WO2016116076A1

WO2016116076A1 - New possibilities of chiral resolution of bedaquiline

Info

Publication number: WO2016116076A1
Application number: PCT/CZ2016/000006
Authority: WO
Inventors: Martin STEFKO; Pavel ZVATORA; Ferenc Faigl; Elemer Fogassy; Bela MATRAVOLGYI; Agnes MIZSAK
Original assignee: Zentiva, K.S.
Priority date: 2015-01-21
Filing date: 2016-01-14
Publication date: 2016-07-28
Also published as: CZ201534A3

Abstract

A method of performing isolation and purification of bedaquiline (la) from a mixture of stereoisomers of 6-bromo-2-methoxy-quinolin-3 -yl)-4-dimethylamino-2-( 1 -naphthyl)- 1 - phenyl-butan-2-ol identified as I-rac, being a mixture of the stereoisomers of formulae la, lb, and Il-rac, being a mixture of the stereoisomers of formulae Ila, lib, with any ratio of individual constituents of the mixture, wherein said mixture is dissolved together with derivatives of N-benzoyl-L-aspartic acid Ilia, wherein R₁ and R₂ independently stand for hydrogen, a primary, secondary or tertiary C₁-C₄ alkyl, a primary or secondary amide, wherein always at least one of the R₁ or R₂ symbols stands for hydrogen; and R₃ is a C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl with one or more heteroatoms, which may be further substituted by a halogen, amino group, carbonyl, or carboxyl, or its functional derivative, preferably phenyl, naphthyl, tolyl, or mesytyl, and the resulting salt is recrystallized from a suitable solvent or mixture, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water and/or their mixtures.

Description

New possibilities of chiral resolution of bcdaquiline Technical Field The invention relates to an isolation method of the solid form of (li?,2S)-l-(6-bromo-2- methoxyquinolin-3-yl)-4-dimethylamino-2-(l -naphthyl)-! -phenyl-butan-2-ol of formula (la)

BEDAQUILIN

(la) known as bedaquiline. Bedaquiline is isolated from a mixture of the corresponding stereoisomers (la - (li?,25)-(6-bromo-2-methoxy-qiunolin-3-yl)-4-dimethylamino-2-(l- naphthyl)-l-phenyl-butan-2-ol, lb - (15',2ii)-(6-bromo-2-methoxy-quinolin-3-yl)-4- dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol, Ila - (lS,2S)-(6-bromo-2-methoxy- quinolin-3-yl)-4-dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol, lib - (l_JR,2i-)-(6-bromo- 2-memoxy-quinolm-3-yl)-4-dimemylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol), or the corresponding racemate I-rac (I-rac = mixture of the la : lb isomers in the 1:1 ratio) by means of crystallization with N-benzoyl-I-aspartic acid (formula III), or its derivatives as a chiral crystallization agent.

la lb Ila lib

I-rac = Ia:Ib in 1:1 ratio II-rac = IIa:IIb in 1:1 ratio

Bedaquiline is isolated from a mixture of the corresponding stereoisomers by means of crystallization with derivatives of iV-benzoyl-I-aspartic acid as a chiral crystallization agent:

RiOOC^_COOR2

In the formula, Ri and R₂ independently stand for hydrogen, a primary, secondary or tertiary C1-C4 alkyl, a primary or secondary amide, wherein always at least one of the R[ or R₂ symbols stands for hydrogen; and

R₃ is a C5-Q2 aryl, or C5-Q2 heteroaryl with one or more heteroatoms, which may be further substituted by a halogen, amino group, carbonyl, or carboxyl; or its functional derivative, preferably phenyl, naphthyl, tolyl, or mesytyl. Background Art

( \R,2S)- 1 -(6-Bromo-2-memoxy-quinolin-3-yl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl- butan-2-ol, which is known as bedaquiline la (CAS no. 843663-66-1), belongs to the group of quinoline derivatives that can be used as microbial inhibitors.

The (6-bromo-2-memoxyquinolin-3-yl)-4-dimethyla^

molecule has two chiral centres, thus its 4 stereoisomers Ia-b and Ila-b are known. However, the {\R,2S) isomer (la) can only be used as a microbial inhibitor.

