HU226038B1 - Process for the preparation of clopidrogel, new intermediate and process for preparing the same - Google Patents

Abstract

(2-Chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl)-acetonitrile is new. It is a valuable intermediate for ''CLOPIDOGREL'', a pharmaceutical compound used for prevention of blood-platelet aggregation and thrombosis.

Description

Scope of the description is 6 pages (including 1 page figure)

EN 226.038 Β1

The present invention relates to a novel pharmaceutical intermediate, to its preparation and to the conversion into a known pharmaceutical active ingredient.

More specifically, the present invention relates to the preparation of (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetonitrile and its salts of formula (I); Refers to the conversion of (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetic acid to methyl ester and its pharmaceutically acceptable acid addition salts.

It is known that S - (+) - (2-chloro-phenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetic acid of formula (IV) methyl ester hydrogen sulphate salt, platelet aggregation inhibiting and antithrombotic, clopidogrel is an international free-name pharmaceutical drug.

The compound of formula (IV) has been reported by the reaction of 4,5,6,7-tetrahydro-thieno [3,2-c] pyridine of formula (II) with the alpha-halophenylacetic acid derivative of formula (V) ( HU-187 111). The disadvantage of the process is that the compound of formula (V) is a heavily relieving and severely irritating substance to the mucosa, which is a health hazard. A further disadvantage of the process is the medium yield.

Another known process for the production of clopidogrel involves reacting the hydrochloride of the compound of formula (VI) with 2-chlorobenzaldehyde (VII) and alkali metal cyanide to convert the nitrile of formula (VIII) to an acid amide of formula (IX), esterifying the resulting acid amide. the resulting compound of formula (X) is then subjected to ring closure (WO 98/51682, WO 98/51681, WO 98/51689). The disadvantage of the process is that during the synthesis pathway two reactive centers - NH and acid function (nitrile, amide, ester) - can cause many side reactions. It is known from the literature that amino acid derivatives can easily acylate each other with the formation of 2,5-piperazindion derivatives [Bruckner Győző: Organic Chemistry, 1-2. Vol. 847-848. side; Schoolbook Publisher, Budapest, (1963); Dr. Lempert Károly: Organic Chemistry, page 709; Technical Publisher, Budapest, (1976)]. For example, for the corresponding (VIII), (IX) and (X) derivatives, a 2,5-piperazindione derivative can be expected.

A further disadvantage of the process is that the melting point of the open-chain derivatives is lower and thus more difficult to purify.

2- (2-Chlorophenyl) -2- (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) acetamide of formula (III) is a known compound (HU 187111). The acid amide of formula (III) is obtained by saponification of the ester of formula (IV) followed by amidation with alcoholic ammonia from the resulting free acid via mixed ester. According to HU 187 111, saponification can be carried out at a yield of 70%, and acid formation at 46%. The conversion of the acid amide (III) to the ester (IV) has not been described in the literature.

It is an object of the present invention to provide a process for the preparation of clopidogrel of formula (IV) in an industrial scale by eliminating the disadvantages of the known processes.

The above object is achieved by using a compound of formula (I) according to the present invention.

The present invention relates to (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) acetonitrile and its salts of formula (I).

The compound of formula (I) forms a salt with inorganic and organic acids. Examples of salt formation include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, malic acid, lactic acid, maleic acid, fumaric acid, malonic acid, and the like. applicable.

The compound of formula (I) has very good physical and chemical properties for use as an intermediate. This compound can be easily recrystallized from crystalline, environmentally friendly solvents (e.g., ethyl alcohol). The compound of formula (I) can be prepared in a very pure state.

It is another object of the present invention to provide a process for the preparation of (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) acetonitrile and its salts according to the invention. The 4,5,6,7-tetrahydro-thieno [3,2-c] pyridine or salt of formula II is reacted with 2-chlorobenzaldehyde (VII) and alkali metal cyanide and, if desired, the resulting compound of formula (I) is converted into a salt.

