# US 12,215,110 B2 · Processes and intermediates for preparing a Btk inhibitor

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- Number: US 12,215,110 B2
- Document ID: US12215110B2
- Status: Granted
- Kind: B2
- Application number: 17/612,082
- Filed: 2020-05-20
- Published: 2022-06-30
- Granted: 2025-02-04
- Earliest claimed: 2019-05-21
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: Philip James Pye; Andras Horvath; Cheng Yi Chen; Yuanyuan Yuan; Jinxiong Su; Shuo Wang; Simon Albert Wagschal
- Web page: https://patentgrep.com/patent/US12215110B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

Disclosed is a process for the preparation of certain intermediates, e.g. a process for preparing a compound of formula (I) wherein, R1, R2 and X1 are as defined in the description, and which intermediate and processes are useful in the preparation of a BTK inhibitor, such as ibrutinib.

## Claims

### Claim 1

A process for preparing a compound of formula (I);
wherein:
R1 is a nitrogen protecting group;
R2 is hydrogen or aryl;
X1 is a leaving group or —N(R3)R4;
at least one of R3 and R4 is a nitrogen protecting group, and the other is hydrogen or an independent nitrogen protecting group;
wherein the process comprises reacting a compound of formula (II);
with an oxidant and a copper-based catalyst.

### Claim 2 (depends on 1)

The process of claim 1, wherein the reaction is performed in the presence of a copper-based catalyst and air (O2).

### Claim 3 (depends on 2)

The compound of claim 2, wherein the catalyst is Cu(OAc)2 or CuBr.

### Claim 4 (depends on 1)

The process of claim 1, wherein:
X1 is halo or —O—Y1; and/or
Y1 is hydrogen; and/or
R2 is phenyl.

### Claim 5 (depends on 1)

The process of claim 1, wherein the compound of formula (II) is prepared by reacting a compound of formula (III):
or a salt thereof, with a compound of formula (IV):
or a salt thereof, wherein X2 is a halo, in the presence of an organolithium base.

### Claim 6 (depends on 5)

The process of claim 5, wherein the compound of formula (III) is prepared by reacting a compound of formula (V):
or a salt thereof, wherein X3 is a suitable leaving group with a compound of formula (VI);
or a salt thereof, under nucleophilic aromatic substitution reaction conditions.

### Claim 7 (depends on 1)

A process for preparing ibrutinib, comprising reacting the compound of formula (I) prepared according to claim 1 with (i) Cl—C(O)—C(H)═CH2 or (ii) 3-chloropropionyl chloride to form a compound of formula (VII):
or a derivative thereof, and subjecting the compound of formula (VII) to an elimination reaction to provide ibrutinib.

### Claim 8 (depends on 7)

A process for preparing a pharmaceutical composition of claim 7, comprising contacting the ibrutinib, or a salt thereof with a pharmaceutically acceptable carrier, diluent and/or excipient.

### Claim 9 (depends on 1)

The process of claim 1, wherein R2 is phenyl.

### Claim 10 (depends on 1)

The process of claim 1, wherein the leaving group is halo or —O—Y1 and Y1 is hydrogen or a sulfone.

### Claim 11 (depends on 10)

The process of claim 10, wherein X1 is tosylate, mesylate, or triflate.

### Claim 12 (depends on 1)

The process of claim 1, wherein the sulfone is —S(O)2—Rx, wherein Rx is C1-3 alkyl optionally substituted by one or more fluoro, or aryl optionally substituted by one or more of halo or C1-3 alkyl, wherein the optional substituents are optionally substituted by one or more fluoro.

### Claim 13 (depends on 12)

The process of claim 12, wherein Rx is phenyl.

### Claim 14 (depends on 1)

The process of claim 1, wherein the oxidant is oxygen.

### Claim 15 (depends on 4)

The process of claim 4, wherein X1 is chloro.

### Claim 16 (depends on 4)

The process of claim 4, wherein R2 is unsubstituted phenyl.

### Claim 17 (depends on 6)

The process of claim 6, wherein the leaving group is halo or O—Y2 and Y2 is a sulfone.

### Claim 18 (depends on 17)

The process of claim 17, wherein the leaving group is chloro, bromo or iodo.

### Claim 19 (depends on 17)

The process of claim 17, wherein Y2 is —S(O)2—Ry, wherein Ry is C1-3 alkyl optionally substituted by one or more fluoro, or aryl optionally substituted by one or more of halo and C1-3alkyl, wherein the optional substituents are optionally substituted by one or more fluoro.

### Claim 20 (depends on 19)

The process of claim 19, wherein the aryl is phenyl.

### Claim 21 (depends on 7)

The process of claim 7, wherein compound (VII) is performed in the presence of aqueous NaHCO3 in Me-THF.

### Claim 22 (depends on 7)

The process of claim 7, wherein the elimination reaction is performed using 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).