Processes and intermediates in the preparation of C5aR antagonists

Patent metadata

Field	Value
Publication number	US-9745268-B2
Application number	US-201514867669-A
Country	US
Kind code	B2
Filing date	Sep 28, 2015
Priority date	Sep 29, 2014
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

Intermediates and methods are provided for the preparation of selected C5aR antagonist compounds.

First claim

What is claimed is:

1. A compound having the formula (i-3):

wherein R is selected from the group consisting of H, C 1-8 alkyl, aryl and aryl-C 1-4 alkyl, or a salt thereof, said compound being substantially free of enantiomeric or diastereomeric impurities.

2. A compound of claim 1 , in salt form as a bis L-DTTA salt.

3. A method of preparing a compound having formula (I):

or a salt thereof, wherein
R 1 is Cl or CF 3 ;
R 2 is F or Cl; and
R 3 is H or CH 3 ;
and wherein said compound of formula (I) is substantially free of enantiomeric or diastereomeric impurities, said method comprising:
(a) contacting a compound having the formula (i-3):

wherein R is selected from the group consisting of H, C 1-8 alkyl, aryl and aryl-C 1-4 alkyl, which is substantially free of enantiomeric or diastereomeric impurities, or a salt thereof, with a compound having the formula:

wherein LG is a leaving group selected from the group consisting of halogen, methanesulfonate (or mesylate), trifluoromethanesulfonate (triflate), benzenesulfonate, methylbenzenesulfonate (tosylate),4-nitrobenzenesulfonate, 4-chiorobenzenesulfonate, and the carboxylate component of a mixed or symmetrical anhydride; R 2 is F or Cl; and R 3 is H or CH 3 ; in the presence of a base to form a compound of formula (i-4):

and
(b) converting said compound of formula (i-4) to said compound of formula (I) wherein said compound of formula (I) is substantially free of enantiomeric or diastereomeric impurities.

4. A method in accordance with claim 3 , wherein step (b) includes contacting said compound of formula (i-4) with an aniline having the formula:

wherein R 1 is Cl or CF 3 ; in the presence of an organoaluminum reagent.

5. A method in accordance with claim 3 , wherein step (b) includes
(b)(1) hydrolyzing said compound of formula (i-4) where R is C 1-8 alkyl, aryl and aryl-C 1-4 alkyl to a compound of formula (i-4) where R is H; and
(b)(2) contacting the compound of formula (i-4) where R is H with an aniline having the formula:

wherein R 1 is Cl or CF 3 ; in the presence of a coupling reagent and a second base to provide said compound of formula (I).

6. A method of claim 3 , wherein R 1 is CF 3 , R 2 is F, and R 3 is CH 3 .

7. A method of claim 3 , wherein R 1 is CF 3 , R 2 is Cl, and R 3 is H.

8. A method of claim 3 , wherein R 1 is Cl, R 2 is F, and R 3 is CH 3 .

9. A process for the preparation of compounds of formula (I), said process comprising any two, three or four of the steps (a), (b), (c), and (d), or optionally steps (d1) and (d2), which steps can be contiguous in the synthetic scheme or non-contiguous:
(a) reacting an ester of 3-(4-nitrophenyl)-3-oxo-propanoate (i-1) wherein R is selected from the group consisting of C 1-8 alkyl, aryl and aryl-C 1-4 alkyl, with (R)-(−)-2-phenylglycinol, and acrolein diethyl acetal or an equivalent thereof, to produce compound (i-2)

(b) reducing (i-2) to produce an intermediate amine and converting the intermediate amine to (i-3) with cyclopentanone and a reducing agent

(c) combining (i-3) with either 2-fluoro-6-methylbenzoyl chloride or 2-chlorobenzoyl chloride in the presence of a first base to provide (i-4)

wherein R 2 is fluoro, R 3 is methyl, and LG is chloro, or R 2 is chloro and R 3 is hydrogen and LG is chloro;
(d) combining (i-4) with 3-chloro-4-methylaniline or 3-trifluoromethyl-4-methylaniline in the presence of an organoaluminum reagent to provide a compound of formula (I)

wherein, R 1 is Cl or CF 3 ; or
(d)(1) converting the ester (i-4) to a carboxylic acid (i-5):

(d)(2) combining (i-5) with 3-chloro-4-methylaniline or 3-trifluoromethyl-4-methylaniline in the presence of a coupling reagent and a second base to provide a compound of formula (I)

wherein R 1 is Cl or CF 3 ; and wherein R 2 is chloro and R 3 is hydrogen, or R 2 is fluoro and R 3 is methyl.

10. A process for the preparation of compounds of formula (I),

or a salt thereof, wherein
R 1 is Cl or CF 3 ;
R 2 is F or Cl; and
R 3 is H or CH 3 ;
comprising any two, three or four of the steps (a), (b), (c), and (d), or optionally steps (d1) and (d2), in place of step (d), which steps can be contiguous or non-contiguous:
(a) reacting an ester of 3-(4-nitrophenyl)-3-oxo-propanoate (i-1) wherein R is selected from the group consisting of C 1-8 alkyl, aryl and aryl-C 1-4 alkyl, with (R)-(−)-2-phenylglycinol, and acrolein diethyl acetal or an equivalent thereof, to produce an intermediate

(b) reducing the intermediate of step (a) to produce an intermediate amine and converting the intermediate amine to (i-3) with cyclopentanone and a reducing agent

(c) combining (i-3) with

 wherein
R 2 is F or Cl;
R 3 is H or CH 3 ; and
LG is a leaving group selected from the group consisting of halogen, methanesulfonate (or mesylate), trifluoromethanesulfonate (triflate), benzenesulfonate, 4-methylbenzenesulfonate (tosylate),4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, and the carboxylate component of a mixed or symmetrical anhydride to provide (i-4)

(d) combining (i-4) with 3-chloro-4-methylaniline or 3-trifluoromethyl-4-methylaniline in the presence of an organoaluminum reagent to provide a compound of formula (I); or

(d)(1) converting the ester (i-4) to a carboxylic acid (i-5):

and
(d)(2) combining (i-5) with 3-chloro-4-methylaniline or 3-trifluoromethyl-4-methylaniline in the presence of a coupling reagent and a base to provide a compound of formula (I).

Assignees

• Chemocentryx Inc

Inventors

• Fan Pingchen
• Kalisiak Jaroslaw
• Krasinski Antoni
• Lui Rebecca
• Powers Jay
• Punna Sreenivas
• Tanaka Hiroko
• Zhang Penglie

Classifications

• A61P9/10

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• A61P37/02

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• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title