MXPA99006189A - Aminoepoxides from aminoaldehydes and in-situ formed halomethyl organometallic reagent - Google Patents

Abstract

A method of preparing an aminoepoxide wherein a protected aminoaldehyde is reacted with a halomethyl organometallic reagent in an appropriate solvent at a temperature above -80°C, wherein said halomethyl organometallic reagent is formed by reaction between an organometallic reagent and a dihalomethane, the improvement comprising flowing said protected aminoaldehyde into a mixing zone maintained at a temperature below 0°C, also flowing said halomethyl organometallic reagent in said mixing zone for contacting in said mixing zone with said protected aminoaldehyde and also withdrawing from said mixing zone reaction products of said protected aminoaldehyde and said halomethyl organometallic reagent. The obtained aminoepoxides are useful, through amine opening of the epoxide ring, as intermediates in the preparation of pharmaceuticals, e.g. HIV protease inhibitors.

Description

AMINOEPOXIDES OF AMINOALDEHYDES AND ORGANOMETALLIC REAGENT OF HALOGENOMETILO FORMED IN-SITU BACKGROUND OF THE INVENTION The synthesis of many pharmaceutical compounds containing a hydroxyethylamine isostera, such as the inhibitors of aspartyl protease-HIV protease, involves the opening of an amine of an epoxide intermediate. Said pharmaceutical compounds contain chiral centers that can be introduced into the synthesis of the drug by the use of a chiral epoxide intermediate. The preparation of said epoxides, including chiral epoxides, may require a multi-step synthesis starting from an L-amino acid such as L-phenylalanine or an amino acid derivative such as an alcohol such as phenylalaninol. Historically, said epoxides were prepared by methods involving the reduction of a chloromethyl ketone intermediate. This can lead to low total returns. Chloromethyl ketone was often prepared by a process that required the use of highly toxic and highly explosive diazomethane. Due to the nature of diazomethane, its use is generally not applicable to large-scale production (multikilograms) of intermediates or end products. In addition, the overall performance for the diastereoselective reduction of chloroketones, especially those used in the preparation of HlV-protease inhibitors, may be low.

An improved process for the preparation of said epoxide intermediates is described in WO 93/23388 and WO 95/14653. The process involves the reaction of a halogenomethyl lithium reagent at low temperature with an aldehyde intermediate. This process is particularly suitable for the preparation of chiral epoxide intermediates, but requires the cooling of large reactors containing large amounts of solvent and reagents. A less convenient and less efficient method for generating a halogenomethyl lithium reagent from lithium metal for reaction with an alpha-aminoaldehyde compound is described in WO 9617821. The present invention relates to an improvement in this addition of halogenomethyl organometallic reagent to a carbonyl aldehyde method for preparing epoxides. In particular, the invention is directed to the diastereoselective production of chiral epoxides using a continuous flow method, wherein a reagent or reagents can be added with or without preparation, more or less at the same time (more or less simultaneously) in uninterrupted form . Roberts et al., Science, 248, 358 (1990), Krohn et al., J. Med. Chem. 334, 3340 (1991) and Getman et al., J. Med. Chem., 346,288 (1993) have previously reported the synthesis. of HIV protease inhibitors containing the isostera of hydroxyethylamine, hydroxyethylurea or hydroxyethylsulfonamide, which included the opening of an epoxide generated in a multi-step synthesis starting from an amino acid. These methods also contain steps which include diazomethane as a reactant in the synthesis of chloromethyl ketones, and the reduction of intermediates of aminocloromethyl ketone to an aminohalogen alcohol prior to the formation of the epoxide. The total yields of this synthesis are low. In addition, as described above, the use of toxic and explosive diazomethane prevents such methods from being useful for the commercial production of drugs or in a pilot plant. Thus, despite the ability of the prior art to synthesize more efficient HIV protease inhibitors, environmentally acceptable and commercially convenient methods are required. Tinker et al., Patent of E.U.A. No. 4,268,688, describe a catalytic asymmetric hydroformylation process for preparing optically active aldehydes from unsaturated olefins. Similarly, Reetz et al., U.S. Patent No. 4,990,669, describe the formation of optically active alpha-aminoaldehydes through the reduction of alpha-aminocarboxylic acids or their esters with lithium-aluminum hydride., followed by oxidation of the resulting protected beta-aminoalcohol by dimethyl sulfoxide / oxalyl chloride or chromium trioxide / pyridine. Alternatively, the protected alpha aminocarboxylic acids or esters thereof can be reduced with diisobutylaluminium hydride to form the protected aminoaldehydes. Reetz et al. (Tet. Lett., 30, 5425 (1989) describe the use of sulfonium and arsonium ylides, and their reactions are protected alpha aminoaldehydes, to form aminoalkyl epoxides.This method requires the use of highly toxic arsenium compounds. , or the use of a combination of sodium hydride and dimethyl sulfoxide, which is extremely dangerous on a large scale Matteson et al., Syn. Lett., 1991, 631 reported the addition of chloromethyl lithium or bromomethyl lithium to achiral or racemic aldehydes. The summary of the article "Development of a large-scale process for an HIV Protease inhibitor", by C. Lui et al., Org. Proc. Res. And Dev., Vol. 1, No.1, of January 1997, published on the Internet on December 15, 1996, describes a continuous process for reacting a chiral aminoaldehyde and a (chloromethyl) lithium and recovering the epoxide by heating the mixture.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of epoxides, in particular chiral epoxides, from aldehydes using a halogenomethyl lithium reagent, which is continuously synthesized in situ at low temperatures. The continuous process of in situ synthesis is more versatile, controllable, efficient and cost effective than the corresponding gradual or intermittent synthesis method used in the prior art. In particular, in accordance with a preferred embodiment of the present invention, an aldehyde of the invention, as described in more detail below, is flowed in and through a mixing zone within which the aldehyde is maintained at a temperature between about -80 ° C to 0 ° C, preferably between about -60 ° C to -10 ° C, and more preferably between -40 ° C to -15 ° C; while the aldehyde is flowed through the mixing zone, a dihalomethane reagent and an organometallic reagent (lithium) are added in such a way that a halogenomethyl lithium reagent is continually generated in situ, and subsequently a chiral epoxide is recovered from the product of the mixing zone.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a method for preparing inhibitors of HIV protease that allows the preparation of commercial quantities of intermediates of the formula: wherein R1 is selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl, arylalkyl and arylthioalkyl, which are optionally substituted with a group selected from alkyl, halogen, NO2, OR9 or SR9, wherein R9 represents hydrogen or alkyl; and R3 represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl, and mono- and di-substituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents together with the nitrogen atom to which they are attached form a heteroaryl or heterocycloalkyl radical. Preferably, R3 represents radicals as defined above that do not contain alpha branching, for example, as in an isopropyl radical or a t-butyl radical. Preferred radicals are those which contain a -CH2-portion between the nitrogen and the remaining portion of the radical. Such preferred groups include, but are not limited to, benzyl, isobutyl, n-butyl, isoamyl, cyclohexylmethyl, and the like. P1 and P2 are independently selected from amine protecting groups including, but not limited to, arylalkyl, substituted arylalkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl and silyl. Examples of arylalkyl include, but are not limited to, benzyl, orthomethylbenzyl, 2,6-dichlorobenzyl, trityl and benzhydryl, which may be optionally substituted with halogen, Ci-Cs alkyl, alkoxy, hydroxy, nitro, alkylene, amino, alkylamino, acylamino and acyl, or their salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthalenyl, Ndanil, anthracenyl, durenyl, 9- (9-phenyl-fluoro-phenyl) and phenanthrenyl, cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals containing Cß-C-cycloalkyls. Suitable acyl groups include carbobenzoxy, t-bucarbonyl, isobucarbonyl, benzoyl, substituted benzoyl such as 2-methylbenzoyl, 2,6-dimethylbenzoyl 2,4,6-trimethylbenzoyl and 2,4,6-triisopropylbenzoyl, 1-naphthoyl, 2-naphthoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, and the like. Additionally, protecting groups P1 and / or P2 can form a heterocyclic ring with the nitrogen atom to which they are attached, for example, 1,2-bis (methylene) benzene, phthalimidyl, succinimidyl, maleimidyl, and the like, and wherein These heterocyclic groups may also include adjunct aryl or cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, for example, nitrophthalimidyl. The term "silyl" refers to a silicon atom optionally substituted by one or more alkyl, aryl or aralkyl groups. Suitable carbamate protecting groups include, but are not limited to, methyl and ethyl carbamate; 9-fluorenylmethyl carbamate; 9- (2-sulfo) fluorenylmethyl carbamate; 9- (2,7-dibromo) fluorenylmethyl carbamate; 2,7-di-t-butyl- [9- (10,10-dioxo-10,10,10-tetrahydrothioxanthyl) methyl carbamate; 4-methoxyphenacyl carbamate; 2,2,2-trichloroethyl carbamate; 2-trimethylsilylethyl carbamate; 2-phenylethyl carbamate; 1- (1-adamantyl) -1-methylethyl carbamate; carbamate of 1, f-dimethyl-2-halogenoethyl; 1, 1-dimethyl-2,2-dibromoethyl carbamate; 1, 1-dimethyl-2,2,2-trichloroethyl carbamate; 1-methyl-1- (4-biphenylyl) -ethyl ester carbamate; 1- (3,5-di-t-butylphenyl) -1-methylethyl carbamate; 2- (2'- and 4'-pyridyl) ethyl carbamate; 2- (N, N-dicyclohexylcarboxamido) ethyl carbamate; t-butyl carbamate; 1 -admantyl carbamate; vinyl carbamate; allyl carbamate; 1-isopropylallyl carbamate; cinnamyl carbamate; 4-nitrocinnamyl carbamate; 8-quinolyl carbamate; N-hydroxypiperidinyl carbamate; alkyldithium carbamate; benzyl carbamate; p-methoxybenzyl carbamate; p-nitrobenzyl carbamate; p-bromobenzyl carbamate; p-chlorobenzyl carbamate; 2,4-dichlorobenzyl carbamate; 4-methylsulfinylbenzyl carbamate; 9-anthrylmethyl carbamate; diphenylmethyl carbamate; 2-methylthioethyl carbamate; 2-methylsulfonylethyl carbamate; 2- (p-toluenesulfonyl) ethyl carbamate; [2- (1, 3-dithianyl) methyl carbamate; 4-methylthiophenyl-2,4-dimethylthiophenyl carbamate; 2-phosphononoethyl carbamate; 2-triphenylphosphonioisopropyl carbamate; 1, 1-dimethyl-2-cyanoethyl carbamate; m-chloro-p-acyloxybenzyl carbamate; p- (dihydroxyboronyl) benzyl carbamate; 5-benzisoxazolylmethyl carbamate; 2- (trifluoromethyl) -6-chromonylmethyl carbamate; m-nitrophenyl carbamate; 3,5-dimethoxybenzyl carbamate; o-nitrobenzyl carbamate; 3,4-dimethoxy-6-nitrobenzyl carbamate; phenyl (o-nitrophenyl) methyl carbamate; phenothiazinyl- (10) -carbonyl derivative; N'-p-toluenesulfonylaminocarbonyl derivative; N'-phenylaminothiocarbonyl derivative; t-amyl carbamate; S-benzyl thiocarbamate; p-cyanobenzyl carbamate; cyclobutyl carbamate; cyclohexyl carbamate; cyclopentyl carbamate; cyclopropylmethyl carbamate; p-decyloxybenzyl carbamate; diisopropylmethyl carbamate; 2,2-dimethoxycarbonylvinyl carbamate; o- (N, N-dimethylcarboxamido) benzyl carbamate; 1, 1-dimethyl-3- (N, N-dimethylcarboxamido) propyl carbamate; 1, 1-dimethylpropynyl carbamate; di (2-pyridyl) methyl carbamate; 2-furanylmethyl carbamate; 2-iodoethyl carbamate; carbamate of sobomil; isobutyl carbamate, isonicotinyl carbamate; p- (p'-methoxyphenylazo) benzyl carbamate; 1-methylcyclobutyl carbamate; 1-methylcyclohexyl carbamate; 1-methyl-1-cyclopropylmethyl carbamate; 1-methyl-1- (3,5-dimethoxyphenyl) ethyl carbamate; 1-methyl-1 - (p-phenylazophenyl) ethyl carbamate; and 1-methyl-1-phenylethyl carbamate. T. Greene and P. Wuts ("Protective Groups In Organic Synthesis", 2nd Ed., John Wiley &Sons, Inc. (1991)) describe the preparation and decomposition of said carbamate protecting groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tertbutyldimethylsilyl, dimethylphenylsilyl, 1,2-bis (dimethylsilyl) benzene, 1,2-bis (dimethylsilyl) ethane and diphenylmethylsilyl. Silylation of the amine functions to provide mono- or bis-disilylamine may provide derivatives of the aminoalcohol, amino acid, amino acid esters and amino acid amide. In the case of amino acids, amino acid esters and amino acid amides, the reduction of the carbonyl function provides the mono- or bis-silyl aminoalcohol required. The silylation of the aminoalcohol can lead to the N, N, O-trisilyl derivative.

