WO2016199049A1

WO2016199049A1 - Process for the preparation of ledipasvir

Info

Publication number: WO2016199049A1
Application number: PCT/IB2016/053387
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Kura Rathnakar Reddy; Bandi Vamsi Krishna; Mogili NARASINGAM
Original assignee: Hetero Research Foundation
Current assignee: Hetero Research Foundation
Priority date: 2015-06-09
Filing date: 2016-06-09
Publication date: 2016-12-15
Anticipated expiration: 2017-12-09

Abstract

The present invention relates to a process for the preparation of Ledipasvir using Bis(triphenylphosphine)palladium(II) dichloride and process for the preparation of intermediates of Ledipasvir.

Description

PROCESS FOR THE PREPARATION OF LEDIPASVIR

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Ledipasvir and process for the preparation of their intermediates.

BACK GROUND OF THE INVENTION

Ledipasvir (Coded as GS-5885), Methyl [(2S)-l-{(6S)-6-[5-(9,9-difluoro-7-{2- [(lR,3S,4S)-2- {(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-lH- benzimidazol-6-yl}-9H-fluoren-2-yl)-lH-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl- 1 -oxobutan-2-yl] carbamate a compound of formula I is marketed by Gilead. Ledipasvir is most commonly used in combination with Sofosbuvir for treatment of Hepatitis C under the trade name HARVONI™

— Formula I

US 8,088,368 B2 (US'368) discloses Ledipasvir and its physiologically acceptable salts. US'368 discloses the following scheme for the preparation of Ledipasvir.

US 2013/0324740 Al (US '740) discloses the process for preparation of Ledipasvir by using metal catalyst chosen from Pd(0) or Pd(II) compounds or Pd or Ni in combination with ligands and base. Further this patent application discloses use of oxalic acid to form salt of the di- protected Ledipasvir. US '740 discloses the preparation of Lediapasvir, which is as follows.

Formula I

Y and Z are independently selected from Br and— BiORXOR¹)

These prior art processes involves the use of catalysts such as PdCl₂[P(t-Bu)₂Ph]₂ Pd(OAc)₂/2- dicyclohexylphosphino-2'-methylbiphenyl in the preparation of Ledipasvir, which are costlier and hence not suitable in commercial scale. However, the present inventors found a process for the preparation of Ledipasvir using Bis(triphenylphosphine)palladium(II) dichloride and process for the preparation of Ledipasvir intermediates which is commercially useful and industrially applicable.

OBJECTIVES OF THE INVENTION

The objective of the present invention is to provide a process for the preparation of Ledipasvir using Bis(triphenylphosphine)palladium(II) dichloride with high yield and high purity.

Another objective of the invention is to provide process for the preparation of intermediates useful in preparation of Ledipasvir. Another objective of the present invention is to provide process for the preparation of Ledipasvir which is economically feasible.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of Ledipasvir of formula I, which comprises:

— Formula I

Formula II

wherein X represents a leaving group, with a compound of formula III

— Formula III

wherein Lg represents a leaving group, in the presence of Bis(triphenylphosphine)palladium(II) dichloride and base.

In another embodiment the present invention relates to intermediate compound of formula III. In another embodiment the present invention relates to a process for the preparation of intermediate compound of formula III.

Formula III

wherein Lg represents a leaving group, which comprises:

a. deprotecting compound of formula V,

Formula V

wherein Lg represents a leaving group, to obtain a compound of formula VI or its salt;

a VI

wherein Lg represents a leaving group

b. reacting compound of formula VI or its salt, with a compound of formula VII,

Formula VII to yield intermediate compound of formula III.

In another embodiment the present invention relates to intermediate compound of formula VI or its salt. In another embodiment the present invention relates to a process for the preparation of intermediate com ound of formula II,

Formula II

wherein X represents a leaving group, which comprises:

a. deprotecting compound of formula VIII,

Formula VIII

wherein X represents a leaving group, Pg is amine protecting group, to obtain compound of formula IV or its salt,

Formula IV

wherein X represents a leaving group; and

b. reacting compound of formula IV or its salt with a compound of formula VII,

Formula VII to yield intermediate compound of formula II.

In another embodiment the present invention relates to intermediate compound of formula IV or its salt.

Formula IV wherin X is a leaving group.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Ledipasvir of formula I, which com rises the condensation of compound of formula II,

Formula II

wherein X is a leaving group, with a compound of formula III

— Formula III

wherein Lg is a leaving group in the presence of Bis(triphenylphosphine)palladium(II) dichloride and base, wherein base is selected from group comprising of propionoate salt, acetate and phosphate.

According to one aspect of the present invention, the propionate salt is selected from alkali metal propionates such as potassium propionate, sodium propionate; acetates are selected from sodium, potassium or cesium acetate; and phosphates are selected from alkali metal phosphate such as sodium or potassium phosphate.

According to another aspect of the present invention, the condensation of compound of formula II and compound of formula III is carried out in the presence of an organic solvent selected from esters such as aliphatic esters or aromatic esters wherein aliphatic esters are selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate or mixtures thereof. According to another aspect, substituents X and Lg used throughout the present invention are independently selected from halogen such as fluorine, chlorine, bromine, iodine and— B(OR)(OR'). In one embodiment of the present invention, when Lg is— B(OR)(OR'), the substituents R and R' are independently selected from the group consisting of hydrogen and straight or branched Ci-8-alkyl, or R and R' together represent a straight or branched Ci-8-alkylene, C3-8- cycloalkylene, or C₆-i2-arylene. Any alkyl, alkylene, cycloalkylene, or arylene as defined herein is optionally substituted with one or more substituents selected from the group consisting of Ci_₆-alkyl,— C(0)N(C_1-6-alkyl)₂, and— C(0)0(C_1-6-alkyl).

In one embodiment of the present invention, when X is halogen, Lg is— B(OR)(OR') and in another embodiment when X is— B(OR)(OR'), Lg is halogen. According to another aspect of the present invention, the condensation of compound of formula II and formula III is carried out at a temperature in the range of 25°C to 100°C.

According to another aspect of the present invention, isolation of compound of formula I is carried out at a temperature in the range of 0°C to 30°C.

In another aspect, the present invention relates to a process for the preparation of intermediate compound of formula III which comprises:

a. deprotecting compound of formula V

— Formula V

wherein Lg is a leaving group, is carried out in the presence of acid selected from hydrohalic acid, nitric acid, sulfuric acid and a solvent, wherein the solvent is halogenated hydrocarbons selected from group comprising of methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride or mixtures thereof to obtain a compound of formula VI or its salt; and

— Formula VI

wherein Lg is a leaving group

b. reacting compound of formula VI or its salt with a compound of formula VII

Formula VII in the presence of EDCI.HC1, HOBt, NMM to yield a compound of formula III.

In another embodiment, the present invention relates to a process for the preparation of intermediate compound of formula II which comprises:

a. deprotecting compound of formula VIII,

Formula VIII

wherein X is a leaving group, Pg is a protecting group is carried out in the presence of acid selected hydrohalic acid, nitric acid, sulfuric acid and a solvent, wherein the solvent is halogenated hydrocarbons selected from group comprising of methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride or mixtures thereof to obtain a compound of formula IV or its salt

Formula IV wherein X is a leaving group

b. reacting compound of formula IV or its salt, with a compound of formula VII

Formula VII in the presence of EDCI.HC1, HOBt, NMM to yield intermediate compound of formula II.

In another embodiment of the present invention, Pg is amine protecting group selected from Carbobenzyloxy, tert-Butyloxycarbonyl, p-Methoxybenzyl carbonyl, 9- Fluorenylmethyloxycarbonyl, Acetyl, Benzoyl, Benzyl, Carbamate, p-Methoxybenzyl, 3,4- Dimethoxybenzyl, p-methoxyphenyl, Tosyl and sulfonamides.

In another embodiment of the present invention, the salts are selected from acids such as hydrohalic acid, nitric acid or sulfuric acid wherein the salt formation is carried out by taking the acid in dioxane.

In another embodiment, hydrohalic acids are selected from hydrochloric acid, hydrobromic acid or hydroiodic acid.

In the present invention abbreviations used have the meanings as below:

EDCI: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide

HOBt: hydroxybenzotriazole

NMM: N-methylmorpholine

DIEA: diisopropylethylamine

DME: dimethoxyethane

HATU:l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium3-oxidhexa fluoro phosphate

MDC: Methylenedichloride

In the following section embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Variants of these examples would be evident to persons ordinarily skilled in the art. EXAMPLES

Reference example

Preparation of (l-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-lH-imidazol-2-yl]-5-aza- spiro[2.4]heptane-5- carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-lH-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5- carboxylic acid benzyl ester (800 mg, 1.38 mmol) was dissolved in DCM (15 mL) and HBr in AcOH (37%, 2 mL) was added and stirring at room temperature was continued. After 180 minutes, the suspension was diluted with hexanes and the solid was collected via filtration and was washed with hexanes and subjected to vacuum. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (4.0 mL) and DIEA (356 mg, 2.76 mmol) was added. A solution of 2-(L)-Methoxycarbonylamino-3-methyl- butyric acid (242 mg, 1.38 mmol), HATU (524 mg, 1.38 mmol) and DIEA (178 mg, 1.38 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 50 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by silica gel chromatography (eluent: EtOAc / hexanes) to yield the slightly impure product (878 mg).

