This application claims priority to Indian patent application numbered IN 7/CHE/2012 filed on Jan 02, 2012 and IN 1878/CHE/2012 filed on May 11, 2012 the contents of which are incorporated by reference in their entirety.

FIELED OF THE INVENTION

The present invention relates to an improved process for the preparation of Azahexane derivatives.

BACKGROUND OF THE INVENTION

Atazanavir sulfate is an azapeptide inhibitor of HIV-1 protease. The chemical name for Atazanavir sulfate is (3S.8S.9S, 12S)-3,12-Bis(1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(pnenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7H2SO4 trade name is REYATAZ®. Atazanavir sulfate has the following structural formula:

Atazanavir sulfate has a good oral bioavailability and its favorable pharmacokinetic profile enabled it to be the first once-a-day protease inhibitor to treat AIDS (Acquired Immunodeficiency syndrome).

Use of Atazanavir sulfate as HIV protease inhibitor was disclosed in U.S. Patent No.5,849,911. This patent also disclosed several methods for the preparation of Azahexane derivatives.

The synthesis of Azahexane derivatives were disclosed in WO 97/40029, J. Med. Chem. 1996, 39, 3203-3216, J. Med. Chem. 1998, 41. 3387-3401 and Org. Proc. Res. Dev. 2002, 6, 323-328. Several limitations of the disclosed process presented scale-up challenges. An updated process was disclosed in WO 97/46514, US 5912352, US 6110946; US 6166004; US 6300519;US 7829720 and Organic Process Research & Development (2008), 12(1), 69-75, Tetrahedron Letters (2009), 50(14), 1586-1587, but scaie-up challenges were still present as environmentally unfriendly solvents, such as highly flammable diethyl ether, were used.

The prior-art processes for the preparation of tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-(4-pyridin-2-ylbenzyl)hydrazinecarboxylate (N-Di BOC intermediate) suffer from more disadvantages such as use of expensive raw materials, hazardous reaction conditions in scale up, multi-step reaction sequences employing unstable intermediates.

The present invention is cost effective, easy to handle, avoid expensive raw meterials and hazardous reactions in preparing Azahexane derivatives thus making it more advantageous at industrial level.

OBJECT AND SUMMARY OF THE INVENTION:

The main aspect of the present invention provides an improved process for the preparation of tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-(4-pyridin- -
ylbenzyl) hydrazinecarboxylate (formula A):

Another aspect of the present invention provides ((2S,3S)-N*-(3-tert-butoxycarbonylamino-2-hydroxy -4-phenyl-butyl)-hydrazine carboxylic acid tert-butyl ester), compound of formula B.

Yet another aspect of the present invention provides a process for the preparation of 2[4-(halomethyl) phenyl] pyridine hydrochloride.

DETAIL DESCRIPTION OF THE INVENTION:

The present invention provides an improved process for the preparation of Azahexane derivatives.

In one embodiment, the present invention provides an improved process for the preparation of tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyt}-2-(4-pyridin- - ylbenzyl) hydrazinecarboxylate (formula A) as depicted below:

In another embodiment, the process for the preparation of tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-(4-pyridin-2-ylbenzyl) hydrazinecarboxylate (formula A) comprises the steps of;

a) dissolving hydrazine intermediate of formula B in an organic solvent,

b) adding a base,

c) adding compound of formula X (2-(4-halomethyl phenyl)pyridine hydrochloride),

d) optionally adding a catalyst, and

d) isolating compound of formula A.

According to present invention tert-butyl-2-{(2S,3S)-3-[(tert-butoxycarbonyl)arnino]-2-hydroxy-4-phenylbutyl}-2-(4-pyridin-2-ylbenzyI) hydrazinecarboxylate (formula A) can be prepared by dissolving ({2S,3S)-N'-(3-tert-butoxycarbonylamino-2-hydroxy -4-phenyl-butyl)-hydrazine carboxylic acid tert-butyl ester) in an organic solvent selected from alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, sec-butanol, isobutanol, tert-butanol, acetonitrle and dimethylformamide or a mixture (s) thereof, adding a base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate and potassium carbonate, optionally adding a catalyst like potassium iodide, sodium iodide, tetrabutylammonium bromide, sodium bromide, potassium bromide, adding 2-(4-halomethyl phenyl) pyridine hydrochloride wherein the halo group is selected form chloro or bromo, raising the temperature, maintaining the reaction till the completion, removing the organic solvent using conventional techniques such as distillation, vacuum distillation, filtration followed by addition of organic solvent selected from ethyl acetate, butyl acetate and water or mixture thereof, filtering the reaction mass, dissolving in a solvent such as acetone, methyl ethyl ketone, cool and filtering obtains tert-butyl-2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-(4-pyridin-2-ylbenzyl)-hydra-zinecarboxylate.

