CS227020B2 - Method of preparing 5,6,7,7a-tetrahydro-4h-thiano (3,2-c) pyridin -2-one derivatives - Google Patents

Abstract

Process for the preparation of derivatives of formula: <IMAGE> in which R denotes hydrogen or a phenyl radical optionally substituted by at least one halogen atom or a lower alkyl, lower alkoxy, nitro, carboxy, alkoxycarbonyl or cyano group; R' denotes hydrogen or a lower alkyl group, and n is zero or an integer from 1 to 4 and their addition salts with inorganic or organic acids, the process being characterised in that: a) a compound of formula II: <IMAGE> in which R, R' and n are as defined above, in solution in a mixture of acetic acid and hydrobromic acid is treated with a solution of aqueous hydrogen peroxide; b) the bromo derivative obtained at the outcome of stage a) and having the formula III: <IMAGE> is converted into an organomagnesium derivative in an anhydrous inert solvent and the organomagnesium derivative obtained is then condensed with t-butyl perbenzoate to obtain the compound of formula IV: <IMAGE> c) the compound of formula IV obtained above is converted into a compound of formula I by heating to temperatures of between 80 and 180 DEG C in the presence of an inorganic or organic acid.

Description

The present invention relates to a novel process for the preparation of 5,6,7,7a-tetriahydro-4H-thieno (3,2-c) pyridin-2-one derivatives of the general formula (I) disclosed in French Patent Specifications No. 2,215,948 and 2,345,150, in the form of its tautomeric form

where

R is a phenyl radical optionally substituted by a halogen atom, a (C1-C4) alkyl group, a nitro group or a cyano group, and

R ¹ represents hydrogen or a C 1 -C 4 alkyl group, as well as their addition salts with mineral or organic acids.

A process for the preparation of these compounds, which exhibits platelet aggregation inhibiting properties and antithrombotic properties, is the subject of U.S. Pat. No. 224,634 (PV 8683-81).

These compounds are also included in

However, none of these compounds has been explicitly described to date.

From a treatise published in J. Am. Chem. Soc., Vol. 72, December 1950, pp. 5543-5546, a process for preparing 2-thienol from 2-bromothiophene via a magnesium intermediate is already known. In this process, the magnesium derivative is converted into an alcohol by oxidation with oxygen in the presence of isopropylmagnesium bromide in the magnesium derivative solution to prevent the formation of undesirable by-products.

The invention therefore relates to a process for the preparation of the compounds of the above general formula (I), which process comprises:

a) to a compound of formula II

where

R and R ¹ are as defined above, dissolved in acetic acid with hydrobromic acid with a solution of hydrogen peroxide,

(b) the brominated derivative formed

where

R and R &lt; ¹ & gt ^; are as defined above, converted into an organomagnesium compound of the formula EMI2.0 in an anhydrous inert solvent by treatment with magnesium metal and an alkyl halide

R and R ¹ have the abovementioned meaning and

X represents a halogen atom which condenses with tert-butyl perbenzoate, and

c) the resulting compound of formula IV

where

R @ ¹ and R @ ¹ as defined above are converted to a compound of formula I by heating at a temperature in the range of 80-180 ° C in the presence of a mineral or organic acid, whereupon the resulting compound of formula I is optionally converted an acid addition salt.

The process according to the invention thus makes it possible to prevent the oxidation of the magnesium intermediate product with oxygen as described in the prior art.

The acetic acid / hydrobromic acid mixture preferably has a composition in the range of 50:50 to 80:20.

The hydrobromic acid used in step a) of the process of the invention is preferably 48% acid and the acetic acid used is preferably pure.

The hydrogen peroxide is used in the form of an aqueous alcoholic solution, for example a 30% methanolic hydrogen peroxide solution.

In step b) of the process according to the invention, an inert solvent such as tetrahydrofuran is used, both in the preparation of the organomagnesium compound and in the subsequent condensation of the obtained magnesium compound with tert-butyl perbenzoate.

The organomagnesium compound is prepared in a conventional manner, for example from magnesium metal and an alkyl halide such as isopropyl bromide, in an anhydrous medium.

