FIELD OF INVENTION
The present invention relates to novel reagent 3-(S)-tetrahydrofuryl -1, 2, 4-triazole-1 -
carboxylate (III) and a novel process for preparation of highly pure (3S)-tetrahydro-3-
furyl N-[(1S,2R)-1-benzyl-2-hydroxy-3-(N-isobutyl-4-nitrobenzenesulphonamido)
propyl] carbamate (II).
BACKGROUND OF THE INVENTION
Fosamprenavir calcium has HIV aspartyl protease inhibitory activity and is
particularly well suited for inhibiting HIV-1 and HIV-2 viruses; it is chemically known
as calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl)
amino]-1-benzyl-2-(phosphonooxy)propyl carbamate and represented by formula I.

Compound (3S)-tetrahydro-3-furyl N-[(1 S,2R)-1-benzyl-2-hydroxy-3-(N-isobutyl-4-
nitrobenzenesulphonamido) propyl] carbamate, represented by formula II is key
intermediate in preparation of fosamprenavir calcium.
The product patent US 6 436 989 describes process for preparation of fosamprenavir
and its sodium salt utilizing the compound of formula II.
Another patent US 5 585 397 covers compound of formula II and also provides
process for preparation of the same, as depicted in scheme 1.

Scheme 1: Process for preparation of compound of formula II as given in US 5
585397
The process of US 5 585 397 involves series of protection and deprotection
reactions, hence is not economically viable.
Example 1 of patent US 6 281 367 describe process for preparation of compound of
formula (II) in 80-82% yield; as depicted in Scheme 2.

Scheme 2: Process for preparation of compound of formula II as given in US 6
281 367.
Repetition of the process of US 6 281 367 provided compound (II) having HPLC
purity of 85.33%. Such a low purity product requires multiple purifications, which
renders the process economically unfavorable and unsuitable for large scale
manufacture.
Another patent US 6 248 775 provides process for synthesis of Carbamic acid, [2R-
hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)
propyl-tetrahydrofuran-3S-yl ester, which is analogues to compound of formula II, by
the process as given in scheme 3.

Scheme 3: Process as given in US 6 248 775
Process disclosed in US 6 248 775 involves purification of product using silica gel
chromatography, which is very laborious and generally unsuitable for large scale
manufacture.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWING
Figure 1: X-ray powder diffraction pattern of novel crystalline form of compound (II).
SUMMARY OF THE INVENTION
The present invention relates to novel reagent 3-(S)-tetrahydrofuryl-1, 2, 4-triazole-1-
carboxylate (III) useful in synthesis of fosamprenavir calcium. The present invention
further relates to novel process for preparation of (3S)-tetrahydro-3-furyl N-[(1S,2R)-
1-benzyl-2-hydroxy-3-(N-isobutyl-4-nitrobenzenesulphonamido) propyl] carbamate,
comprising reaction of 3-(S)-tetrahydrofuryl-1, 2, 4-triazole-1-carboxylate with
(2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzene sulphon
amide. Process provides compound (II) in very high purity.
DETAILED DESCRIPTION OF THE INVENTION
In a preferred embodiment the present invention provides novel reagent 3-(S)-
tetrahydrofuryl-1,2,4-triazole-1-carboxylate (III) and process for its preparation.

The present invention provides process for preparation of compound of formula (III)
by
reaction of compound of formula (V)

