MXPA97009454A - Procedure for the preparation of a compound to inhibit proteasa of the human immunodeficiency virus - Google Patents

Abstract

The present invention relates to a process for the preparation of (2S, 3S, 5S) -5- (NN - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) - L-valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane or an addition salt thereof comprising: a) preparing a mixed anhydrous derivative of N - ((N-methyl-N ((isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine of the formula: wherein R * is straight or branched chain alkyl of 1 to 6 carbon atoms or alkoxy straight or branched chain of 1 to 6 carbon atoms, b) converting the mixed anhydrous derivative of step (a), without isolation of the mixed anhydride derivative, into an activated ester derivative of N - ((N-methyl-N) - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine of the formula: wherein R ** is selected from the group consisting of succinimid-1-yl, benzotriazol-1-yl, phthalimid -1-yl, 5-norbornene-2,3-dicarboximidyl, quinolin-8-yl, 1,2,3-benzotriazin-4- (3H) -on-yl, piperidin- 1-lo, pentachlorophenyl, 2,4,5-trichlorophenyl, 2-nitrophenyl, 4-nitrophenyl and pentafluorophenyl, and c) reacting the activated ester derivative of step (b), without isolation of the activated ester derivative, with (2S, 3S, 5S) -5-amino-2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexa

Description

PROCEDURE FOR THE PREPARATION OF A COMPOUND FOR INHIBITING VIRUS PROTEASE HUMAN IMMUNODEFICIENCY TECHNICAL FIELD The present invention relates to a process for the preparation of (2S, 3S153) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) vanillin) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) -amino) -1,6-diphenyl-3-hydroxyhexane.

BACKGROUND OF THE INVENTION Recently it has been determined that compounds for inhibiting HIV protease are useful for inhibiting HIV protease in. in vitro and in vivo and are also useful to inhibit an infection by HIV (human immunodeficiency virus). Recently it has also been determined that the compounds of the formula I: wherein Ri is a lower alkyl and R2 and R3 are phenyl, they are particularly useful as inhibitors of HIV-1 and HIV-2 protease, and are useful for inhibiting in vitro and in vivo and are also useful for inhibiting HIV infections. In particular, the compound of formula II has been found especially effective as a protease inhibitor of HIV-1 and HIV-2.

II The highly preferred compounds of formula II are (2S, 3S, 53) -5- (N- (N - ((N-me ti lN- ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) - L-valinyl) amino) -2- (N - ((5-ti azolyl) toxic rbonyl) amino) -1,6-di-phe nyl-3-hydroxyhexane (compound III) or an acid addition salt thereof , and (2S, 3S, 53) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) -carbonyl) -D-valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane (compound IV) or an acid addition salt thereof. The preparation of compound III and its use as an HIV protease inhibitor are described in the PCT Patent Application N.

WO94 / 14436, published July 7, 1994, which is incorporated herein by reference. The described method for preparing the compound III is shown in Scheme I. This method involves an amide bond forming a coupling reaction of intermediates 1 and 2 in the presence of 1-hydroxybenzotriazole and a diimide such as dicyclohexylcarbodiimide (DCC) or N-ethyl-N'-dimethylaminopropyl carbodiimide (EDC) and the like. Said process is not suitable for producing a production at III or IV scale since the diimides are toxic, are sensitizers and present a variety of other handling and processing problems. An alternative procedure is shown in Scheme I I. In this process, intermediate 1 is converted to a mixed anhydride (wherein R * is lower alkyl, for example, by reaction with alkyl chloroformate such as isobutyl chloroformate and the like or by reaction with an alkanoyl chloride such as pivaloyl chloride and similar). The mixed anhydride is then reacted (without isolation) with intermediate 2. Due to the high reactivity of the intermediate mixed anhydride, this procedure usually leads to unacceptable amounts of unwanted side products. Therefore, there is a continuing need for an improved coupling procedure for the preparation of III and IV.

