KR20080037791A - Process for preparing (r)-2-hydroxy-2-(chlorophenyl)acetic methyl ester sulfate - Google Patents

Abstract

A process for preparing (R)-2-hydroxy-2-(chlorophenyl)acetic methyl ester sulfate is provided to simplify the preparation procedure, improve preparation yield and purity of compound, and enhance safety to human by removing use of toxic materials in the preparation. A process for preparing (R)-2-hydroxy-2-(chlorophenyl)acetic methyl ester sulfate represented by the formula(7) comprises : a step(a) of dissolving thiophene in organic solvent and reacting the solution in the presence of base and catalyst to prepare N-benzyl-(2-thiopene-2-yl-ethyl)amine represented by the formula(1); a step(b) of dissolving the compound represented by the formula(1) in solvent, adding strong acid into the solution, and heating and stirring the solution to prepare N-benzyl-4,5,6,7-tetrahydro-thieno-[3,2-c]pyridine represented by the formula(2); a step(c) of dissolving the compound represented by the formula(2), adding organic acid and palladium catalyst into the solution at room temperature to prepare 4,5,6,7-tetrahydro-thieno-[3,2-c]pyridine represented by the formula(3), and introducing HCl gas into the compound to prepare hydrochlorate of the compound represented by the formula(3); a step(d) of dissolving (R)-2-hydroxy-2-(2-chlorophenyl) acetate in organic solvent, adding a reaction catalyst into the solution, and stirring the solution to prepare the compound represented by the formula(4), and reacting the compound represented by the formula(4) with sulfonate reaction reagent in the presence of base to prepare (R)-2-benzenesulfonyloxy-2-(2-chlorophenyl)acetic methyl ester represented by the formula(5); a step(e) of dissolving the hydrochlorate of the compound represented by the formula(3) in organic solvent, adding base, reacting the solution with the compound represented by the formula(5) dissolved in dichloromethane to prepare (S)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydro-thieno-[3,2-c]pyridine)acetic methyl ester represented by the formula(6); and a step(f) of dissolving the compound represented by the formula(6) in organic solvent and adding weak sulfuric acid into the solution to prepare (S)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydro-thioeno-[3,2-c]pyridine)acetic methyl ester sulfate represented by the formula(7), and freeze-drying the compound represented by the formula(7). Further, an reacting temperature is -40 to 0 °C, and the organic solvent is one or mixture of anhydrous tetrahydrofuran and dioxane in the step(a).

Description

Process for preparing (R) -2-hydroxy-2- (chlorophenyl) acetic methyl ester sulfate}

The present invention relates to a new and improved method for preparing clopidogrel useful as a therapeutic agent for hypertension.

Formula (6), usually in the synthesized (R) form, is very effective as a therapeutic agent for arteriosclerosis. A method for preparing clopidogrel using thiophene carboxaldehyde (EP 465,358) or o-chloro benzaldehyde or the like (EP 99,803 and EP 281,459) as a starting material is disclosed. However, EP 465,358 shows thiophene carboxaldehyde to 2-thienyl acetaldehyde to 2-thienyl ethylamine, 4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine ( R) -2-chloro-2- (2-chlorophenyl) acetic acid methyl ester is reacted to produce clopidogrel. However, this method is very difficult and complicated to process in eight steps, and the yield is poor.

Prior arts using o-chloro benzaldehyde and the like (EP 99,803 and EP 281,459) are harmful to the human body by using the poisonous sodium cyanide. Obtain Phenyl Glycine Rasemide. This racemide is prepared using (+)-tartaric acid to produce (+)-2-chlorophenyl glycine. However, this method also has a problem that the process is very difficult and complicated, and the yield is low.

Accordingly, the present invention is to solve the problems of the prior art by using the intermediate formulas (1) and 2 to provide a pure and simple process for producing clopidogrel formula (6,7).

In order to achieve the above object, the present invention obtains an important intermediate formula (1) from thiophene as a starting material, reacts with formalin to prepare formula (2), deprotects an amine to obtain formula (3), and obtains an intermediate having a benzenesulfonyl group. By reacting, the present invention relates to a process for obtaining clopidogrel sulfate (Formula 7).

Hereinafter, the present invention will be described as follows.

Formula 7 of the present invention may be prepared by Scheme 1.

The present invention specifically consists of the following step process.

Dissolving thiophene in an organic solvent and preparing N-benzyl- (2-thiophen-2-yl-ethyl) amine of formula 1 using a base and a catalyst at -20 ^° C;

The compound of formula 1 is dissolved in an organic solvent, heated with addition of concentrated acid.

Reflux to prepare N-benzyl-4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine of Formula 2;

The compound of Formula 2 was dissolved in an organic solvent, and an organic acid and a palladium catalyst were added at room temperature to synthesize 4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine of Formula 3, followed by HCl gas. Step 3 to prepare a hydrochloride of Formula 3 by injection;

(R) -2-hydroxy-2- (2-chlorophenyl) acetic acid was dissolved in an organic solvent, a reaction catalyst was added, and the compound of formula 4 obtained by refluxing and stirring was reacted with a sulfonate reaction reagent in the presence of a base. (R) -2-benzenesulfonyloxy-2- (2-chlorophenyl) acetic acid methyl ester;

After dissolving the compound of Formula 3 in an organic solvent and adding a base, the reaction mixture was reacted with the formula 5 dissolved in dichloromethane to reflux. Agitated to (S) -2- (2-chlorophenyl) -2- (4, Preparing 5,6,7-tetrahydro-thieno- [3,2-c] pyridine) acetic acid methyl ester;

(S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydro-thieno- [of Formula 7 produced by dissolving the compound of Formula 6 in an organic solvent and adding 3,2-c] pyridine) acetic acid methyl ester sulfate is a method for preparing (S) -clopidogrel sulfate of formula (7) comprising the step 6 freeze-drying.

Looking at the specific reaction conditions for each reaction step of the present invention,

In step 1, the reaction temperature is -40 to 0 ^o C, and the organic solvent used is a single or mixed solvent of anhydrous tetrahydrofuran, dioxane. As the base used, methyllithium, n-butyllithium, phenyllithium, aziridine protected with amine (where the protecting group is benzyl, benzyloxy carbonyl, t-butyloxy carbonyl, etc.) is used as a catalyst. Dimethylaminopyridine or lithium perchlorate is used.

In step 2, the reaction temperature is 40 to 80 ^o C, and the solvent used is a single or mixed solvent of formalin aqueous solution, tetrahydrofuran, dioxane, and water. In addition, concentrated sulfuric acid or hydrochloric acid is used as a catalyst.

In step 3, the reaction temperature is 0 to 40 ^° C., and the organic solvent used is a single or mixed solvent of methanol and ethanol. In addition, the organic acid used is formic acid at a concentration of 3 to 6%, and Pd-C is used at 5 to 20%.

In step 4, the reaction temperature is from 0 to 100 ^o C, the organic solvent used is methanol and dichloromethane, sulfuric acid, hydrochloric acid or 4-dimethylaminopyridine is used as the reaction catalyst, triethylamine is used as the base, sulfo As the nitrate reagent, chlorobenzene sulfonate, methanesulfonyl chloride, benzenesulfonyl chloride, and the like are used.

In step 5, the reaction temperature is 30 to 100 ^° C., the solvent used is dichloromethane and water, and triethylamine or potassium carbonate is used as a base.

In step 6, the reaction temperature is 0 to 30 ^° C. and the solvent used is a single or mixed solvent of acetone, tetrahydrofuran, dioxane, water. In addition, dilute sulfuric acid is used as the organic acid used.

Example 1 Preparation of N-benzyl- (2-thiophen-2-yl-ethyl) amine (Formula 1)

Thiophene (841 mg, 10 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and 2N n -BuLi (5.5 mL, 11 mmol) was added at -20 ^° C. N-benzyl aziridine (1.332g, 10mmol) and lithium perchlorate (LiClO ₄ , 1.064g, 10mmol) are added to the mixed solution at -20 ^° C and stirred for 1 hour. The reaction solvent is concentrated under reduced pressure. Dichloromethane (50 mL) is added, followed by washing with water (20 mL * 2). The washed organic solution was dried over magnesium sulfate (5 g), filtered, and concentrated under reduced pressure. The concentrated mixture is purified by column chromatography to obtain Formula 1 (1.586 g) (yield: 73%).

¹ H NMR (CDCl ₃ ) δ 2.67 (t, 2H), 2.88 (t, 2H), 3.81 (s, 2H), 6.60 (d, 1H), 6.72 (m, 1H), 6.91 (d, 1H), 7.06-7.14 (m, 5H)

Example 2 Preparation of N-benzyl-4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine (Formula 2)

N-benzyl- (2-thiophen-2-yl-ethyl) amine (3.695 g, 17 mmol) was dissolved in 38% aqueous solution of formalin (7 mL) and concentrated hydrochloric acid (0.7 mL) was added at 60-70 ^° C. for 30 minutes. Stir. The reaction mixture is dissolved in 1,2-dichloroethane (100 mL) and water (100 mL), and the organic solution is separated. The separated organic solution was dried over magnesium sulfate (20 g), filtered, and concentrated under reduced pressure. The concentrate is dissolved in ethyl ether (30 mL) and HCl gas is injected at room temperature to obtain crystals. The crystals were filtered, washed with ethyl ether, and dried under reduced pressure and dried to obtain the chemical formula 2 (3.509 g, 15.3 mmol) (yield: 90%).

¹ H NMR (CDCl ₃ ) δ 2.65 (t, 2H), 2.69 (t, 2H), 3.60 (s, 2H), 3.62 (s, 2H), 6.50 (d, 1H), 6.77 (d, 1H), 7.06-7.14 (m, 5H)

Example 3: Preparation of 4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine hydrochloride (hydrochloride salt of formula 3)

5-Benzyl-4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine (2.293 g, 10 mmol) was dissolved in methanol (20 mL), 4.4% formic acid (1 mL) and 10% Pd. -C (230 mg) was added and stirred at room temperature for 10 hours. After stirring, filtered using celite and washed with methanol (20 mL * 2). The filtrate was concentrated under reduced pressure to 2 mL, concentrated, dissolved in ethyl ether (30 mL), and injected with HCl gas at room temperature to obtain crystals. The crystals were filtered, washed with ethyl ether, and dried under reduced pressure and dried to obtain the formula 3 (1.616 g, 9.2 mmol) (yield: 92%).

¹ H NMR (CDCl ₃ ) δ 2.67 (t, 2H), 3.18 (t, 2H), 4.01 (s, 2H), 3.62 (s, 2H), 6.50 (d, 1H), 6.77 (d, 1H)

Example 4: Preparation of (R) -2-hydroxy-2- (2-chlorophenyl) acetic acid methyl ester (Formula 4)

Dissolve (R) -2-hydroxy-2- (2-chlorophenyl) acetic acid (12 g, 64.3 mmol) in methanol (48 mL), add 95% sulfuric acid (480 mg), and reflux and stir for 2 hours. The reaction mixture is concentrated under reduced pressure, dissolved in dichloromethane (70 mL) and 10% potassium carbonate (25 mL), and the organic solution is separated. The separated organic solution was dried over magnesium sulfate (20 g), filtered, and concentrated under reduced pressure to obtain Chemical Formula 4 (12.44 g, 60.4 mmol) (yield: 94%).

¹ H NMR (CDCl ₃ ) δ 3.60 (broad s, OH), 3.76 (s, 3H), 5.57 (s, 1H), 7.20-7.42 (m, 4H)

Example 5 Preparation of (R) -2-benzenesulfonyloxy-2- (2-chlorophenyl) acetic acid methyl ester (Formula 5)

Dichloromethane (R) -2-hydroxy-2- (2-chlorophenyl) acetic acid methyl ester (12 g, 60 mmol), 4-dimethylaminopyridine (0.72 g, 6 mmol) and triethylamine (7.8 g, 78 mmol) (20 mL) and a solution of benzenesulfonyl chloride (10.6 g, 60 mmol) in dichloromethane (30 mL) were added at 0 ^° C., followed by stirring for 3 hours. 1N hydrochloric acid (24 mL) is added and extracted with dichloromethane (30 mL). The organic solution is washed with dilute hydrochloric acid and water, dried over magnesium sulfate (20 g), filtered, and concentrated under reduced pressure. The concentrate was subjected to column chromatography to obtain the target compound Formula 5 (20.04 g, 58.8 mmol) (yield: 98%).

¹ H NMR (CDCl ₃ ) δ 3.70 (s, 3H), 6.30 (s, 1H), 7.17-7.32 (m, 3H), 7.38-7.50 (m, 3H), 7.55-7.62 (m, 1H), 7.88 (td, 2H)

Example 6 Preparation of (S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine) acetic acid methyl ester 6)

4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine hydrochloride Formula 3 (1.054 g, 6 mmol) was dissolved in dichloromethane (8 mL) and 30% aqueous potassium carbonate (5.7 g) solution was added. Stir for 10 minutes. Methyl (R) -2-benzenesulfonyloxy-2- (2-chlorophenyl) acetic acid ester, Formula 5 (1.704 g, 5 mmol) was dissolved in dichloromethane (3 mL), and the reaction mixture was refluxed and stirred for 30 minutes. do. After the reaction, the reaction mixture is dissolved in 1,2-dichloroethane (50 mL) and water (50 mL), and the organic solution is separated. The separated organic solution was dried over magnesium sulfate (20 g), filtered, and concentrated under reduced pressure to obtain the chemical formula 6 (1.609 g, 5 mmol) (yield: 100%).

¹ H NMR (CDCl ₃ ) δ 2.66 (t, 2H), 2.70 (t, 2H), 3.63 (s, 2H), 3.73 (s, 3H), 4.94 (s, 1H), 6.67 (d, 1H), 7.06 (d, 1H), 7.22-7.32 (m, 2H), 7.42 (m, 1H), 7.72 (m, 1H)

Example 7 (S) -2- (2-Chlorophenyl) -2- (4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine) acetic acid methyl ester (Formula 7)

(S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine) acetic acid methyl ester Formula 6 (1.609g, 5mmol) Is dissolved in cooled acetone (5 mL) and concentrated sulfuric acid (0.2 mL) is dissolved in water (5 mL) and stirred at 0 ^° C. The resulting compound is concentrated to remove the organic solution and freeze-dried to obtain the target compound Formula 7 (2.10 g, 5.0 mmol) (yield: 100%).

Mp: 184 ^o C, [α] ²⁰ _D = + 55.1 ^o (c = 1.891 g / 100 mL; methanol)

The present invention relates to an improved process for the preparation of (R) -2-hydroxy-2- (2-chlorophenyl) acetic acid methyl ester.Sulfate (Formula 7), which is an important intermediate of starting material thiophene. To obtain a formula (2) by reacting with formalin, and to deprotect the amine to obtain a formula (3) to react with an intermediate having a benzenesulfonyl group to give clopidogrel sulfate (Formula 7) in a simpler process.

Claims (7)

Dissolving thiophene in an organic solvent and preparing N-benzyl- (2-thiophen-2-yl-ethyl) amine of formula 1 using a catalyst in the presence of a base; The compound of formula 1 was dissolved in a solvent, concentrated acid was added, and then heated and refluxed to prepare N-benzyl-4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine of formula 2. Step 2; The compound of formula 2 was dissolved in an organic solvent, and an organic acid and a palladium catalyst were added at room temperature to prepare 4,5,6,7-tetrahydro-thieno- [3,2-c] pyridine of formula 3, followed by HCL gas. Step 3 to prepare a hydrochloride of Formula 3 by injecting; (R) -2-hydroxy-2- (2-chlorophenyl) acetic acid was dissolved in an organic solvent, a reaction catalyst was added, and the compound of formula 4 obtained by refluxing and stirring was reacted with a sulfonate reaction reagent in the presence of a base. (R) -2-benzenesulfonyloxy-2- (2-chlorophenyl) acetic acid methyl ester; The hydrochloride salt of formula 3 was dissolved in an organic solvent, and then a base was added to the reaction mixture. The reaction mixture was reacted with formula 5 dissolved in dichloromethane. The reaction mixture was stirred to give (S) -2- (2-chlorophenyl) -2- (4, Preparing 5,6,7-tetrahydro-thieno- [3,2-c] pyridine) acetic acid methyl ester; (S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydro-thieno- [3] produced by dissolving the compound of formula 6 in an organic solvent and adding dilute sulfuric acid A process for preparing (S) -clopidogrel sulfate of formula (7) comprising the step 6 of freezing-drying a 2-, 2,2-c] pyridine) acetic acid methyl ester sulfate.

The method of claim 1, wherein the reaction in step 1 has a reaction temperature of -40 to 0 ^o C, the organic solvent used is a single or mixed solvent of anhydrous tetrahydrofuran, dioxane, and the base used is methyllithium, n Butyllithium, phenyllithium or amines are protected aziridine, and the catalyst used is dimethylaminopyridine or lithium perchlorinated process of (S) -clopidogrel sulfate. The method of claim 1, wherein the reaction in step 2 has a reaction temperature of 40 to 80 ^° C., and the solvent used is a single or mixed solvent of formarin aqueous solution, tetrahydrofuran, dioxane, water, and the catalyst used is concentrated sulfuric acid or Method for producing (S) -clopidogrel sulfate of formula 7 characterized in that the concentrated hydrochloric acid. The method of claim 1, wherein the reaction in step 3 is a reaction temperature of 0 to 40 ^o C, the organic solvent used is a single or mixed solvent of methanol, ethanol, the organic acid used is 3 to 6% formic acid, palladium The catalyst is a method for producing (S) -clopidogrel sulfate of formula 7 characterized in that used in 5 to 20%. The process of claim 1 wherein the reaction in step 4 has a reaction temperature of 0 to 100 ^° C., the organic solvent used is methanol and dichloromethane, the reaction catalyst is sulfuric acid, hydrochloric acid or 4-dimethylaminopyridine, and the base is tri Ethylamine, the sulfonate reaction reagent is chlorobenzenesulfonate, methanesulfonyl chloride or benzenesulfonyl chloride, characterized in that (S) -clopidogrel sulfate of the formula (7). The method of claim 1, wherein the reaction temperature in step 5 is 30 to 100 ^o C, the solvent used is dichloromethane and water, and the base is (ethyl) or potassium carbonate (S)- Method for preparing clopidogrel sulfate. The method of claim 1, wherein the reaction temperature in step 6 is from 0 to 30 ^o C, the solvent used is a single or mixed solvent of water, acetone, tetrahydrofuran, dioxane (S)- Method for preparing clopidogrel sulfate.