# US 10,865,212 B2 · Intermediate for preparing eribulin mesylate and process for preparing the same

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- Number: US 10,865,212 B2
- Document ID: US10865212B2
- Status: Granted
- Kind: B2
- Application number: 16/475,171
- Filed: 2018-01-02
- Published: 2019-11-07
- Granted: 2020-12-15
- Earliest claimed: 2017-01-02
- Assignees: Yonsung Fine Chemical Co., Ltd.
- Applicants: Yonsung Fine Chemical Co., Ltd.
- Inventors: Hyoseon Lee; Hyunik Shin; Keeyoung Lee; Changyoung Oh
- Web page: https://patentgrep.com/patent/US10865212B2

## CPC

- A61P 35/00: Antineoplastic agents
- C07D 493/04: Ortho-condensed systems
- C07D 309/10: Oxygen atoms
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention relates to a process for preparing an intermediate for the preparation of eribulin mesylate with high yields, and an intermediate therefor.

## Claims

### Claim 1

A process for preparing a compound of the following formula (3), which comprises the steps of:
subjecting a compound of the following formula (4) to Wittig reaction to obtain a compound of the following formula (5);
(ii) selectively deprotecting a PG2 group of the compound of the following formula (5) to obtain a compound of the following formula (6);
(iii) subjecting the compound of the following formula (6) to cyclization to obtain a compound of the following formula (7);
(iv) subjecting the compound of the following formula (7) to hydrogenation to obtain a compound of the following formula (8); and
(v) reducing an ester group of the compound of the following formula (8):
wherein,
PG1 represents a diol protecting group forming a 5-membered heterocycle by combining each other, and is derived from cyclopentanone, cyclohexanone, cycloheptanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane or 1,1-dimethoxycycloheptane,
PG2 represents a silyl protecting group, and
R1 represents hydrogen or a C1-C6 alkyl group.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the Wittig reaction of step (i) is carried out using (methoxycarbonylmethylene)triphenylphosphorane or (ethoxycarbonylmethylene)triphenylphosphorane.

### Claim 3 (depends on 1)

The process according to claim 1, wherein the deprotection of step (ii) is carried out using a mixture of a fluoride compound and a buffer.

### Claim 4 (depends on 3)

The process according to claim 3, wherein the buffer is imidazole hydrochloride.

### Claim 5 (depends on 1)

The process according to claim 1, wherein the cyclization of step (iii) is carried out in the presence of a catalyst.

### Claim 6 (depends on 5)

The process according to claim 5, wherein the catalyst is di-μ-chloro-tetracarbonyldirhodium(I).

### Claim 7 (depends on 1)

The process according to claim 1, wherein the hydrogenation of step (iv) is carried out in the presence of Pd/C.

### Claim 8 (depends on 1)

The process according to claim 1, wherein the reduction of step (v) is carried out using diisobutylaluminum hydride.

### Claim 9

A compound of the following formula (3):
wherein,
PG1 represents a diol protecting group forming a 5-membered heterocycle by combining each other, and is derived from cyclopentanone, cyclohexanone, cycloheptanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane or 1,1-dimethoxycycloheptane.