The magnesium compound is not isolated from the reaction medium prior to its condensation with tert-butyl perbenzoate.

In step c) of the process according to the invention, a mineral or organic acid, for example p-toluenesulfonic acid, is added.

The process of the invention is illustrated by the following reaction scheme:

Н ^ НВг

1) MH + 2) C ₅ H ₅ COO-O-tert Ofy

The starting compounds of the general formula (II) are obtained by methods described in the literature, for example those described in the two French patents 2 215 948 and 2 345 150.

The following examples illustrate the invention.

Example 1

5- (2-chlorobenzyl) -5,6,7,7a-tetrahydrothieno (3,2-c) pyridin-2-one of formula I wherein R is 2-C _1-6 C ₄ and R ¹ is hydrogen Compound No. 1.

To a solution of 2.63 g of 5- (2-chlorobenzyl) -4,5,6,7-tetrahydrothieno (3,2-c) pyridine in 10 ml of acetic acid and 6 ml of 48% hydrobromic acid, cooled to 0 ° C , a mixture of 30% hydrogen peroxide and methanol (3 ml / 10 ml) was added dropwise.

After the addition was complete, the reaction mixture was stirred at room temperature for 10 minutes, then sodium bisulfite solution was added, followed by sodium hydroxide solution, and the mixture was extracted with a mixture of benzene and chloroform. The combined organic extracts were washed with water, dried over sodium sulfate and filtered. Methanolic HCl gas solution was added to the filtrate and the mixture was concentrated under reduced pressure. Recrystallization of the solid residue from ethanol yields two grams of beige-colored crystals of 2-bromo-5- (2-chlorobenzyl) -4,5,6,7-tetrahydro-thieno (3,2-c) pyridine hydrochloride with a decomposition temperature of approximately Mp 180 ° C.

A mixture of the resulting free base (1.075 g), magnesium (0.19 g), isopropyl bromide (0.57 g) and anhydrous tetrahydrofuran (10 mL) was heated under reflux for 2 hours. After cooling, 1.5 g of tert-butyl perbenzoate are added and the mixture is stirred for 15 hours at room temperature, then for 1 hour at reflux. The reaction mixture was then poured into an aqueous solution of sodium citrate and sodium hydroxide and extracted with benzene. The organic extracts were washed with water, dried over sodium sulfate and concentrated under reduced pressure. The oily residue was purified by chromatography on a silica column to give 0.25 g of a yellow oil.

100 mg of this liquid is heated with 100 mg of p-toluenesulfonic acid 9 minutes at 150 DEG C. ^q After rapid cooling, the reaction medium is poured into a buffer solution consisting of a mixture of 0.15 M phosphate buffer (pH 5.5) with butanol (20ml / 20 ml). The organic phase is decanted under reduced pressure. Purification of the residue by silica gel column chromatography affords 5- (2-chlorobenzyl) -5,6,7,7a-tetnahydro-4H-thieno- (3,2-c) pyridin-2-one, m.p. to 74.5 ° C (after recrystallization from ethanol).

Oxallan ¹ : mp 168-170 degrees Celsius (from ethanol);

IR (KBr): dCO = 1660 cm &^lt; -1 & gt ^; (wide)

Hydrochloride polohydrate: decomposition temperature about 180 ° C (precipitation from acetone)

Free base: melting point 73-60 ° C

74.5 ^Q C (from ethanol)

NMR Spectrum (CDCl3):

7.1-7.6 (m. 4H);

6.2 (s, 1H).

4.2-4.7 (m, 1H),

3.9 (s, 2H).

1.5-4.2 (m, 6H).

Example 2

5-benzyl-, (5 ₎ 6,7,7a-tetrahydro-4H-thieno (3,2-c) pyridin-2-one of formula I wherein R is phenyl, R ¹ is hydrogen; Compound No. 2.

The title compound is obtained from

5-Benzyl-4,5,6,7-tetrahydrothieno (3,2-c) pyridine according to the procedure of Example 1.

