DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of Indian Provisional Application No. 201941005058 filed February 8, 2019, the contents of which are incorporated herein in their entirety by reference.

BACKGROUND OF THE INVENTION

FIELD OF THE DISCLOSURE
The present disclosure relates to an improved process for the preparation of bedaquiline fumarate.
DESCRIPTION OF THE RELATED ART
Bedaquiline fumarate (trade name SIRTURO) is a medication used to treat tuberculosis. bedaquiline is chemically known as (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-?1 represented by formula-1.

Bedaquiline and its preparation is described in U.S. Patent No. 7,498,343 B2. Bedaquiline belongs to the group of quinoline derivatives that can be used as microbial inhibitors, preparation of this molecule and its use for the treatment of microbial diseases is described in a patent. The said patent describes preparation of the target compound from a mixture with the other three isomers, wherein bedaquiline was isolated by means of fraction crystallization followed by column chromatography on a chiral stationary phase.

Isolation of bedaquiline from a racemic mixture by means of crystallization with the chiral agent (R)-(-)- 1,1 '-binaphthyl-2,2'-diyl hydrogen phosphate or its derivatives is described in U.S. Patent No. 8,039,628 B2.

The above-mentioned facts indicate that resolution by means of diastereomeric salts with chiral acids appears to be the most viable method of industrial preparation of enantiomerically pure bedaquiline.

The chiral purity of the product and reaction yield are influenced by the reaction conditions and selection of the chiral agent used for the crystallization. The preparation of bedaquiline with a high reaction yield, chemical and chiral purity, suitable chiral substances and optimal reaction conditions must be used.

SUMMARY OF THE DISCLOSURE

A first aspect of the present disclosure is to provide an improved process for the preparation of bedaquiline and bedaquiline fumarate.

Another aspect of the present disclosure provides for the preparation of bedaquiline comprising the steps of;
a) reacting the compound of formula 5 with compound of formula 4 or salt thereof in the presence of lithium pyrrolidide in a first solvent to get compound of formula 3;
; and
b) resolving the compound of formula 3 to provide bedaquiline of formula 1,
.

Another aspect of the present disclosure provides a process for the preparation of bedaquiline fumarate, which is as shown in below scheme I


Another aspect of the present disclosure provides a process for preparing racemic bedaquiline of formula 3 comprising, reacting a compound of formula 5 with a compound of formula 4 or salt in the presence lithium pyrrolidide in a first solvent to get compound of formula 3;

Another aspect of the present disclosure provides a compound that is:

(a) formula 3 ,
(b) formula 2, ,
(c) formula 1 or
(d) bedaquiline fumarate,
that is substantially free of or contains less than 0.1 % desbromo impurity by HPLC, wherein the desbromo impurity is of the formula, .

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present disclosure provides a process for the preparation of bedaquiline comprising the steps of;
a) reacting the compound of formula 5 with compound of formula 4 or salt thereof in the presence of lithium pyrrolidide in a first solvent to get compound of formula 3 (racemic bedaquiline);
; and
b) resolving the compound of formula 3 to provide bedaquiline of formula 1,
.
In a first process, compound of formula 5 is reacted with compound of formula 4 or salt in the presence of lithium pyrrolidide in a solvent to get racemic bedaquiline compound of formula 3. Racemic bedaquiline compound of formula 3 may be resolved, for example, by reaction with N-benzoyl L-aspartic acid in a solvent to get diastereomeric bedaquiline N-benzoyl L-aspartic acid salt. This diastereomeric salt may be treated with a base to get bedaquiline free base, which is converted to bedaquiline fumarate.

The first solvent used in steps (a) is an ether solvent. Examples of suitable an ether solvents include but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, and mixtures thereof. In a particular embodiments, the first solvent is tetrahydrofuran.

The resolving of step (b) may comprise reacting the compound of formula 3 with N-benzoyl L-aspartic acid in a second solvent to get compound of formula 2;

The second solvent used in steps (b) may comprise or consist of an ether solvent. Examples of suitable ether solvents include but are not limited to tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, and mixtures thereof. In a particular embodiment, the second solvent is 1,4-dioxane.

Crude racemic bedaquiline of formula 3 may be optionally purified by acid and base treatment to get racemic bedaquiline of formula 3. Examples of suitable acids include but are not limited to orthophosphoric acid, p-toluene sulfonic acid and example of suitable bases include but are not limited to ammonia solution, triethyl amine. In a particular embodiment, the acid is orthophosphoric acid and the base is an ammonia solution.

The resolving may further comprise, in a step (c), salting free of compound of formula 2 in the presence of a base in a third solvent to get bedaquiline of formula 1; and

The third solvent used in step (c) is halogenated hydrocarbon solvents. Examples of suitable aromatic hydrocarbon solvents include but are not limited to toluene, xylene and mixtures thereof. In a particular embodiment, the third solvent is toluene.

