# US 10,308,666 B2 · 7-aminocephem derivative compounds

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,308,666 B2
- Document ID: US10308666B2
- Status: Granted
- Kind: B2
- Application number: 15/920,609
- Filed: 2018-03-14
- Published: 2018-09-13
- Granted: 2019-06-04
- Earliest claimed: 2014-12-23
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Kristos Adrian Moshos; Valdas Jurkauskas
- Web page: https://patentgrep.com/patent/US10308666B2

## CPC

- C07D 501/04: from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

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

## Claims

### Claim 1

A process for making a compound of the formula (II):
comprising the steps of:
(a) forming a reaction mixture comprising phosphorous pentachloride (PCl5) 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).

### Claim 2 (depends on 1)

The process of claim 1, wherein step (a) comprises:
(1) combining PCl5 and dichloromethane; and
(2) adding pyridine.

### Claim 3 (depends on 2)

The process of claim 2, wherein step (1) comprises:
(i) combining 2.0 equivalents PCl5 and 6.0 volumes dichloromethane while maintaining the temperature below 30° C.; and
(ii) adjusting the temperature to 10 to 30° C. and agitating.

### Claim 4 (depends on 2)

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.

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 5)

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

### Claim 7 (depends on 1)

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.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 8)

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

### Claim 10 (depends on 8)

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.

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 11)

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.

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 13)

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.