Process for conversion of oxotomaymycin to tomaymycin

• US 4,427,588 A
• Filed: 11/08/1982
• Issued: 01/24/1984
• Est. Priority Date: 11/08/1982
• Status: Expired due to Fees

• Current Assignee: Bristol Myers Co (Bristol-Myers Squibb Company)
• Original Assignee: Bristol Myers Co (Bristol-Myers Squibb Company)
• Inventors: Kaneko, Takushi, Wong, Henry S. L.
• Primary Examiner(s): BOND, ROBERT
• Application Number:
  US06/439,965
• Time in Patent Office: 442 Days
• Field of Search: 260/239.3 T
• US Class Current: 540/496
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

A new chemical procedure for conversion of the biologically inactive fermentation product, oxotomaymycin, to the antibiotic, tomaymycin is disclosed as well as novel intermediates employed in such procedure.

Claims

1. A process for the preparation of a compound of the formula ##STR18## which comprises the steps of (1) converting oxotomaymycin of the formula ##STR19## to the corresponding 8-OH protected intermediate of the formula ##STR20## wherein R is a conventional phenolic hydroxyl protecting group;

(2) reacting amide intermediate III with phosphorous pentasulfide or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in an inert organic solvent to produce the thioamide intermediate of the formula ##STR21## wherein R is as defined above;

(3) reacting intermediate IV with a (lower)alkyl halide or (lower)alkoxonium salt in an inert organic solvent and in the presence of base to produce the thioiminoether intermediate of the formula ##STR22## wherein R₃ is (lower)alkyl and R is as defined above;

(4) optionally removing the C-8 hydroxyl protecting group of intermediate V to form an intermediate of the formula ##STR23## wherein R₃ is as defined above;

(5) selectively reducing the thioiminoether moiety of intermediate V or intermediate VI in an inert solvent to produce a thiocarbinolamine intermediate of the formula ##STR24## wherein R and R₃ are as defined above; and

(6) reacting intermediate VII or VIII with a mercuric salt in methanol to form the carbinolamine product of the formula ##STR25## wherein R is as defined above; and

, when the product obtained is compound IX, removing the hydroxyl protecting group R from intermediate IX so as to form the desired tomaymycin product I.

2. The process according to claim 1 which includes the additional step of converting tomaymycin to desmethanol tomaymycin of the formula ##STR26##

3. The process according to claim 1 or claim 2 wherein the reducing agent used in step (5) is aluminum amalgam.

4. The process according to claim 1 or claim 2 wherein

(a) in step (1) the C-8 hydroxyl group is protected by a benzoyl group;

(b) in step (2) the thiation reagent is 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide;

(c) in step (3) the alkylation is carried out using methyl iodide in tetrahydrofuran; and

(d) in step (5) the reduction is carried out using aluminum amalgam in an aqueous ether solvent.

5. An intermediate of the formula ##STR27## wherein R is a conventional phenolic hydroxyl protecting group.

6. The intermediate of claim 5 wherein R is benzoyl.

7. An intermediate of the formula ##STR28## wherein R₃ is (lower)alkyl and R is a conventional phenolic hydroxyl protecting group.

8. The intermediate of claim 7 wherein R₃ is methyl and R is benzoyl.

9. An intermediate of the formula ##STR29## wherein R₃ is (lower)alkyl.

10. The intermediate of claim 9 wherein R₃ is methyl.

11. An intermediate of the formula ##STR30## wherein R₃ is (lower)alkyl and R is a conventional phenolic hydroxyl protecting group.

12. The intermediate of claim 11 wherein R₃ is methyl and R is benzoyl.

13. An intermediate of the formula ##STR31## wherein R₃ is (lower)alkyl.

14. The intermediate of claim 13 wherein R₃ is methyl.

15. A process for the preparation of an intermediate of the formula ##STR32## wherein R is a conventional phenolic hydroxyl protecting group, which process comprises reacting an amide intermediate of the formula ##STR33## wherein R is as defined above with phosphorous pentasulfide or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in an inert organic solvent.

16. A process for the preparation of an intermediate of the formula ##STR34## wherein R₃ is (lower)alkyl and R is a conventional phenolic hydroxyl protecting group, which process comprises reacting an intermediate of the formula ##STR35## wherein R is as defined above with a (lower)alkyl halide or (lower) alkoxonium salt in an inert organic solvent and in the presence of base.

17. A process for the preparation of an intermediate of the formula ##STR36## wherein R is (lower)alkyl, which process comprises removing the C-8 hydroxyl protecting group of an intermediate of the formula ##STR37## wherein R is a conventional phenolic hydroxyl protecting group.

18. A process for the preparation of an intermediate of the formula ##STR38## wherein R is a conventional phenolic hydroxyl protecting group, which process comprises selectively reducing in an inert organic solvent and in the presence of base the thioiminoether moiety of an intermediate of the formula ##STR39## wherein R₃ is (lower)alkyl and R is a conventional phenolic hydroxyl protecting group.