FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
As amended by the Patents (Amendment) Act, 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules, 2005
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
A process for the preparation of highly pure Budesonide
INVENTORS
Names Salvi Narendra Jagannath, Patravale Bharat Kumar Surendra and
Chaudhari Subodh Vasant
Nationality : all Indian Nationals
Address : all of Aarti Healthcare Limited
D-53/D-60, MIDC, Phase II, Kalyan Shil Road
Dombivli (E), District Thane - 421204 Maharashtra, India
APPLICANTS
Name : Aarti Healthcare Limited
Nationality: Indian Company
Address : 71, Udyog Kshetra, 2nd Floor
Mulund Goregaon Link Road Mulund (W), Mumbai - 400080 Maharashtra, India
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the nature of this invention and the
manner in which it is to be performed:

Technical Field
The invention relates to the process for the preparation of highly pure 16a, 17a-butylidenedioxy-11β,21-dihydroxypregna-l,4-diene-3,20-dione, a compound of the formula (I).

Formula (I)
Background of the invention :
16α,17α-butylidenedioxy-11β,21-dihydroxypregna-l,4-diene-3,20-dione, a compound of formula (I) is commonly know as Budesonide. Budesonide is a glucocorticoid steroid and is used for the treatment of asthma, non-infectious rhinitis and for the treatment and prevention of nasal polyposis. It is also used for the treatment of inflammatory bowel disease.
US3929768 discloses a process for manufacturing budesonide. In the process, 16a-hydroxyprednisolone is reacted with butanal in dioxane and with perchloric acid as catalyst. The product is recovered by diluting the reaction mixture with methylene chloride and neutralizing the reaction mixture by washing with aqueous potassium carbonate and water. On evaporating the solvent from the reaction mixture, the product crystallizes out from the reaction mixture and is purified by crystallizing it with ether/ligroine. The product is further purified by chromatography to obtain isomeric mixture. R/S ratio of product is not specified. The main disadvantage of the above

process is the use of toxic solvent, dioxane, which has skin penetrating and peroxide formation properties. Another disadvantage of the above process is that the perchloric acid is very strong oxidizing agent and the use of this catalyst results in less selective reaction which leads to subsequent work-up and also requires complicated and expensive purification procedures.
US 5556964 discloses a process for manufacturing budesonide in which 16a-hydroxyprednisolone is reacted with butanal in acetonitrile and with p-toluene sulfonic acid as catalyst at 25° C. After 30 minutes, the product started crystallizing out from the reaction mixture. The reaction is stopped by adjusting pH of the reaction mixture by adding aqueous solution of sodium bicarbonate solution whereupon the product is crystallized out. The product is dissolved in mixture of methylene chloride and methanol and then crystallized out by addition of suitable hydrocarbon selected from ligroine, hexane, cyclohexane and heptane. The product is further purified by crystallization in methanol and water to give pure budesonide with isomer ratio of 1:1.
WO2005/044759 describes acetalization process for the preparation of 16,17-acetals of pregnane derivatives including budesonide from corresponding 16,17-dihydroxy compounds in phosphoric acid. 16a-hydroxyprednisolone is reacted with butanal in p-toluene sulfonic acid as a catalyst at 0-5° C. The product is purified by crystallization with ethyl acetate -methanol to obtain pure budesonide with R, S isomer ratio in the range of 60:40 to 50:50.
Thus, the purification of budesonide is carried out by two steps crystallization or by chromatography or by combination of crystallization and chromatography so as to achieve the desired purity of Budesonide. The purification procedure is tedious and time-consuming. The work-up of the processes reported in the prior art is also laborious.

