700147025
700147025
Field of the invention:
The present invention relates to an improved process for the preparation of Tenofovir, and further conversion to Tenofovir Disoproxil or its pharmaceutically acceptable salts thereof. More particularly the present invention relates to a process for the preparation of Tenofovir by dealkylation of its phosphonate ester of Formula 11(a), preferably of Formula II.



°* '°R fl 1 \ °* '°Et

CH3 CH3
Formula 11(a) Formula II
Background of the Invention:
Tenofovir, also known as (R)-9-(2-phosphonomethoxypropyl) adenine [(R)-PMPA] is represented by the following structure of Formula I:
NH2
CH3
Formula I
Tenofovir is approved for commercial use as in the form of Tenofovir disoproxil Fumarate under the brand name VIREAD® in the form of 150, 200, 250 and 300mg of oral tablets and in combination with other antiviral agents. Tenofovir belongs to the nucleotide reverse transcriptase inhibitor (NtRTI) class of drugs. Tenofovir Alafenamide Fumarate is also a prodrug of Tenofovir
US 5,733,788 A, US 5,922,695 A, WO 2002/008241 A2, US 5,934,946 A, WO 9403467 A2, WO 2006/133632.A1 and CN 102093417 A discloses the process for the preparation of Tenofovir wherein the corresponding phosphonate ester is dealkyiated using bromotrimethylsilane (TMSBr) in acetonitrile.

WO 2008/157657A1, CN 101870713 A, Commun.1995, 60, 1196, Collect Czech. Chem. Communication 1995, 601, 1390, Drugs of the Future 1998, 23, 1279, Journal of the American Chemical Society 1996, 118, 7420-7421 and Tetrahedron Letters 39 (1998) 1853-1856 discloses a process for the preparation of Tenofovir wherein TMSBr is used for dealkylation of phosphonate ester of Formula II. Use of TMSBr for dealkylation of phosphonate esters was disclosed in Tetrahedron letters 2, 155-158, 1977 and J.C.S Chem. Comrn. 739, (1979).
US 6,465,649 B2 discloses a process for the preparation of Tenofovir by dealkylation of compound of Formula II with TMSC1 in a solvent such as chloroform or chlorobenzene under pressure.
CN 101531679B describes a process for the preparation of Tenofovir by the de-ethylation of compound of Formula II using TMSCl/Acetonitrile in the presence of catalytic amounts of sodium halides. Convenient dealkylation of dialkyl phosphonates using TMSC1 in the presence of Sodium iodide was disclosed in Tetrahedron letters 28, 2523-2526, 1978.
US 8,049,009 B2 describes a process for the preparation of Tenofovir which involves dealkylation of phosphonate esters by using mineral acids such as HBr (aq), HCI (aq), HBr in acetic acid or HCI gas in IPA. WO 2011/111074A2 also discloses the preparation of Tenofovir using HBr(aq). IN 292/MUM/2008 describes the process for the preparation of Tenofovir by dealkylation of its phosphonate ester in the presence of an inorganic acid. Organic Phosphorus Compounds Vol. 7, p.9, John Wiley and Sons, New York, 1950 discloses the conversion of dialkyl phosphonates to phosphonic acids is usually accomplished by heating in concentrated HCI or HBr.
WO 2008/134578A2 describes the synthesis of isotopically labeled reverse transcriptase inhibitors; wherein hydrolysis of phosphonate esters is carried using TMSBr in DMF. J Med Chem. 33, 1207-1213 (1990) involves the use of TMSBr in DMF for dealkylation of phosphonate ester.

WO 2008/005555 Al generally relates to compounds and pharmaceutical compositions which selectively activate toll-like receptor 7 (TLR7), and methods of making and using them wherein the process involves use of TMSBr in DMF or THF.
US 2006/122391 Al describes the use of nucleotide analogues and preparation thereof wherein the process involves the use of TMSI/TEA for dealkylation of phosphonate esters.
CN101574356A describes the use of TMSC1/KI for deprotection of phosphonate ester in the preparation of Tenofovir.
IN 3930/CHE/2011 provides a process for the preparation of Tenofovir by dealkylation of its phosphonate ester using ionic complexes selected from the group comprising a complex of a amide and an acid, a complex of aluminium salt and a amide-acid reagent and a complex of aluminium salt and an amine.
Tetrahedron 66 (2010) 8317-8144 describes a rapid, low temperature hydrolysis of compound of Formula II mediated by TMSC1 and NaBr which was demonstrated to be superior to the TMSBr mediated hydrolysis. Organic Process Research and Development 2010, 14, 1 194-1201 also describes hydrolysis of compound of Formula II in the presence of TMSCl/NaBr to obtain Tenofovir, which is converted to Tenefovir disoproxil fumarate by treatment with CMIC in the presence of triethylamine and tetra-butylammonium bromide followed by salt formation with fufnaric acid.
Nucleosides, Nucleotides and Nucleic Acids, 20(4-7), 1299-1302 (2001) shows that TMSC1 completely dealkylate phosphonate esters at elevated temperatures in a sealed reaction vessel. These conditions are tolerated by a variety of functional groups and lead to high conversions of dimethyl, diethyl and diisopropyl phosphonates to their corresponding phosphoriic acids.

