# US 2014/0155588 A1 · Azacitidine process and polymorphs

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- Number: US 2014/0155588 A1
- Document ID: US20140155588A1
- Status: Published application
- Kind: A1
- Application number: 14/174,143
- Filed: 2014-02-06
- Published: 2014-06-05
- Earliest claimed: 2008-08-01
- Assignees: Dr. Reddy's Laboratories, Inc.
- Applicants: Dr. Reddy's Laboratories, Inc.; Dr. Reddy's Laboratories Ltd.
- Inventors: Praveen CHERUKUPALLY; Satish Kumar VUJJINI; Ganesh VARANASI; Sreenadha Charyulu KANDALA; Srinivas AREVELI; Satyanarayana Raju TIRUMALARAJU
- Web page: https://patentgrep.com/patent/US20140155588A1

## CPC

- C07H 17/02: Heterocyclic radicals containing only nitrogen as ring hetero atoms
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07H 13/12: by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
- C07H 19/12: Triazine radicals
- 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)
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Processes for preparing azacitidine. Further included are processes for the preparation of crystalline azacitidine crystalline Form I and mixtures of azacitidine crystalline Forms I and II.

## Claims

### Claim 1

A process for preparing azacitidine, comprising:
a) silylating 5-azacytosine to give a compound of Formula II,
wherein R1 is an optionally substituted C1-C5 alkyl group;
b) coupling a compound of Formula II with a compound of Formula III:
wherein R2 is an optionally substituted acyl or aroyl group, in the presence of a non-Lewis acid compound to provide a compound of Formula V; and
c) converting a compound of Formula V to azacitidine.

### Claim 2 (depends on 1)

The process of claim 1 wherein a non-Lewis acid compound is selected from trifluoromethanesulfonic acid, trichloromethanesulfonic acid, or methanesulfonic acid.

### Claim 3 (depends on 1)

The process of claim 1, wherein coupling in step b) is carried out in the presence of an ester, halogenated hydrocarbon, or nitrile solvent.

### Claim 4 (depends on 1)

The process of claim 1, wherein coupling in step b) is carried out in the presence of ethyl acetate, n-propyl acetate, n-butyl acetate, or t-butyl acetate.

### Claim 5 (depends on 1)

The process of claim 1, wherein the conversion of a compound of Formula V to azacitidine in step c) involves removal of acyl or aroyl protecting groups.

### Claim 6 (depends on 1)

The process of claim 1, wherein the conversion of a compound of Formula V to azacitidine in step c) is conducted in the presence a base or by sparging with ammonia gas.

### Claim 7 (depends on 6)

The process of claim 6 wherein a base comprises an alkali metal hydroxide, metal alkoxide, alkali metal carbonate, or an organic base.

### Claim 8 (depends on 6)

The process of claim 6, wherein a base comprises sodium hydroxide, potassium hydroxide, sodium methoxide, sodium carbonate, or potassium carbonate.

### Claim 9 (depends on 6)

The process of claim 6, wherein a base comprises diethylamine, n-butylamine, or propylamine.

### Claim 10 (depends on 6)

The process of claim 6, wherein a base comprises n-butylamine.

### Claim 11 (depends on 1)

The process of claim 1, wherein b) further comprises:
(i) quenching a reaction mass after coupling, by adding aqueous hydrochloric acid;
(ii) adding a base to the reaction mass; and
(iii) recovering a compound of Formula V.

### Claim 12

A process for preparing azacitidine, comprising converting a compound of Formula V,
wherein R2 is an optionally substituted acyl or aroyl group, to azacitidine in the presence of an alkylamine and a C1-C4 alcohol.

### Claim 13 (depends on 12)

The process of claim 12, wherein an alkylamine comprises one or more of diethylamine, n-butyl amine, and propylamine, and a C1-C4 alcohol comprises one or more of methanol, ethanol, and n-propanol.

### Claim 14

A process for preparing azacitidine, comprising:
a) silylating 5-azacytosine to give a compound of Formula II,
wherein R1 is an optionally substituted C1-C5 alkyl group;
b) coupling a compound of Formula II with a compound of Formula III:
wherein R2 is an optionally substituted acyl or aroyl group, using a non-Lewis acid compound, metallic Lewis acid, or TMS-triflate coupling agent, in the presence of an ester solvent, to provide a compound of Formula V; and
b) converting a compound of Formula V to azacitidine.

### Claim 15 (depends on 14)

The process of claim 14 wherein a non-Lewis acid compound comprises trifluoromethanesulfonic acid, trichloromethanesulfonic acid, or methanesulfonic acid, and a metallic Lewis acid compound comprises SnCl4, TiCl4, ZnCl2, BF3OEt2, FeCl3, AlCl3, or SbCl5.

### Claim 16 (depends on 14)

The process of claim 14, wherein an ester solvent comprises ethyl acetate, n-propyl acetate, n-butyl acetate, or t-butyl acetate.

### Claim 17 (depends on 14)

The process of claim 14, wherein the conversion of a compound of Formula V to azacitidine in step c) is conducted in the presence a base or by sparging with ammonia gas.

### Claim 18 (depends on 17)

The process of claim 17 wherein a base comprises an alkali metal hydroxide, metal alkoxide, alkali metal carbonate, or an organic base.

### Claim 19 (depends on 17)

The process of claim 17, wherein a base comprises sodium hydroxide, potassium hydroxide, sodium methoxide, sodium carbonate, or potassium carbonate.

### Claim 20 (depends on 17)

The process of claim 17, wherein a base comprises diethylamine, n-butylamine, or propylamine.

### Claim 21 (depends on 17)

The process of claim 17, wherein a base comprises n-butylamine.

### Claim at position 22

-38. (canceled)