The base used in step (c) for desaltification is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. In a particular embodiment, the base is potassium carbonate.

Any of the preceding embodiments may further comprise a step (d), reacting the compound of formula 1 with fumaric acid in a fourth solvent to get bedaquiline fumarate.

An alcohol may be used as fourth solvent in step (d) for bedaquiline fumarate preparation. Examples of suitable alcohol solvents include but are not limited to methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. In a particular embodiment, the alcohol solvent is isopropanol.

Another embodiment provides a process for the preparation of bedaquiline fumarate comprising the steps of;
a) reacting the compound of formula 5 with compound of formula 4 or salt in the presence of lithium pyrrolidide in a solvent to get compound of formula 3;

b) reacting the compound of formula 3 with N-benzoyl L-aspartic acid in a solvent to get compound of formula 2;

c) salting free of compound of formula 2 in the presence of a base in a solvent to get bedaquiline of formula 1; and

d) reacting compound of formula 1 with fumaric acid in a solvent to get bedaquiline fumarate.

In one particular aspect, the racemic bedaquiline of formula (3), bedaquiline N-benzoyl L-aspartic acid salt of formula (2), bedaquiline free base of formula (1), or bedaquiline fumarate is substantially free of desbromo impurity.

“Substantially free” as used herein means the bedaquiline fumarate contains less than about 1 % by HPLC of desbromo impurity. “About” as used herein means +/- 10% of the referenced value. In certain embodiments, “about” means +/- 9%, or +/- 8%, or +/- 7%, or +/- 6%, or +/- 5%, or +/- 4%, or +/- 3%, or +/-2 +/- or +/- 1% of the referenced value.

In certain embodiments, “substantially free” means the bedaquiline fumarate contains less than about 2 %, or less than about 1 %, or less than about 0.5 %, or less than about 0.1 % of desbromo impurity.

The prior art bedaquiline fumarate process involves lithium diisopropylamide (n-butyl lithium and diisopropylamine) for condensation reaction. With this reagent, formation of desbromo impurity content is more and difficult to remove in later stages. It requires multiple purification steps to remove desbromo impurity.

Herein, lithium pyrrolidide (e.g., may be generated by the combination of pyrrolidine and a strong base, such as methyllithium, n-butyl lithium, s-butyl lithium, s-butyl lithium, phenyllithium, ) is employed for this condensation and the desbromo impurity formation is reduced to minimal in the preparation of bedaquiline fumarate. Below is the comparison table of desbromo impurity formation for this reaction with lithium diisopropylamide and lithium pyrrolidide.
No Reagent Desbromo impurity content by HPLC (%)
1 n-butyl lithium and diisopropylamine (LDA) 0.39
2 n-butyl lithium and diisopropylamine (LDA) 0.24
3 n-butyl lithium and diisopropylamine (LDA) 0.57
4 n-butyl lithium and diisopropylamine (LDA) 0.21
5 lithium pyrrolidide Not detected
6 lithium pyrrolidide Not detected
7 lithium pyrrolidide Not detected
8 lithium pyrrolidide Not detected
9 lithium pyrrolidide Not detected

From the above comparison there is no formation of desbromo impurity in bedaquiline fumarate prepared by the processes of the disclosure.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES
Example 1: Preparation of 3-(Dimethylamino)-1-(naphthalen-1-yl) propan-1-one hydrochloride
1-acetyl naphthalene (10g), N, N-dimethylamine hydrochloride (6.2g) and paraformaldehyde (2.29 g) was suspended in ethanol (50mL). Hydrochloric acid (0.1mL) was added and reaction mass was stirred at 70-75 °C for 20 hours. The reaction mass was cooled to room temperature to precipitate the solid. The obtained solid was filtered, washed with ethanol and dried to get 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one hydrochloride (11.0 g).

Example 2: Preparation of N-(4-bromophenyl)-3-phenylpropanamide
3-phenylpropanoic acid (10g) in thionyl chloride (16.4g) was heated for 3 hours at 65-70 °C. The excess thionyl chloride was distilled out from the reaction mass and further co-distilled with toluene to remove traces of thionyl chloride. The resulting reaction residue was dissolved in dichloromethane (70mL) and treated with a triethylamine (16.6g) followed by a solution of 4-bromoaniline (11.3g) at 5-10 °C. After completion of the reaction, the solvent was evaporated under vacuum and the residue was taken in water (20mL) and stirred the mixture to precipitate product. The obtained the product was filtered and dried to get N-(4-bromophenyl)-3-phenylpropanamide (17.5 g).

