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SYNTHESIS AND PURIFICATION OF CICLESONIDE [11β , 16α] – 16, 17 – [(CYCLOHEXYLMETHYLENE)BIS(OXY) – 11 – HYDROXY – 21 – (2 – METHYL – 1 – OXOPROPOXY)PREGNA – 1,4 – DIENE – 3, 20 - DIONE]

IP.com Disclosure Number: IPCOM000172509D
Publication Date: 2008-Jul-10
Document File: 3 page(s) / 94K

Publishing Venue

The IP.com Prior Art Database

Abstract

A process to obtain Ciclesonide [11β, 16α] – 16, 17 –[(Cyclohexylmethylene)bis(oxy) – 11 – hydroxy – 21 – (2 – methyl – 1 – oxopropoxy)pregna – 1,4 – diene – 3, 20 - dione] is disclosed.

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SYNTHESIS AND PURIFICATION OF CICLESONIDE [11, 16] - 16, 17 - [(CYCLOHEXYLMETHYLENE)BIS(OXY) - 11 - HYDROXY - 21 - (2 - METHYL - 1 - OXOPROPOXY)PREGNA - 1,4 - DIENE - 3, 20 - DIONE]

ABSTRACT

A process to obtain Ciclesonide [11 , 16˄] - 16, 17 -[(Cyclohexylmethylene)bis(oxy) - 11 - hydroxy - 21 - (2 - methyl - 1 - oxopropoxy)pregna - 1,4 - diene - 3, 20 - dione] is disclosed.

DESCRIPTION

A process for the synthesis of Ciclesonide [11 , 16˄] - 16, 17 -[(Cyclohexylmethylene)bis(oxy) - 11 - hydroxy - 21 - (2 - methyl - 1 - oxopropoxy)pregna - 1,4 - diene - 3, 20 - dione] is disclosed.

The reaction is carried out in 2 steps; the first one comprising the acetalyzation of 16˄ - hydroxy - prednisolone with butyraldehyde, the second one comprising the "one-pot" transacetalyzation with cyclohexanecarboxaldehyde and esterification with isobutyryl chloride.

The crude product is then purified by crystallization in a water-miscible organic solvent or a mixture therefore.

REACTION PATHWAY

O

O

OH

O

OH

O

H

CH3 OH

OH

Butyraldehyde Perchloric acid 70 % Dichloromethane

Cyclohexanecarboxaldehyde Perchloric acid 70 % Triethylamine
4 - Dimethylaminopyridine Isobutyryl chloride Dichloromethane

O

H

CH3 O

O

CH3

CH3

 R H

O

1 2

R = CH2CH2CH3

O

C

H3

H

O

OH

O

O

O

CH3

O

H

CH3 O

O

O

H

CH3 O

O

CH3

 R H

CH3

O

2 3

R = CH2CH2CH3

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EXAMPLES:

Synthesis of [16˄, 17 - [1(R,S) - Buthylidenedioxy]- 11 , 21 - dihydroxypregna - 1,4 - diene - 3, 20 - dione] (2):

16˄ - hydroxyprednisolone (1), dichloromethane and butyraldehyde are mixed at room temperature; the resulting solution is cooled to 15 ÷ 17 °C and perchloric acid 70 % is added dropwise in about 40 minutes. The reaction mixture is stirred for almost 16 hours at 15 ÷ 17 °C and put into aqueous K2CO3 10 %. The mixture is then extracted with dichloromethane, the organic layer washed with water and brine and distilled under vacuum. Methanol is added and distilled under vacuum to obtain a precipitate which is separated by filtration.
[16˄, 17 - [1(R,S) - Buthylidenedioxy]- 11 , 21 - dihydroxypregna - 1,4 - diene - 3, 20 - dione] (2) is obtained and dried under vacuum.

Synthesis of Ciclesonide [11 , 16˄] - 16, 17 -[(Cyclohexylmethylene)bis(oxy) - 11 - hydroxy - 21 - (2 - methyl - 1 - oxopropoxy)pregna - 1,4 - diene - 3, 20 - dione] (3):

Cyclohexanecarboxaldehyde and dichloromethane are stirred at room temperature for about 15 minutes, [16˄, 17 - [1(R,S) - Buthylidenedioxy]- 11 , 21 - dihydroxypregna - 1,4 - diene - 3, 20 - dione] (2) is added and the mixture is heated to 35 ÷ 37 °C. Perchloric acid is added dropwise at 35 ÷ 37 °C in about 40 minutes. Meanwhile a solution of...