FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
Title of the invention: IMPROVED PROCESS FOR PREPARATION OF CARBAMIC ACID, N-[(l S, 2R)-3-[[(4-AMINOPHENYL) SULFONYL] (2-METHYLPROPYL) AMINO]-2-HYDROXY-1-(PHENYLMETHYL) PROPYL]-, (3R, 3AS, 6AR)-HEXAHYDROFURO [2, 3-B] FURAN-3-YL ESTER AND NOVEL INTERMEDIATE USE IN THE PREPARATION THEREOF.
2. Applicant(s)
(a) NAME: Sandoz Private Limited
(b) NATIONALITY: Indian
(c) ADDRESS: MIDC, Plot No.8-A/2, 8-B
TTC Industrial Area,
Kalwe Block, Village Dighe
Navi Mumbai 400 708
India
(a) NAME : Hexal AG
(b) NATIONALITY : German
(c) ADDRESS: Industriestrasse 25
D-83607 Holzkirchen Germany
(a) NAME: Sandoz AG
(b) NATIONALITY : Swiss
(c) ADDRESS: Lichtstrasse 35
4056 Basel Switzerland
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be
performed:

FIELD OF INVENTION
The present invention relates to a process for the preparation of Carbamic acid, N-[(lS,2R)-3-[[(4-aminophenyl)sulfonyl] (2-methylpropyl) amino]-2-hydroxy-l-(phenylmethyl)propyl]-, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester. It further relates to a process for preparation of novel intermediates and their use in said process, which is applicable for industrial scale up.
BACKGROUND OF THE INVENTION
The virus causing the acquired immunodeficiency syndrome (AIDS) is known by different names, including T-lymphocyte virus III (HTLV-III) or lymphadenopathy- associated virus (LAV) or AIDS-related virus (ARV) or human immunodeficiency virus (HIV). Up until now, two distinct families have been identified, i.e. HIV-I and HIV-2. Hereinafter, HIV will be used to generically denote these viruses.
One of the pathways essential for the retroviral life cycle is the processing of polyprotein precursors by retroviral protease. For instance, in the course of the replication cycle of the HIV virus, gag and gag-pol gene transcription products are translated as proteins, which are subsequently processed by a virally encoded protease to yield products such as viral enzymes and structural proteins of the virus core. Most commonly, the gag precursor proteins are processed into the core proteins and the pol precursor proteins are processed into the viral enzymes, e.g., reverse transcriptase and retroviral protease. Consequently, efficient processing of the precursor proteins by the retroviral protease is necessary for the assembly of infectious virions, thus making the retroviral protease an attractive target for antiviral therapy. In particular for HIV treatment, the HIV protease is an attractive target.
Several protease inhibitors are on the market are in a developmental stage. Hydroxyethylamino sulfonamide HIV protease inhibitors, for example 4-aminobenzene hydroxyethylamino sulfonamides, have been described to have

favourable pharmacological and pharmacokinetic properties against wild-type and mutant HIV virus. Amprenavir is a commercially available exponent of this 4-aminobenzene hydroxyethylamino sulfonamide class of protease inhibitors. A process for the synthesis of amprenavir is described in WO 99/48885 (Glaxo Group Ltd.).
4-Aminobenzene hydroxyethylamino sulfonamides may be prepared according to the procedures described in EP 715618, WO 99/67254, WO 99/67417, US 6,248,775 and WO 2007/060253, and in Bioorganic and Chemistry Letters, Vol. 8, pp.687-690, 1998, Bioorganic and Medicinal Chemistry Letters 14 (2004)959-963 and J. Med. Chem. 2005, 48,1813-1822, all of which are incorporated herein by reference.
One of the protease inhibitors which has been approved in the USA for human clinical use for the treatment of retroviral infections is the compound having the USAN approved name darunavir with the chemical name Carbamic acid, N-[(1S,2R)-3- [[(4-aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl]-, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester and the structure of formula (6).

