# US 10,766,900 B2 · Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof

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- Number: US 10,766,900 B2
- Document ID: US10766900B2
- Status: Granted
- Kind: B2
- Application number: 15/857,755
- Filed: 2017-12-29
- Published: 2019-07-04
- Granted: 2020-09-08
- Earliest claimed: 2017-12-29
- Assignees: Formosa Laboratories, Inc.
- Applicants: Formosa Laboratories, Inc.
- Inventors: Hsiang-Yun Lai
- Web page: https://patentgrep.com/patent/US10766900B2

## CPC

- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present disclosure provides a Baricitinib intermediate, a method for preparing the Baricitinib intermediate, and a method for preparing Baricitinib or a pharmaceutically acceptable salt thereof using the Baricitinib intermediate. The method for preparing the Baricitinib intermediate involves the use of a divalent palladium catalyst or a nickel catalyst and provides the Baricitinib intermediate in high yield.

## Claims

### Claim 1

A method for forming a compound of formula (1):
wherein R1 is CH2OC(O)R′, R′ is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group, and R2 is selected from the group consisting of substituted or unsubstituted cyclic ether group, 1-(ethoxy)ethyl group, p-methoxybenzyl group, triphenylmethyl group, diphenylmethyl group, hydroxymethyl group, methoxymethyl group, triisopropylsilyl group and t-butyldimethylsilylmethyl group, comprising:
reacting a compound of formula (2) with a boron-containing compound selected from the group consisting of a compound of formula (3), a compound of formula (4) and a compound of formula (5) in the presence of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2) and in the absence of an additional phosphine ligand, wherein the formula (2), the formula (3), the formula (4), and the formula (5) are as follows:
wherein X is selected from the group consisting of Br, Cl, and I; and R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are each independently H or C1-C4 alkyl group.

### Claim 2 (depends on 1)

The method of claim 1, wherein R′ is a halogen-substituted alkyl group, an ether-substituted alkyl group, an aryl-substituted alkyl group, an oxytrimethylsilyl-substituted alkyl group, an alkyl-substituted cycloalkyl group, a halogen-substituted cycloalkyl group, an ether-substituted cycloalkyl group or an aryl-substituted cycloalkyl group.

### Claim 3 (depends on 1)

The method of claim 1, wherein R′ is —CpH2p+1, and p is an integer from 1 to 15.

### Claim 4 (depends on 1)

The method of claim 1, wherein R1 is —CH2OC(O)C(CH3)3.

### Claim 5 (depends on 1)

The method of claim 1, wherein R2 is selected from the group consisting of substituted or unsubstituted tetrahydropyranyl group, 2,3-dihydropyranyl group, and 1-(ethoxy)ethyl group.

### Claim 6 (depends on 1)

The method of claim 1, wherein R2 is selected from the group consisting of

### Claim 7 (depends on 1)

The method of claim 1, wherein the boron-containing compound is the compound of formula (3).

### Claim 8 (depends on 7)

The method of claim 7, wherein R3, R4, R5, and R6 are methyl group.

### Claim 9 (depends on 1)

The method of claim 1, further comprising reacting the compound of formula (2) with the boron-containing compound in a solvent.

### Claim 10 (depends on 1)

The method of claim 1, wherein reacting the compound of formula (2) and with boron-containing compound is performed under a basic condition.

### Claim 11 (depends on 1)

The method of claim 1, before reacting the compound of formula (2) with the boron-containing compound, further comprising:
reacting a compound of formula (6) with a compound of formula (7) to form the compound of formula (2) in the presence of potassium carbonate, wherein the formula (6) and the formula (7) are as follows:
and Y is selected from the group consisting of Br, Cl, and I.

### Claim 12 (depends on 1)

A method for preparing Baricitinib or a pharmaceutically acceptable salt thereof, comprising:
forming a compound of formula (1) according to the method of claim 1; and
using the compound of formula (1) as an intermediate to form the Baricitinib or the pharmaceutically acceptable salt thereof.