DD202162A5 - PROCESS FOR PREPARING DERIVATIVES OF TETRAHYDRO-5,6-7,7A 4H-THIENO (3,2-C) PYRIDINONE- (2) - Google Patents

Abstract

The present invention relates to a process for the preparation of derivatives of the tetrahydro-5,6,7,7a-4H-thieno (3,2-c) pyridone-2-one of the formula I in which R is hydrogen or an optionally substituted by at least a halogen atom represents substituted phenyl radical or a lower alkyl group, lower alkoxy group, nitro, carboxy, alkoxycarbonyl or cyano group; R 'is hydrogen, a lower alkyl group and n is zero or an integer from 1 to 4, and their addition salts with inorganic or organic acids, characterized in that a) a compound of the following formula II in which R, R' and n are as defined above, is treated in solution in an acetic / hydrobromic acid mixture with a hydrogen peroxide solution; b) the brominated derivative obtained at the end of stage a) is converted into an organomagnesium compound with the following formula III in a dry anhydrous solvent; then the recovered magnesium compound is condensed with t-butyl perbenzoate to obtain the compound of the following formula IV and c) the above-obtained compound of formula IV in a compound of formula I by heating at temperatures between 80 and 180 degrees C in the presence of an inorganic or organic acid is converted.

Description

18/6/82

235204 0 ~ ^ή ~ ^Ap CO7D / 235 204/0

60 020 11

Process for the preparation of derivatives of tetrahydro-5,6,7,7a 4H-thieno (3,2-c) pyridinone- (2)

Field of application of the invention

The present invention relates to a novel process for the preparation of tetrahydro-5,6,7,7a-4H-thieno (3,2-c) pyridinone- (2) of the formula:

(CHR ') _n - R (I)

R represents hydrogen or a phenyl radical optionally substituted by at least one halogen atom, or a lower alkyl group, lower alkoxy group, nitro, carboxy, alkoxycarbonyl or cyano group; R * represents hydrogen, a lower alkyl group; and η is zero or an integer from 1 to 4, and their addition salts with the inorganic or organic acids.

Characteristic of the known technical solutions

These compounds, which have platelet aggregation inhibiting and antithrombotic properties, are the subject of another patent application filed by the Applicant. They are further included in a general formula disclosed in FR-PS Hr. 7,303,503 and No. 7,524,486 are claimed in their following tautomeric form

(CHRM _n - R

2 3 5 2 O L O - ² - * f ° ^11/39

Id, d "o2

However, none of these products is specifically described.

The article in J. Am. Chem. Soc., Vol. 72, December 1950, pp. 5543-5546, discloses a method of preparing thienol (2) from bromo-2-thiophene via a magnesium compound. In this process, the lithium compound is converted to alcohol by oxidation with the aid of oxygen in the presence of isopropyl magnesium bromide in the magnesium-containing compound solution to avoid the formation of undesirable by-products.

Object of the invention

The aim of the invention is to provide an improved, in particular simple and economical process for the preparation of derivatives of tetrahydro-5,6,7,7a 4H-thieno (3,2-c) pyridinone- (2) in high purity and without unwanted by-products ,

Explanation of the essence of the invention

The invention has for its object to find suitable starting materials and simple Hektionsschritte.

The present invention thus includes a process for the preparation of the compounds of formula I described above, characterized in that a) a compound of the following formula II

N- (CHR ') _n H

/. IUU Jn

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in which R, R 'and η are as defined above, in solution in an acetic acid / hydrobromic acid mixture, treated with a hydrogen peroxide solution;

b) that the brominated derivative obtained at the end of stage a) has the following formula III:

N- (CHR *) * R (III),

I i

Il I I

Br.

converted into an organomagnesium compound in an anhydrous solvent; then the recovered magnesium compound is condensed with t-butyl perbenzoate to give the compound of the following formula IV

CH ₃

to get and that

c) the above-obtained compound of formula IV is converted by heating at temperatures between 80 and 180 ⁰ C in the presence of an inorganic or organic acid in a compound of formula I.

Thus, by the method of the present invention, it is possible to avoid oxidation of the magnesium intermediate by oxygen described in the prior art.

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The acetic acid / hydrobromic acid mixture is preferably within the limits of 50/50 to 80/20,

The hydrobromic acid used in stage a) is preferably 48% acid and the acetic acid is preferably pure. The hydrogen peroxide is used in the form of an aqueous alcoholic solution, for example a 30% hydrogen peroxide methanol solution.

