) 95%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.81 (s, 3H), 3.54 (dd, J = 9.3, 5.9 Hz, 1H), 1.93-1.73 (m, 3H), 0.98 (dd, J = 10.3, 5.9 Hz, 6H).

(b) Preparation of 4-ethyl-1-methyl-2-cyano-2-isobutyl succinate

50 ml of DMF was placed in the reactor, sodium hydride (3.08 g, 77 mmol) was added as a 60% emulsion in paraffin in small portions under nitrogen. The mixture was cooled to 10-15 ° C and a solution of 2-cyano-4-methylpentanoic acid methyl ester (10 g, 64 mmol) obtained in step (a) in DMF (20 ml) was slowly added, keeping the temperature of the reaction mixture below 20 ° C. Then the reaction mixture was heated to 50 ° C and stirring was continued for another 1 hour, and a solution of ethyl bromoacetate (12.9 g, 77 mmol) in 25 ml of DMF was slowly added. Then the temperature was lowered to room temperature and stirring was continued for another 24 hours. Add 20 ml of water. The aqueous layer was extracted with dichloromethane (5 × 50 ml). The organic layers were separated, combined, dried with sodium sulfate and evaporated under reduced pressure to give 4-ethyl-1-methyl-2-cyano-2-isobutyl succinate (14.1 g) in 90% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.88 (d, 3H), 0.96 (d, 3H), 1.05 (t, 3H), 1.70-1.89 (m, 3H), 2.8 (d, 1H), 3.02 ( d, 1H), 3.84 (s, 3H), 4.18 (q, 2H).

(c) Preparation of 2-cyano-2-isobutyl succinic acid

4-Ethyl-1-methyl-2-cyano-2-isobutyl succinate (10 g) and water (15 ml) were placed in the flask. With stirring, an aqueous solution of lithium hydroxide (3.6 g LiOH in 15 ml H ₂ O) is added dropwise. Then the reaction mixture was stirred for 12 hours at 70 ° C. After this, the reaction mixture was cooled and the unreacted ether was extracted with diisopropyl ether. The aqueous layer was acidified with hydrochloric acid (to pH = 2) and extracted with ethyl acetate (3 × 35 ml). The combined organic layers were dried with sodium sulfate, the solvent was removed under reduced pressure to give 2-cyano-2-isobutyl succinic acid (7.2 g) in 87% yield as a white solid.

¹ H NMR (400 MHz, DMCO-d ₆ ) δ 0.82-0.89 (d, 3H), 0.96-0.97 (d, 3H), 1.64-1.75 (m, 3H), 2.86 (s, 2H), 13.15 (s, 2H).

(d) Preparation of (RS) -3-cyano-5-methylhexanoic acid by decarboxylation of 2-cyano-2-isobutyl succinic acid

6.0 g of 2-cyano-2-isobutyl succinic acid, 60 ml of ethyl acetate and 0.6 g of concentrated sulfuric acid are placed in the reactor. The reaction mixture was boiled for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure to obtain crude (RS) -3-cyano-5-methylhexanoic acid, which was suspended in water and stirred for 30 minutes. The aqueous layer was extracted with ethyl acetate (2 × 25 ml). The organic layers were combined and dried with sodium sulfate, then the solvent was evaporated under reduced pressure to obtain 3.1 g of (RS) -3-cyano-5-methylhexanoic acid as a yellow oil. Yield 66%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.95 (d, 3H), 0.96 (d, 3H), 1.36-1.38 (d, 1H), 1.59-1.66 (m, 1H), 1 79-1.85 (m, 1H), 2.59-2.61 (dd, 1H), 2.69-2.75 (dd, 1H), 2.98-3.04 (m, 1H) .

(e) Separation of the enantiomers of (RS) -3-cyano-5-methylhexanoic acid and

(f) isolation of (S) -3-cyano-5-methylhexanoic acid (II) from the cichonidine salt (III)

(e) Cichonidine (1.9 g, 6.4 mmol) and ethyl acetate (50 ml) were placed in the reactor, and the resulting mixture was heated to 70 ° C. Then, with stirring, a solution of (RS) -3-cyano-5-methylhexanoic acid (2 g, 12.9 mmol) was added over 15-20 minutes, the reaction mixture was stirred for another 5 hours while boiling and cooled for 12 hours. The resulting cinchonidine salt of (S) -3-cyano-5-methylhexanoic acid (III) is filtered off as a white solid (2.3 g, 95% ee) (according to chiral HPLC analysis). If necessary, the resulting product (III) is further recrystallized from ethyl acetate.