Darunavir is used in its clinical form as an ethanolate solvate. Methods and processes suitable for the preparation of darunavir'are disclosed in WO 99/67417 (USA, The Secretary, Dpt. of Health and Human Services), WO 99/67254 (USA, The Secretary, Dpt. of Health and Human Services and The Board of Trustees of the University of Illinois), and in WO 03/106461 (Tibotec N.V.) and WO 2005/063770 (Tibotec Pharmaceuticals).

EP 1466896 (Ajinomoto KK) relates to a process for producing crystalline benzenesulfonamide derivatives. In particular, it provides a crystallization for (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N- isobutyl -4- amino - benzene -sulfonamide, which is an intermediate of interest for the preparation of darunavir.
The preparation of (S)-1-((S)-oxiran-2-yl)-2-phenylethanamine, compound of formula (1) has first been reported in WO 92/008699 and WO 03/078438. Compound of formula (2) has first been disclosed in WO 99/67417. Compound of formula (4) wherein R is nitro, amino group or amino group having a protective group has been described in JP 09124630. Preparation and reaction of carbamic acid, [(lS)-l-(2S)-oxiranyl-2-phenylethyl]-, (3S)-tetrahydro-3-furanyl ester with an N-alkylsulfonamide has also been described in JP 09124630 (Kissei Pharmaceutical Co., Ltd.), however, yields of 15-59% reported for this reaction can only be considered low to moderate and are therefore not useful for industrial application.
In order for a chemical route to be suitable for industrial scale, it should produce compounds in acceptable yields and purity while comprising a minimal number of steps being carried out easily as well as cost-effectively. As such, there .has been found a new process for the synthesis of darunavir which is applicable in industrial scale.
The present inventor has surprisingly developed a convenient process for the production of darunavir and novel intermediates thereof on an industrial scale. The reagents further used in said process are safe and may be available in bulk. Furthermore, each step of said method is performed at controllable conditions and provides the desired compound in good yields. Moreover, each step of said process is performed stereoselectively, which allows the synthesis of pure stereoisomeric forms of the desired compounds.
The present inventor has found that the novel intermediate of formula (3), can be obtained by a reacting a compound of formula (1) with compound of formula (2)

which is further reacted with a compound of formula (4) in such a way that a compound of formula (5) is obtained in high purity and yield. Therefore, this process is useful for industrial application, which is a significant improvement versus prior art. Furthermore, the design of the process of the present invention involves a minimal number of chemical steps and avoids the usage of a highly reactive species such as an acylating agent in the final step as is disclosed in WO 2005/063770. Therefore, the potential risk having a highly active impurity in the final drug substance is avoided by the design of the process being subject of the invention. Consequently, no further controls in regard of reactive impurities are required.
OBJECT OF INVENTION
It is an object of the present invention to provide improved process for the preparation of compound of formula (6).
It is another object of the present invention to provide novel intermediate of formula (3) used for the preparation of the compound of formula (6).
It is yet another object of the present invention to provide an improved process for the preparation of compound of formula (6) which does not employ any hazardous reagents and conditions and is safer to carry out.
It is a further object of the present invention is to provide an improved process for preparation of compound of formula (6) via novel intermediate of formula (3) in high yield and purity.

SUMMARY OF INVENTION
According to an aspect of the present invention there is provided an improved process for the preparation of compound of formula (5) comprising the steps of:
with a compound of formula (2) in the presence base and organic solvent.
i. Reacting a compound of formula (1) or a salt thereof.


wherein L is a leaving group such as fluoro, chloro, bromo, imidazol, N-hydroxysuccinimide.
to obtain a compound of formula (3).

wherein R is amine, protected amine, nitro
ii. Reacting the compound of formula (3) with a compound of formula (4) in the presence of an inorganic and/or organic base, optionally in the presence of a phase transfer catalyst and organic solvent.


to obtain a compound of formula (5).

wherein R is selected from the group consists of amine, protected amine, nitro.
According to another aspect of the present invention there is provided an improved process for the preparation of compound of formula (6) comprising the steps of:
i. Reducing a nitro group present in a compound of formula (5) i.e compound of formula (5i), preferentially by hydrogenation in the presence of a transition metal catalyst, providing the compound of formula (6).

