Thiadiazolyl-oximinoacetic acid derivative compounds
View Patent ↗Thiadiazolyl-oximinoacetic acid derivatives have been synthesized, which are useful in the manufacture of cephalosporin antibiotic compounds. Compound (1) (TATD) is commercially available (CAS No. 76028-96-1). It has now been discovered that the thiadiazolyl-oximinoacetic acid derivative compound (1) (TATD) can be prepared from dimethyl malonate (SM 1, CAS No. 108-59-8) according to methods described herein. The methods provide products having desirable purity.
1. A process of making a compound of formula (Z-I):
wherein:
P is an acid-labile oxygen protecting group,
R 3 and R 4 are each independently C 1-6 alkyl;
the process comprising admixing a compound of formula Int Z-E:
a thiocyanate salt, and an oxidant,
to provide the compound of formula (Z-I).
2. The process of claim 1 , wherein R 3 is methyl.
3. The process of claim 1 , wherein R 4 is methyl.
4. The process of claim 1 , wherein P is tert-butyl.
5. The process of claim 1 , wherein the oxidant comprises bromine.
6. The process of claim 5 , wherein the amount of bromine is from about 1.35 to about 1.42 equivalents compared with the molar amount of the compound of formula (Z-I).
7. The process of claim 1 , wherein the thiocyanate salt comprises ammonium thiocyanate or potassium thiocyanate.
8. The process of claim 1 , comprising admixing in an alcohol solvent.
9. The process of claim 8 , wherein the alcohol solvent comprises methanol.
10. The process of claim 1 , further comprising making the compound of formula Int Z-E from a compound of formula Int Z-E1:
wherein R 1 and R 5 are each independently C 1-6 alkyl;
comprising the steps of:
(a1) admixing the compound of formula Int Z-E1 and an ammonia source, and
(b1) contacting the admixture with a base;
or
(a2) admixing the compound of formula Int Z-E1 and a base, and
(b2) contacting the admixture with an ammonia source,
to provide the compound of formula Int Z-E.
11. The process of claim 10 , further comprising making the compound of formula Int Z-E1 from a compound of formula Int Z-C:
comprising the steps of:
(a) dehydrating the compound of formula Int Z-C; and
(b) contacting the dehydrate with a compound of formula MOR 5 ,
wherein M is lithium, sodium, or potassium,
to provide the compound of formula Int Z-E1.
12. The process of claim 11 , further comprising making the compound of formula Int Z-C comprising contacting ammonia with a compound of formula Int Z-B:
wherein R 2 is C 1-6 alkyl,
to provide the compound of formula Int Z-C.
13. The process of claim 12 , wherein the reaction temperature is from about −10° C. to about 5° C.
14. The process of claim 1 , wherein the compound of formula (Z-I) has the structure of compound (I):