Example 3: Preparation of 3-Benzyl-6-bromo-2-chloroquinoline
A mixture of phosphorous oxychloride (35.28g) and N, N-dimethylformamide (7.21g) was stirred at 25-35 °C for 30 minutes. Acetonitrile (10mL) was added to the resulting reaction mixture followed by addition of N-(4-bromophenyl)-3-phenylpropanamide (10g) and the reaction mixture was heated to 75-80 °C for 3 hours. Excess phosphorous oxychloride was distilled out and water (140 mL) was added to the reaction mixture and stirred the reaction mass to precipitate product. The obtained the product was filtered and dried to get 3-benzyl-6-bromo-2-chloroquinoline (10.5 g)

Example 4: Preparation of 3-benzyl-6-bromo-2-methoxyquinoline
3-Benzyl-6-bromo-2-chloroquinoline (10g) is dissolved in methanol (20mL) and sodium methoxide solution (4.37g; 30 % in methanol) was added. The mixture was heated to 60-65 °C for 12 hours to complete the reaction. The solvent was distilled out and the residue was taken in water (30mL) and stirred the reaction mass to precipitate product. The obtained the product was filtered and dried to get 3-benzyl-6-bromo-2-methoxy quinoline (9.0 g)
Example 5: Preparation of racemic bedaquiline

A solution of 3-benzyl-6-bromo-2-methoxyquinoline (50g) in tetrahydrofuran (150 mL) was added lithium diisopropylamide (99.02 mL; 2.0 M in tetrahydrofuran) slowly at -75 to -70 °C for period of 3-4 hours and the mixture was stirred at the same temperature for 60 minutes. A solution of 3-(dimethylamino)-1-(naphthalen-1-yl) propan-1-one (41.5 g) in tetrahydrofuran (150mL) was added to the reaction mass over a period of two hours. After maintaining the reaction mass at -75 to -70 °C temperature for 30 minutes, the reaction mixture was quenched with 25 % aqueous ammonium chloride solution (100 mL) and aqueous layer was separated. The organic layer was concentrated under vacuum and the obtained residue was taken in a mixture of acetone (150 mL) and tetrahydrofuran (350 mL) and stirred for 3 hours to precipitate the solid. The obtained solid was filtered and dried to get undesired diastereomer of racemic bedaquiline (23.0 g). The mother liquor was concentrated under vacuum, the residue was dissolved in ethanol (200 mL) and stirred for 5 hours to precipitate the solid. The precipitated solid was filtered, washed with ethanol and dried to get racemic bedaquiline (28.5g, HPLC Purity:78.44%, undesired diastereomer: 6.24%, desbromo impurity: 0.48%).
Example 6: Purification of Racemic bedaquiline

To a suspension of crude racemic bedaquiline (25.0g, HPLC purity:78.44%, undesired diastereomer: 6.24%, desbromo impurity: 0.48%) in acetone (500 mL) was added 85% orthophosphoric acid (5.2g) and heated to 53-56 °C for 90 minutes. The mass was gradually cooled to 25-35 °C and stirred for 70 minutes. Precipitated phosphate salt was filtered, the wet product was dissolved in water (125 mL) and basified with aqueous 10% potassium carbonate solution. The compound was extracted with toluene and concentrated under vacuum to get racemic bedaquiline (20.3g). HPLC purity: 96.82%, undesired diastereomer: 0.72%, desbromo impurity: 0.46%).

Example 7: Preparation of racemic bedaquiline

Pyrrolidine (3.25g) in tetrahydrofuran (150mL) solution was cooled to -30 °C and a n- Butyl lithium (12.44g; 20% solution in toluene) was added slowly. After stirring for 30 minutes, the mixture was further cooled to -75 °C. A solution of 3-benzyl-6-bromo-2-methoxyquinoline (10g; in 60mL tetrahydrofuran) was added slowly over a period of one hour while maintaining reaction mixture temperature at -75 °C. Maintained the stirring for 30 minutes, 3- (dimethylamino)-1-(naphthalen-1-yl) propan-1-one solution (8.29g; in 30 mL tetrahydrofuran) was added over a period of one hour and stirred for 30 minutes. The reaction mixture was quenched with aqueous ammonium chloride 25% solution (50 mL) and aqueous layer were separated. The organic layer was concentrated under vacuum below 50 0C to get residue, which was taken a mixture of acetone (70 mL) and tetrahydrofuran (30 mL) and stirred for 3 hours to get precipitation. Filtered the obtained product and dried to get undesired diastereomer isomer of bedaquiline (2.2g). The mother liquor was concentrated under vacuum below 50 °C and the residue was taken in ethanol (40 mL) stirred for 5 hours to precipitate the solid. The obtained solid was filtered and dried to get racemic bedaquiline (3.5g). HPLC Purity:80.53%, undesired diastereomer: 17.89%, desbromo impurity: 0.06%).
Example 8: Purification of Racemic bedaquiline