Preparation of this molecule and its use for the treatment of microbial diseases is described in a patent (WO 2004/011436). 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 ((/-)-(-)- 1,1 '-bmaphthyl-2,2'-diyl hydrogen phosphate (IV) or its derivatives is described

/125769).

( )-{-)-l,l'-binaphthyl-2,2'-diyl hydrogen phosphate

(IV)

Specialized literature also describes an asymmetrical synthesis of bedaquiline. However, the said procedure represents a 12-stage synthesis with the total yield of 5%, which makes this synthesis unusable in the industrial scale (Y. Saga, R. Motoki, S. Makino, Y. Shimizu, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 7905). A similar synthesis was also described in a patent (JPN T 2011/1096837 (2011, CAN 155:379672))

The biological activity together with the role of bedaquiline in the treatment of infections related to resistant mycobacteria strains is described in an article in Future Medicinal (2011, 3(11), 1345-1360)

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 la.

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. It is clear that for the preparation of bedaquiline with a high reaction yield, chemical and chiral purity, suitable chiral substances and optimal reaction (crystallization) conditions must be used.

Disclosure of Invention

The invention provides isolation of bedaquiline from the I-rac mixture of stereoisomers, or I- rac with admixed Π-rac, wherein I-rac and II-rac are in any ratio, with the use of N-benzoyl- i-aspartic acid or its chiral derivatives Ilia, and methods of its isolation. The isolation is achieved through crystallization of bedaquiline with N-benzoyl-Z-aspartic acid III, or a selected chiral derivative of N-benzoyl-Z-aspartic acid Ilia

Ilia wherein Ri and R₂ independently stand for hydrogen, a primary, secondary or tertiary Ci-C₄ alkyl, a primary or secondary amide, wherein always at least one of the Ri or R₂ symbols stands for hydrogen; and

R₃ is a C5-C₁₂ aryl, or C5-Q2 heteroaryl with one or more heteroatoms, which may be further substituted by a halogen, amino group, carbonyl, or carboxyl; or its functional derivative, preferably phenyl, naphthyl, tolyl, mesytyl,

in a suitable solvent or mixtures of solvents.

In an especially preferred embodiment R^ z stand for hydrogen and R3 is phenyl:

W-benzoyl-I-aspartic acid

("I)

It has been unexpectedly found out that the derivatives of iV-benzoyl-Z-aspartic acid used make it possible to isolate bedaquiline la in a high yield, with a high chemical and diastereomeric purity. The described isolation procedures can be easily transferred into the industrial scale to obtain a sufficient quantity of bedaquiline for commercial use.

A clear advantage of derivatives of JV-benzoyl-i-aspartic acid is the possibility to only use 0.5 molar equivalents of the chiral acid with respect to the input raw material I-rac. Which is a significant innovative element from the point of view of industrial production, its economy and the environmental aspect.

Another advantage of using derivatives of N-benzoyl-Z-aspartic acid is the possibility to isolate the diastereoisomeric salt of bedaquiline directly by crystallization from a mixture of all the four isomers (I-rac or I-rac with admixed Il-rac wherein I-rac and Il-rac are in any ratio). In addition, if the resolution starts from the I-rac mixture with admixed II-rac, only 0.25 molar equivalents of derivatives of N-benzoyl- -aspartic acid with respect to the I-rac content is sufficient. Which clearly represents a considerable advantage from the point of view of industrial production and its economy.

N-benzoyl-Z-aspartic acid III represents a "green reagent" from the point of view of the environmental impact.

Detailed description of the invention The invention provides isolation of the solid form of bedaquiline la from a mixture of the corresponding stereoisomers by means of crystallization with N-benzoyl-Z-aspartic acid and its chiral derivatives Ilia as a crystallization agent and methods of performing the same.

Crystallization of bedaquiline with N-benzoyl-Z-aspartic acid and its chiral derivatives Ilia can be used to isolate bedaquiline la in a solid form in a high yield, with a high chemical and enantiomeric purity.

The isolated solid form of bedaquiline la may have various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of its isolation. For this reason, the invention relates to isolation of bedaquiline with the use of derivatives of N-benzoyl-i-aspartic acid under various conditions with the use of a number of common solvents or their mixtures.

