# US 7,612,202 B2 · Process for preparing temozolomide

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- Number: US 7,612,202 B2
- Document ID: US7612202B2
- Status: Granted
- Kind: B2
- Application number: 11/354,899
- Filed: 2006-02-16
- Published: 2006-08-17
- Granted: 2009-11-03
- Earliest claimed: 2005-02-17
- Assignees: Chemagis Ltd.
- Inventors: Olga Etlin; Mohammed Alnabari; Yana Sery; Edna Danon; Oded Arad; Joseph Kaspi
- Web page: https://patentgrep.com/patent/US7612202B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- B01J 39/07: in the weakly acidic form
- B01J 41/07: in the weakly basic form
- B01J 49/00: Regeneration or reactivation of ion-exchangers; Apparatus therefor (ion-exchange chromatography processes or apparatus B01D15/08)
- B01J 49/06: containing cationic exchangers
- B01J 49/07: containing anionic exchangers
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS

## Abstract

The present invention provides a process for preparing highly pure Temozolomide base which includes recovery from the purification mother liquors by using an anionic exchange resin. By treating Temozolomide hydrochloride with a mixture of an organic acid, a water miscible organic solvent, and water, Temozolomide free base is obtained in an acidic medium. Due to the high sensitivity of Temozolomide to basic pH values the recovery-including process is especially advantageous because it enables obtaining high yields of highly pure Temozolomide base in acidic conditions. The process for producing Temozolomide base includes hydrolysis of the starting material 8-cyano-3-methyl-[3H]-imidazo[5,1-d]-tetrazin-4-one in acidic medium to obtain highly pure Temozolomide hydrochloride in high yield.

## Claims

### Claim 1

A process for preparing Temozolomide base, the process comprising:
contacting Temozolomide hydrochloride with at least one organic acid to produce Temozolomide base; and
isolating the Temozolomide base.

### Claim 2 (depends on 1)

The process of claim 1, wherein the Temozolomide hydrochloride is contacted with the organic acid in a mixture of at least one water miscible organic solvent and water.

### Claim 3 (depends on 1)

The process of claim 1, wherein the process comprises:
charging a reaction vessel with the Temozolomide hydrochloride, the at least one organic acid, at least one water miscible organic solvent, and water to form a mixture;
heating the mixture to an elevated temperature to form a solution and filtering the solution at an elevated temperature;
cooling the solution to form crystals of Temozolomide free base and a mother liquor;
filtering to separate the crystals from the mother liquor, washing the crystals with a mixture of water and at least one organic solvent and drying the crystals; and
optionally recovering additional Temozolomide free base from the mother liquor.

### Claim 4 (depends on 3)

The process of claim 3, wherein the at least one water miscible organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran (THF), 2-methyltetrahydrohan, acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-pyrrolidone (NMP), and mixtures thereof.

### Claim 5 (depends on 4)

The process of claim 4, wherein the at least one water miscible organic solvent is acetone, THF, ethanol, or acetonitrile.

### Claim 6 (depends on 3)

The process of claim 3, wherein the at least one organic acid is selected from acetic acid, propionic acid, citric acid, malonic acid, fumaric acid, malic acid, tartaric acid, oxalic acid, and combinations thereof.

### Claim 7 (depends on 6)

The process of claim 6, wherein the organic acid is acetic acid.

### Claim 8 (depends on 3)

The process of claim 3, wherein said elevated temperature is from about 40° C. to about 80° C.

### Claim 9 (depends on 3)

The process of claim 3, wherein the organic solvent used for washing the crystals of Temozolomide free base is selected from diethyl ether, diisopropyl ether, t-butyl methyl ether, acetone, methylethyl ketone, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tetrahydrofuran (THF), acetonitrile, and mixtures thereof.

### Claim 10 (depends on 9)

The process of claim 9, wherein the organic solvent used for washing the crystals of Temozolomide free base is acetone.