According to yet another aspect of the present invention there is provided an improved process for the preparation of compound of formula (6) comprising the steps of:
i. Deprotecting an amino protecting group present in a compound of formula (5) i.e compound of formula (5ii), providing the compound of formula (6).


According to yet another aspect of the present invention there is provided a compound of formula (3).

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of darunavir [Compound of formula (6)] or a solvate, addition salt or polymorphic or pseudopolymorphic form or prodrug thereof which comprises the step of:
(i) Reacting a compound of formula (1) or a salt thereof:

with a compound of formula (2) in the presence of base and organic solvent.

wherein L is a leaving group such as fluoro, chloro, bromo, imidazol, N-hydroxysuccinimide.

to obtain a compound of formula (3).

(iii)
Reacting a compound of formula (3) with a compound of formula (4)
in the presence of an inorganic and/or organic base, optionally in the
presence of a phase transfer catalyst and organic solvent

wherein R is amine, protected amine, nitro to obtain a compound of formula (5).

wherein R is selected from the group consists of amine, protected amine, nitro.
(iv) Reducing a nitro group, preferentially by hydrogenation in the presence of a transition metal catalyst, or removing an amino protecting group in a compound of formula (5) providing the compound of formula (6).


In an embodiment of the present invention there is provided a compound of formula (3). It is a novel compound and constitutes a further feature of the present invention.

In another embodiment of the present invention there is provided an improved process for the preparation of compound of formula (5)

wherein R is selected from the group consists of amine, protected amine or nitro.
In compound of formula (5) when R = nitro. The compound of formula (5) is designated as compound of formula (5i)


In compound of formula (5) when R = protected amine. The compound of formula (5) is designated as compound of formula (5ii)

In another embodiment of the present invention there is provided an improved process for the preparation of HIV protease inhibitor such as darunavir [Compound of formula (6)] and any pharmaceutically acceptable salt, polymorphic or pseudopolymorphic form or prodrug thereof.
In an embodiment of the present invention there is provided an improved process for the preparation of HIV protease inhibitors such as darunavir [Compound of formula (6)] and any pharmaceutically acceptable salt, polymorphic or pseudopolymorphic form or prodrug thereof via novel intermediate of formula (3).
The term "amino-protecting group" as used herein refers to one or more selectively removable substituents on the amino group commonly employed to block or protect the amino functionality against undesirable side reactions during synthetic procedures and include all conventional amino protecting groups. Examples of amino-protecting groups include the urethane blocking groups, such as t-butoxy-carbonyl ("Boc"), benzyloxycarbonyl ("Z"or"Cbz"), and the like.
The species of amino-protecting group employed is usually not critical as long as the derivatized amino group is stable to the conditions of the subsequent reactions and can be removed at the appropriate point without compromising the remainder of the molecule. Further examples of amino-protecting groups are well known in organic synthesis and the peptide art and are described by, for example P. G. M.

Wuts and T. W. Greene Protective Groups in Organic Synthesis, 4th ed., John Wiley and Sons, New York, Chapter 7, 2007.
Suitable solvents include protic, non-protic and dipolar aprotic organic solvents such as, for example, those wherein the solvent is an alcohol, such as isopropanol, n-butanol, t-butanol, and the like; ketones such as acetone; ethers such as tetrahydrofuran, dioxane and the like; esters such as ethyl acetate; amines such as triethylamine; amides such as N, N-dimethylformamide, or dim ethylacetamide; chlorinated solvents such as dichloromethane and other solvents such as toluene, dimethyl sulfoxide, acetonitrile, and mixtures thereof.
Solvents suitable for the reduction of a nitro moiety may be selected from water, alcohols, such as methanol, ethanol, isopropanol, t-butanol, esters such as ethyl acetate, amides such as dim ethyl form amide, acetic acid, dichloromethane, toluene, xylene, benzene, pentane, hexane, heptane, petrol ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethyl sulfoxide, or mixtures thereof. In general, any solvent susceptible to being used in a chemical reduction process may be used.
Inorganic base which can be use in the present invention is selected from sodium carbonate, potassium carbonate
Organic base which can be use in the present invention is selected from triethylamine, diethylisopropylamine, N-methylmorpholine, N, N-diethylaniline, pyridine.
The process of the present invention can be represented in scheme I as follows:


Scheme I:
The following examples are meant to illustrate the present invention. The examples are presented to exemplify the invention and are not to be considered as limiting the scope of the invention.
EXAMPLE 1
Carbamic acid, N-[(1S,2R)-3-[[(4-aminophenvnsulfonyl](2-
methylpropyl)amino1-2-hydroxy-1-(phenylmethyl)propyl]-, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester [Compound of formula (6)].
Compound of formula (4 i): To isobutylamine (18, 3 g; 0.28 mol) in CH2CI2 (200 ml) were added NEt3 (28.8 g; 0.29mol), and 4-nitrobenzenesulfonyl chloride (52, 85 g; 0.24 mol) at 8 °C. This mixture was stirred at 20°C for 2 hours. Then the reaction mixture was poured into water (500 ml), the layers were separated. The organic layer was washed with IN aqueous HC1 (250 ml) and water (250 ml) and the solvent was evaporated to yield 59.98 g (97%) N-isobutyl-4-nitrobenzenesulfonamide as an orange solid (purity; >97%). 1H-NMR (400 MHz,

d6-DMS0): 8 8.41 (d, 2H), 8.04 (d, 2H), 7.98 (broad t; 1H), 2.61 (m, 2H), 1.63 (m, 1H), 0.80 (d,6H).
b) (3R. 3aS, 6aR)-hexahydrofuro [2, 3-b] furan-3-yl ((S)-1-(S)-oxiran-2-yl)-2-phenylethyl) carbamate [Compound of formula (3)].
(3R, 3aS, 6aR)-hexahydrofuro [2, 3-b] furan-3-ol (130 mg, 1 mmol) in acetonitrile are added to a solution of disuccimidylcarbonate (178 mg, 1.1 mmol) in acetonitrile. Then pyridine (237 mg, 3 mmol) is added and the mixture stirred for one hour. Then (S)-1-((S)-oxiran-2-yl)-2-phenylethanamine 263 mg, 0.95 mmol) and triethylamine (101 mg, 1 mmol) are added and stirred at room temperature until the starting materials were consumed. The reaction mixture is concentrated, diluted with MTBE and washed with 10% Na2CO3-solution, with a mixture of aqueous sulfuric acid and again with 10% Na2CO3-solution, the solvent is evaporated and the residue obtained purified by flash chromatography on silica gel providing compound of formula (3) as a white solid.
c) (3R,3aS,6aR)-hexahvdrofuror2,3-b]furan-3-yl ((2S,3R)-3-hvdroxv-4-(N-isobutyl-4-nitrophenvlsulfonamido)-1-phenylbutan-2-yl) carbamate (5 i):

To a mixture compound of formula (2) (14.08 g, 55 mmol), dry lithium chloride (161 mg; 3.8 mmol), and (3R, 3aS, 6aR)-hexahydrofuro [2,3-b]furan-3-yl ((S)-l-((S)-oxiran-2-yl)-2-phenylethyl) (6.06 g, 19 mmol) 30 ml of dry triethylamine were added and stirred at 60 °C for 2 hours. Then the reaction mixture is concentrated under reduced pressure at room temperature, diluted with 200 ml of ethyl acetate and washed with saturated ammonium chloride solution and brine twice. Then the organic layer is dried over sodium sulfate and the solvent is evaporated. The residue obtained is purified by flash column chromatography on

silica gel (EtOAc: c-Hex/ 1:3) providing a compound of formula (5 i) as off-white solid.
d) Carbaminic acid. [(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[4-[[(1,1-dimethylethoxyl carbonyl]amino] phenyl]sulfonyl] ammo]-1-(phenylmethyl) propyll-. (3R.3aS,6aR)-hexahydrofuror[2,3-blfuran-3-yl ester (5ii):

