# US 8,569,491 B2 · Method for preparing entecavir and intermediate used therein

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- Number: US 8,569,491 B2
- Document ID: US8569491B2
- Status: Granted
- Kind: B2
- Application number: 13/501,414
- Filed: 2010-09-15
- Published: 2012-08-09
- Granted: 2013-10-29
- Earliest claimed: 2009-10-12
- Assignees: Hanmi Science Co., Ltd.
- Applicants: Jae Heon Lee; Gha Seung Park; Jin Hee Kim; Tae Jin Choi; Ji Eun Lee; Jung Hee Han; Hyo Jeong Bang; Sun Young Jung; Young Kil Chang; Gwan Sun Lee; Maeng Sup Kim
- Inventors: Jae Heon Lee; Gha Seung Park; Jin Hee Kim; Tae Jin Choi; Ji Eun Lee; Jung Hee Han; Hyo Jeong Bang; Sun Young Jung; Young Kil Chang; Gwan Sun Lee; Maeng Sup Kim
- Web page: https://patentgrep.com/patent/US8569491B2

## CPC

- C07D 473/04: two oxygen atoms
- A61P 31/14: for RNA viruses
- A61P 31/20: for DNA viruses
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are a novel, high-yield method for preparing entecavir and intermediates used therein.

## Claims

### Claim 1

A method for preparing entecavir of formula (I), comprising the steps of:
(a) hydrolyzing an α-exomethylene derivative of formula (II) to obtain a compound of formula (III);
(b) carrying out a Mitsunobu reaction of the compound of formula (III) with a purine derivative of formula (IV) to obtain a nucleoside compound of formula (V);
(c) subjecting the nucleoside compound of formula (V) to a reaction with tetrabutyl ammonium fluoride to obtain a compound of formula (VI); and
(d) hydrolyzing the compound of formula (VI):
wherein
R1 and R2 are each independently a hydroxy-protecting group, or R1 and R2 are fused together to form a cyclic hydroxy-protecting group;
R3 is benzoyl or arylbenzoyl; and
X is halogen or benzyloxy.

### Claim 2 (depends on 1)

The method of claim 1, wherein the hydroxy-protecting group is selected from the group consisting of methyl having one, two, or three phenyl substituents; benzyl substituted with alkoxy or nitro; benzoyl; benzoyl substituted with alkoxy or nitro; silyl; silyl substituted with at least one substituent selected from the group consisting of alkyl and aryl; allyl; alkoxyalkyl; and tetrahydropyranyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein the cyclic hydroxy-protecting group is selected from the group consisting of benzylidene, naphthylidene, 4-phenylbenzylidene, cyclic acetal, cyclic ketal, cyclic carbonate, cyclic orthoester, and cyclic 1,3-(1,1,3,3-tetraisopropyl)disiloxanediyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein X of the purine derivative of formula (IV) is chloro or benzyloxy group.

### Claim 5 (depends on 1)

The method of claim 1, wherein the Mitsunobu reaction is conducted in the presence of triphenylphosphine and di(C1 to C6 alkyl)azodicarboxylate.

### Claim 6 (depends on 1)

The method of claim 1, wherein the α-exomethylene derivative of formula (II) is prepared by conducting a Mitsunobu reaction of a β-exomethylene derivative of formula (VII):

### Claim 7 (depends on 6)

The method of claim 6, wherein the Mitsunobu reaction is conducted by subjecting the β-exomethylene derivative of formula (VII) to a reaction with triphenyl phosphine and di(C1 to C6 alkyl)azodicarboxylate.

### Claim 8 (depends on 6)

The method of claim 6, wherein the β-exomethylene derivative of formula (VII) is prepared by hydrolyzing an epoxide derivative of formula (VIII):
wherein, Y is alkylsilyl or arylsilyl.

### Claim 9 (depends on 8)

The method of claim 8, wherein the epoxide derivative of formula (VIII) is prepared by subjecting a compound of formula (IX) to a reaction with peroxide:

### Claim 10 (depends on 9)

The method of claim 9, wherein the peroxide is selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, t-butyl hydroperoxide, osmium tetroxide, sodium periodate, and a mixture thereof.

