EP0000453B1 - Process for the preparation of thienopyridine derivatives. - Google Patents

Description

Process for the preparation of thienopyridine derivatives.

The present invention relates to a process for the preparation of thienopyridine derivatives.

We have described in French application 75 03 968 and its first certificate of addition 75 23 786 a process for the preparation of thienopyridine by reaction of a derivative of (β-thienyl-2-ethylamine, optionally substituted, with formaldehyde in the presence of an acid. This reaction is preferably carried out in two stages, firstly by reacting / 3-thienylethylamine with formaldehyde and then cyclizing the product obtained in an anhydrous medium with an anhydrous acid. conversion of the starting material is only of the order of 60 to 65%, which means that the unreacted starting material must be recycled.

In addition, this process does not make it possible to prepare thienopyridine derivatives substituted in position 4 using the Pictet Spengler reaction by the action of an aldehyde on a thienylethylamine derivative.

There is also known a process for the preparation of 1,2,3,4-tetrahydroisoquinolines from N-benzoylated derivatives of beta-arylamine and of chloromethyl methyl ether, described in Chemical Communications, 1969, 1283-4. However, it should be noted that the cyclization takes place on a highly activated benzene nucleus and that the reaction center is an amide.

The object of the present invention is to remedy these drawbacks by providing a process which makes it possible both to access the derivatives substituted in position 4, and to obtain significantly higher yields and conversion rates.

• dans laquelle R, représente un atome d'hydrogène, un radical alcoyle, aryle ou aralcoyle éventuellement substitué, R₂ et R₃ sont identiques ou différents et représentent un atome d'hydrogène, un radical alcoyle inférieur, aryle ou hétérocyclique et R₄ représente un atome d'hydrogène, un radical alcoyle, un radical cycloalcoyle, alcoxy carbonyle, carboxy, aryle ou hétérocyclique, caractérisé en ce qu'on fait réagir un composé de formule
  
• dans laquelle R₁, R₂ et R₃ sont tels que définis cil-dessus, avec un composé de formule
  
• dans laquelle R₄ est tel que défini ci-dessus; X est un atome d'halogène, un groupe alcoxy éventuellement substitué, thioalcoyle éventuellement substitué ou amino éventuellement substitué; Y représente un groupe alcoxy éventuellement substitué, thioalcoyle éventuellement substitué, amino éventuellement substitué ou un groupe de formule
  
• dans laquelle R est un radical alcoyle inférieur ou aryle, ou les deux groupes X et Y forment avec l'atome de carbone sur lequel ils sont fixés un noyau hétérocyclique à six chaînons hexahydro-S-triazinique, trioxannique ou trithianique, dans un solvant inerte, à une tempéra- turé comprise entre 0 et 150°C et dans un milieu anhydre, et éventuellement, on libère la base libre.

It therefore relates to a process for the preparation of compounds of general formula

• in which R represents a hydrogen atom, an optionally substituted alkyl, aryl or aralkyl radical, R ₂ and R ₃ are identical or different and represent a hydrogen atom, a lower alkyl, aryl or heterocyclic radical and R ₄ represents a hydrogen atom, an alkyl radical, a cycloalkyl, alkoxy carbonyl, carboxy, aryl or heterocyclic radical, characterized in that a compound of formula is reacted
  
• in which R ₁ , R ₂ and R ₃ are as defined above, with a compound of formula
  
• wherein R ₄ is as defined above; X is a halogen atom, an optionally substituted alkoxy, optionally substituted thioalkyl or optionally substituted amino; Y represents an optionally substituted alkoxy group, optionally substituted thioalkyl, optionally substituted amino or a group of formula
  
• in which R is a lower alkyl or aryl radical, or the two groups X and Y form, with the carbon atom to which they are attached, a six-membered heterocyclic ring hexahydro-S-triazine, trioxannic or trithianic, in an inert solvent , at a temperature between 0 and 150 ° C and in an anhydrous medium, and optionally, the free base is released.