The removal of silyl function from the silyl ether function is easily achieved by treatment with, for example, an ammonium fluoride reagent or metal hydroxide, either as a defined reaction step or In situ during the preparation of the aminoaldehyde reagent. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride, or their combination products with imidazole or DMF. The methods of amine silylation and removal of silyl protecting groups are well known to those skilled in the art. The methods of preparing these amine derivatives from amino acids, amino acid amides or corresponding amino acid esters are also well known to those skilled in the art of organic chemistry, including amino acid chemistry / amino acid esters or aminoalcohols. Preferably, P1 is selected from aralkyl, substituted aralkyl, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl and aralkoxycarbonyl, P2 is selected from aralkyl and substituted aralkyl, and R1 is selected from aralkyl and substituted aralkyl. Alternatively, when P1 is alkoxycarbonyl or aralkoxycarbonyl, P2 can be hydrogen. More preferably, P1 is t-butoxycarbonyl, phenylmethoxycarbonyl or benzyl, P2 is hydrogen or benzyl, and R1 is benzyl. The protected chiral aminoepoxides of the formula amino chiral protected alpha-hydroxy anides, nitromethylene and acids of the formula R1 wherein X is -CN, -CH2NO2 or -COOH, chiral protected alpha-aminoaldehyde intermediates of the formula and protected chiral alpha-amino alcohols of the formula wherein P1, P2 and R1 are as defined above, are also described herein. As used herein, the term "aminoepoxide" alone or in combination, means a substituted amino alkylene oxide, wherein the amino group may be a primary amino group (substituted with an additional group), or secondary (substituted with two additional groups) ) which contain substituents selected from hydrogen, and alkyl, aryl, aralkyl, alkenyl, alkoxycarbonyl, aralkoxycarbonyl, cycloalkenyl, silyl, cycloalkylalkenyl radicals, and the like, and the epoxide may be alpha for the amine. The term "aminoaldehyde" alone or in combination, means a substituted amino alkylaldehyde, wherein the amino group may be a primary or secondary amino group containing substituents selected from hydrogen, and alkyl, aryl, aralkyl, alkenyl, aralkoxycarbonyl, alkoxycarbonyl, cycloalkenyl, silyl, cycloalkylalkenyl, and the like, and the aldehyde can be alpha for the amine. The term "alkyl", alone or in combination, means a straight or branched chain alkyl radical containing from 1 to about 10, preferably from 1 to about 8, carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl, pentyl, isoamyl, hexyl, octyl, and the like. The term "alkenyl", alone or in combination, means a straight or branched chain hydrocarbon radical having one or more double bonds and containing from 2 to about 18 carbon atoms, preferably from 2 to about 8 carbon atoms. Examples of suitable alkenyl radicals include ethenyl, propenyl, allyl, 1,4-butadienyl, and the like. The term "alkoxy", alone or in combination, means an alkyl ether radical, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like. The term "cycloalkenyl", alone or in combination, means an alkyl radical containing from about 3 to about 8 carbon atoms, and is cyclic and contains at least one double bond in the ring, which is non-aromatic in character. . The term "alkynyl", alone or in combination, means a straight chain hydrocarbon radical having one or more triple bonds, and containing from 2 to about 10 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, (propargyl), butynyl, and the like. The term "cycloalkenylalkyl" means a cycloalkenyl radical as defined above, which is attached to an alkyl radical, the cyclic portion containing from 3 to about 8, preferably from 3 to about 6, carbon atoms. Examples of said cycloalkenyl radicals include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, dihydrophenyl, and the like. The term "cycloalkyl", alone or in combination, means an alkyl radical containing from about 3 to about 8 carbon atoms and is cyclic. The term "Cycloalkylalkyl" means an alkyl radical as defined above, and which is substituted by a cycloalkyl radical containing from about 3 to about 8, preferably from about 3 to about 6, carbon atoms. Examples of said cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "aryl", alone or in combination, means an aromatic carbocyclic system containing one, two or three rings, wherein said rings may be attached to each other in pendent form, or they may be fused together. Examples of "aryl" include phenyl or naphthyl radicals, any of which optionally possesses one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, and the like, as well as p-tolyl, 4-methoxyphenyl, - (tert-butoxy) phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-fanfyl, 2-naphthyl, and the like. The term "aralkyl", alone or in combination, means an alkyl radical as defined above, in which a hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl, and the like. Examples of substituted aralkyl include 3,5-dimethoxybenzyl bromide, 3,4-dimethoxybenzyl bromide, 2,4-d-methoxybenzyl bromide, bromide, 3,4,5-trimethoxybenzyl, 4-nitridebenzyl iodide, 2,6-dichlorobenzyl bromide, 1,4-bis (chloromethyl) benzene, 1,2-bis (bromomethyl) benzene, 1,3-bis (chloromethyl) -benzene, 4-chlorobenzyl chloride, 3-chlorobenzyl chloride , 1,2-bis (chloromethyl) benzene, 6-chloropiperonyl chloride, 2-chlorobenzyl chloride, 4-chloro-2-nitrobenzyl chloride, 2-chloro-6-fluorobenzyl chloride, 1,2-bis (chloromethyl) ) -4,5-dimethylbenzene, 3,6-bis (chloromethyl) durene, 9,10-bis (chloromethyl) anthracene, 2,5-bis (chloromethyl) -p-xylene, 2,5-bis (chloromethyl) - 1,4-dimethoxybenzene, 2,4-bis (chloromethyl) anisole, 4-6- (dicoromethyl) -m-xylene, 2,4-bis (chloromethyl) mesitylene, 4- (bromomethyl) -3,5-dichlorobenzophenone, n- (alpha-chloro-o-tolyl) -benzylamine hydrochloride, 3- (chloromethyl) benzoyl chloride, 2-chloro-4-chloromethyloluene, 3,4-dichlorobenzyl bromide, 6-chloro-8- bromide chloromethylbenzo-1,3-dioxane, 4- (2,6-dichlorobenzylsulfonyl) benzyl bromide, 5- (4-chloromethylphenyl) -3- (4-chlorophenyl) -1,2,4-oxadiazole, 5- (3- chloromethylphenyl) -3- (4-chlorophenyl) -1, 2,4-oxadiazole, 5- (3-chloromethyl) benzoyl chloride, di (chloromethyl) toluene, 4-chloro-3-nitrobenzyl chloride, 1- (dimethylchlorosilyl ) -2- (p, m-cyoromethylphenyl) ethane, 1- (dimethylchlorosilyl) -2- (p, m-chloromethylphenyl) ethane, 3-chloro-4-methoxybenzyl chloride, 2,6-bis (chloromethyl) -4 -methylphenol, 2,6-bis (chloromethyl) -p-tolyl acetate, 4-bromobenzyl bromide, p-bromobenzoyl bromide, alpha, alpha'-dibromo-m-xylene, 3-bromobenzyl bromide, bromide of 2 -bromobenzyl, 1,8-bis (bromomethyl) naphthalene, o-xylylene dibromide, p-xylylene dibromide, 2,2'-bis (bromomethyl) -1, 1'-biphenyl, alpha.alpha'-dibromo-2 , 5-dimethoxy-p-xylene, benzyl chloride, benzyl bromide, 4,5-bis (bromomethyl) phenanthrene, 3- (bromomethyl) benzyltriphenylphosphonium bromide, 4- (bromomethyl) benzyltriphenylphosphonium bromide, 2- (bromide bromomethyl) benc iltriphenylphosphonium, 1- (2-bromoethyl) -2 (bromoethyl) -4-nitrobenzene, 2-bromo-5-fluorobenzyl bromide, 2,6-bis (bromomethyl) fluorobenzene, o-bromomethylbenzoyl bromide, p-bromomethylbenzoyl bromide , 1-bromo-2- (bromomethyl) naphthalene, 2-bromo-5-methoxybenzyl bromide, 2,4-dichlorobenzyl chloride, 3,4-dichlorobenzyl chloride, 2,6-dichlorobenzyl chloride, 2-chloride 3-Dichlorobenzyl, 2,5-dichlorobenzyl chloride, methyldichlorosilyl (chloromethylphenyl) ethane, methyldichlorosilyl (chloromethylphenyl) ethane, methyldichlorosilyl (chloromethylphenyl) ethane, 3,5-dichlorobenzyl chloride, bromide 3,5-dibromo-2-hydroxybenzyl, 3,5-dibromobenzyl bromide, p- (chloromethyl) phenyltrichlorosilane, 1 -trichlorosilyl-2- (p, m-chloromethylphenyl) ethane, 1 -trichlorosilyl-2- (p, m) -chloromethylphenyl) ethane and 1, 2, 4,5-tetrakis (bromomethyl) benzene. The term "arylthioalkyl" means an aryl group attached to an alkyl group by a sulfur atom of a thioether, for example, Ar-S-CH2-. The term "aralkoxycarbonyl" means an aralkoxy group attached to a carbonyl. Carbobenzoxy is an example of aralkoxycarbonyl. The term "heterocyclic ring system" means a monocyclic, bicyclic or tricyclic saturated or partially unsaturated heterocycle, which contains one or more heteroatoms as ring atoms, selected from nitrogen, oxygen, silicon and sulfur, which is optionally substituted in one or more carbon atoms by halogen, alkyl, alkoxy, oxo, and the like, and / or at a secondary nitrogen atom (i.e., -NH-) by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl, or at a nitrogen atom tertiary (ie, = N-) by oxide, and which is bound by a carbon atom. The heteroaryl portion of a heteroalyl, heteroaryloxycarbonyl, heteroaralkoxycarbonyl group or the like is a monocyclic, bicyclic or aromatic tricyclic heterocycle, which contains the heteroatoms and is optionally substituted as defined above with respect to the definition of aryl. Examples of such heterocyclic groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, phthalimide, succinimide, maleimide, and the like. Also included are heterocycles that contain two silicon atoms simultaneously attached to nitrogen, and joined together by carbon atoms. The term "alkylamino", alone or in combination, means an aminosubstituted alkyl group, wherein the amino group may be a primary or secondary amino group containing substituents selected from hydrogen, and alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, and the like. The term "halogen" means fluorine, chlorine, bromine or iodine. The term "dihaloalkyl" means two halogen atoms, identical or different, substituted on the same carbon atom. The term "oxidizing agent" includes a single agent or a mixture of oxidizing reagents. Examples of mixtures of oxidizing reagents include sulfur trioxide-pyridine / dimethyl sulfoxide, oxalyl chloride / dimethyl sulfoxide, acetyl chloride / dimethyl sulfoxide, acetyl anhydride / dimethyl sulfoxide, trifluoroacetyl chloride / dimethyl sulfoxide, bromide of toluenesulfonyl / dimethyl sulfoxide, phosphorus pentachloride / dimethyl sulfoxide, and isobutyl chloroformate / dimethyl sulfoxide.