¹ H NMR (DMCO-D6, 300 MHz): δ 0.89 (d, 3H), 0.91 (d, 3H), 1.30-1.45 (m, 1H), 1.52-1.59 (m, 3H), 1.69-1.82 (m, 4H), 2.38 (broad s, 1H), 2.43-2.55 (dd, 3H), 2.60-2.68 (m, 2H), 2; 97-3.07 (m, 2H), 3.25 (s, 1H), 3.49 (s, 1H), 4.93 (d, 1H), 4.99 (d, 1H), 5.64 (d, 1H), 5.78-5.87 (m, 1H), 7.60-7.64 (m, 2H), 7.75 (t, 1H), 8.04 (d, 1H), 8.36 (d, 1H), 8.86 (d, 1H).

(f) The cichonidine salt of (S) -3-cyano-5-methylhexanoic acid (III) (2.0 g), dichloromethane (100 ml) and aqueous hydrochloric acid (10 ml) are placed in the reactor. The resulting two-phase system is stirred for one hour, the organic layer is separated, the aqueous layer is washed several times with dichloromethane. The combined organic phases are dried with sodium sulfate, filtered, the solvent is removed under reduced pressure and (S) -3-cyano-5-methylhexanoic acid (II) is obtained (750 mg).

¹ H NMR (CD ₃ OD, 300 MHz): 0.91-0.96 (m, 6H), 1.22-1.23 (q, 2H), 1.64-1.74 (q, 1H), 2.20-2-48 (m, 3H), 2.79-3.00 (m, 2H).

(g) Reduction of (S) -3-cyano-5-methylhexanoic acid (II)

A solution of (S) -3-cyano-5-methylhexanoic acid (II) (2 g, 13 mmol) in 100 ml of a methanol-water mixture (70:30) is added to a solution of potassium carbonate (720 mg, 13 mmol) in 20 ml water at room temperature and stirred for 2 hours

The resulting mixture was placed in an autoclave and 1 g of Raney nickel was added. The autoclave is closed and purged with hydrogen (2 × 3 atm). Then the pressure was adjusted to 10 atm and left for 24 hours. The reaction mixture was recovered from the autoclave and filtered through celite. The filtrate was acidified with acetic acid (0.85 ml, 13 mmol) and stirred for 10 minutes. The solvent was removed under reduced pressure to obtain a pasty substance, which was suspended in dimethoxyethane (10 ml) and stirred for 2 hours at 70 ° C, then cooled and stirred for another 5 hours at 5 ° C. Receive (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin) (I) (1.2 g, 99.7% of it according to chiral HPLC) as a white solid. Yield 60%.

Example 2. Obtaining (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)

(a) The interaction of cyanoacetic acid methyl ester, isobutyraldehyde and carbon monoxide in the presence of a catalyst is carried out according to the procedure similar to that described in example 1 (a), with ruthenium trichloride being used as a catalyst, and acetonitrile as a solvent. Temperature 140 ° C. The yield of 2-cyano-4-methylpentanoic acid methyl ester is 83%.

The subsequent steps (b) to (e) are carried out as described in Example 1.

Example 3. Obtaining (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)

(a) The interaction of methyl cyanoacetic acid ester, isobutyraldehyde and carbon monoxide in the presence of a catalyst is carried out according to a procedure similar to that described in example 1 (a), with cobalt carbonyl being used as a catalyst and tetrahydrofuran being used as a solvent. Temperature 160 ° C. The yield of 2-cyano-4-methylpentanoic acid methyl ester is 79%.

The subsequent steps (b) to (e) are carried out as described in Example 1.

Example 4. Obtaining (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)

(a) The interaction of methyl cyanoacetic acid ester, isobutyraldehyde and carbon monoxide in the presence of a catalyst is carried out according to the procedure similar to that described in example 1 (a), with nickel dichloride being used as a catalyst and tetrahydrofuran as a solvent. Temperature 160 ° C. The yield of 2-cyano-4-methylpentanoic acid methyl ester is 80%.

The subsequent steps (b) to (e) are carried out as described in Example 1.

Example 5. Obtaining (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin)

(a) Reaction between cyanoacetic acid ethyl ester, isobutyraldehyde and carbon monoxide in the presence of a catalyst

23 mg (44.2 μmol) of rhodium diacetate, 2.1 ml of ethanol, 400 μl (4.42 mmol) of isobutyraldehyde, 470 μl (4.42 mmol) of cyanoacetic acid ethyl ester are placed in a glass ampoule. The ampoule is placed in an autoclave. The autoclave was closed, purged with carbon monoxide (3 × 10 atm) and heated at 110 ° C for 24 hours. The reaction mixture was filtered through a thin layer of silica gel. The yield of 2-cyano-4-methylpentanoic acid ethyl ester was 92%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.24 (q, J = 7.1 Hz, 2H), 3.50 (dd, J = 9.3, 5.9 Hz, 1H), 1.71-1.92 (m, 3H ), 1.31 (t, J = 7.1 Hz, 3H), 0.96 (d. 1 = 6.2, 3H), 0.95 (d. J = 6.2, 3H).