The compound of formula (II) is preferably used in the form of its hydrochloride. The alkali metal cyanide may be sodium cyanide or potassium cyanide, preferably sodium cyanide. During the reaction, the compound (II) or its salt, the 2-chlorobenzaldehyde and the alkali metal cyanide can be used in a molar ratio of 0.8 to 1.2, preferably in an equimolar ratio. The reaction can be carried out in a mixture of water and water-miscible alcohols 1-3. Preferred alcohols are, for example, methanol, ethanol, n-propanol, and the like. It can be used. The reaction medium is preferably a mixture of water and ethanol. The reaction can be carried out at a temperature of from 0 ° C to 150 ° C, preferably from 10 ° C to 80 ° C. The compound of formula (I) is preferably isolated from the reaction mixture by extraction with an organic solvent. Preferred extraction solvents are halogenated hydrocarbons (e.g., dichloroethane, dichloromethane, chloroform, etc.). The resulting compound of formula (I) may, if desired, be recrystallized, preferably from lower aliphatic alcohols, especially from ethanol.

The compound of formula (I) can be converted into salts with inorganic or organic acids by known methods.

The compound of formula (II) is known from the literature: DE 2059386; DE 1965710; Bull. Soc. Chim. Belg. 79: 415, 416 (1970); Ark. Ask for 32, 217, 223, 227 (1970/1974).

The present invention also provides a process for the preparation of (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) acetic acid methyl ester and its pharmaceutically acceptable salts. (2-chloro-phenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetonitrile of formula (I) (2) ( 2-Chlorophenyl) -2- (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetamide, followed by methanol III esterification of the compound of formula (III). and then converting the resulting base (IV), if desired, into a pharmaceutically acceptable salt.

EN 226.038 Β1

In the first step of the process, the nitrile of formula (I) is converted to the acid amide (III). The process is carried out in a dipolar aprotic solvent in the presence of a base and an oxidizing agent. The preferred oxidizing agent is hydrogen peroxide, sodium peroxide, especially hydrogen peroxide. Examples of dipolar aprotic solvents include dimethylsulfoxide, dimethylformamide, hexamethylphosphoric acid, acetonitrile, preferably dimethyl sulfoxide. Suitable bases include alkali metal hydroxides, ammonium hydroxide, alkali metal carbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, particularly potassium carbonate. The reaction can be carried out at 0-100 ° C, preferably 20-60 ° C. The reaction time is 0.5-2 hours. The product can be isolated by simple methods, for example by pouring the reaction mixture onto ice.

The resulting acid amide (III) is then converted to the compound of formula (IV) by acidification with methanol in an acid medium. The esterification is carried out in the presence of anhydrous acid, preferably in the presence of 100% sulfuric acid or chlorosulfonic acid, particularly preferably 100% sulfuric acid. The excess of methanol used as esterification agent also serves as a solvent. The reaction can be carried out under heating, preferably at the boiling point of the reaction mixture. In order to reduce the reaction time, the reaction is preferably carried out under pressure. The compound of formula (IV) can be isolated from the reaction mixture, preferably after pH adjustment, with an organic solvent extractor. Preferred extraction solvents are halogenated hydrocarbons (e.g., dichloromethane, dichloroethane, chloroform, etc.).

The resulting compound of formula (IV) can be converted into pharmaceutically acceptable acid addition salts in a known manner.

The present invention has the following advantages:

- high yield;

- pure product;

- simple implementation in industrial conditions;

- Eliminating health-damaging starting materials.

The following examples further illustrate the present invention without limiting the invention to the examples.

Example 1 (2-Chloro-phenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetonitrile g (0.085 mol) 4,5,6,7-tetrahydrothieno [3] To a suspension of 2-c] pyridine hydrochloride and 20 ml of distilled water at room temperature in a solution of 4.2 g (0.085 mol) of sodium cyanide in distilled water (20 ml) followed by 12.0 g (0.085 mol) of 2-chlorobenzaldehyde and 20 ml of water. a solution of ethanol was added. The temperature of the reaction mixture rose to 38-45 ° C. Upon completion of the addition, the reaction mixture was heated to 60 ° C and allowed to react at this temperature for 2-3 hours. The reaction mixture was then cooled to room temperature, distilled water (50 mL) and dichloromethane (30 mL) were added and shaken vigorously. The phases are separated. The aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic phases were washed with distilled water (2 x 30 mL) and then with 2% aqueous hydrochloric acid (20 mL). The dichloromethane solution was dried over magnesium sulfate and concentrated in vacuo. 23.1 g (0.080 mol) of the title compound are obtained in the form of a white crystalline solid, yielding 94%.

