FIELD OF THE INVENTION:

The invention generally relates to a novel process for the preparation of Tenofovir. More specifically, the invention relates to process for the preparation of Tenofovir disoproxil Fumarate using catalytic amount of Wittig reagent which can be practiced on an industrial scale.

BACKGROUND OF THE INVENTION:
Tenofovir is approved for commercial use as in the form of Tenofovir disoproxil fumaric acid salt, chemically known as 9-[(R)-2-[[bis [[(isopropoxycarbonyl) oxy]methoxy] phosphinyl] methoxy] propyl] adenine Fumarate is represented by the following structure of Formula:

Tenofovir disoproxil Fumarate is a highly potent antiviral agent and is available in the market under the brand name VIREAD® in the form of 300mg of oral tablets and in combination with other antiviral agents.

U.S. Pat. No. 5,922,695 ("the '695 patent") discloses phosphonomethoxy nucleotide analogs such as Tenofovir disoproxil and the salts, hydrates, tautomers and solvates thereof. The '695 patent further discloses a process for preparation of Tenofovir disoproxil by esterification of Tenofovir with chloromethyl isopropyl carbonate using l-methyl-2-pyrrolidinone and triethylamine. In this patent Tenofovir Disoproxil is converted into its Fumarate salt without isolation.

Various processes for the synthesis of tenofovir disoproxil and its salts has been disclosed in the patent/ patent applications i.e., US2004/0018150, US6465649, US5935946, US5977089.

US 20130005969 describes the process for the preparation of Tenofovir which involves the usage of phase transfer catalyst and it describes the phase transfer catalysts as tertramethyl ammonium bromide, tetrabutyl ammonium bromide, methyl triethyl ammonium bromide, benzyl trimethyl ammonium bromide, benzyl triethyl ammonium bromide, molecular sieves and crown ethers.

WO 2011/111074 describes a process for the preparation of Tenofovir Disoproxil which involves esterifying Tenofovir with chloromethyl isopropyl carbonate in presence of a base, phase transfer catalyst optionally dehydrating agent and converting Tenofovir Disoproxil into its pharmaceutically acceptable salts.

In the above mentioned prior art processes, it is found that a relatively large amount of quaternary ammonium, as a phase transfer catalyst, has been used to proceed up the reaction rapidly. Moreover, a portion of the phase transfer catalyst is usually converted to by-products which often difficult and may be carry over in the final product.

It would be desirable to provide a process for the preparation of Tenofovir disoproxil Fumarate, which is simple, convenient and cost effective manner and on commercial scale using catalytic amount of wittig reagent.

The present invention provides a process for the preparation of Tenofovir disoproxil Fumarate using a catalytic amount of wittig reagent which enhances the rate of reaction. The process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield.

The process for the preparation of Wittig salts especially phosphonium salts has been disclosed in the prior art patents i.e., US3932485, US4122123, US6169209, US6187959 and US6423873.

So far the use of Wittig reagent as a phase transfer catalyst is not used in any prior art processes for the preparation of Tenofovir disoproxil Fumarate.

OBJECTIVE OF THE INVENTION:
The main object of the invention is to provide a novel process for the preparation of Tenofovir Disoproxil Fumarate using Wittig reagent.

Another object of the invention is to provide a simple, cost effective process for the preparation of Tenofovir Disoproxil Fumarate with high purity and without the formation of undesired impurities.
Yet another object of the present invention is to provide an efficient process which avoids the use of large quantities of catalysts.

Further object of the invention is to provide a process for preparation of Tenofovir Disoproxil Fumarate in high yield and purity in short span of time, thereby substantially minimize the product degradation.

SUMMARY OF THE INVENTION:
The present invention encompasses a process for the preparation of Tenofovir Disoproxil and its conversion to pharmaceutically acceptable salts using catalytic amount of Wittig reagent.

Wittig salts are Quaternary phosphonium salts and the same can be defined with the general formula as given below:

RPPh3+X"
Where R=alkyl, benzyl, allylic and aryl and X is halogens.

r
One aspect of the invention provides a novel process by employing additives which can be used in catalytic amount. Also, it has now surprisingly been found that the catalytic amount of additives with dehydrating agent has overcome all the long felt need of an industrial viable process for the preparation of Tenofovir.

