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Process for preparation of an Anti-retroviral salt

IP.com Disclosure Number: IPCOM000246865D
Publication Date: 2016-Jul-08
Document File: 3 page(s) / 295K

Publishing Venue

The IP.com Prior Art Database

Abstract

Process relates to a improved process for preparation of therapeutically acceptable salt of an anti-retroviral substance without utilizing a base and intermittent addition of the required acid.

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 53% of the total text.

Page 01 of 3

Process for preparation of an Anti-retroviral salt

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An Anti-retroviral drug substance, chemically known as (3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8- hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13- pentaazatetradecane dioic acid dimethyl ester, sulfate (1:1) was approved by USFDA for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.

The drug substance is prepared in prior art according to the method disclosed in US 6,087,383 and US 7,829,720.

N

N

N

OH

O

OH

OH

O

N
H N N

H

N

H2

Base / Solvent

N

H2

O

Conc. HCl

N NH2

N NH2

O

Water Miscible Solvent

. 3 HCl

Amino Alcohol

Deprotected amino alcohol trihydrochloride

Deprotected Amino Alcohol

O

O

Coupling Agent

O

  N N

O N H

Water Miscible Solvent

O N H

COOH

Solvent

O

L-moc t-leucine

Active Ester

N

N

Alcohol / Hydrocarbon solvent

OH

O

OH

O

O O

N
H N N

H O

O O

N H

N
H N N

H O

N H

N
H O

O

N
H O

O

Dropwise addition of H SO

. H SO

Free Base

Sulfate Salt

Scheme-1: Preparation of sulfate salt of Anti-retroviral compound (I)

Described herein is a process for preparation of anti-retro viral free base and its sulphate salt (Scheme-
1).

Preparation of free base

The process involves initial preparation of the free base which comprises of treating the t-Boc amino alcohol intermediate with hydrochloric acid in a water-miscible solvent which is miscible with water,

1


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either partly or completely. The water-miscible solvent is selected from the group comprising of tetrahydrofuran, dimethoxyethane, methyl tetrahydrofuran, methyl acetate but preferably methyl tetrahydrofuran and tetrahydrofuran. The deprotection is carried out at a temperature of 30-60°C and slowly a biphasic mixture was formed. The layer containing the trihydrochloride salt of amino alcohol free base was separated after cooling to below ambient temperature.

The oily layer was dissolved in a water-immiscible solvent like dichloromethane and treated with either an organic or inorganic base like aqueous sodium hydroxide or triethyl amine, diisopropylethylamine, but preferably diisopropylethylamine.

The layer containing the free base of the deprotected amino alcohol was treated with L-Moc-tert- leucine in presence of coupl...