DESC:
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of pure bedaquiline and pharmaceutically acceptable salts thereof.

The present invention also relates to novel process for the preparation of 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one.

BACKGROUND OF THE INVENTION:
Bedaquiline fumarate sold under the brand name Sirturo, is a biaryl quinolone antibiotics and it is used to treat multi-drug-resistant tuberculosis (MDR-TB) along with other medications for tuberculosis. The chemical name is (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4- (dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol compound with fumaric acid (1:1). The structural formula is given in formula I:

Formula I

The U.S. patent no 7,498,343 describes the preparation of bedaquiline and pharmaceutically acceptable salts thereof.

The U.S. patent no 8,039,628 describes the process for the preparation of bedaquiline from a mixture of stereoisomers by using optical resolution agent with chiral 4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin 4-oxide or a derivative thereof, in particular (11bR)-4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin 4-oxide.

The PCT application no 2016/116076 describes the process for the preparation of bedaquiline from a mixture of stereoisomers by using optical resolution agent with N-benzoyl-L-aspartic acid (NBLLA).

SUMMARY OF THE INVENTION:
The present invention relates to an improved process for the preparation of pure bedaquiline and pharmaceutically acceptable salts thereof by using bedaquiline NBLAA 2-methyl tetrahydrofuran (bedaquiline NBLAA 2-Me THF) solvate.

The present invention also further relates to a novel process for the preparation of 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one.

DETAILED DESCRIPTION OF THE INVENTION:
One aspect of the present invention relates to an improved process for the preparation of pure bedaquiline and it salts thereof by using key intermediate selected from bedaquiline NBLAA 2-Me THF (BDQ-III) or bedaquiline NBLAA acetone solvate (BDQ-IV).

Scheme-1 is an illustration of the process for the preparation of pure bedaquiline and it salts thereof according to another aspect of present invention.

Scheme-1

Yet another aspect of the present invention relates to an improved process for the preparation of pure bedaquiline comprising steps of;
a) reacting methoxy quinoline (BDQ-VII) with 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one (BDQ-VI) in presence of a base and solvent to give racemic bedaquiline (BDQ-V),

b) reacting racemic bedaquiline (BDQ-V) with N-benzoyl-L-aspartic acid in presence of acetone to give racemic bedaquiline.NBLAA acetone solvate (BDQ-IV),

c) dissolving racemic bedaquiline. NBLAA acetone solvate (BDQ-IV) with 2-methyl tetrahydrofuran to give bedaquiline.NBLAA 2-methyl tetrahydrofuran (BDQ-III),
d) treating bedaquiline.NBLAA 2-methyl tetrahydrofuran solvate (BDQ-III) with a base in presence of solvent to give pure bedaquiline, and
e) optionally, reacting pure bedaquiline with fumaric acid in presence of solvent to give pure bedaquiline fumarate salt.

Another aspect of the present invention relates to one pot process for the preparation of pure bedaquiline by using bedaquiline NBLAA 2-methyl tetrahydrofuran solvate (BDQ-III).

Scheme-2 is an illustration of the one pot process for the preparation of pure bedaquiline and pharmaceutically acceptable salts thereof.

Scheme-2

Yet another aspect of the present invention relates to one pot process for the preparation of pure bedaquiline comprising steps of;
a) reacting methoxy quinoline (BDQ-VII) with 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one (BDQ-VI) in presence of a base and solvent to give racemic bedaquiline (BDQ-V),

b) reacting racemic bedaquiline (BDQ-V) with N-benzoyl-L-aspartic acid in presence of 2-methyl tetrahydrofuran to give bedaquiline.NBLAA 2-methyl tetrahydrofuran solvate (BDQ-III),

c) reacting bedaquiline.NBLAA 2-methyl tetrahydrofuran solvate (BDQ-III) with a base in presence of solvent to give pure bedaquiline, and
d) optionally, reacting pure bedaquiline with fumaric acid in presence of solvent to give pure bedaquiline fumarate salt.

Another aspect of the present invention relates to novel process for the preparation of 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one.

Yet another aspect of the present invention relates to novel process for the preparation of 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one comprising;
a) reacting 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one hydrochloride with a organic base in presence of solvent, and

b) optionally, isolating 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one.

According to the present invention, solvent is selected from alcohol such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether; nitriles such as acetonitrile, butyronitrile, isobutyronitrile, polar aprotic solvents such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone,water or a mixture thereof.

