Synthesis of cyclopropane carboxylic acids
AssigneeTakeda Pharmaceutical Company Limited
InventorsNikolaos Papaioannou, Michael Jonathan Fray, Andreas Rennhack, Sarah Jocelyn Fink
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Abstract
The present disclosure provides methods of preparing substituted cyclopropane compounds.
Claims26
A process for the preparation of a trans racemate of formula (I)
- wherein
- P1 is a protecting group (such as tert-butyl)
- R1 is H or optionally substituted C1-C6 alkyl,
- said process comprising reacting a compound of formula (II):
- wherein R1 is defined above for compounds of formula (I)
- with a nitrogen ylid, optionally formed in situ, prepared by
- reacting an α halo ester, (such as methyl chloroacetate and tert-butyl bromoacetate)
- with a tertiary amine, (such as DABCO),
- to form a quaternary ammonium salt,
- followed by treatment with an alkali metal base (such as Cs2CO3 or K2CO3) and/or an organic base (such as DBU),
- in a polar aprotic solvent (such as acetonitrile)
- at an elevated temperature, (such as 70-80° C.)
- such that the compound of formula (I) is formed (for example with high diastereoselectivity, such as 50:1, over the corresponding cis racemate)
A process according to any preceding claim wherein the alkali metal base is Cs2CO3.
A process according to any preceding claim, wherein the polar aprotic solvent is acetonitrile.
A process according to any preceding claim wherein the elevated temperature is 70-80° C.
A process according to any preceding claim, wherein the reaction is performed for 12 to 30 hours, such as 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, such as 20 hours.
A process according to any preceding claim wherein the protecting group P1 is removed from compounds of formula (I) to liberate the free carboxylic acid of formula (IV):
- as a trans racemate (for example in high diastereomeric purity, in particular that is essentially free of the cis racemate) by:
- a) acidolysis using an organic acid (such as TFA) in a chlorinated solvent (such as DCM);
- or
- b) saponification using an alkali metal hydroxide (such as sodium hydroxide) in an aqueous medium (such THF and water),
- followed by acidification with (for example aqueous hydrochloric acid), to liberate the free acid from the salt so formed.
A process for the resolution of a compound of formula (IV) into essentially one or other of its enantiomeric forms, for example to provide a compound of formula (V) (such as absolute as drawn):
- for example wherein the resolution is effected by reaction with an optically pure chiral amine (such as(S)-1-(naphthalen-2-yl) ethanamine or(S)-1-(naphthalen-1-yl) ethanamine),
- in a suitable solvent (such as ethyl acetate, isopropanol and dimethyl carbonate) to form a mixture of diastereomeric salts from which the preferred diastereomeric salt crystallises and is collected by filtration.
A process according to any preceding claim wherein R1 is C1-3 alkyl, such as methyl, ethyl, propyl or isopropyl, in particular methyl.
A process according to any preceding claim wherein P1 is C1-4 alkyl such as t-butyl.
A process wherein the compound of formula (VII) is reacted with a compound of formula (VIII)
- to provide a compound of formula (IX)
- or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are defined above.
A compound obtained or obtainable from any one of the preceding claims.
A compound of formula (I), (II), (IV), (V), (VI), (VII), (VIIa) (VIII), (IX), (IXa) or (LXb).
Dependencies are inferred from the claim text.