Journal of Medicinal Chemistry, 2006, 49, 3955-3962 related to 2'5-oligoadenylate compounds wherein TMSBr, 2,6-lutidine were used in the preparation of derivatives.
The patent US 6,465,649 Bl discloses that the conventional methods for dealkylating phosphonate ester include reaction with aqueous solutions of Cone. HC1 or HBr. However, many of the functional groups on the phosphonates are acid liable which cannot tolerate harsh acidic conditions for instance amino group as in the case of Tenofovir is readily converted into Keto compound.
Milder reagents to effect dealkylation are trialkylsilylhalides which selectively cleave PO alkyl esters yielding trialkylsilyl esters which are readily hydrolyzed with water. However, the entire prior art processes involve extensive purification steps to obtain high quality end product. Considering the importance of Tenofovir and Tenofovir disoproxil fumarate it would be desirable to provide a process for the preparation of Tenofovir which is simple and cost effective, industrially viable process without sacrifice of overall yield and high quality of the end product.
Object of the Invention:
The main object of the invention is to provide a simple, cost effective process for the preparation of Tenofovir by dealkylation of its phosphonate esters yielding a high purity Tenofovir without formation of undesired impurities.
Another object of the present invention is to provide a process for the preparation of Tenofovir in high yield and purity without involving the redundant purification steps.
Further object of the invention is to provide a process for the preparation of Tenofovir by dealkylation of its phosphonate esters using halotrimethylsilane in the presence of phase transfer catalyst optionally in the presence of solvent.
Yet another object of the invention is to provide an improved process for the preparation of Tenofovir disoproxil fumarate with high yield and purity.

Summary of the Invention:
The present invention relates to an improved process for the preparation of Tenofovir of Formula I:
NH,
O OH

CH3 Formula I
which comprises, dealkylation of compound of Formula 11(a);
NH,
O OR

CH3
Formula II (a)
wherein R represents lower alkyl such as methyl, ethyl, isopropyl, etc.,, using a halotrimethylsilane in the presence of phase transfer catalyst optionally in the presence of a solvent.
In a preferred embodiment the present invention relates to a process for the preparation of Tenofovir of Formula I:


O OH
a
E o o,
o

CH

3

£ Formula I
Q
0 which comprises the dealkylation of compound of Formula II;
CN i
LU
X
o
I
CN
oo
o
CO CD
o
uvy HOOC
N^NVP^ \^0 O CH3 . ^
^~~< \f | COOH
CH3 O CH3
Formula VI
comprising the steps:

a) Preparation of compound of Formula II by reaction of 9-[2-(R)-(hydroxyl)propyl]
o.
£
Q adenine of Formula III with a compound of formula IV;
£ O
NH,

O p;
" \ OH fti°^ OR
Formula HI £H Formula IV(a)
Wherein R is defined above and Rx is represents a leaving group such as mesyl or tosyl and like., to obtain a compound of Formula 11(a); and b) with or without isolation the product obtained in step a) is treated with halotrimethylsilane in the presence of phase transfer catalyst optionally in the presence of a solvent.
A preferred embodiment of the present invention relates to an improved process for the preparation of Tenofovir of Formula (I)
N^r]\ o OH
kN^^0_A)H
CH3 Formula I
which comprises,
a) reaction of 9-[2-(R)-(hydroxyl)propyi] adenine of Formula III with a compound of Formula IV;

•

NH

O OEt
X
TsO^ OEt

Formula m £R Formula IV
to obtain a compound of Formula II; and b) With or without isolation the product obtained in step a) is treated with chlorotrimethylsilane in the presence of tetrabutylammoniumbromide (TBAB) in acetonitrile.

