IL94856A - Method of preparing (+)-(2s,3s)-3-hydroxy-2-(4-methoxyphenyl) -2,3-dihydro-5h-1,5-benzothiazepine-4-one and chlorinated derivatives thereof - Google Patents

Description

Method of preparing and chlorinated derivatives thereof The subject of the present is a method for bearing optionally a chlorine atom on the aromatic These optically pure compounds are synthetic intermediates of compounds with therapeutic as and its chlorinated The reaction scheme is shown on the following In the denotes hydrogen or The first step comprises reacting a vative of general with ropionate of formula A methyl ropionate derivative of general formula IV is obtained via opening the epoxide The step comprises the of this compound in the presence of an The reaction principles of each of the two steps are well They are for in 2037 1 970 where the ester of formula III is used in The first step necessitates several hours of heating to 1 60 and after separation and purification of the ester of the second step is performed by this ester and sting the acid obtained in the presence of sulfuric or acetic in refluxing United States Patent describes the first where the ester of formula reaots with the am in toluene after six hours of heating at Japanese Patent Application which describes the synthesis of the optically pure ester of formula likewise describes the reaction of the latter with aminothiophenol of mula under toluene reflux for European Patent Application 01 54838 describes among others a method that combines the two The reactions are performed without requiring 1 6 hours of heating to 1 and furnishing a mixture of optical isomers of the final compound and is Thus it is clear that none of the known methods is able for economic industrial manufacture of the compounds of mula for various poor elevated the need to purify the intermediate final and long reaction The present invention therefore proposes a method that overcomes the disadvantages of the known and affords the following the two reaction steps can be performed in the one and same so that emptying and cleaning it between the two or using a second is unnecessary reasons of the two steps can be performed in separate but anyway it is not necessary to isolate the intermediate the total yield is high compared with the yields of the known energy consumption is in particular during the first the reaction times are and the final compound is The operating conditions of the method according to the which make it possible to attain all the advantages listed are described The starting ester of formula III is used in optically pure It is described in Japanese Patent Applications 1 1 451 and 1 451 4 The possibility of carrying out the two steps of the tion in the same without evacuation or intermediate fer to another is due to the selection of a unique solvent which highly suitable for each of the Specific solvents for each of the two steps are already known but they different for each step and so do not permit the entire method to take place within the The solvents to be used according to invention are chlorinated organic solvents having a boiling point of more than Examples of suitable solvents These solvents are not only and unexpectedly highly favorable to a good overall but furthermore they are so efficient that the first step necessitates heating only for because the exothermic nature of the reaction is cient for to be maintained without adding external This particular feature was entirely because it had never been found with other the use of these solvents promotes the selectivity of the first With other it is in fact found that an unfavorable mixture of diastereoisomers of formula is Another particular feature of the invention is due to the catalyst used in the second While it is known that takes place better in an acid medium or the catalyst to be used according to the invention is selected from methanesulfonic phosphoric trifluoroacetic perchloric The preferred catalyst is methanesulfonic These which make possible to obtain an excellent yield of the compound are simple to add to the S medium as the first step is The following examples provide a detailed illustration of the method according to the Example 1 an reactor purged with are introduced 3 kg of methyl and 10 1 of and the mixture is heated to Heating is and a solution of 1900 g of in 1 of chlorobenzene introduced in the space of 30 so as not to allow the temperature to exceed and 1 of chlorobenzene also added to rinse inlet funnel and the The temperature is kept at approximately for a ther 30 and then of cthanes l onic acid is and the mixture heated at reflux for 8 with elimination of a mixture of methanol and chlorobenzene by in order not to allow the temperature to drop below boiling point he heating is the mixture allowed to return to it is chilled to for one and the crystals formed rinsed with and are dried in a vacuum at A yield of 3463 g of pure Melting In a 1 liter under an argon atmosphere are introduced 50 g of ropionate ana ml of commercial of and and the is heated at in the apace of 30 ao as not to allow the temperature to exceed of are The temperature is kept at 120 C for a further 30 and then of acid and the mixture is heated at for 3 hours reaction completed after 2 hou The is allowed to it is chi led to for one and the crystals are filtered and washed with and dried g of pure are of are added dropwiec to a solution of 30 g of methyl in 200 ml of at After 30 minutes g of methaneaulfonlo acid is and the mixture is heated at for 6 The mixture is allowed to then chilled and the are washed and dried in at g of pure are Melting 1 the same way ae in Example the reaction and methyl affords 6 insufficientOCRQuality

Claims (1)

1. Claims A method for preparing a compound of the general formula x denotes hydrogen or comprising reacting a compound of general formula with a oC general formula in optical pure form and the intermediate compound of general formula thus obtained in the presence of the method being in that the two reaction steps are performed without isolation of the intermediate by using a from the chlorinated organic having a boiling point Of than The method as defined in claim wherein x denotes he method as defined claim wherein the solvent is The method as defined in claim wherein the solvent The method as defined in claim wherein the solvent is The method as defined in claim wherein sulfonic acid is used to the of the mediate compound formula For Sanford Colb insufficientOCRQuality