WO2015079455A2

WO2015079455A2 - A recycling process for preparing tenofovir alafenamide diastereomers

Info

Publication number: WO2015079455A2
Application number: PCT/IN2014/000734
Authority: WO
Inventors: Suresh Thatipally; Kumara Swamy UDUTHA; Mani Bushan KOTALA; Venkata Lakshmi Narasimha Rao Dammalapati; Seeta Rama Anjaneyulu GORANTLA; Satyanarayana Chava
Original assignee: Laurus Labs Private Limited
Priority date: 2013-11-27
Filing date: 2014-11-27
Publication date: 2015-06-04
Also published as: IN2013CH05455A; WO2015079455A3

Abstract

The present invention relates to an efficient and economical process to recycle the undesired diastereomer of Tenofovir alafenamide to desired diastereomer by racemization of the undesired diastereomer followed by separation of the desired diastereomer from the racemic mixture.

Description

"A RECYCLING PROCESS FOR PREPARING TENOFOVIR ALAFENAMIDE DIASTEREOMERS"

PRIORITY

This application claims the benefit under Indian Provisional Application No. 5455/CHE/2013 filed on 27 November 2013 and. entitled "A recycling process for preparing Tenofovir alafenamide diastereomers", the content of which is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention generally relates to a recycling process for preparation of tenofovir alafenamide diastereomers. .

BACKGROUND OF THE INVENTION

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

Tenofovir Alafenamide (GS 7340)

U.S. Patent No. 7,390,791 discloses Tenofovir alafenamide or pharmaceutically acceptable salts thereof exhibiting potent anti-HTV activity and enhanced ability to deliver parent tenofovir into peripheral blood mononuclear cells (PBMCs) and other lymphatic tissues in vivo. Methods for chemically synthesizing this prodrug is disclosed in this patent by reacting ({ [(2i?)-l -(6-amino-9H-purin-9-yl)propan-2- yl]oxy}methyl)phosphonic acid (PMPA) with phenol in presence of N-methyl pyrrolidinone solvent and Ν,Ν'-Dicyclohexylcarbodiimide to give [(R)-2- (Phenylphosphonomethoxy) propyl] adenine which was further treated with thionyl chloride followed by L-alanine isopropyl ester in the presence of triethylamine to get tenofovir alafenamide. Finally, the obtained tenofovir alafenamide was purified by simulated moving bed chromatography (SMB) over Chiralpak AS column by eluting with 30% methanol in acetonitrile provided 98.7% diastereomeric purity and the resultant required diastereomer was converted into tenofovir alafenamide fumarate.

U.S. Patent No. 8,6.64,386 discloses a process for the selective crystallization of tenofovir alafenamide by subjecting racemic mixture of tenofovir alafenamide to crystallization induced dynamic resolution in the presence of 1,8-Diazabicycloundec- 7-ene, phenol and seed crystals of specific (R,S,S)-isomer to provide epimerization of the phosphorus centre.

U.S. Patent No 8,697,675 discloses tenofovir alafenamide hemifumarate salt and preparation thereof.

Generally, synthesis of tenofovir alafenamide resulted in formation of equal amounts of two diastereomers. These two diastereomers, GS 7339 and GS 7340 were typically separated by chromatography or crystallization. Of these, GS 7340 is desired diastereomer for therapeutic use, while the other GS 7339 is undesired diastereomer, which is the major chiral impurity in the active pharmaceutical ingredient. The two diastereomers are represented by the following structures:

GS 7340 (R,S,S) GS 7339 (R,R,S)

Typically, the undesired diastereomer produced is discarded either at the stage of tenofovir alafenamide preparation or in the final stage of separation of diastereomers by any conventional techniques such as crystallization, RP-HPLC, simulated moving bed technique or batch elution chromatography. Instead of discarding the undesired diastereomer which contributes to production loss, it is beneficial to convert the undesired diastereomer in to the desired one which results in an increase in the product yield thereby decreasing the manufacturing cost.