SCHEME III or IV SCHEME II III or IV DESCRIPTION OF THE INVENTION The present invention relates to processes for the preparation of (2S, 3S, 53) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl ) -L-valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane (compound III) and (2S, 3S, 53) -5- ( N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -D-valinyl) -amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) ) -amino) -1,6-diphenyl-3-hydroxyhexane (compound IV). The procedure is shown in Scheme 3. The procedure comprises three steps performed without isolation of the intermediaries. The first step comprises the formation of an intermediate mixed anhydride derivative 3 (R * is lower alkyl or alkoxy). In the second step, the mixed anhydride (without isolation) is converted to an intermediate activated ester derivative 4 (R ** is selected from the group consisting of succinimid-1-yl, benzoriazol-1-yl, phthalimid-1-yl, 5-norbornene-2,3-dicarboximidyl, quinolin-8-yl, 1,2,3-benzotrazin-4 (3H) -on-3-yl, piperidin- 1 -yl, pentachlorophenyl, 2,4,5-trichlorophenyl, 2-nitrophenyl, 4-nitrophenyl, pentafluorophenyl and the like). In the third step, the activated ester (without isolation) is reacted with intermediate 2 to give the product. This procedure results in the preparation of highly pure III or IV on a manufacturing scale without complex purification procedures and without exposure to highly reactive reagents. toxic or corrosive. In particular, the process of this invention comprises reacting intermediate 1 with a lower alkyl chloroformate (e.g., isobutyl chloroformate or ethyl chloroformate or 2-ethoxy.1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) or -isobutoxy-2-isobutoxycarbonyl-1,2-dihydroquinoline (II DQ) and the like) or with a lower alkyl acid chloride (e.g., pivaloyl chloride, and the like) to provide an intermediate mixed anhydride 3. The reaction is performs by reacting compound 1 with from about 0.9 molar equivalents to about 1.0 molar equivalents (based on the amount of compound 1) of the chloroformate or the acid chloride or similar reagent in an inert solvent such as ethyl acetate or THF or acetonitrile or toluene and the like, at a temperature of about -20 ° C to about 30 ° C. This reaction is preferably carried out in the presence of about 1.0 molar equivalent to about 3.0 molar equivalents (based on the amount of compound 1) of an acid scavenger such as N-methylmorpholine or triethylamine or pyridine and the like. To the resulting solution were added approximately 1. 0 molar equivalents to about 2.0 molar equivalents (based on the amount of compound 1 of R ** OH, keeping the temperature of the solution from about -20 ° C to about 30 ° C to provide the activated ester. of the activated ester was added a solution of intermediate compound 2 in an inert solvent such as ethyl acetate or THF or DMF or acetonitrile or toluene and the like, at a temperature from about -20 ° C to about 60 ° C. The resulting product III or IV can then be purified by recrystallization. The first step of the process is preferably carried out by reacting the intermediate compound 1 with about 1.0 molar equivalents of isobutyl chloroformate in ethyl acetate at about -15 ° C in the presence of about 1.5 molar equivalents of N-methylmorpholine. The second step of the process is preferably carried out by adding about 1.0 molar equivalents of N-hydroxysuccinimide to the mixed anhydride solution resulting from step one and maintaining the temperature of the solution at about 0 ° C. The third step of the process is preferably carried out by adding to the solution of the activated ester, resulting from step two, a solution of about 0.9 to about 1.0 molar equivalents of compound 2 in ethyl acetate at a temperature of about 0 ° C. This mixture was allowed to warm to about room temperature and was stirred for about 24 hours. The crude product can be purified by recrystallization from heptane / ethyl acetate.

SCHEME III R "-OH III or IV The acid addition salts of the compounds of the invention can be derived from the reaction of a compound containing an amine of the invention with an inorganic or organic acid. These salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, cyclopentan-propionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate , heptanoate, hexanoate, furmarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, malonate, glutarate, malate, mandelate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate , propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Examples of acids that can be used to form acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid, as well as the other acids mentioned above. The term "lower alkyl", as used herein, refers to a straight or branched chain alkyl radical containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso -propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. The term "alkoxy", as used herein, refers to RO-, wherein R is a lower alkyl group. The term "alkanoyl", as used herein, refers to R '(O) -, where R' is a lower alkyl group. As used herein, the terms "S" and "R" configurations are as defined by IUPAC 1974 Recommendations for Section E, Fundamental Sterochemistry, Puré Appl. Chem. (1976) 45, 13-30.

