Europaisches Patentamt
European Patent Office
Office europeen des brevets
EUROPEAN
©
©
© Publication number:
PATENT
Date of publication of patent specification: 15.11.95
0 494
942
B1
SPECIFICATION
Int. CI.6: C07J
©
71/00
© Application number: 90915222.5
@ Date of filing: 27.09.90
©
International application number:
PCT/SE90/00619
©
International publication number:
WO 91/04984 (18.04.91 91/09)
&) PROCESS FOR THE MANUFACTURE OF BUDESONIDE.
©
Priority: 02.10.89 SE 8903219
©
Date of publication of application:
22.07.92 Bulletin 92/30
©
Publication of the grant of the patent:
15.11.95 Bulletin 95/46
©
S-151 85 Sodertalje (SE)
©
Inventor: HOFSTRAAT, Robert, Gerrit
Zwanenveld 25-32
NL-6538 NK Nijmegen (NL)
Inventor: RAIJMAKERS, Petrus, Hendricus
Cellostraat 19
NL-5402 AA Uden (NL)
Inventor: VRIJHOF, Pieter
Margrietlaan 10
NL-5351 BX Berghem (NL)
©
Representative: Danielsson, Sten Ove et al
AB ASTRA
Patent and Trademark Department
S-151 85 Sodertalje (SE)
@ Designated Contracting States:
AT BE CH DE DK ES FR GB IT LI LU NL SE
©
00
CM
Proprietor: Astra Aktiebolag
References cited:
EP-A- 0 164 636
GB-A- 0 916 996
US-A- 4 925 933
CHEMICAL ABSTRACTS, Vol. 106, No. 9, 2
March 1987, (Columbus, Ohio, US), see page
641, Abstract 67573q, ES, A, 543211 (Process
for the preparation of budesonide) 16 February 1986.
Note: Within nine months from the publication of the mention of the grant of the European patent, any person
may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition
shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee
has been paid (Art. 99(1) European patent convention).
Rank Xerox (UK) Business Services
(3. 10/3.09/3.3.3)
EP 0 494 942 B1
Description
Technical field
5
The present invention relates to a novel process for the manufacture
butylidenedioxy-1 1/3,21 -dihydroxypregna-1 ,4-diene-3,20-dione (budesonide)
of (22 R,S)-16a,17a-
w
15
20
by reacting 11/3,16a,17a,21-tetrahydroxypregna-1 ,4-diene-3,20-dione (16a-hydroxyprednisolone)
CX,0B
30
35
40
with butanal, CH3CH2CH2CHO, in a solvent medium in the presence of an acid catalyst.
45
50
55
Prior art
According to a previously known process disclosed in GB patent no. 1 429 922 Budesonide is
manufactured by reacting 16a-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 neutralising
by washing with aqueous potassium carbonate and water, evaporating the solvent followed by crystallisation
from ether/ligroine. The product was further purified by chromatography e.g. an 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 3 less selective reaction, which in turn makes the subsequent work-up and purification process
complicated and expensive.
2
EP 0 494 942 B1
Disclosure of the invention
5
io
is
20
25
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. nonoxidizing 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
16a-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 5-15 °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
30
The crude budesonide is dissolved in methanol at about 60 ° C. The solution is filtered through a cloned
filter and the product is 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 hazardous compared to prior art processes.
35
Working example
40
45
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 16a-hydroxyprednisolone and 17.6 ml butanal are added. The
temperature rises to 25 °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 » 1:1 (HPLC), [«]g5 100.0° (c = 0.2; CH2CL2); M+ 430 (theor. 430.5)
Claims
50
1.
Process for the manufacture of (22 R,S)-1 6a, 17a-butylidenedioxy-1 1/3,21 -dihydroxypregna-1 ,4-diene3,20-dione
55
3
EP 0 494 942 B1
5
10
15
by reacting 11/3,1 6a, 17a,21 -tetrahydroxypregna-1 ,4-diene-3,20-dione
with butanal, CH3CH2CH2CHO in a solvent medium in the presence of a catalyst, characterised in
that the reaction is performed in acetonitrile with p-toluenesulphonic acid as a catalyst.
35
2.
Process according to claim 1, characterized in that the reaction is terminated by the addition of water
and by adjustment of the pH of the reaction mixture.
40
3.
Process
reaction
addition
product,
45
Patentanspruche
1.
according to claim 1 or 2, characterized in that the crystals obtained upon termination of the
are filtered off, dissolved in methylene chloride and methanol and are then crystallized by the
a suitable hydrocarbon, such as ligroine, hexane, cyclohexane or heptane, giving a crude
which is then recrystallized in methanol/water to give pure budesonide.
Verfahren zur Herstellung von (22R,S)-1 6a, 17a-Butylidendioxy-1 1/3,21 -dihydroxypregna-1 ,4-dien-3,20dion
50
55
4
EP 0 494 942 B1
durch das Umsetzen von 11/3,1 6a, 17a,21-Tetrahydroxypregna-1 ,4-dien-3,20-dion
CH.OH
mit Butanal, CH3CH2CH2CHO, in einem Losungsmittelmedium in Anwesenheit eines Katalysators,
dadurch gekennzeichnet, dal3 die Reaktion in Acetonitril mit p-Toluolsulfonsaure als Katalysator durchgefuhrt wird.
2.
Verfahren nach Anspruch 1, dadurch gekennzeichnet, dal3 die Reaktion durch den Zusatz von Wasser
und durch die Einstellung des pH der Reaktionsmischung beendet wird.
3.
Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, dal3 die bei der Beendigung der Reaktion
erhaltenen Kristalle abfiltriert, in Methylenchlorid und Methanol gelost und dann durch den Zusatz eines
geeigneten Kohlenwasserstoffs, wie Ligroin, Hexan, Cyclohexan oder Heptan, kristallisiert werden,
wobei ein Rohprodukt erhalten wird, das dann in Methanol/Wasser umkristallisiert wird, wobei reines
Budesonid erhalten wird.
Revendicatlons
1.
Procede pour la fabrication de (22 R,S)-16a, 17a-butylidenedioxy-1 1/3,21 -dihydroxypregna-1 ,4-diene3,20-dione
EP 0 494 942 B1
C-0
par la reaction de la 11/3,16a,17a,21-tetrahydroxypregna-1 ,4-diene-3,20-dione
CH.OH
avec du butanal, CH3CH2CH2CHO, dans un milieu dissolvant en presence d'un catalyseur, procede
caracterise en ce qu'on effectue la reaction dans de I'acetonitrile avec I'acide p-toluene sulfonique
comme catalyseur.
Procede selon la revendication 1, caracterise en ce qu'on arrete la reaction par I'addition d'eau et par
I'ajustement du pH du melange reactionnel.
Procede selon la revendication 1 ou 2, caracterise en ce qu'on separe par filtration les cristaux obtenus
lors de I'arret de la reaction, on les dissout dans du chlorure de methylene et du methanol, puis on les
fait cristalliser par I'addition d'un hydrocarbure convenable, comme de la ligroine, de I'hexane, du
cyclohexane ou de I'heptane, ce qui donne un produit brut, que Ton fait ensuite recristalliser dans un
systeme methanol/eau, ce qui donne du budesonide pur.