Although processes have been described in the art for the preparation of tenofovir alafenamide and salts thereof and techniques to separate the resulting diastereomers, there still remains an ongoing need for processes which are more efficient and/or produce higher yields of the desired diastereomer which is addressed by the present invention and described hereinafter. It is therefore the object of the present invention is to develop a simple iterative process, whereby the undesired diastereomer can be recycled to produce the desired diastereomer with higher yield and greater purity in a simple manner, which is economical and applicable on an industrial scale.

The process described in the present invention represents a valuable alternative to those described in the art and permits convenient recycling of the undesired diastereomer on a commercial scale as the entire process is simple with improved overall recoveries of the desired diastereomer.

SUMMARY OF THE INVENTION

The present invention relates to a recycling process for preparation of tenofovir alafenamide diastereomers by an iterative process via racemization of (R,R,S)- diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer, followed by separation of the (R,S,S)-diastereomer to increase the overall yield and diastereomeric purity of the tenofovir alafenamide.

In accordance with one embodiment, the present invention provides a process for racemization of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)- diastereomer of tenofovir alafenamide, said method comprising treating the (R,R,S)- diastereomer or the mixture ^having (R,S,S) & (R,R,S)-diastereomer with a suitable base in a suitable organic solvent.

In accordance with a second embodiment, the present invention provides a process for the preparation of (R,S,S)-diastereomer of tenofovir alafenamide or pharmaceutically acceptable salts thereof, comprising:

a) providing a solution or suspension of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide in a suitable organic solvent,

b) reacting the step a) mixture with a suitable base to obtain a racemate, c) separating the (R,S,S)-diastereomer of tenofovir alafenamide;

wherein the suitable base is selected from the group consisting of organic amine bases such as primary, secondary, tertiary amines, cyclic amines and the like; Or inorganic bases such as alkali metal hydroxide, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal alkoxides, alkali metal aryloxides and the like;

wherein the suitable organic solvent is selected from the group consisitng of amides, alkylated glycols, ethers, esters, ketones, aromatic hydrocarbons, halogenated hydrocarbons, nitriles, sulfoxides, sulfones and the like. In accordance with a third embodiment, the present invention provides a process for the preparation of (R,S,S)-diastereomer of tenofovir alafenamide or pharmaceutically acceptable salts thereof, comprising:

b) reacting the step a) mixture with a suitable base to obtain a racemate, c) subjecting the resultant racemate to chromatography, and

d) separating the (R,S,S)-diastereomer of tenofovir alafenamide.

In accordance with a fourth embodiment, the present invention provides a process for the preparation of (R,S,S)-diastereomer of tenofovir alafenamide or pharmaceutically acceptable salts thereof, comprising:

b) reacting the step a) mixture with a suitable base to obtain a racemate, c) subjecting the resultant racemate to simulated moving bed chromatography or Preparative HPLC, and

d) separating the (R,S,S)-diastereomer of tenofovir alafenamide.

In accordance with a fifth embodiment, the present invention provides a process for the preparation of (R,S,S)-diastereomer of tenofovir alafenamide or pharmaceutically acceptable salts thereof, comprising:

a) providing a solution or suspension of (R,R,S)-diastereomer or a mixture having

(R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide in a suitable organic solvent,

d) separating the (R,SvS)-diastereomer of tenofovir alafenamide;

wherein the suitable organic solvent is selected from the group consisitng of amides, alkylated glycols, ethers, esters, ketones, aromatic hydrocarbons, halogenated hydrocarbons, nitriles, sulfoxides, sulfones and the like. In accordance with a sixth embodiment, the present invention provides a process for separation of diastereomers of tenofovir alafenamide, comprising: subjecting the mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide to simulated moving bed chromatography or Preparative HPLC, and separating the (R,S,S)- ^'diastereomer of tenofovir alafenamide.

