Title of Invention

SIMPLE & IMPROVED PROCESS FOR THE PREPARATION OF ANDROSTANE INTERMEDIATES USEFUL FOR PREPARATION OF ANTI-INFLAMMATORY COMPOUNDS

Abstract Disclosed herein is a simple, one-pot process for the preparation of fluticasone propionate comprising treating the compound of formula II with piperdine to obtain compound of formula III, which is reacted in situ with bromo fluoro methane in the absence of any inorganic base to yield a compound of formula (I). The invention also discloses process for preparation of compound of formula III.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION: "Simple and one-pot process for the preparation of androstane intermediates useful for preparation of anti-inflammatory compounds"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008,
Maharashtra, India

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner
in which it is to be performed.


Field of the Invention
This invention relates to simple, and one-pot process for the preparation of androstane intermediates useful for preparation of anti-inflammatory compounds more particularly relates to processes for the synthesis of fluticasone propionate.
Background of prior art
Fluticasone dipropionate is a compound, which belongs to the class of corticosteroid. Corticosteroids are hormones produced naturally by the adrenal glands that have many important functions, including control of inflammatory responses. Fluticasone propionate is chemically termed as S-(fluoromethyl)-6a,9a-difluoro-llp-ihydroxy-17a-propionyloxy 16a-methyl-3-oxoandrosta-1,4-diene-17 P -carbothioate, 17-propionate. Fluticasone propionate is lipophilic and has a strong affinity for the glucocorticoid receptor. Like other topical corticosteroids, fluticasone propionate has antiinflammatory, antipruritic, and vasoconstrictive properties.
Fluticasone is a synthetic corticosteroid and is used to decrease inflammation in the lungs. When inhaled into the lungs it is absorbed into the cells of the lungs and airways. Here it works by preventing the release of certain chemicals from the cells. These chemicals are important in the immune system and are normally involved in producing immune and allergic responses that result in inflammation. By decreasing the release of these chemicals in the lungs and airways, inflammation is reduced. In asthma, the airways tighten due to inflammation and can also be blocked by mucus. This makes it difficult for air to get in and out of the lungs. By preventing the inflammation and excess mucus formation, fluticasone helps prevent asthma attacks. It is not used to treat an asthma attack. Amongst other application in the form of ointments, cream etc, fluticasone is also used via an inhaler device this delivers the medicine directly into the lungs where it is needed.
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Fluticasone propionate and its intermediates are synthesized via various pathways as given in US 4578221, US 4335121, WO0162722, GB 2088877A, Scheme below shows one of the most commonly used pathway for the synthesis of fluticasone propionate.