Yet another embodiment of the present invention is to provide an improved process for preparation of Tenofovir Disoproxil ester of Formula V or its pharmaceutical^ acceptable salts, comprising the steps:
a) reaction of 9- [2-(R)-(hydroxyl)propyl] adenine of Formula III with a compound of formula IV(a);
NH2
N^N OH Ri°^ N°R
Formula III £R Formula IV(a)
a
E o o,
o
wherein R is defined above and Ri is represents a leaving group such as mesyl or tosyl and like., to obtain a compound of Formula 11(a).
NH,
O OR
o
0) Q
Jo
S CH3
CM
^ Formula II (a)
o b) with or without isolation the product obtained in step a) is treated with
CN
oo
o
CO CD
o
CN
halotrimethylsilane in the presence of phase transfer catalyst.
c) with or without isolation, the product obtained in step b) is further reacted with Chloro methyl isopropyl carbonate optionally in the presence of a base; and
:frrr:FFe^E^£FH^^- .-^ESsfEBET^ffiEzzS^Bg
CO
o

d) Converting the obtained Tenofovir disoproxil ester of Formula V to its pharmaceutically acceptable salts.
The pharmaceutically acceptable salts according to the present invention are selected from fumarate, succinate, citrate, oxalate, besylate, maleate, tosylate, phosphate and like.
In one embodiment of the present the reaction of compound of Formula III with compound of Formula IV (a) or IV of step a) is carried by conventional methods. One such method involves use of metal alkoxide such as Lithium tert butoxide, magnesium isopropoxide and magnesium tert-butoxide and sodium tert-butoxide.
A preferred embodiment of the present invention is to provide an improved process for preparation of Tenofovir Disoproxil Fumarate of Formula VI;

HOOC,
CH3 Formula VI

COOH

comprising the steps:
a) Preparation of compound of Formula II by reaction of 9-[2-(R)-(hydroxyl)propyl] adenine of Formula III with a compound of formula IV;

NH,
N- ^r\ °* 'OEt

N^N OR TsO-^ OEt
Formula III £R Formula IV
b) dealkylation of compound of Formula II

O OEt
NH

OEt

CH3
Formula TI
using chlorotrimethyisilane in the presence of tetrabutylammoniumbromide
(TBAB); c) with or without isolation, the product obtained in step b) is further reacted with Chloro methyl isopropyl carbonate optionally in the presence of a base to obtain Tenofovir Disoproxil of Formula V; and


CH3
Formula V
d) Converting the obtained Tenofovir disoproxil ester of Formula V to Tenofovir disoproxil fumarate using Fumaric acid.
_0)
a
E o
.2 Yet another embodiment of the present invention is to provide an improved process
In one embodiment of the present invention, esterification of Tenofovir is carried out
by conventional methods. One such method includes carrying out reaction in presence
^ of base wherein base is selected from organic amine like trialkylamine such as
triethylamine, diisopropyl ethyl amine, preferably triethylamine
o for the preparation of Tenofovir Disoproxil ester of Formula V or its pharmaceutical^
9 acceptable salts, comprising the steps::
S a) Dealkylation of compound of Formula II (a):
LU
X
o
I
^-
CN
oo
o
CO CO
o
3 CO
o

O OR
V
N ^
NH,

CH3 Formula II (a)
using halotrimethylsilane in the presence of phase transfer catalyst;
b) With or without isolation, the product obtained in step a) is reacted with Chloro methyl isopropyl carbonate optionally in the presence of base; and
c) Converting the obtained Tenofovir disoproxil ester to its pharmaceutically acceptable salts.
A preferred embodiment of the present invention is to provide an improved process for the preparation of Tenofovir disoproxil Fumarate of Formula VI:
CH3
5
0-A CH3
y %/ HOOC
N / x~
W V/° °\/0 O CH3 . ^
CH3 O CH3
Formula VI
which comprises:
a) Dealkylation of compound of Formula II:
O OEt OEt
CH3
Formula II
using chlorotrimethylsilane in the presence of tetrabutylammoniumbromide (TBAB) in acetonitrile;
b) With or without isolation, the product obtained in step a) is reacted with Chloro
methyl isopropyl carbonate optionally in the presence of base; and

