Dismiss
InnovationQ will be updated on Sunday, Oct. 22, from 10am ET - noon. You may experience brief service interruptions during that time.
Browse Prior Art Database

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

IP.com Disclosure Number: IPCOM000210887D
Publication Date: 2011-Sep-14

Publishing Venue

The IP.com Prior Art Database

Abstract

A process to obtain pure Etonogestrel [(17α)-13-ETHYL-17-HYDROXY-11-METHYLENE-18,19-DINORPREGN-4-EN-20-YN-3-ONE] and its crystalline form are disclosed.

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 33% of the total text.

Page 01 of 7

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

ABSTRACT

A process to obtain pure Etonogestrel [(17α)-13-ETHYL-17-HYDROXY-11-METHYLENE-18,19- DINORPREGN-4-EN-20-YN-3-ONE] and its crystalline form are disclosed.

DESCRIPTION

A process for the synthesis of Etonogestrel [(17α)-13-ethyl-17-hydroxy-11-methylene-18,19- dinorpregn-4-en-20-yn-3-one] and its crystalline form are disclosed.

The reaction is carried out in four steps. The 1st step consists in the protection of the 3-keto group of the starting material [13beta-ethyl-11-methylene-gon-4(5)-ene-3,17-one-17beta-ol] by using ethylene glycol, triethylorthoformate and p-toluensulphonic acid in dichloromethane to obtain 13beta-ethyl-11-methylene-gon-4(5)-ene-17-ol-3,3-ethylene oxoketal (Etonogestrel 1st

intermediate). The 2nd step consists in the oxidation, with aluminium isopropilate and acetone, of the 17-hydroxy group to give 13beta-ethyl-11-methylene-gon-4(5)-ene-17-one-3,3-ethylene oxoketal (Etonogestrel 2nd intermediate). The third step is characterized by the introduction of an alkynyl group in 17-alpha position by using lithium acetylide ethylendiamine complex in tetrahydrofuran to obtain 13beta-ethyl-11-methylene-18,19-dinor-17alpha-pregn-4-en-20-yn-3,3- ethylene oxoketal (Etonogestrel 3rd intermediate). The last step comprises the hydrolysis of the 3- ketal group with hydrochloric acid in acetone to give (17α)-13-ethyl-17-hydroxy-11-methylene- 18,19-dinorpregn-4-en-20-yn-3-one (crude Etonogestrel).

The crude product is then purified by two crystallizations; the first one with acetone/n-hexane, the second one with methanol/water.

REACTION PATHWAY

C

H3

C

H2

C

H3

C

H2

OH

1 2

OH

1) Ethylene Glycol
2) Triethoxymethane
3) p-toluensulphonic

acid
4) Dichloromethane

O

O

O


Page 02 of 7

C

H3

C

H2

OH

O

1) Aluminum Isopropilate
2) Acetone

C

H3

C

H2

O

O

O

O

2 3

C

H3

C

H2

C

H3

C

H2

O

O

H

CH

1) Lithium acetylide

ethylenediamine complex
2) Tetrahydrofuran

O

O

O

O

3 4

1) Conc. HCL
2) Acetone

C

H3

C

H2

O

H

C

H3

C

H2

O

H

CH

CH

O

O

O

4 5


Page 03 of 7

Synthesis of Etonogestrel 1st intermediate [13beta-ethyl-11-methylene-gon-4(5)-ene-17-ol-3,3- ethylene oxoketal] (2):

Dichloromethane, ethylene glycol, 13beta-ethyl-11-methylene-gon-4(5)-ene-3,17-one-17beta-ol (1), triethylorthoformate and p-toluensulphonic acid are mixed, stirred and heated up to 40 °C. The reaction is checked by HPLC control. When the reaction is finished, the mass is cooled down to room temperature (20 to 25 °C). The reaction mixture is transferred in a mixture of dichloromethane and potable water, and the aqueous phase is extracted two times with dichloromethane; the organic phases are washed with a solution of sodium chloride in potable water and then the solvent is distilled, under vacuum, at about 40 °C. Methanol is charged and the solvent is distilled again at 40 °C and under vacuum until the density of the distilled solvent is about 0.79 g/ml. The m...