Process for the preparation of carbamoylamino pyrazole derivatives

Patent metadata

Field	Value
Publication number	US-10351533-B2
Application number	US-201615738016-A
Country	US
Kind code	B2
Filing date	Jun 28, 2016
Priority date	Jun 29, 2015
Publication date	Jul 16, 2019
Grant date	Jul 16, 2019

Abstract

The present invention relates to a process for the preparation of carbamoylamino pyrazole derivatives using diacetoxyiodobenzene (PhI(OAc)2) in combination with a non-nucleophilic base.

First claim

The invention claimed is:

1. Process for production of a compound of formula

wherein
R 1 is H, straight or branched C 1 -C 6 alkyl, optionally substituted by 1 to 5 hydroxy groups which may be protected or halogen atoms,
R 2 is H, straight or branched C 1 -C 6 alkyl or an amino protecting group, or R 1 and R 2 are bonded together to form C 1 -C 6 alkylene or C 2 -C 6 alkenylene,
R 3 is H, straight or branched C 1 -C 6 alkyl or an amino protecting group, wherein R 3 is not H if R 2 is H,
R 4 is

wherein
a is 0, 1, 2, 3, 4, 5 or 6,
R 5 is H or hydroxy which may be protected, and
R 6 is H, C 1 -C 6 straight or branched alkyl, mono or di straight or branched C 1 -C 6 alkylamino, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl amino, C 6 -C 12 aryl, C 6 -C 12 aryl amino, protected amino, protected guanidino or a saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms, wherein the cycloalkyl or aryl is optionally substituted by one or more C 1 -C 3 straight or branched alkyl and the heterocyclic group is optionally substituted by one or more protected amino groups
comprising reacting a compound of formula

wherein R 1 , R 2 and R 3 are as defined above
with a compound of formula

wherein a, R 5 and R 6 are as defined above
and PhI(OAc) 2 in the presence of a non-nucleophilic base to produce the compound of formula I.

2. The process according to claim 1 , wherein R 1 is straight or branched C 1 -C 6 alkyl.

3. The process according to claim 1 , wherein R 2 is an amino protecting group.

4. The process according to claim 1 , wherein R 3 is H.

5. The process according to claim 1 , wherein
R 4 is

wherein
a is 0, 1, 2, 3, 4, 5 or 6,
R 5 is H or hydroxy which may be protected, and
R 6 is H, mono or di straight or branched C 1 -C 6 alkylamino or straight or branched C 1 -C 6 alkoxycarbonylamino.

6. The process according to claim 1 , wherein
R 4 is

wherein a is 1, 2, or 3,
R 5 is H, and

R 6 is straight or branched C 1 -C 6 alkoxycarbonylamino.

7. The process according to claim 1 , wherein
R 1 is methyl,
R 2 is an amino protecting group,
R 3 is H, and
R 4 is

wherein a is 2,
R 5 is H, and

R 6 is protected amino.

8. The process according to claim 1 , wherein
R 1 is methyl,
R 2 is Boc or trityl,
R 3 is H, and
R 4 is

wherein a is 2,
R 5 is H, and
R 6 is NH-Boc.

9. The process according to claim 1 , wherein the non-nucleophilic base is 1,8-diazabicycloundec-7-ene.

10. The process according to claim 1 , wherein production of the compound of formula I is conducted in a non-nucleophilic solvent.

11. The process according to claim 1 , wherein production of the compound of formula I is conducted under anhydrous conditions.

12. The process according to claim 1 , wherein the compounds of formula II and formula III are used in a molar ratio of 1/1.2 to 1/3.

13. The process according to claim 1 , wherein the compound of formula II and PhI(OAc) 2 are used in a molar ratio of 1/1.1 to 1/1.9.

14. The process according to claim 1 , wherein the compound of formula II is prepared by a process of converting a compound of formula

wherein R 1 and R 2 are as defined in claim 1 , and R 3′ is straight or branched C 1 -C 6 alkyl or an amino protecting group
into the compound of formula II.

15. A process for preparation of Ceftolozane or a salt thereof which comprises
a) preparing a compound of formula I by the process according to claim 1 wherein R 1 is methyl, R 2 is H or an amino protecting group, R 3 is an amino protecting group, and
R 4 is

wherein a is 2,
R 5 is H,
and R 6 is protected amino,

b) reacting the compound of formula I, optionally after deprotection, with at least one other intermediate product and removing any remaining protection group to obtain Ceftolozane or salt thereof.

Assignees

• Sandoz Ag

Inventors

• Schöne Olga
• Spitzenstätter Hans-Peter
• Kaufmann Marius

Classifications

• C07D231/40 Primary

  Acylated on said nitrogen atom · CPC title

• C07D501/04

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

• C07D501/46 Primary

  with the 7-amino radical acylated by carboxylic acids containing hetero rings · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title