WO2018122724A1

WO2018122724A1 - Temozolomide process

Info

Publication number: WO2018122724A1
Application number: PCT/IB2017/058394
Authority: WO
Inventors: Prasada Raju Vnkv VETUKURI; Rajesh Kumar Rapolu; Rama Krishna Reddy Narayana; Krishna Prasad CHIGURUPATI; Akshay Kant CHATURVEDI
Original assignee: Granules India Limited
Priority date: 2016-12-27
Filing date: 2017-12-25
Publication date: 2018-07-05

Abstract

The present invention relates to improved process for the preparation of Temozolomide Formula I. Said Temozolomide (I) is useful in the treatment of cancer.

Description

TEMOZOLOMIDE PROCESS

FIELD OF THE INVENTION

The present invention relates to an improved and industrially applicable process for the preparation Temozolomide of Formula (I).

Said Temozolomide (I), indicated for treating patients with cancer.

BACKGROUND OF THE INVENTION

Temozolomide of formula I, is an antitumor drug and is chemically known as 3- methyl-4-oxo-3,4-dihydroimidazo[5,l-i ][l ,2,3,5]tetrazine-8-carboxamide.

It is indicated for treating patients with malignant glioma such as cancer, breast cancer, refractory anaplastic, astrocytoma, i.e. patient at first relapse who have experienced disease progression in malignant glioma, glioblastoma multiform and anaplastic astrocytoma, on a drug containing a nitrosourea and procarbazine. It is sold in the US market as hard capsules containing 5 mg, 20 mg, 100 mg or 250 mg as Temodar® by Schering Corporation.

Temozolomide and compounds having similar activity (higher alkyl analogues at the 3-position) are reported by Lunt et.al. in US patent 5,260,291. The total synthesis of temozolomide has been reported in J.Med.Chem.1984, 27,196-201 is shown in following Scheme:

5- Ami nr.- 1 H-mi sda/ok 5-Dia/o- 1 H-imida/oIo-1 - 4-carboxamide caiboxamide j^'emo/.ololomide

In the above synthesis, 5-amino-lH-imodazolo-4-carboxamide is converted into 5- diazo-l H-imidazole-4-carboxamide which is further reacted with methylisocynate in dichloromethane (DCM) to yield temozolomide (I). However, methylisocynate is highly toxic reagent and is avoided transporting on industrial scale, hence alternative methods are suitable for large scale synthesis as most of the starting material 5-amino-l H-imidazole-4- carboxamide remains un-reacted thus the yields obtained are poor.

Shen-Chun Kuo et.al. in US patent 6,844,434 describes synthesis of temozolomide by cyclization of 5-amino-l-(N-rnethyl-hydrazinocarbonyl)-lH-imidazole-4-carboxylic acid in the presence of tetra butyl nickel and periodic acid to form a reaction mixture which is concentrated under reduce pressure and resulting residue was treated with acetonitrile and filtered. The filtrate was concentrated and chromatographed on a column of silica gel to give temozolomide. Use of time consuming and cumbersome technique i.e. column chromatography for isolation of product makes the process not suitable to employ at industrial level. The scheme is as shown below:

Shen-Chun uo et.al. in US patent 7,087,751 discloses a process for the preparation of temozolomide from protected imidazole intermediate. The process involves reaction of 1- methyl-3-carbamoyliminomethyl-urea with N- protected amino cyano acetamide in the presence of acetic acid in a suitable solvent to form an N- protected imidazole intermediate which is then cyclized in the presence of lithium chloride to minimize undesired cyclisation product. After cyclisation, the protected group has to be removed which makes the process more laborious with more number of steps.

The above method can be extended to make N-alkyl compounds using alkyl substituted hydrazines. However, this approach is also more tedious in its operations and suffers low overall yields.

