FI93213C - Process for the preparation of (+) - (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-5H-1,5-benzothiazepin-4-one and its chlorinated derivatives - Google Patents

Description

93213

The present invention relates to a process for the preparation of (+) - (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-5H-1,5-benzothiazepin-4-one and its chlorinated derivatives. is a process for the preparation of (+) - (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-5H-1,5-benzothiazepin-4-one, the aromatic the ring optionally has a chlorine atom.

These optically pure compounds are synthetic intermediates of therapeutically active compounds, such as (+) - (2S, 3S) -3-acetyloxy-5- (2-dimethylaminoethyl) -2- (4-methoxyphenyl) -2.3 -dihydro-5H-1,5-benzothiazepin-4-one and its chlorinated derivatives.

The reaction scheme is shown below.

15 In the formulas, X represents hydrogen or chlorine. 1 · 2 - 9321 3

Reaction scheme OCH3 - g (II) CH3O - ^ (III) 0 '' 0CH3 'e d h2n S- / (IV)

A-OH

CH 3 O-Y

Ό

CH3S03H

0CH3 ▼ / - 0. 1-y- ° "u) H 0 tl 9321 3 3

In a first step, a 2-aminothiophenol derivative of general formula II is reacted with (-) - (2R, 3S) -2,3-epoxy-3- (4-methoxyphenyl) propionate of formula III. Opening of the epoxide ring gives a methyl (2S, 3S) -3 - [(32-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionate derivative of general formula IV.

In the second step, this compound is cyclized in the presence of an acid.

10 The reaction principles of each of the two steps are well known.

They are described, for example, in Chem. Pharm. Bull., 18, 2028-2037 (1970), using an ester of formula III in racemic form. In the first step, it is necessary to heat the reaction to 150-160 ° C for several hours, and after the ester of formula IV has been separated and purified, the second step is carried out by hydrolyzing this ester and cyclizing the resulting acid to sulfuric or acetic acid. in the presence of -20 sa, at reflux in xylene.

U.S. Patent 4,116,819 discloses a first step in which an (racemic) ester of formula III reacts with aminothiophenol (II) in toluene after heating at reflux for six .25 hours.

JP Patent Application 145 160/1986, which describes the synthesis of optically pure esters of formula III, also describes a reaction in which the latter compound is reacted with an aminothiophenol of formula II in toluene, refluxing for 10 hours.

4,93213

Finally, EP patent application 0 154 838 describes, inter alia, a method combining said two steps. The reactions are carried out without solvent, heating to 160 ° C for 16 hours to give a mixture of the optical isomers of the final product and its intermediate.

Thus, it is clear that none of the known methods is suitable for the industrial and economic preparation of the compounds of the formula I for a number of reasons: poor yields, elevated temperatures, the intermediate and / or the final products have to be purified, and long reaction times.

The present invention thus provides a process which overcomes known disadvantages and has the following advantages: the reaction steps can be performed in one and the same reaction vessel so that emptying and purification of the reaction vessel between steps or the use of another reaction vessel is unnecessary (for convenience, the two steps can be performed in separate reaction vessels, but without the need to isolate the ester intermediate); the overall yield is high compared to the yields of known methods; energy consumption is lower, especially during the first phase; reaction times are short; and the end product is pure.

The conditions for carrying out the method according to the invention, by means of which it is possible to achieve all the advantages listed above, are described below.

The starting ester of formula III is used in optically pure form. It is described in JP patent applications 145 159/1986, 145 160/1986 and 145 174/1986.

It is possible to carry out two steps of the reaction in 30 in the same reaction vessel without transferring the intermediate to another reaction vessel due to the unique choice of solvent, and the solvent is very suitable for both steps.

Certain solvents used in each of the two steps are, of course, already known (dichloroethane, toluene, xylene, etc.), but they are different solvents for each step and thus it is not possible to carry out the whole process in the same reaction vessel. According to the present invention, chlorobenzene, which is a chlorinated organic solvent having a boiling point higher than 70 ° C, is used as the solvent. This solvent not only - and unexpectedly - gives good overall yields, but is also so effective that in the first lie it is only necessary to heat at the beginning, because due to the exothermic nature of the reaction the heat is retained without the addition of external energy. This particular property was completely unpredictable, as it has never been observed for other solvents.

In addition, the use of this solvent promotes first stage threo / erythro selectivity. It has been found that other solvents give an unfavorable mixture of diastereomers of formula IV.

Another particular feature of the invention relates to the catalyst used in the second step. Although it is known that the cyclization takes place better in an acid medium (sulfuric or acetic acid), the catalyst used according to the present invention is selected from methanesulfonic acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, perchloric acid, paratoluenesulfonic acid. The preferred catalyst is meta-30-sulfonic acid.

These acids, which make it possible to obtain the cyclized compound (I) in excellent yield, are simply added to the reaction medium as soon as the first lie is completed.

The following examples illustrate the method of the present invention.

