Claims:We Claim:

1. An improved process for the preparation of 2,5-diamino-1,6-diphenylhexan-3-ol of Formula (I)

Formula (I)
or it’s derivatives or its acid addition salts; wherein R1 and R2 are non-acid labile groups and R3 is hydrogen or an acid labile amino protecting group; wherein the process comprises:
reducing compound of Formula (II)

Formula (II)
wherein R1 and R2 are non-acid labile groups; in an aqueous alcoholic solvent, in presence of one or more reducing agents; one or more acids and optionally reacting with one or more acid labile amino reagents in suitable solvents to produce intermediate compound of Formula (I).

2. The process as claimed in claim 1, wherein the process for the preparation compound of Formula (IA)

Formula (IA)
or an acid addition salt thereof, wherein R1 and R2 are non-acid labile groups, wherein the process comprises:
reducing compound of Formula (II)

Formula (II)
wherein R1 and R2 are non-acid labile groups; in an aqueous alcoholic solvent, in presence of one or more reducing agents and one or more acids to produce intermediate compound of Formula (IA).

3. The process as claimed in claim 1, wherein the process for the preparation of compound of Formula (IB)

Formula (IB)
or an acid addition salt thereof; wherein R1 and R2 are non-acid labile groups; wherein the process comprises:
reducing compound of Formula (II)

Formula (II)
wherein R1 and R2 are non-acid labile groups; in an aqueous alcoholic solvent, in presence of one or more reducing agents; one or more acids and reacting with one or more t-butoxy carbonyl, t-butoxy carbonyl anhydride or esters in suitable solvents to produce intermediate compound of Formula (IB).

4. The process as claimed in claim 1, wherein the reducing agent is selected from borane, borane-tetrahydrofuran, borane-dimethyl sulfide, sodium borohydride, sodium cyanoborohydride, lithium borohydride, potassium borohydride, boron trifluoride-etherate complex, 9-borabicyclo[3.3.1]nonane, (R)-B- isopinocampheyl-9-borabicyclo[3.3.1]nonane or (S)-B-isopinocampheyl-9- borabicyclo[3.3.1]nonane and the like, or mixtures thereof.

5. The process as claimed in claim 1, wherein the acid is an inorganic acid selected from hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, nitric acid; an organic acid selected from formic acid, acetic acid, propionic acid, anhydrides of carboxylic acids, methanesulphonic acid, 4-toluenesulphonic acid or mixtures thereof.

6. The process as claimed in claim 1, wherein the non-acid labile amino protecting groups as used herein is hydrogenation labile amine protecting group, wherein the hydrogenation labile amine protecting group is benzyl.

7. The process as claimed in claim 1, wherein the acid labile amino protecting reagent as used herein is an amine protecting group, wherein the amine protecting groups are selected from tert-butoxycarbonyl (BOC), and 2-(4-biphenyl)-isopropoxy carbonyl.

8. The process as claimed in claim 1, wherein the solvent is hydrocarbon selected from xylene, toluene, cyclohexane, hexane, heptane; keto solvents selected from acetone, butanone, methyl isobutyl ketone; ester solvents selected from ethyl acetate, propyl acetate; chlorinated solvents selected from dichloromethane, dichloroethane, chloroform and/or mixtures thereof.

9. The process as claimed in claim 1, wherein the acid addition salt of compound of Formula (I) prepared by contacting the compound of Formula (I) with an acid, wherein the acids are employed to form pharmaceutically acceptable acid addition salts include inorganic acids selected from hydrochloric acid, sulphuric acid and phosphoric acid and organic acids selected from oxalic acid, maleic acid, succinic acid and citric acid.

Dated this Second (02nd) day of February, 2021

_____________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883
, Description:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR PREPARATION OF
2,5-DIAMINO-1,6-DIPHENYLHEXAN-3-OL OR IT’S DERIVATIVES OR SALTS THEREOF

We, DISCOVERY LABORATORIES PRIVATE LIMITED,
a company incorporated under the companies act, 1956 having address at
MIGH– 172, NAMASKAR House, KPHB Colony, Kukatpally, Road No. 1, Medchal, Malkajgiri, Hyderabad, Telangana, 500085, India

The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 2,5-diamino-1,6-diphenylhexan-3-ol of Formula (I)

Formula (I)
or its derivatives or an acid addition salt thereof; wherein R1 and R2 are non-acid labile groups and R3 is hydrogen or an acid labile amino protecting group.

The present invention specifically relates to an improved process for the preparation of compound of Formula (I) or it’s derivatives or an acid addition salts which can be used as key intermediates in the preparation of HIV protease inhibitors Lopinavir and Ritonavir of Formula A and B respectively.

BACKGROUND OF THE INVENTION
Lopinavir is chemically known as [1S-[1R*,(R*),3R*,4R*]]-N-[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-a-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide or an acid addition salt thereof and structurally represented by Formula (A).

Formula A

Ritonavir is chemically known as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester [5S-(5R*,8R*,10R*,11R*)]- and structurally represented by Formula B.

Formula B

Lopinavir is known to have utility for the inhibition of HIV protease and the inhibition of HIV infection. Lopinavir is particularly effective for the inhibition of HIV protease and for the inhibition of HIV infection when co-administered with Ritonavir. Lopinavir, when combined with Ritonavir, is also particularly effective for the inhibition of HIV infection when used in combination with one or more reverse transcriptase inhibitors and/or one or more other HIV protease inhibitors. Lopinavir is indicated in combination with Ritonavir for the treatment of HIV-infection and is manufactured under the trade name of Kaletra®.

Ritonavir is an inhibitor of the HIV-1 and HIV-2 proteases with in vitro and in vivo activity against the Human Immunodeficiency Virus (“HIV”), and is presently sold in a soft gelatin capsule dosage form for oral administration under the trade name Norvir® and is indicated for use in combination with other antiretroviral agents for the treatment of HIV-infection.

US 5,491,253 discloses a process for the preparation of compound of Formula 3 in three alternate methods which are shown below:

Preferred intermediates of the Formula 3 are the compounds wherein
(i) R6, R7 and R8 are each hydrogen or
(ii) R6 and R7 are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy, halo and phenyl, or R6 and R7 taken together with the nitrogen atom to which they are bonded are
(iii)
wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl and R8 is hydrogen or t-butyloxycarbonyl or
(iii) R6 and R7 are hydrogen and R8 is t-butyloxycarbonyl.
Journal of Organic Chemistry 1995, 59, 4040-4041 discloses a similar process for the preparation of (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane with optimized mole ratio of sodium borohydride and methane sulfonic acid to produce (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane with diastereomeric mixture of 93:7.

Organic Process Research and Development 1999, 3, 94-100 also discloses a process for the preparation of (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane using sodium tris(trifluoroacetoxy)borohydride and trifluoroacetic acid to produce (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane diastereo selectively (84%) with 83% yield.

WO 2006/0090264 A1 describes improved process for preparing 2-amino-5-protected-amino-3-hydroxy-1,6-diphenylhexane compounds or acid addition salts thereof as shown below:

2,5-diamino-1,6-diphenylhexan-3-ol of Formula (I) or it’s derivatives or an acid addition salt thereof prepared by the above prior-art processes is typically an oily mass and it is contaminated with undesired impurities which are carried forward as impurities to the finished product Lopinavir/Ritonavir. Removal of these impurities in the final stage is often proved to be difficult and requires repeated crystallizations, which finally results in the low yield of Lopinavir and Ritonavir.

Hence, there is a need to develop a process which 2,5-diamino-1,6-diphenylhexan-3-ol of Formula (I) or it’s derivatives or an acid addition salt thereof of which is a key intermediate in the preparation of Lopinavir and Ritonavir with essentially high purity.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of 2,5-diamino-1,6-diphenylhexan-3-ol of Formula (I)

Formula (I)
or it’s derivatives or an acid addition salts thereof; wherein R1 and R2 are non-acid labile groups and R3 is hydrogen or an acid labile amino protecting group.

Another objective of the present invention is to provide an improved process for the preparation of compound of Formula (IA)

Formula (IA)
or an acid addition salt thereof; wherein R1 and R2 are non-acid labile groups.

Another objective of the present invention is to provide an improved process for the preparation of compound of Formula (IB)

Formula (IB)
or an acid addition salt thereof, wherein R1 and R2 are non-acid labile groups.

Yet another objective of the present invention is to provide an improved process for the preparation of substantially pure 2,5-diamino-1,6-diphenylhexan-3-ol of Formula (I)

Formula (I)
or it’s derivatives or an acid addition salt thereof, wherein R1 and R2 are non-acid labile groups and R3 is hydrogen or an acid labile amino protecting group.

Another objective of the present invention is to provide an improved process for the preparation of compound of Formula (I) or it’s derivatives or its acid addition salts which can be used as key intermediates in the preparation of HIV protease inhibitors Lopinavir and Ritonavir of formula A and B respectively.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of 2,5-diamino-1,6-diphenylhexan-3-ol of Formula (I)

Formula (I)
or it’s derivatives or its acid addition salts; wherein R1 and R2 are non-acid labile groups and R3 is hydrogen or an acid labile amino protecting group; wherein the process comprises:
reducing compound of Formula (II)

Formula (II)
wherein R1 and R2 are non-acid labile groups; in an aqueous alcoholic solvent, in presence of one or more reducing agents; one or more acids and optionally reacting with one or more acid labile amino reagents in suitable solvents to produce intermediate compound of Formula (I).

In another embodiment, the present invention provides an improved process for the preparation compound of Formula (IA)

Formula (IA)
or an acid addition salt thereof, wherein R1 and R2 are non-acid labile groups, wherein the process comprises:
reducing compound of Formula (II)

Formula (II)
wherein R1 and R2 are non-acid labile groups; in an aqueous alcoholic solvent, in presence of one or more reducing agents and one or more acids to produce intermediate compound of Formula (IA).

In another embodiment, the present invention provides an improved process for the preparation of compound of Formula (IB)

Formula (IB)
or an acid addition salt thereof; wherein R1 and R2 are non-acid labile groups; wherein the process comprises:
reducing compound of Formula (II)

Formula (II)
wherein R1 and R2 are non-acid labile groups; in an aqueous alcoholic solvent, in presence of one or more reducing agents; one or more acids and reacting with one or more t-butoxy carbonyl, t-butoxy carbonyl anhydride or esters in suitable solvents to produce intermediate compound of Formula (IB).

In yet another embodiment, the present invention provides purification of 2,5-diamino-1,6-diphenylhexan-3-ol of Formula (I) or it’s derivatives or an acid addition salt thereof of by making its crystalline acid addition salt, which can be used as such to produce Lopinavir/Ritonavir with high purity and yield.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides improved process for the preparation of intermediate of Formula (I) or it’s derivatives or its acid addition salts.

In the process of the invention, the compound of Formula (II) is reduced in presence of one or more reducing agents and in presence of one or more acids. The reduction reaction can be carried out in "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like. The reaction is carried out below -15 oC.

Suitable reducing agents include those that are known to one of ordinary skill in the art including, for example, borane, borane-tetrahydrofuran, borane-dimethyl sulfide, sodium borohydride, sodium cyanoborohydride, lithium borohydride, potassium borohydride, boron trifluoride-etherate complex, 9-borabicyclo[3.3.1]nonane, (R)-B- isopinocampheyl-9-borabicyclo[3.3.1]nonane or (S)-B-isopinocampheyl-9- borabicyclo[3.3.1]nonane and the like, or mixtures thereof. A preferred reducing agent is sodium borohydride.

Suitable acids include those that are known to one of ordinary skill in the art. The acid used can be one or more inorganic acids, for example, hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, nitric acid and the like or mixtures thereof. The acid can also be one or more organic acids, for example, formic acid, acetic acid, propionic acid, anhydrides of carboxylic acids, methanesulphonic acid, 4-toluenesulphonic acid and the like, or mixtures thereof.

The residue obtained is reacted with one or more acid labile amino protecting reagents to form compounds of Formula I. The reaction can be carried out at room temperature and the resulting product can be used directly in a subsequent reaction step without further purification. The reduction of compound of Formula (II) and protection with one or more acid labile amino protecting groups can be carried out in one step in situ.
The phrase "non-acid labile amino protecting groups," as used herein is known are hydrogenation labile amine protecting group” which are readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile amine protecting group is benzyl.

The phrase "acid labile amino protecting reagent," as used herein, is known to a person of ordinary skill in art. Acid labile amine protecting group” means an amine protecting group as defined above which is readily removed by treatment with acid while remaining relatively stable to other reagents. Preferred acid labile amine protecting groups include tert-butoxycarbonyl (BOC), and 2-(4-biphenyl)-isopropoxy carbonyl.

These for example, the t-butyloxycarbonyl group can be incorporated by reaction with di-t-butyl dicarbonate or other activated t-butyloxycarbonyl esters or azides.

The process is carried out in in a solvent selected from hydrocarbon such as xylene, toluene, cyclohexane, hexane, heptane; keto solvents like acetone, butanone, methyl isobutyl ketone; ester solvents like ethyl acetate, propyl acetate; chlorinated solvents such as dichloromethane, dichloroethane, chloroform and/or mixtures thereof.

In yet another embodiment, the compound of Formula (I) can also be converted to its acid addition salt by contacting the compound of Formula (I) with an acid. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.

The novelty of the present invention is attributed to the reduction being carried out in alcoholic solvent. The advantage of the process of the present invention is that the product is isolated as solid in high purity unlike the prior-art process which is results in oily mass. This oily mass has to be purified / crystallized to isolate as solid.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1: Preparation of (2R)-5-Amino-2-(dibenzylamino)-1,6-diphenylhexan-3-ol:
A solution comprising (2S)-5-amino-2-(N,N-dibenzyl)amino-3-oxo-1,6-di phenylhex-4-ene (100 gr) was added in 250ml of methanol at temperature below -15 ºC and was added methane sulphonic acid (157 gr) followed by sodium borohydride solution (30 gr in 60 ml 1 molar sodium hydroxide solution drop wise. After completion of addition, reaction was maintained for 1 hr then was added 30 gr of triethanol amine at -15 ºC. The reaction was maintained for 1hr and was added 102 gr of NN-dimethylacetamide and 10 gr of sodium borohydride. The reaction was maintained for 3 hrs at 10 ºC. After completion of the reaction, the reaction mixture was quenched with 500ml of ice water followed by toluene (1000 ml). Organic layer was separated and washed with ammonium chloride solution (500 ml). Finally, organic layer was distilled under vacuum to obtain 85 gr of titled compound.

Example 2: Preparation of (2R)-5-Amino-2-(dibenzylamino)-1,6-diphenylhexan-3-ol:
A solution comprising (2S)-5-amino-2-(N,N-dibenzyl)amino-3-oxo-1,6-di phenylhex-4-ene (100 gr) was added in 250 ml of ethanol at temperature below -15 ºC and was added methane sulphonic acid (157 gr) followed by sodium borohydride solution(30 gr in 60 ml 1molar sodium hydroxide solution drop wise .After completion of addition, the reaction was maintained 1 hr then was added 30 gr of triethanolamine at -15 ºC. The reaction was maintained for 1 hr and added 102 gr of NN-dimethylacetamide and 10 gr of sodium borohydride. The reaction was maintained for 3 hrs at 10 ºC. After completion of the reaction, the reaction mixture was quenched with 500ml of ice water followed by toluene (1000 ml). Organic layer was separated and washed with ammonium chloride solution (500 ml). Finally organic layer distilled under vacuum to obtain 97 gr of title compound.

Example 3: Preparation of (2R)-5-Amino-2-(dibenzylamino)-1,6-diphenylhexan-3-ol:
A solution of (2S)-5-amino-2-(N,N-dibenzyl)amino-3-oxo-1,6-di phenylhex-4-ene (100 gr) was added in 250 ml of IPA at a temperature below -15 ºC and was added methane sulphonic acid (157 gr) followed by sodium borohydride solution (30 gr) in 60 ml 1 molar sodium hydroxide solution drop wise. After completion of addition, reaction was maintain for 1 hr then was added 30 gr of NaOH at 15 ºC. The reaction was maintained for 1 hr then was added 102 gr of NN- dimethylacetamide and 10 gr of sodium borohydride. Reaction was maintained for 3 hrs at 10 ºC. After completion of the reaction, the reaction was quenched with 500 ml of ice water followed by extraction with toluene (1000 ml). Organic layer was separated and washed with ammonium chloride solution (500 ml). Finally Organic layer was distilled under vacuum to obtain 95 gr of title compound.

Example 4: Preparation of (2R)-5-Amino-2-(dibenzylamino)-1,6-diphenylhexan-3-ol:
A solution comprising (2S)-5-amino-2-(N,N-dibenzyl)amino-3-oxo-1,6-di phenylhex-4-ene (100 gr) was added in 250 ml of n-butanol at temperature below -15 ºC and was added methane sulphonic acid (157 gr) followed by sodium borohydride solution(30 gr in 60ml 1molar sodium hydroxide solution drop wise. After completion of addition the reaction was maintain for 1 hr then added 30 gr of triethanolamine at -15 ºC. The reaction was maintained for 1hr and was add 102 gr of NN-dimethylacetamide and 10 gr of sodium borohydride. The reaction was maintained for 3 hrs at 10 ºC. After completion of the reaction, the reaction was quenched with 500 ml of ice water followed by toluene (1000 ml). Organic layer was separated and washed with ammonium chloride solution (500 ml). Finally organic layer distilled under vacuum to obtain 100 gr of title compound.

Example 5: Preparation of (2R)-5-Amino-2-(dibenzylamino)-1,6-diphenylhexan-3-ol:
A solution comprising (2S)-5-amino-2-(N,N-dibenzyl)amino-3-oxo-1,6-di phenylhex-4-ene (100 gr) was added in 250 ml of tertiary butanol at temperature below -15 ºC and was added methane sulphonic acid (157 gr) followed by sodium borohydride solution (30 gr) in 60ml 1molar sodium hydroxide solution drop wise. After completion of addition, the reaction was maintained for 1 hr then added 30 gr of triethanolamine at -15 ºC. The reaction was maintained for 1hr and was added 102 gr of NN-dimethylacetamide and 10 gr of sodium borohydride. The reaction was maintained for 3hrs at 10 ºC. After completion of the reaction, the reaction mixture was quenched with 500 ml of ice water followed by toluene (1000 ml). Organic layer was separated and washed with ammonium chloride solution (500 ml). Finally organic layer was distilled under vacuum to obtain 65 gr of title compound.

Example 6: Preparation of (2R)-5-Amino-2-(dibenzylamino)-1,6-diphenylhexan-3-ol:
A solution comprising (2S)-5-amino-2-(N,N-dibenzyl)amino-3-oxo-1,6-di phenylhex-4-ene (100 gr) was added in 250 ml of 2-propanol at temperature below -15 ºC and was added methane sulphonic acid (157 gr) followed by sodium borohydride solution (30 gr) in 60 ml 1 molar sodium hydroxide solution drop wise. After completion of addition, the reaction was maintained for 1 hr then was added 30 gr of triethanolamine at -15 ºC. The reaction was maintained for 1hr and was add 102 gr of NN-dimethylacetamide and 10 gr of sodium borohydride. The reaction was maintained for 3hrs at 10 ºC. After completion of the reaction, the reaction mixture was quenched with 500 ml of ice water followed by toluene (1000 ml). Organic layer was separated and washed with ammonium chloride solution (500ml). Finally organic layer distilled under vacuum to obtain 65 gr of title compound.

Example 7: Preparation of [2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane:
A solution of (2S)-5-amino-2(N,N-dibenzyl)amino-3-oxo-1,6-diphenylhex-4-ene (100 gr) was added in 250 ml of IPA at temperature below -15 oC followed by addition of methane sulphonic acid (157 gr). After addition is complete, sodium borohydride solution (30 gr) in 60 ml 1 molar sodium hydroxide solution was added dropwise. Subsequently, completion of addition maintain 1hr then add 30 gr of triethanolamine and maintain for 1hr then add 102 gr of N,N-dimethylacetamide and sodium borohydride 10 gr was added and the reaction was maintained for 3 hrs at 10 oC. After completion of the reaction, the reaction mixture was quenched in 500 ml of ice water followed by extraction with toluene. The obtained organic layer was washed with ammonium chloride solution. The organic layer was distilled under vacuum. The obtained crude compound was dissolved in 500 ml toluene and allowed to stir. 50 gr of aqueous potassium carbonate solution and 63 gr of di-tert-butyl dicarbonate was added. The reaction mixture was maintained for 1 hr at ambient temperature. After completion of the reaction, the pH of the reaction mixture was adjusted with citric acid and the organic layer was separated, washed with sodium chloride solution. The organic layer was distilled under vacuum to provide 150 gr of the title compound.

Example 8: Preparation of [2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane:
A solution of (2S)-5-amino-2(N,N-dibenzyl)amino-3-oxo-1,6-diphenylhex-4-ene (100 gr) was added in 250 ml of methanol at temperature below -15 oC followed by addition of methane sulphonic acid (157 gr). After addition is complete, sodium borohydride solution (30 gr) in 60 ml 1 molar sodium hydroxide solution was added drop wise. Subsequently, Then add 30 gr of triethanolamine maintain for 1 hr then 102 gr of N,N-dimethylacetamide and sodium borohydride 10 gr was added and the reaction was maintained for 3 hrs at 10 oC. After completion of the reaction, the reaction mixture was quenched in 500 ml of ice water followed by extraction with toluene. The obtained organic layer was washed with ammonium chloride solution. The organic layer was distilled under vacuum. The obtained crude compound was dissolved in 500 ml toluene and allowed to stir. 50 gr of aqueous potassium carbonate solution and 63 gr of di-tert-butyl dicarbonate was added. The reaction mixture was maintained for 1 hr at ambient temperature. After completion of the reaction, the pH of the reaction mixture was adjusted with citric acid and the organic layer was separated, washed with sodium chloride solution. The organic layer was distilled under vacuum to provide 150 gr of the title compound.

Example 9: Preparation of [2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane:
A solution of (2S)-5-amino-2(N,N-dibenzyl)amino-3-oxo-1,6-diphenylhex-4-ene (100 gr) was added in 250 ml of ethanol at temperature below -15 oC followed by addition of methane sulphonic acid (157 gr). After addition is complete, sodium borohydride solution (30 gr) in 60 ml 1 molar sodium hydroxide solution was added drop wise. Subsequently, Then add 30 gr of triethanol amine maintain for 1 hr then 102 gr of N,N-dimethylacetamide and sodium borohydride 10 gr was added and the reaction was maintained for 3 hrs at 10 oC. After completion of the reaction, the reaction mixture was quenched in 500 ml of ice water followed by extraction with ethylactate. The obtained organic layer was washed with ammonium chloride solution. The organic layer was distilled under vacuum. The obtained crude compound was dissolved in 500 ml ethylacetate and allowed to stir. 50 gr of aqueous potassium carbonate solution and 63 gr of di-tert-butyl dicarbonate was added. The reaction mixture was maintained for 1 hr at ambient temperature. After completion of the reaction, the pH of the reaction mixture was adjusted with citric acid and the organic layer was separated, washed with sodium chloride solution. The organic layer was distilled under vacuum to provide 150 gr of the title compound.

Example 10: Preparation of [2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane:
A solution of (2S)-5-amino-2(N,N-dibenzyl)amino-3-oxo-1,6-diphenylhex-4-ene (100 gr) was added in 250 ml of n-butanol at temperature below -15 oC followed by addition of methane sulphonic acid (157 gr). After addition is complete, sodium borohydride solution (30 gr) in 60 ml 1 molar sodium hydroxide solution was added drop wise. Subsequently, Then add 30 gr of triethanolamine maintain for 1 hr then 102 gr of N,N-dimethylacetamide and sodium borohydride 10 gr was added and the reaction was maintained for 3 hrs at 10 oC. After completion of the reaction, the reaction mixture was quenched in 500 ml of ice water followed by extraction with toluene. The obtained organic layer was washed with ammonium chloride solution. The organic layer was distilled under vacuum. The obtained crude compound was dissolved in 500 ml of dichloroethane and allowed to stir. 50 gr of aqueous potassium carbonate solution and 63 gr of di-tert-butyl dicarbonate was added. The reaction mixture was maintained for 1 hr at ambient temperature. After completion of the reaction, the pH of the reaction mixture was adjusted with citric acid and the organic layer was separated, washed with sodium chloride solution. The organic layer was distilled under vacuum to provide 150 gr of the title compound.