Microbial n-and o-demethylation of a thebaine derivative
View Patent ↗The invention provides a process for the N-demethylation or the N- and O-demethylation of a thebaine derivative which process comprises fermenting the derivative with a biocatalyst selected from the filamentous fungi from Cunninghamella dalmatica NRRL 1394, Cunninghamella echinulata NRRL 1387, Cunninghamella echinulata NRRL 1384, Cunninghamella echinulata ATCC 36190, Cunninghamella echinulata ATCC 11585 a, Cunninghamella echinulata ATCC 9244, Cunninghamella polymorpha NRRL 1395, or Rhizopus nigricans Z5/1 in a basal fermentation medium at a temperature of at least 25° C. and not more than 34° C., for a period of time of at least 3 days.
1. A process for the N-demethylation or the N- and O-demethylation of the compound of the formula
which process comprises fermenting the said compound of Formula I with a biocatalyst selected from the filamentous fungi from
Cunninghamella dalmatica NRRL 1394,
Cunninghamella echinulata NRRL 1387,
Cunninghamella echinulata NRRL 1384,
Cunninghamella echinulata ATCC 36190,
Cunninghamella echinulata ATCC 11585a,
Cunninghamella echinulata ATCC 9244,
Cunninghamella polymorpha NRRL 1395, or
Rhizopus nigricans Z5/1
in a basal fermentation medium at a temperature of at least 25° C. and not more than 34° C., for a period of time of at least 3 days.
2. A process according to claim 1 wherein the biocatalyst is Cunninghamella echinulata NRRL 1384.
3. A process according to claim 1 wherein the fermentation is carried out for a period of from 7 to 10 days.
4. A process according to claim 1 wherein the fermentation is carried out with vigorous shaking or stirring of the fermentation medium.
5. A process according to claim 1 wherein the fermentation medium comprises 2% w/v glucose, 0.5% w/v Corn Steep solids and has a pH of 6.2.
6. A process according to claim 1 wherein the N- or N- and O-demethylated products are separated from the fermentation medium by chromatography, crystallisation or extraction procedures.
7. A process according to claim 1 wherein the fermentation is carried out at a pH in the range of from 5 to 6.
8. A process for the preparation of buprenorphine, which process includes the step of the N-demethylation or the N- and O-demethylation of a compound of the formula
which process comprises fermenting the said compound of Formula I with a biocatalyst selected from the filamentous fungi
Cunninghamella dalmatica NRRL 1394,
Cunninghamella echinulata NRRL 1387,
Cunninghamella echinulata NRRL 1384,
Cunninghamella echinulata ATCC 36190,
Cunninghamella echinulata ATCC 11585a,
Cunninghamella echinulata ATCC 9244,
Cunninghamella polymorpha NRRL 1395, or
Rhizopus nigricans Z5/1
in a basal fermentation medium at a temperature of at least 25° C. and not more than 34° C. for a period of time of at least 3 days.
9. A process claim 8 wherein the compound produced by the N- and O-demethylation step is a compound having the following formula
which is isolated from the fermentation medium and converted to buprenorphine by N-alkylation in order to introduce a cyclopropylmethyl group onto the N-atom.
10. A process according to claim 9 wherein the N-alkylation is carried out using a cyclopropylmethyl halide.
11. A process according to claim 8 wherein the compound produced by the N-demethylation step is a compound having the following formula
which is isolated from the fermentation medium and converted to buprenorphine by the following reaction stages:
(a) subjecting the compound of formula (III) to N-alkylation in order to introduce a cyclopropylmethyl group into the N-atom; and
(b) subjecting the compound produced in step (a) to O-demethylation in order to produce buprenorphine.
12. A process according to claim 11 wherein the N-alkylation is carried out using a cyclopropylmethyl halide.
13. A process according to as claimed in claim 11 wherein the O-demethylation is carried out with potassium hydroxide in diethylene glycol at an elevated temperature of from 200 to 245° C.