In accordance with a seventh embodiment, the present invention provides a process for separation of diastereomers of tenofovir alafenamide, comprising: subjecting the mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide to simulated moving bed chromatography or Preparative HPLC using a suitable eluent, and separating the (R,S,S)-diastereomer of tenofovir alafenamide; wherein the suitable eluent comprising an alcohol solvent, an ester solvent and mixtures thereof.

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

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a process for recycling undesired (R,R,S)-diastereomer of tenofovir alafenamide produced during the manufacturing process or the purification process by an iterative process via racemization of undesired (R,R,S)- diastereomer followed by separation of the desired (R,S,S)-diastereomer to increase the overall yield and diastereomeric purity of the tenofovir alafenamide.

In accordance with one embodiment, the present invention provides a process for the racemization of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)- diastereomer of tenofovir alafenamide, said method comprising treating the (R,R,S)- diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer with a suitable base in a suitable organic solvent.

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

b) .reacting the step a) mixture with a suitable base to obtain a racemate, c) subjecting the resultant racemate to chromatography, and

d) separating the (R,S,S)-diastereomer of tenofovir alafenamide. In a preferred embodiment, the present invention provides a process for the preparation of (R,S,S)-diastereomer of tenofovir alafenamide or pharmaceutically acceptable salts thereof, comprising:

a) providing a solution or suspension of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide^' in a suitable organic solvent,

d) separating the (R,S,S)-diastereomer of tenofovir alafenamide.

The starting compound, either (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide can be prepared by any known methods, for example starting compound may be obtained by chromatography fractions according to U.S. patent No's 7,390,791.

As used herein, the term "racemate", relates to a mixture of equal quantities of (R,S,S) & (R,R,S)-diastereomers. As used herein, the term "catalytic amount" when referring to a base, relates to 0.01 to about 0.2 equivalents compared to the starting tenofovir alafenamide diastereomers.

Step a) of the foregoing process includes providing a solution or suspension of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide in a suitable organic solvent. Alternatively, such a solution or suspension may be obtained directly from a reaction mixture in which (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer is formed and used as such without isolation or it may be obtained after separation of diastereomers by chromatographic separation. Examples of suitable organic solvent include but are not limited to ethers such as _f diisopropyl ether, di n-butyl ether, dimethoxy ethane, methyl tert-butyl ether, ethyl isopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, anisole and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; alkylated glycols such as 1,1- diethoxymethane, 1,2-dimethoxyethane, 2-ethoxyethanol, 2-n-butoxyethanol and the like; amides such as dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide, dimethylpropionamide and the like; nitriles such as acetonitrile, propionitrile and the like; sulfoxides and sulfones such as dimethyl sulfoxide, sulfolane and the like; and mixtures thereof; preferably tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide,^' dimethylacetamide, dimethyl sulfoxide and mixtures thereof.

Examples of bases for use in step b) of the foregoing process includes but are not limited to organic amine bases such as primary, secondary, tertiary amines, cyclic amines and the like; or inorganic bases such as alkali metal hydroxide, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal alkoxides, alkali metal aryloxides and the like. Suitable organic amines include but are not limited to trimethylamine, butylamine, isopropylamine, diethylamine, ethanolamine, dicyclohexylamine and the like. Suitable inorganic bases include but are not limited to- sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, sodium hydrogen carbonate,^' potassium hydrogen carbonate, sodium methoxide, sodium ethoxide, potassium fert-butoxide, sodium phenoxide and the like; preferably sodium phenoxide, sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium tert-butoxide and the like and mixtures thereof. Preferably, the base is added in a catalytic amount. More preferably, the base is added in an amount of about 0.01 to about 0.2 equivalents of the starting tenofovir alafenamide diastereomers.

