Specification
Field of the Invention:
The present invention relates to a novel and improved process for the preparation of Tenofovir and its prodrugs. 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.
Background of the Invention:
Tenofovir, also known as (R)-9-(2-phosphon0methoxypropyl) adenine [(R)-PMPA] is represented by the following structure of Formula I:
Fonnula 1
Tenofovir disOproxil Fumarate is k prodrug of Tenofovri", commercialized under the brand name VIREAD® in the forfii of 150, 200, 250 and 300mg oral tablets and in combination with other antiviral agents. Tenofovir Al&fenarfiide Funiarate is also a prodrug of Tenofovir, is appr6ved ifl combination with C6bicistat, Elvitegravir, Emtricitabine under the brand name GENVOYA . Tenofovir belongs to the nucleotide reverse transcriptase inhibitor (NtRTI) class of drugs.
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 Al and CN 102093417 A discloses the process for the preparation of Tenofovir wherein the corresponding phosphonate ester is dealkylated 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. Comm. 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 101531679 B 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 ift 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 Tehofbvir 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 6f 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 Y6rk, 1950 discloses the conversion of dialkyl phosphonates t6 ph6sphonic acids is usually accbrnplished 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.
CN 101574356 A describes the use of TMSCl/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 TM^Cl/NaBr td obtain tenofovir, which is converted to tenefovir disoproxil fumarate by treatment with £MIC iii the presence of triethylamine and tetra-butylanlmonium bromide followed by salt formation with fumaric 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 phosphonic 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.
Most of the prior art processes involve trialkylsilylhalides like bromotrimethylsilane and chlorotrimethylsilane which &re expensive and highly corrosive reagents and require special handling procedures which is very difficult in commercial scale operations.
The patent US 6,465,649 Bl describes 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.
However, the entire prior art processes involve extensive purification steps to obtain high quality end product Considering the importance Of Tenofovir aftd Tenofovir disoproxil fumarate it would be desirable to provide & process for the preparation of Tenofovir which is simple and cost effective, industrially viable process without sacrifice of overall yield and Quality of the end product.
US 6,160,008A describes a process for the alkylation Of Thiourea with appropriate dialkylphosphates Of trialkylphosphates by heating itt an organic solvent t6 form Phosphorous containing salts of S-alkylisothiouronium. The inventors of the present invention have applied the thought of reacting dialkylphosphates of trialkylphosphates with thiourea or its derivatives for
dealkylation of Tenofovir ester using compound of Formula A through the formation of novel intermediate, Tenofovir thiourea adduct. The inventors have thus found a novel process for the preparation of Tenofovir through a novel intermediate compound, which proceeds with good yields while achieving a good chemical purity.
Object of the Invention:
The main object of the invention is to provide a simple, cost effective, novel and robust process for the preparation of Tenofovir by dealkylation of its phosphonate esters yielding a high yield, high purity Tenofovir without formation of undesired impurities and 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 thiourea or its derivatives, through the formation of Tenofovir-thiourea adduct, followed by hydrolysis using an acid.
Yet another object of the invention is to provide a novel process for the preparation of Tenofovir prodrugs.
Summary of the Invention:
The present invention relates to a novel and improved process for the preparation 6f Tenofovir of formula I:
which comprises the steps of:
a) reacting the Compound of Formula 11(a):
Wherein X represents O, S and NH; optionally iii the presence of a solvent to obtain compound of Formula 111(a);
Formula IH(a)
Wherein X is as described above; R represents lower alkyl such as methyl, ethyl, isopropyl, etc.,, and Rj, R2, R3 and R4 are independently hydrogen or Ci.6 alkyl., amino, C6.12 aryl, b) hydrolyzing the compound obtained in step a) with or without isolation to obtain a compound of Formula I.
In One embodiment, the present invention relates td art improved process for the preparation of Tenofovir of Forrnula I:
which comprises the steps of:
a) reacting 9- [2-(R)-(hydroxyl)propyl] adenine of Formula IV with a compound of Formula V(a);
Formula IV
Formula V(a)
wherein R is defined above and R5 represents a leaving group such as mesyl or tosyl and like; to obtain a compound of Formula 11(a);
b) treating the compound obtained in step a) with or without isolation, with
compound of Formula A,
Wherein X, Rl5 R2, R3 and R4 is as described above; optionally in the presence of a solvent to a obtain a compound of Formula 111(a); and
c) hydrolyzing the compound obtained in step b) with or without isolation to obtain a
compound of Formula I.
In an preferred embodiment, the present invention relates to a novel cortipound of Formula III (a):
Whereih X represents 0, S and NH; and Ri, R2, R3 and R4 &re independently hydrogen or Ci_6 alkyl, amino, C6_i2 aryl; R represents lower alkyl.
