US2012130097A1PendingUtilityA1
Process for the preparation of cyclopropyl carboxylic acid esters and derivatives
Est. expiryJun 2, 2020(expired)· nominal 20-yr term from priority
C07C 51/60C07C 2601/02C07C 247/22C07C 211/40C07B 2200/07C07C 67/347C07C 51/38C07C 69/753C07C 51/09C07C 57/60C07C 57/66C07C 61/40C07C 2601/14C07D 487/04
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Claims
Abstract
The invention relates to a novel process for the preparation of certain cyclopropyl carboxylic acid esters and other cyclopropyl carboxylic acid derivatives; a novel process for the preparation of dimethylsulfoxonium methylide and dimethylsulfonium methylide; to the use of certain cyclopropyl carboxylic acid esters in a process for the preparation of intermediates that can be used in the synthesis of pharmaceutically active entities; and to certain intermediates provided by these processes.
Claims
exact text as granted — not AI-modified1 . A process for the preparation of a compound of formula (I):
wherein:
R is phenyl substituted with one or more halogen;
Y is OR 1 , where R 1 is a straight chain alkyl, branched alkyl, cycloalkyl, or a substituted bicycloheptyl group;
which comprises contacting a compound of formula (II):
where R and Y are as defined above, with dimethylsulfoxonium methylide in the presence of a solvent at a temperature of −10° C.-90° C.
2 . A process for the preparation of a compound of formula (I) as claimed in claim 1 comprising the steps of;
i) reacting a trimethylsufoxonium salt with a solid metal hydroxide in dimethyl sulfoxide at ambient or an elevated temperature to produce dimethylsulfoxonium methylide; and
ii) contacting compound of formula (II) with dimethylsulfoxonium methylide in the presence of a solvent at a temperature of −10° C.-90° C.
3 . A process according to claim 2 in which the metal hydroxide is sodium hydroxide.
4 . A process according to claim 1 in which the compound of formula (II) is prepared from a compound of formula (III):
where R is as defined in claim 1 , by reaction with a chlorinating agent in the presence of an inert solvent and a catalyst at a temperature of 0-200° C., and than reacting the resulting solution with YH or Y, where Y is as defined in claim 1 , at an elevated temperature.
5 . A process according to claim 4 in which a compound of formula (III) is reacted with thionyl chloride in the presence of an inert solvent and pyridine at a temperature of 0-200° C., and the resulting solution is then reacted with YH or Y, where Y is as defined above at an elevated temperature.
6 . A process according to claim 1 in which YH represents L-menthol.
7 . A process according to claim 4 in which a compound of formula (III) is prepared by contacting a compound of formula (IV):
where R is as defined above, with malonic acid in the presence of pyridine and piperidne at elevated temperatures.
8 . A process for the preparation of a compound of formula (V):
where R is as defined in claim 1 , comprising base hydrolysis of a compound of formula (I).
9 . A process according to claim 8 wherein base hydrolysis is achieved using an alkali metal hydroxide and solvent at 10-100° C.
10 . A process for the preparation of a compound of formula (VI):
where R is as defined in claim 1 , from a compound of formula (V) by reaction with thionyl chloride in the presence of solvent and a catalyst at 0-200° C.
11 . A process for the preparation of a compound of formula (VII):
where R is as defined in claim 1 , from a compound of formula (VI), by reaction with an alkali metal azide in the presence of a phase transfer catalyst, aqueous potassium carbonate and an inert solvent.
12 . A process for the preparation of a compound of formula (VIII):
where R is as defined in claim 1 , from a compound of formula (VII), by rearrangement in toluene at elevated temperatures, and subsequent reaction with hydrochloric acid at elevated temperatures.
13 . A process for the preparation of a compound of formula (IX):
where R is as defined in claim 1 , by adjusting to pH 10 or more an aqueous solution of the salt of a compound of formula (VIII).
14 . A process for the preparation of a compound the mandelic acid salt of a compound of formula (IX) by addition of R-(−)-mandelic acid to the compound of formula (IX) as made in claim 13 , at ambient or an elevated temperature.
15 . A process according to claim 1 in which R is phenyl substituted by one or more fluorine atoms.
16 . A process according to claim 15 in which R is 3,4-difluorophenyl.
17 . A process according to claim 1 in which Y is chiral.
18 . A process according to claim 17 in which Y is L-menthoxy.
19 . A process according to claim 1 in which a compound of formula (I) is resolved to yield a compound of formula (Ia):
where R and Y are as defined in claim 1 , by crystallisation or by chromatrographic methods.
20 . A process according to claim 19 in which the resolution is carried out by extracting a compound of formula (I) into heptane and then effecting crystallisation from the heptane extracts.
21 . The intermediate compounds of formulae (I), (Ia), (II), (III), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX) and (IXa) above.
22 . The intermediate compounds;
(1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl trans-2-(3,4-difluorophenyl)cyclopropanecarboxylate; (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl trans- (1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate; (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl(E)-3-(3,4-difluorophenyl)-2-propenoate; (E)-3-(3,4-difluorophenyl)-2-propenoic acid; (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride; trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid; trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride; trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide; trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl amine; and trans-(1 R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate.Cited by (0)
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