Microbiological process for the production of 7-substituted 11-hydroxy steroids, 7,17-substituted 11-Halogen steroids and uses thereof
A novel method of synthesis for the manufacture of upstream products for the production of compounds with general formulas 8, 10, and 12 is described. In this synthesis, compounds with general formula 4,B are produced in a microbiological reaction. The meanings of R 7 , R 10 , R 11 , R 13 , R 17 and R 17′ as well as of the grouping U—V—W—X—Y—Z are indicated in the claims
1. A microbiological process for the production of a 7α-substituted 11α-hydroxy steroids of formula 4,B
wherein
R 7 is P—Q, wherein P is a C 1 - to C 4 -alkylene, and Q is hydrogen, C 1 - to C 4 -alkyl- or C 1 - to C 4 -fluoroalkyl, and wherein P—Q is bonded via P to the steroid skeleton,
R 10 is either in α- or β-position and is H, CH 3 or CF 3 , and
R 13 is methyl or ethyl,
comprising hydroxylating and oxidizing of a 7α-substituted steroid of formula 3,A,
wherein R 7 , R 10 and R 13 are as indicated above, with use of a microorganism which is Aspergillus sp., Beauveria sp., Glomerella sp., Gnomonia sp., Haplosporella sp. or Rhizopus sp.
2. A process according to claim 1 , wherein the microorganism is Aspergillus awamori, Aspergillus fischeri, Aspergillus malignus, Aspergillus niger, Beauveria bassiana, Glomerella cingulata, Gnomonia cingulata, Haplosporella hesperedica or Rhizopus stolonifer.
3. A microbiolociical process for the production of 7α-substituted 11 α-hydroxy steroid of formula 4,B
wherein
R 7 is P—Q, wherein P is a C 1 - to C 4 -alkylene and Q is hydrogen, a C 1 - to C 4 -alkyl- or C 1 - to C 4 -fluoroalkyl, and wherein P—Q is bonded via P to the steroid skeleton,
R 10 is either in α- or β-position and is H, CH 3 or CF 3 , and R 13 is methyl or ethyl,
comprising hydroxylating of a 7α-substituted steroid of formula 3,A in 11α-position,
wherein R 7 , R 10 and R 13 are as previously indicated, using a first microorganism which is Aspergillus sp., Beauveria sp., Gibberella sp., Glomerella sp., Gnomonia sp., Metarrhizium sp., Nigrospora sp., Rhizopus sp. or Verticillium sp., to form a 7α-substituted 11α-hydroxy steroid of formula C:
wherein R 7 , R 10 and R 13 are as indicated above, and oxidizing the 7α-substituted 11α-hydroxy steroid product of formula C with use of a second microorganism which is Bacillus sp., Mycobacterium sp., Nocardia sp. or Pseudomonas sp.
4. A process according to claim 3 , wherein the first microorganism is Aspergillus malignus, Aspergillus melleus, Aspergillus niger, Aspergillus ochraceus, Beauveria bassiana, Gibberella fujikuroi, Gibberella zeae, Glomerella cingulata, Glomerella fusaroides, Gnomonia cingulata, Metarrhizium anisopliae, Nigrospora sphaerica, Rhizopus oryzae, Rhizopus stolonifer or Verticillium dahliae.
5. A process according to claim 3 , wherein the second microorganism is Bacillus lactimorbus, Bacillus sphaericus, Mycobacterium neoaurum, Mycobacterium smegmatis, Nocardia corallina, Nocardia globerula, Nocardia minima, Nocardia restrictus, Nocardia rubropertincta, Nocardia salmonicolor or Pseudomonas testosteroni.
6. A microbiological process for the production of a 7α-substituted 11α-hydroxy steroids of formula 4,B
wherein
R 7 is P—Q, wherein P is a C 1 - to C 4 -alkylene, and Q is hydrogen, C 1 - to C 4 -alkyl- or C 1 - to C 4 -fluoroalkyl, and wherein P—Q is bonded via P to the steroid skeleton,
R 10 is either in α- or β-position and is H, CH 3 or CF 3 , and
R 13 is methyl or ethyl,
comprising hydroxylating 7α-substituted steroids of formula D:
wherein R 7 , R 10 and R 13 are as indicated above, using a microorganism which is Beauveria sp., Curvularia sp., Gibberella sp., Glomerella sp., Gnomonia sp., Haplosporella sp., Helicostylum sp., Nigrospora sp., or Syncephalastrum sp.
7. A process according to claim 6 , wherein the microorganism is Beauveria bassiana, Curvularia lunata, Gibberella zeae, Glomerella cingulata, Glomerella fusaroides, Gnomonia cingulata, Haplosporella hesperedica, Helicostylum piriformae, Nigrospora sphaerica , or Syncephalastrum racemosum.
8. A microbiological process according to claim 1 , wherein R 7 stands for CH 3 .
9. A microbiological process according to claim 1 , wherein R 10 stands for H.
10. A microbiological process according to claim 1 , wherein R 13 stands for CH 3 .