Background of the Invention :
Tenofovir alafenamide is chemically known as 9-[(R)-2-[[(S)-[[(SH-(isopropoxycarbonyl) ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine (Formula II). Tenofovir alafenamide is a prodrug (or pharmaceutical^ acceptable salts thereof), which exhibits potent anti-HIV activity and enhanced delivery of tenofovir into peripheral blood mononuclear cells (PBMCs) and other lymphatic tissues in vivo as reported in US7390791.

Mono phenyl tenofovir is the key intermediate in the synthesis of tenofovir alafenamide fumarate salt (Formula III). Synthesis of mono phenyl tenofovir was disclosed in US7390791 (Scheme-I and Scheme-ll) and US8664386 (Scheme-Ill) as shown below.



Chinese patent application, CN 104628773, disclosed an improved process for the preparation of mono phenyl tenofovir using triphenyl phosphite and pyridine as base (Scheme-Ill) instead of TEA and DMAP.
Another Chinese patent application, CN105153231, disclosed a method for the preparation of mono phenyl tenofovir (Scheme IV) as shown below by reacting Tenofovir with (diphenoxyphosphoryl)methyl-4-methylbenzenesulfonate in presence of magnesium tert butoxide. The diphenyl tenofovir was hydrolyzed with aqueous sodium hydroxide.


Dimethyl amino pyridine (DMAP) is widely used as a hyper nucleophilic acylation catalyst. In some reactions DMAP is also used as a base. In the prior art process of US8664386 two bases, triethyl amine (2eq) and DMAP (leq) were used in combination to complete the reaction between tenofovir with triphenyl phosphite to produce the mono phenyl tenofovir. A high amount of DMAP was required to promote the reaction between tenofovir and triphenyl phosphite. Triphenylphosphite (TPP) is less electrophilic in nature due to the presence of lone pair of electrons on phosphorous atom. Moreover, after reaction, the liberated diphenyl phosphoric acid is required to be decomposed suitably for environmental safety, which is laborious and becomes a burden to large-scale process besides adding to cost.
There is thus a need for improved methods for preparing mono phenyl tenofovir to provide higher yields, be easier to perform, use less expensive and / or less toxic reagents.

Summary of the Invention :
A new method for the preparation of mono phenyl tenofovir by reacting tenofovir with diphenyl phosphonate is described for the first time. There are no reported methods known where diphenyl phosphonate is used for phenol transfer to phosphoric acid. Accordingly, there is provided a method for preparing mono phenyl tenofovir of formula-l,
c
with diphenyl phosphonate of formula-V.
Detailed description of the invention :
To overcome the drawbacks involved in the prior art process, diphenyl phosphonate was selected as a possible reagent for the preparation of mono phenyl tenofovir. The phosphorous atom of the diphenyl phosphonate exists in +5 oxidation state. The absence of lone pair of electrons and presence of the double bonded oxygen on phosphorous atom in the diphenyl phosphonate increase its electrophilic nature. The more electrophilic nature of the phosphorous atom in the diphenyl phosphonate should favor a facile reaction with tenofovir. To our satisfaction, diphenyl

phosphonate improved the reaction remarkably completing in short time and reducing the requirement of additional base DMAP. To our surprise the reaction also proceeded to mono phenyl tenofovir even in the absence of DMAP base and even without solvent, i.e. neat reaction. The progress of the reaction in the absence of the DMAP base or with reduced amounts of DMAP may be attributed to the high reactivity of diphenyl phosphonate. In the current process the requirement of DMAP is greatly reduced to 0.01 to 0.1 equivalents compared to at least 1 equivalent as reported in prior art.
In one embodiment there is thus provided a method for preparation of mono phenyl tenofovir of formula-l by reacting tenofovir with diphenyl phosphonate in presence of base in a suitable organic solvent or in the absence of organic solvent.

The reaction can be carried out in any suitable solvent. For example, it can be carried out in an aprotic organic solvent, like ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, tertiary butyl acetate, diethyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, acetone, methyl ethyl ketone, methyl tert-butyl ether, toluene, or acetonitrile, or mixtures thereof.
The reaction can be carried out in the presence of any suitable base. For example, the reaction can be carried out in the presence of a base selected from triethyl amine, diisopropyl ethyl amine, tributyl amine, diisopropyl amine, 4-dimethyl amino pyridine, 1, 8-Diaza bicycle [5.4.0] undec-7-ene (DBU) or mixtures thereof.