In yet another embodiment, the present invention provides ((2S,3S)-N'-(3-tert-butoxycarbonylamino-2-hydroxy -4-phenyl-butyl)-hydrazine carboxyiic acid tert-butyl ester), compound of formula B.

In yet another embodiment, the present invention relates to a process for the preparation of (2S,3S)-NX3-tert-butoxycamonylamino-2-hydroxy -4-phenyl-butyl)-hydrazine carboxyiic acid tert-butyl ester (compound of formula B) as depicted below:

In yet another embodiment, the process for the preparation of a compound of formula B comprising the steps of:

a) dissolving t-Butyl carbazate in an organic solvent,

b) adding (1S,2R)-Boc epoxide,

c) optionally heating the reaction mass, and

d) isolating compound of formula B.

According to the present invention, compound of formula B can be prepared by dissolving (2R,3S)-3-(tert-butoxy carbonyl)amino-1,2-epoxy-4-phenylbutane, t-Butyl carbazate in an organic solvent selected from alcohols such as methanol, ethanol, n-propanol, n-butanol, sec-butanol, isobutanol, tert-butanol, acetonitrile Dimethyl sulphoxide and water or mixture (s) thereof, heating the reaction mass, stirring the reaction mass up to completion of the reaction, removing the solvent by using conventional techniques such as distillation, filtration, obtains a solid, washing the solid with Methyl tert-butyl ether, Isopropyl ether or diethylether ethyiacetate to obtain compound formula B.

Yet another embodiment, the process for the preparation of a compound of formula B comprises the steps of:

a) adding (1S,2R)-Boc epoxide, organic solvent, water or mixture thereof, butyl carbazate.

b) heating the reaction mass,

c) removing the solvent,

d) adding second solvent and raising the temperature, and d) isolating compound of formula B.

According to the present invention, dissolving (2R,3S)-3-(tert-butoxycarbonyl)amino-1,2-epoxy-4-phenyl butane, t-butyl carbazate, in an alcoholic solvent such as methanol and purified water into a round bottom flask and stirred the reaction mass at room temperature, raising the temperature, removing methanol completely under vacuum, cooling the reaction mass to 25 - 30°C, adding MTBE (237ml) and methanol (13ml) at 25 - 30°C. Raising the temperature to reflux and maintaining at reflux temp, cooling the mass and filtering obtains compound of formula B.

In yet another aspect, the present invention provides a novel process for the preparation of 2[4-(chloromethyl) phenyl] pyridine hydrochloride, an intermediate in the preparation of compound of formula A, as depicted below:

Yet in another embodiment, the present invention provides a process for the preparation of 2[4-(chloromethyl) phenyl] pyridine hydrochloride comprising;

a) dissolving 4-(pyridine-2-yl)benzaldehyde in an organic solvent,

b) adding a reducing agent,

c) optionally isolating [4-(pyridine-2-yl)phenyl]methanol,

d) adding chlorinating agent and organic solvent to step c,

e) removing the solvent and.

f) isolating pure 2[4-(chloromethyl) phenyl] pyridine hydrochloride.