The reaction may be advantageously carried out at a suitable temperature such as 20°C to about reflux temperature. Preferably, the reaction is carried out at 20°C and 80°C, more preferably at about 25° to about 35°C. The reaction is allowed to stir for a period of time from about 20 mins until complete racemization, preferably about 30 mins to about 4 hrs. Then, the racemized product from the reaction mass may be isolated by methods known in the art, for example reaction mass may be diluted with water and extracted with a suitable water immiscible organic solvent such as ethyl acetate, toluene, chloroform or dichloromethane and the like and concentrating the resultant organic layer under reduced pressure to obtain a oily residue. The resultant product may be purified if required by silica gel column chromatography by eluting with suitable solvent such as acetone to obtain tenofovir alafenamide diastereomers as racemate.

The desired (R,S,S)-diastereomer can be separated from the resultant racemic tenofovir alafenamide diastereomers by a suitable chromatographic purification system. The present invention provides a process for the purification of tenofovir alafenamide, , comprising subjecting the racemic mixtures of tenofovir alafenamide diastereomers obtained by the racemization process described as above to chromatography such as simulated moving bed chromatography or Preparative HPLC using suitable eluent.

·

The present invention provides a process for purification of diastereomers of tenofovir alafenamide; comprising subjecting the racemic mixtures of tenofovir alafenamide diastereomers obtained by the racemization process described as above to a simulated moving bed chromatography using suitable stationary chiral phase and suitable eluent. The suitable eluent comprising an alcohol, an ester solvent and mixtures thereof; preferably the eluent is selected from the group consisting of ethanol, methanol, isopropanol, ethyl acetate, methyl acetate, propyl acetate and mixtures thereof; more preferably ethanol, ethyl acetate and mixtures thereof. Suitable chiral stationary phases are in particular those which contain the derivatives of polysaccharides, optically active poly (acryl) amides, chiral polyacrylates or optically active network polymers and which are optionally and preferably applied to a support material. The suitable stationary chiral phases those are preferred which have derivatives of polysaccharides including the preferred ranges mentioned and are applied to silica gel. Such chiral phases are commercially available, for example, under the name CHIRALPAK® (IA, IB, IC, ID, IE, IF, AD, AS, AY, AZ)™ or CHIRALCEL® (OA, OB, OC, OD, OF, OG, OJ, OK, OX, OZ)™ from Daicel.

The particles of the support material advantageously have an average diameter (based on the particle size) of 5μπι to 500mm, preferably ΙΟμιη to 100 μηι, more preferably 20 μηι. The present invention also provides a process for purification of tenofovir alafenamide, comprising subjecting the racemic mixtures of tenofovir alafenamide diastereomers obtained by the process described as above to a Preparative FIPLC using suitable eluent.

The present invention provides a process for separation of diastereomers of tenofovir alafenamide; comprising subjecting the racemic mixtures of tenofovir alafenamide diastereomers obtained by the racemization process described as above to a Preparative HPLC. The Preparative HPLC can be performed using preparative chiral column and an eluent. The Preparative HPLC column may be selected by any chiral columns known in the art, for example, preferably chiral columns as described just as above for simulated moving bed chromatography can be used; preferably Chiral Pak IA (500x50) mm, 20 μπι. The suitable eluent comprising an alcohol, an ester solvent and mixtures thereof; preferably the eluent is selected from the group consisting of ethanol, methanol, isopropanol, . ethyl acetate, methyl acetate, propyl acetate and mixtures thereof; more preferably ethanol, ethyl acetate and mixtures thereof. Flow- rate of the mobile phase may be selected from about 30 ml to 150 ml per minute, preferably about 40 ml to 100 ml per minute, more preferably about 60 ml per minute. Conditions for the Preparative HPLC are known to the person skilled in the art.

To get higher yields of the desired (R,S,S)-diastereomer according to the present invention, the undesired (R,R,S)-diastereomer typically must be separated, racemized and the desired diastereomer has to be separated and isolated. Again the resulting undesired diastereomer can be recycled as per the procedure described above after the separation step to produce more of the desired diastereomer. As one of skilled in the art would appreciate, the recycling step can be repeated many times to recycle as much of the undesired diastereomer as possible.

