# US 11,897,889 B2 · Process and intermediates for preparing a JAK1 inhibitor

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- Number: US 11,897,889 B2
- Document ID: US11897889B2
- Status: Granted
- Kind: B2
- Application number: 17/404,461
- Filed: 2021-08-17
- Published: 2022-02-24
- Granted: 2024-02-13
- Earliest claimed: 2020-08-18
- Assignees: Incyte Corporation
- Applicants: Incyte Corporation
- Inventors: Jiacheng Zhou; Shili Chen; Pingli Liu; David J. Meloni; Yongchun Pan; Naijing Su; Michael Xia
- Web page: https://patentgrep.com/patent/US11897889B2

## CPC

- C07D 487/04: Ortho-condensed systems
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 401/14: containing three or more hetero rings
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention is related to processes for preparing itacitinib, or a salt thereof, and related synthetic intermediates related thereto.

## Claims

### Claim 1

A process of preparing itacitinib, or a salt thereof, comprising:
reacting a compound of formula 3:
or a salt thereof, with a reagent selected from (i) a salt of formula 2a, or a salt thereof, and (ii) a compound of formula 2b:
wherein X− is a counter anion.

### Claim 2

A process of preparing itacitinib, or a salt thereof, comprising:
reacting a compound of formula 3:
or a salt thereof, with a reagent selected from (i) a salt of formula 2a, and (ii) a compound of formula 2b:
wherein X− is a counter anion.

### Claim 3 (depends on 1)

The process of claim 1, wherein X− is selected from Cl−, BF4−, PF6−, AsF6−, SbF6−, and ClO4−.

### Claim 4 (depends on 1)

The process of claim 1, wherein X− is Cl−.

### Claim 5 (depends on 1)

The process of claim 1, wherein the reagent is the salt of formula 2a.

### Claim 6 (depends on 1)

The process of claim 1, wherein the reagent is the compound of formula 2b.

### Claim 7 (depends on 1)

The process of claim 1, wherein the salt of formula 2a or the compound of formula 2b is prepared by a process comprising:
reacting the compound of formula 1a:
or a salt thereof, with a Vilsmeier reagent formed from dimethylformamide.

### Claim 8 (depends on 7)

The process of claim 7, wherein the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

### Claim 9 (depends on 8)

The process of claim 8, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, and triphosgene.

### Claim 10 (depends on 8)

The process of claim 8, wherein the chlorinating agent is oxalyl chloride.

### Claim 11 (depends on 7)

The process of claim 7, wherein the product of the reacting with the Vilsmeier reagent has formula 2d:

### Claim 12 (depends on 11)

The process of claim 11, wherein further comprising reacting a salt of formula 2d:
with a base to form a salt of formula 2c:

### Claim 13 (depends on 7)

The process of claim 7, wherein the reacting with the Vilsmeier reagent produces a salt of formula 2c:

### Claim 14 (depends on 12)

The process of claim 12, further comprising:
reacting the salt of formula 2c:
with a salt of formula M+X− to form the salt of formula 2a, wherein:
M+ is a counter cation; and
X− is a counter anion other than Cl−.

### Claim 15 (depends on 12)

The process of claim 12, wherein the compound of formula 2b is prepared by a process comprising reacting the salt of formula 2a or the salt of formula 2c with a base to form the compound of formula 2b.

### Claim 16 (depends on 7)

The process of claim 7, wherein the compound of formula 1a, or the salt thereof, is prepared by a process comprising:
deprotecting a compound of formula 1aP:
wherein P1 is an amino protecting group.

### Claim 17 (depends on 16)

The process of claim 16, wherein P1 is selected from (R1)3Si, wherein R1 is C1-6 alkyl.

### Claim 18 (depends on 17)

The process of claim 17, wherein R1 is methyl, ethyl, propyl, isopropyl, butyl or t-butyl.

### Claim 19 (depends on 16)

The process of claim 16, wherein the compound of formula 1aP is prepared by a process comprising:
reacting a compound of formula 2P:
with MeMgBr in the presence of a Grignard catalyst,
wherein P1 is an amino protecting group.

### Claim 20 (depends on 19)

The process of claim 19, wherein the compound of formula 2P is prepared by a process comprising:
protecting a compound of formula 12a:
to form the compound of formula 2P.

### Claim 21 (depends on 20)

The process of claim 20, wherein the protecting comprises reacting the compound of formula 12a with an alkali metal hydride and P1—Y, wherein Y is halo.

### Claim 22 (depends on 21)

The process of claim 21, wherein P1—Y is (R1)3Si—Y, wherein Y is halo and R1 is C1-6 alkyl.