### Claim 11 (depends on 3)

A method for preparing Temozolomide free base, the method comprising:
producing a mother liquor according to claim 3;
eluting the mother liquor through a column containing a weakly basic ion exchange resin, to produce an eluate containing Temozolomide free base;
combining Temozolomide hydrochloride with the eluate to produce a mixture of the eluate and Temozolomide hydrochloride;
heating the mixture to an elevated temperature to produce a solution, and filtering the solution at an elevated temperature;
cooling the solution to crystallize Temozolomide free base;
filtering the crystals, washing the crystals with a mixture of water and at least one organic solvent and drying the crystals; and
optionally regenerating the resin and repeating the previous steps.

### Claim 12 (depends on 11)

The method of claim 11, wherein the ion exchange resin is a weakly basic anionic resin selected from Lewatit Mono Plus™ MP 64, Dowex Marathon WBA, Dowex Marathon WBA-2, Resindion A-329, and Amberlite 93.

### Claim 13 (depends on 12)

The method of claim 12, wherein the ion exchange resin is Lewatit Mono Plus™ MP 64, and the ratio between the resin and the volume of the loaded mother liquor solution is about 1/5 (gram/ml).

### Claim 14 (depends on 11)

The method of claim 11, wherein the mother liquor is eluted with a solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, acetone, methylethyl ketone, diethyl ketone, methylpropyl ketone, tetrahydrofuran (THF), acetonitrile, and mixtures thereof.

### Claim 15 (depends on 14)

The method of claim 14, wherein the mother liquor is eluted with a mixture of water and acetonitrile, wherein the ratio between the water and the acetonitrile is 55/45 v/v.

### Claim 16 (depends on 11)

The method of claim 11, further comprising regenerating the resin after eluting the mother liquor.

### Claim 17 (depends on 16)

The method of claim 16, wherein the the regeneration comprises washing the resin with a 1% solution of NaOH and washing the resin with an 8% solution of NaCl.

### Claim 18 (depends on 3)

The process of claim 3, wherein the product is obtained in about 90% yield, and in a purity of at least 98.5%.

### Claim 19 (depends on 3)

The process of claim 3, wherein the product is obtained in about 90% yield, and in a purity over 99.8%.

### Claim 20 (depends on 1)

The process of claim 1, further comprising preparing the Temozolomide hydrochloride by hydrolyzing 8-cyano-3-methyl-[3H]-imidazo-[5,1-d]-tetrazin-4-one with aqueous hydrochloric acid, to thereby produce a reaction mixture containing Temozolomide hydrochloride,
adding an organic solvent to the reaction mixture to thereby produce crystals of Temozolomide HCl;
filtering the crystals of Temozolomide HCl, washing the crystals with an organic solvent and drying the crystals.

### Claim 21 (depends on 20)

The process of claim 20, wherein the aqueous hydrochloric acid reagent has a concentration of from 36.5-38% and the weight/volume ratio between the starting material 8-cyano-3-methyl-[3H]-imidazo-[5,1-di-tetrazin-4-one and the hydrochloric acid solution is about 1/5 gram/ml.

### Claim 22 (depends on 20)

The process of claim 20, wherein the organic solvent in the reaction mixture is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, secbutanol, isobutanol, acetone, methylethyl ketone, diethyl ketone, methylpropyl ketone, tetrahydrofuran (THF), acetonitrile, and mixtures thereof.

### Claim 23 (depends on 22)

The process of claim 22, wherein the organic solvent is acetone.

### Claim 24 (depends on 20)

The process of claim 20, wherein the hydrolysis is carried out at a temperature of from 32-35° C.

### Claim 25 (depends on 20)

The process of claim 20, wherein the purity of Temozolomide hydrochloride obtained is at least 98.5% (by HPLC).

### Claim 26 (depends on 20)

The process of claim 20, wherein the purity of Temozolomide hydrochloride obtained is at least 99.5% (by HPLC).