• a) - un halogénométhyl éther du type
  
  • dans lequel X est un atome d'halogène tel que Clou Br et R_s est un radical alcoyle inférieur ou aryle.
• b) - un halogénométhyl thio éther du type
  
  • dans lequel X est un atome d'halogène tel que CI ou Br et Rg est un radical alcoyle inférieur ou aryle.
• . c) - un halogénométhyl ester du type
  
  • dans lequel X est un atome d'halogène tel que CI ou Br et R₇ est un radical alcoyle inférieur ou aryle.
• d)-une S -hexahydro-S-triazine de formule
  
  • ou un dérivé aminé de formule
    
  • dans lesquelles R₈, Rg, R₁₀, R₁₁, R₁₂ sont des radicaux alcoyles inférieurs qui forment éventuellement entre eux un pont azoté ou des radicaux aryles, identiques ou différents.
• e) - un trioxanne de formule
  
  • ou un dérivé de polyoxyméthylène de formule
    
  • dans lesquelles R₁₃ et R₁₄ sont des atomes hydrogènes ou des radicaux alcoyles inférieurs ou aryles, identiques ou différents, et n ≥ 1.
• f) - un trithiane de formule
  
  • ou un dérivé de polythiométhylène de formule
    
  • dans lesquelles R₁₅ et R₁₆ sont des radicaux alcoyles inférieurs ou aryles, identiques ou différents et n ≥ 1.

The compounds of formula III which are used in the process of the invention can be illustrated according to the nature of X and Y by the following compounds.

• a) - a halomethyl ether of the type
  
  • in which X is a halogen atom such that Clou Br and R _s is a lower alkyl or aryl radical.
• b) - a halomethyl thio ether of the type
  
  • in which X is a halogen atom such as CI or Br and Rg is a lower alkyl or aryl radical.
• . c) - a halomethylethyl ester of the type
  
  • in which X is a halogen atom such as CI or Br and R ₇ is a lower alkyl or aryl radical.
• d) -a S -hexahydro-S-triazine of formula
  
  • or an amino derivative of formula
    
  • in which R ₈ , Rg, R ₁₀ , R ₁₁ , R ₁₂ are lower alkyl radicals which optionally form between them a nitrogen bridge or aryl radicals, identical or different.
• e) - a trioxane of formula
  
  • or a polyoxymethylene derivative of formula
    
  • in which R ₁₃ and R ₁₄ are identical or different hydrogen atoms or lower alkyl or aryl radicals, and n ≥ 1.
• f) - a trithiane of formula
  
  • or a polythiomethylene derivative of formula
    
  • in which R ₁₅ and R ₁₆ are identical or different lower alkyl or aryl radicals and n ≥ 1.

The reaction between the compound of formula II and the compound of formula III is carried out in an inert solvent at a temperature between 0 ° C and 150 ° C, but preferably between room temperature and the boiling point of the most compound volatile which is generally one of the solvents used.

This reaction probably involves the formation of an intermediate compound which is not isolated, but cyclized in situ, as will be explained below.

However, the cyclization of this intermediate compound requires the presence of an acid which is either generated in the medium by the reaction of formation of the intermediate, or is added when this reaction of formation of the intermediate does not provide any. The formation of acid in situ depends on the nature of the compound of formula III, thus for the compounds of formula III of types a, b, c, we observe the formation of such an acid of formula XH which serves as an agent. cyclization, whereas for the compounds of formula III of types d, e, and f, no acid is formed.

• un acide minéral anhydre, tel que les acides chlorohydrique, sulfurique, bromhydrique, phosphorique, un acide organique, carboxylique, tel que les acides oxalique, acétique, monochlor- acétique ou sulfonique, tel que les acides méthanesulfonique, benzènesulfonique.