Most of the above said references it is very clear that is to develop an alternative and improved process suitable synthetic route for industrial scale up. The process of present invention overcome disadvantages of prior art by avoiding use of hazardous reagent such as methyl isocyanate and also involving easy isolation of temozolomide cither by filtration or by using less amount of the solvent. Thus, present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of temozolomide, which provides temozolomide and the intermediates useful for its synthesis in high overall yield and purity.

SUMMARY OF INVENTION

Particular aspects of the present invention relates to a process for the preparation of Temozolomide (I). Temozolomide obtained by the process of the present invention is found to substantially pure and stable.

in one aspect of the present invention, it relates to process for the preparation of Temozolomide (I):

comprising the steps of:

a. reacting the methyl amine or a salt with phenyl chloroformate in the

presence of base in an organic solvent at temperature 10-50 °C to obtain a compound of formula IV;

(IV) wherein R - I I. N0₂, F, CH₃, C₂H₅, tertiary butyl, OCH₃; b. reacting the compound phenyl chloroformate of Formula (IV) with a compound of Formula (I

in the presence of base in an organic solvent at temperature ranging between 20-50 °C to obtain a compound of Formula (II);

c. diazotizing and cyclizing compound of Formula (II) in the presence of source of nitrous acid and a suitable acid at temperature ranging between -

5°C-20°C; d. isolating Temozolomide (I );

e. Optionally purifying Temozolomide (I).

In another aspect of the present invention relates to isolating Temozolomide (I) comprising the steps of:

i) providing a solution of Temozolomide (1) in a mixture of organic solvents: ii) removing one of the solvent to obtain Temozolomide suspension;

iii) cooling the Temozolomide suspension at temperature 05 -30°C;

iv) slurrying the solid obtained in a solvent at temperature 30 -50 °C;

v) separating pure Temozolomide (I).

In yet another aspect of the present invention relates to isolating pure Temozolomide (I) comprising the steps of:

i. providing a solution of Temozolomide (I) in a mixture of dimethylsulfoxide and dichloromethane;

ii. removing dichloromethane solvent to obtain Temozolomide suspension; iii. cooling the Temozolomide suspension at temperature 10 -20°C;

iv. slurrying the solid obtained in a ethyl acetate solvent at temperature 30 - 50 °C;

v. separating pure Temozolomide (I).

In a further aspect of the present application also relates to a pharmaceutical composition comprising Temozolomide of the present application and atleast one or more pharmaceutically acceptable excipients.

In another aspect of the present invention relates to substantially pure Temozolomide (I) having HPLC purity of atleast 99.5%.

Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

DETAILED DESCRIPTION

As set forth herein, embodiments of the present invention provide an efficient process for the preparation of Temozolomide (I). Temozolomide (I) obtained by the process of the present invention is found to be substantially pure.

In another embodiment according to present application, it provides a process for the preparation of Temozolomide (I):

comprising the steps of:

a. reacting the methyl amine or a salt with phenyl chloroformate in the

wherein R = H, N0₂, F, CH₃, C₂H₅, tertiary butyl, OCH₃; b. reacting the compound phenyl chloroformate of Formula (IV) with a compound of Formula (I

5°C-20°C; d. isolating Temozolomide (I );

e. Optionally purifying Temozolomide (I).

Individual steps of the embodiments are detailed herein below.

In process step (a), methyl amine or salt is selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid is condensed with substituted phenyl chloroformate in solvent.

In one of the particular embodiment according to present invention, substituted phenyl chloroformate is selected from phenyl chloroformate, 4-methylphenylchloro formate, 4- nitrophenylchloroformate, 4-fluoro-3-methylphenylchloro formate, 4-

Ethylphenylchloro formate, 4-tert.butylphenylchloro formate.

In another particular embodiment according to present invention, substituted phenyl chloroformate is 4-nitrophenylchloroformate.

In one of the particular embodiment according to present application, salt is methyl amine hydrochloride.