This process is valuable as well as viable for the production of Tenofovir with minimal reaction time and less by-products.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS:
The present invention relates to an improved process for the preparation of Tenofovir Disoproxil and its pharmaceutically acceptable salts comprising the steps of:

a) Esterifying Tenofovir with chloromethyl isopropyl carbonate in presence of a base, Wittig reagent and dehydrating reagent in a suitable solvent.

b) Optionally purifying Tenofovir disoproxil

c) Converting Tenofovir disoproxil into its pharmaceutically acceptable salts.
In one embodiment of the present invention, the esterification of Tenofovir monohydrate is carried out in the presence of a base and Wittig reagent, wherein base is selected from organic amine like trialkyl amine such as triethylamine, diisopropyl ethyl amine preferably triethylamine and the wittig reagent is selected from the group comprising Isopropyl triphenylphosphonium iodide, triphenylphosphonium bromide, n-propyl triphenyl phosphonium bromide, -propyl triphenyl phosphonium iodide, ethyl triphenylphosphonium iodide, ethyl triphenylphosphonium bromide, tert-butyl triphenylphosphonium iodide, tert-butyl triphenylphosphonium bromide.

In another embodiment of the present invention esterification of Tenofovir monohydrate is carried out in the presence of a dehydrating agent. The dehydrating agent is selected from silylated dehydrating agent such as trialkylsilylhalides, bis(trimethylsilyl)acetamide (BSA) and hexamethyldisilazane (HMDS), preferably trialkly silyl halides, more preferably trimethyl silyl chloride.

In another embodiment of the present invention esterification of Tenofovir monohydrate is carried out in a solvent selected from Acetonitrile, dimethyl formamide, N-methyl pyrrolidine, cyclohexane, ethyl acetate, isopropyl acetate, n-hepatne, isopropyl alcohol and water or mixtures thereof, preferably N-methyl pyrrolidine.

In another embodiment of the present invention, Tenofovir Disoproxil is converted into its pharmaceutically acceptable salt preferably Fumarate salt by the conventional methods.

During the esterification reaction it has been observed that due to prolonged heating of the reaction mass product starts degrading resulting impurities such as monoester. In view of this observation it is important to complete the esterification reaction in minimum possible time. Probably the esterification reaction takes place through the formation of triethyl amine salt of Tenofovir. The triethyl amine salt of Tenofovir is very limited solubility in the reaction media resulting in the formation of heterogenous reaction system. We have observed that addition of Wittig reagent such as n-propyl triphenylphosphonium bromide, Isopropyl triphenylphosphonium Iodide etc., improved the rate of reaction.

According to the present invention, by using Wittig reagent along with dehydrating agents the yield of Tenofovir Disoproxil and its pharmaceutically acceptable salts is increased from 50% to 90%. The dimer impurity formed by the prior art processes is minimized by using this invention.

The following are the advantages of the present invention over the prior art process:
• Less catalytic amounts of Wittig salts are used which is tenfold less than the prior art processes
• Reaction completes within short span of time
• Ease of handling and recycling of Wittig salts

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

Example-1
Preparation of Tenofovir disoproxil free base

Cyclohexane (700ml) and 9-[(R)-2-(Phoshonomethoxy) propyl] adenine monohydrate (lOO.Og, (1.0X)) were taken at 30±5°C under nitrogen atmosphere. To this triethyl amine (66.0g) was added and heated to 80±5°C. Water was collected azeotropically at 80±5°C. After completion of water removal, NMP (350ml), trimethyl silyl chloride (7.12g) was charged and stirred for 30 mins at 30°±5. Triethylamine (79.57g) was added and heated the reaction mass to 52±2°C. To the reaction mass, Chloromethyl isopropyl carbonate (250.0g) and n-propyl triphenylphosphonium bromide (12.62g, O.leq) was added and maintained for 5.0hrs±lhr. The reaction was monitored by HPLC (Conversion usually 84.3%). Pre-cooled process water (12.0 X) was added after reaction completion and isolated by filtration and wet cake washed with water & followed by cyclohexane. The wet Tenofovir disoproxil was charged into methylene dichloride (600ml) and again washed with water at 12± 3°C and treated with sodium sulphate. The dried organic layer was concentrated under vacuum below 35°C. MDC traces are removed by adding cyclohexane and followed by distillation under vacuum below 35°C. To this reaction mass ethyl acetate was added and maintained for 1.0hrs±5min at 22±2°C. Then cooled to -3±2°C, maintained for 3.0hrs±5min. Reaction mass was filtered and washed with pre-cooled ethyl acetate and Cyclohexane mixture. The isolated wet product was dried completely under vacuum at 32.5 ± 2.5°C. Yield: 145.0g; HPLC Purity: 99.58%