The following examples will serve to illustrate the methods of the invention.

EXAMPLE 1 (2S.3S.53? -5-Amino-2- (N - ((5-thiazolyl? MethoxycarbonM) amino} -1,6-diphenyl-3-hydroxyhexane To a glass lined reactor of 2838 liters was charged (2S, 3S, 5S) -2-amino-3-hydroxy-5- (t-butyloxycarbonylamine) -1,6-d-faith nil-hexane - 0.5 of succinic acid salt (75.0 kg, 169 moles), 5- (p-nitrophenyloxycarbonyloxymethyl) thiazole hydrochloride (65.0 kg, 205 moles) and sodium bicarbonate (70.0 kg, 833 moles). Ethyl acetate (826 kg, 918 L) was added and the stirrer was activated. Tap water (788 kg) was added and the mixture was heated to 30 ° C and stirred for 2.5 hours until all the solids dissolved. After fixing for 30 minutes, the aqueous layer was separated and discarded. The organic layer was heated to 60 ° C and stirred for 12 hours. The solution was then cooled to 30 ° C and 28% ammonia water (9.0 kg, 148 moles) was added. The mixture was stirred for 3 hours at 25-30 ° C. The mixture was then washed three times with a 10% potassium carbonate solution (903 kg each). The aqueous layers were drained and discarded after each wash. Concentrated hydrochloric acid (59.0 kg, 600 moles) was added to the ethyl acetate solution and heated to 50 ° C with stirring for 3 hours.

The mixture was then cooled to 40 ° C and the resulting precipitate was isolated by centrifugation. Five batches were obtained separately with a wet weight of 26 to 51 kg, and each batch was rinsed with 50 kg of ethyl acetate. The wet solids were combined and charged to the reactor and a slurry was formed with ethyl acetate (723 kg, 803 L). Diluted ammonia water (approximately 9.4% ammonia, approximately 190 L) was charged to give a final aqueous pH of about 10.5. The aqueous layer was drained and discarded. The organic layer was washed with 25% sodium chloride solution (513 kg) and the aqueous layer was drained and discarded. The organic layer was filtered in a 1135.2 liter glass lined reactor and the solvent was styled under vacuum at an internal temperature of 40 ° C or less. The residue was dissolved in ethyl acetate (576 kg, 640 L) and the solvent was distilled under vacuum until a volume of about 290 L was reached.

EXAMPLE 2 (2S.3S.53) -5-IN- (N-NIIN-methyl-N- -IÍ2-isopropyl-4-thiazolyl) methyl) amypo) carbonyl) -L- * / al inyl) amino) -2 - (-ÍÍ5- thiazole iUmethoxycarbonylamino) -1, 6 -difen il-3-hydroxyh? exano To a 2838 liter glass lined reactor was charged N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine (57.0 kg, 182 moles) and ethyl acetate (916 kg, 1018 L). The mixture was stirred until everything was in the solution and then it was charged N- methylmorpholine (28.0 kg, 277 moles) to the reactor and the resulting solution was cooled to -18 ° C. In a separate reactor, a solution of isobutyl chloroformate (24.4 kg, 180 moles) in ethyl acetate (101 kg, 112 L) was prepared. The isobutyl chloroformate solution was charged (for about 50 minutes) to the cold solution of the valine derivative and the N-methylmorpholine prepared above, maintaining the temperature between -18 ° C and -14 ° C. After stirring at -14 ° C for about 30 minutes, N-hydroxysuccinimide (21.2 kg, 184 moles) was added to the mixture. After stirring for an additional 30 minutes, the mixture was heated to about 0 ° C and stirred for about one hour. The resulting solution of Example 1 was cooled to about 0 ° C and slowly charged to the previous solution. A reactor rinse of 1135.2 liters was also added with ethyl acetate (50 kg, 56 L). The reaction mixture was heated to 25 ° C and stirred for 24 hours. The reaction mixture was washed twice with 10% of a potassium carbonate solution (2x 711 kg), once with 10% of a citric acid solution (1025 kg) and once with water (640 kg). The aqueous layers were drained and discarded after each separation. The solvent was distilled under vacuum at an internal temperature of about 50 ° C or less. The residue was dissolved in ethyl acetate (576 kg, 640 L) and the solvent was distilled once more. The residue was dissolved in ethyl acetate (500 kg, 556L) and heated to about 60 ° C until a clear solution was obtained. The solution was filtered to a clean reactor of 1135.2 liters and a rinse was also filtered of ethyl acetate (77 kg, 86 L) in the 1135.2 liter reactor. Heptane (218 kg, 320 L) was charged to the ethyl acetate solution in the 1135.2 liter reactor. The mixture was heated to about 80 ° C until a clear solution was obtained. The solution was cooled to a rate of less than 25 ° C per hour at a final temperature of 22 ° C and stirred for 12 hours after the product started to crystallize. The thick mud was centrifuged in four separate charges to isolate the product. Each isolated charge was washed with approximately 45 kg of a 2: 1 (v / v) solution of ethyl acetate / heptane. The last wash was used to also rinse the reactor. The product was dried in a mixer dryer under vacuum at 55 ° C for about 24 hours to provide 101.9 kg of the desired product. P.f. 121-123 ° C. 1 H NMR: (CD 3 OD, 300 MHz) d 7.78-7.96 (m, 1 H), 7.85 (s, 1 H), 7.07-7.33 (m, 11 H), 6.68-6.75 (m, 1 H), 6.17-6.28 (m, 1H), 5.22 (s, 2H), 4.47-4.67 (m, 2H), 4.32-4.45 (m, 1H), 3.98-4.10 (m, 2H), 3.72-3.82 (m, 1H), 3.28-3.40 ( m, 1H), 3.02 (s, 3H), 2.67-2.92 (m, 4H), 1.92-2.08 (m, 1H), 1.56-1.80 (m, 2H), 1.37-1.46 (m, 6H), 0.84- 0.96 (m, 6H). 13C NMR; (CD3OD, 75 MHz) d 176.0, 169. 8, 155.7, 153.7, 152.4, 149.3, 139.3, 139.2, 135.8, 135.2, 126.0, 124. 9, 124.8, 122.9, 122.8, 111.2, 111 1, 66.5, 57.6, 57.5, 54.5, 52.9, 52.8, 45.4, 37.3, 35.7, 34.9, 30.9, 30.0, 27.7, 19.3, 19.2, 15.7, EXAMPLE 3 (2S, 3S.53) -5- (N- (N - ((N-methyl-N- (2-isopropyl-4-thiazolyl) methylamino) -carbonyl) -D-valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) - 1,6-diphenyl-3-hydroxyhexane The title compound was prepared following the procedure of Example 2 with the replacement of N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine with N- ( (N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -D-valine. P.f. 68-69 ° C. 1 H NMR: (DMSO-d 6) d 0.56 (d, J = 6 Hz, 3 H), 0.63 (d, J = 6 Hz, 3 H), 0.63 (d, J = 6 Hz, 3 H), 1.28 (d, J = 7 Hz, 6H), 1.47 (m, 2H), 1.77 (octet, J = 6 Hz, 1H), 2.5-2.7 (m, 4H), 2.85 (s, 3H), 3.20 (heptet, J = 7 Hz , 1H), 3.4 (m, 1H), 3.6 (m, 1H), 3.90 (dd, J = 8, 6 Hz, 1H), 3.93 (m, 1H), 4.43 (AA ', 2H), 4.65 (d , J = 6 Hz, 1H), 5.15 (AA ', 2H), 6.02 (br d, J = 9 Hz, 1H), 6.90 (br d, J = 9 Hz, 1H), 7.1-7.2 (m, 11H ), 7.70 (br d, J = 9 Hz, 1H), 7.85 (s, 1H), 9.04 (s, 1H). Mass spectrum: (M + H) + = 721.