In the preferred embodiment, the reaction of (S)-3-hydroxy tetrahydrofuran (V) and
1,1'-carbonyl-1,2,4-triazole (VI), can be carried out in an organic solvent selected
from esters such as ethyl acetate, butyl acetate etc; chlorinated hydrocarbons such
as dichloromethane, chloroform, ethylene dichloride etc; nitriles such as acetonitrile,
propionitrile etc; ether such as diethyl ether, diisopropyl ether, t-butyl methyl ether,
tetrahydrofuran, dioxan etc; amides such as dimethylformamide, dimethylacetamide,
N-methyl pyrrolidone etc.; aromatic hydrocarbons such as benzene, toluene, xylene
etc.; or mixtures thereof; preferably dichloromethane.
In the reaction (S)-3-hydroxy tetrahydrofuran (V) can be employed in the range of 0.9
to 2.0 molar equivalent of 1,1'-carbonyl-1, 2, 4-triazole (VI), preferably in the range of
0.9 to 1.5 molar equivalent.
The reaction can be carried out at an ambient temperature, mostly in the range of 0-
40°C, preferably 20-40°C.
Another embodiment of the present invention relates to novel process for preparation
of (3S)-tetrahydro-3-furyl N-[(1 S,2R)-1-benzyl-2-hydroxy-3-(N-isobutyl-4-nitro
benzene
sulphonamido) propyl] carbamate of formula (II),

which is a key intermediate in manufacture of fosamprenavir calcium.
Compound of formula (II) is obtained in very high purity by reaction of novel reagent
3-(S)-tetrahydrofuryl-1,2,4-triazole-1-carboxylate (III) with (2R,3S)-N-(3-amino-2-
hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzene sulphon amide compound of
formula (IV)

