US 2014/0350301 A1Published application

Novel processes for the preparation of phenylcyclopropylamine derivatives and use thereof for preparing ticagrelor

AssigneeActavis Group Ptc Ehf

InventorsAnil Shahaji KHILE, Vignesh NAIR, Nikhil TRIVEDI, Nitin Sharadchandra PRADHAN

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Abstract

Provided herein are novel processes for the preparation of phenylcyclopropylamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Provided particularly herein are novel, commercially viable and industrially advantageous processes for the preparation of a substantially pure ticagrelor intermediate, trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine. Provided further herein are novel acid addition salts of trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine, and process for their preparation. The intermediate and its acid addition salts are useful for preparing ticagrelor, or a pharmaceutically acceptable salt thereof, in high yield and purity.

Claims15

Dependent claims

A process for preparing substituted phenylcyclopropylamine derivatives of formula II:

or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, or an acid addition salt thereof;
wherein R1, R2, R3, R4 and R5 are, each independently, selected from hydrogen and a halogen atom, with the proviso that the benzene ring in formula II is substituted with one or more halogen atoms, wherein the halogen atom is F, Cl, Br or I;
comprising:
a) reacting the substituted cyclopropanecarboxylic acid compound of formula III:
or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, or an acid addition salt thereof, wherein R1, R2, R3, R4 and R5 are as defined in formula II;
with an azide compound, with the proviso that the azide does not include sodium azide, in the presence of an alcohol and a base, optionally in the presence of a first solvent, to produce a substituted cyclopropanecarbamate compound of formula IX:
or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, wherein ‘R’ is an alkyl, cycloalkyl, aryl or aralkyl group;
and wherein R1, R2, R3, R4 and R5 are as defined in formula II;
and
b) subjecting the cyclopropanecarbamate compound of formula IX to acidic hydrolysis with an acid in a second solvent to produce the substituted phenylcyclopropylamine derivatives of formula II or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, and optionally converting the compound of formula II obtained into an acid addition salt thereof.

7 more elements

A process for preparing substituted phenylcyclopropylamine derivatives of formula II:

or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, or an acid addition salt thereof;
wherein R1, R2, R3, R4 and R5 are, each independently, selected from hydrogen and a halogen atom, with the proviso that the benzene ring of formula II is substituted with one or more halogen atoms, wherein the halogen atom is F, Cl, Br or I;
comprising:
a) reacting the substituted cyclopropanecarboxylic acid compound of formula III:
or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, or an amine salt thereof, wherein R1, R2, R3, R4 and R5 are as defined in formula II;
with an activating agent in the presence of a base, optionally in the presence of a racemisation suppressant, in a first solvent to produce an intermediate compound, followed by amidation with hydroxylamine or an acid addition salt thereof to produce a cyclopropanecarboxamide compound of formula X:
or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, wherein R1, R2, R3, R4 and R5 are as defined above;
b) reacting the cyclopropanecarboxamide compound of formula X with an activating agent, followed by treatment with an alcohol, optionally in the presence of a second solvent, to produce a substituted cyclopropanecarbamate compound of formula IX:
or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, wherein ‘R’ is an alkyl, cycloalkyl, aryl or aralkyl group;
and wherein R1, R2, R3, R4 and R5 are as defined in formula II;
and
c) subjecting the cyclopropanecarbamate compound of formula IX to acidic hydrolysis with an acid in a third solvent to produce the substituted phenylcyclopropylamine derivatives of formula II or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, and optionally converting the compound of formula II obtained into an acid addition salt thereof.

9 more elements

A one pot process for preparing substituted phenylcyclopropylamine derivatives of formula II:

or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, or an acid addition salt thereof;
wherein R1, R2, R3, R4 and R5 are, each independently, selected from hydrogen and a halogen atom, with the proviso that the benzene ring of formula II is substituted with one or more halogen atoms, wherein the halogen atom is F, Cl, Br or I;
comprising:
a) reacting the substituted cyclopropanecarboxylic acid compound of formula III:
or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, or an amine salt thereof, wherein R1, R2, R3, R4 and R5 are as defined in formula II;
with an acid activating agent in the presence of a base in a solvent to produce an intermediate compound, followed by amidation with hydroxylamine or an acid addition salt thereof to produce a cyclopropanecarboxamide compound of formula X:
or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, wherein R1, R2, R3, R4 and R5 are as defined above;
b) reacting the cyclopropanecarboxamide compound of formula X, in-situ, with a carbonyl source to produce a cyclopropanedioxazol compound of formula XI:
or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, wherein R1, R2, R3, R4 and R5 are as defined in formula II;
c) subjecting the cyclopropanedioxazol compound of formula XI, in-situ, to thermal rearrangement at boiling temperature of the reaction solvent to produce a cyclopropaneisocyanate compound of formula XII:
or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, wherein R1, R2, R3, R4 and R5 are as defined in formula II;
d) reacting the cyclopropaneisocyanate compound of formula XII, in-situ, with an alcohol at the boiling temperature to produce a cyclopropanecarbamate compound of formula IX:
or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, wherein ‘R’ is an alkyl, cycloalkyl, aryl or aralkyl group;
and wherein R1, R2, R3, R4 and R5 are as defined in formula II;
and
e) subjecting the cyclopropanecarbamate compound of formula IX to acidic hydrolysis with an acid to produce the substituted phenylcyclopropylamine derivatives of formula II or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, and optionally converting the compound of formula II obtained into an acid addition salt thereof.

13 more elements

Solid state form of an acid addition salt of trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine, wherein the acid addition salt is a tartrate salt, a di-p-toluoyl-tartrate salt, an (S)-ketopinate salt, a (D)-malate salt, a (D)-camphorsulfonate salt, a (R)-(−)-α-methoxyphenyl acetate salt, a fumarate salt, a phosphate salt or a sulfate salt.

Dependencies are inferred from the claim text.

Facts

Application: 14/298,319Filed 6 Jun 2014
Priority: IN 1841/CHE/201030 Jun 2010
Published: 27 Nov 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07C 209/62
Preparation of compounds containing amino groups bound to a carbon skeleton: by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or…
C07C 209/56
By rearrangement reactions: from carboxylic acids involving a Hofmann, Curtius, Schmidt, or Lossen-type rearrangement
C07C 211/35
Of a saturated carbon skeleton: containing only non-condensed rings
C07C 211/40
Of an unsaturated carbon skeleton: containing only non-condensed rings