The process, unlike conventional resolution methods, yields, after recycle over several batches, the desired (R,S,S)-diastereomer in high yields with high diastereomeric purity. Such racemization is environmentally desirable, and permits direct recycle of the undesired diastereomer, thus ultimately resulting in virtually complete conversion of undesired diastereomer to the desired diastereomer.

In another embodiment, tenofovir alafenamide obtained by the racemization process described as-above, having diastereomeric purity of at least about 98% as measured by chiral HPLC, preferably at least about 99.8%) as measured by chiral HPLC and less than 0.2% by chiral HPLC of (R,R,S)-diastereomer, preferably less than 0.1% by chiral HPLC.

The present invention also provides preparation of pharmaceutically acceptable salts of tenofovir alafenamide, the process comprising reacting tenofovir alafenamide, as starting material or as an intermediate, with pharmaceutically acceptable salts as per saltification procedure known in the art.

The pharmaceutical acceptable salts include acid addition salts formed with inorganic acids or with organic acids. The inorganic acids may be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, and the like; organic acids such as acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, mandelic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, p-hydroxy benzoic acid, vanillic acid, syringic acid, 4-(4- phenoxybenzoyl) benzoic acid, gentisic acid, protocatechuic acid, gallic acid, lipoic acid, aspartic acid, and the like, preferably fumaric acid.

The following scheme illustrates the isolation of the desired diastereomer from the undesired diastereomer according to the present invention:

(R,R,S)-diastereomer (R,S,S)-diastereomer (R,R,S)-diastereomer

Separation

NH

o ¹

(R,S,S)-diastereomer

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

The present invention provides tenofovir alafenamide, obtained by the process described herein, as analyzed using the chiral high performance liquid chromatography ("chiral HPLC") with the conditions described below:

Column : Chiralpak - IA (250 x 4.6) mm,5 mm

Flow rate : 1.0 mL/min

Detection wavelength : 265 nm

Injection volume : 10 μΐ,

Elution Mode : Isocratic

Column temperature : 25°C

Mobile phase : Ethyl acetate : Ethanol (80:20 v/v )

Sample concentration : l.Omg/mL

Run time : 15 min 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: Racemization of tenofovir alafenamide (R,R,S)-diastereomer.

Tenofovir alafenamide (R,R,S)-diastereomer (10 gms, 0.021 mol) (chiral purity: 99.98%) and sodium phenoxide (in THF, 0.24 gms, 0.0021 mol) in dimethyl sulfoxide (20 ml) was stirred at room temperature for 1 hr. Water was added to the reaction mass and extracted with dichloromethane. The resulting organic layer was separated and concentrated under reduced pressure to obtain an oily residue. The obtained oily residue was purified by column chromatography over silica gel by eluting with acetone (100%). Pure product fractions were concentrated under reduced pressure to get residue. Acetonitrile was charged to the residue and the mixture was distilled under reduced pressure to get 6.0 gms of racemic Tenofovir alafenamide diastereomers as foamy solid.

Chiral Purity by HPLC (% area): 50.83: 49.17 (R,S,S : R,R,S).

Example 2: Separation of tenofovir alafenamide (R,S,S)-diastereomer from racemic tenofovir alafenamide diastereomers using simulated moving bed chromatography.

Racemic tenofovir alafenamide diastereomers (6.0 gms) was purified by continuous simulated moving bed chromatography over 10 cm by 5 cm, 20 μιη Chiral pack IA coated on silica gel (from chiral technologies Inc). The columns were eluted with 20% ethanol in ethyl acetate. Product bearing fractions were concentrated to the minimum volume and solids were observed on standing. The solids were filtered and dried under reduced pressure to get 3.0 gms of the title compound.

Chiral Purity by HPLC (% area): 99.86: 0.14 (R,S,S : R,R,S)

Example 3: Racemization of tenofovir alafenamide (R,R,S)-diastereomer.