A general scheme for the preparation of aminoepoxides, useful as intermediates in the synthesis of HIV protease inhibitors, is shown in Scheme I below.

OH The economical and safe large scale method for preparing protease inhibitors of the present invention can alternatively use amino acids or aminoalcohols to form the N, N-protected alpha-amino alcohol of the formula: R1 wherein P1, P2 and R1 are as described above. When the compounds of formula II are formed from amino acids or aminoalcohols, said compounds have the amine protected with the groups P1 and P2 as described above. The nitrogen atom can be alkylated, such as by the addition of suitable alkylating agents in a suitable solvent in the presence of base. Alternative bases used in the alkylation include sodium hydroxide, sodium bicarbonate, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium hydroxide, magnesium hydroxide, calcium hydroxide or calcium oxide, or bases of tertiary amine such as triethylamine, diisopropylethylamine, N-methylpiperidine, pyridine, dimethyl-aminopyridine and azabicyclononane. The reactions can be homogeneous or heterogeneous. Suitable solvents are water and protic solvents or water-miscible solvents, such as methanol, ethanol, isopropyl alcohol, tetrahydrofuran and the like, with or without added water. Dipolar aprotic solvents can also be used with or without added protic solvents, including water. Examples of dipolar aprotic solvents include acetonitrile, dimethylformamide, dimethylacetamide, acetamide, tetramethylurea and its cyclic analogue, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, nitromethane, and the like. The reaction temperature may vary between about -20 ° C to 100 ° C, with the preferred temperature being about 25 to 85 ° C. The reaction can be carried out under an inert atmosphere such as nitrogen or argon, or normal or dry air, under atmospheric pressure or in a sealed reaction vessel under positive pressure. The most preferred alkylating agents are benzyl bromide or benzyl chloride or monosubstituted aralkyl halides or polysubstituted alalkyl halides, such as 2,6-dichlorobenzyl chloride. The sulfate or sulfonate esters are also suitable reagents to provide the corresponding benzyl analogs, and can be preformed from the corresponding benzyl alcohol, or they can be formed in situ by methods well known to those skilled in the art. Trityl, benzhydryl, substituted trityl and substituted benzhydryl groups, independently, are also effective amine protecting groups [P1, P2], as are also the allyl and substituted allyl groups. Their halide derivatives can also be prepared from the corresponding alcohols by methods well known to those skilled in the art., such as treatment with chloride or thionyl bromide or with tri- or pentachloride, bromide or phosphorus iodide, or the corresponding phosphoryl trihalogenide. Examples of groups that can be substituted on the aryl ring include alkyl, alkoxy, hydroxy, nitro, halogen and alkylene, amino, mono- and dialkylamino and acylamino, acyl and water solubilizing groups such as phosphonium salts and salts of ammonium. The aryl ring can be derived, for example, from benzene, naphthalene, indane, anthracene, 9- (9-phenyl-fluorenyl, durene, phenanthrene, and the like.) In addition, 1,2-bis (substituted alkylene) halides can be used. aryl or sulphonate esters to form a non-aromatic or aryl nitrogen-containing heterocyclic derivative [with p1 and p2] or bis-heterocycles: cycloalkylenealkyl or substituted cycloalkylene radicals containing from 6 to 10 carbon atoms and the alkylene radicals, they constitute an additional acceptable group of substituents on nitrogen, prepared as described above and including, for example, cyclohexylenemethylene The compounds of formula II can also be prepared by reductive alkylation, for example, by compounds and intermediates formed from the addition of an aldehyde with the amine and a reducing agent, reduction of a Schiff base, carbinolamine or enamine, or reduction of an amine derivative The reducing agents include metals (platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium and the like) with hydrogen transfer or hydrogen gas transfer molecules such as cyclohexene or cyclohexadiene or hydride agents such as hydride lithium-aluminum, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride or lithium-tri-tert-butoxyaluminum hydride. Additives such as sodium or potassium bromide, or sodium or potassium iodide, can catalyze or accelerate the aminoalkylation rate especially when benzyl chloride is used as the nitrogen alkylating agent. The phase transfer catalysis, wherein the amine to be protected and the nitrogen alkylating agent are reacted with a base in a solvent mixture in the presence of a reagent, catalyst or phase transfer promoter, is another method for rent the nitrogen from an amine. The mixture may consist, for example, of toluene, benzene, ethylene dichloride, cyclohexane, methylene chloride or the like with water or an aqueous solution of a water-miscible organic solvent such as THF. Examples of catalysts or phase transfer reagents include chloride or iodide or tetrabutylammonium bromide, tetrabutylammonium hydroxide, tri-butyloctylammonium chloride, dodecyltrihexylammonium hydroxide, methyltrihexylammonium chloride, and the like. A preferred method for forming substituted amines involves the aqueous addition of about 3 moles of organic halide to an amino acid or about 2 moles to an aminoalcohol. In a more preferred method for forming a protected aminoalcohol, about 2 moles of benzyl halide are used in a basic aqueous solution. In an even more preferred method, the alkylation occurs from 50 ° C to 80 ° C with potassium carbonate in water, ethanol / water or denatured ethanol / water. In a more preferred method for forming a protected amino acid ester, about 3 moles of benzyl halide are added to a solution containing the amino acid. The protected amino acid ester is further reduced to the aminoalcohol protected in an organic solvent. Preferred reducing agents include lithium-aluminum hydride, lithium borohydride, sodium borohydride, borane, lithium-tri-tert-butoxyaluminum hydride, and borane THF complex. More preferably, the reducing agent is diisobutylaluminum hydride (DiBAL-H) in toluene. These reduction conditions provide an alternative to the reduction of lithium-aluminum hydride. Purification by chromatography is possible. In the preferred purification method, the alpha aminoalcohol can be purified by quenching the reaction with acid, such as with hydrochloric acid, and the resulting salt can be purified as a solid, and the aminoalcohol can be released as by acid / base extraction. The protected alpha aminoalcohol is oxidized to a chiral aminoaldehyde of the formula: (lll) Acceptable oxidizing reagents include, for example, sulfur trioxide-pyridine complex and DMSO, oxalyl chloride and DMSO, acetyl chloride or anhydride and DMSO, trifluoroacetyl chloride or anhydride and DMSO, methanesulfonyl chloride and DMSO or S-tetrahydrothiophene oxide, toluenesulfonyl bromide and DMSO, trifluoromethanesulfonyl anhydride (triflic anhydride) and DMSO, phosphorus pentachloride and DMSO, dimethylphosphoryl chloride and DMSO and isobutyl chloroformate and DMSO. The oxidation conditions reported by Reetz et al. [Angew Chem., 99, p. 1186, (1987)], Angew Chem. Int. Ed. Engl., 26, p. 1141, 1987) used oxalyl chloride and DMSO at -78 ° C. The preferred oxidation method described in this invention utilizes sulfur trioxide-pyridine, triethylamine and DMSO complex at room temperature. This system provides excellent yields of the desired chiral protected aminoaldehyde usable without the need for purification, that is, the need to purify kilograms of intermediates by chromatography is eliminated, and large-scale operations become less hazardous. The reaction at room temperature also eliminated the need to use a low temperature reactor, which makes the process more suitable for commercial production. The reaction can be carried out under an inert atmosphere such as nitrogen or argon, or normal or dry air, under atmospheric pressure or in a sealed reaction vessel under positive pressure. A nitrogen atmosphere is preferred. Alternative amine bases include, for example, tributyl amine, tri-isopropyl amine, N-methylpiperidine, N-methyl morpholine, azabicyclononane, diisopropylethylamine, 2,2,6,6-tetramethylpiperidine, N, N-dimethylaminopyridine, or mixtures thereof. these bases. Triethylamine is a preferred base. Alternatives to pure DMSO as a solvent include mixtures of DMSO with non-protic or halogenated solvents such as tetrahydrofuran, ethyl acetate, toluene, xylene, dichloromethane, ethylene dichloride, and the like. Dipolar aprotic cosolvents include acetonitrile, dimethylformamide, dimethylacetamide, acetamide, tetramethyl urea and its cyclic analog, N-methylpyrrolidone, sulfolane, and the like. More than N, N-dibenzylphenylalaninol as the aldehyde precursor, the phenylalaninol derivatives described above can be used to provide the corresponding N-monosubstituted (either p1 or p2 = H) or corresponding N, N-disubstituted aldehyde. carrying out the reduction with hydride of an amide derivative or ester of the nitrogen protected phenylalanine, substituted phenylalanine or cycloalkyl analog of the corresponding alkyl, benzyl or cycloalkenyl phenylalanine derivative to provide a compound of formula III. The hydride transfer is an additional method of synthesis of aldehyde under conditions where aldehyde condensations are avoided, for example, by oxidation of Oppenauer The aldehydes of this process can also be prepared by methods for reducing the protected phenylalanine and phenylalanine analog or its derivatives. amide or ester, for example, by sodium amalgam with HCl in ethanol or lithium, sodium, potassium or calcium in ammonia. The reaction temperature may be from about -20 ° C to about 45 ° C, preferably from about 5 ° C to about 25 ° C. Two other methods for obtaining the nitrogen-protected aldehyde include oxidation of the corresponding alcohol with bleach in the presence of a catalytic amount of free radical of 2,2,6,6-tetramethyl-1-pyridyloxy. In a second method, the oxidation of the alcohol to the aldehyde is achieved by a catalytic amount of tetrapropylammonium perruthenate in the presence of N-methylmorpholine N-oxide. Alternatively, an acid chloride derivative of a protected phenylalanine or phenylalanine derivative as described above, can be reduced with hydrogen and a catalyst such as Pd over barium carbonate or barium sulfate., with or without an additional catalytic moderating agent, such as sulfur or a thiol (Rosenmund reduction). An important aspect of the present invention is a reaction involving the addition of chloromethyl lithium or bromomethyl lithium to the alpha aminoaldehyde. Although the addition of chloromethyl lithium or bromomethyl lithium to aldehydes is known, essentially continuous in situ synthesis and the accompanying addition of said species to racemic or chiral aminoaldehydes under the conditions described below to form aminoepoxides of the formula R1 It is novel. The addition of chloromethyl lithium or bromomethyl lithium to a chiral aminoaldehyde by this method is highly diastereoselective. Chloromethyl lithium or bromomethyl lithium is generated in situ from the reaction of a dihalogenomethane and n-butyl lithium. Acceptable methylene halogenomethanes include chloroiodomethane, bromochloromethane, dibromomethane, diiodomethane, bromofluoromethane, and the like. The sulfonate ester of the addition product, for example, from hydrogen bromide to formaldehyde, is also a methyleneizing agent. Tetrahydrofuran is the preferred solvent; however, alternative solvents such as toluene, dimethoxyethane (DME), ethylene dichloride (EDC), methylene chloride (ME) or tert-butyl methyl ether (TBME) can be used as pure solvents or as a mixture. Dipolar aprotic solvents such as acetonle, DMF or N-methylpyrrolidone are useful as solvents or as part of a mixture of solvents. The reaction can be carried out under an inert atmosphere such as ngen or argon. In the case of n-butyl lithium, other organometallic reagents such as methyl lithium, tert-butyl lithium, sec-butyl lithium, phenyl lithium, phenyl sodium, and the like can be substituted. Organometallic reagents are usually used as solutions in solvents such as hexane, toluene and the like. Lithium metal has also been used to generate the halogenomethyl lithium reagent. It may be added as received, pretreated or activated with, for example, a solvent, lithium naphthalide, by ultrasound, scoring, grinding, defatting and / or removal of lithium hydroxide. The halogenomethylene generation according to the present invention can be carried out at temperatures between about -80 ° C to 0 ° C, but preferably between about -60 ° C to -10 ° C. The most preferred reaction temperatures are between -40 ° C to -15 ° C. The reagents can be added individually or at the same time as will be described later. The preferred pressure of the reaction is atmospheric; however, a positive pressure is valuable under certain conditions such as a high humidity environment. A negative pressure can be used and it can be useful, for example, to mobilize reagents, mixtures or reaction solutions from one flask to another, or between addition systems. The atmosphere of the reaction is usually an inert gas or gas mixture such as ngen, helium or argon. The addition of n-butyl lithium to the dihalogenomethane such as BrCH2CI, and aldehyde solution (III), is an extremely exothermic reaction. In the case of a gradual or intermittent addition system as described in the prior art, the speed of addition of n-BuLi is limited, for example, by the ability of the cooling system to maintain a constant temperature and avoid problems. As a result, the gradual addition of, for example, n-butyl lithium to the other reagents is practiced, and the procedure requires frequent, tedious and relatively small additions of this reagent.

For multikilogram preparations, the total addition time can be extended for more than 24 hours. The use of lithium metal requires preparing and handling a solid. The addition of a solid metal to a halide reagent may require frequent openings and closures of the reaction flasks, heat generation and problems in the reaction flask or reaction solution and on the surface of the metal, thus causing speed differences between the batches and / or the individual addition steps. These variables and difficulties can be applied or occur through or between preparations (batches) or within the same preparation or batch. It is also virtually impossible to supply exactly the appropriate number of chemical equivalents of pure metal that react completely and accurately with a haloalkyl or dihaloalkyl reagent. As a rule, these factors can make the metal reagent system inconvenient, expensive, and a security risk, especially in a large-scale system. The continuous and novel in situ synthesis method of the present invention provides epoxide (IV) with improved or at least comparable performance consistently with safety and operational simplicity. The process also allows the most efficient, and therefore reduced, use of these costly reagents. An example of an arrangement for implementing the continuous in situ synthesis method of the present invention involves a reactor A, which can be stirred with or without a controlled atmosphere and / or maintained at room temperature, cooled or heated, as desired . From the reactor A, a reagent or reagents with or without solvent (preferably the aldehyde (III) with a small amount of the reactant of dihalogenomethane) can be pumped (mechanical pumping, by gas pressure differential, or gravity) or passed through a siphon in a mixing zone comprising a mixer B or comprising a mixer B and a mixer B 'which is substantially equal to the mixer B, and connected as the mixer B to the reactor A. The mixer B and the mixer B' can be interconnected or interact in series or in parallel. Mixer B and / or B 'can be maintained at low, high or ambient temperature, have a controlled atmosphere, can contain provisions to increase mixing by mechanical means such as vanes or vanes such as those used in Morton flasks, provide mixing static by means of reagent feed systems, provide mechanical mixing or agitation systems or a combination of methods, as desired. The mixers may also be equipped with a method or device such as that described above for reactor A, which allows the addition of a new reagent or reagents and / or an additional amount of a previous or currently used reagent or mixtures of reagents directly in the mixers. The product of mixer B and / or mixer B 'is transferred by any of the means described above in reactor B. Reactor B may be equipped as reactor A, for example, to heat or cool the reaction mixture, and be equipped for the addition of reagents or solvents, as required, to continue a chemical synthesis or to prepare a chemical synthesis reaction to provide the desired intermediate or final product. There are several methods to implement the continuous in situ synthesis procedure to prepare the epoxide IV. For example, an organometallic reagent can be continuously added to a mixture of dihalogenomethane and aldehyde III, an organometallic reagent can be added continuously, and independently, a dihalogenomethane can be continuously added to an aldehyde III, an organometallic reagent can be added continuously and can continuously add additional dihalogenomethane to a mixture of dihalogenomethane and an aldehyde III, a mixture of an organometallic reagent and a dihalogenomethane can be continuously added to an aldehyde III, separate streams of an organometallic reagent, a dihalogenomethane and an aldehyde can be continuously mixed using a mixer, or an organometallic reagent and a dihalogenomethane and an aldehyde can be continuously mixed using two mixers. As described above, preferably the aldehyde is prepared with at least a portion of the dihalogenomethane reagent and then the organometallic reagent is added continuously, usually with the simultaneous addition of additional dihalogenomethane, for continuous in situ synthesis of the halogenomethyl reagent lithium. Rather than using a preformed organometallic reagent, a mixture of a metal and an organic halide can also be used. An example is the use of N-butyl bromide and lithium metal. A preferred method for implementing the present invention involves the continuous mixing of an organometallic reagent, for example, n-butyl lithium with a preformed mixture of the aldehyde III and dihalogenomethane.

Other exchanges will be recognized by those skilled in the art. Alternative methods of conversion to the epoxides of this invention include substitution of other charged methylene precursor species, followed by their treatment with a base to form the analogous anion. Examples of these species include trimethylsulfoxonium tosylate or triflate, tetramethylammonium halide and methyldiphenylsulfoxonium halide, wherein the halogenide is chlorine, bromine or iodine. The conversion of the aldehydes of formula III is its epoxide derivative has also been carried out in multiple stages. For exampleWhat. , the addition of the thioanisole anion prepared from, for example, a butyl or aryl lithium reagent, to the protected aminoaldehyde, and the oxidation of the resulting protected aminosulfide alcohol with well-known oxidizing agents such as hydrogen peroxide, terpene hypochlorite, -butyl, bleach or sodium periodate, give a sulfoxide. Alkylation of the sulfoxide with, for example, methyl iodide or bromide, methyl tosylate, methyl mesylate, methyl triflate, ethyl bromide, isopropyl bromide, benzyl chloride, and the like, occurs in the presence of an organic base or inorganic Alternatively, the protected aminosulfide alcohol can be alkylated with, for example, the above alkylation agents, to provide sulfonium salts which are subsetly converted to the present epoxides with ter-amine or mineral bases. The desired epoxides are obtained, using the preferred conditions of the invention, diastereoselectively at ratios of about 85:15 (S: R). The product can be purified by chromotagraphy to give the diastereomeric and enantiomerically pure product, but the product is more conveniently used directly, without purification, to prepare the HIV protease inhibitors. The epoxide is then reacted, in a suitable solvent system, with an equal amount or preferably an excess of an amine (R3NH2) to form the aminoalcohol of formula I: R1 'where R3 is as defined above. The reaction can be carried out over a wide range of temperatures, for example, from about 10 ° C to about 100 ° C, but preferably, but not necessarily, it is carried out at a temperature at which the solvent starts to return to flow Suitable solvent systems include those in which the solvent is an alcohol, such as methanol, ethanol, isopropanol, and the like, ethers such as tetrahydrofuran, dioxane and the like, and toluene, N, N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. A preferred solvent is Sopropanol Examples of amines corresponding to the formula R3NH2 include benzylamine, isobutylamine, n-butylamine, isopentylamine, isoamylamine, cyclohexanomethylamine, naphthylene-methylamine, and the like. In some cases, the amine (R3NH2) itself can be used as a solvent, such as isobutylamine. Alternatively, the protected aminoaldehyde of the formula III can also be reacted with a cyanide salt, such as sodium cyanide or potassium cyanide to form a chiral cyanohydrin of the formula: Preferably, a reaction rate enhancer, such as sodium bisulfite, is used to increase the rate of cyanohydrin formation. Alternatively, trimethylsilylnitrile can be used to form an intermediate of trimethylsilyloxycyan, which can be rapidly hydrolyzed to the cyanohydrin. The reaction can be carried out at temperatures between about -5 ° C to 5 ° C, but preferably between about 0 ° C to 5 ° C. The desired cyanohydrins are obtained, using sodium cyanide and sodium bisulfite, diastereoselectively at a ratio of about 88:12 (S: R). The product can be purified by chromatography to give the diastereomeric and enantiomerically pure product. The cyano group can be reduced to the amine of formula V: R1 The reduction can be carried out using various reducing reagents, such as hydride transfer, metal reductions and catalytic hydrogenation, which are well known to those skilled in the art. Examples of hydride reagents with and without heavy metals or heavy metal salts such as adjunct reagents include, for example, lithium-aluminum hydride, tri-tert-butoxyaluminum lithium hydride, lithium trimethoxy aluminum hydride, aluminum hydride, diborane ( or borane), borane / THF, borane / dimethyl sulfide, borane / pyridine, sodium borohydride, lithium borohydride, sodium borohydride / cobalt salts, sodium borohydride / Raney nickel, sodium borohydride / acetic acid, and Similar. Solvents for the reaction include, for the more reactive hydrides, THF, diethyl ether, dimethoxyethane, diglyme, toluene, heptane, cyclohexane, methyl tertiary butyl ether, and the like. Solvents or solvent mixtures for the reductions using reagents such as sodium borohydride, in addition to the non-protic solvents mentioned above, may include ethanol, n-butanol, tert-butyl alcohol, ethylene glycol, and the like. Reductions of metal include, for example, sodium and ethanol. The reaction temperatures may vary between the reflux of the solvent and -20 ° C. Usually an inert atmosphere such as nitrogen or argon is preferred, especially when there is the possibility of using flammable gas or the production / evolution of solvent is possible. The catalytic hydrogenation (metal catalyst plus hydrogen gas) can be carried out in the same solvents as described above with metals or metal salts such as nickel, palladium chloride, platinum, rhodium, platinum oxide or palladium on carbon or other catalysts known to those skilled in the art. These catalysts can also be modified with, for example, phosphine ligands, sulfur, or sulfur-containing compounds, or amines such as quinoline. The hydrogenations can be carried out at atmospheric pressure or at elevated pressures at about 105.45 kg / cm2 at temperatures between 0 ° C and about 250 ° C. The most preferred reducing agent is diborane-tetrahydrofuran, preferably at room temperature under an atmosphere of nitrogen and atmospheric pressure. The amine of formula V can then be reacted with R3L, wherein L is a residual group selected from halogen, tosylate, and the like, and R3 represents alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl and heteroaralkyl. Alternatively, the primary amino group of formula V can be reductively alkylated with an aldehyde to introduce the R3 group. For example, when R3 is an isobutyl group, treatment of the compound of formula V with α-butyraldehyde under reductive amination conditions, produces the desired compound of formula I. Similarly, when R3 is an isoamyl group, treatment of the compound of formula V with isovaleraldehyde under reductive amination conditions yields the desired compound of formula I. Other aldehydes can be used to introduce several R3 groups. Reductive amination can be carried out using various reaction conditions well known to those skilled in the art. For example, the reductive amination of the compound of formula V with an aldehyde can be carried out with a reducing agent such as sodium cyanoborohydride or sodium borohydride in a suitable solvent, such as methanol, ethanol, tetrahydrofuran, and the like. Alternatively, the reductive amination can be carried out using hydrogen in the presence of a catalyst such as palladium or platinum, palladium on carbon or platinum on carbon, or various other metal catalysts known to those skilled in the art, in a solvent suitable such as methanol, ethanol, tetrahydrofuran, ethyl acetate, toluene, and the like. Alternatively, the amine of formula I can be prepared by reduction of the protected amino acid of the following formula: (commercially available from Nippon Kayaku, Japan) up to the corresponding alcohol of formula: R1 The reduction can be carried out using a variety of reducing conditions and reducing reagents. A preferred reducing reagent is diborane tetrahydrofuran. The alcohol is then converted to a residual group (L ') by tosylation, mesylation, or conversion to a halogen group, such as chlorine or bromine: R1 Finally, the residual group (L ') is reacted with R 3 NH 2 as described above to form the amino alcohol of formula I. Alternatively, treatment of the alcohol with a base can result in the formation of the amino epoxide of formula IV. A valuable intermediary in this procedure is the metal salt of the alcohol: R1 shown in structure VI: The preferred metal M + is lithium when the salt is formed under anhydrous conditions, but sodium and potassium are satisfactory. Any of these salts, as well as the quaternary ammonium salts are satisfactory, when the reaction is carried out under conditions where a protic solvent or co-solvent is used. The term protic solvent includes water. The metal can also be a species with two charges, so that it can be derived from calcium, magnesium, copper, and the like. It should be noted that it is also thought that structure VI is an intermediate in the continuous process of forming halonomethyl lithium reagent and reaction with an aldehyde as described below. The above preparation of the aminoalcohol of formula I is applicable to mixtures of optical isomers, as well as in resolved compounds. If a particular optical isomer is desired, it can be selected by choosing the starting material, for example, L-phenylalanine, D-phenylalanine, L-phenylalaninol, D-phenylalaninol, D-hexahydrophenylalaninol and the like, or the resolution may occur in a intermediate or final step. Chiral auxiliaries such as one or two equivalents of camphorsulfonic acid, citric acid, camphoric acid, 2-methoxyphenylacetic acid and the like can be used to form salts, esters or amides of the compounds of this invention. These compounds or derivatives can be crystallized or separated chromatographically using a chiral or achiral column, as is well known to those skilled in the art. An additional advantage of the present method is that the materials can be carried through the above steps without purification of the intermediates. However, if it is desired to carry out the purification, the described intermediates can be prepared and stored in a pure state. The practical and efficient synthesis described herein has been successfully expanded to prepare large quantities of intermediates for the preparation of HIV protease inhibitors. It offers several advantages for multikilogram preparations: 1) it does not require the use of dangerous reagents such as diazomethane, 2) purification by chromatography is not required, but it can be used, 3) it is fast and efficient, 4) it uses economical commercial reagents and easily obtainable, and 5) produces alpha amino-epoxies with satisfactory enantiomeric purity. In particular, the process of the invention produces enantiomerically clean epoxides as required for the preparation of enantiomerically clear intermediates for the further synthesis of HIV protease inhibitors. It is also expected that the present invention will allow the most efficient use of the dihalogenomethane and organometallic reagents with respect to the stepwise addition process of the prior art. The novel process of continuous synthesis in situ has several additional advantages that are especially valuable when applied to large-scale multikilogram preparations. Eliminates the frequent and intermittent addition of reagents, thus demanding less time for the chemist. It also requires monitoring the reactions for less time. In the continuous in situ synthesis procedure of this invention, the temperature control of the container or reaction vessel (mixers), where the mixing of the reagents occurs, is much easier and less expensive, since smaller containers are required. Large, expensive, low-temperature reactors are not required due to the rapid and continuous flow through the aldehyde (III) and the halogenomethyl lithium reagent generated in situ. The improvements in the control of the temperature also allow to make additional choices regarding the characteristics of temperature and speed of reaction. Amino-epoxides were prepared using the following procedure as described in scheme II below.

SCHEME II In scheme II, a synthesis is shown for the epoxide, N, N, chiral a-S-tris (phenylmethyl) -2S-oxiranemethanamine. The synthesis starts from L-phenylalanine. The aldehyde is prepared in three steps from L-phenylalanine or phenylalinol. The L-phenylalanine is converted to the benzyl ester of N, N-dibenzylamino acid using benzyl bromide under aqueous conditions. The reduction of the benzyl ester is carried out using isobutylaluminum hydride (DIBAL-H) in toluene. Instead of purification by chromatography, the product is purified by quenching the reaction with acid (hydrochloric acid), and the hydrochloride salt is filtered as a white solid, and then released by acid / base extraction. After recrystallization, chemical and optically pure alcohol is obtained. Alternatively, and preferably, the alcohol can be obtained in one step with 88% yield by benzylation of phenylalaninol using benzyl bromide under aqueous conditions. The oxidation of alcohol to aldehyde is also modified to allow the most convenient operation during the enlargement. Instead of the standard Swern procedures using oxalyl chloride and DMSO in methylene chloride at low temperatures (very exothermic reaction), sulfur trioxide used-pyridine / DMSO (Parikh, J., Doering, W., J. Am. Chem. Soc, 89, p. 5505, 1967), which is a reaction that can conveniently be carried out at room temperature to give excellent yields of the desired aldehyde with high chemical and enantiomeric purity that does not require further purification.

In the present invention, chloromethyl lithium or bromomethyl lithium is generated in situ from chloroiodomethane (or bromochloromethane) or dibromomethane and n-butyl lithium at a temperature on the scale of about - 80 ° C at about -0 ° C in THF in the presence of aldehyde. Preferred temperatures are between -60 ° C to -10 ° C. The most preferred reaction temperatures are between -40 ° C to -15 ° C. It is thought that the products of this reaction are: the chlorohydrin and / or its lithium salt, as shown above. The metal salt is the initial and intermediate product from the addition of the organometallic reagent of halogenomethyl to the aldehyde. It is also an intermediate in the transformation of halogenhydrin to epoxide. The desired chlorohydrin or bromohydrin is formed as demonstrated by TLC analysis. After warming to room temperature, the desired epoxide is formed diastereoselectively at a ratio of 85:15 (S: R). The product can be purified by chromatography to give the diastereomerically pure product as a colorless oil, but more conveniently it is used directly without purification. Scheme II also shows an example of the preparation of a valuable urea such as compound (9). The same intermediate (10) can be used similarly to prepare novel and valuable such as those shown in Example 33. The sulfonamides lll scheme illustrates the preparation of aminopropilurea (9) using protected amine of phenylalaninol mixed, where BOC is t-butoxycarbonyl, and Bn is benzyl.

SCHEME lll (BOC) 20, solvent (3) (4) Scheme IV illustrates an alternative preparation of the amino epoxide (5) using a sulfur ylide.

SCHEME IV (BOC) 20, solvent (1) Trimet-lysulfonium or trimethersulfoxonium haloalide, base.solvent (3) (4) (5) Aminopropylurea (9) was also prepared using the procedure as described in scheme V below.

SCHEME V (7) (7) In Scheme V, was reacted an amine protected phenylalaninal mixed, where BOC is t-butoxycarbonyl and Bn is benzyl, with potassium cyanide to form the desired stereoisomeric cyanohydrin (12) in high yield. In addition to the stereospecific character of the cyanohydrin reaction, this process has the additional advantage of being easier and less expensive, because the temperature of the reactions need not be less than -5 ° C. Aminourea (9) was also prepared using the procedure as described in scheme VI below.

SCHEME VI The procedure of Scheme VI required only one protecting group, BOC, for the hydroxy amino acid amine. This process has the advantage of having the desired stereochemistry of the benzyl and hydroxy groups established in the starting material. Thus, chirality does not need to be introduced, with the resulting loss of material due to the preparation of diastereomers. The above schemes illustrate the reaction of butanediamines 1-amino-2-hydroxy-3- (protected) amino-4-substituted with an isocyanate to produce a urea as a key intermediate in the preparation of HIV protease inhibitors. For example, the treatment of 1-amino-2-hydroxy-3- (protected) amino-4-substituted butanediamines with sulfonyl chloride will provide a key intermediary in the synthesis of inhibitors of HIV sulfasamide protease.

EXAMPLE 1 ß-2-rbis (phenylmethyl) amino-1-benzene Method 1: Step 1: Benzylation of L-phenylalanine A solution of L-phenylalanine (50.0 g, 0.302 mole), sodium hydroxide (24.2 g, 0.605 mole) and potassium carbonate (83.6 g, 0.605) was heated at 97 ° C. moles) in water (500 ml). Then benzyl bromide (108.5 ml, 0.605 mole) was slowly added (addition time of 25 minutes). The mixture was stirred at 97 ° C for 30 minutes under a nitrogen atmosphere. The solution was cooled to room temperature and extracted with toluene (2 x 250 ml). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to an oil. The identity of the product was confirmed in the following manner. Analytical TLC (10% ethyl acetate / hexane, silica gel) showed that the main component at a value of Rf = 0.32, is the desired tribencylated compound, phenylmethyl ester of N, N-bis (phenylmethyl) - L-phenylalanine. This compound can be purified by column chromatography (silica gel, 15% ethyl acetate / hexanes). Usually, the product is quite pure to be used directly in the next step without further purification. The 1 H NMR spectrum was consistent with published literature. 1 H NMR (CDCL3) d, 3.00 and 3.14 (system ABX, 2H, JAB = 14.1 Hz, JAX = 7.3 HZ and JB? = 5.9 Hz), 3.54 and 3.92 (System AB, 4H, JAB = 13.9 Hz), 3.71 ( t, 1 H, J = 7.6 Hz), 5.1 1 and 5.23 (System AB, 2H, JAB = 12.3 Hz) and 7.18 (m, 20 H). EIMS: m / z 434 (M-1).

Step 2: ßS-2-ibs (phenylmethyl) amino-1-benzenepropanol from the reduction of phenylmethyl ester of N, N-bis (phenylmethyl) -L-phenylalanine with DIBAL The benzylated phenylalanine phenylmethyl ester (0.302 moles) was dissolved ) of the above reaction in toluene (750 ml), and cooled to -55 ° C. A solution of 1.5 M DIBAL in toluene (443.9 ml, 0.666 moles) was added at such a rate to maintain the temperature between -55 and -50 ° C (1 hour addition time). The mixture was stirred for 20 minutes under a nitrogen atmosphere, and then warmed to -55 ° C by the slow addition of methanol (37 ml). The cold solution was then poured into cold (5 ° C) solution of HCl at 1.5 N (1.8 L). The precipitated solid (approximately 138 g) was filtered and washed with toluene. The solid material was suspended in a mixture of toluene (400 ml) and water (100 ml). The mixture was cooled to 5 ° C, and treated with NaOH a 2. 5 N (186 ml), and then stirred at room temperature until the solid remained dissolved. The toluene layer was separated from the aqueous phase and washed with water and brine, dried over magnesium sulfate, filtered and concentrated to a volume of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml) were added to the residue, after which the desired alcohol product began to crystallize. After 30 minutes, another 50 ml of hexane was added to promote further crystallization. The solid was filtered and washed with 50 ml of hexane to give 34.9 g of product from the first culture. A second crop of product (5.6 g) was isolated by refiltering the stock solution. The two cultures were combined and recrystallized from ethyl acetate (20 ml) and hexane (30 ml) to give 40 g of βS-2- [bis (phenylmethyl) amino] benzenepropanol, in 40% yield from L-phenylalanine. Another 7 g (7%) of product can be obtained from the recrystallization of the concentrated stock solution. TLC of the product gave Rf = 0.23 (10% ethyl acetate / hexane, silica gel); 1 H NMR (CDCl 3) d 2.44 (m, 1 H), 3.09 (m, 2 H), 3.33 (m, 1 H), 3.48 and 3.92 (System AB, 4 H, JAB = 13.3 HZ), 3.52 (m, 1 H) and 7.23 (m, 15H); [a] D25 + 42.4 (c 1.45, CH2Cl2); DSC 77.67 ° C; Analysis calculated for C23H25ON: C, 83.34; H, 7.60; N, 4.23.