The process step (a) is carried out in the presence of a base selected from the group consisting inorganic base as sodium hydroxide, sodium carbonate, ammonia, ammonium hydroxide and calcium carbonate or organic base as triethylamine, isopropyl ethyl amine, tertiary butyl ethyl amine, isopropyl ethyl amine, diisopropyl ethylamine.

In one of the particular embodiment according to present application, base in the process step a) is sodium carbonate.

The suitable organic solvents that can be used in step (a) is selected from the group comprising of ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or nitrile solvents as acetonitrile or alcoholic solvents as methanol, ethanol, isopropanoL n-butanol, ketones as acetone, methyl ethyl ketone, methyl isobutyl ketone or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or ether solvents as diethyl ether, diisopropyl ether, tetrahydrofuran or hydrocarbon solvents as methyl cyclohexane, cyclohexane, n-hexane, n-heptane or water and mixtures thereof.

In one of the particular embodiment according to present application, solvent used in the process step a) is dichloromethane.

The process step (a) is performed at room temperature to about boiling point of an organic solvent or mixture of solvents used over a period of about 20 minutes to about 30 hours. In one of the particular embodiment according to present invention, the process step

(a) was performed at room temperature for 24 hours.

The process step (b) is carried out in the presence of a base selected from the group consisting organic base as triethylamine, isopropyl ethyl amine, tertiary butyl ethyl amine, isopropyl ethyl amine, diisopropyl ethyl amine (DIPEA).

In one of the particular embodiment according to present invention, in the process step (b) base is diisopropyl ethyl amine (DIPEA).

The suitable organic solvents that can be used in step (b) is selected from the group comprising of ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or nitrile solvents as acetonitrile or alcoholic solvents as methanol, ethanol, isopropanol, n-butanol, ketones as acetone, methyl ethyl ketone, methyl isobutyl ketone or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or ether solvents as diethyl ether, diisopropyl ether, tetrahydrofuran or hydrocarbon solvents as methyl cyclohexane, cyclohexane, n-hexane, n-heptane or water and mixtures thereof.

In one of the particular embodiment according to present invention, in the process step (b) is carried using acetonitrile as solvent.

The process step (b) is performed at room temperature to a boi ling point of an organic solvent used for the reaction for about 30 minutes to 15 hours.

In one of the particular embodiment according to present invention, the process step

(b) was performed at room temperature for 24 hours.

The process step (c) is carried out in the presence of a source of nitrous acid selected from sodium nitrite, potassium nitrite, isoamyl nitrite, ethyl nitrite, n-butyl nitrite, tert-butyl nitrite, ammonium nitrite and the like.

In one of the particular embodiment according to present invention, source of nitrous acid in the process step (c) is sodium nitrite.

The process step (c) is carried out in the presence of a Ci-C₈ carboxylic acids, HC1,

H₂S0₄

In one of the particular embodiment according to present invention, C]-C₈ carboxylic acids selected from lower alkanoic acid such as acetic acid, formic acid, tartaric acid, lactic acid.

In another particular embodiment according to present invention, acid in the process step (c) is acetic acid. The suitable organic solvents that can be used in the process step (c) is selected from the group consisting of alcohols such as water or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or halogenated solvents as methylene chloride, ethylene dichloride, chloroform or nitrile solvents as acetonitrile or ketones as acetone, methyl ethyl ketone, methyl isobutyl ketone or halogenated solvents as methylene chloride, ethylene dichloride, chloroform or ether solvents as diethyl ether, diisopropyl ether, tetrahydrofuran or hydrocarbon solvents as methyl cyclohexane, cyclohexane, n-hexane, n-heptane or water and mixtures thereof.

In one of the particular embodiment according to present invention, solvent used in the process step (c) is water.

The process step (c) is performed at temperature range between 0-10°C and over a period of about 1 to 5 hours, preferably, at 0-5°C for about 2 to about 3 hours. After the completion of the reaction, it is optional and advantageous to add a saturating agent to reaction mixture to saturate the reaction mixture, to make the extraction of the product from the reaction mixture easy and convenient. Saturating agent includes solid calcium chloride, sodium chloride and the like. After the addition of saturating agent, the reaction mixture is optionally stirred for few minutes to few hours and desired compound of Temozolomide (I) can be isolated from the reaction mixture.