The described isolation procedures are suitable for isolation of bedaquiline la in a solid form with high chemical and optical purity; they can be easily transferred into the industrial scale to provide a sufficient quantity of bedaquiline for commercial use.

Isolation of bedaquiline la is carried out with the use of crystallization with N-benzoyl-I- aspartic acid or its chiral derivatives Ilia as a crystallization agent, in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles, or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water and/or their mixtures. Aliphatic Q- C₄ alcohols, C5-C7 alkanes, esters of C C₄ acids with primary C C₄ alcohols, secondary C₃-C₆ alcohols, cyclic ethers or their mixtures are preferred. The most commonly used solvents are ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, hexane, heptane or their mixtures.

The final product is typically precipitated or crystallized at temperatures in the range of -30°C to the boiling point of the solvent. Preparation of a mixture of the Ia-b Ila-b stereoisomers of 6-bromo-2-methoxy-3-quinolyl-4- dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol and isolation of the I-rac racemic mixture is described in a patent (WO 2004/011436).

Bedaquiline la can be isolated from the racemic mixture in a solid form by means of chiral HPLC (WO 2004/011436) and/or with the use of (Λ)-(-)-Μ '-binaphthyl-2.2'-diyl hydrogen phosphate (WO 2006/125769). It has been found out that chiral derivatives of N-benzoyl-I- aspartic acid can be advantageously used for isolation of bedaquiline as the chiral crystallization agent in a suitable solvent or a mixture of solvents.

A clear advantage of N-benzoyl-Z-aspartic acid or its chiral derivatives is the possibility to only use 0.5 molar equivalents of the chiral acid with respect to the input raw material I-rac. Which is a significant innovative element from the point of view of industrial production, its economy and the environmental aspect.

Another advantage of using derivatives of JV-benzoyl-I-aspartic acid or its chiral derivatives is the possibility to isolate the diastereoisomeric salt of bedaquilme directly by crystallization from a mixture of all the four isomers (I-rac or I-rac with admixed II-rac, wherein I-rac and II-rac are in any ratio). In addition, if the resolution starts from a I-rac mixture with admixed II-rac, only 0.25 molar equivalents of derivatives of JV-benzoyl-Z-aspartic acid with respect to the I-rac content is sufficient. Which clearly represents a considerable advantage from the point of view of industrial production and its economy.

The free base of bedaquiline la can be released from the given salt with the use of a suitable base, e.g. carbonate or phosphate base. K2CO3, KHCO3, Na₂C0₃, NaHC0₃, Na₃P0_4s or Na₂HP0₄ can be preferably used. As an example, extraction of the free base with the use of toluene and an aqueous solution of Κ₂00₃ can be mentioned; wherein the base is, after releasing, in the organic layer, which can be separated, and after its evaporation bedaquiline la can be isolated as a solid substance.

A crystalline form of the free base of bedaquiline la with the melting point of 118°C is described in a patent (WO 2004/011436).

The invention is clarified in a more detailed way using the working examples below. These examples, which illustrate the improvement of the procedure in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect. Experimental part

High-performance liquid chromatography (HPLC)

Separation of the enantiomers of bedaquiline and verification of the optical purity of the products were carried out in an OJ-3R column, 150x4.6 mm ID, 3 μιη, with the use of the triemylamine buffer pH 8 - acetonitrile (40+60) mobile phase at the flow rate of 1 ml/min and separation temperature of 35°C. The injection volume of the analyzed sample, which was dissolved in methanol to the concentration of 0.5 mg/ml, was 5 μΐ. Bedaquiline was detected by UV detection at 227 nm. Examples

Example 1

Preparation of the mixture of the Ia-b Ila-b stereoisomers was performed by modification of the procedure described in the patent WO 2004/011436.