Example-2
Preparation of Tenofovir disoproxil free base
Cyclohexane (350ml) and 9-[(R)-2-(Phoshonomethoxy) propyl] adenine monohydrate (50.0g) were taken at 30±5°C under nitrogen atmosphere. To this triethyl amine (33 g) was added and heated to 80±5°C. Water was collected azeotropically at 80±5°C. After completion of water removal, NMP (150ml), trimethyl silyl chloride (3.56 g) was charged and stirred for 30 mins at 30°±5. Triethylamine (79.57g) was added and heated the reaction mass to 52±2°C. Chloromethyl isopropyl carbonate (125.0 g), and Isopropyl triphenylphosphonium Iodide (7.08 g, 0.1 eq) were added to the reaction mass and maintained for 5.0hrs±lhr. The reaction was monitored by HPLC (Conversion usually 80-85%). Pre-cooled process water (12.0 X) was added after reaction completion and isolated by filtration and wet cake was washed with water & followed by cyclohexane. The wet Tenofovir Disoproxil was charged into methylene dichloride (6.0 X) and again washed with water at 12± 3°C and treated with sodium sulphate. The dried organic layer was concentrated under vacuum below 35°C. MDC traces are removed by adding cyclohexane and followed by distillation under vacuum below 35°C. To this reaction mass ethyl acetate was added and maintained for 1.0hrs±5min at 22±2°C. Cyclohexane was added and maintained for 1.0hrs±5min at 22±2°C, cooled to -3±2°C; maintained for 4.0hrs±5min. Reaction mass was filtered and washed with pre-cooled cyclohexane and ethyl acetate mixture followed by Cyclohexane. The isolated wet product was dried completely under vacuum at 32.5 ± 2.5°C. Yield: 61.0g; HPLC Purity: 93.07%

Example-4
Preparation of Tenofovir disoproxil free base
Cyclohexane (28 L) and 9-[(R)-2-(Phoshonomethoxy) propyl] adenine monohydrate (4.0kg) were taken at 30±5°C under nitrogen atmosphere. Triethyl amine (2.64 kg) was added and heated to 80±5°C. Water was collected azeotropically at 80±5°C. After completion of water removal, NMP (14.4kg), trimethyl silyl chloride (0.285 kg) was charged and stirred for 30 mins at 30°±5.Triethylamine (3.18Kg) was added and heated the reaction mass to 52±2°C. To the reaction mass added chloromethyl isopropyl carbonate (10.0 kg), n-propyl triphenylphosphonium bromide (0.505kg, O.leq) and maintained for 5.0hrs±lhr. The reaction was monitored by HPLC (Conversion usually 80-85%). Pre-cooled process water (12.0 X) was added after reaction completion and isolated by filtration and wet cake washed with water & followed by cyclohexane. The wet Tenofovir Disoproxil was charged into methylene dichloride (6.0 lit X) and again washed with water at 12± 3°C and then dilute Aq. Ammonia washed to remove the MonoPOC PMPA impurity and treated with sodium sulphate. The dried organic layer was concentrated under vacuum below 35°C. MDC traces are removed by adding cyclohexane and followed by distillation under vacuum below 35°C. To this reaction mass ethyl acetate was added and maintained for 1.0hrs±5min at 22±2°C. Then added Cyclohexane and maintained for 1.0hrs±5min at 22±2°C, cooled to -3±2°C; maintained for 4.0hrs±5min. Reaction mass was filtered and washed with pre-cooled cyclohexane and ethyl acetate mixture followed by Cyclohexane. The isolated wet product was dried completely under vacuum at 32.5 ± 2.5°C. Yield: 5.30 kg; HPLC Purity: 98.20%