Objects of the invention :
An object of the invention is to provide a process for the preparation of budesonide by reacting 16a-hydroxyprednisolone with butanal in acetonitrile and with benzene sulfonic acid as a catalyst where budesonide obtained by the above process is in highly pure form with R, S isomer in 1:1 ratio without using any purification procedure which is expensive, tedious and time-consuming thereby making the process cost-effective.
Another object of the invention is to provide a process for the preparation of budesonide by reacting 16a-hydroxyprednisolone with butanal in acetonitrile and with benzene sulfonic acid as a catalyst where budesonide obtained by the above process is in highly pure form with R,S isomer in 1:1 ratio without laborious work-up thereby making the process simple to carry out.
Detailed Description of the invention :
According to the invention there is provided a process for the preparation of highly pure 16α,17α-butylidenedioxy-11β,21-dihydroxypregna-l,4-diene-3,20-dione (Budesonide) of the formula (I);


HO
Formula (I)
which process comprises;
a) reacting 11β, 16α, 17α, 21-tetrahydoxypregna-l-diene-3,20-dione of the formula (II)

with butanal of the formula (III) in the presence of acetonitrile as a solvent and with benzene sulfonic acid as a catalyst at 25 to 30° C;
b) neutralizing the reaction mixture by adding aqueous solution of sodium bicarbonate solution with stirring and
c) recovering the compound of formula (I) from the reaction mixture by filtration to obtain the compound of the formula (I) in about 99.6 % purity with R,S-isomer in the 1:1 ratio.
The butanal (butyraldehyde) is added in step (a) for about 40 to 60 minutes with continuous stirring. The reaction mixture is stirred till completion of reaction as monitored by HPLC. According to the invention it has been possible to obtain the compound of the formula (I) in about 99.6 % purity with R, S isomer ratio of 1:1 as established by HPLC without using any purification procedure. Thus the process of the invention is cost-effective and is simple to carry out.
The following experimental example is illustrative of the invention but not limitative of the scope thereof
Example 1
16a-hydroxy prednisolone (75 gm) was added to 750 ml of acetonitrile and 42 gm of benzenesulphonic acid. Butyraldehyde (35 gm) was added to the reaction mixture over a period of 45 to 60 minutes at 25 - 30°C. The reaction mixture was stirred and the completion of reaction was monitored by HPLC. After the reaction was completed, 10 %

aqueous solution of sodium bicarbonate was added to the reaction mixture for neutralization. After stirring the reaction mixture for 15 - 20 minutes at room temperature, the reaction mixture was filtered to obtain pure product, Budesonide. R, S-isomer ratio 1:1 as established by HPLC
Yield : 70 gm
Purity: 99.6 %

We claim:
1. A process for the preparation of highly pure 16α,17α-butylidenedioxy-11β,21-dihydroxypregna-l,4-diene-3,20-dione (Budesonide) of the formula (I);

Formula (I)
which process comprises;
a) reacting 11β, 16α, 17α, 21-tetrahydoxypregna-l-diene-3,20-dione of the formula (II)

with butanal of the formula (III) in the presence of acetonitrile as a solvent and with of benzene sulfonic acid as a catalyst at 25 to 30° C;
b) neutralizing the reaction mixture by adding aqueous solution of sodium bicarbonate solution with stirring and
c) recovering the compound of formula (I) from the reaction mixture by filtration to obtain the compound of the formula (I) in about 99.6 % purity with R,S-isomer in the 1:1 ratio.

2. 16a, 17a-butylidenedioxy-11β,21 -dihydroxypregna-1,4-diene-3,20-dione (Budesonide) of the formula (I);

Formula (I)
in about 99.6 % purity with R,S-isomer in the 1:1 ratio as obtained by the process as claimed in claim 1.

ABSTRACT
A simple and cost-effective process for manufacturing the budesonide with purity of about 99.6 % with R,S-isomer in 1:1 ratio without using any purification procedure. The process involves reaction of 11β, 16α, 17α, 21-tetrahydoxypregna-l-diene-3,20-dione of formula (II) with butanal in the presence of acetonitrile and with benzene sulfonic acid as catalyst at 25 to 30° C and neutralizing the reaction mixture by adding aqueous solution of sodium bicarbonate. The pure compound is recovered by simple filtration.