The product obtained is dissolved in ethanol under reflux, the solution is clarified with charcoal, filtered hot, and the filtrate is cooled. The product was filtered and washed with ethanol. 20.1 g (0.069 mol) of the title compound are obtained. Yield 81%.

Melting point: 127-129 ° C

Molecular Weight: 288.80 Formula: c ₁₅ h ₁₃ cin ₂ sec

IR (KBr): 3111, 2270, 1475, 732.

¹ H-NMR (CDCl ₃ , 400): 7.68 (m, 1H), 7.43 (m, 1H),

7.35 (m, 2H), 7.06 (d, J = 5.2 Hz, 1H), 6.69 (d,

J = 5.1 Hz, 1H), 5.30 (s, 1H), 3.78 (d, J = 13.8 Hz,

1H), 3.64 (d, J = 13.7 Hz, 1H), 2.97 (m, 2H), 2.92 (m,

1H), 2.83 (m, 1H).

¹³ C-NMR (CDCl 3, 400): 134.54, 132.84, 132.44,

130.77, 130.51, 130.44, 129.96, 126.78, 125.00,

123.06, 115.14, 59.18, 49.38, 47.73, 25.54.

NOÉ (CDCl3, I400): 5.30- (3.78, 3.64, 2.97),

3.78- (7.68, 6.69, 5.30, 3.64, 2.97).

HSQC (CDCl3, I400): 7.68-130.44, 7.43-130.51,

7.35- (130.77, 126.78), 7.06-123.06, 6.69-125.00,

5.30-59.18, (3.78, 3.64) -49.38, 2.97-47.73, (2.92,

2.83) -25.54.

HMCC (CDCl3, I400): 7.68-130.77, 7.43-126.78,

7.35- 130.44, 7.06- (132.84, 125.00), 6.69- (132.84,

132.44, 123.06), 5.30- (134.54, 130.44, 129.96,

115.14, 49.38, 47.73), (3.78, 3.64) - (132.44, 47.73),

2.97- (132.84, 25.54).

Example 2

2- (2-Chlorophenyl) -2- (6,7-dihydro-4H-thieno [3,2-c] pyridine-5-yl) -acetamide

11.52 g (39.8 moles) of (2-chloro-phenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetonitrile obtained in Example 1 80 Dissolve 0.8 g of potassium carbonate in 8 ml of dimethyl sulfoxide and 8 ml of water. The reaction mixture was cooled to ca. In 10 minutes, 8 ml of 30% hydrogen peroxide are added dropwise. The reaction mixture was allowed to warm to room temperature and then stirred at 50 ° C for 30 minutes, poured into ice-water (700 mL) and stirred cold for one hour. The mixture was filtered, washed with cold water and dried. The crude product obtained is recrystallized from isopropanol. Yield: 10.36 g (84.7%), mp 122-124 ° C. Molecular weight: 306.82 Molecular formula: Ci5H ₁₅ CIN ₂ OS

IR (KBr): 3182, 1658, 695.

^1H-NMR (CDCl3, i400): 7.50 (m, 1H), 7.43 (m, 1H);

7.27 (m, 2H), 7.13 (b, 1H), 7.07 (d, J = 5.1 Hz, 1H),

6.67 (d, J = 5.1 Hz, 1H), 6.06 (b, 1H), 7.91 (s, 1H),

3.66 (d, J = 14.3 Hz, 1H), 3.58 (d, J = 14.3 Hz, 1H),

2.90 (m, 4H).

EN 226.038 Β1

C-NMR _(CDCl3, i400): 173.69, 135.35, 13.45, 133.06, 133.03, 130.31, 130.01, 129.42, 126.99, 125.20, 123.00, 69.15, 50.81.49.13, 25.86.