Tenofovir alafenamide (R,R,S)-diastereomer (60 gms, 0.125 mol) ) (chiral purity: 99.98%) and sodium phenoxide (in THF, 1.4 gms, 0.0l25mol) in dimethyl sulfoxide (132 gms) was stirred at room temperature for 30 mins. The reaction mass was allowed to cool to 10-15°C, added water and extracted with dichloromethane. The resulting organic layer was separated, dried over sodium sulfate and solvent was concentrated under reduced pressure to get an oily residue. Acetone (142 gms) was charged to the residue and concentrated under reduced pressure to obtained an oily residue which was purified by column chromatography over silica gel by eluting with acetone (100%). Pure product fractions were concentrated under reduced pressure to get residue. Acetonitrile was charged to the residue and the mixture was distilled under reduced pressure to get 47 gms of racemic Tenofovir alafenamide diastereomers as foamy solid.

Chiral Purity by HPLC (% area): 50.53: 47.98 (R,S,S : R,R,S)

'

Example 4: Separation of tenofovir alafenamide (R,S,S)-diastereomer from racemic tenofovir alafenamide diastereomers using simulated moving bed chromatography.

Racemic tenofovir alafenamide diastereomers (47 gms) was purified by continuous simulated moving bed chromatography over 10 cm by 5 cm, 20 μπι Chiral pack LA coated on silica gel (from chiral technologies Inc). The columns were eluted with 20% ethanol in ethyl acetate. Product bearing fractions were concentrated to the minimum volume and solids were observed on standing. The solids were filtered and dried under reduced pressure to get 20 gms of the title compound.

Chiral Purity by HPLC (% area): 99.90: 0.10 (R,S,S : R,R,S)

Example 5: Separation of tenofovir alafenamide (R,S,S)-diastereomer from racemic tenofovir alafenamide diastereomers using preparative HPLC. Racemic tenofovir alafenamide diastereomer (100 gms) was purified by preparative HPLC using Chiral Pak IA (500x50) mm column under the following chromatography conditions:

All pure fractions were collected, concentrated under vacuum at 40°C to a crystalline mass and dried under reduced pressure to get 40 gms of product as a crystalline powder.

Chiral Purity by HPLC (% area): 99.5 Example 6:

Racemization of tenofovir alafenamide (R,R,S)-diastereomer (chiral purity: 99.98%) using a procedure analogous to that employed in Example 1 was carried out using different bases as described in the following table:

S. Base Solvent Chemical Purity (% area): No (R,S,S: R,R,S)

01 Sodium hydroxide dimethyl sulfoxide 47.05 : 49.44

02 . Sodium phenoxide dimethyl formamide 45.03 : 47.54

03 Potassium hydroxide dimethyl sulfoxide 38.50 : 53.88

04 Potassium t-butoxide dimethyl sulfoxide 37.50 : 54.27

05 Sodium phenoxide dimethyl sulfoxide 47.98 : 50.53

06 Sodium ethoxide dimethyl sulfoxide 33.87 : 40.81

Example 7: Preparation of Tenofovir alafenamide fumarate.

To a solution of tenofovir alafenamide (R,S,S)-diastereomer (100 gms, 0.209 mol) in acetonitrile (1890 gms), fumaric acid (22 gms, 0.188 mol) was added and heated to reflux to dissolve the solids. The reaction mass was filtered in hot condition, allowed to cool to 5°C and stirred for 16 hours! The product was isolated by filtration, rinsed with acetonitrile (707 gms), and dried under reduced pressure to get 92 gms of product as a white crystalline powder.

[α] -43.42° (c 1.0, acetic acid). Chiral HPLC purity: 99.78%.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

CLAIMS:

Claim 1 : A process for racemization of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide, said method comprising treating the (R,R,S)-diastereomer or the mixture having (R,S,S) & (R,R,S)- diastereomer with a suitable base in a suitable organic solvent.

Claim 2: The process of claim 1, wherein the base is an inorganic or organic base. . Claim 3: The process of claim 2, wherein the base is inorganic base selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal alkoxides, alkali metal aryloxides and mixtures thereof. Claim 4: The process of claim 3, wherein the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium methoxide, sodium ethoxide, potassium fert-butoxide, sodium phenoxide and mixtures thereof.

Claim 5: The process of claim 4, wherein the inorganic base is selected from the group consisting of sodium phenoxide, sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium tert-butoxide and mixtures thereof.

Claim 6: The process of claim 1 , wherein the base is added in a catalytic amount.

Claim 7: The process of claim 6, wherein the base is added in an amount of about 0.01 to about 0.2 equivalents of the starting tenofovir alafenamide diastereomers.

Claim 8: The process of claim 1, wherein the suitable organic solvent is selected from the group consisting of amides, alkylated glycols, ethers, esters, ketones, aromatic hydrocarbons, halogenated hydrocarbons, nitriles, sulfoxides, sulfones and mixtures thereof.

Claim 9: The process of claim 8, wherein the suitable organic solvent is selected from the group consisting of tetrahydrofuran, 2 -methyl tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and mixtures thereof.

Claim 10: The process of claim 9, wherein the organic solvent is dimethyl sulfoxide or dimethylformamide. Claim 11 : The process of claim 1, wherein the racemization is carried out at a temperature of about 20°C and about 80°C. Claim 12: The process of claim 11, wherein the racemization is carried out at a temperature of about 25°C and about 35°C.

Claim 13: A process for the preparation of (R,R,S)-diastereomer of tenofovir alafenamide or pharmaceutically acceptable salts thereof, comprising: subjecting the racemic mixtures of tenofovir alafenamide diastereomers obtained according to claims 1-12 to chromatography using suitable eluent and separating the (R,R,S)-diastereomer of tenofovir alafenamide.

Claim 14: The process of claim 13, wherein the chromatography is either simulated moving bed chromatography or Preparative HPLC.

Claim 15: The process of claim 13, wherein the suitable eluent comprising an alcohol solvent, an ester solvent and mixtures thereof. Claim 16: The process of claim 15, wherein the suitable eluent is selected from the group ethanol, methanol, isopropanol, ethyl acetate, methyl acetate, propyl acetate and mixtures thereof.

Claim 17: The process of claim 16, wherein the suitable eluent is selected from ethanol, ethyl acetate and mixtures thereof. _*

Claim 18: A process for separation of diastereomers of tenofovir alafenamide, comprising: subjecting the mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide to simulated moving bed chromatography or Preparative HPLC using a suitable eluent, and separating the (R,S,S)-diastereomer of tenofovir alafenamide; wherein the suitable eluent comprising an alcohol solvent, an ester solvent and mixtures thereof.

Claim 19: The process of claim 18, wherein the suitable eluent is selected from the group ethanol, methanol, isopropanol, ethyl acetate, methyl acetate, propyl acetate and mixtures thereof.

Claim 20: The process of claim 19, wherein the suitable eluent is selected from ethanol, ethyl acetate and mixtures thereof. Claim 21 : A process for the preparation of (R,S,S)-diastereomer of tenofovir alafenamide or pharmaceutically acceptable salts thereof, comprising:

d) separating the (R,S,S)-diastereomer of tenofovir alafenamide.

Claim 22: The process of claim 21, wherein the suitable organic solvent is dimethyl sulfoxide or dimethylformamide.

Claim 23: The process of claim 21, wherein the suitable base is selected from the group consisting of sodium phenoxide, sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium tert-butoxide and mixtures thereof.

Claim 24: The process of claim 21, wherein the step b) is carried out at a temperature of about 25 °C and about 35 °C.

Claim 25: The process of claim 21, wherein the step c) is carried out using a suitable eluent comprising an alcohol solvent, an ester solvent and mixtures thereof.

Claim 26: The process of claim 25, wherein the suitable eluent is selected from ethanol, ethyl acetate and mixtures thereof.