c) Converting the obtained Tenofovir disoproxil ester to Tenofovir disoproxil fumarate using Fumaric acid.
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.The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention.
Examples:
Example 1: Preparation of (R)-9-[2-(diethylphosphono methoxy) propyl] adenine.
A clean 3Necked-lL round bottom falsk is charged with DMF (85 ml) and cooled to 16-18°C and charged sodium-t-butoxide (24.8 gm) and stirred. Magnesium chloride (12.3gm) is added in portions about 30 min and stirred. Raising the temparature to 60-65°C and charged 9-[2-(R)-(hydroxy)propyl] adenine (25gm) and stirred. Diethyl(tosyloxy) methylphosphonate (83.5 gm) was added slowly for 120 mins at 65-70°C and maintained for 5-8 hours. After completion of the reaction, the reaction mixture is distilled of and the crude is added with acetonitrile at 25-30°C. pH is adjusted to neutral with acetic acid soluton and stirred. The reaction mass is filtered and washed with acetonitrile followed by through hyflow bed. The filtrate obatined is distilled off to obtain orange oil of (R)-9-[2-(diethylphosphono methoxy) propyl] adenine.
Example 2: Preparation of (R)-9-(2-phosphonomethoxypropyl) adenine [(R)-PMPA].
A clean 3Necked-lL round bottom falsk is charged with (R)-9-[2-(diethylphosphono methoxy) propyl] adenine (Ex-1) and acetonitrile (50 ml) and stirred. Tetrabutylammonium bromide (200 gm) is added is added to the reaction mass and slowly chlorotrimethylsilane (74 gm) is added. Reaction mass temparature is raised to 67°C and maintained for 15-20 hours. Filter the raection mass and wash acetonitrile. ^giltr^
19

and cooled to 5-10°C and filtered. Filtrate is taken and adjusted the pH to 2.8-3.2 with 48% lye. Stitted for 15 hours then cooled to 0-5°C and maintained for 4 hous. Filtered the solid and washed with acetone (20ml). wet material is added with water and heated at 98°C and stirred. Cooled to 0-5°C. maintained for 4 hours and filtered to give (R)-9-(2-phosphonomethoxypropyl) adenine (19 gm). HPLC purity 98.7%.
Example 3: Preparation of Tenofovir Disoproxil Fumarate.
Toluene (300 ml) and (R)-9-(2-phosphonomethoxypropyl) adenine (30 gms) is added into a round bottom flask and heated to remove water and the solvent was distilled off under vacuum, the reaction mass was cooled to room temperature N-methyl pyrrolidinone (124 gm) and triethyl amine (29.88 gm) were added to the reaction mixture. Strired and chloromethyl isopropyl carbonate (75 gm) was added. The reaction mass was heated to 50-60°C and maintained for 4-8 hrs. and then cooled to 0° C. cool the reactiona mass and slowly add the reaction mass into a RBF containing Methylene chloride (480 ml) and cool to 12°C. water is added into reaction mass. Separate the two layers and organic layer is washed with water and dried with sodium sulphate. Distill of the sovlent completely and stripout with IPA. Reaction mass is cooled to 25- 35°C and cyclohexane (300ml) is charged at 25-35°C while reaction mass becomes thick solid. Reaction mass is stirred for 1 hr at 25-35°C and 1 hr at 10-15°C. The precipitated product is filtered and washed with chilled cyclohexane (30 ml). In another flask Fumaric acid (15.7 gm) and Isopropyl alcohol (217.2 ml) were added and stirred. The reaction mass heated to 50°C and added with obatined wet cake, maintianed at 50°C. Filter the reaction mass and filtrate is cooled to obatin the precipitate. The above precipitate is filtered and then added with isopropyl acetate (60gm) and stirred. Agin added with Di-n-butylether (210 gm). Maintained at 27°C. Filted and washed with isopropyl acetate and Di-n-butylether and recrystallized using isopropyl acetate to give high pure Tenofovir disoproxil fumarate (42 gm). HPLC purity 99.1%
20

