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AN IMPROVED PROCESS FOR PREPARATION OF [2-[(1R)-3-(DI(PROPAN-2-YL)AMINO)-1-PHENYLPROPYL]-4-(HYDROXYMETHYL)PHENYL] 2-METHYLPROPANOATE.

IP.com Disclosure Number: IPCOM000223224D
Publication Date: 2012-Nov-11
Document File: 5 page(s) / 36K

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AN IMPROVED PROCESS FOR PREPARATION OF [2-[(1R)-3-(DI(PROPAN-2- YL)AMINO)-1-PHENYLPROPYL]-4-(HYDROXYMETHYL)PHENYL] 2-

METHYLPROPANOATE.

    [2-[(1R)-3-(Di(propan-2-yl)amino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl] 2- methylpropanoate, referred as 'compound ( I)' , has following formula:

Compound (I)

    Described hereinafter, is an improved process for preparation of compound (II), a key intermediate and the metabolite of Compound I The process can be illustrated by the following scheme:

H3C

OH

Cl

O

N

+

N

H3C

(VI)

(V)

OH

O

O

N

Pd/C, MeOH

N

O H

N

OH

OH

(II)

(III)

(IV)

    For the purpose of clarity and as an aid in the understanding of the process, as disclosed herein, the following terms and abbreviations are defined below:


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Compound I [2-[(1R)-3-(Di(propan-2-yl)amino)-1-phenylpropyl]-4- (hydroxymethyl)phenyl] 2-methylpropanoate

Compound II 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl) phenol

Compound III (4-(benzyloxy)-3-((R)-3-(diisopropylamino)-1-phenylpropyl) phenyl) methanol

Compound IV 4-(benzyloxy)-3-((R)-3-(diisopropylamino)-1-phenylpropyl)benzaldehyde

Compound V R)-3-(2-(benzyloxy)-5-methylphenyl)-N-ethyl-N-isopropyl-3- phenylpropan-1-amine

Compound VI 2-((R)-3-(diisopropylamino)-1-phenylpropyl)-4-methylphenol

Impurity A 1-((benzyloxy)methyl)benzene

Impurity B (R)-N-benzyl-3-(2-(benzyloxy)-5-methylphenyl)-N-isopropyl-3- phenylpropan-1-amine hydrochloride

Impurity C 4-(benzyloxy)-3-((R)-3-(diisopropylamino)-1-phenylpropyl)benzoic acid

Impurity D (4-(benzyloxy)-3-((R)-3-(diisopropylamino)-1- phenylpropyl)phenyl)methanol-N-Oxide

Impurity E 4-(benzyloxy)-3-((R)-3-(diisopropylamino)-1-phenylpropyl)benzoic acid- N-Oxide

Impurity F (4-(benzyloxy)-3-((R)-3-(isopropylamino)-1- phenylpropyl)phenyl)methanol

Impurity G (3-((R)-3-amino-1-phenylpropyl)-4-(benzyloxy)phenyl)methanol

Impurity H 3-((R)-3-(diisopropylamino)-1-phenylpropyl)-4-hydroxybenzoic acid

Impurity I 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(methoxymethyl)phenol

Impurity J 4-(hydroxymethyl)-2-((R)-3-(isopropylamino)-1-phenylpropyl)phenol


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Impurity K 2-((R)-3-amino-1-phenylpropyl)-4-(hydroxymethyl)phenol

The above process comprises the steps of;

i. protecting the hydroxyl group of compound of formula (VI) or its salts (for example, protecting with benzyl chloride),

ii. oxidizing the methyl group of compound of formula (V) to aldehyde of compound (IV) iii. reducing the aldehyde group of compound (IV) to alcohol of compound (III), and
iv. deprotecting or debenzylating compound (III) to (II).

    The compound of formula (VI) can be prepared for example according to the procedure describe in Example 12 and Example 22 of US5382600.

    The protecting of the compound of formula VI of Step (i) can be done for example by benzylating the compound of formula (VI) or its pharmaceutically acceptable salt thereof with a benzylating reagent in the presence of a base to obtain the compound of formula (V).

    During the benzylating of the compound of formula (VI),...