The present invention generally relates to an improved process for the preparation of tenofovir alafenamide or a pharmaceutically acceptable salt thereof. The present invention also relates crystalline forms of [(i?)-2-(Phenylphosphonomethoxy) propyl] adenine ("monophenyl PMPA") which is an important intermediate of tenofovir alafenamide and their preparation.

The present invention further relates to novel crystalline form of tenofovir alafenamide hemifumarate, its preparation process and pharmaceutical compositions comprising the same.

BACKGROUND OF THE INVENTION

Tenofovir alafenamide is chemically known as 9-[(R)-2-[[(S)-[[(S)-l-(isopropoxycarbonyl) ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine (GS-7340); and represented by the following structure:

Tenofovir Alafenamide

U.S. Patent No 7,390,791 discloses prodrugs of methoxyphosphonate nucleotide analogs, in particular tenofovir alafenamide or pharmaceutically acceptable salts thereof and its preparation process. This patent provided ways to separate the diastereomers of tenofovir alafenamide by solvent crystallization from acetonitrile by seeding, batch elution chromatography, SMB chromatography or C18 RP-HPLC, which techniques are tedious,

uneconomical and not advantageous on large scale. This patent further provided reaction of tenofovir alafenamide with fumaric acid in acetonitrile solvent to obtain tenofovir alafenamide monofumarate with a melting point of 119.7°C-121.1°C.

U.S. Patent No 8,664,386 discloses process for the preparation of tenofovir alafenamide in high diastereomeric purity. The disclosed process involves preparing intermediate compounds that are at least about 90% diastereomerically pure with >97% conversion as a prerequisite in order to obtain tenofovir alafenamide in high diastereomeric purity. Specifically the disclosed process involves chlorination of monophenyl PMPA with thionyl chloride in toluene, stirring for 48-96 hours until reaction conversion is >97% and diastereomeric enrichment is >90: 10 to provide chlorinated product which is as such reacted with L-alanine isopropyl ester followed by purification from a mixture of toluene and acetonitrile (4: 1) to obtain tenofovir alafenamide with 97.5: 2.5 diastereomeric ratio. This process provided improved diastereomeric purity but could attain only 97.5% diastereomeric purity which required crystallization induced dynamic resolution process to obtain the required diastereomeric purity.

This process suffers from several disadvantages such as it requires undue monitoring of reaction, increased reaction times, preset targets of reaction conversion and diastereomeric purity, cumbersome crystallization induced dynamic resolution process which not only adds an additional process step but also increases process cost.

U.S. Patent No 8,754,065 ("the '065 patent") discloses tenofovir alafenamide hemifumarate characterized by the following powder X-ray diffraction (PXRD) pattern having peaks at 6.9±0.2°, 8.6±0.2°, 10.0+0.2°, 11.0+0.2°, 12.2+0.2°, 15.9+0.2°, 16.3+0.2°, 20.2±0.2° and 20.8±0.2° and differential scanning calorimetry (DSC) onset endotherm at 131°C. This patent also disclosed processes for preparation of tenofovir alafenamide hemifumarate which involved seeding with tenofovir alafenamide hemifumarate seed crystals. According to this patent processes, tenofovir alafenamide hemifumarate in essentially pure form is obtained only when the process comprises the step of adding seed crystals of tenofovir alafenamide hemifumarate, otherwise mixture of tenofovir alafenamide monofumarate and tenofovir alafenamide hemifumarate is obtained.

PCT Publication no. 2015/040640 discloses a process for the preparation of tenofovir alafenamide. Further, this publication discloses different salts of tenofovir alafenamide and their preparation.

PCT Publication no. 2015/079455 discloses a process for the racemization of undesired diastereomer of tenofovir alafenamide and its conversion to the desired diastereomer of tenofovir alafenamide.

C.N. Publication No. 104558036 discloses novel crystalline form of tenofovir alafenamide hemifumarate which is characterized by PXRD and DSC. This publication also disclosed various methods for the preparation of the novel crystalline form.

PCT Publication no. 2016/108205 disclosed amorphous tenofovir alafenamide hemifumarate.

PCT Publication no. 2016/205141 disclosed co-crystals, salts and crystalline forms of tenofovir alafenamide such as tenofovir alafenamide sesquifumarate and tenofovir alafenamide sesquifumarate solvates wherein the solvent is selected from isopropanol, methyl ethyl ketone, tetrahydrofuran and acetone. This publication further provided salts of tenofovir alafenamide such as oxalate, malonate, L-malate, saccharin, mucate, maleate, hydrochloride, ethanesulfonate, methanesulfonate, benzenesulfonate, sulfate and crystal forms thereof. This publication further disclosed the process for the preparation of said forms along with their characterization details.

C.N. Publication No. 105646584 disclosed crystal forms of tenofovir alafenamide fumarate such as Form A, Form B, Form C and Form D. This publication further disclosed the process for the preparation of said forms along with their characterization details.

PCT Publication no. 2017/037608 discloses novel solid forms of tenofovir alafenamide monofumarate; novel solid forms of tenofovir alafenamide hemifumarate and to processes for the preparation of tenofovir alafenamide hemifumarate.

Other processes have been reported in the art for the preparation of tenofovir alafenamide by preparing protected compounds, for example in WO 2015/161781 & WO 2015/161785, or use of chiral acid compounds for the diastereomer enrichment of tenofovir alafenamide, for example in WO 2015/107451; which require additional process steps of protection-deprotection or saltification-desaltification, which are uneconomical, and labor intensive and hence, not suitable on large scale.

Despite all prior advances, available methods for synthesizing tenofovir alafenamide or a pharmaceutically acceptable salt thereof remain labor intensive, and time consuming, hence not suitable on large scale. Further, the prior art methods lack efficient methods for the synthesis of tenofovir alafenamide or a pharmaceutically acceptable salt thereof in high diastereomeric purity without compromising time and cost.

Thus, there remains a need for a simple, cost effective, industrially feasible and scalable process for the synthesis of tenofovir alafenamide or a pharmaceutically acceptable salt thereof which is addressed by the present invention.

Further in order to improve the efficiency of the process for preparing tenofovir alafenamide or a pharmaceutically acceptable salt thereof, it is advantageous to have

intermediates which are readily prepared and are obtained in a high degree of purity. The present invention provides such an intermediate namely the monophenyl PMPA in crystalline forms.

On the other hand, the isolation of this synthesis intermediate in crystalline form is very advantageous, especially on an industrial scale, and contributes to obtaining the final product tenofovir alafenamide or a pharmaceutically acceptable salt thereof with high yield and purity. Thus according to one aspect, the present invention provides crystalline forms of monophenyl PMPA and their preparation process.

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal lattice. Discovering new polymorphic forms, solvates or co-crystals of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate forms that facilitate conversion to other solid-state forms. New polymorphic forms, solvates or co-crystals of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, better purity, improved dissolution profile, or improved shelf-life.

In view of the foregoing, it would be desirable to provide novel crystalline form of tenofovir alafenamide hemifumarate. Therefore, the present invention addresses the need in the art for pharmaceutically useful crystalline form of tenofovir alafenamide hemifumarate that may have improved physicochemical properties, such as a higher solubility and dissolution rate, desirable bioavailability, enhanced flow properties and enhanced stability.

Further, there is a need for methods to prepare such crystalline form of tenofovir alafenamide hemifumarate, which may provide higher polymorphic purity by providing an efficient, economic and reproducible process, particularly on large scale without need for the step of addition of seed crystals.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof. The present invention also provides crystalline forms of monophenyl PMPA, an important intermediate of tenofovir alafenamide and their preparation process.

The present invention also provides novel crystalline form of tenofovir alafenamide hemifumarate, processes for its preparation and pharmaceutical compositions containing the same.

In accordance with one embodiment, the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof.

In accordance with another embodiment, the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I;

comprising:

a) reacting PMPA of Formula II with phenol in presence of a base and a condensing agent in a suitable organic solvent selected from ethers, ketones, esters, aromatic hydrocarbons and mixtures thereof to obtain monophenyl PMPA of Formula III;

b) reacting the monophenyl PMPA of Formula III with a suitable chlorinating agent in the presence of a catalyst in a suitable organic solvent to obtain a compound of formula IV;

iv

c) reacting the compound of formula IV with L-alanine isopropyl ester or salt thereof of formula V

V

in presence of a suitable base to obtain tenofovir alafenamide;

d) purification of tenofovir alafenamide in a suitable organic solvent selected from the group consisting of alcohols, ethers and mixtures thereof; and

e) converting the tenofovir alafenamide of step d) in to pharmaceutically acceptable salts thereof of formula I.

In accordance with another embodiment, the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I; comprising:

a) reacting PMPA of Formula II with phenol in presence of a base and a condensing agent in a suitable organic solvent selected from ethers, ketones, esters, aromatic hydrocarbons and mixtures thereof to obtain monophenyl PMPA of Formula III; b) purifying the monophenyl PMPA of Formula III from a suitable organic solvent selected from ketone, alcohol, water and mixtures thereof; and

c) converting the monophenyl PMPA of Formula III in to tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I.

In accordance with another embodiment, the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I substantially free of (R,R,S)-diastereomer, comprising:

a) providing a solution or suspension of a mixture having (R,S,S)- & (R,R,S)- diastereomer of tenofovir alafenamide in a suitable organic solvent selected from the group consisting of alcohols, ethers, and mixtures thereof;

b) optionally cooling the step a) reaction mass;

c) optionally seeding with tenofovir alafenamide (R,S,S)-diastereomer;

d) recovering (R,S,S)-diastereomer of tenofovir alafenamide substantially free of

(R,R,S)-diastereomer; and

e) converting the (R,S,S)-diastereomer of tenofovir alafenamide substantially free of (R,R,S)-diastereomer in to pharmaceutically acceptable salts thereof of formula I.

In accordance with another embodiment, the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I substantially free of (R,R,S)-diastereomer; comprising:

a) reacting PMPA of Formula II with phenol in presence of a base and a condensing agent in a suitable organic solvent selected from ethers, ketones, esters, aromatic hydrocarbons and mixtures thereof to obtain monophenyl PMPA of Formula III; b) purifying the monophenyl PMPA of Formula III from a suitable organic solvent selected from ketone, alcohol, water and mixtures thereof;

c) reacting the monophenyl PMPA of Formula III with a suitable chlorinating agent in the presence of a catalyst in a suitable organic solvent to obtain a compound of formula IV;

d) reacting the compound of formula IV with L-alanine isopropyl ester or salt thereof of formula V in presence of a suitable base to obtain tenofovir alafenamide;

e) purifying the tenofovir alafenamide in a suitable organic solvent selected from the group consisting of alcohols, ethers and mixtures thereof to obtain (R,S,S)- diastereomer of tenofovir alafenamide; and

f) converting (R,S,S)-diastereomer of tenofovir alafenamide in to pharmaceutically acceptable salts thereof of formula I.

In accordance with another embodiment, the present invention provides crystalline form of monophenyl PMPA.

In accordance with another embodiment, the present invention provides crystalline Form of monophenyl PMPA, hereinafter designated as crystalline Form I.

In accordance with another embodiment, the present invention provides crystalline Form I of monophenyl PMPA characterized by powder X-ray diffraction pattern substantially in accordance with Figure 1.

In accordance with another embodiment, the present invention provides crystalline Form I of monophenyl PMPA characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2.

In accordance with another embodiment, the present invention provides crystalline Form I of monophenyl PMPA characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 3.

In accordance with another embodiment, the present invention provides a process for the preparation of Form I of monophenyl PMPA comprising:

a) slurrying monophenyl PMPA in a suitable solvent selected from ketones, alcohols, water and mixtures thereof;

b) filtering the step a) reaction mass; and

c) drying at a temperature of about 70°C to about 100°C.

In accordance with another embodiment, the present invention provides crystalline Form of monophenyl PMPA, hereinafter designated as crystalline form II.

In accordance with another embodiment, the present invention provides crystalline Form II of monophenyl PMPA characterized by powder X-ray diffraction pattern substantially in accordance with Figure 4.

In accordance with another embodiment, the present invention provides crystalline Form II of monophenyl PMPA characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 5.

In accordance with another embodiment, the present invention provides crystalline Form II of monophenyl PMPA characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 6.

In accordance with another embodiment, the present invention provides a process for the preparation of Form II of monophenyl PMPA, comprising:

a) slurrying monophenyl PMPA in a suitable solvent selected from the group consisting of alcohols, ketones, water and mixtures thereof; and

b) Isolating Form II of monophenyl PMPA.

In accordance with another embodiment, the present invention provides crystalline Form of monophenyl PMPA, hereinafter designated as crystalline form III.

In accordance with another embodiment, the present invention provides crystalline Form III of monophenyl PMPA characterized by powder X-ray diffraction pattern substantially in accordance with Figure 7.

In accordance with another embodiment, the present invention provides crystalline Form III of monophenyl PMPA characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 8.

In accordance with another embodiment, the present invention provides crystalline Form III of monophenyl PMPA characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 9.

In accordance with another embodiment, the present invention provides a process for the preparation of Form III of monophenyl PMPA, comprising:

a) slurrying monophenyl PMPA in a suitable solvent selected from alcohols, water and mixtures thereof;

b) filtering the step a) reaction mass; and

c) drying at a temperature of about 50°C to about 75°C.

In accordance with another embodiment, the present invention provides crystalline forms of monophenyl PMPA and the use thereof for preparing the tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula (I).

In accordance with another embodiment, the present invention provides novel crystalline form of tenofovir alafenamide hemifumarate.

In accordance with another embodiment, the present invention provides crystalline form of tenofovir alafenamide hemifumarate characterized by a PXRD pattern comprising peaks at about 5.2° and 7.4° ± 0.2° 2Θ.

In accordance with another embodiment, the present invention provides crystalline form of tenofovir alafenamide hemifumarate characterized by a PXRD pattern having peaks at about: 5.18, 7.37, 9.69, 10.33, 10.90, 11.18, 11.89, 12.22, 12.82, 14.28, 14.82, 15.25, 16.70, 17.48, 18.87, 19.43, 20.48, 21.20, 21.69, 22.30, 22.83, 23.42, 24.31, 25.33, 26.49, 28.87, 29.92, 31.80 and 35.62° ± 0.2° 2Θ.

In accordance with another embodiment, the present invention provides crystalline form of tenofovir alafenamide hemifumarate characterized by powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 13.

In accordance with another embodiment, the present invention provides crystalline form of tenofovir alafenamide hemifumarate characterized by differential scanning calorimetry (DSC) curve having an onset endothermic peak at about 103°C.

In accordance with another embodiment, the present invention provides crystalline form of tenofovir alafenamide hemifumarate characterized by differential scanning calorimetry (DSC) curve having onset endothermic peaks at about 103°C and 130°C.

In accordance with another embodiment, the present invention provides crystalline form of tenofovir alafenamide hemifumarate characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 14.

In accordance with another embodiment, the present invention provides a process for the preparation of crystalline form of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution or suspension of tenofovir alafenamide and fumaric acid in a first organic solvent;

b) adding a second organic solvent to the step a) reaction mass or vice versa; and c) isolating the crystalline form of tenofovir alafenamide hemifumarate.

In accordance with another embodiment, the present invention provides a process for the preparation of crystalline form of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution or suspension of tenofovir alafenamide and fumaric acid in a first organic solvent;

b) optionally heating the solution or suspension at a temperature of about ambient to about reflux temperature;

c) cooling to a temperature of about -10°C to about 40°C;

d) adding a second organic solvent or vice versa; and

e) isolating the crystalline form of tenofovir alafenamide hemifumarate.

In accordance with another embodiment, the present invention provides a process for the preparation of crystalline form of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution or suspension of tenofovir alafenamide hemifumarate in a first organic solvent;

b) adding a second organic solvent to the step a) reaction mass or vice versa; and c) isolating the crystalline form of tenofovir alafenamide hemifumarate.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution or suspension of tenofovir alafenamide in water at a temperature of ambient to reflux temperature;

b) adding fumaric acid to the step a) solution or suspension, or vice versa; and c) cooling the step b) solution to less than 10°C; and

d) filtering the crystalline form of tenofovir alafenamide hemifumarate.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution or suspension of tenofovir alafenamide hemifumarate in water at a temperature of ambient to reflux temperature;

b) cooling the step a) solution to less than 10°C; and

c) filtering the crystalline form of tenofovir alafenamide hemifumarate.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising tenofovir alafenamide or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising crystalline form of tenofovir alafenamide hemifumarate described above and at least one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS :

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline Form

I of monophenyl PMPA.

Figure 2 is the characteristic DSC thermogram of crystalline Form I of monophenyl PMPA.

Figure 3 is the characteristic TGA curve of crystalline Form I of monophenyl PMPA.

Figure 4 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline Form

II of monophenyl PMPA.

Figure 5 is the characteristic DSC thermogram of crystalline Form II of monophenyl PMPA.

Figure 6 is the characteristic TGA curve of crystalline Form II of monophenyl PMPA.

Figure 7 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline Form III of monophenyl PMPA.

Figure 8 is the characteristic DSC thermogram of crystalline Form III of monophenyl PMPA.

Figure 9 is the characteristic TGA curve of crystalline Form III of monophenyl PMPA.

Figure 10 is the characteristic powder X-ray diffraction (PXRD) pattern of tenofovir alafenamide, obtained according to Example: 4.

Figure 11 is the characteristic DSC thermogram of tenofovir alafenamide, obtained according to Example: 4.

Figure 12 is the characteristic TGA curve of tenofovir alafenamide, obtained according to Example: 4.

Figure 13 is the characteristic PXRD pattern of crystalline form of tenofovir alafenamide hemifumarate.

Figure 14 is the characteristic TGA curve of crystalline form of tenofovir alafenamide hemifumarate.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof.

In accordance with another embodiment, the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I;

comprising:

a) reacting PMPA of Formula II with phenol in presence of a base and a condensing agent in a suitable organic solvent selected from ethers, ketones, esters, aromatic hydrocarbons and mixtures thereof to obtain monophenyl PMPA of Formula III;

b) reacting the monophenyl PMPA of Formula III with a suitable chlorinating agent in the presence of a catalyst in a suitable organic solvent to obtain a compound of formula IV;

IV

c) reacting the compound of formula IV with L-alanine isopropyl ester or salt thereof of formula V

V

in presence of a suitable base to obtain tenofovir alafenamide;

d) purifying the tenofovir alafenamide in a suitable organic solvent selected from the group consisting of alcohols, ethers, and mixtures thereof; and

e) converting the tenofovir alafenamide of step d) in to pharmaceutically acceptable salts thereof of formula I.

In a preferred embodiment, the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I substantially free of (R,R,S)-diastereomer; comprising:

a) reacting PMPA of Formula II with phenol in presence of a base and a condensing agent in a suitable organic solvent selected from ethers, ketones, esters, aromatic hydrocarbons and mixtures thereof to obtain monophenyl PMPA of Formula III; b) purifying the monophenyl PMPA of Formula III from a suitable organic solvent selected from ketone, alcohol, water and mixtures thereof;

c) reacting the monophenyl PMPA of Formula III with a suitable chlorinating agent in the presence of a catalyst in a suitable organic solvent to obtain a compound of formula IV;

d) reacting the compound of formula IV with L-alanine isopropyl ester or salt thereof of formula V in presence of a suitable base to obtain tenofovir alafenamide;

e) purifying the tenofovir alafenamide in a suitable organic solvent selected from the group consisting of alcohols, ethers and mixtures thereof to obtain (R,S,S)- diastereomer of tenofovir alafenamide; and

f) converting (R,S,S)-diastereomer of tenofovir alafenamide in to pharmaceutically acceptable salts thereof of formula I.

The starting compound PMPA of Formula II is known in the art and can be prepared by any known methods, for example starting compound of Formula II may be synthesized according to U.S. patent No's: 4,808,716; 5,922,695 and 6,653,296.

The step a) of the foregoing process include reacting PMPA of Formula II with phenol in presence of a base and a condensing agent in a suitable organic solvent selected from ethers, ketones, esters, aromatic hydrocarbons and mixtures thereof.

Examples of bases include but are not limited to primary, secondary or tertiary amines such as methyl amine, triethyl amine, diisopropyl amine and the like, preferably triethyl amine.

Examples of suitable organic solvent include but are not limited to ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tertiary butyl ether, cyclopentyl methyl ether and the like; ketones such as acetone, methyl isobutyl ketone and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tert butyl acetate and the like; aromatic hydrocarbon solvents such as toluene, xylene and the like; and mixtures thereof; preferably cyclopentyl methyl ether, methyl isobutyl ketone, toluene, n-butyl acetate and mixtures thereof.

Suitable condensing agents include but are not limited to N, N'-dicyclohexylcarbodiimide (DCC), l-ethyl-3-[3-dimethylaminopropyl]-carbodiimide (EDC), 1, 1-carbonyl diimidazole (CDI) and the like, preferably Ν,Ν'-dicyclohexylcarbodiimide (DCC).

The reaction may typically be carried out at a suitable temperature such as 40°C to reflux temperature of the solvent. Preferably, the reaction temperature is about 60°C to about 140°C. The reaction is allowed to stir for a period of time from about 5 hrs to until completion of the reaction, preferably 8 - 26 hrs.

After completion of the reaction, the resultant reaction mass may be cooled to 30°C to 60°C, diluted with water and the by-products formed, if any, during the reaction were separated by filtration. Then, the filtrate may be basified with a suitable base to adjust pH of the solution to about 9 to 12. The suitable bases include but are not limited to sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate and the like; preferably sodium hydroxide and is in the aqueous solution medium. Then, the resultant product containing aqueous layer may be separated and pH may be readjusted back to about 2 to 5 with an acid such as hydrochloric acid and the like to precipitate out the monophenyl PMPA of Formula III. Isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like. Optionally seeding with monophenyl PMPA of formula III may be done prior to isolation of the product. Alternatively, the aqueous layer containing the product may be treated with a suitable solvent such as acetone to form slurry and the resulting product may be isolated.

The resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 50°C to about 110°C, preferably from about 55°C to about 75°C.

After isolation of monophenyl PMPA of Formula III, additional purification may be carried out by process such as crystallization or solvent slurry techniques.

In another embodiment, the present invention provides a process for purification of monophenyl PMPA of Formula III, comprising treating monophenyl PMPA of Formula III with a suitable organic solvent selected from ketone, alcohol, water and mixtures thereof and isolating the pure monophenyl PMPA of Formula III.

Suitable organic solvent for purification of monophenyl PMPA of formula III include ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like; alcohols such as methanol, ethanol, isopropanol, n- propanol, n-butanol, isobutanol, tert-butanol and the like; water and mixtures thereof; preferably acetone, methanol, ethanol, isopropanol, tert-butanol, water and mixtures thereof.

The step of treating monophenyl PMPA with a suitable organic solvent involves slurring the contents at a temperature of about 20°C to about reflux temperature of the solvent, preferably at about 25 °C to about 110°C for about 30 minutes to about 6 hours.

Isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like and the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 50°C to about 110°C, preferably from about 60°C to about 100°C.

Step c) of the aforementioned process involves reaction of monophenyl PMPA of formula III with a chlorinating agent such as thionyl chloride, phosphorous oxychloride, oxalyl chloride, phosphorous pentachloride and the like, preferably thionyl chloride, to obtain a reactive derivative of formula IV, which is then reacted with L-alanine isopropyl ester or salt thereof in presence of a suitable base in an organic solvent to obtain tenofovir alafenamide.

Examples of suitable catalyst for use in step c) includes but are not limited to N,N-dimethyl formamide or bases such as primary, secondary or tertiary amine bases such as diethyl amine, diisopropyl amine, triethyl amine, piperidine, morpholine, and the like, preferably Ν,Ν-dimethyl formamide or triethyl amine.

The organic solvent for use in step c) includes but are not limited to ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane and the like; ketones such as acetone, methyl isobutyl ketone and the like; halogenated solvents such as dichloromethane, chloroform and the like; hydrocarbon solvents such as cyclohexane, methyl cyclohexane and the like; aromatic hydrocarbon solvents such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like and mixtures thereof, preferably toluene, acetonitrile and mixtures thereof.

The chlorination reaction is typically carried out at a suitable temperature such as 60°C to 130°C. Preferably the reaction temperature is about 60°C to about 90°C and is allowed to stir for a period of time from about 30 mins until completion of the reaction, preferably 5-40 hrs.

The reported process for the preparation of compound of formula IV in high diastereomeric purity involved preparation of compound of formula IV that are at least about 90% diastereomerically pure with >97% conversion as a prerequisite in order to obtain tenofovir alafenamide in high diastereomeric purity that took about 48 to 96 hrs for reaction completion. The disadvantages associated with this process are, it requires undue monitoring of reaction, increased reaction times, preset targets of reaction conversion and diastereomeric purity, which not only increases process cost, but is cumbersome on large scale.

In contrast, the chlorination reaction of the present invention when carried out in the presence of catalyst such as N, N-dimethyl formamide or triethyl amine reduced the reaction time drastically to about 12-36 hrs from 48-96 hrs, thus providing a process which affords cost effective route which can be advantageously practiced on an industrial scale and eliminates the requirement of undue monitoring of the reaction. Further, the present invention is so effective that it does not require the intermediate compound IV to be obtained in high diastereomeric purity, instead compound IV obtained in any diastereomeric ratio may be made and later purified by the process of the present invention.

The resulting compound of formula IV is then reacted with L-alanine isopropyl ester or salt thereof of formula V in presence of a suitable base in an organic solvent to obtain tenofovir alafenamide of formula I. Alternatively, the reaction mass may be distilled under vacuum and co-distilled with solvent such as toluene to obtain a residue which is taken up in an organic solvent and reacted with L-alanine isopropyl ester or salt thereof of formula V in presence of a suitable base.

Salts of compound of formula V include but not limited to hydrochloride, sulfate, methanesulfonate, paratoluene sulfonate, benzenesulfonate and the like, preferably hydrochloride.

Examples of suitable base includes but are not limited to primary, secondary or tertiary amine such as triethyl amine, diisopropyl amine, and the like, preferably triethyl amine.

In one embodiment, compound of formula IV is reacted with L-alanine isopropyl ester hydrochloride salt of formula V in presence of a triethyl amine to obtain tenofovir alafenamide of formula I.

The suitable organic solvent used herein for the reaction of compound of formula IV with L-alanine isopropyl ester, includes but are not limited to ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane and the like; ketones such as acetone, methyl isobutyl ketone and the like; halogenated solvents such as dichlorome thane, chloroform and the like; amides such as dimethyl formamide and the like; hydrocarbon solvents such as cyclohexane, methyl cyclohexane and the like; aromatic hydrocarbon solvents such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like and mixtures thereof. Preferably, the solvent is dichloromethane, toluene and mixtures thereof.

Typically, the reaction is carried out at a suitable temperature such as about -50°C to about 50°C. Preferably the reaction temperature is about -40°C to about 40°C and is allowed to stir for a period of time from about 30 mins to until completion of the reaction, preferably 30 mins to 10 hrs.

Then, the resultant tenofovir alafenamide of formula I can be isolated by known techniques, for example, the organic layer may be concentrated to get residue by any method known in the art at the end of the reaction, such as distillation, evaporation, rotational drying (such as with the Buchi Rotavapor), preferably distillation under vacuum. After isolation of tenofovir alafenamide, additional purification may be carried out by process such as crystallization, solvent slurry techniques or any chromatography techniques.

The diastereomeric purity of tenofovir alafenamide can be further increased by crystallizing the tenofovir alafenamide from suitable organic solvent. The resulting diastereomerically pure tenofovir alafenamide can then be used to prepare tenofovir alafenamide salts thereof having low levels of (R,R,S)-diastereomer.

Step e) of the foregoing process involves purification of tenofovir alafenamide in a solvent selected from the group consisting of alcohols, ethers and mixtures thereof.

The alcohols include, but are not limited to methanol, ethanol, isopropanol, n- propanol, n-butanol, isobutanol and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; and mixtures thereof, preferably isopropanol, methyl tertiary butyl ether and mixtures thereof.

Typically, a solution or suspension of tenofovir alafenamide in the organic solvent is prepared and stirred at a temperature of about 20°C to about reflux temperature, if necessary, cooled to a temperature of about 20°C to about 40°C and isolated the product.

Isolation of tenofovir alafenamide may be carried out by crystallization, solvent precipitation, and concentration by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like. Preferably, the reaction may be cooled to a temperature from about 40°C or less such that the tenofovir alafenamide can be recovered by conventional techniques, for example filtration.

The resultant tenofovir alafenamide may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 25°C to about 100°C.

In another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I substantially free of (R,R,S)-diastereomer, comprising:

a) providing a solution or suspension of a mixture having (R,S,S) & (R,R,S)- diastereomers of tenofovir alafenamide in a suitable organic solvent selected from the group consisting of alcohols, ethers and mixtures thereof;

b) optionally cooling the step a) reaction mass;

c) optionally seeding with tenofovir alafenamide (R,S,S)-diastereomer;

d) recovering (R,S,S)-diastereomer of tenofovir alafenamide substantially free of (R,R,S)-diastereomer; and

e) converting the (R,S,S)-diastereomer of tenofovir alafenamide substantially free of (R,R,S)-diastereomer in to pharmaceutically acceptable salts thereof of formula I.

Mixture having (R,S,S)- & (R,R,S)-diastereomers of tenofovir alafenamide for use in step a) of the foregoing process may be obtained according to the process of the present invention or according to the processes reported in the art.

As used herein, the term "mixture having (R,S,S)- & (R,R,S)-diastereomer", relates to any quantity of (R,R,S)-diastereomer present in the mixture.

The alcohols include, but are not limited to methanol, ethanol, isopropanol, n- propanol, n-butanol, isobutanol and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; and mixtures thereof, preferably isopropanol, methyl tertiary butyl ether and mixtures thereof.

Mixture having (R,S,S)- & (R,R,S)-diastereomers of tenofovir alafenamide is stirred in the suitable solvent at a temperature of about 20°C to about reflux temperature, preferably about 25 °C to about 70°C.

Isolation of (R,S,S)- diastereomer of tenofovir alafenamide can be carried out by crystallization, solvent precipitation, concentration by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like.

Optionally, the reaction mass may be cooled to a temperature from about 40°C or less, if necessary by adding seed crystals of (R,S,S)- diastereomer such that the tenofovir alafenamide can be recovered by conventional techniques, for example filtration.

In accordance with one embodiment, tenofovir alafenamide is purified from a mixture of isopropanol and methyl tertiary butyl ether.

Preparation of tenofovir alafenamide according to the reported processes does not result in tenofovir alafenamide with high diastereomeric purity and involves preparation of intermediate compound of formula IV in at least about >90% diastereomeric purity as a prerequisite to obtain tenofovir alafenamide with high diastereomeric purity. Further, the reported processes involve crystallization induced dynamic resolution or use of chiral acids for enhancing the diastereomeric purity or use of chromatographic techniques for separation of diastereomers which not only adds extra steps, but are tedious, labor intensive and not economical on large scale.

CLAIMS:

Claim 1 : An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I;

comprising:

a) reacting PMPA of Formula II with phenol in presence of a base and a condensing agent in a suitable organic solvent selected from ethers, ketones, esters, aromatic hydroc f to obtain monophenyl PMPA of Formula III;

b) reacting the monophenyl PMPA of Formula III with a suitable chlorinating agent in the presence of a catalyst in a suitable organic solvent to obtain a compound of formula IV;

IV

c) reacting the compound of formula IV with L-alanine isopropyl ester or salt thereof of formula V

V

in presence of a suitable base to obtain tenofovir alafenamide;

d) purifying the tenofovir alafenamide in a suitable organic solvent selected from the group consisting of alcohols, ethers, and mixtures thereof; and

e) converting the tenofovir alafenamide of step d) in to pharmaceutically acceptable salts thereof of formula I.

Claim 2: The process of claim 1, wherein the solvent in step a) is selected from the group comprising tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tertiary butyl ether, cyclopentyl methyl ether, acetone, methyl isobutyl ketone, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tert butyl acetate, toluene, xylene and mixtures thereof.

Claim 3 : The process of claim 2, wherein the solvent is selected from the group consisting of cyclopentyl methyl ether, methyl isobutyl ketone, toluene, n-butyl acetate and mixtures thereof.

Claim 4: The process of claim 1, wherein the base in step a) is selected from the group consisting of methyl amine, triethyl amine, diisopropyl amine and mixtures thereof.

Claim 5 : The process of claim 1 , wherein the condensing agent in step a) is selected from the group consisting of N, N'-dicyclohexylcarbodiimide (DCC), l-ethyl-3-[3-dimethylaminopropyl]-carbodiimide (EDC), 1,1-carbonyl diimidazole (CD I).

Claim 6: The process of claim 1, wherein the base is triethyl amine and the condensing agent is N, N'-dicyclohexylcarbodiimide (DCC).

Claim 7: The process of claim 1, wherein the step a) further comprises purifying the monophenyl PMPA of Formula III from a suitable organic solvent selected from ketone, alcohol, water and mixtures thereof.

Claim 8: The process of claim 7, wherein the suitable organic solvent is selected from the group comprising acetone, methyl isobutyl ketone, methyl ethyl ketone; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, water and mixtures thereof.

Claim 9: The process of claim 7, wherein the suitable organic solvent is selected from the group consisting of acetone, methanol, ethanol, isopropanol, tert-butanol, water and mixtures thereof.

Claim 10: The process of claim 1, wherein the suitable catalyst of step b) is selected from the group comprising of Ν,Ν-dimethyl formamide, diethyl amine, diisopropyl amine, triethyl amine, piperidine, morpholine.

Claim 11 : The process of claim 1 , wherein the suitable chlorinating agent is selected form the group consisting of thionyl chloride, phosphorous oxychloride, oxalyl chloride, phosphorous pentachloride.

Claim 12: The process of claim 1, wherein the suitable catalyst of step b) is selected from Ν,Ν-dimethyl formamide or triethyl amine.

Claim 13: The process of claim 1, wherein salts of compound of formula V is selected from the group comprising of hydrochloride, sulfate, methanesulfonate, paratoluene sulfonate or benzenesulfonate.

Claim 14: The process of claim 1, wherein the base in step c) is selected from the group consisting of triethyl amine or diisopropyl amine.

Claim 15: The process of claim 1, wherein the suitable solvent of step d) is selected from the group comprising methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof.

Claim 16: The process of claim 1, wherein suitable solvent of step d) is selected from isopropanol, methyl tertiary butyl ether and mixtures thereof.

Claim 17: The process of claim 1, wherein suitable solvent of step d) is a mixture of isopropanol and methyl tertiary butyl ether.

Claim 18: A process for preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I substantially free of (R,R,S)-diastereomer, comprising:

a) providing a solution or suspension of a mixture having (R,S,S)- & (R,R,S)- diastereomers of tenofovir alafenamide in a suitable organic solvent selected from the group consisting of alcohols, ethers and mixtures thereof;

b) optionally cooling the step a) reaction mass;

c) optionally seeding with tenofovir alafenamide (R,S,S)-diastereomer;

d) recovering (R,S,S)-diastereomer of tenofovir alafenamide substantially free of (R,R,S)-diastereomer; and

e) converting the (R,S,S)-diastereomer of tenofovir alafenamide substantially free of (R,R,S)-diastereomer in to pharmaceutically acceptable salts thereof of formula I.

Claim 19: The process of claim 18, wherein the suitable organic solvent is selected from the group comprising of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof.

Claim 20: The process of claim 18, wherein the suitable organic solvent is a mixture of isopropanol and methyl tertiary butyl ether.

Claim 21: The process of claim 18, wherein the solution or suspension is formed at a temperature of about 20°C to about reflux temperature.

Claim 22: The process of claim 18, wherein recovery of (R,S,S)-diastereomer of tenofovir alafenamide of step d) is carried out by crystallization, solvent precipitation, concentration by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum or agitated thin film evaporator (ATFE).

Claim 23: Crystalline form I of monophenyl PMPA characterized by an X-ray powder diffraction pattern (XRPD) substantially in accordance with Figure 01.

Claim 24: A process for the preparation of Form I of monophenyl PMPA comprising: a) slurrying monophenyl PMPA in a suitable solvent selected from alcohols, ketones, water and mixtures thereof;

b) filtering the step a) reaction mass; and

c) drying at a temperature of about 70°C to about 100°C.

Claim 25: The process of claim 24, wherein the step a) reaction is carried out at a temperature of about 25°C to about 50°C.

Claim 26: The process of claim 24, wherein the suitable solvent is selected from the group comprising methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, acetone, methyl isobutyl ketone, methyl ethyl ketone and mixtures thereof.

Claim 27: The process of claim 24, wherein the suitable solvent is a mixture of acetone and water.

Claim 28: Crystalline form II of monophenyl PMPA characterized by an X-ray powder diffraction pattern (XRPD) substantially in accordance with Figure 04.

Claim 29: A process for the preparation of Form II of monophenyl PMPA, comprising:

a) slurrying monophenyl PMPA in a suitable solvent selected from the group consisting of alcohols, ketones, water and mixtures thereof; and

b) Isolating Form II of monophenyl PMPA.

Claim 30: The process of claim 29, wherein the suitable solvent is selected from the group comprising ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone and mixtures thereof.

Claim 31: The process of claim 29, wherein the suitable solvent is selected from the group comprising acetone, isopropanol, ethanol, t-butanol, water and mixtures thereof.

Claim 32: The process of claim 29, wherein the step a) process is carried out at a temperature of about 25°C to about 100°C.

Claim 33: The process of claim 29, wherein step b) further comprises drying at a temperature from about 40°C to about 90°C.

Claim 34: The process of claim 29, wherein step b) further comprises drying at a temperature from about 50°C to about 80 °C.

Claim 35: Crystalline Form III of monophenyl PMPA characterized by an X-ray powder diffraction pattern (XRPD) substantially in accordance with Figure 07.

Claim 36: A process for the preparation of Form III of monophenyl PMPA, comprising:

a) slurrying monophenyl PMPA in a suitable solvent selected from alcohols, water and mixtures thereof;

b) filtering the step a) reaction mass; and

c) drying at a temperature of about 50°C to about 75 °C.

Claim 37: The process of claim 36, wherein the suitable solvent is selected from the group comprising methanol, n-propanol, n-butanol, iso-butanol and mixtures thereof.

Claim 38: The process of claim 36, wherein the suitable solvent is a mixture of methanol and water.

Claim 39: The process of claim 36, wherein step a) is carried out at a temperature of about 10°C to about 50°C.

Claim 40: The process of claim 36, wherein the drying is carried out at a temperature from about 50°C to about 75°C.

Claim 41: A crystalline form of tenofovir alafenamide hemifumarate characterized by a PXRD pattern comprising peaks at about 5.2° and 7.4° ± 0.2° 2Θ.

Claim 42: A crystalline form of tenofovir alafenamide hemifumarate of claim 39 further characterized by powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 13.

Claim 43: A process for the preparation of crystalline form of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution or suspension of tenofovir alafenamide and fumaric acid in a first organic solvent,

b) optionally heating the solution or suspension at a temperature of about ambient to about reflux temperature,

c) cooling to a temperature of about -10°C to about 40°C;

d) adding a second organic solvent or vice versa; and

e) isolating the crystalline form of tenofovir alafenamide hemifumarate.

Claim 44: The process of claim 43, wherein the first organic solvent is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, formamide, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, N-methyl-2-pyrrolidone and mixtures thereof.

Claim 45: The process of claim 43, wherein the first organic solvent is selected from n-pentanol, n-butanol or N-methyl-2-pyrrolidone.

Claim 46: The process of claim 43, wherein the step a) reaction is heated at about 40°C to about 100°C.

Claim 47: The process of claim 43, wherein the second organic solvent is selected from n-heptane, cyclohexane or tertiary butyl acetate.

Claim 48: A process for the preparation of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution or suspension of tenofovir alafenamide in water at a temperature of ambient to reflux temperature;

b) adding fumaric acid to the step a) solution or suspension, or vice versa; and c) cooling the step b) solution to less than 10°C; and

d) filtering the crystalline form of tenofovir alafenamide hemifumarate.

Claim 49: The process of claim 48, wherein the fumaric acid is added at temperature of about 40°C to about 100°C.

Claim 50: The process of claim 48, wherein the step c) is carried out by cooling the step b) solution directly to a temperature of less than about 10°C.

Claim 51: The process of claim 50, wherein step c) is carried out by cooling the step b) solution first to not less than 20°C then followed by further cooling to less than about 10°C.