According to present invention, dissolving 4-(pyridine-2-yl)benzaldehyde in an organic solvent selected from alcohols such as methanol, ethanol, n-propanol, n-butanol, sec-butanol, isobutanoi,
tert-butanol, cooling the reaction mass, adding reducing reagent such as sodium borohydride, heating the reaction mass, stirring the reaction mass up to completion of the reaction, removing the solvent under vacuum, adding an organic solvent such as methylene dichloride and water, separating both the layers, treating the organic layer with sodium bicarbonate and aqueous sodium chloride solution, distill out methylene chloride, obtains a residue, slurring the solid in a organic solvent such as methylene chloride, chloroform, ethylene dichloride, carbon tetrachloride, m-chloro benzene, adding chlorinating agent selected from thionyl chloride, PCI5, POCI3, removing the solvent and recrystalizing from a solvent selected from such as acetone, ethyl acetate and toluene yields pure 2-[4-(chloromethyl) phenyl] pyridine hydrochloride.

Yet in another embodiment, the present invention involves 2-(4-bromomethyl phenyl) pyridine hydrochloride in place of 2-[4-(chloromethyl) phenyl] pyridine hydrochloride which is prepared by adding carbon tetrachloride, 2-p-tolyl pyridine, N-bromosuccinimide and benzoyl peroxide at room temperature, raising the temperature, maintaining the reaction mass and cooling the mass, adding second lot of N-bromosuccinimide (57.5gms) and raising the temperature, separating the salts by filtration and removing carbon tetrachloride under reduced, cooling the residue to 25-30°C and added acetone, adjusting the pH to 2.0 - 3.0 by using CP HCI followed by cooling obtains 2-(4-bromomethyl phenyl) pyridine hydrochloride which is then washed with chilled acetone.

Yet in another embodiment, the present invention involves the replacement of 2-(4-bromomethyl phenyl) pyridine hydrochloride by using 2-[4-(chloromethyl) phenyl] pyridine hydrochloride to avoid following impurity of formula D in final compound.

Formula D

Yet in another embodiment, the present invention relates to a process for the preparation of Atazanavir or its salts as shown in scheme below:

The following examples are merely shown as representative examples of the present invention but are not intended to be limiting.

EXAMPLES:

Example -1: Preparation of [4-(pyridine-2-yl) phenyl] methanol Charged 4-(pyridine-2-yl)benzaldehyde(60gms) and methanol(300ml) into a round bottom flask, cooled the reaction mass to 0-5°C, and added sodium borohydride (12.4gms sodium borohydride in 68ml purified water and 0.2gms sodium hydroxide). Stirred the reaction mass, raised the temperature to 25-30°C, distilled off solvent under vacuum completely.

The obtained residue was cooled to 25-30°C, charged MDC and purified water, stirred the reaction mass, separated the organic layer and distilled off MDC completely under vacuum obtained the title compound. Wt of the compound -54gm.

Example - 2: Preparation of 4-(pyridyl) benzyl chloride hydrochloride (or) 2[4-(chloromethyl) phenyl] pyridine hydrochloride.

Charged MDC (400ml) and [4-(pyridine-2-yl) phenyl]-methanol(50gms) into round bottom flask and cooled the reaction mass to 0-5°C. Added DMF (1ml) and followed by thionyl chloride (73.8gms), slowly raised the temperature to reflux and maintained for 5hrs at reflux temperature. Distilled off MDC completely under vacuum <50°C. Again striped out with MDC (2X50ml). Cooled the compound to 25 - 30°C. Added acetone (300ml) and raised the temperature to reflux, Cooled the reaction mass to 25 - 30°C Filtered the mass and washed with acetone(50ml). Dried the compound at 40 - 45°C under vacuum. Wt of the compound - 59.9gms Purity -96.0%.

Example - 3: Preparation of (2S, 3S)-N'-(3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-hydrazine carboxylic acid tert-buty lester.

Charged (2R,3S)-3-(tert-butoxycarbonyl)amino-1,2-epoxy-4-phenyl butane (50gms), t-butyl carbazate(125.4gms), methanol (675ml) and purified water(75ml) into a round bottom flask and stirred the reaction mass 30min at 25 - 30°C.Raised the temperature to 40 - 45°C.Maintain 12 -14hrs at 40 - 45°C, Distilled off methanol completely under vacuum. The reaction mass was cooled to 25 - 30°C. Added MTBE (237ml) and methanol (13ml) at 25 - 30°C. Raised the temperature to reflux and maintained for 30min at reflux temp. Cooled the mass, filtered the reaction mass and washed with MTBE (50ml), dried the compound at 50 - 55°C thus obtained the title compound. Wt of the compound - 55.0gms Purity-98.0%.