In the latter case, a reaction solvent is used which contains an acid which can be, for example:

• an anhydrous mineral acid, such as hydrochloric, sulfuric, hydrobromic, phosphoric acids, an organic, carboxylic acid, such as oxalic, acetic, monochloroacetic or sulfonic acids, such as methanesulfonic, benzenesulfonic acids.

In cases where the acid is generated in the medium, it is preferred to add the compound of formula III to the solution of the compound of formula II, although the reverse is also possible. In the other cases, it is preferred to add a mixture of the compounds of formulas II and III to the reaction solvent containing the cyclization acid.

The reaction is most often quick, but it does. can sometimes be advantageous to heat at the end of the reaction to speed it up.

One can operate at atmospheric pressure or under a higher pressure, but atmospheric pressure is generally sufficient.

The reaction is carried out in a solvent inert with respect to the reagents, in particular the compounds of formula III. This solvent must be anhydrous because water breaks down the compounds of formula III. Preferably an aprotic solvent is used which can be polar in nature, such as dimethylformamide, dimethylsulfoxide, hexamethyl phosphorotriamide or another solvent, such as benzene, toluene, a chlorinated solvent, such as a chlorinated hydrocarbon or light ethers.

It is advantageous to carry out the reaction in a solvent in which the halide of the compound of formula I is little or not soluble because, in fact, the salt of the compound of formula 1 can then be isolated, at the end of the reaction, by filtration of the precipitate formed. This procedure allows, in addition to ease of implementation, to obtain excellent yields.

The compounds of formula II and III are reacted in stoichiometric amounts, or optionally with a molar excess of the compound of formula III of up to approximately 50%.

Although not wishing to be bound by a reaction mechanism, the Applicant believes that it must indicate that the reaction takes place in two stages given in the reaction scheme below, these two stages not being distinct in practice.

Cyclization therefore takes place with the formation of an alcohol, a mercaptan, an amine or water.

This cyclization is obtained with very good yields and conversion rate of the starting product. Thus, in the cyclizations where the reagent is chloromethyl methyl ether, or chloromethyl methylthioether, the conversion rate of the compound of formula II is close to 100% and the yields of the order of 90 to 95%.

Furthermore, thanks to the method of the invention. it is possible to obtain thienopyridine derivatives in which the group R ₄ is an aryl group such as the phenyl group, a heterocyclic group such as the 2-thienyl group, an aliphatic or cycloaliphatic radical or a functional group such as alkoxycarbonyl, carboxy.

The preparation of the starting reagents of formula III is easily carried out by methods known in the literature and which do not fall within the scope of the invention. Some of the compounds of formula III are unstable and it is therefore necessary to prepare them just before their use in the process of the invention where they are used without purification.

The following nonlimiting examples are given by way of illustration of the process of the invention.

Example 1

Preparation of (2-chloro-benzyl) hydrochloride - 5 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine

A solution of 50.8 g (0.2 M) of N - (2-chloro-benzyl) (2-thienyl) - 2 ethylamine in 70 cm ³ of dimethylformamide, heated to 60 ° C., is added in 7 minutes 22 , 7 g (0.24 M) of chloromethylmethylether. The temperature of the reaction medium is maintained at 60 ° C. throughout the addition phase by cooling with water. Thirty minutes after the end of the addition of chloromethyl methyl ether the medium is cooled to 20 ° C. The expected product, which has precipitated, is filtered and washed with twice 70 cm ³ of acetone. 45.1 g of (2-chloro-benzyl) -5 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine hydrochloride are obtained. (Yield: 75%).

The treatment of the filtrates makes it possible to recover a further 9 g of the desired compound (yield 90% - m.p. = 190 ° C).

Example 2

Preparation of (2-chloro-benzylJ-5 ethoxy carbonyt-4 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine hydrochloride.

25.1 g (0.1 M) of N- (2-chloro-benzyl) (2-thienyl) -2 ethylamine dissolved in 30 cm ³ of dimethylformamide are introduced into a 250 cm ³ three-necked flask. 18.3 g (0.11 M) of 2-chloro-2-ethoxy-ethyl acetate are then added over 6 minutes and the mixture is heated for 4 hours at 80 ° C.

