Process for the manufacture of budesonide

Information

  • Patent Grant
  • 5556964
  • Patent Number
    5,556,964
  • Date Filed
    Friday, December 16, 1994
    29 years ago
  • Date Issued
    Tuesday, September 17, 1996
    27 years ago
Abstract
The present invention relates to a novel process for the manufacture of (22 R,S)-16.alpha., 17.alpha.-butylidenedioxy-11.beta., 21-dihydroxypregna-1,4-diene-3,20 dione (I) by reacting 11.beta., 16.alpha., 17.alpha. 21-tetrahydroxypregna-1,4-diene (II) with butanal, CH.sub.3-- CH.sub.2 --CH.sub.2 --CHO, in acetonitrile in presence of p-toluenesulphonic acid as a catalyst.
Description

TECHNICAL FIELD
The present invention relates to a novel process for the manufacture of (22 R,S)-16.alpha.,17.alpha.-butylidenedioxy-11.beta.,21-dihydroxypregna-1,4-diene-3,20-dione (budesonide) ##STR1## by reacting 11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregna-1,4-diene-3,20-dione (16.alpha.-hydroxyprednisolone) ##STR2## with butanal, CH.sub.3 CH.sub.2 CH.sub.2 CHO, in a solvent medium in the presence of an acid catalyst.
PRIOR ART
According to a previously known process disclosed in GB patent no. 1 429 922 Budesonide is manufactured by reacting 16.alpha.-hydroxyprednisolone with butanal in dioxane and with perchloric acid as a catalyst. The product is recovered by diluting the reaction mixture with methylene chloride, and neutralizing by washing with aqueous potassium carbonate and water evaporating the solvent followed by crystallization from ether/ligroine. The product was further purified by chromatography e.g. on Sephadex. The main disadvantages of dioxane are its skin penetrating and peroxide formation properties. Another disadvantage with this prior art process is perchloric acid, which is a strong oxidizing agent and the use of this catalyst results in a less selective reaction, which in turn makes the subsequent work-up and purification process complicated and expensive.
DISCLOSURE OF THE INVENTION
The object of the invention is to create a novel process, which gives a more selective reaction and a more simple and economic work-up and purification process.
This is achieved with the process according to the present invention, wherein the reaction is performed in acetonitrile with p-toluenesulphonic acid as a catalyst.
The combination of the less basic (compared to dioxane) solvent acetonitril and the weaker, i.e. non-oxidizing p-toluenesulphonic acid gives a more selective reaction, and also a more simple and exonomic work-up and purification process compared to the above discussed prior art process using dioxane and perchloric acid.
According to a preferred embodiment of the invention the reaction is stopped by the addition of water and adjustment of the Ph of the reaction mixture. This might be done by the addition of sodium hydrogen carbonate in water. The product then crystallizes. The crystals are filtered off, dissolved in methylene chloride and methanol and are then crystallized by the addition a suitable hydrocarbon, such as ligroine, hexane, cyclohexane or heptane, giving a crude product, which is then recrystallized in methanol/water to give pure budesonide.
The process according to the invention for the manufacture of budesonide thus consists of two steps.
Step 1. Budesonide crude
16.alpha.-hydroxyprednisolone is reacted with butanal in acetonitrile. p-Toluenesulphonic acid is added as a catalyst. The reaction mixture is diluted with water and aqueous sodium hydrogen carbonate. After cooling to 5.degree.-15.degree. C. the crystallized product is filtered off and washed with water. The wet or dried substance is then dissolved in methylene chloride. If the substance used is wet the water phase formed upon dissolution is removed. Methanol is added and the resulting crude budesonide is precipitated by the addition of ligroine or another suitable hydrocarbon (e.g. hexane, heptane or cyclohexane) and is then filtered off.
Step 2. Budesonide
The crude budesonide is dissolved in methanol at about 60.degree. C. The solution is filtered through a closed filter and the product is crystallized by the addition of water. After cooling to 5.degree.-20.degree. C., filtration and washing with methanol/water the budesonide is dried in vacuum at 40.degree.-45.degree. C.
This process is simplified, more economic and less health hazardous compared to prior art processes.





WORKING EXAMPLE
The reaction is carried out in a nitrogen atmosphere. 15,4 g p-toluenesulphonic acid is dissolved into 200 ml acetonitrile. To the solution 50,0 g 16.alpha.-hydroxyprednisolone and 17.6 ml butanal are added. The temperature rises to 25.degree. C. After 30 min most of the material is dissolved. Shortly thereafter the product starts to crystallize. After 3 hours the reaction is stopped by the addition of 75 ml aqueous saturated sodium hydrogen carbonate solution, whereupon the product crystallizes. The dried product is dissolved in methylene chloride and methanol and is crystallized by the addition of ligroine (b.p. 40-65) giving crude budesonide.
The crude budesonide product is recrystallized from methanol/water giving pure budesonide with isomer ratio A:B.apprxeq.1:1 (HPLC), [.alpha.].sub.D.sup.25 100.0.degree. (c=0.2; CH.sub.2 CL.sub.2); M.sup.+ 430 (theor. 430.5)
Claims
  • 1. A process for preparing the compound (22 R,S)-16.alpha., 17.alpha.-butylidene-dioxy-11B,21-dihydroxpregna-1,4-diene 3,20-dione (formula I) ##STR3## which compromises reacting the compound 11B, 16.alpha., 17.alpha., 21-tetrahydroxypregna-1,4-diene-3,20-dione (formula II) ##STR4## with butanal in acetonitrile in the presence of p-toluenesulfonic acid as a catalyst.
  • 2. The process according to claim 1, wherein the reaction is terminated by adding water and adjusting the Ph of the reaction mixture.
  • 3. The process according to claim 2 or which further comprises steps wherein crystals that are obtained upon termination of the reaction are filtered off, dissolved in methylene chloride and methanol and then crystallized by the addition of a suitable hydrocarbon selected from the group consisting of, ligroin, hexane, cyclohexane and heptane, giving a crude product, which is then recrystallized in methanol/water to give pure budesonide.
Priority Claims (1)
Number Date Country Kind
89032197 Oct 1989 SEX
Parent Case Info

This application is a continuation of application Ser. No. 07/844,574, filed, filed as PCT/SE90/00619, published as WO91/04984 Apr. 18, 1991, now abandoned.

US Referenced Citations (2)
Number Name Date Kind
3077471 Fried et al. Feb 1963
4925933 Jakupovic et al. May 1990
Foreign Referenced Citations (5)
Number Date Country
0164636 Dec 1985 EPX
0054010 Jun 1992 EPX
543211 May 1985 ESX
916996 Jan 1963 GBX
1429922 Mar 1976 GBX
Non-Patent Literature Citations (2)
Entry
Linan et al., Chemical Abstracts, vol. 106, 1987 Abstract 675739.
Chem. Abst. vol. 106, No. 9, p. 641, 67573 (Mar. 2, 1987).
Continuations (1)
Number Date Country
Parent 844574 Mar 1992