6 9321 3

Example 1

3 kg of methyl (-) - (2R, 3S) -2,3-epoxy-3- (4-methoxyphenyl) propionate and 10 l of chloro-5-benzene are placed in an enamelled, 25-liter nitrogen-fed reaction vessel, and the mixture is mixed. heated to 100 ° C. Stop heating and add a solution of 1900 g of 2-aminothiophenol in 1.5 liters of chlorobenzene over 30 minutes without raising the temperature above 120 ° C and add 3,5 l of chlorobenzene to rinse the dropping funnel and piping. .

The temperature is maintained at about 115 ° C for a further 30 minutes, then 37.5 ml of methanesulphonic acid are added and the mixture is heated at reflux for 8 hours, removing the mixture of methanol and chlorobenzene by distillation to prevent the temperature from falling below 132 ° C ( boiling point of chlorobenzene).

The heating is stopped; allowing the mixture to return to 20 ° C; it is cooled to 5 [deg.] C. per hour and the crystals formed are filtered off, rinsed with chlorobenzene 20 and dried in vacuo at 100 [deg.] C.

A total yield of 3463 g of pure (+) - (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-5H-1,5-benzodiazepin-4-one is obtained. Melting point; [200.3-201.8.8 ° C. [α] 0 ° to + 114 ° (c - 0.1; DMF)] Example 2 (not according to the invention) '* 1 To a 1 liter flask containing an argon atmosphere is placed 50 g of methyl - (-) - (2R, 3S) -2,3-Epoxy-3- (4-methoxyphenyl) propionate and 350 ml of dichlorobenzene (commercial mixture of o-, m- and p-isomers) and mixture 30 are heated at 115 ° C. 31.8 g of 2-aminothiophenol are then added over a period of 30 minutes so that the temperature is not allowed to rise above 120 ° C.

The temperature is maintained at 120 ° C for a further 30 minutes and then 0.62 ml of methanesulphonic acid are added and the mixture is heated at 150 ° C for three hours (the reaction is complete after two hours).

»I 93213 7

The mixture is allowed to cool; it is cooled to 5 [deg.] C. per hour and the crystals are filtered off and washed with dichlorobenzene and dried in vacuo.

49.5 g of pure (+) - (2S, 3S) -3-hydroxy-3-5 (4-methoxyphenyl) -2,3-dihydro-5H-1,5-benzothiazepin-4-one are obtained. Melting point 203-204 ° C.

Example 3 (not according to the invention) 18.8 g of 2-aminothiophenol are added dropwise to a solution of 30 g of methyl (-) - (2R, 3S) -2,3-epoxy-3- (4-methoxyphenyl) propionate in 200 ml: 1,2,3-trichloropropane at 110-115 ° C. After 30 minutes, 0.35 g of methanesulfonic acid is added and the mixture is heated at 145-150 ° C for six hours. The mixture is allowed to cool, then cooled and filtered: the crystals are washed with 1,2,3-tri-15-chloropropane and dried in vacuo at 50 ° C. 33.8 g of pure (+) - (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-5H-1,5-benzothiazepin-4-one are obtained. Melting point 202 , 8-204.1 ° C.

Example 4 In the same manner as in Example 1, if the reaction of 2-amino-5-chlorothiophenol and methyl (-) - (2R, 3S) -2,3-epoxy-3- (4-methoxyphenyl) propionate is reacted, (+ ) - (2S, 3S) -8-chloro-3-hydroxy-2- (4-methoxy-phenyl) -2,3-dihydro-5H-l, 5-benzothiazepin-4-one. Melting point, .25 point: [237-241 ° C. [α] D = +91.9 ° (c = 0.1; DMF)].

Vertailuesimerkkl

In order to demonstrate the advantage of the process according to the invention over the process known from EP application 154 838, comparative experiments were carried out using three different solvents as solvent 30, namely chlorobenzene (solvent according to the invention), toluene and xylene. Prepared from (+) - (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-5H-1,5-benzodiazepin-4-one, starting from 2-aminothiophenol and optically pure 35 (-) - (2R, 3S) -2,3-epoxy-3- (4-methoxyphenyl) propionate.

8 93213

The reactions (method according to Example 1) used said three solvents, and all reaction conditions were similar except for the reaction temperature (due to the different boiling points of the solvents). The 2-aminothiophenol used as the second starting material was from two different sources. The results are shown in Table 1.

The results show that the use of chlorobenzene as a reaction solvent according to the invention achieves an excellent threo / erythro ratio, short reaction times and high yields, and in addition the final product can be isolated without further washing as a second solvent, regardless of the origin of the 2-aminothiophenol used.

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Claims (3)

93213 A process for the preparation of a compound of general formula (I) wherein X is hydrogen or chlorine by reacting a compound of general formula (II) for 20 h 2n sh to react with an optically pure, levorotatory form of a compound of general formula (III) 25 OCH, .0 \ p (ΐ11 '30 y cHj0- <V o and then cyclizing the intermediate of general formula (IV) thus obtained in the presence of 35 II · 9S213 och3 ΆΡ (iv) OH CH3O / Ό 10 acid, known from that said two reaction steps are carried out without isolating the intermediate, using chlorobenzene as the solvent. Process according to Claim 1, characterized in that X represents hydrogen. Process according to Claim 1, characterized in that methanesulfonic acid is used to catalyze the cyclization of the intermediate of general formula (IV). r · 9321 3