According to the present invention, organic base is selected from triethylamine, N-methyl-di-isopropylamine, Lithium diisopropylamide (LDA), tri-n-butylamine, tri-n-octylamine, 1,4-diazabicyclo(2.2.2)octane (DABCO), 1,5-diazabicyclo(4.3.0)non-5-ene(DBN), 1,8-diazabicyclo(5.4.0)undec-7-ene(DBU), N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylpiperazine or mixtures thereof.

Experimental Method:
1) HPLC Instrument and method details:
Instrument : HPLC equipped with Pump, injector, UV detector and Recorder.
Column : Zorbax SB-Aq (4.6 x 250mm), 5µm.
Wavelength : UV Detector 215 nm
Flow rate : 1.5mL/min
Injection volume : 5?L.
Auto sampler temperature : 10°C
Column oven temperature : 20°C.

The present invention described in the following examples; it should be noted that the scope of present invention not limited by the examples.

Examples:
Example-1: Process for the preparation of 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one.
3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one hydrochloride (0.96Kg) was dissolved in tetrahydrofuran (2 L), stirred the mass for 30 min and added triethylamine (1.06 L) to obtained 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one.

Example-2: Process for the preparation of Racemic Bedaquiline NBLAA acetone solvate.
3-benzyl-6-bromo-2-methoxyquinoline (1 kg) was dissolved in tetrahydrofuran (14 L), stirred the reaction mass for 30 min and cooled the reaction mass to -80°C. Lithium diisopropylamide (2.3 L) was added to above precooled reaction mass over a period of 60 min. Reaction mass was stirred for 30 min and added 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one.Mixture of tetrahydrofuran (0.75 L), glacial acetic acid (0.75L) and added water (6L) to the reaction mass, stirred the mass for 90 min. The organic layer was separated and concentrated, isopropyl alcohol was added to the concentrated reaction mass, reaction mass was stirred at 60°C for 2 hr. After completion of reaction, reaction mass was cooled to room temperature and filtered to give racemic bedaquiline wet cake. Acetone (10 L) and N-benzoyl-L-aspartic acid was added to the racemic bedaquiline wet cake, reaction mass was stirred for 4 hr at reflux temperature. The reaction mass was cooled to room temperature for 2 hr. Reaction mass was filtered and dried to obtained racemic bedaquiline NBLAA acetone solvate.

Example-3: Process for the preparation of Racemic Bedaquiline
3-benzyl-6-bromo-2-methoxyquinoline (1 kg) was dissolved in tetrahydrofuran (14 L), stirred the reaction mass for 30 min and cooled the reaction mass to -80°C. Lithium diisopropylamide (2.3 L) was added to above precooled reaction mass over a period of 60 min. Reaction mass was stirred for 30 min and added 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one.Mixture of tetrahydrofuran (0.75 L) and glacial acetic acid (0.75L) and added water (6L) to the reaction mass, stirred the mass for 90 min. The organic layer was separated and concentrated, the cis diastereomer (having two isomers) is filtered off from THF and desired enriched trans diastereomer is isolated from IPA as solvent and dried to give racemic bedaquiline.

Example-4: Process for the preparation of Bedaquiline NBLAA 2-me THF solvate.
Racemic bedaquiline NBLAA acetone solvate (1 Kg) was dissolved in 2-methyl tetrahydrofuran (5 L), stirred the reaction mass for 30 min and heated the mass to 80-90°C for 2-4 hr. The reaction mass was cooled to room temperature and further cooled to 0-5°C, reaction mass was filtered and the wet cake was dried to obtained bedaquiline NBLAA 2-Me THF solvate.

Example-5: Process for the preparation of Bedaquiline NBLAA 2-me THF solvate.
Racemic bedaquiline (1 Kg) was dissolved in 2-methyl tetrahydrofuran (5 L), N-benzoyl-L-aspartic acid was added to the above reaction mixture, stirred the reaction mass for 30 min and heated the mass to 80-90°C for 2-4 hr. The reaction mass was cooled to room temperature and further cooled to 0-5°C. The cis diastereomer (having two isomers) is filtered off from THF and desired enriched Trans diastereomer is isolated from IPA as solvent and dried. The isolated trans diastereomer is then subjected to salt formation with NBLAA using 2-methyl THF as solvent, filtered, dried to get Bedaquiline NBLAA Saltreaction mass was filtered and the wet cake was dried to obtained bedaquiline NBLAA 2-Me THF solvate.

Example-6: Process for the preparation of pure Bedaquiline.
Bedaquiline NBLAA 2-me THF solvate was suspended in water (10 L), sodium carbonate and dichloromethane mixture was added to the reaction mass, the organic layer was separated and concentrated. Isopropyl alcohol (3 L) was added to the concentrated mass, filtered the solid under vacuum to obtained pure bedaquiline.

Example-7: Process for the preparation of pure Bedaquiline Fumarate.
Bedaquiline (1 Kg) was suspended in isopropyl alcohol (23 L), fumaric acid (0.21 Kg) was added to the reaction mass and heat the reaction mass to 80-85°C.Stirred the reaction mass for 90 min, cooled the reaction mass to room temperature and filtered the reaction mass to obtained pure solid bedaquiline fumarate.
Purity: 99.8% by HPLC
,CLAIMS:
1. An improved process for the preparation of pure bedaquiline fumarate salt comprising steps of;
a) reacting methoxy quinoline (BDQ-VII) with 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one (BDQ-VI) in presence of a base and solvent to give racemic bedaquiline (BDQ-V),

b) reacting racemic bedaquiline (BDQ-V) with N-benzoyl-L-aspartic acid in presence of acetone to give racemic bedaquiline NBLAA acetone solvate (BDQ-IV),

c) dissolving racemic bedaquiline NBLAA acetone solvate (BDQ-IV) with 2-methyl tetrahydrofuran to give bedaquiline NBLAA 2-methyl tetrahydrofuran (BDQ-III),
d) treating bedaquiline NBLAA 2-methyl tetrahydrofuran solvate (BDQ-III) with a base in presence of solvent to give pure bedaquiline, and
e) optionally, reacting pure bedaquiline with fumaric acid in presence of solvent to give pure bedaquiline fumarate salt.

2. A process for the preparation of pure bedaquiline fumarate salt comprising the steps of:
a) reacting methoxy quinoline (BDQ-VII) with 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one (BDQ-VI) in presence of a base and solvent to give racemic bedaquiline (BDQ-V),

b) reacting racemic bedaquiline (BDQ-V) with N-benzoyl-L-aspartic acid in presence of 2-methyl tetrahydrofuran to give bedaquiline NBLAA 2-methyl tetrahydrofuran solvate (BDQ-III),

c) reacting bedaquiline.NBLAA 2-methyl tetrahydrofuran solvate (BDQ-III) with a base in presence of solvent to give pure bedaquiline, and
d) optionally, reacting pure bedaquiline with fumaric acid in presence of solvent to give pure bedaquiline fumarate salt.

3. The process according to claims 1 and 2 wherein, base is selected from triethylamine, N-methyl-di-isopropylamine, tri-n-butylamine, tri-n-octylamine, Lithium diisopropylamide (LDA), 1,4-diazabicyclo(2.2.2)octane (DABCO), 1,5-diazabicyclo(4.3.0)non-5-ene(DBN), 1,8-diazabicyclo(5.4.0)undec-7-ene(DBU), N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylpiperazine or mixtures thereof.

4. The process according to claims 1 and 2 wherein, solvent is selected from alcohol such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether; nitriles such as acetonitrile, butyronitrile, isobutyronitrile, polar aprotic solvents such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, water or a mixture thereof.

5. A novel process for the preparation of 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one comprising the steps of;
a) reacting 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one hydrochloride with a organic base in presence of solvent, and

b) optionally, isolating 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one.

6. The process according to claim 5 wherein, base is selected from triethylamine, N-methyl-di-isopropylamine, tri-n-butylamine, tri-n-octylamine, Lithium diisopropylamide (LDA), 1,4-diazabicyclo(2.2.2)octane (DABCO), 1,5-diazabicyclo(4.3.0)non-5-ene(DBN), 1,8-diazabicyclo(5.4.0)undec-7-ene(DBU), N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylpiperazine or mixtures thereof.

7. The process according to claim 5 wherein, solvent is selected from alcohol such as methanol, ethanol, isopropanol, n-propanol, tertiary- butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether; nitriles such as acetonitrile, butyronitrile, isobutyronitrile, polar aprotic solvents such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, water or a mixture thereof.

8. Process for the preparation of pure bedaquiline fumarate comprising the steps of;

(a) suspending bedaquiline in an organic solvent,
(b) adding fumaric acid,
(c) heating the reaction mass, and
(d) isolating pure bedaquiline fumarate.

9. The process as claimed in claim 8, wherein the organic solvent is isopropyl alcohol.

10. The process as claimed in claim 8, wherein the pure bedaquiline fumarate having purity 99.8% by HPLC.