The starting material (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-
nitrobenzene sulphonamide (IV) can be prepared by the methods known in literature.
The reaction of compound III and compound IV can be carried out with or without an
organic base in an organic solvent.
The organic base can be selected from trialkylamines such as triethylamine, N, N-
diisopropyl ethylamine; pyridine, dimethyl aminopyridine, N-methyl piperidine, N, N-
diethyl aniline, etc.; preferably triethylamine.
The organic solvent is selected from esters such as ethyl acetate, butyl acetate etc;
chlorinated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride
etc; nitriles such as acetonitrile, propionitrile etc; ether such as diethyl ether,
diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxan etc; amides such as
dimethylformamide, dimethylacetamide, N-methyl pyrrolidone etc.; aromatic
hydrocarbons such as benzene, toluene, xylene etc.; or mixtures thereof.
In the reaction compound III can be employed in the range of 0.9 to 2 molar
equivalents with respect to compound IV, preferably in the range of 1 to 1.2 molar
equivalents.
The reaction can be carried out at a temperature of 30 to 100°C, preferably at a
temperature of 40 to 80°C.
The compound of formula (II) is purified by crystallization from alcohol, selected from
methanol, ethanol, isopropanol, butanol etc or mixtures thereof, preferably methanol.
Crystallization from methanol provided a novel crystalline form of compound (II). The
X-ray powder diffraction pattern is as shown in Figure 1. Intense diffraction peaks
characteristic of this crystalline form occur at the following 2theta angels (± 0.2): 5.40,
6.10, 7.53, 7.75, 8.18, 8.92, 9.45, 9.95, 14.24, 14.57, 15.53, 16.29, 16.78, 18.14,
18.35, 18.88, 19.29, 19.63, 20.37, 20.90, 21.50, 23.69, 25.13, 25.23.
The compound of formula (II) as obtained by the present invention can be converted
to fosamprenavir calcium by methods known in the literature. The fosamprenavir
calcium obtained has an HPLC purity of >99%.
In the present invention, manufacture of compound of formula (II) has the following
advantages over the prior art methods:
a. Provides compound of formula (II) in high purity,
b. Process is simple, does not involve series of protections/deprotection steps
and tedious column chromatography,
c. The reagent 3-(S)-tetrahydrofuryl -1,2,4-triazole-1-carboxylate (III) is solid in
nature and hence easy to handle,
d. Process is highly economical and commercially viable, and
e. Process is easy to operate on plant scale.
The present invention is further illustrated by the following representative examples
and does not limit the scope of the invention.
EXAMPLES
Example 1: Preparation of 3-(S)-tetrahydrofuryl-1, 2, 4-triazole-1-carboxylate
(III)
Mixture of 5.1 g (0.031 mol) 1, 1'-carbonyl-1,2,4-traizole (VI) and 2.5 g (0.028 mol)
(S)-3-hydroxy tetrahydrofuran (V) in 12.5 ml of dichloromethane was stirred at a
ambient temperature for 4-5 hours. The reaction mass was filtered and the filtrate
concentrated. To the concentrate was added 25 ml diisopropyl ether and stirred. The
solid filtered, washed with diisopropyl ether and dried. Yield: 4.5 g (80.35%); Melting
point: 46.7-47.2°C; M/z: 183.85 (M+); 1H NMR (dmso-d6): 2.16-3.31 (m, 2H); 3.36-4.0
(m, 4H); 5.56 (S, 1H); 8.28 9 (s, 1H); 9.26 (s, 1H). IR: 1215, 1307, 1732, 1768 cm -1.
Example 2: Preparation of (3S)-tetrahydro-3-furyl N-[(1S,2R)-1-benzyl-2-
hydroxy-3-(N-isobutyl-4-nitrobenzenesulphonamido) propyl] carbamate (II).
Mixture of 4 g (0.009 mol) (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-
4-nitrobenzene sulphonamide (IV) and 2.17 g (0.011 mol) 3-(S)-tetrahydrofuryl-1, 2,
4-triazole-1-carboxylate (III) in 40 ml dichloromethane was heated at 38-40°C for 18-
19 hours. Cooled to 20-25° and extracted with 10% sodium bicarbonate solution. The
organic layer was separated, washed with water and concentrated. To the
concentrated mass was added 100 ml methanol and heated to 60-65° for 10-15
minutes. Cooled to 25°C and solid was filtered, washed with methanol and dried.
Yield: 3.4 g (66.9%); HPLC purity: 99.23%.'
Example 3: Preparation of fosamprenavir calcium (I).
Mixture of 18 g (0.033 mol) (3S)-tetrahydro-3-furyl N-[(1S,2R)-1-benzyl-2-hydroxy-3-
(N-isobutyl-4-nitrobenzene sulphonamido) propyl] carbamate (II) obtained in Example
2 and 13.5 ml pyridine in 90 ml methylisobutyl ketone was cooled to 0-5°C and 12.89
g (0.084 mol) of POCI3 was added. The reaction mixture was stirred at ambient
temperature for 4-5 hours. Cooled to 10°C and 30 ml 1:1 cone. HCI- water was
added. Mixture was heated to 50°C for 1 hour. The reaction mass cooled to 25-30°C.
Organic layer was separated, washed with water and partially concentrated; 90 ml
water and 5.59 g sodium bicarbonate was added and stirred. The organic layer was
separated and 18 ml ethylacetate, 72 ml methanol and 1.8 g Pd/C was added. The
reaction mass was stirred under hydrogen pressure for 4 hours at 30°C. The mixture
was filtered, catalyst washed with methanol. The filtrate was heated to 50°C and 5.93
g (0.033) calcium acetate monohydrate in 18 ml water was added and stirred for 30
minutes. Cooled to 30°C and stirred. Solid was filtered, washed with 1:1 mixture of
methanol-water and dried to obtain crude fosmaprenavir calcium. Yield: 16.87 g
(80.05%).
Example 4: Crystallization of crude fosamprenavir calcium (I).
Mixture of 40 g (0.06 mol) crude fosamprenavir calcium as obtained in Example 3
and 600 ml denatured ethanol was heated to 70-72°C. Water (136 ml) was added
and mixture stirred for 30 minutes. Cooled to ambient temperature and stirred. Solid
filtered, washed with 1:1 ethanol-water and dried. Yield: 37.2 g (93%); HPLC:
99.32%; Impurity 1: 0.23% (RRT=2.21) and all other impurities less than 0.1%.
We Claim:
1. A process for preparation of compound of formula (III)

by reacting compound of formula (V)

with compound of formula (VI)