The expected product begins to precipitate. After the medium has cooled, the product is filtered and recrystallized three times from 20 cm ³ of acetone. 20.5 g of (2-chloro-benzyl) 5-ethoxy-carbonyl-4 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine hydrochloride are obtained (yield: 55%).

The treatment of the filtrates again gives 10 g of crude product (m.p .: 156 ° C). The crude product is obtained analytically pure by recrystallization from an isopropyl ethanol ether mixture (total yield: 81.8%).

Example 3

Preparation of hydrochloride (2-chloro benzyl) -5 (thienyl 2) - 4 tetrahydro 4, b, b, / thieno [3,2-c] pyridine.

a) Preparation of (2-thienyl) chloromethylmethylether.

112 g (1 M) of (2-thienyl) carboxaldehyde, 50 g (1.55 M) of methanol, 125 cm ³ of methylene chloride and 150 g of sodium sulfate are loaded into a flask, with stirring. The reaction medium is cooled to -35 ° C. and a stream of dry gaseous hydrochloric acid is passed until saturation, preventing the temperature from exceeding -20 ° C. After stopping the bubbling of hydrochloric acid, the reaction medium is left at -20 ° C., with stirring, for 2 hours. The methylene chloride is then evaporated at -20 ° C to obtain the crude (2-thienyl) chlormethyl-methyl ether.

b) Preparation of (2-chloro-benzyl) hydrochloride - 5 (2-thienyl) - 4 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine.

The N - (2-chloro-benzyl) (thienyl - 2) - 2 ethylamine is reacted on the ether prepared under (a) above in a manner analogous to that described in Example 1 to obtain the compound sought (base melting point: 109 ° C).

Examples 4 and 5

• le chlorhydrate de (chloro-2 benzyl) - 5 phényl - 4 tétrahydro 4,5,6,7 thiéno [3,2-c] pyridine (P.F. de la base : 95°C),
• le chlorhydrate de (chloro-2 benzyl) - 5 iso- propyl - 4 tétrahydro 4,5,6,7 thiéno [3,2-c]. (P.F. de la base : 172°C),
• respectivement à partir de N - (chloro-2 benzyl) (thiényl-2) - 2 éthylamine et des composés suivants:
• ―α chlorobenzyl-méthyléther,
• - chloro-1 éthoxy-1 méthyl-2 propane

The following compounds are prepared, in a manner analogous to that described in Example 1:

• (2-chloro-benzyl) - 5-phenyl - 4-tetrahydro 4,5,6,7 thieno [3,2-c] pyridine hydrochloride (base mp: 95 ° C),
• (2-chloro-benzyl) 5-isopropyl-4 tetrahydro 4,5,6,7 thieno [3,2-c] hydrochloride. (Base PF: 172 ° C),
• respectively from N - (2-chloro-benzyl) (2-thienyl) - 2 ethylamine and the following compounds:
• ―Α chlorobenzyl-methylether,
• - 1-chloro-1-ethoxy-2-methyl propane

Example 6 Preparation of tetrahydro hydrochloride 4,5,6,7 thieno [3,2-c] pyridine

To a solution of 12.7 g (0.1 M) of (2-thienyl) - 2-ethylamine in 20 cm ³ of dimethylformamide, heated to 55 ° C., 8.05 g (0.1 M) chloromethyl methyl ether diluted in 10 cm ³ of dimethylformamide. After the addition of chloromethyl methyl ether, the medium is kept for 2 hours at 70 ° C. and then cooled to room temperature. The expected product, which has precipitated, is rinsed with acetone. 5.5 g of tetrahydro hydrochloride 4,5,6,7 thieno [3,2-c] pyridine are obtained (mp: 225 ° C). (Yield: 31%).