EXAMPLE 4 Alternative Preparation of (2S, 3S.53) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-tiazolyl) methyl) amino) carbon.pL-valinyl ) amino) -2- (N - ((5-thiazolyl) rnetoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane To a 250 ml 4-necked round bottom flask equipped with a mechanical stirrer, nitrogen atmosphere, funnel addition of 60 ml side arm and a thermocouple was charged N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine (5.03 g, 16 mmol) and ethyl acetate (93 ml). The mixture was stirred until all solids were dissolved and then cooled to -15 ° C. To the cooled solution was added N-methylmorpholine (1.77 ml, 16 mmol). The mixture was cooled to -18 ° C. isobutyl chloroformate (2.08 ml, 16 mmol) in ethyl acetate (8 ml) was added, keeping the temperature of the reaction mixture below -14.5 ° C. After stirring for 1 h at -17 ° C, 1-hydroxybenzotriazole (2.46 g, 16 mmol) was added in one portion. The resulting slurry was heated to 0 ° C and maintained at or below 0 ° C, as (2S, 3S, 53) -5-amino-2- (N - ((5-thiazolyl) methoxycarbonyl) was added. -amino) -1,6-diphenyl-3-hydroxyhexane (6.4 g, 15 mmol) in ethyl acetate (25 ml). The resulting mixture was stirred at 0 ° C for 1 hour and then allowed to warm to room temperature and stirred for 15 hours. 75 ml of 5% aqueous sodium bicarbonate was added to the reaction mixture. The organic layer was separated and washed again with 75 ml of 5% aqueous sodium bicarbonate, followed by double washing with 75 ml of 10% aqueous citric acid each time and, finally, with 75 ml of water. The solvent was removed under vacuum and the residue was crystallized from 270 mL of heptane / ethyl acetate 1: 1 to provide 9.25 g of the desired product.

EXAMPLE 5 Alternative Preparation of (2S.3S.53) -5- (N- (N - ((N-methyl-N- (2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valinipam No) -2- (N - ((5- thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane Into a three-liter flask, N- ((N-meth? N) - ((2-? Soprop? L-4-t? Azol? L) met? L) am? No) carbon? L-valine (1966 g, 0627 moles) and 1-hydroxybenzotrol azol (107 g, 0701 moles) and THF (1 6 L) A solution of dicyclohexylcarbodnmide (1294 g, 0627 moles) in THF ( 200 ml) was added in one portion. The resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered and the filter cake was washed with THF (500 ml). The filtrate was added to a solution of (2S, 3S , 53) -5-am? No-2- (N - ((5-t? Azol? L) methox? Carbon? L) -am? No) -1,6-d? Phen? L-3-h Drox? -hexane (2389 g, 561 moles) and dissolved in THF (35 L) at room temperature) after stirring for 4 hours, the THF was evaporated under reduced pressure. The residue was dissolved in methylene chloride (2 L) and washed with 05 M aqueous NaOH (1 25 L) and then with V_ saturated aqueous sodium bicarbonate (1 L). The organic solution was then washed with 1% aqueous KH S04 (1 L). The resulting mixture was filtered. The organic solution was washed with 1 L of a mixture of 1 liter of aqueous sodium chloride and pH regulator of aqueous phosphate with a pH of 7 saturated. The organic solution was then dried over Na 2 SO 4. and the solvent evaporated to give a tan foam The crude product was dissolved in methylene chloride (1.1 L) and the solvent was evaporated to provide a brittle foam. This foam was dissolved in 1 M aqueous HCl (3 L) at 10 ° C. The resulting insoluble material was filtered and the filter cake was washed with 1 M aqueous HCl (100 ml). In a 12 L Morton flask, the filtrate was combined with KH2 PO (100 g) and methylene chloride (2.2 L). With rapid stirring, the solution was neutralized to a pH of 6 with 2 M aqueous NaOH. The bottom layer was drained and the aqueous layer was extracted with methylene chloride (2 x 500 mL). The combined organic layers were dried over Na2SO4, diluted with ethyl acetate (1 L) and concentrated to a colorless foam. The resulting solid was recrystallized by dissolving in hot ethyl acetate (2 L), diluting with hot hexane (1 L), adding seed crystals, stirring until cooling and allowing to stand at room temperature overnight to provide the desired product as a solid white. P.f. 122 ° C. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the modalities described. Variations and changes, which are obvious to a person skilled in the art, are intended to be within the scope and nature of the invention, which are defined in the appended claims.

