FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"ONE POT PROCESS FOR SYNTHESIS OF TRIAMCINOLONE
ACETONIDE"
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.

ONE POT PROCESS FOR SYNTHESIS OF TRIAMCINOLONE ACETONIDE
Technical field of the Invention
The present invention relates to a process for preparation of Triamcinolone acetonide.
More particularly, the invention relates to one-pot process for the preparation of
Triamcinolone acetonide with high yields and purity.
Background and prior art
Corticosteroids are known to have anti-inflammatory and immunomodulatory properties
useful in the treatment of numerous diseases, including autoimmune and inflammatory
diseases.
Triamcinolone, a corticosteroid of pregnadiene series, with glucocorticoid activity, was
first disclosed in US patent 2789118. Later it was found that 16a, 17a-methylenedioxy
steroids had high anti-inflammatory activity compared to Triamcinolone.
Triamcinolone acetonide (I) belongs to 16a, 17a-substituted methylenedioxy steroids of pregnane series that possess glucocorticoid and anti-inflammatory activity and is chemically termed as 9a-fluoro-lip,21-dihydroxy-16a,17a-isopropylidenedioxy-l,4-pregnadiene-3,20-dione.
Triamcinolone acetonide (I) is represented by following structure:

Triamcinolone acetonide is more effective topical anti-inflammatory agent than many other steroids for treatment of arthritis and related diseases.
2

There are various chemical as well as microbiological methods cited as the prior art for synthesis of triamcinolone acetonide as well as for the various intermediates used.
Triamcinolone Acetonide compound was first disclosed in US patent 2990401. The process for its preparation as disclosed comprises reaction of 9a-fluoro-11b, 16a, 17a 21-tetrahydroxy-l,4-pregnadiene-3,20-dione (Triamcinolone) in hot acetone and concentrated hydrochloric acid and isolation by recrystallization with a mixture of acetone and petroleum ether. This patent provides an alternate process for preparation of triamcinolone acetonide which comprises reaction of 9a-fluoro-l ip, 16a, 17a 21-tetrahydroxy-l,4-pregnadiene-3,20-dione in acetone and perchloric acid (72%). US patent 299401 further provides a process which comprises reaction of 9P,1 ip-epoxy-16a,17a-isopropylidinedioxy -1,4- pregna diene-3,20-dione in methylene chloride with tetrahydrofuran in presence of hydrogen fluoride at -30°C to yield 9a-fluoro-llb-hydroxy-16a, 17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione.
All the processes disclosed in the US patent 299401 require either reduced temperatures or prolonged reaction times that make them tedious and difficult for industrial scale up.
The other prior art references (Fried and Sabo, J.Am.Chem.Soc.76, 1455, 1954) teach that 9a-fluoro-lip-hydroxy steroids having glucocorticoidal activity can be prepared by reaction of hydrofluoric acid in chloroform free of ethanol with corresponding 9b,11b-epoxy compound. The yields obtained by this process were very poor. To overcome the low yields, further modifications were done to the process by addition of tetrahydrofuran to achieve yields of 65-75% (Hirschman, J.Am.Chem.Soc.78, 4957,1956). However, it was found that by altering the ratio of hydrofluoric acid: tetrahydrofuran, the reaction gets inhibited and commercially acceptable yields could not be realized. Tetrahydrofuran employed in the prior art processes causes ring opening at 9p, lip position as well as at the 16a, 17a position resulting in formation of diols. Thus, formation of the acetonide ring at 16a, 17a position is difficult in presence of tetrahydrofuran. This is the major drawback of the prior art methods.
A process for preparation of 9b,lip-epoxy-16a,17a,21-trihydroxy-4-pregnene-3,20-dione as an intermediate in preparation of triamcinolone comprising reaction of 16b,21-
3