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

a) Preparation of chloromethylmethylthioether

In a three-necked flask with a capacity of 1 _'liter was charged with 274 g (2.3 M) of thionyl chloride and 400 cm ³ of methylene chloride.

The mixture is heated to reflux (41 ° C.) and 156 g of dimethyl sulfoxide are added slowly. Throughout the addition, there is a significant release of gas consisting of SO ₂ and HCl. A slight heating must be maintained to keep the medium at reflux. At the end of the addition of dimethyl sulfoxide, a stream of nitrogen is passed to remove the dissolved hydrochloric acid. The reaction medium (333 g) is used as it is in the cyclization operation described below.

• - chlorométhylméthylthioéther : 56,77%
• - chlorure de méthylène : 33%

A quantitative assay by gas chromatography gives the following results:

• - chloromethylmethylthioether: 56.77%
• - methylene chloride: 33%

b) (2-chloro-benzyl) hydrochloride - 5 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine.

To 52 g (0.2 M) of N - (2-chloro-benzyl) (2-thienyl) - 2 ethylamine dissolved in 60 cm ³ of dimethyl sulfoxide and heated to 60 ° C., 51 g (0) are added over 30 minutes. , 3 M) of crude chloromethylmethylthioether prepared in step (a) described above. The temperature of the reaction medium then progressively rises and it is maintained between 80 and 85 ° C throughout the addition phase by cooling with water. At the end of the addition of chloromethylmethylthioether the medium is cooled to 6 ° C. The expected product easily precipitates. After filtration and washing with 2 x 70 cm ³ of acetone, 44.1 g of (2-chloro-benzyl) hydrochloride - 5 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine are obtained (yield 73.5%). The treatment of the filtrates makes it possible to recover a further 10 g of the desired compound (yield: 90% - MP = 190 ° C).

The crude product thus obtained contains from 1 to 2% of impurities and can be made analytically pure by recrystallization from ethanol.

Example 8 Preparation of (2-chloro-benzylJ - 5 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine hydrochloride

The same compound as in Example 1 is prepared as follows.

66.5 g (0.44 M) of chloromethyl pivalate are reacted, under heating for 3 hours, over a solution of 103 g (0.4 M) of N - (2-chloro-benzyl) (thienyl- 2) - 2 ethylamnine _. in 300 cm ³ of dimethylsulfoxide, to obtain, with a yield of 51%, the compound indicated in the title.

Example 9 Preparation of (2-chloro-benzylJ-5 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine hydrochloride.

A 42 cm ³ of dimethylformamide in which 0.25 mol of gaseous hydrochloric acid was dissolved and which was heated to 40 ° C., a mixture of 25.15 g (0.1 M) is added in 2 minutes N - (2-chloro-benzyl) (2-thienyl) - 2 ethylamine and 15.3 g (0.033 M) of s. hexa o.chlorobenzylamine hydrotriazine. The reaction is exothermic and during the addition, water must be cooled to keep the temperature of the reaction medium below 70 ° C. At the end of the addition, the mixture is left stirring for 30 minutes and then cooled. The expected product is filtered and washed twice with acetone. 17.3 g of hydrochloride (2-chloro-benzyl) - 5 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine are obtained. The treatment of the filtrates makes it possible to recover an additional 10 g of the expected product (overall yield: 90%).

Examples 10 to 12 Preparation of (2-chloro-benzyl) hydrochloride - 5 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine

• - la s. hexahydrotriazine de la n.butylamine (rendement ≃ 90%)
• - l'urotropine (rendement : 60%)
• -le paraformaldéhyde (rendement : 83%)

According to the same procedure as described in Example 9, the compound indicated in the title is obtained by replacing the s.hexahydrotriazine of o.chlorbenzylamine by:

• - the ace. n.butylamine hexahydrotriazine (yield ≃ 90%)
• - urotropin (yield: 60%)
• - paraformaldehyde (yield: 83%)