2. A process according to claim 1, wherein the reaction is carried out in an
organic solvent selected from esters such as ethyl acetate, butyl
acetate; chlorinated hydrocarbons such as dichloromethane, chloroform,
ethylene dichloride; nitriles such as acetonitrile, propionitrile; ether
such as diethyl ether, diisopropyl ether, t-butyl methyl ether,
tetrahydrofuran, dioxan; amides such as dimethylformamide,
dimethylacetamide, N-methyl pyrrolidone; aromatic hydrocarbons such as
benzene, toluene, xylene; or mixtures thereof; preferably dichloromethane.
3. A process according to claim 1, wherein compound of formula (V) is
employed in the range of 0.9 to 2 molar equivalent of compound of
formula (VI), preferably in the range of 0.9 to 1.5 molar equivalent.
4. A process according to claim 1, wherein the reaction is carried out at a
temperature in the range of 0-40°C, preferably 20-40°C.
5. A process for preparation of compound of formula II

by reacting compound of formula (III)

with compound of formula (IV)

6. The process according to claim 5, wherein the reaction of compound of
formula (III) and formula (IV) is carried out in an organic solvent selected from
esters such as ethyl acetate, butyl acetate; chlorinated hydrocarbons such as
dichloromethane, chloroform, ethylene dichloride; nitriles such as acetonitrile,
propionitrile; ether such as diethyl ether, diisopropyl ether, t-butyl methyl
ether, tetrahydrofuran, dioxan; amides such as dimethylformamide,
dimethylacetamide, N-methyl pyrrolidone; aromatic hydrocarbons such as
benzene, toluene, xylene; or mixtures thereof.
7. The process according to claim 5, wherein the reaction is carried out
optionally in presence of an organic base, selected from trialkylamines such
as triethylamine, N, N-diisopropyl ethylamine; pyridine, dimethyl
aminopyridine, N-methyl piperidine, N,N-diethyl aniline; preferably
triethylamine.
8. The process according to claim 5, wherein compound of formula (III) is
employed in the range of 0.9 to 2 molar equivalent of compound of formula
(IV), preferably in the range of 1 to 1.2 molar equivalent.
9. The process according to claim 5, wherein the reaction is carried out at a
temperature of 30 to 100°C, preferably at a temperature of 40 to 80°C.
10. The process according to claim 5, wherein compound of formula (II) is
crystallized from an alcohol, selected from methanol, isopropanol, butanol or
mixtures thereof; preferably methanol.
11. A compound of formula (III)

12. A compound of formula (III), adapted for use in the preparation of
fosamprenavir calcium.
13. Compounds of formula (II) and formula (III) obtained by any of the preceding
claims, adapted for use in the preparation of fosamprenavir calcium.
14. Crystalline Form of compound (II), wherein X-ray powder diffraction pattern
has diffraction peaks at the following 2theta angels (± 0.2): 5.40, 6.10, 7.53,
7.75, 8.18, 8.92, 9.45, 9.95, 14.24, 14.57, 15.53, 16.29, 16.78, 18.14, 18.35,
18.88, 19.29, 19.63, 20.37, 20.90, 21.50, 23.69, 25.13, 25.23.

The present invention relates to novel reagent 3-(S)-tetrahydrofuryl-1, 2, 4-triazole-1-
carboxylate (III) useful in synthesis of fosamprenavir calcium. The present invention
further relates to novel process for preparation of (3S)-tetrahydro-3-furyl N-[(1S,2R)-
1-benzyl-2-hydroxy-3-(N-isobutyl-4-nitrobenzenesulphonamido) propyl] carbamate
(II), comprising reaction of 3-(S)-tetrahydrofuryl-1, 2, 4-triazole-1-carboxylate (III)
with (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzene
sulphon amide (IV). The compound (II) is a key intermediate in preparation of
fosamprenavir calcium.