US patent 3021347 recites a process for preparation of triamcinolone by heating in the range of 50-110°C, 9a-fluoro-16a,17a-isopropylidenedioxy-lip,21-dihydroxy-l,4-pregnadiene-3,20-dione with aqueous formic acid (20-60%).
US patent 3493563 provides novel intermediates used for preparation of triamcinolone acetonide and related compounds. The processes for preparation of intermediates are also disclosed. These intermediates are further converted to triamcinolone acetonide. However, these processes involve multistep reactions that makes them time consuming and less economical.
EP patent 1700862 discloses a process for a stable polymorph of triamciniolone acetonide obtained by crystallizing or precipitating dissolved triamcinolone acetonide in water and/ or methanol at -80 to 200 °C under 10-5000 hPa.
Another disadvantage of prior art processes is the necessity for maintaining excessively low temperatures ranging from 0 to -60 °C. Most of the known processes involve multiple steps of synthesis employing various intermediates and various temperature conditions at each step that makes those processes cumbersome.
There is a need for new processes for synthesis of Triamcinolone Acetonide that are simple, convenient, safe and economical. The present invention relates to a novel process for synthesis of Triamcinolone Acetonide (I) characterized by a single step using less number of reagents under moderate reaction conditions with high yield and purity.
Objectives of the invention
It is an object of the present invention to provide one pot process for synthesis of Triamcinolone Acetonide.
In another object, the present invention provides a very simple process that overcomes all the difficulties faced by prior art methods for synthesis of Triamcinolone Acetonide.
Yet another object of present invention is to provide a process comprising less number of reagents, inexpensive and feasible for industrial scale up.
4

Summary of the invention
The present invention provides a new process for preparation of Triamcinolone Acetonide comprising one step conversion of 9p, lip-epoxy-16a,17a, 21-triol-pregna-l,4-diene-3,20-dione-21 -acetate of formula (II) to Triamcinolone Acetonide of formula (I).
CH2OCOCH3

(II)
Detailed description of the invention
In one aspect, the present invention describes a novel, simple, economical and easy scale-up process for synthesis of Triamcinolone Acetonide of formula (I) with substantial yield and purity.
CH2OH

TRIAMCINOLONE ACETONIDE (I)
In one embodiment, the present invention relates to one step synthesis of Triamcinolone Acetonide comprising following three types of reactions occurring concurrently:
1) acetonide ring formation at 16a, 17a position ;
2) epoxide ring opening with formation of 9a-fluoro-11 p-hydroxy compound ;
5

3) Hydrolysis of acetate group at 21 position
In another embodiment, the process for preparation of compound (I) comprises reaction of 9b,11b-epoxy-16a,17a,21-triol-pregna-l,4-diene-3,20-dione-21-acetate of formula (II) with aqueous hydrogen fluoride (40%) in presence of acetone . The reaction is carried out at a temperature preferably at 20-30°C. The mixture is stirred for 36-48 hours to ensure completion of the reaction. After completion of reaction, the reaction mixture is quenched at a temperature preferably at 20-30°C, in an alkaline medium such as sodium carbonate, sodium bicarbonate and potassium carbonate, preferably sodium carbonate.
Subsequently the reaction mixture is stirred at alkaline pH of 8-9 and at a temperature preferably at 20-30°C for 30 minutes to get a residue of triamcinolone acetonide which is then filtered and dried under vacuum.
Further, it is recrystallized from a suitable polar or non-polar organic solvent such as acetone, toluene, benzene, petroleum ether, isopropyl alcohol, more preferably acetone or a mixture of solvents such as acetone and petroleum ether, acetone and benzene, benzene and toluene, benzene and acetonitrile, more preferably mixture of acetone and petroleum ether to yield 9a-fluoro-llb,21-dihydroxy-16a,17a-isopropylidenedioxy-l,4-pregnadiene-3,20-dione i.e. compound of formula (I).
The reaction scheme of present invention is represented as follows: Scheme I
6

