IL31666A - Process for the resolution of 6-phenyl-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole - Google Patents

Description

PEOCESS FOR THE RESOLUTION OF THIS INVENTION relates to a process for the resolution of racemic of the into its optical It is already known to use the racemic mixture of the said principally in the form of the base or the as an anthelmintic It is also known that the laevorotatory isomer v is responsible for the anthelmintic activity of the racemic mixture whilst the dextrorotatory isomer is practically ineffective as an anthelmintic No process for the separation of the optical isomers is hitherto known exoept a process which uses the optical isomers of its practical realisation requires the use of relatively low temperatures of the order to It has now been found and this forms the subject of the that the optical isomers of racemic can be separated at ambient temperatures and up to 35 by fractional solubilisation ia or by fractional crystallisation from or containing at least mediumj of the neutral or of The starting mixture equimolecular mixture of the or of the dextrorotatory and laevorotatory isomers of is obtained by known for example by reaction of an optically active tartaric or an metal salt with the racemic base or an acid addition salt of the racemic base The solvent for the fractional or crystallisation containing at least of this initial mixture is water or the an alcohol containing 1 carbon such as or It poooiblo to or of The fractional zation or crystallisation temperature can vary within wide limits but i practice temperatures of between are preferably The fractional separation is advantageously carried out in the presence of an alkali metal in particular a sodium Starting the neutral dibenzoyltartrate of the opticall pure imidazothiazole isolated in this it is possible to obtain the optically pure and its other acid addition by known According to a preferred feature of the or an acid addition salt the is reacted with tartaric or an alkali metal salt in or an containing at least and the resulting tartrate of is separated from the reaction mixture by fractional and converted to by treatment with a sodium Advantageousl the various steps are carried out at a temperature between and The following Examples illustrate the EXAMPLE 1 Sodium hydroxide solution in methanol mole of sodium is added over the course of 15 minutes and at to a solution of acid 1 in methanol A solution of in methanol cc is poured into the resulting homogeneous solution over the course of 20 minutes and at between Further water is added to the homogeneous solution The major part of the methanol is and the mixture then evaporated under reduced pressure at between 20 and until crystals are After isolating the crystals by evaporation of the filtrate is continued under reduced pressure until crystals are again On repeating the four lots of crystals are obtained after washing with water and yield the neutral of having a specific optical rotation solution containing of In order to prepare the hydrochloride of the laevorotatory the base is first formed and then combined with hydrogen chloride as Sodium hydroxide solution 0 26 is added over the course of minutes at to a mixture of the neutral of water and methylene chloride After decanting the lower organic layer and extracting the aqueous phase with methylene chloride x 550 the organic layers are combined and washed with water 4 x 550 of the water from the fourth wash is The organic solution is treated with carbon black 50 for 15 minutes at and then filtered through a filtration aid and the filter is washed with methylene chloride x 25 Gaseous hydrogen chloride is bubbled into the filtrate until the pH reaches to The hydrochloride It is filtered off at and washed with methylene chloride x 100 and acetone x 100 A white crystalline anhydrous product is 25 o thus having a specific optical rotation solution containing 8 of melting at and having a chlorine content equal to the theoretical The yield of laevorotatory hydrochloride relative to the theoretical yield is thus calculated on the initial racemic EXAMPLE 2 5N Sodium hydroxide solution is run over the course of 10 minutes and at into a stirred suspension of acid in water and is then added over the course of 15 minutes at between Stirring is continued at for a further 1 hour 30 minutes after the completion of the and the reaction mixture is then filtered at The precipitate is washed on the filter with water x 100 and then A white crystalline dry product the neutral of is thus having a specific optical rotation solution containing of tartrate yields hydrochloride melting at yield of laevorotatory hydrochloride relative to the racemle base ie thus of add 1 and hydrochloride in water sodium hydroxide solution is added over the course of 10 minutes and at between and to this mixture homogenised by and the mixture ie kept constantly stirred at between and for 2 hours minutes after the end of the addition of the sodium hydroxide stirring is the reaction is filtered at and precipitate is with water x 100 White crystals of are thus obtained after having a specific optical rotation in methanol containing 4 of By proceeding as in Example crystals of hydrochloride at are this represents a yield of relative to the hydrochloride o the Example 4 3 In a flask of 2 litres were adde of isopropanol and 150 of then added acid and the temperature was maintained at product vas a percipltate which was Isolated by the filtered liquid being saved as the medium of separation for the subsequent step while the washed with 50 of water and process was repeated four times tho liquid the filtrate of the previous total of 166 g of the neutral of having a specific rotation ranging from for the first percipitate to for fifth thus insufficientOCRQuality

Claims (1)

1. iE CLAIM . 1. Process for the separation of the optical isomers of carbon atoms or a mixture of such an alcohol with water. 3· Process according to claim 2 in which the alcohol is methanol, ethanol or n-propanol. k. Process according to claim 1, 2 or in' which the fractional solubilisation or fractional crystallisation of. the neutral optically active dibenzoyltartrate salts of the thiazole is effected at a temperature of between 0° and 35°C. 5» Process according to any one of the preceding claims in which the fractional separation is effected in the presence of a ' alkali metal salt. V 6. Process according to any one of the preceding claims in which dl^-phenyl-2,3,5,6-tetrahy5»6-tetrahydro-imidazoC2?l-b]thiazole by treatment with a base. 8. Process for the separation of racemic 6-phenyl-2,3»5»6-tetraIiydro-imicla-5oC2,l-b3thiazole into its optical isomere substantially as described in any one of Examples 1 to 3· 9. The optical isomers of 6-phenyl-2,3»5»6-tetrahydro-imidazo[2,l-b3thiazole when prepared by the process claimed in any one of claims 1 to 8. Attorney for Applica¾is