Example 13 Preparation of tetrahydro hydrochloride 4,5,6,7 thieno [3,2-c] pyridine

To 73 cm ³ of dimethylformamide heated to 45 ° C., in which 0.45 mol of gaseous hydrochloric acid has been dissolved, a mixture of 17 g (0.2 M) of s.hexa-- hydrotriazine is added in 25 minutes n.butylamine and 26 g of (2-thienyl) - 2 ethylamine. The temperature of the medium is maintained at 45 ° C. during the addition using a cold water bath. At the end of the addition, the expected product precipitates. By filtration, 22.16 g of tetrahydro hydrochloride 4,5,6,7 thieno [3,2-c] pyridine are obtained (65% yield).

Example 14 Preparation of (2-chloro-benzyl) hydrochloride - 5 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine

To 2.25 g (0.075 M) of paraformaldehyde in suspension in 20 cm ³ of dimethylformamide, 9.61 g (0.1 M) of methanesulfonic acid is added. The temperature of the medium being at 72 ° C., 13 g (0.05 M) of N- (2-chloro-benzyl) (2-thienyl) - 2 ethylamine dissolved in 5 cm ³ of dimethytl-formamide are added over 2 minutes. The temperature of the medium reaches 90 ° C. The medium is then cooled to 20 ° C and poured onto 50 cm ³ of 4N sodium hydroxide. Extraction is then carried out with 30 cm ³ , then 20 cm ³ of methylene chloride. The organic phases are combined, dried over sodium sulfate and evaporated. An oil is obtained which is taken up in 30 cm ³ of ethanol in which 0.15 mol of gaseous hydrochloric acid has been dissolved. After partial evaporation of the ethanol, the expected product precipitates. It is filtered, washed with acetone and dried. 11.35 g of N- (2-chloro-benzyl) -5 tetrahydro 4,5,6,7 thieno [3,2-c] pyridine hydrochloride are obtained (yield 75.6%).

Claims (6)

1. Process for the preparation of compounds having the general formula:

in which : R, represents a hydrogen atom, an optionally substituted alkyl, aryl or aralkyl radical; R₂ and R₃ are the same or different and represent independently a hydrogen atom, a lower alkyl, aryl or heterocyclic radical; and R₄ represents a hydrogen atom or an alkyl, cycloalkyl, alkoxy carbonyl, carboxy, aryl or heterocyclic radical, comprising reacting a compound having the formula :

in which R" R₂ and R₃ are as defined above, with a compound having the formula :

in which R₄ is as defined above; X is a halogen atom, or an optionally substituted alkoxy, thioalkyl or amino group; and Y represents an optionally substituted alkoxy, thioalkyl or amino group, or a group of the formula :

in which R is a lower alkyl or aryl radical, or both the groups X and Y, together with the carbon atom to which they are attached, form a 6- membered hexahydro-S-triazinic, trioxannic or trithianic heterocyclic nucleus, in an inert solvent to which is added an inorganic or organic acid or carboxylic or sulfonic type when X is other than a halogen atom, at a temperature between 0 and 150°C and in an anhydrous medium and, if desired, liberating the free base.

2. Process as claimed in claim 1, wherein the reaction is effected between room temperature and the boiling point of the more volatile compound.

3. Process as claimed in claim 1, wherein said inert solvent is a polar aprotic solvent such as dimethylformamide, dimethylsulfoxyde, hexamethylphosphorotriamide, or benzene or a chlorinated solvent such as chlorinated hydrocarbon or a light ether.

4. Process as claimed in claim 1, wherein said acid is hydrochloric acid or methane sulfonic acid.

5. Process as claimed in claim 3, wherein the solvent is selected so as to be a non-solvent for the halide of the compound of the formula (I).

6. Process as claimed in claim 1, wherein the compound of the formula (III) is reacted in an amount comprised between the stoichiometric amount and a molar excess of 50% with respect to the compound of the formula (II).