Chemical process for preparing phenylpiperidinyl indole derivatives

Patent metadata

Field	Value
Publication number	US-11208398-B2
Application number	US-201917260393-A
Country	US
Kind code	B2
Filing date	Jul 15, 2019
Priority date	Jul 16, 2018
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

The present invention relates to a method of synthesizing a compound of formula (I) also referred to as 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid, or a pharmaceutically acceptable salt thereof, and/or intermediates thereof, their use as pharmaceuticals and pharmaceutical compositions and the use of intermediates for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof.

First claim

The invention claimed is:

1. A process for preparing a compound of formula (C15),

or a salt thereof,
wherein R is C 1 -C 6 alkyl;
the process comprising the step of reacting a compound of formula (II),

or a salt thereof,
wherein R is C 1 -C 6 alkyl;
with a compound of formula (III),

or a salt thereof,
wherein P 3 is a nitrogen protecting group;
in the presence of an Iridium catalyst;
under hydrogen pressure;
to provide the compound of formula (C15), or a salt thereof.

2. A process for preparing a compound of formula (S)-(C4),

or a salt thereof,
wherein
R is C 1 -C 6 alkyl;
P 1 is a nitrogen protecting group;
comprising the step of reacting a compound of formula (C6),

or a salt thereof,
wherein P 1 is a nitrogen protecting group;
with an aryl-boronyl compound of formula (C7),

or a salt thereof,
wherein B(X 1 )(X 2 ) is selected from the group consisting of B(OH) 2 , B(OC(CH 3 ) 2 C(CH 3 ) 2 O), and 9-BBN;
in the presence of a catalyst; and
a ligand;
to obtain the compound of formula (S)-(C4), or a salt thereof.

3. The process of claim 2 , wherein X 1 and X 2 of the aryl-boronyl compound of formula (C7), or a salt thereof, are OH; the catalyst is Rh(acac)(C 2 H 4 ) 2 ; and the ligand is (S)-(−)XylBINAP (1,1′-Binaphthalene-2,2′-diylbis[bis(3,5-dimethylphenyl)phosphine]) or (R,R)-Ph-BPE ((+)-1,2-Bis((2R,5R)-2,5-diphenylphospholano)ethane).

4. The process of claim 3 , wherein the catalyst and the ligand form a catalyst-ligand complex and wherein the catalyst-ligand complex is (S)-XylBINAP-Rh(Acac) (1,1′-Binaphthalene-2,2′-diylbis[bis(3,5-dimethylphenyl)phosphine]-rhodium(acetylacetone) or (R, R)-Ph-BPE-Rh(Acac) ((+)-1,2-Bis((2R,5R)-2,5-diphenylphospholano)ethane)-rhodium(acetylacetone).

5. A process for preparing a compound of formula (S)-(C5),

or a salt thereof,
wherein
R is C 1 -C 6 alkyl;
P 1 is a nitrogen protecting group;
the process comprising the steps of:
(i) providing a compound of formula (S)-(C4),

or a salt thereof,
wherein R is C 1 -C 6 alkyl; P 1 is a nitrogen protecting group; and
(ii) treating the compound of formula (S)-(C4), or a salt thereof, under reductive enzymatic conditions;
to obtain the compound of formula (S)-(C5), or a salt thereof.

6. The process of claim 5 , wherein the reductive enzymatic condition comprises treating a compound of formula (S)-(C4), or a salt thereof, with:
an enzyme;
a co-factor;
in an aqueous buffer solution;
to provide a compound of formula (S)-(C5), or a salt thereof.

7. A process for preparing a compound of formula (S)-(C9),

or a salt thereof,
wherein R is C 1 -C 6 alkyl;
P 1 is a nitrogen protecting group;
the process comprising the steps of
(i) reacting the compound of formula (S)-(C5),

or a salt thereof,
wherein R is C 1 -C 6 alkyl, P 1 is a nitrogen protecting group, with an oxygen protecting group P 2 , to obtain a compound of formula (S)-(C8),

or a salt thereof,
wherein
R is C 1 -C 6 alkyl;
P 1 is a nitrogen protecting group;
P 2 is an oxygen protecting group; and
(ii) reacting the compound of formula (S)-(C8), or a salt thereof, with an ethylating reagent;
to obtain a compound of formula (S)-(C9), or a salt thereof.

8. The process of claim 7 , further comprising the step of reacting the compound of formula (S)-(C9), or a salt thereof, to remove the nitrogen protecting group P 1 , to obtain the compound of formula (II), or a salt thereof.

9. A compound of formula (C13),

or a salt thereof,
wherein P 3 is a nitrogen protecting group.

10. A process for preparing a compound of formula (C13),

or a salt thereof,
wherein P 3 is a nitrogen protecting group, the process comprising the steps of reacting a compound of formula (C12),

or a salt thereof,
wherein P 3 is a nitrogen protecting group;
with a Grignard reagent;
in the presence of an aldehyde source;
to obtain the compound of formula (C13), or a salt thereof.

11. The process of claim 10 , wherein the Grignard reagent is MeMgBr, and the aldehyde source is paraformaldehyde.

12. A process for preparing a compound of formula (III),

or a salt thereof,
wherein P 3 is a protecting group;
the process comprising reacting the compound of formula (C13),

or a salt thereof,
wherein P 3 is a nitrogen protecting group;
with an inorganic base;
in the presence of a methylating agent;
to obtain a compound of formula (III), or a salt thereof.

13. A process for preparing a compound of formula (III),

or a salt thereof,
wherein P 3 is a protecting group;
the process comprising the steps of:
(i) reacting a compound of formula (C12)

or a salt thereof, wherein P 3 is a nitrogen protecting group;
with a Grignard reagent, in the presence of an aldehyde source, to obtain a compound of formula (C13),

wherein P 3 is a nitrogen protecting group, and
(ii) reacting the compound of formula (C13), or a salt thereof, with an inorganic base, in the presence of a methylating agent,
to obtain the compound of formula (III), or a salt thereof.

14. A process for preparing a compound of formula (I),

or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound of formula (C15) of claim 1 under hydrolyzing conditions to obtain the compound of formula (I), or a pharmaceutically acceptable salt thereof.

15. A process for preparing a pharmaceutical composition, the process comprising mixing the compound of formula (I), or

Assignees

• Novartis Ag

Inventors

• Fu Peng
• Gai Yu
• Gao Feng
• Kong Weiyong
• Lu Yadong
• Min Zhongcheng
• Rong Shaofeng
• Shu Chutian
• Wang Can
• Wang Ruidong
• Zhao Jibin
• Zhao Xianglin
• Zhao Yi
• Zhou Jianguang
• Martin Benjamin

Classifications

• A61P37/02

  Immunomodulators · CPC title

• C07D211/74

  Oxygen atoms · CPC title

• C07D211/46

  having a hydrogen atom as the second substituent in position 4 · CPC title

• C12P17/12

  containing a six-membered hetero ring · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title