Reactions of thiadiazolyl-oximinoacetic acid derivative compounds
View Patent ↗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.
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):
methanesulfonyl chloride, and potassium carbonate particles having a D90 of 70-180 micrometers.
31. The composition of claim 30 , comprising a total of about 1.05 to 1.30 equivalents of potassium carbonate relative to the amount of the compound (I).
32. The composition of claim 30 , having a temperature of about 0 to 15 degrees C.
33. The composition of claim 30 , further comprising compound (Ib):