The reaction can also be carried out at any temperature in the range of about 25" C to about 125° C preferably at a temperature of about 80° C.
In another embodiment there is also provided a method for preparation of tenofovir alafenamide using the mono phenyl tenofovir synthesized from the above method. The mono phenyl tenofovir so obtained was converted to tenofovir alafenamide by reacting with thionyl chloride in an organic solvent medium, distilling the volatiles and further reacting the residue obtained with L-alanine isopropyl ester in presence of organic base in a solvent medium.
In yet another embodiment the tenofovir alafenamide so obtained was converted to the pharmaceutical^ acceptable hemi fumarate salt by reacting it with fumaric acid in a solvent medium.
In summary, an efficient method for the preparation of mono phenyl tenofovir using diphenyl phosphonate was developed, reducing or even eliminating the use of DMAP base without affecting the purity of the product.
Examples :
Example 1: Preparation of Mono phenyl tenofovir using diphenyl phosphonate
Anhydrous tenofovir (30g, 0.104moles), diphenyl phosphonate (57.4g, 0.245moles), DMAP (O.lg, 0.0008moles) and triethyl amine (54.6g, 0.54moles) were refluxed in tertiary butyl acetate for 24hours. After completion of the reaction, 50ml of water was added and organic layer separated. Aqueous layer was treated with dilute hydrochloric acid to pH about 2. The off-white solid formed was filtered and dried in vacuum. Yield: 31.8g (84%), Melting point: 236-238°C, *H NMR (300MHZ, D20): 61.30 (d, 3H), 3.55 (dd, 1H), 3.82 (dd, 1H), 4.07 (m, 1H), 4.25 (dd, 1H), 4.42(dd, 1H), 6.74 (d, 2H), 7.12 (t, 1H), 7.22(t, 2H), 8.25 (s, 1H), 8.32 (s, 1H).
Example 2: Preparation of Mono phenyl tenofovir in neat reaction :
Anhydrous tenofovir (15g, 0.052moles) was reacted with of diphenyl phosphonate (28.7g, 0.122moles) in presence of DMAP (0.05g, 0.0004moles) and triethyl amine (27.3g, 0.27moles) The reaction mixture was stirred for 24h at 90°C. After completion of the reaction, 15ml of water

was added and the aqueous layer was washed with ethyl acetate. The pH of aqueous layer was adjusted to about 2 with dilute HCI. The off-white solid formed was filtered and dried on vacuum. Yield: 15.1g(80%)
Example 3: Preparation of Mono phenyl tenofovir without DMAP :
Anhydrous tenofovir (30g, 0.104moles) was reacted with diphenyl phosphonate (57.4g, 0.245moles) in presence of triethyl amine (54g, 0.534moles} in tertiary butyl acetate at reflux temperature for 24h. After completion of the reaction, 50ml of water was added and organic layer separated. The pH of aqueous layer was adjusted to about 2 with dilute HCI solution. The off-white solid formed was filtered and dried in vacuum. Yield: 30.3g (80%).
Example 4: Preparation of tenofovir alafenamide :
Mono phenyl tenofovir (20g, 0.069moles) was reacted with thionyl chloride (13g, 0.109moles) in acetonitrile at reflux temperature. After complete conversion of starting material, volatiles were distilled, 100ml of dichloromethane added to the residue, cooled to -30 to -35°C and a solution of alanine isopropyl ester (10.7g, 0.081moles) in 100 ml of dichloromethane was added followed by addition of triethyl amine (16.6g, 0.164moles). After conversion of the starting material, 100ml of water added to the reaction and organic layer separated. The organic layer was dried with anhydrous sodium sulfate and concentrated in vacuum to tenofovir alafenamide (Yield 13g; 49.5%). The product obtained was further purified by recrystallization from acetonitrile. Melting point: 117-120°C, JH NMR (300MHZ, CDCI3): 61.22 (m, 9H), 1.29(d, 3H), 3.61 (dd, 1H), 3.74(m, 5H) 4.32 (dd, 1H), 4.99 (m, 1H), 5.80 (bs, 2H), 6.97 (m, 5H), 8.99 (s, 1H), 8.35 (s, 1H)
Example 5: Preparation of tenofovir alafenamide hemi fumarate :
Tenofovir alafenamide (llg, 0.023moles) was treated with fumaric acid (1.33g, O.Ollmoles) in 110ml of acetonitrile at 70-75°C for 45minutes. The clear solution formed was cooled to 20-25°C to form a white solid, which was filtered by vacuum suction to get 11.lg (90%) of tenofovir alafenamide hemi fumarate, Melting point: 132-134°C. JH NMR (300MHZ, DMSO d6): 61.05 (d, 3H), l.ll(m, 9H), 3.72 (m, 4H), 4.1 (dd, 1H), 4.25 (dd, 1H), 4.80 (heptet, 1H), 5.62 (t, 1H), 6.63 (s, 1H), 7.02 (d, 2H), 7.11 (t, 1H), 7.24 (dd, 4H), 8.11 (s, 1H), 8.14(s, 1H) _

We Claim :
1. A method for the preparation of mono phenyl tenofovir of formula-l, comprising reacting
tenofovir (formula IV) with diphenyl phosphonate (formula V) in presence of a suitable base

2. As per method of claim 1, suitable base used is triethylamine or a mixture of triethyl amine and catalytic amount of dimethyl amino pyridine.
3. Converting the mono phenyl tenofovir obtained as per claim 1 to tenofovir alafenamide and / or its hemi fumarate salt.

A new method for preparing mono phenyl tenofovir (Formula-I) using diphenyl phosphonate is provided.