Crude racemic bedaquiline (15g, purity 80.53%, undesired diastereomer: 17.89%, desbromo impurity: 0.06%) was dissolved in acetone (300 mL) orthophosphoric acid (3.73g) was added and heated to reflux at 40-50 °C for 5 hours to get a clear solution. The solution was gradually cooled to 25-35 °C and stirred for 10 hours to precipitate the phosphate salt. The obtained phosphate salt was filtered, the wet compound was dissolved in water (40 mL) and basified with aqueous potassium carbonate solution (10 %, 40mL). The product was extracted in toluene (50 mL), concentrated under vacuum below 50 °C to get the residue. The obtained residue was stirred with ethanol (60mL) for 2 hours to precipitate product, filtered and dried to get racemic bedaquiline (10.8g). HPLC purity:98.59%, undesired diastereomer: 0.20%, Desbromo impurity: 0.05%).

Example 9: Preparation of bedaquiline

Racemic bedaquiline (2.0 g) was suspended in 1,4-Dioxane (10mL) and heated to 60-65 °C to get a clear solution. N-benzoyl L-aspartic acid (0.85 g) was added to the hot solution and stirred for 15 minutes. The reaction mixture was cooled to 25-35 °C and added a seed of bedaquiline (10mg) and stirred for 15 hours to precipitate the solid. The precipitated solid was filtered, washed with 1,4-dioxane/hexane mixture (1:1; 5 mL) and dried to get bedaquiline- N-benzoyl L-aspartic acid salt (1.2 g, chiral purity: 96.1 %). The salt was suspended in toluene (20 mL) and basified with 10% aqueous potassium carbonate solution (6 mL). Aqueous layer was separated, and organic layer was concentrated to get bedaquiline (0.65 g). HPLC purity: 99.62 %, Desbromo impurity: 0.05%).

Example 10: Preparation bedaquiline fumarate

Bedaquiline (15 g) and fumaric acid (3.13g) were suspended in isopropanol (450 mL) and heated to 75-80 °C to get a clear solution. Charcoal (1.0 g) was added at same temperature and stirred for 30 minutes. The solution was filtered through micro filter, cooled to 25-35 °C and stirred for 5 hours to get precipitation. The precipitated product was filtered, washed with isopropanol (15 mL) and dried to get bedaquiline fumarate (15.0g). HPLC purity: 99.64 %, Desbromo impurity: Not detected).
,CLAIMS:1. Process for the preparation of bedaquiline comprising the steps of;
a) reacting the compound of formula 5 with compound of formula 4 or salt thereof in the presence of lithium pyrrolidide in a first solvent to get compound of formula 3;
; and
b) resolving the compound of formula 3 to provide bedaquiline of formula 1,

2. The process of claim 1, wherein the resolving comprises reacting the compound of formula 3 with N-benzoyl L-aspartic acid in a second solvent to get compound of formula 2; and

3. The process of claim 2, wherein the resolving further comprises salting free of compound of formula 2 in the presence of a base in a third solvent to get bedaquiline of formula 1; and

4. The process of any one of claims 1-3, further comprising reacting compound of formula 1 with fumaric acid in a fourth solvent to get bedaquiline fumarate.

5. A process for preparing racemic bedaquiline of formula 3 comprising, reacting a compound of formula 5 with a compound of formula 4 or salt thereof in the presence of lithium pyrrolidide in a first solvent,
.
6. Process for the preparation of bedaquiline fumarate containing less than 0.1 % desbromo impurity, comprising the steps of:
a) reacting the compound of formula 5 with compound of formula 4 or salt thereof in the presence of lithium pyrrolidide in a first solvent to get compound of formula 3;

b) resolving the compound of formula 3 with N-benzoyl L-aspartic acid in a second solvent to get compound of formula 2;

c) salting free of compound of formula 2 in the presence of a base in a third solvent to get bedaquiline of formula 1; and

d) reacting compound of formula 1 with fumaric acid in a fourth solvent to get bedaquiline fumarate.

7. The process as claimed in claims 3 or 6, wherein base used for salting free is selected from sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate.

8. The process as claimed in any one of claims 1-6, wherein the first solvent and second solvent is selected the group consisting of ether solvents such as tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane or mixtures thereof; the third solvent is selected from toluene, xylene or mixtures thereof and the fourth solvent is selected from the group consisting of alcohol solvents such as methanol, ethanol, isopropanol, n-propanol, t-butanol and mixtures thereof.

9. The process of claims 1-6, wherein the lithium pyrrolidide is prepared from pyrrolidine and a base selected from the group consisting of n-butyl lithium, methyllithium, s-butyl lithium, t-butyl lithium, and phenyllithium.

10. A compound that is:

(a) formula 3 ,
(b) formula 2, ,
(c) formula 1 or
(d) bedaquiline fumarate prepared as claimed in claims 1-4, substantially free of or contains less than 0.1 % desbromo impurity by HPLC, wherein the desbromo impurity is of the formula,