Example -4: Preparation of tert-Butyl-2-{(2S, 3S)-3-[(tert-butoxy carbonyl) amino]-2-hydroxy-4-phenylbutyl}-2-(4-pyridin-2-ylbenzyl) hydrazine carboxylate.

Charged (2S,3S)-N'-(3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-hydrazine carboxylic acid tert-butylester (50gms), sodium bicarbonate (23.4gms), potassium iodide(lgm) into round bottom flask. Added dimethyl formamide and 4-(pyridyl)benzyl chloride (31.8gms). Raised the temperature to 70 - 75°C and maintained the reaction mass at 70 - 75°C for 2 hours. Cooled the the reaction mass to 25 - 30°C. Quenched the reaction mass to purified water (500ml) and ethylacetate (500ml) and raised the temperature to 60 - 65°C. Stirred for 30min. and settle for 15min. Separated the organic layer. Organic layer was washed with saturated sodium bicarbonate solution (200ml) followed by sodium chloride solution (200ml). Distilled off ethyl acetate completely under vacuum. Striped out with acetone (50ml). Cooled the compound to 25 -30°C. Added acetone (250ml) at 25 - 30°C. Raised the temperature to reflux and maintained at reflux for 30min. Filtered the reaction mass, washed with acetone (50ml) and dried the compound at 60 - 65°C under vacuum thus obtained the title compound. Wt of compound - 58gms Purity - 99.64%.

Example-5: Preparation of 2-p-tolyl pyridine.

Charged Tetrahydrofuran (200ml), magnesium turnings (15.6gms) and iodine (0.3gms) into round bottom flask at 25-30°C. Stirred the contents for 30min. Added p-bromotoluene solution (100gms p-bromo toluene in 200ml THF) over a period of two hrs at 25-30°C. Stirred the reaction mass at 25-30°C for 30min (Part-A). Mean while charged toluene (200ml) and 2-chloro pyridine (66.2gms) into another round bottom flask at 25-30°C, cooled the reaction mass to -5°C to 0°C. Added [1,3-Bis(diphenylphosphino)propane]nickel(ll) Chloride (DPPP) (3.5gms), and added the above Part-A solution slowly over a period of 3 hrs at 0 - 5°C. Stirred the reaction mass for 3 hrs at 0 - 5°C. Distilled off THF under reduced pressure at below 50°C and cooled the residue to 25-30°C. The concentrated reaction mass was added into dilute hydrochloric acid solution (purified water 700ml and CP HCI 130ml) at 5 - 10°C in 60min. Stirred the reaction mass for 2 hrs at 5-10°C. Separated the solid by Titration and wet cake taken into toluene (300ml) and purified water (600ml) at 25-30°C. Cooled to 10-15°C, adjusted the pH to 6.0 - 6.5 with 20% sodium hydroxide solution (~180ml). Separated the organic layer and distilled off toluene under reduced pressure at below 55°C to obtain the title compound.

Example - 6: Preparation of 2-(4-bromomethyl phenyl) pyridine hydrochloride.

Carbon tetrachloride (1000ml) and 2-p-tolyl pyridine (100gms) were charged into RBF at 25-30°C. Added N-bromosuccinimide (100gms) and benzoyl peroxide (5gms) at 25-30°C. Raised the temperature to 72-76°C and stirred for a period of 4 hrs at 72-76°C. Cooled the reaction mass to 50°C and added N-bromosuccinimide (57.5gms) at 50°C. Again, raised the temperature to 72-76°C and stirred for a period of 5 hrs at 72-76°C. Cooled the reaction mass, separated the salts by filtration and distilled off carbon tetrachloride under reduced pressure at below 50°C. Cooled the residue to 25-30°C and added acetone (100ml), then adjusted the pH to 2.0 - 3.0 by using CP HCI. Cooled the mass to 0-5°C and stirred the mass for 2hrs at 0 - 5°C. Filtered and washed the compound with chilled acetone (25ml).