Compound of formula III is the key intermediate for the synthesis of fluticasone propionate. Various prior art methods are known for the synthesis of this key intermediate and synthesizing fluticasone propionate using this intermediate. These prior art processes have certain disadvantages and are described below.
GB 2088877A discloses a process for the preparation of compound of Formula III wherein compound of formula II is hydrolysed using very high volumes of diethyl amine at reflux temperature under nitrogen for about 6 hours. This process yields a brown reaction mass and leads to a product with 66 % yield and having purity not more than 85%. The product isolated further needs to be purified which leads to a very low yield of about 36% product on the basis of crude product. The compound III is reacted with
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bromo chloro methane in presence of a base and then converted to a bromo compound which is reacted with sodium iodide and finally with silver fluoride to give fluticasone propionate.
WOO 162722 A2 also discloses a process to make compound of formula III by using alkali metal alkoxide, thioalkoxide, hydrated sufide salt as hydrolyzing agents, using dimethyl acetamide as solvent at a temperature of -15°C, after the reaction pH of the reaction mass is adjusted to 6 with hydrochloric acid to give the product in 80% yield. The compound III is then reacted with chloro fluoro methane in presence of an inorganic base at -10°C to give fluticasone propionate. Sodium thiomethoxide is a corrosive and moisture sensitive reagent, Use of this reagent generates toxic methyl mercaptan during acidification. Amongst the hydrolyzing agents used Sodium hydrosulfide is an unstable reagent and decomposes on storage, there is generation of toxic hydrogen sulfide fumes during the reaction . This makes the process hazardous to health and environment. Hence is not an industrially suitable process.
PCT application WO2004/001369 A2 discloses another process for the synthesis of fluticasone. It describes the formation of compound of formula III by hydrolysis using alkali-metal carbonate-alcohol system. This is then converted to fluticasone propionate by reacting with bromo fluoro methane in presence of a base.
In the prior art processes compound III is reacted with alkyl halide always in presence of an inorganic base. The process of the present invention avoids the use of any inorganic base. In the processes disclosed in prior art, the compound of formula (III) was isolated from the reaction mixture and then subsequently converted into fluticasone propionate.
In chemistry, one pot synthesis is a strategy with the aim to improve the efficiency of a chemical reaction whereby, the reactant is subjected to successive reactions in one and the same pot. The one pot synthesis is much desired by the chemist to avoid the excess cost and time involved in the isolation and purifications of the intermediates.
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In light of the above disadvantages of the prior art there is a need for simple and one-pot process for the synthesis of fluticasone propionate, the present invention provide such process.
Objectives of the Invention:
The main objective of the present invention is to ameliorate one or more disadvantages
associated with the prior art.
Another objective is to provide a process for preparation of fluticasone propionate in
good yield and purity.
Further objective is to provide a process with the aim of improving the efficiency by
carrying out the reaction in one and the same pot.
Summary of the Invention:
In one aspect, the present invention discloses a process for preparation of fluticasone propionate which process comprises the reaction of the compound of formula II with piperidine in dimethyl acetamide solvent to obtain the compound of formula (III). The compound of formula (III) further reacted in situ with bromo fluoro methane in absence of any inorganic base to get fluticasone propionate, which is crystallized from a suitable solvent preferably a mixture of acetone and ethyl acetate.
In another aspect, the invention provides a process for preparation of compound of formula III, wherein the compound of formula II was treated with piperidine to obtain the compound of formula III and the product was isolated from water. The compound of formula III further converted into fluticasone propionate by the methods known in the art.
Detailed description of the Invention:
In accordance with the above objective, the present invention provides a simple and one pot process for the synthesis of fluticasone propionate wherein
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piperidine

F (III)
Not Isolated

0wSCH2F
(I)

the compound of formula II is treated in with a solution containing piperidine at a temperature range of 10-30° C to obtain compound of formula (III). The solution contains an organic solvent preferably dimethylacetamide. The compound of formula (III) is further reacted in situ with bromo fluoro methane in the absence of any inorganic base at a temperature of 0-10° C to obtain fluticasone propionate.
The compound of formula I is crystallized from a suitable solvent preferably a mixture of acetone and ethyl acetate.
The reactions are carried out at a temperature range of 0 to 35°C.
In another embodiment, the present invention provides a process for the synthesis of fluticasone propionate of formula (I)

which comprises treating compound of formula (II)

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with an amine consisting of either aliphatic amines ,aromatic amines, cyclic amines or mixtures thereof and isolating the pure compound of formula (III) from water. One preferred amine is piperidine. The reaction is suitably carried out at a temperature of 10-30°C.