Claims (3)

1. - A process for the preparation of (2S, 3S, 53) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L- valinyl) -amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane or an acid addition salt thereof, which comprises converting a mixed anhydride derivative of (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine to an activated ester derivative of (N - ((N-methyl-N- ((2-isopropyl-4-thiazolyl) methyl) amino) -carbonyl) -L-valine, followed by reaction of the activated ester with (2S, 3S, 5S) -5-amino-2- (N - (( 5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane

2. The process according to claim 1, which comprises converting a compound of the formula: wherein R * is lower alkyl or alkoxy, to an activated ester derivative of (N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valine, followed by the reaction of the activated ester with ( 2S, 3S, 5S) -5-ami non-2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-d-phenyl-3-hydroxy hexa no.

3. The process according to claim 1, comprising reacting a compound of the formula: wherein R * is lower alkyl or alkoxy with R ** OH, wherein R ** is selected from the group consisting of succinimid-1-yl, benzoriazol-1-yl, phthalimid-1-yl, 5-norbornene-2 , 3-dicarboximidyl, quinolin-8-yl, 1,2,3-benzotrazin-4 (3H) -on-3-yl, piperidin-1-yl, pentachlorophenyl, 2,4,5-trichlorophenyl, 2-nitrophenyl, 4-nitrophenyl, and pentafluorophenyl to provide an activated ester of the formula: followed by reacting the activated ester with (2S, 3S, 5S) -5-amino-2- (N - ((5-thiazolyl) me toxic rbonyl) amino) -1,6-di fe nyl-3-hydroxy- Hexane 4 - A process for the preparation of (2S, 3S, 53) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L -valinyl) -amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) -amino) -1,6-diphenyl-3-hydroxy-hexane or an acid addition salt thereof, which comprises reacting a compound of the formula: where R * is isobutoxy with R ** OH, where R ** is succinimid-1-yl to provide an activated ester of the formula: followed by reaction of the activated ester with (2S, 3S, 53) -5-amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) -amino) -1,6-diphenyl-3-idroxyhexane. 5. A process for the preparation of (2S, 3S, 53) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) -carbonyl) -D-valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxyhexane or an acid addition salt thereof, which comprises converting a mixed anhydride derivative of N - ((N-methyl-N - ((2-isopro-yl-4-thiazolyl) methyl) amino) carbonyl) -D-valine to an activated ester derivative of N - ((N-methyl-N- ((2-isopropyl-4-thiazolyl) methyl) amino) -carbonyl) -D-valine, followed by reaction of the activated ester with (2S, 3S, 5S) -5-amino-2- (N - (( -thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxy-hexane. 6 - The method according to claim 5, which comprises converting a compound of the formula: wherein R * is lower alkyl or alkoxy to an activated ester derivative of N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) -carbonyl) -D-valine, followed by the reaction of the activated ester with (2S, 3S, 5S) -5-amino-2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxy-hexane. 7 - The process according to claim 5, which comprises reacting a compound of the formula: - wherein R * is lower alkyl or alkoxy with R ** OH, wherein R ** is selected from the group consisting of succinimid-1-yl, benzoriazol-1-yl, phthalimid-1-yl, 5-norborne 2,3-dicarboximidyl, quinolin-8-yl, 1,2,3-benzothrazin-4 (3H) -on-3-yl, pi-peridin-1-yl, pentachlorophenyl, 2,4,5-trichlorophenyl, -nitrophenyl, 4-nitrophenyl, and pentafluorophenyl to provide an activated ester of the formula: followed by reaction of the activated ester with (2S, 3S, 5S) -5-amino-2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxy-hexane. 8. A process for the preparation of (2S, 3S, 53) -5- (N- (N - ((N-methyl-N - ((2-isopropyl-4-thiazolyl) methyl) amino) -carbonyl) -D-valinyl) -amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1,6-diphenyl-3-hydroxy-hexane or an acid addition salt, which comprises reacting a compound of the formula: where R * is isobutoxy with R ** OH, where R ** is succinimid-1-yl to provide an activated ester of the fla: followed by reaction of the activated ester with (2S, 3S, 5S) -5-amino-2- (N - ((5-thiazolyl) methoxycarbonyl) -amino) -1,6-diphenyl-3-hydroxyhexane.