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New method for synthesis and purification of Drospirenone {Spiro[17H-dicyclopropa(6,7:15,16)cyclopenta[a]phenanthrene-17,2'(5'H)-furan]-3,5'(2H)-dione}

IP.com Disclosure Number: IPCOM000244372D
Publication Date: 2015-Dec-07
Document File: 8 page(s) / 1M

Publishing Venue

The IP.com Prior Art Database

Abstract

A novel process for synthesis and subsequent purification of Drospirenone {Spiro[17H-dicyclopropa(6,7:15,16)cyclopenta[a]phenanthrene-17,2'(5'H)-furan]-3,5'(2H)-dione} is disclosed.

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New method for synthesis and purification of Drospirenone {Spiro[17H- dicyclopropa(6,7:15,16)cyclopenta[a]phenanthrene-17,2'(5'H)-furan]-3,5'(2H)-dione}

ABSTRACT

A novel process for synthesis and subsequent purification of Drospirenone {Spiro[17H- dicyclopropa(6,7:15,16)cyclopenta[a]phenanthrene-17,2'(5'H)-furan]-3,5'(2H)-dione} is disclosed.

DESCRIPTION

A process for preparation and purification of Drospirenone {Spiro[17H-dicyclopropa(6,7:15,16)cyclopenta[a]phenanthrene-17,2'(5'H)-furan]-3,5'(2H)-dione}
is disclosed. The synthesis is performed in 4 steps, starting with the selective acetylation of 17-(3- Hydroxypropyl)-6β,7β:15β,16β-dimethyleneandrostane-3β,5β,17β-triol (1): the first step therefore is carried out in dichloromethane, in addiction with 4DMAP as catalyst and acetic anhydride as reactant. The second step comprises a dehydration in C5 with the consequent double bond formation in C4-C5, using thionyl chloride as dehydrating agent in DCM, 4DMAP as catalyst: the reaction gives Androst-4-ene-3β,17β, 17- (3-acetylpropyl)-, triacetate (3) as product. The following deprotection is performed in methanol in order to obtain Androst-4-ene-3β,17β-, 17-(3-hydroxypropyl)-, triol (4). The last step provides Drospirenone after cyclisation of this intermediate through an oxoammonium catalyzed oxidation performed with

n-butylammonium bromide (TBAB)and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). Is it possible to perform a different step instead of using sodium Hypochlorite, i.e. adding (diacetoxyiodo)benzene (BAIB) with TEMPO in order to perform the oxoammonium catalyzed oxidation. In both cases, using of BAIB or sodium hypochlorite, it is possible to prepare Drospirenone with high yield and purity.

Tetra-


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REACTION PATHWAY (Synthesis)

DCM

4-DMAP Ac2O

Methanol

NaOH AcOH glac.

1 2

DCM

4-DMAP Thionyl Chloride

4 3

DCM

TEMPO TBAB

Drospirenone crude (5)



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REACTION PATHWAY (Purification)

Dioxane

H2O


Drospirenonecrude Drospirenone1°ps

AcOEt

tBME

Drospirenone2°ps



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EXAMPLES:

Synthesis of [17-(3-Acetylpropyl)-6β,7β:15β,16β-dimethyleneandrostane-3β,17β-triacetate] (2):

The starting material, 17-(3-Hydroxypropyl)-6β,7β:15β,16β-dimethyleneandrostane-3β,5β,17β-triol (1), is mixed in dichloromethane at room temperature and the suspension is cooled to T<15 °C before the addiction of 4-DMAP. After that Ac2O is added dropwise into the stirring mix, monitoring carefully the temperature in order to keep it under 15°C, the suspension turn in a yellow solution. The mixture afterwards is brought back to 30°C and stirred until the end of reaction (checked by TLC ) and then the solution is poured in aqueous NaHCO3 10%. The aqueous phase is extracted again with dichloromethane and then the organic phases are gathered and washed two times with brine. Finally the organic phase is distilled under vacuum to dryness.

Synthesis of Androst-4-ene-3β,17β-, 17- (3-acetylpropyl)-, triacetate (3):

[17-(3...