Reactions of thiadiazolyl-oximinoacetic acid derivative compounds

Patent metadata

Field	Value
Publication number	US-9695196-B2
Application number	US-201515319104-A
Country	US
Kind code	B2
Filing date	Jun 19, 2015
Priority date	Jun 20, 2014
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

This disclosure relates to an improved synthesis of cephalosporin antibiotic compounds such as ceftolozane, and compositions and methods of use thereof. Thiadiazolyl-oximinoacetic acid compounds such as TATD can be reacted to yield the activated thiadiazolyl-oximinoacetic acid methanesulfonate ester compounds useful in the manufacture of cephalosporin antibiotic compounds.

First claim

What is claimed is:

1. A process for preparing a compound of formula (Z-Ib-1):

wherein:
W 1 is an acid-labile protecting group,
X 1 is Cl, Br, or I, and
R S is a C 1 -C 6 alkyl;
which comprises admixing a compound of formula (Z-I):

with a compound of formula R S SO 2 X 1 ,
in the presence of alkali metal carbonate particles having at least about 50% of the particles by weight in a range of from about 70 to about 250 micrometers,
to give the compound of formula (Z-Ib-1).

2. The process of claim 1 , wherein the alkali metal carbonate particles have at least about 70% of the particles by weight in a range of from about 70 to about 250 micrometers.

3. The process of claim 1 , wherein the alkali metal carbonate particles have at least about 80% of the particles by weight in a range of from about 70 to about 250 micrometers.

4. The process of claim 1 , wherein the alkali metal carbonate particles have at least about 90% of the particles by weight in a range of from about 70 to about 250 micrometers.

5. The process of claim 1 , wherein the alkali metal carbonate is potassium carbonate.

6. The process of claim 1 , wherein W 1 is tert-butyl.

7. The process of claim 1 , wherein R S is CH 3 .

8. The process of claim 1 , wherein the molar equivalent ratio of the compound of formula (Z-I) to the alkali metal carbonate is in a range of from about 0.6 to about 1.4.

9. The process of claim 1 , wherein the reaction temperature is in a range of from about −5 to about 20° C.

10. The process of claim 1 , wherein X 1 is Cl.

11. The process of claim 1 , wherein the molar equivalent ratio of the compound of formula R S SO 2 X 1 to the compound of formula (Z-I) is in a range of from about 1.3 to about 3.0.

12. The process of claim 1 , further comprising reacting the compound of formula (Z-Ib-1) with a compound of formula (Z-II):

to give a compound of formula (Z-III):

wherein:
X is Cl, Br, or I; and
W 2 is tert-butyl, para-methoxybenzyl, ortho-methoxybenzyl, or diphenylmethyl.

13. The process of claim 12 , further comprising reacting the compound of formula (Z-III) with a compound of formula (Z-IV):

to give a compound of formula (Z-V):

wherein:
W 3 and W 4 are each independently triphenylmethyl, tert-butyl, tert-butoxycarbonyl, or para-methoxybenzoyl; and
Anion1 is Cl, Br, I, trifluoroacetate, trifluoromethanesulfonate, or hydrogen sulfate.

14. The process of claim 13 , further comprising converting the compound of formula (Z-V):

to a compound of formula (Z-VI):

wherein
Anion3 is Cl, Br, I, methanesulfonate, toluenesulfonate, hydrogen sulfate, or sulfate.

15. The process of claim 1 , comprising reacting a compound (I):

with methanesulfonyl chloride in the presence of potassium carbonate particles having a D90 of 70-250 micrometers, to obtain a compound (Ib):

16. The process of claim 15 , wherein a total of about 1.05 to 1.30 equivalents of potassium carbonate are combined with compound (I).

17. The process of claim 15 , wherein the reaction of compound (I) occurs in a solution at a temperature of about 0-13 degrees C.

18. The process of claim 15 , wherein:
(a) a total of about 1.05 to 1.30 equivalents of potassium carbonate are combined with compound (I); and
(b) the reaction of compound (I) occurs in a solution at a temperature of about 0-13 degrees C.

19. The process of claim 18 , wherein at least about 90% of compound (I) is converted to compound (Ib).

20. The process of claim 15 , wherein the process further comprises reacting compound (Ib) with compound (II):

to give compound (III):

21. The process of claim 20 , wherein the process further comprises reacting compound (III) with compound (IV):

to give compound (V):

22. The process of claim 21 , wherein the process further comprises converting compound (V):

to compound (VI):

23. A process comprising reacting compound (I):

with methanesulfonyl chloride in the presence of an amount of potassium carbonate particles having a pre-determined D90 and at a temperature effective to provide at least 90% conversion of compound (I) to compound (Ib):

24. The process of claim 23 , wherein the reaction is performed at a temperature of about 0 to 15 degrees C.

25. The process of claim 23 , wherein the reaction is performed without an increase in temperature of greater than about 10 degrees C.

26. The process of claim 23 , wherein the reactants are maintained in contact for about 3 hours before isolating the compound (Ib).

27. The process of claim 23 , wherein at least about 97% of compound (I) is converted to compound (Ib) within about 3 hours.

28. The process of claim 23 , wherein the molar ratio of potassium carbonate to compound (I) is between about 1.05 and 1.30 in the reaction.

29. The process of claim 23 , wherein:
(a) the reaction is performed at a temperature of about 0 to 15 degrees C., and the reaction is performed without an increase in temperature of greater than about 10 degrees C.;
(b) the reaction is performed within about 1-3 hours;
(c) at least about 97% of compound (I) is converted to compound (Ib); and
(d) the molar ratio of potassium carbonate to compound (I) is between about 1.05 and 1.30 in the reaction.

30. A composition comprising compound (I):

Assignees

• Merck Sharp & Dohme

Inventors

• Moshos Kristos Adrian
• Jurkauskas Valdas
• Scanu Manuel
• Benotti Michele

Classifications

• C07D501/04 Primary

  from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents · CPC title

• C07D285/08

  1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles · CPC title