Preparation of 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryI)- 5-aza- spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-lH-benzoimidazol-2-yl]-2- aza- bicyc!o(2.2.1]heptane-2-carboxylic acid tert-butyl ester

(l-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-lH-imidazol-2-yl]-5-aza-spiro[2.4]heptane- 5- carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (840 mg, 1.4 mmol), 3-[6-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)- 1 H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane- 2- carboxylic acid tert-butyl ester (615 mg, 1.4 mmol), Pd(PPh₃)4 (161 mg, 0.14 mmol), K₂C0₃ (579 mg, 4.2 mmol), were dissolved in DME (15 mL) / water (3 mL) under an argon atmosphere. The mixture was heated for 120 minutes at 85 - 90°C (oil bath). After 120 minutes additional boronate ester (61 mg, 0.14 mmol) was added and heating was continued. After 3 hours, the reaction was cooled to room temperature. Most of the DME was removed in vacuo and the crude reaction mixture was diluted with EtOAc. The mixture was washed with brine and was dried over sodium sulfate. Filtration and evaporation of solvents gave the crude reaction product, which was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield the product (878 mg).

Preparation of (l-{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl- butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-irnidazol-4-yl}-9H-fluoren-2-yl)-lH- benzoimidazol-2-yI]-2-aza-bicyclo(2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept- 6-yl]-3H-imidazol-4-yl } -9H-fluoren-2-yl)- 1 H-benzoimidazol-2-yl] -2-aza-bicyclo[2.2.1 ] heptane-2-carboxylic acid tert-butyl ester (115 mg, 0.138 mmol) was dissolved in DCM (2 mL) and HC1 in dioxane (4M, 2 mL) was added and stirring at room temperature was continued. After 20 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and DIEA (53.4 mg, 0.414 mmol) was added. A solution of 2- (Z-) Methoxycarbonylamino-3-methyl-butyric acid (24.2 mg, 0.138 mmol), HATU (52.4 mg, 0.138 mmol) and DIEA (17.8 mg, 0.138 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (76 mg).

Example 1.

Preparation of Ledipasvir

Step A:

Preparation of 2-((lR,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-benzo[d]imidazole hydrochloride

tert-Butyl(lR,3S,4S)-3-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[d] imidazole -2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (10.0 gm, 22.76 mmol) was taken in methylene dichloride, and 4N HC1 in dioxane was added at 0°C. The reaction mixture was stirred at room temperature for 8 hours and all volatiles were removed in vacuum to yield 2- ((lR,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-benzo[d] imidazole hydrochloride. Yield: 8.0 gm.

Step B:

Preparation of Methyl ((S)-3-methyl-l-oxo-l-((lR,3S,4S)-3-(6-(4,4,5,5-tetramethyl- 1,3,2— dioxaborolan-2-yl)-lH-benzo[d]imidazole-2-yl)-2-azabicyclo[2.2.1]heptan-2- yl)butan-2-yl)carbamate

(Methoxycarbonyl)-L-valine (5.12 gm, 29.28 mmol), EDCI.HC1 were added to HOBt in dimethylformamide at 0°C. Added a solution of 2-((lR,3S,4S)-2-azabicyclo[2.2.1]heptan-3- yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[d]imidazole hydrochloride (10.0 gm, 26.61 mmol) in dimethylformamide and NMM at 0°C. The reaction mixture was stirred for 12 hours and was diluted with ethylacetate, washed with sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 12.0 gm of Methyl ((S)-3-mefhyl-l-oxo-l-((lR,3S,4S)-3-(6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[d]imidazole-2-yl)-2-azabicyclo[2.2.1]heptan- 2-yl)butan-2-yl)carbamate.

Step C:

Preparation of (S)-6-(5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-lH-imidazol-2-yl)-5- azaspiro [2.4] heptane hydrochloride

tert-Butyl(S)-6-(5-(7-bromo-9,9- difluoro-9H-fluoren-2-yl)-lH-imidazol-2-yl)-5-azaspiro[2,4] heptane-5-carboxylate (10.0 gm, 18.44 mmol) was taken in methylene dichloride and 4N HC1 in dioxane was added at 0°C. The reaction mixture was stirred at room temperature for 8 hours and all volatiles were removed in vacuum to yield 8.0 gm of (S)-6-(5-(7-Bromo-9,9-difluoro- 9H-fluoren-2-yl)-lH-imidazol-2-yl)-5-azaspiro[2.4]heptane hydrochloride.

Step D:

Preparation of Methyl ((S)-l-((S)-6-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-lH- imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-l-oxobutan-2-yl)carbamate:

(Methoxycarbonyl)-L-valine (4.02gm, 29.28 mmol), EDCI.HC1 were added to HOBt in dimethylformamide at 0°C. Added a solution of (S)-6-(5-(7-Bromo-9,9-difluoro-9H-fluoren-2- yl)-lH-imidazol-2-yl)-5-azaspiro[2.4]heptane hydrochloride (10.0 gm, 20.88 mmol) in dimethylformamide and NMM at 0°C. The reaction mixture was stirred for 12 hours and was diluted with ethylacetate, washed with sodium bicarbonate and brine. The organic phase was dried, filtered and concentrated under reduced pressure to yield 11.0 gm of Methyl ((S)-1-((S)- 6-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-lH-imidazol-2-yl)-5-azaspiro [2.4]heptan-5-yl)- 3 -methyl- 1 -oxobutan-2-yl)carbamate.

Step E:

Preparation of Ledipasvir

Methyl ((S)-l-((S)-6-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-lH-imidazol-2-yl)-5-azaspiro [2,4]heptan-5-yl)-3-methyl-l-oxobutan-2-yl)carbamate(10.0 gm, 16.69 mmol), Methyl ((S)-3- methyl-l-oxo-l-((lR,3S,4S)-3-(6-(4,4,5,5-tetramethyl-l,3,2— dioxaborolan-2-yl)-lH- benzo[d]imidazole-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-yl)carbamate(9.11 gm, 18.36 mmol), PdCi₂(PPh₃)₂ (820 mg, 1.17 mmol),Potassium propionate(5.61 gm, 50.08 mmol) were taken in isopropylacetate and then added aqueous K₃PO₄. The reaction mixture was heated to 75° C under N₂ atmosphere further cooled to room temperature and quenched with saturated sodium bicarbonate aqueous solution. Organic phase was extracted with ethylacetate, dried, filtered and concentrated to yield 12.0 gm of Ledipasvir.

Claims

We Claim:

1. A process for the preparation of Ledipasvir of formula I, which comprises:

— Formula I

reactin compound of formula II,

Formula II

wherein X is halogen, with a compound of formula III,

— Formula III

wherein Lg is— B(OR)(OR'), the substituents R and R' are independently selected from the group comprising of hydrogen, straight or branched C_1-8-alkyl, or R and R' together represent a straight or branched Ci-8-alkylene, C3_8-cycloalkylene, or C₆-i2-arylene in the presence of Bis(triphenylphosphine)palladium(II) dichloride and base.

2. The process according to claim 1, wherein the base is propionate salt selected from the group comprising of potassium propionate, sodium propionate; acetates selected from group comprising of sodium acetate, potassium acetate or cesium acetate; and phosphates selected from group comprising of sodium phosphate or potassium phosphate.

1

3. A process for the preparation of intermediate compound of formula III, which comprises:

Formula III

a. deprotecting compound of formula V,

Formula V

to obtain a compound of formula VI or its salt;

Formula VI

b. reacting compound of formula VI or its salt, with a compound of formula VII,

Formula VII to yield intermediate compound of formula III; wherein Lg is— B(OR)(OR'), the substituents R and R' are independently selected from the group comprising of hydrogen, straight or branched Ci-8-alkyl, or R and R' together represent a straight or branched Ci-8-alkylene, C₃_8- cycloalkylene, or C₆-i2-arylene.

4. A process for the preparation of intermediate compound of formula II,

2 Formula II

which comprises:

a. deprotecting compound of formula VIII,

Formula VIII

wherein Pg is amine protecting group, to obtain compound of formula IV or its salt; and

— Formula IV

b. reacting compound of formula IV or its salt with a compound of formula VII,

Formula VII

wherein X is halogen to yield intermediate compound of formula II.

5. The process according to claims 3 and 4 wherein step a is carried out in the presence of an acid selected from the group comprising of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and step b is carried out in the presence of EDCI.HCl, HOBt, NMM.

6. Intermediate compounds of formula III, formula IV and formula VI or its salt thereof.

Formula III

Formula IV

— Formula VI

wherein X is halogen; Lg is— B(OR)(OR'), the substituents R and R are independently selected from the group comprising of hydrogen, straight or branched Ci-8-alkyl, or R and R together represent a straight or branched Ci-8-alkylene, C3_8-cycloalkylene, or C₆-i2-arylene.

4