The subsequent stages (b) - (e) are carried out similarly as described in example 1.

Thus, the claimed invention allows to improve the known method for producing pregabalin, to reduce the total number of stages due to the synthesis of intermediate alkyl ether (B) in one stage, using a previously unknown reaction of reductive alkylation of carbon monoxide. As a result, the yield of the target product is increased and the need to use auxiliary compounds, for example, bases, which lead to the formation of by-products polluting the main product and increasing the amount of waste, is eliminated. Replacing hydrogen with carbon monoxide reduces the likelihood of leakage in the reactor and thus reduces the likelihood of explosive gas-air mixture formation. The method allows the use of carbon monoxide with a low degree of purity (technical), which may contain impurities such as nitrogen, carbon dioxide, helium, argon, hydrogen, methane, ethane, propane, butane, neon, krypton, radon and other gaseous compounds. The method uses catalysts based on compounds of cheaper metals (ruthenium, rhodium, nickel, cobalt, etc.) than in the prototype, and in smaller quantities (not more than 1 mol%, in the prototype not less than 2%). The method does not require the use of socialization. Reducing the load of the metal catalyst and the absence of cocatalysts makes the method safer for the environment. In the dicarboxylic acid diester production step (b), cheap and affordable sodium hydride is used as the base.

The technical result is a reduction in the number of stages in the preparation of the main intermediate (B), a decrease in the number of products entering the waste, and an increase in environmental safety.

Since CO is used for the industrial production of the starting isobutyraldehyde, its use in stage (a) is an undoubted advantage of the method from a technological point of view and can lead to the creation of a logistically effective technology for the preparation of pregabalin.

Claims (1)

The method of obtaining (S) - (+) - 3-aminomethyl-5-methylhexanoic acid (pregabalin) of the formula (I)

,
including
(a) the interaction of the alkyl ester of cyanoacetic acid CNCH ₂ COOR (A) and isobutyraldehyde, resulting in the production of alkyl ester of 2-cyano-4-methylpentanoic acid (B)

;
(b) reacting the obtained ester (B) with alpha-haloacetic acid ethyl ester (Hal = Cl, Br, I) in the presence of a base at a temperature of 10-90 ° C., which is carried out either without a solvent or in a solvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide and dimethoxyethane to give 4-ethyl-1-methyl-2-cyano-2-isobutyl succinate (C)

;
(c) hydrolysis of compound (C) under the action of a base, such as an alkali metal hydroxide, at a temperature of 20-80 ° C, which gives 2-cyano-2-isobutyl succinic acid

;
(d) decarboxylation of the obtained 2-cyano-2-isobutyl succinic acid in the presence of a mineral acid, for example sulfuric or hydrochloric acid, in an organic solvent, for example ethyl acetate, at a temperature of 70-80 ° C. to form (RS) -3-cyano-5- methylhexanoic acid

;
(e) separating the enantiomers of the obtained (RS) -3-cyano-5-methylhexanoic acid through the formation of the corresponding salt with cichonidine in an organic solvent such as ethanol, methanol, 1,4-dioxane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane and diglyme, at a temperature of 20-80 ° C, the isolation of the cinchonidine salt of (S) -3-cyano-5-methylhexanoic acid and its further purification by repeated salt formation in ethyl acetate;
(f) treating the resulting cichonidine salt of (S) -3-cyano-5-methylhexanoic acid with a mixture of ethyl acetate and dilute hydrochloric acid (1: 1) at room temperature, isolating the resulting (S) -3-cyano-5-methylhexanoic acid (II ) from the organic layer

;
(g) hydrogenation of the isolated optically pure (S) -3-cyano-5-methylhexanoic acid (II) catalyzed by Raney nickel to form the desired product - (S) - (+) - 3-aminomethyl-5-methylhexanoic acid (pregabalin ) (I),
characterized in that
at the stage (a), the interaction of the alkyl ester of cyanoacetic acid CNCH ₂ COOR, where R = C ₁ -C ₄ -alkyl, with isobutyraldehyde, resulting in the production of 2-cyano-4-methylpentanoic acid alkyl ester (B), is carried out under the influence of carbon monoxide at a pressure of from 1 to 200 atm and a temperature of from 20 to 200 ° C in a polar solvent such as methanol, ethanol, water, 1,4-dioxane, tetrahydrofuran, acetonitrile, dimethoxyethane and diglyme, and cobalt, nickel compounds are used as a catalyst ruthenium or rhodium;
in step (b), sodium hydride is used as the base.