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SYNTHESIS AND PURIFICATION OF NORGESTIMATE [(17α)-17-(ACETYLOXY) 13-ETHYL-18,19-DINOR-PREGN-4-EN-20-YN-3-ONE-3-OXIME]

IP.com Disclosure Number: IPCOM000208408D
Publication Date: 2011-Jul-07
Document File: 4 page(s) / 163K

Publishing Venue

The IP.com Prior Art Database

Abstract

A process to obtain pure Norgestimate [(17α)-17-(ACETYLOXY) 13-ETHYL-18,19-DINOR-PREGN-4-EN-20-YN-3-ONE-3-OXIME] is disclosed.

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This is the abbreviated version, containing approximately 53% of the total text.

Page 01 of 4

SYNTHESIS AND PURIFICATION OF NORGESTIMATE [(17α)-17- (ACETYLOXY) 13-ETHYL-18,19-DINOR-PREGN-4-EN-20-YN-3-ONE-3- OXIME]

ABSTRACT

A process to obtain pure Norgestimate [(17α)-17-(ACETYLOXY) 13-ETHYL-18,19-DINOR- PREGN-4-EN-20-YN-3-ONE-3-OXIME] is disclosed.

DESCRIPTION

A process for the synthesis of Norgestimate [(17α)-17-(acetyloxy) 13-ethyl-18,19-dinor-pregn-4-en- 20-yn-3-one-3-oxime] is disclosed.

The reaction is carried out in two steps. The 1st step consists in the acetylation of Levonorgestrel [(17α)13-ethyl-17-hydroxy-18,19-dinorpregn-4en-20-yn-3-one] by using acetic anhydride and 4-dimethylaminopyridine in dichlorometane as solvent to obtain Levonorgestrel Acetilated (Norgestimate 1st intermediate). The 2nd step consists in the introduction of the oxime group in the 3-position of Levonorgestrel Acetilated by using hydroxylamine hydrochloride in pyridine as solvent.

The crude product is then purified by two crystallizations with methanol.

REACTION PATHWAY

C

H3 OH

O

C

H3 O

CH3

CH

CH

H

H

H H

H H

1) Dichloromethane
2) Acetic anhydride
3) 4-Dimethylaminopyridine

H H

O

O

Levonorgestrel C21H28O2 ; MW 312.45

Levonorgestrel acetylated C23H30O3 ; MW 354.48

1 2


Page 02 of 4

O

O

C

H3 O

CH3

C

H3 O

CH3

CH

C

H

H H

H H

H H

H H

O

N

Levonorgestrel acetylated C23H30O3 ; MW 354.48


1) Pyridine

2) Hydroxylamine hydrochloride

3) Hydrochloric acid

OH

Norgestimate crude C23H31NO3 ; MW 369.49

2 3

Synthesis of Norgestimate 1° intermediate [(17α)-17-(acetyloxy) 13-ethyl-18,19-dinor-pregn-4-en- 20-yn-3-one] (2):

Levonorgestrel [(17α) 13 - ethyl - 17 - hydroxyl - 18, 19 - dinorpregn - 4 en - 20 - yn - 3 - one] (1), dichloromethane, acetic anhydride and 4-dimethylaminopyridine are mixed, under stirring and nitrogen atmosphere, at room temperature (20 to 25 °C). At the end of the reaction, the mixture is washed twice with potable water by separation of the phases. The organic phase is concentrated under stirring and then cooled to room temperature to allow the addiction of methanol to the mixture. After the solvent is distillated, the mixture is cooled down to 0 to 5 °C and kept in these conditions and under stirring. The reaction product is separated by filtration. Norgestimate 1°intermediate (2) is obtained and dried under vacuum.

Synthesis of Norgestimate crude [(17α)-17-(acetyloxy) 13-ethyl-18,19-dinor-pregn-4-en-20-yn-3- one-3-oxime] (3):

Norgestimate 1st intermediate (2), pyridine and hydroxylamine hydrochloride are mixed under stirring at room temperature (20 to 25 °C). At the end of the reaction, the mixture is transferred to a solution of hydrochloride acid in potable water and dichloromethane previously cooled to 5 to 10 °C. The organic phase obtained by separation is washed with a solution of hydrochloride acid in potable water and then with a solutio...