Title of Invention

PROCESS FOR THE PRODUCTION OF 9-CIS RETINOIC ACID

Abstract

ABSTRACT A new industrially applicable process for the production of 9-(Z)-retinoic acid is described which is characterized by the conversion of an alkali metal salt of 3-methyl-4-oxocrotonic acid with a C15-triphenyl-phosphonium salt. 9-(Z)-retinoic acid is a versatile compound for the treatment of numerous dermatological diseases. A new industrially applicable process for the production of 9-(Z)-retinoic acid is described which is characterized by the conversion of an alkali metal salt of 3-methyl-4-oxocrotonic acid with a C15-triphenyl-phosphonium salt. 9-(Z)-retinoic acid is a versatile compound for the treatment of numerous dermatological diseases.

Full Text

The present invention is concerned with a process for the production of 9-(Z)-retinoic acid (9-(Z)-RA). 9-(Z)-RA is a versatile compound which is claimed to be useful for the treatment of numerous dermatological diseases as e.g. disclosed in WO 99/09969. The EP-A 0 659739 discloses a process for the preparation of 9-(Z)-RA which is characterised by the Wittig-reaction of an alkyl P-formylcrotonatewith a C\5-triarylphosphonium salt in the presence of a base and by the subsequent saponification of the so formed retinoic acid ester with a base. This process suffers from the disadvantage that it requires two steps involving a change of solvent for the saponification of the retinoic acid ester. Since the saponifaction needs quite drastic temperature conditions a significant formation of unwanted isomers has also been observed. Object of the present invention therefore was to find an improved alternative for the manufacture of 9-(Z)-RA which does not include the disadvantages known from the process known in the art. The objective has been achieved with the process of the present invention which is characterised by the reaction of an alkali metal salt of 3-methyl-4-oxocrotonic acid of the formula wherein M stands for sodium or potassium with the (Z)-isomer of a Cis-triphenyl phosphonium salt of the formula wherein Ph stands for phenyl and X stands for a halogen, in the presence of a base. The alkali metal salt of methyl-4-oxocrotonic acid is in a preferred embodiment prepared in situ from an alkyl-3-methyl-4-oxocrotonate which is hydrolysed in the presence of an alkali hydroxide and without its isolation is used for the subsequent reaction step. However, the alkali metal of methyl-4-oxocrotonic acid can of course also be isolated before using it for the reaction with the (Z)-isomer of a C15-triphenyl phosphonium salt of formula II. Most preferably the potassium salt of methyl-4-oxocrotonic acid is prepared from efhyl-3-methyl-4-oxocrotonate by hydrolysis with potassium hydroxide. It has been found that the hydrolysis is preferably performed in the presence of a lower alcohol, most preferably in ethanol at temperatures between -10°C and 10°C, ideally between 0°C and 5°C. The preferred potassium hydroxide is conveniently applied in the form of an aqueous solution, e.g. of 50%. The (Z)-isomer of the Cj5-tripnenyl phosphonium salt occurs in the form of an isomeric mixture together with the (E)-isomer in a mother liquor which is obtained in the preparation of |3-c3rotene.(Riieggetal., HeJv. 44, 985 (1961)). This mother liquors as a rule contains both the (Z)- and the (E)-isomer in a ratio which may vary but as a rule is about 2:1. The (Z)-isomer of the Qs-triphenyi phosphonium salt can in a preferred embodiment of the invention be isolated from this mother liquor according to the following steps: a) extraction of a concentrate of the mother liquor with methylene chloride b) taking up of the organic phase in ethylacetate / n-butanol c) distilling off ethylacetate/ methylene chloride, d) replacing the distilled amount by ethyl actetate, e) crystallising out the (Z)-isomer and 0 filtering and drying It has been found that in step b) the n-butanol content in the ethylacetate is advantageously chosen in the range of 3% to 10%, preferably 3% to 5%. It may be necessary that crystallisation has to be initiated by seeding with crystals of 9-(Z)-isomer. Preferred Qs-tripbenyl phosphonium salt of formula II is the chloride salt. Delivery of the (Z)-isomer to the subsequent conversion into the 9-(Z)-RA advantageously takes place