The compound of formula (III) can be further converted into fluticasone propionate (I) and its analogues using the processes known in the art.
The following specific examples are presented to illustrate the preferred mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the forgoing description.
Example 1
Preparation of S-(fluoromethyl)-6,9-difluoro-l 1β-ihydroxy-17a-propionyloxyl6a-methyl-3 -oxoandrosta-1,4-diene-17p-carbothioate, 17-propionate. 6a,9a-difluoro-11 (3-hydroxy-16a-methyl-3-oxo-androsta, 1 -4-diene, 17-N,N(dimethyl-thiocarbamoyl)-17-a-propionate 20.0 gm(0.037 moles) was stirred with 60 ml N,N dimethyl acetamide. The contents were cooled to 20°C. Piperidine 15 ml (0.152 moles) was added and the reaction mass was stirred for 3 hrs. at 25-30°C. The reaction mass was further cooled to 0-5°C and bromo fluoro methane (5.5 gms, 0.0043 moles) was added maintaining the temperature below 10°C. The reaction mass was stirred at 10°C for additional 1 hr. Water 180 ml was added slowly to the reaction mass maintaining temp below 20°C. The pH of the resulting suspension was adjusted to 3 using dilute HC1 50 ml (1:1 ,water :Conc HC1). The suspension was stirred for l hr. filtered and washed with water till neutral pH. The solid obtained was dried under vacuum at 60-65°C to get 17.8
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gms of the titled compound. The product is further crystallized from mixture of acetone and ethyl acetate to obtain 8.6 gms of the product having HPLC purity 99.2%.
Example 2
Preparation of 6,9-difluoro-ll(3-ihydroxy-16a-methyl-3-oxo-androstal,4-diene,17 --
propionyloxy-17-β-carbothioic acid
6a,9a-difluoro-11 |3-hydroxy-16a-methyl-3-oxo-androsta, 1 -4-diene, 17-N,N(dimethyl-
thiocarbamoyl)-17-a-propionate 100 gms (0.185 moles) was treated with piperidine 200
ml (2moles) at 20-30°C for 3hrs. After completion of reaction the reaction mass was
diluted with 300 ml toluene and then quenched with 300 ml water at 10-20°C. The pH of
the resulting suspension was adjusted to 3 at 10-20°C using dilute HCl 50 ml (1:1,
water:Conc HCl). The suspension was stirred for l hr. filtered and washed with water till
neutral pH. The solid obtained was dried under vacuum at 60-65°C for 12 hrs to yield 84
gms of the titled compound.
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We Claim,

1. One-pot synthesis for the preparation of Fluticasone propionate of Formula (I), comprising the steps of:






(a) treating a compound of Formula (II)



with a solution containing piperidine at a suitable temperature to obtain the compound of formula (III);

F OH)
(b) reacting the compound of formula (III) in situ with bromo fluoro methane in the absence of any inorganic base at a suitable temperature to yield a compound of formula (I); and crystallizing the compound of formula (I) from a suitable solvent.
2. The process as claimed in claim 1, wherein said solution includes an organic solvent, preferably dimethylacetamide.
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3. The process as claimed in claim 1, wherein the solvent used for crystallization of compound of formula (I) is a mixture of acetone and ethyl acetate.
4. The process as claimed in claim 1, wherein, said reaction (a) is carried out at a temperature of 10 to 30° C.
5. The process as claimed in claim wherein, said reaction (b) is carried out at a temperature of 0-10°C.
6. The process as claimed in claim 1, wherein said compound of formula III is prepared by a process comprising:











treating the compound of formula (II)


F (III)
10
with piperidine at a suitable temperature and isolating the pure compound of formula (III) from water.

7. The process as claimed in claim 5, wherein said reaction is carried out at a temperature of 10-30°C.
8. One-pot synthesis for the preparation of Fluticasone propionate of Formula (I) and the preparation of compound of formula (III) as substantially described herein with reference to the description and examples.
Dated this 3rd day of April 2006
Dr. Gopakumar G. Nair Agent for the Applicant
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ABSTRACT:
Disclosed herein is a simple, one-pot process for the preparation of fluticasone propionate comprising treating the compound of formula II with piperidine to obtain compound of formula III, which is reacted in situ with bromo fluoro methane in the absence of any inorganic base to yield a compound of formula (I). The invention also discloses process for preparation of compound of formula III.