Detailed Description of the Invention:
The present invention provides a process for the preparation of Tenofovir of Formula I, which comprises the reaction of phosphonate estes of Formula 11(a)
wherein X represents O, S and NH; and Ru R2, R3 and R4 are independently hydrogen or Ci_6 alkyl, amino, C6.i2 aryl; optionally in the presence of solvent to obtain Tenofovir adduct of Formula 111(a):
wherein X, R, Rl5 R2, R3 and R4 are represented as described above; and hydrolyzing the compound of Formula 111(a) to obtaih Tenofovir 6f Formula I.
In one embodiment, the present invention relates to an improved process f6r the preparatiott of Tenofovir of Formula I:
which comprises the steps of:
a) reacting 9-[2-(R)-(hydroxyl)propyl] adenine of Formula IV with a compound of Formula V(a);
wherein R is defined above and R5 represents a leaving group such as mesyl or tosyl and like; to obtain a compound of Formula 11(a):
a)
b) treating the compound Obtained in step a) vvith or without isolation, with
10 compound of Formula A in the presence Of a solvent to a obtain a compound Of
Formula 111(a):
Formula 111(a)
c) hydrolyzifig the cofhpOund obtained in step b) with Or without isolation to obtain a cOmoOund Of Formula!.
Yet another embodiment of the present invention is to provide an improved process for preparation of Tenofovir prodrug of Formula VI or its pharmaceutical^ acceptable salts:
NH2
N w° %
5 wherein Gpi and Gp2 are independently same or different selected from:
CH3
comprising the steps of:
a) reacting 9-[2-(R)-(hydroxyl)propyl] adenine of Formula IV with a compound of Formula V(a);
Formula IV Formula V(a)
vvhereift ft. is defined as above and R5 represents a leaving group such as mesyl or tosyl and like., to obtain a compound of Formula 11(a);
NH2
N
fcH3 Formula 11(a)
b) treating the C6mp0und obtained in step a) with 6r without isolation, with
15 C6fhp0und of formula A in the presence 6f a solvent to a Obtain a compound of
Formula Ill(a); 6) hydrolyzing the Compound obtained in step b) with 6r without isolatidn;
d) converting the obtained Tenofovir of Formula I iftt6 compound Of Formula VI Or its pharmaceutical^ acceptable salts.
The pharmaceutically acceptable salts according to the present invention are selected 5 from tumarate, succinate, citratfc, oxalate, besylate, maleate, tosylate, phosphate and like.
In an embodiment, the present invention relates t6 a hovel compound of Formula 111(a):
Wherein X represents O, S and NH; Rh R2, R3 and &4 are indepefldeiltly hydrogen or Ci_6 alkyl; & represents lower alkyl.
A preferred embodiment of the present invention relates to a process for the 15 preparation of Tenofovir of Formula I, which comprises the steps Of: a) reacting phosphoftate ester of Formula II:
Formula II
Formula A(i)
in the presence of solvent to obtain compound of Formula III(i):
Formula III(i)
b) hydrolyzing the compound of Formula III (i) to obtain a compound of Formula I
A preferred embodiment of the present invention relates t6 a process for the preparation Of Tenofovir of Formula I:
Formula I
which comprises the steps of:
a) reacting 9- [2-(R)-(hydroxyl)propyl] adenine of Forinula IV with a compound of formula V;
NH2
tforfnuki IV Formula V
to obtain a compound of formula II:
Formula II
b) treating the compound obtained in step a) with or without isolation with Urea formula A(i) in the presence of a solvent to a obtain & dompound Of Forrnula III(i):
Formula III(i)
c) hydrolyzing the compound of step b) with or without isolation to obtain a Compound of Formula I.
In a preferred embodiment, the present invention relates to a novel compound of Formula III(i):
CH3
Formula IH(i)
A preferred embodiment of the present invention relates to a process for the preparation of Tenofovir of Formula I, which comprises the steps df: a) reacting phosphonate ester of Formula II:
with thiourea Of Fonnula A(ii):
in the presence of solvent to obtain compound of Formula Ill(ii)
CH3
Formula Hl(ii)
b) hydrolyzing the compound of Formula III (ii) to obtain a compound of Formula I.
A preferred embodiment of th6 present invention relates to a process for preparation of Tenofovir of Formula I:
Formula I
which comprises the steps of:
a) reacting 9-[2-(R)-(hydroxyl)propyl] adenine of Formula IV with a compound Formula V;
Formula IV formula V
to Obtaih a compound Of Formula II:
formula II
b) treating the compound obtained in step a) with Or without isolation with thiourea of Formula A(ii) in the presence of a solvent to a obtain a compound of Formula Ill(ii):
Formula Ill(ii)
c) hydrolyzing the compound of step b) with or without isolation to obtain a compound of Formula I.