Example 2

Preparation of the racemic mixture I-rac was performed by modification of the procedure described in the patent WO 2004/011436. Example 3

Isolation of bedaquiline la with the use of 0.5 equivalents of N-benzoyl-L-aspartic acid ΠΙ in 1,4-dioxane ^'

300.5 mg (0.5414 mmol) of I-rac was dissolved in 0.9 ml of 1,4-dioxane at 60°C. Subsequently, 64.2 mg (0.2707 mmol) of N-benzoyl-Z-aspartic acid HI was added and the mixture was stirred at 60°C for 15 minutes. The clear solution was cooled down to 24°C during 60 minutes and further stirred for 2 hours. Inoculation of the solution with prepared crystallization inocula can also be used. The resulting white crystals were filtered off, washed with a dioxane/hexane mixture (1:1 V:V, 2 x 0.3 ml) and dried in a vacuum drier at 40°C (for 12 h), which provided 165 mg (77%) of the diastereoisomeric salt of bedaquiline la with N- benzoyl-Z-aspartic acid III with the chiral purity of 95%. Example 4

Recrystallization of the diastereoisomeric salt of bedaquiline la with N-benzoyl-Z-aspartic acid HI prepared in Example 3. 165 mg of the diastereoisomeric salt of bedaquiline with N-benzoyl-Z-aspartic acid with the optical purity of 95 % was dissolved in a hot state in 1.1 ml of 1.4-dioxane. After cooling of the solution to 24°C, solid matter separated during continuous stirring in the course of 2 h, which was filtered, washed with a dioxane/hexane mixture (1:1 l x 0.3 ml, 2 x 0.2 ml) and dried in a vacuum drier at 40°C for 16 hours. Crystallization yield 119 mg (72%). The solid fraction obtained by filtration contained the salt of bedaquiline la with N-benzoyl-X- aspartic acid III with the chiral purity of 99% ee.

Example 5

Isolation of bedaquiline la by means of 1 equivalent of N-benzoyl-i-aspartic acid III in 1,4- dioxane

1.0 g (1.8 mmol) of I-rac was dissolved at 60 °C in 0.9 ml of 1,4-dioxane, containing 0.5% of water. Subsequently, 427 mg (1.8 mmol) of N-benzoyl-Z-aspartic acid III was added and the mixture was stirred at 60°C for 15 minutes. The clear solution was inoculated with the diastereomeric salt la with III and left to slowly cool down. When 40°C was achieved, hexane (1 ml) was added, the mixture was slowly cooled down to 24°C and further stirred for 2 hours. The resulting white crystals were filtered off, washed with a dioxane/hexane mixture (1:1 V:V, 3 x 0.5 ml) and dried in a vacuum drier at 40°C (for 12 h), which provided 662 mg (89%) of diastereoisomeric salt of bedaquiline la with N-benzoykL-aspartic acid III with the chiral purity of 98% ee.

Example 6

Recrystallization of the diastereoisomeric salt of bedaquiline la with N-benzoyl-I-aspartic acid III prepared in Example 5. 660 mg of the diastereoisomeric salt of bedaquiline la with JV-benzoyl-i-aspartic acid III with the optical purity of 98% ee was dissolved in a hot state in 3.3 ml of 1.4-dioxane. After cooling of the solution to 24°C, solid matter separated during continuous stirring in the course of 2 h, which was filtered, washed with a dioxane/hexane mixture (1:1 V:V, 1 x 0.5 ml, 2 x 0.4 ml) and dried in a vacuum drier at 40°C for 16 hours. The crystallization yield was 527 mg (80 %) of the salt of bedaquiline la with N-benzoyl-Z-aspartic acid III with the chiral purity of 99.9% ee. Example 7

Isolation of the base of bedaquiline la from its diastereoisomeric salt with N-benzoyl-Z- aspartic acid

135.6 mg (0.171 mmol) of the diastereoisomeric salt of bedaquiline la with N-benzoyl-Z- aspartic acid III with the optical purity of 99.9% was suspended in 2 ml of toluene. After addition of 2 ml of an aqueous solution of potassium carbonate (70 mg, 0.500 mmol) and subsequent intensive stirring for 15 minutes, the organic layer was separated, dried over Na₂S0 and concentrated in vacuo. The obtained solid fraction contained the bedaquiline base (93 mg, 98%) with the chiral purity of > 99.9 ee %. Example 8

Isolation of bedaquiline la from the I-rac : II-rac stereoisomer mixture by means of N- benzoyl-Z-aspartic acid III

100 mg (0.180 mmol) of the equimolar mixture of the I-rac, II-rac stereoisomers was dissolved in 0.6 ml of 1,4-dioxane at 60°C. 10.6 mg (0.25 equiv., 0.045 mmol) of N-benzoyl- I-aspartic acid was added to the solution and stirred at 60°C for 15 minutes. After cooling of the solution to 24°C, solid matter separated during continuous stirring in the course of 30 minutes, which was filtered and dried in a vacuum drier at 40 °C for 16 hours. (Inoculation of the solution with prepared crystallization inocula can also be used). Crystallization yield 32 mg (23%; 91% calculated to the salt of bedaquiline with III only). The solid fraction obtained by filtration contained the salt of bedaquiline la with N-benzoyl-Z-aspartic acid III with the chiral purity of 86%.