Maleate: beige-colored crystals melting at 132 to 134 ^Q C (from isopropanol)

IR (KBr): in CO: 1680 cm ^-1

Free policy:

NMR (CDC1 _3):

7.25 (m, 5H).

5.90 (s, 1H),

3.60 (s, 2 H).

Example 3

5- (4-chlorobenzyl) -5,6,7,7a-tetrahydro-4H-thieno (3,2-c) pyridin-2-one of formula I, wherein R represents 4-Cl-C ₆ H ₄ and R ¹ is hydrogen; Compound No. 3.

The title compound was prepared from 5- (4-chlorobenzyl) -4,5,6,7-tetrahydro-thieno (3,2-c (pyridine by the procedure of this example).

1.

Maleic: beige colored crystals, m.p. 158-160 ° C (from ethanol).

IR spectrum (KBr): ν CO = 1680 cm ^-1

Free policy:

NMR Spectrum (CDCl3):

7.30 (m, 4H).

6.0 (s, 1H);

3.50 (s, 2 H).

Example 4

5- (2-methylbenzyl) -5,6,7,7a-tetrahydro-4H-thieno (3,2-c) pyridin-2-one of formula (I) wherein R is 2-N-Z-N ₄ -, R ¹ is hydrogen; Compound No. 4.

The title compound is prepared from 5- (2-methylbenzyl) -4,5,6,7-tetrahydrothieno (3,2-c) pyridine according to the method of Example

1.

Melting point: 195 to 197 ° C (from methanol)

IR spectrum (KBr): ν CO = 1690 cm ^-1

Free policy:

NMR (CDC1 _3):

7.10 (s, 4H).

5.90 (s, 1H),

3.55 (s, 2H).

2.30 (s, 3 H).

Example 5

5- (1- (2-chlorophenyl) ethyl) -5,6,7,7a-tetrahydro-4H-thieno (3,2-c) pyridin-2-one of formula I wherein R is 2- Cl-C ₆ H ₄ -, R ^{1 is} known to methyl &; compound no. 5.

The title compound is obtained from 5- (1- (2-chlorophenyl) ethyl) -4,5,6,7-tetrahydrothieno (3,2-c) pyridine according to the procedure of Example 1.

Hydrochloride: yellow crystals, m.p. 140-142 ° C

IR spectrum (KBr): ν CO = 1690 cm ^-1

Free policy:

NMR (CDC1 _3):

7.30 (m, 4H).

6.05 and 5.95 (2s, 1H), (2 diastereoisomers).

Example

5- (1- (2-Chloro-phenyl) -propyl] -5,6,7,7a-tetr ahydro-4H-thieno (3,2-c) pyridin-2-one of Formula I wherein R is Group 2 -S 1 -Se ₄ , R ¹ is ethyl; Compound No. 6.

The title compound is obtained from 5- [1- _; (2-chlorophenyl) propyl] -4,5,6,7-tetrahydrothieno (3,2-c) pyridine according to the procedure of Example 1.

Hydrochloride: beige colored crystals, m.p. 124-126 ° C.

IR spectrum (KBr): ν CO = 1690 cm ^-1

Free Basis:

NMR (CDC1 _3):

7.30 (m, 4H).

6.05 and 5.90 (2s, 1H), (2-dlastereoisomers).

Example 7

5- (2-kyan.obenzyl) -5,6,7,7a-tetrahydro-4H-thieno (3,2-c) pyridin-2-one of formula I, wherein R = _2-CN-4 CBH - R ¹ is hydrogen; Compound No. 7.

Oxalate: beige-colored crystals of tep227020

The title compound was prepared according to the procedure of Example 1, starting from 5- (2-cyanobenzyl) -4,5,6,7-tetrahydrothieno (3,2-c) pyridine.

Oxalate: beige colored crystals, m.p. 176-178 ° C (from acetonitrile)

IR spectrum (KBr): λ CO = 1700 cm ^-1 , ν CN = 2210 cm ⁴

Free policy:

NMR (CDC1 _3):

7.50 (m, 4H).

6.00 (s, 1 H),

3.80 (s, 2 H).

