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SYNTHESIS, PURIFICATION AND CRYSTALLINE FORM DATA OF DIENOGEST [17α-CYANOMETHYL-17β-HYDROXY-ESTRA-4,9-DIENE-3-ONE]

IP.com Disclosure Number: IPCOM000212002D
Publication Date: 2011-Oct-24
Document File: 5 page(s) / 581K

Publishing Venue

The IP.com Prior Art Database

Abstract

A process to obtain pure Dienogest [17α-cyanomethyl-17β-hydroxy-estra-4,9-di-ene-3-one] and its crystalline form data are disclosed.

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Page 01 of 5

SYNTHESIS, PURIFICATION AND CRYSTALLINE FORM DATA OF DIENOGEST [17α-CYANOMETHYL-17β-HYDROXY-ESTRA-4,9-DIENE-3- ONE]

ABSTRACT

A process to obtain pure Dienogest [17α-cyanomethyl-17β-hydroxy-estra-4,9-di-ene-3-one] and its crystalline form data are disclosed.

DESCRIPTION

A process for the synthesis of Dienogest [17α-cyanomethyl-17β-hydroxy-estra-4,9-di-ene-3-one] and its crystalline form data are disclosed.

The reaction is carried out in two steps, consisting in the alkylation of Ethylene Deltenone [3- Ethylenedioxy-estra-5(10), 9(11)-diene-17-one] with N-hexyllithium and acetonitrile followed by hydrolysis of the 3-ketal group with an acid, such as hydrochloric acid.

The crude product is purified with tetrahydrofuran and then with methanol/purified water.

REACTION PATHWAY

O

CH3 O

CH3 OH

N-hexyllithium, Acetonitrile, THF

HCl, aceton

N

O

O

O

1 2

CH3 OH

CH3 OH

N

N

O

O

O

2 3



Page 02 of 5

Synthesis of 17β-hydroxy-17α-cyanomethyl-3-ethylenedioxy-estra-5(10), 9(11)-diene (2):

A solution of N-hexyllithium 2,3 M in hexane is dropped in THF, under nitrogen flow, at a temperature ≤ 0 °C; the mixture is then cooled to a temperature of -7 °C and acetonitrile is added. The reaction mixture is maintained under stirring at -7 ÷ 0 °C and Ethylene Deltenone [3- Ethylenedioxy-estra-5(10), 9(11)-diene-17-one] (1) in tetrahydrofuran is added.

The reaction is checked by TLC. At the end of the reaction, the mixture is added to cold water (0 ÷ 5 °C) and extracted with ethyl acetate. The organic phase is washed with water and then with an aqueous solution of sodium chloride.

The solvent is distilled at 40 ÷ 45 °C under vacuum until a yellow oil is obtained.

Synthesis of Dienogest [17α-CYANOMETHYL-17β-HYDROXY-ESTRA-4,9-DIENE-3-ONE]

(3):

A solution of 17β-hydroxy-17α-cyanomethyl-3-ethylenedioxy-estra-5(10), 9(11)-diene (2) in acetone is cooled to 0 ÷ 5 °C and hydrochloric acid is dropped in the solution at 20 ÷ 25 °C. The reaction mixture is maintained under stirring at 20 ÷ 25 °C until the reaction is completed.

At the end of the reaction, the mixture is added to a solution of sodium bicarbonate in water cooled at 0 ÷ 5 °C and stirred.

A precipitate is filtered and suspended in potable water; after stirring at 20 ÷ 25 °C for about 3,5 hours, the precipitate is filtered and dried under vacuum.

First purification of Dienogest [17α-CYANOMETHYL-17β-HYDROXY-ESTRA-4,9-DIENE-3-

ONE] (3):

A suspension of crude Dienogest [17α-CYANOMETHYL-17β-HYDROXY-ESTRA-4,9-DIENE-3- ONE] (3) in THF is heated to reflux until a solution is obtained. Active charcoal is added and, after filtration, the s...