in the form of an alcoholic solution, most preferably in the form of an ethanolic solution. The process is expediently performed at a temperature between -15°C and 15X, preferably at a temperature between 0"C and 5°C. Temperatures outside this range either lead to a slowdown of the reaction or to an increased by-product formation Advantageously the reaction is performed in the presence of a lower alcohol, preferably in ethanol. Suitable base for the conversion into the 9-(Z)-RA is an alkali hydroxide. Preferably sodium hydroxide or potassium hydroxide, most preferably potassium hydroxide in the form of an aqueous solution of e.g. 50% is used. The work up of the reaction mixture can take place by the following steps: a) extraction with an organic solvent, preferably with methylene chloride, b) setting the pH of the water phase to about 3 to 4 with a suitable mineral acid e.g. with phosphoric acid c) extraction with methylene chloride d) exchange of solvent towards methanol by distilling off methylene chloride and, preferably at the same time continuous introduction of methanol e) separation of the 9-(Z)-RA which is crystallising from the mixture. Further purification of 9-(Z)-RA can be achieved by a recrystallisation in a lower alcohol, preferably in isopropanol. With regard to the sensitivity of the reactants and of the product it is crucial that the reaction steps are performed largely under the exclusion of light and oxygen. The following examples shall illustrate the invention without limiting it. WE CLAIM: 1. A process for the preparation of 9- (Z)-retinoic acid characterized in that an alkali metal salt of 3-methyl-4-oxocrotonic acid of the formula wherein M stands for sodium or potassium, which is prepared in situ from an alkyl -3-methyl~4-oxocrotonate which is hydrolysed in the presence of an alkali hydroxide, is reacted with the (Z) -isomer of a C15- triphenyl phosphonium salt of the formula wherein X stands for a halogen in the presence of a base. 2. The process as claimed in claim 1, wherein M stands for potassium and in that the potassium salt of methyl-4-oxocrotonic acid is prepared in situ from ethyl-3-methyl-4-oxocrotonate, which is hydrolysed in the presence of potassium hydroxide. 3. The process as claimed in claim 1, wherein X in formula II stands for chlorine. 4. The process as claimed in claim 1, wherein the (Z) -isomer of a Cis-triphenyl phosphonium salt is isolated from a mother liquor used in the J3-carotene synthesis containing an isomeric mixture of the (Z) -isomer together with the (E)-isomer, comprising the steps: a) extraction of a concentrate of the mother liquor with methylene chloride b) taking up of the organic phase in ethylacetate/n-butanol c) distilling off ethylacetate/methylene chloride d) replacing the distilled amount by ethylactetate e) crystallising out the (Z)-isomer f) filtering and drying 6. The process as claimed in any of claims 1 to 5, wherein the reaction is performed at a temperature between -15°C and 15°C. 7. The process as claimed in any of claims 1 to 6, wherein the reaction is performed in the presence of a lower alcohol. 8. The process as claimed in any of claims 1 to 7, wherein the base is an alkali hydroxide. 9. The process as claimed in claim 8, wherein the base is potassium hydroxide. 10. The process as claimed in any of claims 1 to 9, wherein the work up of the reaction mixture follows the steps: a) extraction with methylene chloride, b) setting the pH of the water phase to 3 to 4 with a suitable mineral acid c) extraction with methylene chloride d) exchange of solvent towards methanol by distilling off methylene chloride and continuous introduction of methanol e) separation of the 9- (Z)-retinoic acid which is crystallising from the mixture.

Documents:

2568-chenp-2005 abstract dupliccate.pdf

2568-chenp-2005 abstract.pdf

2568-chenp-2005 claims dupliccate.pdf

2568-chenp-2005 claims.pdf

2568-chenp-2005 correspondence others.pdf

2568-chenp-2005 correspondence po.pdf

2568-chenp-2005 description (complete) dupliccate.pdf

2568-chenp-2005 description (complete).pdf

2568-chenp-2005 form-1.pdf

2568-chenp-2005 form-18.pdf

2568-chenp-2005 form-26.pdf

2568-chenp-2005 form-3.pdf

2568-chenp-2005 form-5.pdf

2568-chenp-2005 others.pdf

2568-chenp-2005 pct.pdf

2568-chenp-2005 petition.pdf