Process for the production of 21-methoxy-11-beta-phenyl-19-nor-pregna-4,9-diene-3,20-dione derivatives

Patent metadata

Field	Value
Publication number	US-9683010-B2
Application number	US-201515108026-A
Country	US
Kind code	B2
Filing date	Feb 16, 2015
Priority date	Feb 17, 2014
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The present invention relates to a process for the synthesis of compounds of formula (I),

wherein the meaning of R is dimethylamino or acetyl group, using the compound of formula (III) or (IV), wherein the meaning of R′ is dimethylamino or 2-methyl-1,3-dioxan-2-yl group, as starting material and methoxymethyl lithium as reagent.

First claim

The invention claimed is:

1. Process for the synthesis of compound of formula (I)

wherein the meaning of R is dimethylamino or acetyl group, characterized by
a) reacting the compound of formula (III) or (IV),

wherein the meaning of R′ is dimethylamino or 2-methyl-1,3-dioxolan-2-yl group,
with methoxymethyl lithium,
b) removing the protective groups of the so obtained intermediate, and
c) acylating the hydroxyl group in position 17 of the so obtained compound of formula (II)

2. The process according to claim 1 , characterized by synthesizing the methoxymethyl lithium reagent the following way:
a) an isolated or a condensed ring aromatic hydrocarbon is dissolved in an ether type solvent,
b) lithium metal is added to the so obtained solution under inert atmosphere,
c) the mixture is stirred at 0-20° C. until lithium is dissolved,
d) the mixture is cooled to (−78)-(−40)° C. and methoxymethyl chloride is added.

3. The process according to claim 2 , characterized by using naphthalene or biphenyl as an isolated or a condensed ring aromatic hydrocarbon.

4. The process according to claim 2 , characterized by using tetrahydrofuran as an ether type solvent.

5. The process according to claim 2 , characterized by carrying out the reaction of step c) of claim 2 at a temperature between 5-10° C.

6. The process according to claim 2 , characterized by carrying out the reaction of step d) of claim 2 at a temperature of −55° C.

7. The process according to claim 1 characterized by removing the protective groups by acid hydrolysis and dehydration.

8. The process according to claim 1 , characterized by synthesizing the methoxymethyl lithium reagent in situ.

9. The process according to claim 1 , wherein R and R′ are dimethylamino.

Assignees

• Richter Gedeon Nyrt

Inventors

• Mahó Sándor
• Sánta Csaba
• Csörgei János
• Szabó Gábor
• Schäfer Tamás
• Béni Zoltán

Classifications

• C07J5/0053 Primary

  not substituted in position 16 · CPC title

• C07J41/0083 Primary

  substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings · CPC title

• C07J51/00

  Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00 · CPC title

• C07J21/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton · CPC title

• C07J9/00 Primary

  Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane · CPC title