Example 4: Preparation of Tenofovir Disoproxil Fumarate.
DMF (34.8)gms is cooled to 18°C and added with sodium tert-butoxide (24.8 gm) and strirred. Magnesium chloride is added in portion for 25-30 fnin. raised the temparature to 65-60°C and charged with 9-[2-(R)-(hydroxy)propyl] adenine (lOgfn) and stirred. Diethyl(tosyloxy) methylphosphonate (33.4 gm) was added slowly for 120 mins at 67°C and maintained for 5-8 hours, the reaction mixture is distilled of and the crude is added with acetonitrile at 25-30°C. pH is adjusted to neutral with acetic acid soluton and stirred. The reaction mass is filtered and washed with acetonitrile followed by through hyflow bed. The filtrate obatined is concentrated by distillation and added with acetonitrile (20 ml) and Tetrabutylammonium bromide (83.2 gm). Chlorotrimethylsilane (29.9 gm) was added slowly and raised the temparature to 65-68°C and maintained for 20 hours. Reaction mass is filtered and filtrate is distilled to remove the solvent completely. Charged N-methyl pyrrolidinone (92 gm) and triethylamine (22.2 gm) and stirred, chloromethyl isopropyl carbonate (55.75 gm) was added slowly. The reaction mass was heated to 50-60°C and maintained for 4-8 hrs. and then cooled to 0° C. cool the reactiona mass and slowly add the reaction mass into a RBF containing Methylene chloride (357 ml) and cool to 12°C. water is added into reaction mass. Separate the two layers and organic layer is washed with water and dried with sodium sulphate. Distill of the sovlent completely and stripout with IPA. Reaction mass is cooled to 25- 35°C and cyclohexane (300ml) is charged at 25-35°C while reaction mass becomes thick solid. Reaction mass is stirred for 1 hr at 25-35°C and 1 hr at 10-15°C. The precipitated product is filtered and washed with chilled cyclohexane (30 ml).). In another flask Fufnaric acid (15.7 gin) and Isopropyl alcohol (217.2 ml) were added and stirred. The reaction mass heated to 50°C and added with obatined wet cake, maintianed at 50°C. Filter the reaction mass and filtrate is cooled to obatin the precipitate. The above precipitate is filtered and then added with isopropyl acetate (60gm) and stirred. Agin added with Di-n-butylether (210 gm). Maintained at 27°C. Filted and washed with isopropyl acetate and Di-n-butylether and recrystallized using isopropyl acetate to give high pure Tenofovir disoproxil fumarate (42 gm). HPLC purity 99.1%
21

700147028
„, t . 700147028
We claim:
1. A process for the preparation of Tenofovir of Formula I: which comprises. dealkylation of compound of Formula 11(a);

CH3 CH3
Formula II (a) Formula I
wherein R represents lower alkyl such as methyl, ethyl, isopropyl, etc.,, using a halotrimethyl silane in the presence of phase transfer catalyst optionally in the presence of a solvent.
2. The process according to claim 1, halotrimethylsilane may be seleceted from bromotrimethylsilane, chlorotrimethylsilane and iodotrimethylsiiane.
3. The process according to claim 1, Phase transfer catalyst may be seleceted from tetramethyl ammonium bromide, tetrabutyl ammonium bromide, methyl triethyl ammonium bromide, benzyl trimethyl ammonium bromide, benzyl triethyl ammonium bromide, triethyl benzyl ammonium chloride (TEBA), tetrabutylammonium chloride (TBAC), Tetrabutylammonium fluoride (TBAF) andTetrabutylammonium iodide (TBAI) ; preferably tetrabutyl ammonium bromide.
4. The process accoridng to Claim 1, solvent may be selected from noii polar aprotic solvents such as C6.7 aromatic and C5.7 aliphatic hydrocarbons, C3.4 alkoxy, C3.8 ethers, C2.6 esters of acids, C3.8 ketones, C2.4 nitriles, C2_3 amides, C3.5 organic carbonates and mixtures thereof.
5. The process accoridng to Claim 1, wherin the reaction recation is carried in chlorotrimethylsilane in the presence of tetrabutylammoniumbromide (TBAB) in acetonitrile.
22

6. A process for the preparation of Tenofovir Disoproxil ester of Formula V or its pharmaceutical^ acceptable salts,
CM3

P~i CH3
2
> °v°
IUU7 X,
\^\^>s^^n3
N ^1^ n O^ O
N" N
\^/° Ov ^ UV HOOC
N N Q^ 0
V^o VYYttt3 ■ -COOH
CH, O CH
O
3
I
CN Formula VI
oo
o
CO
g which comprises:

U)
3
CO
o

23

a) Dealkylatioii of compound of Formula II:


O OEt

CH3 Formula II
using chlorotrimethylsilane in the presence of tetrabutylammoniumbromide (TBAB) in acetonitrile;
b) With or without isolation, the product obtained in step a) is reacted with Chloro methyl isopropyl carbonate optionally in the presence of base; and
c) Converting the obtained Tenofovir disoproxil ester to Tenofovir disoproxil fumarate using Fumaric acid.

8. The process according claim 6 and 7, base used in step b) may be selected from organic amine like trialkylamine such as triethylamine, diisopropyl ethyl amine, preferably triethylamine
9. An improved, process for the preparation of Tenofovir Disoproxil Fumarate such as herein described in accompanying description and examples

ith
Date this Fourth (4m) day of August 2016.

Cg^s^

E
jo (Authorized Signatory)
S Shrikant Hanumantappa Havale
o
CN ■
LU
X
o
I
^-
CN
oo
o
CO CO
o
For SMS Pharmaceuticals Ltd.