In one of the particular embodiment according to present invention, saturating agent used in the process step (c) is calcium chloride.

The process step (d) of isolating Temozolomide (I) comprising the steps of:

i) providing a solution of Temozolomide (I) in a mixture of organic solvents; ii) removing one of the solvent to obtain Temozolomide suspension;

iii) cooling the Temozolomide suspension at temperature 05 -30°C;

iv) slurrying the solid obtained in a solvent at temperature 30 -50°C;

v) separating pure Temozolomide (I).

The suitable solvents that can be used in the process step (d) include but are not limited to water; alcohols organic solvent selected from wherein solvents are selected from water or halogenated solvents as methylene chloride, ethylene dichloride, chloroform or ketones as acetone, methyl ethyl ketone, methyl isobutyl ketone or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or ether solvents as diethyl ether, diisopropyl ether, tetrahydrofuran, 1 ,4-dioxan, dimethylsulfoxide ( DM SO). N,N-dimethyl formamide (DMF) or mixture thereof. In one of the particular embodiment according to present invention, solvents used in the process step (d) are mixture of dimethylsulfoxide (DMSO) and methylene dichloride.

The process step (d) is performed at room temperature to about boiling point of solvents used over a period of about 1 hour to about 5 hours.

In one of the particular embodiment according to present invention, the process step (d) is performed for 2 to about 3 hours.

In one of the particular embodiment according to present invention, solvents used in the process step (d) are mixture of dimethylsulfoxide (DMSO) and methylene dichloride.

It is highly advantageous to use mixture of dimethylsulfoxide and dichloromcthane for the extraction of temozolomide from the reaction mixture, as it circumvents the need of use of large amount of the solvent for the purpose of extraction of the desired compound. Preferably, 100 to 500 times solvent is used for the extraction purposes. The ratio of the solvent used can be 1 : 10 to 1 : 50, preferably 1 : 19 to 1 : 40. After the recovery of dichloromethane, the product along with the impurity remains in residual dimethylsulfoxide. The product along with the impurities at the level of 1.0 to 30% can be crystallized from the dimethylsulfoxide at 0 to -10°C.

In another particular embodiment according to the present invention, it provides a process for the preparation of pure Temozolomide (I), which is comprising the steps of:

ii. removing dichloromethane solvent to obtain Temozolomide suspension;

iii. cooling the Temozolomide suspension at temperature 10 -20°C;

iv. slurrying the solid obtained in a ethyl acetate solvent at temperature 30 -50 °C; v. separating pure Temozolomide (I).

Temozolomide, thus obtained by the process of present invention, can be optionally, purified by employing suitable purification method to enhance the purity as well as to minimize the amount of impurities present in the final product. Specifically, temozolomide can be dissolved in a suitable solvent at a temperature of 10 to 80°C for few minutes to few hours, preferably till the complete dissolution. It is optional to add activated charcoal along with solvent to reaction mixture to improve the color of material. The reaction mixture is then filtered to remove activated charcoal and other undissolved materials. Suitable solvents for purification include alkyl nitriles such as acetonitrile, propionitrile; ketones such as acetone, diethyl ketone; ethers such as tetrahydrofuran, 1 , 2-dimethoxyethane, 1, 2-diethoxyethane; water; polar aprotic solvent such as dimethylsulfoxide, Ν,Ν-dimethyl formamide and the like or mixture thereof. Crystallization is initiated either by cooling or concentration of the reaction mixture followed by cooling of the remaining solution. The precipitation can be optionally initiated with seeding of a particular polymorph to give the corresponding polymorph of the final product. The crystallized product is then isolated from the mixture by suitable techniques such as filtration, centrifugation and the like.

