PROCESS FOR THE MANUFACTURE OF BUDESONIDE

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-3,20-dione (II) with butanal, CH3CH2CH2CHO in acetonitrile with p-tolyuenesulphonic acid as a catalyst.

Description: Process for the manufacture of Budesonide Technical field The present invention relates to a novel process for the manufacture of (22 R,S)-16α,17α-butylidenedioxy-llβ,21- dihydroxypregna-1,4-diene-3,20-dione (budesonide) GB-OH by reacting llβ,16α,17α,21-tetrahydroxγpregna-l,4-diene- 3,20-dione (16α-hydroxyprednisolone) with butanal, -I^CF^CR-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 16α-hyd- roxyprednisolone with butanal in dioxane and with perchloric acid as a catalyst. The product is recovered by diluting the re¬ action mixture with methylene chloride,and neutralising by washing with aqueous potassium carbonate and water, evaporating the solvent followed by crystallisation from ether/iigroine. 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 oxidi¬ zing agent and the use of this catalyst results in a less selec¬ tive reaction, which in turn makes the subsequent wor -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 in¬ vention, 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-toluenesulpho¬ nic acid gives a more selective reaction, and also a more simpl 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 reac¬ tion 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 -.hen crystal lizes. The crystals are filtered off, dissolved in merhylene chloride and methanol and are then crystallized by the addition a suitable hydrocarbon, such as ligroine, hexane, cyclohexane heptane, giving a crude product, which is then recrystallized 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 16α-hydroxyprednisolone is reacted with butanal in acetonitri p-Toluenesulphonic acid is added as a catalyst. The reaction mixture is diluted with water and aqueous sodium hydrogen carb nate. After cooling to 5-15°C the crystallized product is filt red 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 dissolutj.on is removed. Methan 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 o C. T solution is filtered through a closed filter and the product i crystallized by the addition of water. After cooling to 5-20-C filtration and washing with methanol/water the budesonide is dried in vacuum at 40-45°C. This process is simplified, more economic and less health haza dous compared to prior art processes. Working example The reaction is carried out in a nitrogen atmosphere. 15,4 g p toluenesulphonic acid is dissolved inco 200 ml acetonitrile. T the solution 50,0 g 16σ-hydroxyprednis lone and 17.6 ml butana are added. The temperature rises to 25 C C. After 30 min most of the material is dissolved. Shortly thereafter the product star 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 produc 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 F*1:1 (HPLC) , [α] 25 100.0° (c = 0.2; CH 2 CL 2 ); + 430 (theor. 430.5) ^

Claims: l a i m s 1. Process for the manufacture of (22 R,S) -16 ,17α-butylide dioxy-1lβ,21-dihydroxypregna-1,4-diene-3,20-dione CH 2 OH by reacting llβ,16σ,17α,21-tetrahydroxypregna-1,4-diene-3,20- dione CH,0H with butanal, CH3CH2CH2CHO in a solvent medium in the presence of a catalyst, c h a r a c t e r i s e d in that the reaction is performed in acetonitrile with p-toluenesulphonic acid as a catalyst. 2. Process according to claim 1, c h a r a c t e r i z e d that the reaction is terminated by the addition of water and b adjustment of the pH of the reaction mixture. 3. Process according to claim 1 or 2, c h a r a c t e r ! - z e d in that the crystals obtained upon termination of the reaction 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 metha- nol/water to give pure budesonide.

Inventors: HOFSTRAAT ROBERT GERRIT, RAIJMAKERS PETRUS HENDRICUS, VRIJHOF PIETER, HOFSTRAAT, ROBERT, GERRIT, RAIJMAKERS, PETRUS, HENDRICUS, VRIJHOF, PIETER
Applicants: ASTRA AB, AKTIEBOLAGET ASTRA
Application year: 1990
Main classification: C07J71
IPC codes: C07J5, C07J71, C07J75