# US 11,028,119 B2 · Synthetic route to 2′-deoxy-2′,2′-difluorotetrahydrouridines

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- Number: US 11,028,119 B2
- Document ID: US11028119B2
- Status: Granted
- Kind: B2
- Application number: 16/717,811
- Filed: 2019-12-17
- Published: 2020-04-23
- Granted: 2021-06-08
- Earliest claimed: 2013-10-29
- Assignees: Otsuka Pharmaceutical Co., Ltd.
- Applicants: Otsuka Pharmaceutical Co., Ltd.
- Inventors: Hyeong-wook Choi; Steven Mathieu; Frank Fang; Bryan Matthew Lewis
- Web page: https://patentgrep.com/patent/US11028119B2

## CPC

- C07H 19/06: Pyrimidine radicals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 57/00: Separation of optically-active compounds
- C07H 1/00: Processes for the preparation of sugar derivatives
- C07H 1/06: Separation; Purification
- C07H 19/04: Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07B 2200/07: Optical isomers
- C07H 17/02: Heterocyclic radicals containing only nitrogen as ring hetero atoms
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to methods and intermediates for synthesizing 2′-deoxy-2′,2′-difluorotetrahydrouridine compounds.

## Claims

### Claim 1

A method of producing compound 1:
or a salt thereof;
comprising the steps of:
(a) hydrogenating the starting compound of Formula IV:
wherein R is a hydroxyl protecting group,
to produce the compound of Formula IIa:
(b) reducing the compound of Formula IIa to produce the compound of Formula IIIa:
(c) deprotecting the compound of Formula IIIa to produce compound 2:
and
(d) precipitating or crystallizing compound 2 in the presence of a catalyst to produce compound 1:
or a salt thereof;
wherein the catalyst is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), acetic acid, trifluoroacetic acid, diisopropylethylamine, or ammonium hydroxide; and
wherein the hydrogenating in step (a) is carried out in the presence of a palladium catalyst.

### Claim 2 (depends on 1)

The method of claim 1, wherein the catalyst is about 1 mol % to about 20 mol % DBU.

### Claim 3 (depends on 2)

The method of claim 2, wherein the catalyst is about 5 mol % to about 10 mol % DBU.

### Claim 4 (depends on 3)

The method of claim 3, wherein the catalyst is about 5 mol % DBU.

### Claim 5 (depends on 1)

The method of claim 1, wherein the catalyst is acetic acid, trifluoroacetic acid, diisopropylethylamine, or ammonium hydroxide.

### Claim 6 (depends on 1)

The method of claim 1, wherein the final product is recrystallized or slurrified.

### Claim 7 (depends on 1)

The method of claim 1, wherein step (d) is carried out in the presence of a solution comprising acetonitrile.

### Claim 8 (depends on 1)

The method of claim 1, wherein step (d) is carried out in the presence of a solution comprising acetone or tetrahydrofuran.

### Claim 9 (depends on 1)

The method of claim 1, wherein step (b) is carried out in the presence of CeCl3.

### Claim 10 (depends on 1)

The method of claim 1, further comprising a step of reducing the particle size of compound 1.

### Claim 11 (depends on 10)

The method of claim 10, wherein the particle size is reduced to about 50 μm or less.

### Claim 12 (depends on 1)

The method of claim 1, wherein the palladium catalyst is palladium on charcoal.