The purification process can be repeated with same or different solvent till the temozolomide of desired purity is obtained. Temozolomide obtained from the present invention is highly pure and free from undesired impurities.

In one of the particular embodiment Temozolomide. displays purity of more than 99.5%. The purity of the Temozolomide samples was measured using chromatography. Chromatography was performed with Waters Alliance 11 PLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 separation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.

The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Stage-1: Preparation of 4-nitrophenyI methylcarbamate

To a stirred solution of methyl amine hydrochloride (20g, 0.296 mol) in dichloromethane (250 mL) was added sodium carbonate (79.0 g, 0.7452 mol) at 20-25°C. The suspension was stirred for 10 min and 4-nitrophenyl chloroformate (50g, 0.248 mol) in dichloromethane (250 mL) was added slowly at 20-25°C. The reaction mixture was stirred at room temperature for 24h. After consumption of starting material, the reaction mixture was filtered and cake washed with dichloromethane (50 mL). The wet cake was slurried in 200 ml . dichloromethane, filtered and washed with dichloromethane (50 mL). The combined filtrate was concentrated under reduced pressure to obtain 4-nitrophenyl methylcarbamate (30.9 g) as light yellow solid. The crude material used in the next step without further purification.

! H NMR (CDC1₃): δ 8.24 (d, J = 7.6 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 5.24 (bs, 1H), 2.93 (s, 3H). Stage-2: Preparation of 5-amino-Nl-methyl-lH-imidazoIe-l,4-dicarboxamide

To a stirred suspension of 5-amino-l H-imidazole-4-carboxamide hydrochloride ( l Og, 0.0615 mol) in acetonitrile (80 mL) was added diisopropylethylamine [DIPEA ( 12g, 0.0958 mol)] at room temperature. The reaction mixture was stirred at room temperature for 1 Omin followed by 4-nitrophenyl methylcarbamate (25g, 0.1270 mol) was added. The reaction mixture was stirred at room temperature for 24h. After consumption of starting material, the reaction mixture was filtered and the cake washed with acetonitrile (20 mL). The obtained solid was slurried in acetonitrile (80 mL), filtered and cake washed with acetonitrile (20 mL). The obtained solid dried at room temperature for 24h to afford 5-amino-Nl -methyl- l H-imidazole- 1 , 4-dicarboxamide (10 g) as an off white solid.

' iTNMR (DMSO-d₆): δ 8.41 (q, 1H), 7.59 (s, I I I ), 6.86 (bs, 1 H), 6.77 (bs, 1 H), 6.35 (s, 211 ).

2.78 (d, J = 3.2 Hz. 3H);

Mass (m/z): 183.9 (M+); HPLC purity: 98.13%.

Stage-3: Preparation of Temozolomide (3-methyl-4-oxo-3,4-dihydroimidazo[5,l- d] [l ,2,3₅5]tetrazine-8-carboxamide)

To a stirred suspension of 5-amino-N 1 -methyl- l H-imidazole- 1 , 4- dicarboxamide (5g, 0.0272 mol) and acetic acid (4.5 mL) was added sodium nitrite (2.5g, 0.0362 mol) in water (5.0 L) at -5 to 0°C at a rate so that temperature does not rise above 0-5°C. The reaction mixture was stirred at 0-5°C for 2h. After consumption of starting material, ice bath was removed and calcium chloride (12.5 g) was added to the reaction mixture and stirred at room temperature for another two hours. The reaction mass was extracted with a 2.5% solution of dimethyl sulfoxide in dichloromethane (5 X 500 mL). Combined organic layer was dried over sodium sulfate and the solvent was distilled below 40°C. After removing the dichloromethane completely, the dimethyl sulfoxide suspension was cooled to 10-20°C and filtered the solid. The solid was washed with ethyl acetate (15 mL) and dried at room temperature. The obtained solid was slurried in ethyl acetate (40 mL) and heated at 40-45°C for lh. The solid was filtered and dried at room temperature to yield Temozolomide (1 .5g) as an off white solid.