Example-4
Preparation of Tenofovir disoproxil Fumarate
Cyclohexane (1400ml) and 9-[(R)-2-(Phoshonomethoxy) propyl] adenine monohydrate (200.0g) were taken at 30°C to 35°C under nitrogen atmosphere. Triethyl amine (132.0g) was added and heated to 80°C to 85°C. Water was collected azeotropically at 80°C to 85°C. Cyclohexane was distilled off completely after removal of water. NMP (700ml) and trimethyl silyl chloride (14.24g) was charged and stirred for 30mins.Triethyl amine (66.0g) was added and the reaction mass was heated to 52°C to 54°C. To the reaction mass added chloromethyl isopropyl carbonate (500 g), n-propyl triphenylphosphonium bromide (25.2 g, O.leq) and maintained for 4.0hrs±5min. The reaction mass was monitored by HPLC (Conversion usually 80-85%). Pre-cooled process water (2400 ml) was added after reaction completion and isolated by filtration and wet cake slurry with Pre-chilled water & followed by cyclohexane wash (800ml).The wet Tenofovir Disoproxil was charged into methylene dichloride (300ml) and again washed with water at 12±3°C and then dilute Aq. Ammonia wash to remove the MonoPOC PMPA impurity and finally washed with dilute fumaric acid solution treated with sodium sulphate. The dried organic layer was added to the Isopropyl alcohol/Fumaric acid solution at 52±3°C. The methylene dichloride/Isopropyl alcohol was distilled out (4.0X) and cooled to 25-35°C, reaction mass was stirred for lhr. The reaction mass was cooled to 8±2°C and maintained for 4hrs at 8±2°C. Then cooled to 2±3°C and maintained for lhr.Filtered the product and washed with Isopropyl alcohol. The wet product was dried at 38°C to 40°C under reduced pressure to provide the title compound.

Yield: 250 g; HPLC Purity: 99.11 %
Example-5
Preparation of Tenofovir disoproxil Fumarate
Tenofovir free base (50.0g), fumaric acid (15.2g) were charged into isopropyl alcohol (440ml) and heated to 53±2°C to get a clear solution. Reaction mass was filtered through micron filter paper. The filtrate was allowed to crystallize out gradually by natural cooling for 12.0hrs±2hrs to 25±5°C. The reaction mass was maintained at 25±5°C for 1.0hr±5min and cooled to 10±2°C under nitrogen atmosphere. Then it was maintained for 4 hours ± 5 min at 10±2°C. The reaction mass was further cooled slowly to 0±2°C and maintained for 1.0hr±5min. The wet material was isolated by filtration and washed with isopropyl alcohol and dried completely under vacuum at 38±2°C to yield Tenofovir disoproxil Fumarate. Yield: 53.0 g, HPLC Purity: 99.70%

Claims

1. A novel process for the preparation of Tenofovir disoproxil Fumarate using wittig reagents.

2. An improved method for the preparation of Tenofovir disoproxil Fumarate which comprises of the following steps.

a) Condensation of Tenofovir with chloromethyl isopropyl carbonate in the presence of base, Wittig reagent and a dehydrating agent in a solvent.

b) Optionally purifying Tenofovir Disoproxil and

c) Reacting Tenofovir disoproxil with fumaric acid and isopropyl alcohol to obtain Tenofovir disoproxil Fumarate.

3. The wittig reagent according to claim 1 is selected from Isopropyl triphenylphosphonium iodide, triphenylphosphonium bromide, n-propyl triphenyl phosphonium bromide, -propyl triphenyl phosphonium iodide, ethyl triphenylphosphonium iodide, ethyl triphenylphosphonium bromide, tert-butyl triphenylphosphonium iodide, tert-butyl triphenylphosphonium bromide.

4. The dehydrating agent according to claim 2 is selected from Trimethyl sillyl chloride, acetic anhydride, Magnesium oxide, Calcium Oxide, Calcium chloride.

5. The solvent according to claim 2 is selected from Acetonitrile, dimethyl formamide, N-methyl pyrrolidine, cyclohexane, ethyl acetate, isopropyl acetate, n-heptane, isopropyl alcohol and water or mixtures thereof.

6. Use of Wittig reagent as a Phase transfer catalyst for the preparation of Tenofovir Disoproxil Fumarate.