### Claim 23 (depends on 20)

The process of claim 20, wherein the compound of formula 12a is prepared by a process comprising:
reacting a compound of formula 11a:
or a salt thereof, with a strong acid.

### Claim 24 (depends on 23)

The process of claim 23, wherein the compound of formula 11a, or a salt thereof, is prepared by a process comprising:
reacting a compound of formula 10a:
or a salt thereof, with (methoxymethyl)triphenylphosphonium chloride and a base.

### Claim 25 (depends on 24)

The process of claim 24, wherein the compound of formula 10a, or a salt thereof, is prepared by a process comprising:
reacting a compound of formula 9a:
with ammonia.

### Claim 26 (depends on 25)

The process of claim 25, wherein the compound of formula 9a is prepared by a process comprising:
reacting a compound of formula 8a:
with a Vilsmeier reagent formed from dimethylformamide.

### Claim 27 (depends on 26)

The process of claim 26, wherein the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

### Claim 28 (depends on 20)

The process of claim 20, wherein the compound of formula 12a is prepared by a process comprising:
reacting a compound of formula 15a:
with a chlorinating agent.

### Claim 29 (depends on 28)

The process of claim 28, wherein the compound of formula 15a is prepared by a process comprising:
reacting a compound of formula 14a:
with formamidine acetate and an alkali metal hydroxide to generate a compound of formula 14aa:
and
reacting the compound of formula 14aa with a strong acid.

### Claim 30 (depends on 29)

The process of claim 29, wherein the compound of formula 14a is prepared by a process comprising:
reacting a compound of formula 13a:
with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide.

### Claim 31 (depends on 7)

The process of claim 7, wherein the compound of formula 1a, or the salt thereof, is prepared by a process comprising:
reducing a compound of formula 23P:
wherein P2 is an amino protecting group.

### Claim 32 (depends on 31)

The process of claim 31, wherein the reducing of the compound of formula 23P is accomplished by a process comprising reacting the compound of formula 23P with hydrogen gas in the presence of a catalyst.

### Claim 33 (depends on 31)

The process of claim 31, wherein the compound of formula 23P is prepared by a process comprising:
reacting a compound of formula 22P:
with MeMgBr in the presence of a Grignard catalyst,
wherein P2 is an amino protecting group.

### Claim 34 (depends on 33)

The process of claim 33, wherein the compound of formula 22P is prepared by a process comprising:
protecting a compound of formula 22a:
to form the compound of formula 22P.

### Claim 35 (depends on 34)

The process of claim 34, wherein the protecting comprise reacting the compound of formula 22a with an alkali metal hydride and P2—Y, wherein Y is halo.

### Claim 36 (depends on 35)

The process of claim 35, wherein P2 is (R1)3 Si, wherein R1 is C1-6 alkyl.

### Claim 37 (depends on 7)

The process of claim 7, wherein the compound of formula 1a, or the salt thereof, is prepared by a process comprising:
reacting a compound of formula 18a:
or a salt thereof, with an acid to form the compound of formula 1a.

### Claim 38 (depends on 37)

The process of claim 37, wherein the compound of formula 18a, or a salt thereof, is prepared by a process comprising:
reacting a compound of formula 17a:
or a salt thereof, with formamidine acetate and triethyl orthoformate to form the compound of formula 18a, or a salt thereof.

### Claim 39 (depends on 38)

The process of claim 38, wherein the compound of formula 17a, or a salt thereof, is prepared by a process comprising:
reacting a compound of formula 20a:
or a salt thereof, with a compound of formula 21a:
to form the compound of formula 17a, or a salt thereof.

### Claim 40 (depends on 39)

The process of claim 39, wherein the compound of formula 20a, or a salt thereof, is prepared by a process comprising:
reacting a compound of formula 19a:
with bromo-1,1-dimethoxyethane and a base to form the compound of formula 20a.

### Claim 41 (depends on 40)

The process of claim 40, wherein the base is an alkali metal carbonate.

### Claim 42 (depends on 38)

The process of claim 38, wherein the compound of formula 17a, or a salt thereof, is prepared by a process comprising:
reacting a compound of formula 16a:
with ethyl acetate and a base to form the compound of formula 17a, or a salt thereof.

### Claim 43 (depends on 42)

The process of claim 42, wherein the base is an alkali metal alkoxide.

### Claim 44 (depends on 2)

The process of claim 2, wherein the salt of formula 2a or the compound of formula 2b is prepared by a process comprising:
reacting the compound of formula 5a:
or a salt thereof, with a Vilsmeier reagent formed from dimethylformamide.

### Claim 45 (depends on 44)

The process of claim 44, wherein the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

### Claim 46 (depends on 45)

The process of claim 45, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, and triphosgene.