### Claim 11 (depends on 9)

The method of claim 9, wherein the compound of formula (IX) is a crystalline solid.

### Claim 12 (depends on 9)

The method of claim 9, wherein the compound of formula (IX) is prepared by subjecting a triflic enolate derivative of formula (X) to a reaction with alkylsilylmethyl magnesium chloride or arylsilylmethyl magnesium chloride in the presence of a metallic catalyst:
wherein, Tf is trifluoromethane sulfonyl.

### Claim 13 (depends on 12)

The method of claim 12, wherein the metallic catalyst is tetrakis(triphenylphosphine)palladium.

### Claim 14 (depends on 12)

The method of claim 12, wherein the triflic enolate derivative of formula (X) is prepared by conducting a reaction of a compound of formula (XI) with a triflating agent in the presence of a base:

### Claim 15 (depends on 14)

The method of claim 14, wherein the reaction is conducted at a temperature ranging from 20° C. to −29° C.

### Claim 16 (depends on 14)

The method of claim 14, wherein the base is selected from the group consisting of lithium hexamethyldisilazane, potassium hexamethyldisilazane, sodium hexamethyldisilazane, lithium diisopropylamide, n-(C1 to C6 alkyl)lithium, lithium tetramethylpiperidide, potassium butoxide, potassium pentoxide, potassium amylate, and a mixture thereof.

### Claim 17 (depends on 14)

The method of claim 14, wherein the triflating agent is selected from the group consisting of trihalomethane sulfonic anhydride; triflimide having a C1 to C6 alkyl or a C6 to C18 aryl N-substituent; and a mixture thereof.

### Claim 18 (depends on 14)

The method of claim 14, wherein the compound of formula (XI) is prepared by a method comprising the steps of:
preparing a cyclopentanol compound of formula (XIII) as a crystalline solid by treating a cyclopentene derivative of formula (XII) with (+)-diisopinocampheyl borane and H2O2, extracting the resulting mixture with a hydrocarbon-based solvent to induce the separation of an organic layer, washing the separated organic layer with a mixture of water and alcohol, and inducing the crystallization of the compound of formula (XIII) by adding a solvent as a crystallization aid; and
conducting oxidation of the cyclopentanol compound of formula (XIII) with a mixture of pyridine.SO3 complex, trialkylamine, and dimethylsulfoxide:

### Claim 19 (depends on 18)

The method of claim 18, wherein the washing process is conducted three or more times by using a mixture of water and alcohol mixed in a weight ratio ranging from 1:1 to 1:3.

### Claim 20 (depends on 18)

The method of claim 18, wherein the washing process is conducted five times by using any of the mixtures of water and alcohol having a mix weight ratio of 1:1, 1:1.5, 1:2, 1:2.5, or 1:3.

### Claim 21 (depends on 18)

The method of claim 18, wherein the solvent used as the crystallization aid is selected from the group consisting of hexane, heptane, octane, methanol, ethanol, isopropyl alcohol, water, and a mixture thereof.

### Claim 22 (depends on 1)

The method of claim 1, which further comprises the step of:
treating the compound obtained from the hydrolysis of step (d) with dimethylformamide to obtain a crystalline solvate form of entecavir dimethylformamide of formula (XIV); and
re-crystallizing the solvate of entecavir dimethylformamide of formula (XIV) from water:

### Claim 23

A solvate of crystalline entecavir dimethylformamide of formula (XIV) whose X-ray diffraction spectrum obtained using Cu-Kα radiation shows peaks having a peak intensity of 10% or more at diffraction angles (2θ±0.2) of 10.2, 14.4, 14.5, 16.6, 17.9, 18.8, 19.3, 19.8, 21.4, 21.9, 24.5, 25.5, 25.8, 26.7, 29.3, and 30.2:
wherein, DMF is dimethylformamide.

### Claim 24 (depends on 23)

A method for preparing the solvate of crystalline entecavir dimethylformamide of claim 23, comprising the steps of: dissolving the entecavir compound of formula (I) in a solvent containing dimethyl formamide; and inducing the crystallization of the compound of formula (XIV) therefrom: