DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 3237/CHE/2015 filed on June 26, 2015; Indian Provisional Patent Application No. 4204/CHE/2015 filed on August 12, 2015 and Indian Provisional Patent Application No. 5207/CHE/2015 filed on September 29, 2015.
BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of ledipasvir or its pharmaceutically acceptable salts.
BACKGROUND
Ledipasvir (GS-5885) is a hepatitis C virus NS5A inhibitor being developed for the treatment of hepatitis C virus (HCV).

Ledipasvir is chemically named methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7­{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2­azabicyclo [2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5­ azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate and is represented by the following chemical structure:

Ledipasvir is approved in combination with sofosbuvir for the treatment of chronic hepatitis C virus infection under the brand name of HARVONI®, marketed by Gilead Sciences.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for the preparation of ledipasvir or its pharmaceutically acceptable salts, which may include the following steps:
a) reacting the compound of formula 6 with a compound of formula 5 to obtain compound of formula 4;

b) coupling the compound of formula 4 with a compound of formula 3 in the presence of metal catalyst to yield compound of formula 2; and

c) converting the compound of formula 2 to ledipasvir of formula 1.

wherein X is halogen; R1 and R2 are independently selected from halogen, wherein
when R1 is halogen, then R2 is and
when R1 is , then R2 is halogen.

Formula 1 may be further converted to a pharmaceutically acceptable salt by salification steps well known in the art.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the invention.
The present invention provides novel synthetic schemes for the synthesis of ledipasvir. Within the context of the present invention, novel intermediates are generated as part of the novel synthetic schemes. Together, these schemes and intermediates provide an improved, efficient method for the synthesis of ledipasvir or pharmaceutically acceptable salts thereof.
One aspect of the present invention provides a process for the preparation of ledipasvir or pharmaceutically acceptable salts thereof.
In one embodiment, ledipasvir or pharmaceutically acceptable salts thereof may be prepared by the following steps:
a) reacting the compound of formula 6 with a compound of formula 5 to obtain compound of formula 4;

b) coupling the compound of formula 4 with a compound of formula 3 in the presence of metal catalyst to yield compound of formula 2; and

c) converting the compound of formula 2 to ledipasvir of formula 1.

wherein X is halogen; R1 and R2 are independently selected from halogen, wherein
when R1 is halogen, then R2 is and
when R1 is , then R2 is halogen.

In particular embodiments of the present invention X and R1 are selected from Br and R2 is .
Formula 1 may be converted into a pharmaceutically acceptable salt by methods well known in the art. Within the context of the present invention, pharmaceutically acceptable salts include acid addition salts, formed with inorganic acids such as hydrochloric acid, hydro bromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, inaleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chiorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like. Pharmaceutically acceptable salts further include basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component selected from among Na+, K+, Mg2+, Ca2+, and NHgR-4-g +; in which R- is a C1-3 alkyl and g is a number selected from among 0, 1, 2, 3, or 4. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.

According to this embodiment, the compound of formula 6 is treated with the compound of formula 5 to get compound of formula 4. This reaction may be carried out in the presence of base and solvent.

Within the context of the embodiment, the base employed may be an organic base. Examples of suitable organic bases include, but are not limited to, pyridine, imidazole, methyl amine, N,N-diisopropylethylamine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, and mixtures thereof. In some embodiments, N,N-diisopropylethylamine was found to be a particularly useful base. One of the skill in the art will recognize numerous well-known organic bases that may be useful within the context of this embodiment.
Within the context of the embodiment, the solvent employed may be a polar aprotic solvent or an aromatic hydrocarbon. Examples of suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, and mixtures thereof. Examples of aromatic hydrocarbons include, but are not limited to, toluene, xylene, and mixtures thereof. In some embodiments, acetonitrile is used as the solvent. One of the skill in the art will recognize numerous polar aprotic solvents and aromatic hydrocarbons that may be useful within the context of this embodiment.
According to this embodiment, the compound of formula 4 is then coupled with the compound of formula 3 to get compound of formula 2. This reaction may be carried out in the presence of base, metal catalyst, and solvent.

Within the context of this embodiment, the metal catalyst employed may be selected from Pd(0) and Pd(II) compounds such as Pd(PPh3)4, PdCl2(PPh3)2, Pd(OAc)2, PdCl2(P(t-Bu)2Ph)2, and Pd(dppf)2Cl2.
Within the context of this embodiment, the solvent employed may be selected from ester solvents such as isopropyl acetate, ethyl acetate, and butyl acetate; alcohols such as methanol, ethanol, isopropyl alcohol, and tert-amyl alcohol; ether solvents such as dimethoxy ethane and di(2-methoxyethyl) ether; and mixtures thereof. In some embodiments, isopropyl acetate is used as the solvent.

Within the context of this embodiment, the base employed in this step may be selected from a propionate salt such as potassium propionate; acetates such as sodium acetate, potassium acetate, and cesium acetate; phosphates such as sodium phosphate and potassium phosphate; carbonates such as sodium carbonate and potassium carbonate; and mixtures thereof. In some embodiments, potassium phosphate is used as base.

Within the context of this embodiment, the compound of formula 3 is prepared in situ, thereby allowing subsequent coupling step to proceed. In this embodiment, the process comprises contacting the compound of formula (7)
with a source of palladium and then borylating agent comprising the moiety in the presence of base; wherein X is a halide, preferably Br.

In some embodiments of the invention, the borylation reagent is selected from bis(pinacolato)diboron and bis(neopentylglycolato)diboron; the palladium source employed may be selected from Pd(0) and Pd(II) compounds such as Pd(PPh3)4, PdCl2(PPh3)2, Pd(OAc)2, PdCl2(P(t-Bu)2Ph)2, and Pd(dppf)2Cl2; the base employed for this step may be selected from a propionate salt such as potassium propionate; acetates such as sodium acetate, potassium acetate, and cesium acetate; phosphates such as sodium phosphate and potassium phosphate; carbonates such as sodium carbonate and potassium carbonate; and mixtures thereof.
Another embodiment of the present invention provides a process for the preparation of ledipasvir or its pharmaceutically acceptable salts as shown in scheme I.

Scheme-I

Another embodiment of the present invention provides a process for the preparation of ledipasvir or its pharmaceutically acceptable salts, which is as shown in scheme-II.

Scheme-II
wherein L is amino protecting group; R1 and R2 are independently selected from halogen, wherein
when R1 is halogen, then R2 is and
when R1 is , then R2 is halogen.

Another embodiment the present invention provides a process for the preparation of ledipasvir or its pharmaceutically acceptable salts, which is as shown in scheme-III.

Scheme-III
wherein L, R1, and R2 are defined as above.

Another embodiment of the present invention provides a process for the preparation of ledipasvir or its pharmaceutically acceptable salts, which is as shown in scheme-IV.

Scheme-IV

wherein L, R1, and R2 are defined as above.

The compound of formula 6 may be prepared by the following process.

The compound of formula 7 may be prepared by the following process:

With all of the reactions disclosed above, one of skill in the art will recognize that the reaction conditions (e.g., reaction time and temperature) may be adjusted to achieve appropriate yield without undertaking undue experimentation and without departing from the scope of the present disclosure. Additionally, one of skill in the art will recognize that, when appropriate, various separation and isolation techniques may be applied to isolate the final ledipasvir product or any intermediate disclosed above. For example, such techniques as thin layer chromatography, high performance liquid chromatography, filtration, distillation, and crystallization may be employed.

The ledipasvir generated using the methods of the present invention may be administered to patients who are suffering from a chronic hepatitis C virus infection. Ledipasvir or its pharmaceutically acceptable salts produced by the methods of the present invention may be included in a pharmaceutical dosage form, including oral pharmaceutical dosage forms such as a tablet or capsule. Ledipasvir may be included as the only active pharmaceutical ingredient, or it may be combined with other bioactive drugs, such as sofosbuvir. When formulated as a tablet, pharmaceutical excipients may also be included. Suitable pharmaceutical excipients for tablet formulation of ledipasvir include colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Tablets so formulated may be film-coated with materials such as dyes, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. When included in pharmaceutical dosage forms, ledipasvir may be present in a pharmaceutically effective amount, such as 90 milligrams. One of skill in the art will be familiar with a variety of excipients and formulations that may be used to prepare desirable dosage forms with desired release characteristics and pharmacokinetic properties without undue experimentation.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. The examples below provide representative reaction conditions suitable for conducting the reactions disclosed therein. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to encompass all such changes and modifications that are within the scope of this disclosure.
Example 1: Preparation of 3-(6-Bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane (formula 23)
(1R,3S,4S)-2-Azabicyclo[2.2.1]heptane-2-carboxylicacid,3-(6-bromo-1H- benzimidazole-2-yl)-,1,1-dimethylethyl ester (50 g), acetonitrile (250 mL), and Cp HCl solution (1:1; 80 mL) were charged to a vessel. The temperature was raised to 60 65 °C and maintained until TLC complied (~3 hours). The reaction mass was allowed to 25-30 °C, acetonitrile was added and then cooled to 0-5 °C, maintained for 2 hours, and then filtered to get 3-(6-bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane.

Example 2: Preparation of Carbamic acid, N-[(1S)-1-[[(1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]hept-2-yl]carbonyl]-2-methylpropyl]-, methyl ester (formula 7)
Hydroxybenzotriazole (HoBT) (15.8 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl) (22.4 g), Moc-L-valine (20.1 g), dimethyl formamide (DMF) (175 mL), and ethyl acetate (175 mL) were charged to a vessel and then cooled to 0-5°C. 3-(6-bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane (35 g) and N-methylmorpholine (NMM) (34 g) were charged. The reaction mass was allowed to 25-30 °C and maintained until TLC complied (~16 hours). Ethyl acetate (175 mL) and water (175 mL) were then charged to the reaction mass. The organic layer was separated and washed with water (2 x 175 mL) followed by 5% sodium bicarbonate washing (175 mL) then again washed with water (2 x 175 mL). Finally, the organic layer was distilled under vacuum and isolated the carbamic acid, N-[(1S)-1-[[(1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]hept-2-yl]carbonyl]-2-methylpropyl]-methyl ester in cyclohexane (175 mL).

Example 3: Preparation of (S)-5-Azaspiro[2.4]heptane-6-carboylix acid ethyl ester (formula 21)
(S)-5-(tert-butoxy carbonyl)-5-Azaspiro[2.4]heptane-6-carboylix acid (25 g) was dissolved in 150 mL of ethanol and DMF (1 mL) under nitrogen atmosphere and cooled to 5-10 °C. Thionyl chloride (18.4 g) added and maintained for 4 hours at 20-25 °C and then for 5 hours at 75-80 °C until TLC complied. Distilled off solvent normally U/N2 and co-distilled with ethyl acetate (2 x 100 mL). Finally, the resulting residue was diluted with ethyl acetate (75 mL) and quenched in a mixture of NMM (21 g) in ethyl acetate at 10 °C to separate the salts. The organic layer contains (S)-5-azaspiro[2.4]heptane-6-carboylix acid ethyl ester used for next step.

Example 4: Preparation of (S)-5-Azaspiro[2.4]heptane-6-carboxylic acid, 5-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl] (Formula 6)
HoBT (18 g), EDC.HCl (25.5 g), moc-L- valine (23.4g), DMF (150 mL) were charged to a vessel and then cooled to 0-5 °C. (S)-5-Azaspiro[2.4]heptane-6-carboylix acid ethyl ester (eq 17.4 g) and NMM (10.4 g) were charged to the vessel. The reaction mass was allowed to warm to 25-30 °C and was maintained until TLC complied (~16 hours). Ethyl acetate (175 mL) and water (175 mL) were charged. An organic layer was separated and washed with water (2 x 175 mL) followed by 10% ammonium chloride washing (3 x175 mL) further washed with water (3 x 175 mL). Finally, the organic layer was distilled under vacuum. To the residue, tetrahydrofuran (THF) (175 mL) and lithium hydroxide solution were charged (17.4 g dissolved in 175 mL of water). That mixture was maintained until TLC complied (18 hours) at 45-50 °C. Solvent was distilled out under reduced pressure. The resulting mass was diluted with water (175 mL) and washed with ethyl acetate (2 x 87 mL). The aqueous layer was pH adjusted to 1.0 with HCl solution at 10-20 °C, followed by extracted with dichloromethane (MDC) (2 x 175 mL). The MDC layer was distilled under reduced pressure and the compound (S)-5-azaspiro[2.4]heptane-6-carboxylic acid, 5-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl] was isolated.

Example 5: Preparation of compound of formula 4a
(S)-5-Azaspiro[2.4]heptane-6-carboxylic acid, 5-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl] (2.5 g), compound of formula 5a (2.5 g), and acetonitrile (50 mL) were charged to a vessel. N,N-diisopropylethylamine (DIPEA) was added at 5-10°C over 20 minutes. The reaction mass was maintained at 40-45 °C until TLC complied (7 hours). Water (200 mL) and ethyl acetate (200 mL) were charged. Organic layer washed with ethyl acetate (200 mL). The Organic layer was distilled under reduced pressure, and compound of formula 4a was isolated in 50 mL of cyclohexane.