### Claim 47 (depends on 45)

The process of claim 45, wherein the chlorinating agent is oxalyl chloride.

### Claim 48 (depends on 44)

The process of claim 44, wherein the product of the reacting with the Vilsmeier reagent has formula 2d:

### Claim 49 (depends on 48)

The process of claim 48, further comprising reacting the salt of formula 2d:
with a base to form a salt of formula 2c:

### Claim 50 (depends on 44)

The process of claim 44, wherein the reacting with the Vilsmeier reagent produces a compound of formula 2c:

### Claim 51 (depends on 49)

The process of claim 49, further comprising:
reacting the salt of formula 2c:
with a salt of formula M+X− to form the salt of formula 2a, wherein:
M+ is a counter cation; and
X− is a counter anion other than Cl−.

### Claim 52 (depends on 49)

The process of claim 49, wherein the compound of formula 2b is prepared by a process comprising reacting the salt of formula 2a or the salt of formula 2c with a base to form the compound of formula 2b.

### Claim 53 (depends on 44)

The process of claim 44, wherein the compound of formula or the salt thereof, is prepared by a process comprising:
hydrolyzing a compound of formula 27a:
in water in the presence of a base.

### Claim 54 (depends on 53)

The process of claim 53, wherein the base, present for the hydrolyzing of the compound of formula 27a, is sodium hydroxide; and the compound of formula 5a, or the salt thereof, is a sodium salt of the compound of formula 5a.

### Claim 55 (depends on 54)

The process of claim 54, further comprising reacting the sodium salt of the compound of formula 5a with a strong acid.

### Claim 56 (depends on 53)

The process of claim 53, wherein the compound of formula 27a is prepared by a process comprising:
reacting a compound of formula 26P:
with a strong acid, wherein P1 is an amino protecting group.

### Claim 57 (depends on 56)

The process of claim 56, wherein P1 is p-toluenesulfonyl.

### Claim 58 (depends on 56)

The process of claim 56, wherein the compound of formula 26P is prepared by a process comprising:
reacting a compound of formula 25P:
with alkali metal alkoxide to form the compound of formula 26P, wherein P1 is an amino protecting group.

### Claim 59 (depends on 58)

The process of claim 58, wherein the compound of formula 25P is prepared by a process comprising:
reacting a compound of formula 2P:
with diethyl malonate and a base, wherein P1 is an amino protecting group.

### Claim 60 (depends on 1)

The process of claim 1, wherein the itacitinib, or the salt thereof, is itacitinib adipate.

### Claim 61 (depends on 60)

The process of claim 60, wherein the itacitinib adipate is prepared by a process comprising reacting the itacitinib with at least one equivalent of adipic acid.

### Claim 62 (depends on 1)

The process of claim 1, wherein the compound of formula 3, or the salt thereof, is formed by a process comprising:
reacting a compound of formula A1:
with hydrazine.

### Claim 63

A process of preparing itacitinib, or a salt thereof, comprising reacting a salt of formula 2c:
with a compound of formula 3:
or a salt thereof, to form the itacitinib, or the salt thereof.

### Claim 64 (depends on 63)

The process of claim 63, further comprising reacting the itacitinib with at least one equivalent of adipic acid.

### Claim 65 (depends on 63)

The process of claim 63, wherein the itacitinib, or the salt thereof, is itacitinib adipate.

### Claim 66 (depends on 63)

The process of claim 63, wherein the salt of formula 2c is prepared by a process comprising reacting a salt of formula 2d:
with a base to form the salt of formula 2c.

### Claim 67 (depends on 66)

The process of claim 66, wherein the salt of formula 2d is prepared by a process comprising:
reacting a compound of formula 2P:
with MeMgBr in the presence of a Grignard catalyst to form a compound of formula 1aP:
deprotecting the compound of formula 1aP to form a compound of formula 1a:
or a salt thereof; and
reacting the compound of formula 1a, or the salt thereof, with a Vilsmeier reagent formed from dimethylformamide and a chlorinating agent to form the salt of formula 2d;
wherein P1 is an amino protecting group.

### Claim 68 (depends on 66)

The process of claim 66, wherein the salt of formula 2d is prepared by a process comprising:
reacting a compound of formula 22P:
with MeMgBr in the presence of a Grignard catalyst to form a compound of formula 23P:
reducing the compound of formula 23P to form a compound of formula 1a:
or a salt thereof; and
reacting the compound of formula 1a, or the salt thereof, with a Vilsmeier reagent formed from dimethylformamide and a chlorinating agent to form the salt of formula 2d;
wherein P2 is an amino protecting group.

### Claim 69

A compound of formula 3, having the formula:
or a salt thereof.