Example 8

5- (2-nitrobenzyl) -5,6,7,7a-tetrahydro-4H-thieno (3,2-c) pyridin-2-one of formula I wherein R is 2-NO 2 -C ₆ H ₄ - R ¹ is hydrogen; Compound No. 8.

The title compound was prepared according to the procedure of Example 1 from 5- (2-nitro-phenyl) -4,5,6,7-tetrahydro-thieno (3,2-c) pyridine.

Oxalate: beige colored crystals, m.p. 186-188 ° C (from isopropanol / ethanol)

Free policy:

NMR (CDC1 _3):

7.50 (m, 4H).

5.95 (s, 1 H),

3.90 (s, 2 H).

Example 9

5- (2-bromobenzyl) -5,6,7,7a-tetrahydro-4H-thieno (3,2-c) pyridin-2-one of formula I wherein R is 2-Br-C ₆ H ₄ - R ^J is hydrogen; Compound No. 9.

The title compound was prepared according to the procedure for EXAMPLE 1, starting from 5- (2-bromobenzyl) -4,5,6,7-tetrahydrothieno (3,2-c) pyridine.

Oxalate: beige-colored crystals, m.p. 151-153 ° C (from isopropanol)

IR spectrum (KBr): δ CO - 1690 cm ^-1

Free policy:

NMR (CDC1 _3):

7.30 (m, 4H).

5.95 (s, 1 H),

3.75 (s, 2 H).

Proton NMR spectra were obtained with a Hitachi-Perkin-Elmer R-24 A instrument, chemical shifts are expressed in ppm, based on TMS as an internal standard.

IR spectrum: v CO = 1685 cm ¹

Claims (7)

SUBJECT OF THE INVENTION A process for the preparation of 5,6,7,7a-tetrahydro-4H-thleno (3,2-c) pyridin-2-one derivatives of formula (I) wherein: R is a phenyl radical optionally substituted by a halogen atom, a (C1-C4) alkyl group, a nitro group or a cyano group, and R ¹ represents hydrogen UEBO alkyl having 1 to 4 carbon atoms, and their addition salts with mineral or organic acids, characterized in that a compound of formula II R ¹ and R ¹ , as defined above, dissolved in a mixture of acetic acid and hydrobromic acid, are treated with a hydrogen peroxide solution to form a brominated derivative of the general formula III wherein: R ^{1 and} R ¹ are as defined above, are converted into an organomagnesium compound of the general formula in an anhydrous inert solvent by the action of magnesium metal and an alkyl halide R and R ¹ have the abovementioned meaning and X represents a halogen atom which is condensed with tert-butyl perbenzoate, and the resulting compound of formula IV wherein R @ ¹ and R @ ¹ as defined above are converted to a compound of formula I by heating at a temperature in the range of 80 to 180 degrees Celsius in the presence of a mineral or organic acid, followed by optionally converting the resulting compound of formula I with a pharmaceutically acceptable mineral or organic acid. its acid addition salt. 2. A process according to claim 1, wherein an aqueous-alcoholic hydrogen peroxide solution is used, for example a 30% methanolic hydrogen peroxide solution. 3. The process according to claim 1, wherein a mixture of acetic acid and hydrobromic acid in a ratio of 50:50 to 80:20 is used. 4. A process according to any one of claims 1 to 3, wherein anhydrous tetrahydrofuran is used as the inert solvent in the conversion of the brominated compound of formula III into an organomagnesium compound. 5. A process according to any one of claims 1 to 4, wherein the conversion of the brominated compound of formula III to an origano-magnesium derivative is carried out by treatment with magnesium metal and an alkyl halide, preferably isopropyl bromide, in an anhydrous medium. 6. The process of claims 1 to 5, wherein the condensation reaction of the organomagnesium compound with tert-butyl perbenzoate is carried out in the same reaction vessel used to prepare the organomagnesium compound without isolating the organomagnesium compound. 7. A process according to any one of claims 1 to 6, wherein the acid is p-toluenesulfonic acid used in the conversion of the compound of formula IV by heating to the compound of formula I.