In the course of stage b) an inert solvent such as tetrahydrofuran is used simultaneously for the preparation of the organomagnesium compound and for later condensation of the magnesium compound obtained with t-butyl perbenzoate. The Organomagnesiumderivat is in a conventional manner, for. B. with the aid of metallic magnesium and an alkyl halide such as isopropyl bromide prepared in anhydrous medium The magnesium compound is not isolated from the medium before its condensation with the t-butyl perbenzoate »

During stage c), an inorganic or organic acid, e.g. For example, p-toluenesulfonic acid added.

The process according to the invention is represented by the following reaction scheme:

Q /. IUH 4QQ <) * fH

235204 0

60 020 11/39 18.6.82

A.D

H ₂ 0 ₂ / HBr

(III)

(I)

H"

CH ₃ -CO

N- (CHRO _n R

(IV)

1) Mg

2) C ₆ H ₅ COOH C ₄ H ₉

N- (CHR ") _n R

(V)

The starting materials of formula (II) were prepared by methods described in the literature, e.g. Example, according to the method described in the already mentioned FR-PS 7 303 503 and FR-PS 7 524 486 ·

exemplary

The following examples illustrate the invention.

example 1

(Chloro-2-benzyl) -5-tetrahydro-5,6,7,7a-4H-thieno (3,2-c) pyridinone- (2), of formula (I) (R = 2-Cl-CgH; R '= H; η = 1) derivative no. 1

A mixture of 30% hydrogen peroxide and methanol (3 cnr / 10 cnr) of a cooled to 0 ⁰ C solution of 2.63 g (chloro-2-benzyl) -5-tetrahydro-4,5,6,7 thieno is added dropwise (3,2-c) pyridine in 10 cc acetic acid and 6 cnr 40% hydrobromic acid added.

After the addition is complete, stir at ambient temperature for 10 minutes, add a sodium hydrosulfite solution, then add a soda solution and mix with a benzene-chloroform mixture

2 3 5 2 U 4 U 18.6.82

extracted. The organic extracts are washed with water, dried over sodium sulfate and filtered off. A solution of hydrogen chloride in methanol is added to the filtrate and concentrated in vacuo. Recrystallization of the solid residue in ethanol affords 2.0 g of flat-beige crystals of bromo-2- (cis-1-loro-2-benzyl) -5-tetrahydro-4,5,6,7-thieno (3,2-c) pyridine chlorohydrate (P: decomposition at 180 ^° C.).

A mixture of a free base (1.075 g), magnesium (0.19 g), isopropyl bromide (0.57 g) and anhydrous tetrahydrofuran (10 cm) is refluxed for 2 hours under a nitrogen atmosphere. After cooling, 1.5 g of tertiobutyl perbenzoate are added, it is stirred for 15 hours at ambient temperature, then refluxed for one hour. The whole is poured onto an aqueous solution of sodium citrate and soda and extracted with benzene. The organic extracts are washed with water, dried over sodium sulfate and concentrated under reduced pressure. The oily residue is purified by chromatography over a silica column. There are obtained 0.25 g of a yellow oil. 100 mg of this substance and ίήό mg paratoluene sulfonic acid are heated for 9 min at 150 ⁰ C. After rapid cooling, the medium is poured onto a buffer mixture of phosphate 0.15 M (pH 5 »5) butyl alcohol (20 cm- ³ /20 cnr). The organic phase is decanted under reduced pressure. Chromatographic purification of the residue over the silica column results in (chloro-2-benzyl) -5-tetrahydro-5,6,7,7a 4H-thieno (3,2-c) pyridinone- (2). P = 73-74.5 ⁰ C (ethanol).

oxalate; P = 168-170 ⁰ C (ethanol); IR (KBr): ^ CO * 1660 cm " ¹ (wide)

Chlorhydrate, hemihydrate: P = decomposition at 180 ^° C. (precipitation in acetone)

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Base; F = 73-74.5 ⁰ G (ethanol), RMN (CDCl ₃ ); 7.1-7.6 (m, 4H); 6.2 (s, 1H); 4.3-4.7 (m, 1H); 3.9 (s, 2H); 1.5 4.2 (m, 6H).