In k preferred embodiment, the present invention relates to a novel compound of Formula Ill(ii):
NH2 H3C.
Formula Ill(ii)
In fc preferred embodiment, the present invention relates to a process for the preparation 6f Tenofovir of Fortfiula I:
Formula I
which comprises the steps of:
a) reacting of the compound of Formula II:
Formula II with Guanidine of Formula A(iii):
Formula A(iii)
in the presence of a solvent to obtain compound of Formula Ill(iii);
Formulil IH(iii)
b) hydrolyzing the compound obtained ift Step a) with or without isolation to 6bt&in compound 6f Formula I.
A preferred embodiment of the present invention relates to a process for the preparation of Tetiofovir of Formula I:
Formula I
which comprises the steps of:
a) reacting 9- [2-(R)-(hydroxyl)propyl] adenine of Formula IV with a compound of formula V;
Formula IV
Formula V
to obtain a compound of Formula II:
CH3 Formula II
b) treating the compound obtained in step a) with or withbut isolation with guahidine
of Formula A(iii) in the presence of a solvent to a obtain a compound of Formula
10 Ill(iii):
CH
Formula Ill(iii)
c) hydrolyzihg the compound 6f step b) with Or without isolation to obtain a cohlpound of F6rrnula I.
In a preferred embodiment, the present invention relates to a novel compound of Formula Ill(iii):
Formula IH(iii)
5 In an embodiment the present invention, the reaction of compound of Formula 11(a) with compound of Formula A is carried optionally in the presence Or absence of catalyst.
The catalyst used may selected from Potassium iodide, Iodine, tetra methyl LO ammonium bromide, tetra butyl ammonium bromide (TBAB), methyl triethyl ammonium bromide, benzyl trimethyl ammdnium bromide, benzyl triethyl ammonium bromide, triethyl benzyl ammonium chloride (TEBA), tetrabutylammonium chloride (TBAC), Tetrabutylammonium fluoride (TBAF) and Tetrabutylammonium iodide (TBAI); preferably tetra butyl ammonium bromide.
L5
In an embodiment the present invention, hydrolysis of compound of Formula 111(a) or III(i), Ill(ii) and Ill(iii) is carried out in the presence of an acid or a base, optionally in the presence of a solvent; wherein acid is selected from group of Inorganic or Organic acids, the Inorgaftic acid is selected from the group consisting df Hydrochloride gas,
20 Hydrochloric acid, Sulphuric acid, Hydrobromide, A &3 and R4 are represented as described above; and hydrolyzing the compound of Formula 111(a) to obtain Tenofovir of Formula I.2. A process according to claim 1, the solvent is non-polar aprotic solvent such as n-heptane, toluene, dimethoxyethane, ethyl acetate, THF, acetone, acetonitrile or dimethyl carbonate, dimethylformamide, dimethylsulfoxide and N-Methyl-2- 5 pyrrolidone more preferably Dimethylformamide and Toluene.
3. A process according to claim 1, hydrolysis is carried in the presence of acid.
4. A process for the preparation of Tenofovir of Formula I,
Formula II
which comprises the steps of: a) reacting phosphonate ester of Formula II:with thiourea of Formula A(ii):
H2N NH2 Formula A(ii) in the presence of solvent to obtain compound of Formula Ill(ii)
5 Formula Ill(ii) b) hydrolyzing the compound of Formula III to obtain a compound of Formula I.
5. The process according to claim 4, iTenofovir of Compound of forrfiul& I is prepared by a process which comprises the steps of: L0 a) reacting 9- [2-(R)-(hydroxyl)propyl] adenine of Formula IV with a compound of Formula V;
Formula IV Formula V
to obtain a compound of Formula II:
CH3 Formula II
b) treating the compound obtained in step a) with or without isolation with thiourea
of Formula A(ii) in the presence of a solvent to a obtain a compound of Formula Ill(ii):
5 c) hydrolyzing the compound of step b) with or without isolation to obtain a compound of Formula I.
6. A compound of Formula 111(a):
Formula 111(a)
7. The compound accoridng to Claim 6, represents a compound of Formula III(i)
Formula III(i)
8. The compound accoridng to Claim 6, represents a compdund of Formula Ill(ii).
Formula UI(ii)
9. The compound accoridng to Claim 6, represents a compound of Formula Ill(iii),
Formula Ill(iii)