Found: C, 83.43; H, 7.59; N, 4.22. CLAR on chiral stationary phase: column Ciclobond I SP (ID of 250 x 4.6 mm), mobile phase: pH regulator methanol / triethylammonium acetate, pH 4.2 (58:42, v / v), flow rate 0.5 ml / min, detection with detector at 230 nm and at a temperature of 0 ° C.

Retention time: 1. 1.25 min., Retention time of the enantiomer of the desired product: 12. 5 min.

Method 2: Preparation of: βS-2-bis (phenylmethyl) amino-1-benzenepropanol from the NN-dibenzylation of L-phenylalaninol: L-phenylalaninol (176.6 g, 1168 mole) was added to a stirred solution of potassium carbonate ( 484.6 g, 3.506 moles) in 710 ml of water. The mixture was heated to 65 ° C under a nitrogen atmosphere. A solution of benzyl bromide (400 g, 2339 moles) in 3M ethanol (305 ml) was added at such a rate that the temperature was maintained between 60 and 68 ° C. The biphasic solution was stirred at 65 ° C for 55 minutes, and then allowed to cool to 10 ° C with vigorous stirring. The oily product solidified into small granules. The product was diluted with 2.0 liters of tap water, and stirred for 5 minutes to dissolve the inorganic byproducts. The product was isolated by filtration under reduced pressure, and washed with water until the pH was 7. The obtained crude product was dried in the air overnight to give a semi-dry solid (407 g), which was recrystallized from of 1.1 I of ethyl acetate / heptane (1: 10 by volume). The product was isolated by filtration (at -8 ° C), washed with 1.6 I of cold ethyl acetate (-10 ° C) / heptane (1: 10 by volume), and air-dried to give 339 g ( 88% yield) of ßS-2- [bis (phenylmethyl) amino] benzenepropanol, mp 71.5-73.0 ° C.

More product can be obtained from the stock solution, if necessary. The other analytical characterization was identical to the compound prepared as described in method 1.

EXAMPLE 2 aS-rbis (phenylmethyl) amino-1-benzenepropanaldehyde Method 1: βS-2- [bis (phenylmethyl) amino] benzenepropanol (200 g, 0.604 mol) was dissolved in triethylamine (300 ml, 2.15 mol). The mixture was cooled to 12 ° C, and a solution of sulfur tyridide / pyridine complex (380 g, 2.39 mol) in DMSO (1.6 I) was added at such a rate to maintain the temperature between 8 and 17 ° C ( 1.0 hour addition time). The solution was stirred at room temperature under a nitrogen atmosphere for 1.5 hours, at which time the reaction was terminated by TLC analysis (33% ethyl acetate / hexane, silica gel). The reaction mixture was cooled with ice water, and quenched with 1.6 I of cold water (10-15 ° C) for 45 minutes. The resulting solution was extracted with ethyl acetate (2.0 L), washed with 5% citric acid (2.0 L) and brine (2.2 l), dried over MgSO (280 g), and filtered.

The solvent was stirred on a rotary evaporator at 35-40 ° C, and then dried under vacuum to give 198.8 g of aS- [bis- (phenylimethyl) amino] -benzenepropanaldehyde as a pale yellow oil (99.9%). The obtained crude product was sufficiently pure to be used directly in the next step without purification. The analytical data of the compound were consistent with the published literature. [a] D25 = -92.9 ° (c 1.87, CH2Cl2); 1 H NMR (400 MHz, CDCl 3) d, 2.94 and 3.15 (ABX system, 2H, JAB = 13.9 Hz, J? X = 7.3 Hz and JBX = 6.2 Hz), 3.56 (t, 1 H, 7.1 Hz), 3.69 and 3.82 (AB system, 4H, JAB = 13.7 Hz), 7.25 (m, 15 H) and 9.72 (s, 1 H); HRMS calculated for (M + 1) C 23 H 24 NO 330,450, found: 330.1886. Analysis calculated for C23H23ON: C, 83.86; H, 7.04; N, 4.25. Found: C, 83.64; H, 7.42; N, 4.19. CLAR on chiral stationary phase: (S, S) Pirkle-Whel column -0 1 (ID of 250 x 4.6 mm), mobile phase: hexane / isopropanol (99.5: 0.5, v / v), flow rate: 1.5 ml / min, detection with UV light detector at 210 nm. Retention time of the desired S-isomer: 8.75 min., Retention time of the R-enantiomer, 10.62 min.

Method 2: A solution of oxalyl chloride (8.4 ml) was cooled to -74 ° C., 0.096 moles) in dichloromethane (240 ml). A solution of DMSO (12.0 ml, 0.155 mole) in dichloromethane (50 ml) was then slowly added at such a rate to maintain the temperature at -74 ° C (addition time of about 1.25 hours). The mixture was stirred for 5 minutes, followed by the addition of a solution of βS-2- [bis (phenylmethyl) amino] benzenepropanol (0.074 mol) in 100 ml of dichloromethane (addition time of 20 min, temp. ° C to -68 ° C). The solution was stirred at -78 ° C for 35 minutes under a nitrogen atmosphere. Triethylamine (41.2 ml, 0.295 moles) (temp. -78 ° C to -68 ° C) was then added over 10 minutes, after which the ammonium salt was precipitated. The cold mixture was stirred for 30 minutes, and then water (225 ml) was added. The dichloromethane layer was separated from the aqueous phase, and washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was diluted with ethyl acetate and hexane, and then filtered to remove the ammonium salt better. The filtrate was concentrated to give a S - [bis (phenylmethyl) amino] benzene propane aldehyde. The aldehyde was brought to the next step without purification.

Method 3: To a mixture of 1.0 g (3.0 mmoles) of βS-2- [bis (phenylmethyl) amino] benzenepropanol, 0.531 g (4.53 mmoles) of N-methyl morpholine, 2.27 g of molecular sieves (4A) and 9.1 ml of acetonitrile, 53 mg (0.15 mmoles) of tetrapropylammonium perruthenate (TPAP) were added. The mixture was stirred for 40 minutes at room temperature, and concentrated under reduced pressure. The residue was suspended in 15 ml of ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure to give a product containing about 50% aS-2- [bis (phenylmethyl) amino] benzene propane aldehyde as a pale yellow oil.

Method 4: To a solution of 1.0 g (3.02 mmol) of βS-2- [bis (phenylmethyl) amino] benzenepropanol in 9.0 ml of toluene was added 4.69 mg (0.03 mmol) of 2,2,6,6-tetramethyl- 1-piperidinyloxy, free radical (TEMPO), 0.32 g (3.1 1 mmol) of sodium bromide, 9.0 ml of ethyl acetate and 1.5 ml of water. The mixture was cooled to 0 ° C, and an aqueous solution of 2.87 ml of 5% household bleach containing 0.735 g (8.75 mmoles) of sodium bicarbonate and 8.53 ml of water was slowly added over 25 minutes. The mixture was stirred at 0 ° C for 60 minutes. Two more additions (1.44 ml each) of bleach were made, followed by stirring for 10 minutes. The two-phase mixture was allowed to separate. The aqueous layer was extracted twice with 20 ml of ethyl acetate. The combined organic layer was washed with 4.0 ml of a solution containing 25 mg of potassium iodide and water (4.0 ml), 20 ml of 10% sodium thiosulfate aqueous solution, and then brine solution. The organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1.34 g of crude oil containing a small amount of the desired product aldehyde, aS- [bis (phenylmethyl) amino] benzene propane aldehyde.

Method 5: Following the same procedures as described in Example 2 (method 1) except that 3.0 equivalents of sulfur trioxide / pyridine complex were used and aS- [bis (phenylmethyl) -amino] benzene-propanaldehyde was isolated in yields comparable.

