# US 2021/0276970 A1 · Process for preparing indole carboxamide compounds

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

- Number: US 2021/0276970 A1
- Document ID: US20210276970A1
- Status: Published application
- Kind: A1
- Application number: 16/328,447
- Filed: 2017-08-31
- Published: 2021-09-09
- Earliest claimed: 2016-09-02
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Junying Fan; Peng Geng; Neil A. Strotman; Alina Borovika; Jason Michael Stevens; Dimitri Skliar
- Web page: https://patentgrep.com/patent/US20210276970A1

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed is a process for preparing (S)-4-(3-(but-2-ynamido)piperidin fluoro-2,3-dimethyl-1H-indole-7-carboxamide, comprising the steps of: preparing a compound of Formula (III); converting the compound of Formula (III) to a compound of Formula (V); and reacting the compound of Formula (V) with a compound of Formula (VI) to provide (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide.

## Claims

### Claim 1

A process for preparing a compound of Formula (V):
comprising the steps of:
(a) reacting a compound of Formula (I) and a compound of Formula (II):
to provide a compound of Formula (III):
and
(b) converting said compound of Formula (III) to said compound of Formula (V) by steps (b1), (b2), and (b3), in any order:
(b1) forming an indole group by reaction with a compound of Formula (IVa) or a compound of Formula (IVb):
(b2) converting said —NR4R5 group to —NH2; and
(b3) converting said —OR3 group to —NH2+;
wherein:
X1 is halo, —NO2, —OS(O)2R, or —N2+;
X2 is Cl, Br, I, —OH, —OS(O)2R, acyloxy, or trialkylsiloxy;
R1 and R2 are independently selected from H, benzyl, substituted benzyl, 4-methoxyphenyl, acyl, —S(O)2Ar, tert-butoxycarbonyl, or benzyloxycarbonyl;
R3 is H, C1-8 alkyl, aryl, or heteroaryl;
R4 and R5 are independently selected from H, benzyl, 4-methoxybenzyl, 4-methoxyphenyl, acyl, —S(O)2R, tert-butoxycarbonyl, or benzyloxycarbonyl;
R8 is H, C1-3 alkyl, or aryl; and
each R is independently C1-3 alkyl or aryl.

### Claim 2 (depends on 1)

The process according to claim 1 wherein in Step (b), said compound of Formula (III) is converted to said compound of Formula (V) by:
reacting said compound of Formula (III) with said compound of Formula (IVa) or said compound of Formula (IVb) and converting said —NR4R5 group to —NH2, either in a consecutive or concurrent order, or both, to provide a compound of Formula (Va)
and converting said —OR3 group attached to said compound of Formula (Va) to —NH2 to provide said compound of Formula (V).

### Claim 3 (depends on 1)

The process according to claim 1 wherein in Step (b), said compound of Formula (III) is converted to said compound of Formula (V) by:
converting said —OR3 group attached to said compound of Formula (III) to —NR6R7 to provide said compound of Formula (IIIa):
reacting said compound of Formula (IIIa) with said compound of Formula (IVa) or said compound of Formula (IVb) to provide a compound of Formula (Vb):
and converting each of said —NR4R5 group and said —NR6R7 group attached to the compound of Formula (Vb) to —NH2, either in a consecutive or concurrent order, or both; wherein R6 and R7 are individually selected from H, benzyl, 4-methoxybenzyl 4-methoxyphenyl, allyl, acyl, formyl, —OH, —OR, tert-butoxycarbonyl, benzyloxycarbonyl or —S(O)2R.

### Claim 4 (depends on 1)

The process according to claim 1 wherein in Step (b1), said indole group is formed by reaction with said compound of Formula (IVa).

### Claim 5 (depends on 1)

The process according to claim 1 wherein in Step (b1), said indole group is formed by reaction with said compound of Formula (IVb).

### Claim 6 (depends on 1)

The process according to claim 1 further comprising the step of reacting the compound of Formula (V) with a compound of Formula (VI)
to provide a compound of Formula (VII):
wherein X3 is —OH, halo, —OCH3, —O(aryl), —OC(O)R, —OS(O)2R, —OS(O)R, —OP(O)R2, or —OP(O)(OR)2.

### Claim 7

A compound have the structure of Formula (Va):
or a salt thereof, wherein:
R3 is Cl-6 alkyl unsubstituted or substituted with one or more Ra, benzyl unsubstituted or substituted with one or more Ra, or silyl; and
each Ra is independently F or Cl.

### Claim 8 (depends on 7)

The compound according to claim 7 wherein R3 is H or —CH3.

### Claim 9 (depends on 1)

The process according to claim 1 wherein:
X1 is halo, —NO2, —OS(O)2R; and
R is C1-3 alkyl.

### Claim 10 (depends on 1)

The process according to claim 1 wherein:
X2 is Cl, Br, I, —OH, —OS(O)2R, acyloxy, or trialkylsiloxy; and
R is C1-3 alkyl or aryl.

### Claim 11 (depends on 1)

The process according to claim 1 wherein R2 is H or benzyl.

### Claim 12 (depends on 1)

The process according to claim 1 wherein R3 is H or —CH3.

### Claim 13 (depends on 1)

The process according to claim 1 wherein:
R4 is H; and
R5 is benzyl, tert-butoxycarbonyl, or benzyloxycarbonyl.

### Claim 14 (depends on 1)

The process according to claim 1 wherein:
R1 is H;
R2 is H;
R3 is —CH3;
R4 is H;
R5 is tert-butoxycarbonyl;
X1 is F; and
X2 is —OH.

### Claim 15 (depends on 1)

The process according to claim 1 wherein step (a) is conducted in the presence of one or more synthesis adjuvants independently selected from organic bases, inorganic bases, nucleophilic catalysts, and transition metal catalysts.

### Claim 16 (depends on 1)

The process according to claim 1 wherein step (a) is conducted at a reaction temperature in the range of from about 40° C. to about 140° C.

### Claim 17 (depends on 1)

The process according to claim 1 wherein one or both of step (b1) and step (b2) are conducted in the presence of one or more synthesis adjuvants independently selected from diphenylphosphoric acid, dibenzylphosphoric acid, diphenylphosphinic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, phosphoric acid, trichloroacetic acid, tin(II) chloride, tin(II) triflate, ytterbium triflate, aluminum triflate, bismuth triflate, zirconium chloride, titanium chloride, scandium triflate, and iron(III) triflate.

### Claim 18 (depends on 1)

The process according to claim 1 wherein one or both of step (b1) and step (b2) are conducted at a temperature in the range of from about 40° C. to about 100° C.

### Claim 19 (depends on 1)

The process according to claim 1 wherein step (b2) is conducted in the presence of one or more synthesis adjuvants independently selected from sodium formamide or 1,5,7-triazabicyclo[4.4.0]dec-5-ene.

### Claim 20 (depends on 1)

The process according to claim 1 wherein step (b2) is conducted in a temperature in the range of from about 0° C. to about 100° C.