Example - 7): Preparation of (2S,3S)-N-(3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl butyl) hydrazine carboxylic acid tert-butylester t-Butyl carbazate (80gms) and methanol (200ml) were charged into a RBF, raised the temperature to 40 - 45°C. Added (2R, 3S)-3-(tert-butoxycarbonyl) amino-1, 2-epoxy-4-phenyl butane solution (50gms dissolved in 300ml methanol) over a period of 1hr at 40-45°C. Stirred the reaction mass for 8hrs at 40-45°C. Distilled off methanol under reduced pressure at below 45°C up to reaction volume~250ml. Cooled the reaction mass to 25 - 30°C and added purified water (250ml) at 25 - 30°C in 30min. Stirred the reaction mass for 1hr at 25 - 30°C. Filtered the solid and wash with purified water (50ml). The obtained solid was slurred in ethyl acetate (450ml) at 55-60°C for 10-15 min. Cooled the slurry mass at 25-30°C and maintain for 30min. Filtered and washed the compound with ethyl acetate to obtain the title compound.

Example - 8): Preparation of (tert-butyl)-2-{(2S, 3S)-3-[(tert-butoxycarbonyl) amino]-2-hydroxy-4-phenylbutyl}-2-(4-pyridin-2-ylbenzyl) hydrazine carboxylate) (2S, 3S)-N-(3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl butyl) hydrazine carboxylicacid tert-butylester (25gms) was dissolved in isopropyl alcohol (175ml) and added sodium bicarbonate (12.5gms) and 2-(4-bromomethyl phenyl) pyridine hydrochloride (21gms) . Raised the temperature to 78-82°C. After completion of reaction, distilled off IPA completely under reduced pressure at below 60°C. Added ethyl acetate (50ml) and water (75ml) to the resultant mass and stirred for 30min. Filtered and washed the solid with purified water (50ml). The obtained wet cake was dissolved in acetone (75ml) at 50-55°C and cooled the reaction mass to 25-30°C and stirred for 60min. at 25 - 30°C.

Filtered the reaction mass and washed the with acetone (13ml) to obtain the title compound.

We claim:

1. An improved process for the preparation of tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyyl)amino]-2-hydroxy-4-phenylbutyl}-2-(4-pyridin-2-ylbenzyl) hydrazinecarboxylate (formula A) comprising the steps of;

a) dissolving hydrazine intermediate of formula B in an organic solvent,

b) adding a base,

c) adding a compound of formula

d) optionally adding a catalyst, and

e) isolating compound of formula A

2. The process according to claim 1, wherein the organic solvent is selected from alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, sec-butanol, isobutanol, tert-butanol, acetonitrle and dimethylformamide or a mixture (s) thereof, base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate and catalyst is selected from potassium iodide, sodium iodide, tetrabutylammonium bromide, sodium bromide, potassium bromide.

3. A process for the preparation of a compound of formula B as depicted below:

4. The process for the preparation according to claim 3 comprising the steps of:

a) dissolving (1S,2R)-Boc epoxide in an organic solvent, water or mixture thereof,

b) adding butyl carbazate,

c) optionally heating the reaction mass,

d) removing the solvent, and

d) isolating compound of formula B.

5. The process according to claim 4, wherein the organic solvent selected from alcohols such as methanol, ethanol, n-propanol, n-butanol, sec-butanol, isobutanol, tert-butanol, acetonitrile Dimethyl sulphoxide and water or mixtures thereof.

6. A process for the preparation of compound of formula A, an intermediate in the preparation of atazanavir sulfate comprising the steps of:

a) dissolving 4-(pyridine-2-yl) benzaldehyde in an organic solvent,

b) adding a reducing agent,

c) optionally isolating [4-(pyridine-2-yl)phenyl]methanol,

d) adding chlorinating agent and organic solvent to step c,

e) optionally removing the solvent, and

f) isolating pure 2[4-(chloromethyl) phenyl] pyridine hydrochloride.

7. The process according to claim 6, wherein the organic solvent selected from alcohols such as methanol, ethanol, n-propanol, n-butanol, sec-butanol, isobutanol, tert-butanol, reducing agent is selected from sodium borohydride, chlorinating agent is selected from thionyl chloride, PCI5 or POCI3.

8. A process for the preparation of atazanavir or its salts using compound of formula A and formula B comprising steps;