Example 6: Preparation of compound of formula 2
Carbamic acid, N-[(1S)-1-[[(1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]hept-2-yl]carbonyl]-2-methylpropyl]-, methyl ester (2.5 g), bis(neo pentylglycolate)diborane (2.7 g), potassium propionate (3 g), Pd/cat (0.2 g), and IPA acetate (30 mL) were charged under inert atmosphere and maintained for 3 hours at 69-72 °C. The reaction mass was cooled to room temperature. The compound of formula 4a (2.5 g) and degassed K3PO4 solution (4.2 g in 24 mL water) were charged at 20-25 °C, maintained for 2 hrs at 65-72 °C, and then cooled to 20-25 °C. Layers were separated and the organic layer was diluted with isopropyl acetate (IPA) (30 mL) followed by washing with 5% NaCl solution (2 x 37.5 mL). To the organic layer, N-aetyl–L–cysteine (1.0 g) was charged at 20-25 °C and maintained for 18 hours at 20-25 °C. Hyflo (0.25 g) and sodium hydroxide solution (0.25 g in 25 mL water) were charged. The mass was filtered through hyflo and washed with IPA acetate (10 mL). The organic layer was separated and washed with 5% NaCl solution (3 x 25 mL). Finally, the organic layer was distilled under reduced pressure and compound of formula 18 was isolated in IPE (25 mL).

Example 7: Preparation of ledipasvir (Formula 1)
The compound of formula 2 (2 g), toluene (20 mL), 2-methoxy ethanol (0.6 g), and ammonium acetate (0.83 g) were charged to a vessel. The reaction mass was maintained for 5 hours at 100-102 °C, subsequently cooled to 20-25 °C, and charged with ethyl acetate (20 mL). The organic layer was washed with water (2 x 20 mL), followed by 5% sodium bicarbonate solution (20 mL), then water (2 x 20 mL). Finally, the organic layer was distilled under reduced pressure. The residue stirred with acetone (22 mL) for 18 hours at 20-25 °C and ledipasvir acetone solvate isolated through filtration with 99.2% (HPLC).

,CLAIMS:What is claimed is:
1. A process for the preparation of ledipasvir, comprising:
a) reacting the compound of formula 6 with a compound of formula 5 to obtain compound of formula 4;

b) coupling the compound of formula 4 with a compound of formula 3 in the presence of metal catalyst to yield compound of formula 2; and

c) converting the compound of formula 2 to ledipasvir of formula 1 or its pharmaceutically acceptable salts.

wherein X is halogen; R1 and R2 are independently selected from halogen, wherein
when R1 is halogen, then R2 is and
when R1 is , then R2 is halogen.

2. The process according to claim 1, wherein step a) is performed in presence of a organic base, which is selected from the group consisting of pyridine, imidazole, methyl amine, N,N-diisopropylethylamine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, and mixtures thereof.

3. The process according to claim 1, wherein step b) is performed in presence of a base and a metal catalyst.

4. The process according to claim 3, wherein the base is potassium propionate, sodium acetate, potassium acetate, cesium acetate, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, or mixtures thereof.
5. The process according to claim 3, wherein the metal catalyst is a Pd(0) compound or a Pd(II) compounds and is selected from the group consisting of Pd(PPh3)4, PdCl2(PPh3)2, Pd(OAc)2, PdCl2(P(t-Bu)2Ph)2, and Pd(dppf)2Cl2.
6. The process according to claim 1, wherein X and R1 are bromide and R2 is .

7. The process according to claim 6, further comprising the step of in situ generation of the compound of formula 3 , comprising
sequentially contacting a compound of formul a 7with a source of palladium and then a borylation agent in presence of base.
8. The process according to claim 7, wherein borylation agent is bis(neopentylglycolato)diboron.
9. The process according to claim 7, wherein the source of palladium is Pd(PPh3)4, PdCl2(PPh3)2, Pd(OAc)2, PdCl2(P(t-Bu)2Ph)2, Pd(dppf)2Cl2, or mixtures thereof.
10. The process according to claim 7, wherein the base is selected from the group consisting of potassium propionate, sodium acetate, potassium acetate, cesium acetate, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, or mixtures thereof.