CH2OCOCH3

9p, 11 b-epoxy-16a, 17a,21 -triol-pregna-3,20-dione-21 -acetate (II)
i) Acetone
ii) Aqueous HF
CH2OH

TRIAMCINOLONE ACETONIDE (I)
In one aspect of the present invention, the conditions employed in the process of the present invention are advantageous. Acetone under the conditions of process of present invention facilitates acetonide ring formation and aqueous hydrogen fluoride (40%) helps in opening of the epoxide ring at 90, 11b position. Further the reaction conditions also help for hydrolysis of acetate group at 21 position. This aspect of present invention overcomes the difficulties faced by the prior art processes using tetrahydrofuran.
7

The conversion of compound of formula (II) to Triamcinolone acetonide (I) occurs at a temperature preferably at 20-30°C. There is no external heating or cooling required as disclosed in prior art processes. These moderate conditions of the present invention overcome the difficulties associated with the prior art methods and this forms another aspect of the present invention.
The process of the present invention is also applicable by using other starting materials such as:
1) 9b, 11 P-epoxy-16a, 17a-isopropylidinedioxy-21 -hydroxy-pregna-1,4-diene-3,20-dione-21 -acetate wherein conversion to triamcinolone aceonide occurs through epoxide ring opening at 9b, lip position and hydrolysis of acetate group at 21 position.
2) 9b, lip-epoxy-16a,17a,21-triol-pregna-l,4-diene-3,20-dione wherein conversion of triamcinolone acetonide occurs through acetonide ring formation at 16a, 17a position and epoxide ring opening at 9b, lip position.
There follow, by way of non-restrictive explanation of the present invention, the following examples.
Examples
Example 1
9b, 11 b-epoxy-16a, 17a, 2l-triol-pregna-l,4-diene-3,20-dione-21 -acetate (5gms) was charged in a vessel. Acetone (50 ml, 10 volumes) and 40 % aqueous hydrogen fluoride (100 ml, 8 volumes) were added. The mixture was stirred at 20-30°C for 48 hours. The reaction mass was quenched in water and bH of the reaction mass was adjusted between 8-8.5 with 10 % aqueous sodium carbonate solution. The precipitate was filtered and the cake was washed with water till neutral bH. Recrystallized from acetone to yield 2.8 gms of 9a-fluoro-11b, 21-dihydroxy-16a, 17a-isopropylidenedioxy-l, 4-pregnadiene-3, 20-dione.
8

Example 2
Charged 9b, lip-epoxy-16a, 17a-isopropylidinedioxy-21-hydroxy-pregna-1, 4-diene-3, 20-dione-21-acetate (5gms) in a vessel. Acetone (50 ml, 10 volumes) and 40 % aqueous hydrogen fluoride (100 ml, 8 volumes) were added. The mixture was stirred at 20-30°C for 48 hours. The reaction mass was quenched in water and bH of the reaction mass was adjusted between 8-8.5 with 10 % aqueous sodium carbonate solution. The precipitate was filtered and the cake was washed with water till neutral bH and recrystallized from acetone to yield 2.5 gms of 9a-fluoro-11b, 21-dihydroxy-16a,17a-isopropylidenedioxy-l,4-pregnadiene-3,20-dione.
Example 3
9b,l1b-epoxy-16a,17a,21-triol -pregna-1,4-diene-3,20-dione (5gms) was charged in a vessel. Acetone (50 ml, 10 volumes) and 40 % aqueous hydrogen fluoride (100 ml, 8 volumes) were added to the vessel. The mixture was stirred at 20-30°C for 48 hours. The reaction mass was quenched in water and bH of the reaction mass was adjusted between 8-8.5 with 10 % aqueous sodium carbonate solution. The precipitate was filtered and the cake was washed with water till neutral pH. Recrystallized from acetone to yield 9a-fluoro-11b, 21 -dihydroxy-16a, 17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione.
Dated this 15th day of May 2007

Dr. Gopakumar G. Nair Agent for the applicant