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Documents:

438-mum-2005-abstract (complete).doc

438-mum-2005-abstract (complete).pdf

438-MUM-2005-ABSTRACT(3-4-2006).pdf

438-MUM-2005-ABSTRACT(GRANTED)-(11-4-2012).pdf

438-MUM-2005-CANCELLED PAGES(15-3-2012).pdf

438-mum-2005-claims (complete).doc

438-MUM-2005-CLAIMS(3-4-2006).pdf

438-MUM-2005-CLAIMS(AMENDED)-(15-3-2012).pdf

438-MUM-2005-CLAIMS(AMENDED)-(19-12-2011).pdf

438-MUM-2005-CLAIMS(GRANTED)-(11-4-2012).pdf

438-MUM-2005-CLAIMS(MARKED COPY)-(15-3-2012).pdf

438-MUM-2005-CLAIMS(MARKED COPY)-(19-12-2011).pdf

438-mum-2005-claims.pdf

438-mum-2005-correspondance-received-ver-020505.pdf

438-mum-2005-correspondance-received-ver-030405.pdf

438-mum-2005-correspondance-received.pdf

438-MUM-2005-CORRESPONDENCE(24-12-2008).pdf

438-MUM-2005-CORRESPONDENCE(3-4-2006).pdf

438-MUM-2005-CORRESPONDENCE(IPO)-(12-4-2012).pdf

438-mum-2005-description (complete).pdf

438-mum-2005-description (provisional).pdf

438-MUM-2005-DESCRIPTION(COMPLETE)-(3-4-2006).pdf

438-MUM-2005-DESCRIPTION(GRANTED)-(11-4-2012).pdf

438-MUM-2005-DESCRIPTION(PROVISIONAL)-(6-4-2005).pdf

438-MUM-2005-FORM 1(2-5-2005).pdf

438-MUM-2005-FORM 1(6-4-2005).pdf

438-MUM-2005-FORM 18(26-12-2008).pdf

438-MUM-2005-FORM 2(COMPLETE)-(3-4-2006).pdf

438-MUM-2005-FORM 2(GRANTED)-(11-4-2012).pdf

438-MUM-2005-FORM 2(PROVISIONAL)-(6-4-2005).pdf

438-MUM-2005-FORM 2(TITLE PAGE)-(COMPLETE)-(3-4-2006).pdf

438-MUM-2005-FORM 2(TITLE PAGE)-(GRANTED)-(11-4-2012).pdf

438-MUM-2005-FORM 2(TITLE PAGE)-(PROVISIONAL)-(6-4-2005).pdf

438-MUM-2005-FORM 26(19-12-2011).pdf

438-mum-2005-form-26.pdf

438-mum-2005-form-3.pdf

438-mum-2005-form-5.pdf

438-MUM-2005-MATERIAL SAFETY DATA SHEET(15-3-2012).pdf

438-MUM-2005-REPLY TO EXAMINATION REPORT(19-12-2011).pdf

438-MUM-2005-REPLY TO HEARING(15-3-2012).pdf


Patent Number 251843
Indian Patent Application Number 438/MUM/2005
PG Journal Number 15/2012
Publication Date 13-Apr-2012
Grant Date 11-Apr-2012
Date of Filing 06-Apr-2005
Name of Patentee CIPLA LIMITED
Applicant Address 289, BELLASIS ROAD, MUMBAI CENTRAL, MUMBAI-400 008.
Inventors:
# Inventor's Name Inventor's Address
1 RAO, DHARMARAJ RAMACHANDRA 4/403, GARDEN ENCLAVE, POKHRAN ROAD 2, THANE (W)-400 601.
2 PANDE, VIDYADHAR PURSHOTTAM D-1-15/27, RADHANAGAR, KALYAN (WEST)-421 301.
3 KANKAN, RAJENDRA NARAYANRAO A-3/5, N.B.D. SOCIETY, N.S.S. ROAD, GHATKOPAR, MUMBAI-400 084.
PCT International Classification Number A61K31/00 C07J1/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA