WO2017221189A1

WO2017221189A1 - An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof

Info

Publication number: WO2017221189A1
Application number: PCT/IB2017/053724
Authority: WO
Inventors: Ravindra Babu Bollu; Veera Venkata Krishna Kishore Jammula; Narendra Babu TALLURI; Lakshmana Rao NAMBURU; Chinnapotuluraiah CHIRRA; Ram Thaimattam; Venkata Sunil Kumar Indukuri
Original assignee: Laurus Labs Limited
Priority date: 2016-06-22
Filing date: 2017-06-22
Publication date: 2017-12-28

Abstract

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

Description

"AN IMPROVED PROCESS FOR THE PREPARATION OF TENOFOVIR ALAFENAMIDE OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF" PRIORITY

This application claims the benefit under Indian Provisional Application No(s). 201641021377 filed on 22^nd June 2016 entitled "An improved process for the preparation of Tenofovir alafenamide or pharmaceutically acceptable salts thereof and 201641021369 filed on 22^nd June 2016 entitled "Crystalline form of tenofovir alafenamide hemifumarate, process for its preparation and pharmaceutical compositions thereof; the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

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;

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.

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.

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.

comprising:

IV

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

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:

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. The present invention is an improvement to currently known processes. It provides an alternate/better method to obtain high diastereomeric purity tenofovir alafenamide by further crystallizing the tenofovir alafenamide from a mixture of isopropanol and methyl tertiary butyl ether. Unexpectedly, tenofovir alafenamide having high diastereomeric purity was obtained even when the intermediate compound of formula IV is obtained in 45-85% diastereomeric purity, by purification of tenofovir alafenamide from a mixture of isopropanol and methyl tertiary butyl ether, without the need for undue monitoring of reaction conditions and preset targets and laborious techniques.

The present invention provides tenofovir alafenamide as obtained by the process described herein is substantially free of (R,R,S)-diastereomer.

The present invention provides tenofovir alafenamide as obtained by the process described herein, having diastereomeric purity of at least about 98% as measured by HPLC, preferably at least about 99% as measured by HPLC, more preferably at least about 99.5% as measured by HPLC.

As used herein, the term "substantially free" refers to tenofovir alafenamide having less than the about 1% of (R,R,S)-diastereomer as measured by HPLC, preferably less than 0.8% of (R,R,S)-diastereomer as measured by HPLC.

In another embodiment, tenofovir alafenamide obtained by the present invention is converted to the pharmaceutically acceptable salts thereof, for e.g. tenofovir alafenamide monofumarate or hemifumarate according to processes known in the art.

Tenofovir alafenamide thus formed may contain substantial amounts of individual impurities such as PMPA of Formula II, monophenyl PMPA of formula III, PMPA anhydrate of formula VI and/or any unknown impurity in the range of about 0.1-1.5% which needs to be removed by purification in order to meet regulatory requirements.

VI

Hence, it is an object of the present invention to provide a process for the preparation of substantially pure tenofovir alafenamide comprising purification of tenofovir alafenamide from water.

Typically the purification process is carried out by treating tenofovir alafenamide with water and the reaction mass may be further heated to a temperature of 30°C to reflux temperature, preferably 40°C to about 60°C and stirred over a period of 30 min to 4 hours. Then the resulting reaction mass can be cooled to a temperature of about 20°C to about 50°C and stirred for a period of time to recover highly pure tenofovir alafenamide by conventional techniques, for example by filtration and the resultant product may optionally be further dried by methods known in the art.

In another embodiment, the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof having less than 0.1% by wt, as measured by HPLC of PMPA of Formula II, monophenyl PMPA of formula III, PMPA anhydrate of formula VI and/or any other unknown impurity, comprising preparing the tenofovir alafenamide by process described as above and converting the same in to tenofovir alafenamide or pharmaceutically acceptable salts thereof. In another embodiment, the present invention provides crystalline forms of monophenyl PMPA of formula III ("monophenyl PMPA) which is an important intermediate of tenofovir alafenamide.

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

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

In 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 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 another embodiment, the present invention provides crystalline Form I of monophenyl PMPA characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 1; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2; and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 3.

In 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 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.

Step a) of the foregoing process involves slurrying the monophenyl PMPA in a suitable solvent selected from alcohols, ketones, water and mixtures thereof at a temperature of about 25°C to about 50°C, preferably 25°C to about 35°C, for a sufficient period of time of about 30 minutes to about 24 hours.

The alcohols include, but are not limited to methanol, ethanol, isopropanol, n- propanol, n- butanol, isobutanol and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; and mixtures thereof. Preferably, the suitable solvent for slurrying is selected from acetone, water and mixtures thereof. Form I of monophenyl PMPA can be isolated by filtering the resultant reaction mass followed by drying the solids under vacuum at about 70°C to about 100°C. 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.

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 crystalline Form II of monophenyl PMPA characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 4; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 5; and/or 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:

b) Isolating Form II of monophenyl PMPA.

The alcohols include, but are not limited to ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; and mixtures thereof; preferably acetone, ethanol, isopropanol, tert butanol, water and mixtures thereof.

Typically, the step a) process is carried out at a temperature of about 25 °C to about reflux temperature, preferably 25 °C to about 110°C, for a sufficient period of time of about 30 minutes to about 24 hours.

Isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like. 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 40°C to about 90°C, preferably from about 50°C to about 85°C. 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 a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 9. In accordance with another embodiment, the present invention provides crystalline Form III of monophenyl PMPA characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 7; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 8; and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 9.

b) filtering the step a) reaction mass; and

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

Step a) involves slurrying the monophenyl PMPA in suitable solvent selected from alcohols; water and mixtures thereof. Suitable alcohol solvent include but are not limited to methanol, n-propanol, n-butanol, iso-butanol and the like; preferably, methanol, water and mixtures thereof.

Typically the slurrying step may be accomplished by stirring at a temperature of about 10°C to about 50°C, preferably at 25°C to about 35°C for a period of time from about 30 mins to about 24 hrs.

The resultant product may be isolated by filtering followed by drying the solids. 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 75°C, preferably from about 60°C to about 65°C.

In another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide comprising converting the crystalline forms of monophenyl PMPA as described herein before in to tenofovir alafenamide. For instance, the process may comprises reacting a crystal form of monophenyl PMPA as described herein with L- alanine isopropyl ester or salt thereof of formula V to form tenofovir alafenamide or pharmaceutically acceptable salts thereof of formula I by any process known in the art or by the process as disclosed in the present invention.

In another embodiment, the present invention provides a pharmaceutical composition comprising tenofovir alafenamide or pharmaceutically acceptable salts thereof obtained by the process of the present invention and at least one or more pharmaceutically acceptable excipients.

In accordance with one embodiment, the present invention provides novel crystalline form of tenofovir alafenamide hemifumarate, processes for its preparation and pharmaceutical compositions containing the same.

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 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 thermogravimetric analysis (TGA) substantially in accordance with Figure 14.

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

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.

The starting tenofovir alafenamide used in the present invention is known in the art and can be synthesized by any known methods, for example starting compound may be obtained by chromatography fractions according to U.S. patent No's 7,390,791; 8,664,386; PCT Publication No's. 2015/040640 and 2015/107451. Alternatively, the starting tenofovir alafenamide may be obtained as a solution directly from a reaction mixture in which tenofovir alafenamide is formed and used as such without isolation.

The step a) of providing a solution or suspension includes combining tenofovir alafenamide with a first organic solvent at a suitable temperature and adding fumaric acid to the resulting solution or suspension; or combining fumaric acid with first organic solvent and adding tenofovir alafenamide to the resulting solution or suspension. Alternatively, the mixture may be formed by adding tenofovir alafenamide and fumaric acid at the same time in to the first organic solvent. Further, fumaric acid is added either as solid in a single lot or slowly in multiple lots or as a solution in first organic solvent by drop wise addition.

Examples of first organic solvent for use in step a) of the foregoing process includes but are not limited to alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol and the like; amides such as formamide, N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, and mixtures thereof; preferably n-pentanol, n-butanol, or N-methyl-2-pyrrolidone. In another embodiment, step a) involves providing a solution or suspension of tenofovir alafenamide by direct use of a reaction mixture containing tenofovir alafenamide that is obtained in the course of its synthesis and that comprises a suitable first organic solvent. Step b) of the foregoing process may optionally include heating the step a) reaction mass to a temperature of ambient to about reflux temperature, preferably at about 40°C to about 100°C and stirring for a period of time from about 5 mins to about 10 hrs. Suitable temperature depends on the amount of tenofovir alafenamide and/or amount of solvent in the reaction mass.