'l lNMR (DMSO-d₆): δ 8.81 (s, 1H), 7.78 (bs, 1 11 ). 7.66 (bs, 1 11 ). 3.86 (s, 3H); Mass (m/z):

1 94.8 (M+);

HPLC purity: 99.61 %. While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can he made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

Claims

We Claim:

1 ) A process for the preparation of Temozolomide of Formula (I)

comprising the steps of:

a. reacting the methyl amine or a salt with phenyl chloroformate in the

wherein R = H, N0₂, F, CH₃, C₂H₅, tertiary butyl, OCH₃;

b. reacting the compound phenyl chloroformate of Formula (IV) with a

compound of Formula (II

(II) c. diazotizing and cyclizing compound of Formula ( 11) in the presence of

source of nitrous acid and a suitable acid at temperature ranging between - 5°C-20°C;

d. isolating Temozolomide (I);

e. Optionally purifying Temozolomide (I).

2) A process for the preparation of Temozolomide (I) according to claim 1 , where in step a) salt is selected from hydrochloric acid salt, sulfuric acid salt or phosphoric acid salt.

3) A process for the preparation of Temozolomide (I) according to claim 1 , where in base in step a) is selected from inorganic base as sodium hydroxide, sodium carbonate, ammonia, ammonium hydroxide and calcium carbonate or organic base as triethylamine, isopropyl ethyl amine, tertiary butyl ethyl amine, isopropyl ethyl amine, diisopropylethylamine.

4) A process for the preparation of Temozolomide (1) according to claim 1 , wherein solvents are selected from ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or nitrile solvents as acetonitrile or alcoholic solvents as methanol, ethanol, isopropanol, n-butanol, ketones as acetone, methyl ethyl ketone, methyl isobutyl ketone or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or ether solvents as diethyl ether, diisopropyl ether, tetrahydrofuran or hydrocarbon solvents as methyl cyclohexane, cyclohexane, n-hexane, n-heptane or water and mixtures thereof.

5) A process for the preparation of Temozolomide (I) according to claim 1 , wherein source of nitrous acids in the step c) is selected from sodium nitrite, potassium nitrite, isoamyl nitrite, ethyl nitrite, n-butyl nitrite, tert-butyl nitrite or ammonium nitrite.

6) A process for the preparation of Temozolomide (I) according to claim 1 , wherein suitable acid utilized in step c) is selected from Ci-Cs carboxylic acids, HQ, H₂SO₄.

7) A process for the preparation of Temozolomide (I) according to claim 6, wherein Q-Cs carboxylic acids selected from lower alkanoic acid selected from acetic acid, formic acid, tartaric acid, lactic acid or p-toluene sulfonic acid. 8) A process for the preparation of Temozolomide (I), according to claim 1 . where in step d) of isolating Temozolomide (I) comprising the steps of:

i. providing a solution of Temozolomide (I) in a mixture of organic solvents;

ii. removing one of the solvent to obtain Temozolomide suspension;

iii. cooling the Temozolomide suspension at temperature 05 -30°C;

iv. slurrying the solid obtained in a solvent at temperature 30 -50 °C;

v. separating pure Temozolomide (I).

9) A process for the preparation of Temozolomide (I), according to claim 8, wherein organic solvents are selected from dimethylsulfoxide or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or ketones as acetone, methyl ethyl ketone, methyl isobutyl ketone or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or ether solvents as diethyl ether, diisopropylether, tetrahydrofuran and mixtures thereof.

10) A process for the preparation of pure Temozolomide (I), which is comprising the steps of: i. providing a solution of Temozolomide (I) in a mixture of dimethylsulfoxide and dichloromethane;

ii. removing dichloromethane solvent to obtain Temozolomide suspension;

iii. cooling the Temozolomide suspension at temperature 10 -20°C;