Example 3 (2-Chloro-phenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetic acid methyl ester hydrochloride

After stirring 32.8 ml of anhydrous methanol and 7.2 ml of 100% sulfuric acid, the solution was refluxed for one hour and then cooled to room temperature. 9.2 g (30 mmol) of 2- (2-chlorophenyl) 2- (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) prepared according to Example 2 are obtained. acetamide and reflux for 80-120 hours. After completion of the reaction, methanol was distilled off in vacuo, and dichloromethane (90 ml) was added and the pH was adjusted to 7 with 10% sodium hydroxide under vigorous stirring and cooling. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic phases are washed with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. 7.2 g of methyl 2-chlorophenyl (6,7-dihydro-4H-thieno (3,2-c) pyridin-5-yl) acetic acid are obtained. Yield 74%.

To 7.2 g of the above base was added 20 ml of acetone and 1.82 ml

Hydrochloric acid (37%) was added. The mixture is left to stand in a refrigerator overnight. The crystals were filtered, washed with cold acetone and dried. 7.4 g (66%) of the title compound are obtained, m.p.

Molecular weight: 358.29 Molecular formula: Ci5H ₁₅ CIN ₂ OS

IR (KBr): 2800-2000 (HCl), 1753 (C = O), 760 (Cl) cm ^-1 . 1 H-NMR (DMSO-d ₆ + D ₂ O, δ, 400): 7.72 (dd, J = 1.8,

7.5 Hz, 1H), 7.68 (dd, J = 1.4, 7.9 Hz, 1H), 7.61-7.51 (m, 2H), 7.44 (d, J = 5 , 2 Hz, 1H), 6.88 (d, J = 5.2 Hz, 1H), 5.66 (s, 1H), 4.30, 4.20 (d, J = 14.8 Hz, 2H ), 3.77 (s, 3H), 3.74-3.45 (m, 2H), 3.11 (m, 2H) ppm.

C-NMR (DMSO-d6, etc., g200): 167.9, 134.3, 131.9, 131.8, 130.6, 130.5, 129.4, 128.3, 125.6, 124 , 7, 65.9, 55.0, 53.4, 50.3, 48.7, 22.8 ppm.

Claims (11)

PATENT CLAIMS 1. (2-Chloro-phenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetonitrile and its salts. Process for the preparation of (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetonitrile and its salts according to claim 1, characterized in that: reacting the 4,5,6,7-tetrahydrothieno [3,2-c] pyridine of formula (II) or a salt thereof with 2-chlorobenzaldehyde of formula (VII) and an alkali metal cyanide and optionally obtaining the resulting compound of formula (I): compound is converted to a salt. 3. The process according to claim 2, wherein the hydrochloride of the compound of formula II is used. Process according to claim 2 or 3, characterized in that the alkali metal cyanide is sodium cyanide or potassium cyanide. 5. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out in a mixture of water and C 1-3 alcohols. 6. A process according to claim 5, wherein the alcohol is preferably ethanol. 7. A process according to any one of claims 1 to 4, wherein the compound of formula (II) or its salt, the 2-chlorobenzaldehyde and the alkali metal cyanide are 0.8-1.2: 0.8-1.2: 0.8-1 In a molar ratio of 2, preferably 1: 1: 1. A process for the preparation of (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetic acid methyl ester of formula IV and pharmaceutically acceptable salts thereof. characterized in that the (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) acetonitrile of formula (I) is represented by the 2- (2-chlorophenyl) -chlorophenyl) -2- (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetamide and the resulting compound (III) is converted to the compound (IV) by esterification with methanol, then converting the resulting base of formula (IV) to a pharmaceutically acceptable salt, if desired. 9. The process according to claim 8, wherein the nitrile of formula I is converted to the compound of formula III by reaction with a base and an oxidizing agent, preferably hydrogen peroxide, in a dipolar aprotic solvent. The process according to claim 9, wherein the dipolar aprotic solvent is dimethyl sulfoxide. 11. The process according to claim 8, wherein the compound of formula (III) is converted into the compound of formula (IV) by reaction with methanol in the presence of anhydrous inorganic acid, preferably sulfuric acid.