Step c) of the foregoing process may include allowing the reaction mass obtained in step b) to gradually cool to a temperature of at least -10°C to about 40°C, preferably cooling the solution to about -5°C to about 30°C prior to addition of second organic solvent. Then, a second organic solvent is added to the reaction mass for precipitating out the crystalline form of tenofovir alafenamide hemifumarate.

The suitable second organic solvent includes but are not limited to aliphatic hydrocarbons, such as pentane, hexane, heptane, and the like; cyclic hydrocarbons, such as cyclohexane, methyl cyclohexane, cycloheptane and the like; esters, such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tertiary butyl acetate and the like; and mixtures thereof, preferably n-heptane, cyclohexane or tertiary butyl acetate. Mode of adding the second organic solvent is not critical and may include adding the solution or suspension obtained in step c) to the second organic solvent, or adding second organic solvent to the solution or suspension obtained in step c) to effect the crystallization of the product. In one embodiment, the second organic solvent may be cooled to a temperature of at least about -10°C to about 40°C, preferably -5°C to about 20°C, and then the reaction mass may be added to second organic solvent.

The reaction is allowed to stir for a period of time from about 30 minutes to until completion of the salt formation, preferably about 10 mins to about 24 hrs.

Thereafter, isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like. 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 20°C to about 90°C, preferably from about 20 °C to about 70 °C, for a period ranging from about 1 hour to about 20 hours. 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 comprising tenofovir alafenamide hemifumarate in a first organic solvent;

The starting tenofovir alafenamide hemifumarate used in the present invention is known in the art and can be synthesized by any known methods, for example tenofovir alafenamide hemifumarate may be synthesized as disclosed in U.S. Patent No. 8,754,065 and C.N. publication No. 104558036 or it may be obtained as a solution directly from a reaction mixture in which tenofovir alafenamide hemifumarate is formed and used as such without isolation.

The step of providing a solution or suspension includes mixing any form of tenofovir alafenamide hemifumarate with a first organic solvent. The temperature suitable for dissolving or suspending the tenofovir alafenamide hemifumarate in first organic solvent depends on the amount of tenofovir alafenamide hemifumarate and/or first organic solvent in the reaction mass. Examples of first organic solvent for use in step a) of the foregoing process includes but are not limited to alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol and the like; amides such as formamide, N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, and mixtures thereof; preferably n-pentanol, n-butanol, or N-methyl-2-pyrrolidone.

Typically, the solution or suspension is heated at a temperature of ambient to about reflux temperature, preferably at about 40°C to about 100°C and stirring for a period of time from about 5 mins to about 10 hrs. Suitable temperature depends on the amount of tenofovir alafenamide hemifumarate and/or amount of solvent in the reaction mass.

Then, crystalline form of tenofovir alafenamide hemifumarate can be precipitated by mixing a second organic solvent with the reaction mass. The second organic solvent may be either added to reaction mass or the reaction mass is added to second organic solvent. The reaction mass may be gradually cooled to a temperature of at least about -10°C to about 40°C prior to addition of second organic solvent. Preferably the reaction mass is cooled gradually to -5°C to about 20°C.

Alternatively, the second organic solvent may be cooled to a temperature of at least about -10°C to about 40°C, preferably -5°C to about 20°C, and then the reaction mass may be added to second organic solvent. The suitable second organic solvent includes but are not limited to aliphatic hydrocarbons, such as pentane, hexane, heptane, and the like; cyclic hydrocarbons, such as cyclohexane, methyl cyclohexane, cycloheptane and the like; esters, such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tertiary butyl acetate and the like; and mixtures thereof, preferably n-heptane, cyclohexane or tertiary butyl acetate.

The reaction mass is allowed to stir for an appropriate period of time to aid complete precipitation of the product. Preferably, the reaction mass is stirred for about 10 mins to about 24 hours.

Isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like. 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 20°C to about 90°C, preferably from about 20°C to about 70°C.

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

d) filtering the crystalline form of tenofovir alafenamide hemifumarate.

The starting tenofovir alafenamide used in the present invention is known in the art and can be synthesized by any known methods, for example starting compound may be obtained by chromatography fractions according to U.S. patent No's 7,390,791 ; 8,664,386; PCT Publication No's. 2015/040640 and 2015/107451. Alternatively, the starting tenofovir alafenamide may be obtained as a solution directly from a reaction mixture in which tenofovir alafenamide is formed and used as such without isolation.

Typically, the solution or suspension is heated at a temperature of ambient to about reflux temperature, preferably at about 40°C to about 100°C and stirring for a period of time from about 5 mins to about 10 hrs.

Then adding fumaric acid to the resulting solution or suspension at temperature of about ambient to about reflux temperature; preferably at about 40°C to about 100°C and then cooling the solution to precipitate out the product. The cooling step may be involved directly to a temperature of less than about 10°C from the temperature involved at step b) or may involve cooling the solution first to not less than 20°C then followed by cooling to less than about 10°C. Preferably, first cooling the reaction temperature to not less than about 20°C and stirred for about 10 minutes to about 5 hours followed by again cooling the reaction mass to less than about 10°C and stirred for about 10 minutes to about 5 hours. The precipitated solids may be isolated by any of the conventional techniques such as filtration, centrifugation and the like. 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 20°C to about 90°C, preferably from about 30°C to about 70°C.

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

c) filtering the crystalline form of tenofovir alafenamide hemifumarate.

Typically, the solution or suspension is heated at a temperature of ambient to about reflux temperature, preferably at about 40°C to about 100°C, stirring for a period of time from about 5 mins to about 10 hrs and then cooling the solution to precipitate out the product. The cooling step may be involved directly to a temperature of less than about 10°C from the temperature involved at step a) or may involve cooling the solution first to not less than 20°C then followed by less than about 10°C. Preferably, first cooling the reaction temperature to not less than about 20°C and stirred for about 10 minutes to about 5 hours followed by again cooling the reaction mass to less than about 10°C and stirred for about 10 minutes to about 5 hours. The precipitated solids may be isolated by any of the conventional techniques such as filtration, centrifugation and the like. 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 20°C to about 90°C, preferably from about 30°C to about 70°C. In another embodiment, crystalline form of tenofovir alafenamide hemifumarate recovered using the process described just as above is substantially pure tenofovir alafenamide hemifumarate crystalline form, which is 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 another embodiment, the present invention provides crystalline form of tenofovir alafenamide hemifumarate, obtained by the process described herein with a chemical purity of at least about 98% as measured by HPLC, preferably at least about 99% as measured by HPLC.

The crystalline form of tenofovir alafenamide hemifumarate of the present invention is produced by an efficient, economic and highly reproducible process and does not involve any seed crystals to induce product formation rendering the process amenable particularly in large scale preparation.

The crystalline form of tenofovir alafenamide hemifumarate of the present invention may have greater stability, bioavailability, and having desired pharmacological, pharmacokinetic and pharmacodynamic effects as compared to the known polymorphic forms.

The crystalline forms of monophenyl PMPA and the crystalline form of tenofovir alafenamide hemifumarate of the present invention of the present invention were characterized by one or more of the techniques such as PXRD, TGA and DSC techniques.

The X-Ray powder diffraction can be measured by X-ray powder diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 30kV, 15 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°20; step width=0.020°; and scan speed=5° 2#/minute. Alternatively, the X-Ray powder diffraction can also be measured by X-ray powder diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 45kV, 40 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=2-45°20; step size=0.01°., Time per step=22 sec; and scan speed=5° 2#/minute. All TGA data reported herein were analyzed using TGA Q500 V 20.13 build 39 in platinum pan with a temperature rise of about 10°C/min in the range of about RT to about 250°C. All DSC data reported herein were analyzed in low-mass pan crimped aluminium pan, with a blank low-mass pan crimped aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute with an Indium standard. EXAMPLES

The present invention is further illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. Example 1: Preparation of monophenyl PMPA (Form II)

To a round bottom flask equipped with reflux condenser, PMPA (400 gms), cyclopentyl methyl ether (3.2 Lit) and triethyl amine (268 gms) were added, heated to 100-106°C and water removed azeotropically. Phenol (248 gms), triethyl amine (240 gms) and DCC (440 gms) were added to the reaction mass. The temperature of the reaction mass was raised to 100-106°C and maintained for 20-24 hrs at the same temperature. The reaction mass was cooled to 40-50°C, diluted with water (600 mL) and filtered to remove the precipitate. The pH of the filtrate was made alkaline with addition of 25% (w/w) aqueous sodium hydroxide solution and organic layer was separated. The pH of the aqueous layer was made acidic with slow addition of dilute HC1. The precipitated white solid was filtered and washed with water (400 mL). The crude material was slurred in mixture of acetone (1600 ml) and water (400 ml) at room temperature for 2-3 hrs and filtered. The resulting wet material was dried at 60-65°C for 12 hrs to afford Form II of monophenyl PMPA (390 gms).

Example 2: Preparation of monophenyl PMPA (Form II)

In a round bottom flask equipped with reflux condenser, PMPA (50 gms) in methyl isobutyl ketone (400 mL) was heated to 110-120°C and water removed azeotropically. The mixture was cooled and phenol (30.8 gms), triethyl amine (33.2 gms) and DCC (55 gms) were added. The temperature of the reaction mixture was raised to 110-120°C and maintained for another 6-12hrs at the same temperature. The mixture was cooled to 40- 50°C, diluted with water (75 mL) and the insoluble material filtered to remove the precipitate. The pH of the filtrate was made alkaline with addition of 25% (w/w) aqueous sodium hydroxide solution. The pH of the resulting aqueous layer was made acidic with dilute HC1, acetone (150 mL) was added and the reaction mass was slurred for 6hrs. The precipitated material was filtered, dried at 60-65°C for 12hrs to afford Form II of monophenyl PMPA (30.6 gms). Example 3: Preparation of monophenyl PMPA (Form II)

To a round bottom flask equipped with reflux condenser, PMPA (100 gms), cyclopentyl methyl ether (800 mL) and triethyl amine (67 gms) were added, heated to 100-106°C and water removed azeotropically. Phenol (62 gms), triethyl amine (60 gms) and DCC (110 gms) were added to the reaction mass. The temperature of the reaction mass was raised to 100-106°C and maintained for 20-24 hrs at the same temperature. The reaction mass was cooled to 40-50°C, diluted with water (150 mL) and filtered to remove the precipitate. The pH of the filtrate was made alkaline with addition of 25% (w/w) aqueous sodium hydroxide solution and organic layer was separated. The pH of the aqueous layer was made acidic with slow addition of dilute HC1 and seed crystals of tenofovir alafenamide ( 1 gm) were added. The precipitated white solid was filtered and washed with water. The crude material was slurred in mixture of acetone (400 ml) and water (100 ml) at room temperature for 2-3 hrs and filtered. The resulting wet material was dried at 60-65 °C for 10-12 hrs to afford Form II of monophenyl PMPA (85 gms).

Example 4: Preparation of Tenofovir alafenamide

In a round bottom flask equipped with reflux condenser, a suspension of monophenyl PMPA (50 gms) in toluene (600 mL) was heated to 110°C and water removed azeotropically. The reaction was cooled to 50°C, and N, N-dimethyl formamide (0.5 mL) and thionyl chloride (25 gms) were added. The temperature of the reaction mixture was raised to 67-73 °C and maintained at the same temperature for 12-24hrs. The reaction mixture was concentrated under vacuum and the residue obtained was co-evaporated with toluene. To the resulting residue, toluene (250 mL) and dichloromethane (300 mL) were added and the resultant slurry was gradually cooled to -30°C. To the slurry, L-Alanine isopropyl ester hydrochloride (66 gms) and triethyl amine (40 gms) were sequentially added, temperature was allowed to raise to 25-35°C and stirred at the same temperature. The mixture was cooled to 13°C and sequentially washed with aq NaH₂P0₄, aq NaHC0₃ and water. The resulting organic layer was dried over sodium sulphate and then concentrated under vacuum. The obtained residue was treated with a mixture of isopropyl alcohol (50 mL) and methyl tertiary butyl ether (200 mL) at RT, seeded with tenofovir alafenamide and stirred for another 4-6hrs. The precipitated solid was filtered, and the wet material in a mixture of isopropyl alcohol (35 mL) and methyl tertiary butyl ether (140 mL) was heated to a temperature of 55-61°C and stirred for 3hrs. The reaction mass was cooled to room temperature and stirred for 4hrs at the same temperature. The resulting solids were filtered and dried under vacuum at 45-55°C for 12-16hrs to afford Tenofovir alafenamide (33.4 gms). HPLC purity: 99.4%; RRS diastereomer: 0.5%. Example 5: Preparation of Tenofovir alafenamide Following the process disclosed in example 3 using N, N-dimethyl formamide as catalyst, chlorination reaction was carried out for 24 hrs followed by conversion to tenofovir alafenamide and purification process according to the process disclosed in example 3 to provide tenofovir alafenamide. HPLC purity: 99.3% and (R,R,S)-diastereomer: 0.5%.

Example 6: Preparation of Tenofovir alafenamide

Following the process disclosed in example 3 using triethyl amine as catalyst, chlorination reaction was carried out for 30 hrs followed by conversion to tenofovir alafenamide and purification process according to the process disclosed in example 3 to provide tenofovir alafenamide. HPLC purity: 99.3% and (R,R,S)-diastereomer: 0.5%.

Example 7: Preparation of Tenofovir alafenamide Following the process disclosed in example 3 using a mixture of toluene and acetonitrile solvents and triethyl amine as catalyst, chlorination reaction was carried out for 34-36 hrs followed by conversion to tenofovir alafenamide and purification process according to the process disclosed in example 3 to provide tenofovir alafenamide. HPLC purity: 99.2% and (R,R,S)-diastereomer: 0.8%.

Example 8: Purification of Tenofovir alafenamide

In a round bottom flask equipped with reflux condenser, a suspension of Tenofovir alafenamide (25 gms; HPLC purity: 97 %; PMPA content: 1%; monophenyl PMPA content: 0.72% and PMPA anhydrate content: 0.67%) in water (125 ml) was heated to 45- 55°C and stirred for l-2hrs. The reaction mass temperature was gradually cooled to 25- 35 °C over a period of 1-2 hrs and stirred at the same temperature for 1-2 hrs. The resulting solids were filtered and dried under vacuum at 45-55°C for 6-8hrs to afford Tenofovir alafenamide (21.2 gms). HPLC purity: 99.6%; PMPA content: 0.1%; monophenyl PMPA content: 0.1 % and PMPA anhydrate content: 0.03%).

Example 9: Preparation of Tenofovir alafenamide hemifumarate

In a round bottom flask equipped with reflux condenser, a suspension of tenofovir alafenamide (25 gms) and fumaric acid (3.05 gms) in acetone (450 mL) was heated to 50- 60°C and maintained at the same temperature until complete dissolution. The resulting solution was clarified with activated carbon (1.25 gms) and filtered. The filtrate was heated to 50-60°C, stirred for 10-15 mins and then cooled to 45-50°C. The obtained reaction mass was seeded with tenofovir alafenamide hemifumarate (-20 mg) and stirred for 30 min at 45-50°C. Later the reaction mass was gradually cooled to 15-25°C and then stirred for another 4-6 hrs. The precipitated material was filtered, washed with acetone (25 mL) and dried at 45-55°C for 10-16 hrs to afford tenofovir alafenamide hemifumarate (22 gms). HPLC purity of 99.7%; PMPA: 0.04%; unidentified impurity (0.27 rrt): 0.02%. Example 10: Preparation of monophenyl PMPA (Form I)

To a round bottom flask equipped with reflux condenser, monophenyl PMPA (10 gms), acetone (40 ml) and water (10 ml) were added at room temperature and slurred for 2-3 hrs at room temperature and filtered. The resulting wet material was dried at 70-75°C for 12 hrs to afford Form-I of monophenyl PMPA (9 gms).

Example 11: Preparation of monophenyl PMPA (Form I) To a round bottom flask equipped with reflux condenser, monophenyl PMPA (10 gms), acetone (40 ml) and water (10 ml) were added at room temperature, slurred for 2-3 hrs at room temperature and filtered. The resulting wet material was dried at 95-100°C for 6 hrs to afford Form-I of monophenyl PMPA (8.7 gms). Example 12: Preparation of monophenyl PMPA (Form II)

To a round bottom flask equipped with reflux condenser, monophenyl PMPA (10 gms), isopropanol (40 ml) and water (10 ml) were added at room temperature, slurred for 2-3 hrs at room temperature and filtered. The resulting wet material was dried at 60-65 °C for 12 hrs to afford Form-II of monophenyl PMPA (9.3 gms).

Example 13: Preparation of monophenyl PMPA (Form II)

To a round bottom flask equipped with reflux condenser, monophenyl PMPA (10 gms), ethanol (40 ml) and water (10 ml) were added at room temperature, slurred for 2-3 hrs at room temperature and filtered. The resulting wet material was dried at 60-65°C for 12 hrs to afford Form-II of monophenyl PMPA (9 gms).

Example 14: Preparation of monophenyl PMPA (Form II)

To a round bottom flask equipped with reflux condenser, monophenyl PMPA (10 gms), tert-butanol (40 ml) and water (10 ml) were added at room temperature, slurred for 2-3 hrs at room temperature and filtered. The resulting wet material was dried at 60-65 °C for 12 hrs to afford Form-II of monophenyl PMPA (9.3 gms).

Example 15: Preparation of monophenyl PMPA (Form II)

To a round bottom flask equipped with reflux condenser, monophenyl PMPA (10 gms), water (50 ml) were added at room temperature and the resulting reaction mass was heated to a temperature of 90-100°C and stirred for 30mins. The reaction mass was cooled to room temperature, stirred for 6hrs and filtered. The resulting material was dried at 70-80°C for 12 hrs to afford Form-II of monophenyl PMPA (7 gms).

Example 16: Preparation of monophenyl PMPA (Form III) To a round bottom flask equipped with reflux condenser, monophenyl PMPA (10 gms), methanol (40 ml) and water (10 ml) were added and slurred at room temperature for 2-3 hrs. The resulting solids were filtered and dried at 60-65°C for 12 hrs to afford Form III of monophenyl PMPA (8.6 gms).

Example 17: Preparation of monophenyl PMPA (Form II)

Following the process disclosed in example 2 using n-butyl acetate or toluene as solvent instead of methyl isobutyl ketone, Form II of monophenyl PMPA has been prepared and summarized in the following table:

Example 18: Comparative example:

To a slurry of monophenyl PMPA (10.0 gms) in toluene (60 mL) at ambient temperature was added thionyl chloride (3.0 mL). The slurry was heated to 70° C and agitated for 48 to 96 hours until reaction and diastereomeric enrichment were deemed complete by HPLC (Target: >97.0% and >90: 10 diastereomeric ratio). The mixture was concentrated to dryness by vacuum distillation, and the dry residue was taken up in toluene (50 mL). This mixture was added to a solution of isopropyl L-alanine ester (4.50 eqts) in DCM (80 mL) at -25° C over a minimum of 45 minutes, maintaining the internal temperature≤-20° C. The mixture was then held at a temperature≤-20° C for at least 30 minutes, and the pH checked using water wet pH paper. If the pH was <4, it was adjusted with triethylamine to pH 4 to 7. The pot temperature was adjusted to room temperature. The mixture was transferred to a separatory funnel and washed sequentially with 10% w/v aqueous solution of sodium phosphate monobasic, 15% w/v aqueous solution of potassium bicarbonate, and water. The final organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a viscous amber oil. The oil was dissolved in toluene/acetonitrile (4: 1) (50 mL), and the solution was seeded with 9-{(R)-2-[((R,S)-{ [(S)-l- (isopropoxycarbonyl) ethyl] amino Jphenoxyphosphinyl) methoxy] propyl} adenine (about 1 mg, 99: 1 diastereomeric ratio) and stirred for 2 hrs at ambient temperature. The resultant slurry was filtered and the filter cake was washed with toluene/acetonitrile (4: 1) and dried in a vacuum oven at 40° C for 16 hrs to give the product, 9-{(R)-2-[((R,S)-{ [(S)-l- (isopropoxycarbonyl)ethyl] amino} phenoxy phosphinyl) methoxyjpropyl } adenine, as a white solid (10.0 gms, 97.5:2.5 diastereomeric ratio).

Example 19: Preparation of crystalline form of tenofovir alafenamide hemifumarate (n- pentanol - n-heptane) To a round bottom flask equipped with reflux condenser, tenofovir alafenamide (1 gm), fumaric acid (122 mg) and n-pentanol (4 ml) were added. The reaction mass was heated to 67-73°C, stirred for 15 mins and cooled to 23-27°C. The resulting reaction mass was further cooled to -2 to 2°C and stirred for 30 mins. n-heptane (20 ml) was added to the reaction mass at -2 to 2°C and stirred for 1 hr at the same temperature. The resulting solids were filtered, washed with chilled n-heptane and dried at 50°C under vacuum for 6 -10 hrs to obtain tenofovir alafenamide hemifumarate crystalline form (0.98 gms). The PXRD is set forth in Figure 13 and the TGA is set forth in Figure 14.

Example 20: Preparation of crystalline form of tenofovir alafenamide hemifumarate (n- pentanol - n-heptane)

To a round bottom flask equipped with reflux condenser, tenofovir alafenamide (0.5 gms), fumaric acid (61 mg) and n-pentanol (2 ml) were added. The reaction mass was heated to 62-68°C and stirred for 1 hr. The resulting solution was cooled to 33-37°C and stirred for 10 mins at the same temperature. This solution was added to n-heptane (6 ml) pre-cooled to 3 to 7°C and stirred for 45 mins at 3 to 7°C. The resulting solids were filtered, washed with chilled n-heptane and dried at 40°C under vacuum for 17 hrs to obtain tenofovir alafenamide hemifumarate crystalline form (0.39 gms). The PXRD is set forth in Figure 13 and the TGA is set forth in Figure 14.

Example 21: Preparation of crystalline form of tenofovir alafenamide hemifumarate (n- butanol - cyclohexane)

To a round bottom flask equipped with reflux condenser, tenofovir alafenamide hemifumarate (0.4 gms) and n-butanol (0.8 ml) were added. The reaction mass temperature was raised to 78-82°C and stirred for 15 mins at the same temperature. The resulting solution was allowed to cool to 3-7°C and cyclohexane (4 ml) was added. The reaction mass was stirred at 3-7°C for 3 hrs, filtered and washed with cyclohexane. The resulting solid was dried at 40°C under vacuum for 17 hrs to obtain tenofovir alafenamide hemifumarate crystalline form (301 mg). The PXRD is set forth in Figure 13 and the TGA is set forth in Figure 14.

Example 22: Preparation of crystalline form of tenofovir alafenamide hemifumarate (n- pentanol - n-heptane)

To a round bottom flask equipped with reflux condenser, tenofovir alafenamide hemifumarate (0.4 gms) and n-pentanol (0.8 ml) were added. The reaction mass temperature was raised to 78-82°C and stirred for 15 mins at the same temperature. The resulting solution was allowed to cool to 3-7°C and heptane (6 ml) was added. The reaction mass was stirred at 3-7°C for 3 hrs, filtered and washed with heptane. The resulting solid was dried at 40°C under vacuum for 17 hrs to obtain tenofovir alafenamide hemifumarate crystalline form (335 mg). The PXRD is set forth in Figure 13 and the TGA is set forth in Figure 14.

Example 23: Preparation of crystalline form of tenofovir alafenamide hemifumarate (N- methyl-2-pyrrolidone - tertiary butyl acetate)

To a round bottom flask equipped with reflux condenser, tenofovir alafenamide hemifumarate (0.4 gms) and N-methyl-2-pyrrolidone (0.4 ml) were added. The reaction mass was heated to 57-63°C and stirred for 10 mins. The resulting solution was added to tertiary butyl acetate (6 ml) pre-cooled to 3-7°C and stirred for 1 hr at 3-7°C. The resulting solids were filtered, washed with chilled tertiary butyl acetate and dried at 40°C under vacuum for 17 hrs to obtain tenofovir alafenamide hemifumarate crystalline form (0.25 gms). The PXRD is set forth in Figure 13 and the TGA is set forth in Figure 14.

Example 24: Preparation of crystalline form of tenofovir alafenamide hemifumarate (water)

To a round bottom flask equipped with reflux condenser, tenofovir alafenamide (2.5 gms) and water (15 ml) were added. The reaction mass was heated to 70-80°C and stirred for 10 mins. To the solution, fumaric acid (0.3 gms) was added at same temperature and stirred for 10 mins. Then, the reaction solution was allowed to cool to 20-30°C and stirred for about 30 minutes at 20-30°C. Again reaction mass further allowed to cool to 0-10°C and stirred for about 3 hours at 0-10°C. The precipitated solid was filtered off and dried at 50°C under vacuum for about 10 hours to obtain tenofovir alafenamide hemifumarate crystalline form (2.14 gms). The PXRD is set forth in Figure 13 and the TGA is set forth in Figure 14.

Example 25: Preparation of crystalline form of tenofovir alafenamide hemifumarate (water)

To a round bottom flask equipped with reflux condenser, tenofovir alafenamide hemifumarate (2.5 gms) and water (30 ml) were added. The reaction mass was heated to 75-85°C and stirred for 10 mins. The reaction solution was allowed to cool to 25°C and stirred for about 30 minutes at 20-30°C. Again reaction mass further allowed to cool to 5°C and stirred for about 3 hours at 0-10°C. The precipitated solid was filtered off and dried at 50°C under vacuum for about 10 hours to obtain tenofovir alafenamide hemifumarate crystalline form (2.0 gms). The PXRD is set forth in Figure 13 and the TGA is set forth in Figure 14.

Claims

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;

IV

V

in presence of a suitable base to obtain tenofovir alafenamide;

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;

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:

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:

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;

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.