Example 9

Isolation of bedaquiline la from the I-rac : II-rac stereoisomer mixture by means of N- benzoyl-Z,-aspartic acid (III)

300 mg (0.54 mmol) of the equimolar mixture of the I-rac, II-rac stereoisomers was dissolved in 1.2 ml of 1,4-dioxane, containing 0.5% of water, at 60°C. 128 mg (0.54 mmol) of N- benzoyl-Z-aspartic acid III was added to the solution and stirred at 60°C for 15 minutes. The clear solution was inoculated with the diastereomeric salt la with III and left to slowly cool down. When 40°C was achieved, hexane (0.3 ml) was added, the mixture was slowly cooled down to 24°C and further stirred for 2 hours. The resulting white crystals were filtered off, washed with a dioxane/hexane mixture (1:1 V:V_t 3 .1 ml) and dried in a vacuum drier at 40°C (for 12 h), which provided 57 mg (49% calculated to the salt of bedaquiline with III only) of the diastereoisomeric salt of bedaquiline la with N-benzoyl-X-aspartic acid III with the chiral purity of 99% ee.

Claims

1. A method of performing isolation and purification of bedaquiline (la) from a mixture of stereoisomers of (6-bromo-2-memoxy-quinolin-3-yl)-4-dimethylamino-2-( 1 -naphthyl)- 1 - phenyl-butan-2-ol identified as I-rac, being a mixture of the stereoisomers of formulae la,

I-rac = Ia:Ib with any ratio of individual constituents of the mixture, characterized in that said mixture is dissolved together with derivatives of N-benzoyl-L-aspartic acid of formula Ilia

O

HN R₃

RiOOC^_COOR2

(IHa) wherein Ri and R₂ independently stand for hydrogen, a primary, secondary or tertiary Q- C alkyl, a primary or secondary amide, wherein always at least one of the R_\ or R₂ symbols stands for hydrogen; and

R3 is a Cs-C₁ aryl, C₅-C₁₂ heteroaryl with one or more heteroatoms, which may be further substituted by a halogen, amino group, carbonyl, or carboxyl, or its functional derivative, preferably phenyl, naphthyl, tolyl, or mesytyl,

and the resulting salt is recrystallized from a suitable solvent or mixture, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water and/or their mixtures.

2. The method according to claim 1, characterized in that the isolation from the mixture of (1R.2S)- (1S.2R)- (1S,2S)- (1R,2R) (la, lb, Ila, lib; I-rac with admixed II-rac) is accomplished through crystallization of a salt with N-benzoyl-L-aspartic acid of formula

Ill

(III)

3. The method according to claim 1 or 2, characterized in that the isolation is accomplished, from a mixture of (la, lb) (1R,2S)- and (lS,2R)-(2-bromo-6-methoxy-quinolin-2-yl)-3- dimethylamino-4-(2-naphthyl)- 1 -phenyl-butan- 1 -ol.

4. The method according to claim 3, characterized in that the isolation is accomplished with 0.5 equivalents of N-benzoyl-L-aspartic acid.

5. The method according to claim 3, characterized in that the isolation is accomplished with 1 equivalent of N-benzoyl-L-aspartic acid.

6. The method according to any of the previous claims, characterized in that the isolation is accomplished from dioxane as the solvent.

7. The method according to any of the previous claims, characterized in that the isolation is accomplished from dioxane as the solvent with addition of a co-solvent.

8. The method according to claim 7, characterized in that the co-solvent is a C5-C7 alkane or substituted benzene.

9. The method according to claim 8, characterized in that the co-solvent is hexane, heptane, toluene or xylene, or their mixture.