Example 2

Benzyl-5-tetrahydro-5,6,7,7a 4H-thieno (3,2-c) pyridinone- (2) of the formula (I) (R = CgH ₅ ; R "= H; η = 1) derivative no. 2 Eb is prepared according to the procedure of Example 1 starting from benzyl-5-tetrahydro-4,5,6,7-thieno (3,2-c) pyridine.

maleate; Beige colored crystals, m.p. = 132-134 ⁰ C (isopropanol) IR (KBr): CO: I68O cm ^"1

Bases RMN _(CDCl3): 7.5 (m, 5H); 5.90 (s, 1H); 3.60 (s, 2H).

Example 3

(Chloro-4-benzyl) -5-tetrahydro-5,6,7,7a-4H-thieno (3,2-c) pyridonone- (2) - of formula (I) (R = 4-Cl-CgH ₄ ; = H; η = 1) derivative no. 3

It is prepared according to the procedure of Example 1 starting from (chloro-4-benzyl) -5-tetrahydro-4,5,6,7 thieno (3,2-c) pyridine.

Maleate: Beige crystals, F = 158 - I60 ⁰ C (ethanol) IR (KBr) s Jf CO = 1680 cm ^-1

Base; RMN _(CDCl3): 7.30 (m, 4H); 6.0 (s, 1H); 3.50 (s, 2H).

Example 4

(Methyl-2-benzyl) -5-tetrahydro-5,6,7,7a-4H-thieno (3,2-c) pyridinone- (2) of the formula (I) (R = 2-CH ₃ -C ₆ H ₄ - R ^f = H; η = 1) derivative no. 4

It is prepared according to the procedure of Example 1 starting from (methyl-2-benzyl) -5-tetrahydro-4,5,6,7 thieno (3,2-c) pyridine.

IUM

235204 0 - ° - £ Γ «

oxalate; Beige crystals; F = 195-197 ⁰ C (methanol) IR (KBr): f = CO I69O cm "" ¹

Base: RMN _(CDCl3): 7.10 (s, 4H); 5.90 (s, 1H); 3.55 (s, 2H) 2.30 (b, 3H).

Example 5

/ TChloro 2-phenyl) -1 ethyl7-5 tetrahydro-5,6,7,7a 4H-thieno (3,2-o () pyridinone (2) of the formula I) (R = 2-Cl C ₆ H ₄ R ^ = CH ₃ ; η = 1) derivative no. 5

It is prepared according to the procedure of Example 1 starting from / TChloro-2 phenyl) -1 ethyl7-5> tetrahydro-4,5,6,7 thieno (3,2-c) pyrodine

hydrochloride; Yellow crystals, P = 14Ο - 142 ⁰ C, IR (KBr):

· { CO = 1690 cm " ¹

Base: RMN _(CDCl3): 7.30 (m, 4H); 6.05 and 5.95 (2s, 1H) (2 diastereoisomers) ^:

Example 6

/ TChlor-2-phenyl) -1-propyl-7-5-tetrahydro-5,6,7,7a-4H-thieno (3,2-c) pyridinone- (2) of the formula (I), (R = 2-Cl-C ₆ H ₄ ; R "= C ₂ Hc; η = 1) derivative no. 6

It is prepared according to the procedure of Example 1 starting from / TChloro-2 phenyl) -1 propyl 7-5 tetrahydro-4,5,6,7 thieno (3,2-c) pyridine,

hydrochloride; Beige crystals, P = 124 - 126 ⁰ C IR (KBr): ^ CO = 1690 cm " ¹

Base: RMN _(CDCl3): 7.30 (m, 4H); 6.05 and 5.90 (2s, 1H) (2 diastereoisomers)

Example 7

(Cyano-2-benzyl) -5-tetrahydro-5,6,7,7a 4H-thieno (3,2-c) pyridonone- (2) of the formula (I), (R = 2-CN-C ₆ H ₄ ; R »* H, η = 1) derivative no. 1

_ - 9 - 60 020 11/39

235 20 4 0 ¹⁸ · ⁶ · ⁸²

It is prepared according to the procedure of Example 1 starting from (cyano-2-benzyl) -5-tetrahydro-4,5,6,7 thieno (3,2-c) pyridine.

oxalate; Beige colored crystals, m.p. = 176-178 ⁰ C (Acetoniktril) IR (KBr): ^ CO: 1700 cm ^"1; ^ CN 2210 cm" ¹ base; RMN _(CDCl3): 7.50 (m, 4H); 6.00 (s, 1H); 3.80 (s, 2H)

Example 8

(JSTitro-2-benzyl) -5-tetrahydro-5,6,7,7a-4H-thieno (3,2-c) pyridinone- (2) of the formula (I) (R = 2 -NO ₃ -C ₆ H ₄ ; R · = H; η = 1) derivative Nr, 8

It is prepared according to the procedure of Example 1, starting from (nitro-2-benzyl) -5-tetrahydro-4,5,6,7 thieno (3,2-c) pyridine.