Compound of formula (3) (591 mg, 1mmol) in methanol (5 mL) are treated with hydrochloric acid 37% (1 mL) and heated to reflux. After complete conversion methanol is removed by distillation. The precipitation is performed in a mixture of MeOH/water/iPrOH. To the residue cold sodium hydroxide solution (30%) is dosed until a pH value of pH> 12.5 is reached. 4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzenesulfonamide is obtained as a white precipitate which is filtered off, washed with water and isopropanol, and dried in vacuum.
e) Carbarnic acid, N-r(lS,2R)-3-[[(4-aminophenyl)sulfonyl](2-
methylpropyl)aminol-2-hydroxy-1-(phenylmethyl)propyl]-. (3R,3aS,6aR)-
hexahydrofuro[2.3-b]furan-3-yl ester [compound of formula (6)]:
Method A: from (5i): To a compound of formula (5i) (577 mg, 1 mmol) methanol (5 ml) is added at room temperature. After forming an inert atmosphere, 20% palladium hydroxide on carbon (15 mg) is added, and after forming a hydrogen atmosphere (pressure 1 atm), the mixture is stirred at 40 °C for 6 hrs. The catalyst is filtered off and washed with methanol (5 ml). Then the solvent is evaporated under reduced pressure and the residue is purified by flash column

chromatography on silica gel providing compound of formula (6) as an off-white solid.
Method B: from (5ii): Compound of formula (5ii) (670 mg, 1 mmol) is subjected to TFA in CH2CI2 (4 mL, 20%) for 20 min at room temperature. Then the solvent is co-evaporated with toluene. The residue is dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and brine, and dried over sodium sulfate. The solvent is evaporated and the residue obtained is purified by chromatography on silica gel providing compound of formula (6) as an off-white solid.

We Claim:
1. An improved process for the preparation of compound of formula (5) comprising the steps of:
i. Reacting a compound of formula (1) or a salt thereof.

with a compound of formula (2) in the presence of base and organic solvent.

wherein L is a leaving group such as fluoro, chloro, bromo, imidazol, N-hydroxysuccinimide.
to obtain a compound of formula (3).

wherein R is amine, protected amine, nitro
ii. Reacting the compound of formula (3) with a compound of formula (4) in the presence of an inorganic and/or organic base, optionally in the presence of a phase transfer catalyst and organic solvent.


to obtain a compound of formula (5).

wherein R is selected from the group consists of amine, protected amine, nitro.
2. An improved process for the preparation of formula (5) as claimed in claim 1 wherein the base of step (i) is selected from triethylamine or pyridine.
3. An improved process for the preparation of formula (5) as claimed in claim 1 wherein the organic solvent use in step (i) is acetonitrile.
4. The improved process for the preparation of formula (5) as claimed in claim 1 wherein the inorganic bases of step (ii) are selected from sodium carbonate, potassium carbonate.
5. The improved process for the preparation of formula (5) as claimed in claim 1 wherein the organic bases of step (ii) are selected from triethylamine, diethylisopropylamine, N-methylmorpholine, N, N-diethylaniline.
6. An improved process for the preparation of compound of formula (6) comprising the steps of:
i. Reducing a nitro group present in a compound of formula (5), obtained by the process as claimed in claim 1 i.e compound of formula (5i), preferentially by hydrogenation in the presence of a transition metal catalyst, providing the compound of formula (6).


7. The improved process for the preparation of formula (6) as claimed in claim 6 wherein the reduction take place using H2/Pd catalyst and organic solvent.
8. An improved process for the preparation of compound of formula (6) comprising the steps of:

9. A compound of formula (3).
i. Deprotecting an amino protecting group present in a compound of formula (5), obtained by the process as claimed in claim 1 i.e compound of formula (5ii) to obtain the compound of formula (6).