7-aminocephem derivative compounds

Patent metadata

Field	Value
Publication number	US-10308666-B2
Application number	US-201815920609-A
Country	US
Kind code	B2
Filing date	Mar 14, 2018
Priority date	Dec 23, 2014
Publication date	Jun 4, 2019
Grant date	Jun 4, 2019

Abstract

This disclosure provides methods of making certain 7-aminocephem derivatives useful in the manufacture of cephalosporin antibiotic compounds.

First claim

We claim:

1. A process for making a compound of the formula (II):

comprising the steps of:
(a) forming a reaction mixture comprising phosphorous pentachloride (PCl 5 ) and pyridine;
(b) adding a compound of the formula (IIa) to the reaction mixture:

(c) adding isobutyl alcohol;
(d) adding a solvent comprising water;
(e) adding ethyl acetate; and
(f) obtaining the compound of the formula (II).

2. The process of claim 1 , wherein step (a) comprises:
(1) combining PCl 5 and dichloromethane; and
(2) adding pyridine.

3. The process of claim 2 , wherein step (1) comprises:
(i) combining 2.0 equivalents PCl 5 and 6.0 volumes dichloromethane while maintaining the temperature below 30° C.; and
(ii) adjusting the temperature to 10 to 30° C. and agitating.

4. The process of claim 2 , wherein step (2) comprises:
(i) adjusting the temperature to −10 to −5° C.;
(ii) adding 2.0 equivalents of pyridine while maintaining the temperature at −10 to 5° C.; and
(iii) adjusting the temperature to −5 to 0° C. and agitating.

5. The process of claim 1 , wherein step (b) comprises:
(1) adding 1.0 equivalent compound (IIa) to the reaction mixture of step (a) while maintaining the temperature of the mixture at −10 to 0° C.; and
(2) stirring the mixture at −10 to 0° C.

6. The process of claim 5 , wherein the mixture of step (2) comprises ≤5.0% compound (IIa) relative to compound (II)+compound (IIa).

7. The process of claim 1 , wherein step (c) comprises:
(1) adjusting the temperature of the mixture to −20 to −10° C.;
(2) adding 2.0 volumes of isobutyl alcohol dropwise while maintaining the temperature of the mixture at −20 to 5° C.; and
(3) agitating the mixture at −10 to 0° C.

8. The process of claim 1 , wherein step (d) comprises:
(1) adding a solvent comprising water to the mixture of step (c) while maintaining the temperature of the mixture at −10 to 5° C.;
(2) agitating the mixture at −5 to 5° C.; and
(3) separating a lower organic phase from the mixture and collecting the lower organic phase.

9. The process of claim 8 , wherein the solvent comprising water is a mixture of ethanol and water.

10. The process of claim 8 , which further comprises:
(4) adding dichloromethane to the mixture at −10 to 0° C.;
(5) agitating the mixture at −10 to 0° C.; and
(6) separating a lower organic phase from the mixture and collecting the lower organic phase.

11. The process of claim 1 , wherein step (e) comprises:
(1) concentrating the organic phase to 4 to 5 volumes;
(2) adjusting the temperature to −10 to −5° C.;
(3) adding 2.1 volumes of ethyl acetate dropwise while maintaining the temperature of the mixture at −10 to −5° C.; and
(4) agitating the mixture at −10 to 5° C.

12. The process of claim 11 , wherein step (e) further comprises:
(5) observing the formation of a precipitate;
(6) concentrating the organic phase to 4 to 5 volumes;
(7) adjusting the temperature of the mixture to −10 to −5° C.;
(8) adding 2.1 volumes of ethyl acetate while maintaining the temperature of the mixture at −10 to −8° C.; and
(9) agitating the mixture at −10 to −5° C.

13. The process of claim 1 , wherein step (f) comprises:
(1) centrifuging the mixture to produce a cake; and
(2) collecting the cake.

14. The process of claim 13 , wherein step (f) further comprises:
(3) adding 2.2 volumes of ethyl acetate;
(4) adjusting the temperature to −10 to −5° C.;
(5) agitating at −10 to −5° C.;
(6) centrifuging to produce a cake;
(7) collecting the cake; and
(8) drying the cake at 5 to 20° C.

Assignees

• Merck Sharp & Dohme

Inventors

• Moshos Kristos Adrian
• Jurkauskas Valdas

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