Oxalate: beige crystals; F = 186-188 ⁰ C (isopropanol-ethanol) RI: ^ CO = 1685 cm ^"1 Base: RM _(CDCl3): 7.50 (m, 4H), 5.95 (s, 1H), 3.90 (s, 2H).

Example 9

(Bromo-2-benzyl) -5-tetrahydro-5,6,7,7a 4H-thieno (3,2-c) pyridonone- (2) of formula (I) (R = 2-Br-CgH; R * = H; η = 1) derivative No ₀ 9

It is prepared according to the procedure of Example 1 starting from (bromo-2-benzyl) -5-tetrahydro-4,5,6,7 thieno (3,2-c) pyridine.

oxalate; Beige colored crystals, m.p. = 151-153 ⁰ C (isopropanol) IR (KBr) j tf CO = 1690 cm "" ¹

Baset _(CDCl3): 7.30 (m, 4H); 5.95 (s, 1H); 3.75 (s, 2H).

The RMN spectra of the proton were realized on the Hitachi-Perkin-Elmer R-24A instrument, the chemical shifts are expressed in ppm compared to TMS as an internal reference.

Claims (7)

2OCOH / A - ¹⁰ ~ ^6o ° ^{20 11/39} J D L U K U 18.6.82 Erfindungsansρruch 1. A process for the preparation of the derivatives of tetrahydro-5,6,7,7a 4H-thieno (3,2-c) pyrodinone- (2) of the formula (CHR) _n - R R represents hydrogen or a phenyl radical optionally substituted by at least one halogen atom, or a lower alkyl group, lower alkoxy group, nitro, carboxy, alkoxycarbonyl or cyano group; R ^{1 is} hydrogen, a lower alkyl group and η is zero or an integer from 1 to 4, and their addition salts with the inorganic or organic acids, characterized in that a) a compound of the following formula II (CHRM _n - R in which R, R ¹ and η are as defined above, in solution in an acetic acid / hydrobromic acid mixture is treated with a hydrogen peroxide solution; b) that the obtained at the end of stage a) brominated derivative having the following formula III (CHR · V - R Br ^ - VS / ^ "" (III) t \% mn 20 a 0 - "- 60 020 11/39 18/6/82 in a sluggish, anhydrous solvent in one
Organomagnesium compound is converted
then the recovered magnesium compound is condensed with t-butyl perbenzoate to obtain the compound of the following formula IV (CHRM _n - R c) the above-obtained compound of formula IV in a
Compound of formula I is converted by heating at temperatures between 80 and 180 ⁰ C in the presence of an inorganic or organic acid. Method according to item 1, characterized in that the hydrogen peroxide solution is an aqueous alcoholic
Solution, z. B. is a 30% hydrogen peroxide methanol solution. 3. The method according to any one of the preceding points, characterized in that the acetic acid / hydrobromic acid mixture in the limits between 50/50 to 80/20. 4. Method according to one of the preceding points, characterized in that the inert solvent used in stage b) is anhydrous tetrahydrofuran. « 5. The method according to any one of the preceding points, characterized in that the organomagnesium compound prepared in stage b) by the action of metallic magnesium and a Alky! Halide such as isopropyl 2UÜR. 1982 * 018 233 - 12 - 60 020 11/39 235 20 /. 0 bromide is recovered in anhydrous medium. 6. The method according to any one of the preceding points, characterized in that the condensation reaction with the t-butyl perbenzoate in the course of stage b) in the same reaction vessel as that for the preparation of
Magnesium compound used and realized without isolation of the latter. 7. The method according to any one of the preceding points, characterized in that the acid used in the course of the stage c) p-Touluensulfonsäure. IkIU ΛΙΛ O Cl : t \ α α ο % a