EXAMPLE 3 N, N, aS-Tris (phenylmethyl) -2S-oxiranemethanamine Method 1: A solution of aS- [bis (phenylmethyl) amino] benzenepropanaldehyde (191.7 g, 0.58 mol) and chloroiodomethane (56.4 mL, 0.77 mol) in tetrahydrofuran (1.8 L) was cooled to -30 to -35 ° C (temperature colder than -70 ° C also worked well but warmer temperatures are more easily achieved in large scale operations) in a stainless steel reactor under a nitrogen atmosphere. A solution of N-butyllithium in hexane (1.6 M, 365 mL, 0.58 mol) was then added at a rate that maintained the temperature below -25 ° C. After the addition the mixture was stirred at -30 to -35 ° C for 10 minutes. Further additions of reagents were carried out as follows: (1) Additional chloroiodomethane (17 ml) was added, followed by n-butylithium (1 10 ml) at < -25 ° C. After the addition the mixture was stirred at -30 to -35 ° C for 10 minutes. This was repeated once. (2) Additional chloroiodomethane (8.5 mL, 0.1 1 mol) was added, followed by n-butylithium (55 mL, 0.088 mol) at < -25 ° C. After the addition the mixture was stirred at -30 to -35 ° C for 10 minutes. This was repeated 5 times. (3) Additional chloroiodomethane (8.5 mL, 0.11 mol) was added, followed by n-butylithium (37 mL, 0.059 mol) at < - 25 ° C. After the addition the mixture was stirred at -30 to -35 ° C for 10 minutes. This was repeated once. The external cooling was stopped and the mixture was warmed to room temperature for 4 to 16 hours when TLC (silica gel, 20% ethyl acetate / hexane) indicated that the reaction was complete. The reaction mixture was cooled to 10 ° C and quenched with 1452 g of 16% ammonium chloride solution (prepared by dissolving 232 g of ammonium chloride in 1220 ml of water), keeping the temperature below 100 ° C. 23 ° C. The mixture was stirred for 10 minutes and the organic and aqueous layers separated. The organic phase was extracted with ethyl acetate (2x 500 mL). The ethyl acetate layer was combined with the tetrahydrofuran layer. The combined solution was dried over magnesium sulfate (220 g), filtered and concentrated on a rotary evaporator at 65 ° C. The brown oil residue was dried at 70 ° C in vacuo (0.8 bar) for 1 hour to give 222.8 g of crude material. (The weight of raw product was >100% Due to the relative instability of the product on silica gel, the crude product is normally used directly in the next step without purification). The diastereomeric ratio of the crude mixture was determined by proton NMR: (2S) / (2R): 86: 14. The minor and major epoxide diastereomers were characterized in this mixture by TLC analysis (silica gel, 10% ethyl acetate / hexane) Rf = 0.29 and 0.32, respectively. An analytical sample of each of the diastereomers was obtained by purification on silica gel chromatography (3% ethyl acetate / hexane) and characterized as follows: N, N, aS-Tris (phenylmethyl, -2S-oxiranemethanamine 1 H NMR (400 MHz, CDCl 3) d 2.49 and 2.51 (System AB, 1 H, JAB = 2. 82), 2.76 and 2.77 (AB System, 1 H, JAB = 4.03), 2.83 (m, 2H), 2.99 and 3.03 (System AB, 1 H, JAB = 10.1 Hz), 3.15 (m, 1 H), 3.73 and 3.84 (System AB, 4H, JAB = 14.00), 7.21 (m, 15H); 13 C NMR (400 MHz, CDCl 3) d 139.55, 129.45, 128. 42, 128.14, 128.09, 126.84, 125.97, 60.32, 54.23, 52.13, 45.99, 33.76; HRMS calculated for C24H26NO (M + 1) 344.477, discovered 344.2003.

N, N, aS-Tris (phenylmethyl, -2R-oxiranemetanamine 1 H NMR (300 MHz, CDCl 3) d 2.20 (m, 1 H), 2.59 (m, 1 H), 2.75 (m, 2H), 2.97 (m, 1 H), 3.14 (m, 1 H), 3.85 (System AB, 4H), 7.25 (m, 15H). HPLC on chiral stationary phase: 1 Pirkle-Whelk-O column (250 x 4.6 mm ID), mobile phase: hexane / isopropanol (99.5: 0.5, v / v), flow rate 1.5 ml / min, detection with UV detector at 210 nm. Retention time of (8): 9.38 min., Retention time of enantiomer of (4): 13.75 min.

Method 2: A solution of the crude aldehyde 0.074 mol and chloroiodomethane (7.0 ml, 0.096 mol) in tetrahydrofuran (285 ml) was cooled to -78 ° C, under a nitrogen atmosphere. A 1.6 M solution of n-butyllithium in hexane (25 ml, 0.040 mol) was then added at a rate to maintain the temperature at -75 ° C (addition time -15 min.). After the first addition, additional chloroiodomethane (1.6 ml, 0.022 mol) was added again, followed by n-butylithium (23 ml, 0.037 mol), maintaining the temperature at -75 ° C. The mixture was stirred for 15 minutes. Each of the reagents, chloroiodomethane (0.70 ml, 0.010 mol) and n-butylithium (5 ml, 0.008 mol) were added 4 more times for 45 minutes at -75 ° C. The cooling bath was then stirred and the solution was warmed at 22 ° C for 1.5 hours. The mixture was poured into a 300 ml solution of saturated aqueous ammonium chloride. The tetrahydrofuran layer was separated. The aqueous phase was extracted with ethyl acetate (1 x 300 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the brown oil (27.4 g). The product could be used in the next step without purification. The desired diastereomer can be purified by recrystallization at a subsequent step. The product could also be purified by chromatography.

Method 3: A solution of aS- [Bis (phenylmethyl) amino] benzene-propanaldehyde (178.84 g, 0.54 mol) and bromochloromethane (46 mL, 0.71 mol) in tetrahydrofuran (1.8 L) was cooled to -30 to -35 ° C (Cooler temperature such as -70 ° C also worked well but warmer temperatures are more easily achieved in large-scale operations) in a stainless steel reactor under a nitrogen atmosphere. A solution of n-butyllithium in hexane (1.6 M, 340 mL, 0.54 mol) was then added at a rate that maintained the temperature below -25 ° C. After the addition the mixture was stirred at -30 to -35 ° C for 10 minutes. Further additions of reagents were carried out as follows: (1) additional bromochloromethane (14 ml) was added, followed by n-butylithium (102 ml) at < -25 ° C. After the addition the mixture was stirred at -30 to -35 ° C for 10 minutes. This was repeated once. (2) Additional bromocloromethane (7 mL, 0.1 1 mol) was added, followed by n-butylithium (51 mL, 0.082 mol) at < -25 ° C. After the addition the mixture was stirred at -30 to -35 ° C for 10 minutes. This was repeated 5 times. (3) Additional bromocloromethane (7 mL, 0.1 1 mol) was added, followed by n-butylithium (51 mL, 0.082 mol) at < -25 ° C. After the addition the mixture was stirred at -30 to -35 ° C for 10 minutes. This was repeated once. The external cooling was stopped and the mixture was heated to room temperature for 4 to 16 hours when TLC (silica gel, 20% ethyl acetate / hexane) indicated that the reaction was complete. The reaction mixture was cooled to 10 ° C and quenched with 1452 g of 16% ammonium chloride solution (prepared by dissolving 232 g of ammonium chloride in 1220 ml of water), keeping the temperature below 23 ° C. The mixture was stirred for 10 minutes and the organic and aqueous layers separated. The aqueous phase was extracted with ethyl acetate. The ethyl acetate layer was combined with the tetrahydrofuran layer. The combined solution was dried over magnesium sulfate (220 g), filtered and concentrated on a rotary evaporator at 65 ° C. The brown oil residue was dried at 70 ° C in vacuo (0.8 bar) for 1 hour to give 222.8 g of crude material.

Method 4: Following the same procedures as described in Example 3 (method 3) except that the reaction temperature was -20 ° C. The resulting N, N, aS-tris (phenylmethyl) -2S-oxiranemetanamine was a diastereomeric mixture of less purity than that of method 3.

Method 5: Following the same procedures as described in Example 3 (method 3) except that the reaction temperatures were at -70 - 78 ° C. The resulting N, N, aS-tris (phenylmethyl) -2S-oxiranemethanamine was a diastereomeric mixture, which was used directly in the subsequent steps without purification.

Method 6: Following the same procedures as described in Example 3 (method 2) except that dibromomethane was used instead of chloroiodomethane. After the reaction and the finishing procedures as described in example 3 (method 2), the desired N, N, aS-tris (phenylmethyl) -2S-oxirane-methanamine was isolated.

Method 7: In a round bottom vessel equipped with mechanical stirrer, thermometer, addition fun THF (760 ml) was added followed by aS- [Bis (phenylmethyl) amino] benzene-propanaldehyde (76 g, 230.7 mmol) under nitrogen . The solution was then cooled to -30 ° C and BrCH2CI (39.7 g, 306. 8 mmoles) was then charged into the reaction mixture. The solution was stirred for 5 minutes and the temperature was maintained at -35 +/- 5 ° C. In this experiment, the addition of n-butyllithium was continuous with periodic additions of additional amounts of dihalogenomethane reagent. A first portion of n-BuLi (144 ml) was added to the reactor through an addition fun A small portion of BrCH2Cl (6 ml) was rapidly introduced into the reaction mixture using syringe without stopping the charge of n-BuLi. After an additional 44 ml of n-BuLi (continuous addition) had been added into the reaction mixture, another small portion of BrCH2CI (6 ml) was transferred into the reaction mixture in the same way. After an additional 44 ml of n-BuLi were added into the reaction mixture, again BrCH2CI (3 ml) was charged into the reaction mixture and followed by 22 ml of n-BuLi. This sequence of addition was repeated 7 times without interrupting the charge of n-BuLi. The reaction mixture was then warmed to room temperature and stirred for an additional 4 hours. A small aliquot was then taken and checked by TLC for the completion of epoxide formation. The reaction mixture was then quenched with 16% NH 4 Cl (aq) (440 ml). After phase separation, the organic layer was condensed at 60 ° C under reduced pressure to give 82.2g of crude oil containing the desired N, N, S-tris (phenylmethyl) -2S-oxirane-methanamine.

Method 8: To a round bottom vessel equipped with mechanical stirrer, thermometer, THF (220 ml) was added followed by aS-Bis (phenylimethyl) amino] benzene-propanaldehyde (25g, 75.9 mmole) under nitrogen. The solution was then cooled to -35 ° C and BrCH2CI (5.7 ml, 87.7 mmol) was then charged into the reaction mixture. The solution was stirred for 5 minutes and the temperature was maintained at -35 +/- 5 ° C. Bromochloromethylene (BrCH2CI) (6.8ml) and 1.6M n-BuLi (104.2ml) were introduced approximately simultaneously into the reactor by syringe pump with addition rates of 0.16 ml / min and / or 2.5ml / min respectively. After the addition was complete, the reaction mixture was then warmed to room temperature and stirred for 4 hours. The resulting reaction mixture was then quenched with 16% NH CI (aq) (190ml) and the resulting phases were separated. The organic layer was washed with water (190ml) and then condensed under reduced pressure at 60 ° C. The residue oil was azeotroped with toluene (30 ml x 2) to give 27.14 g of crude oil. HPLC analysis showed 40.2% by weight of the desired N, N, aS-tris (phenylmethyl) -2S-oxirane-methanamine (41.8% yield).

Method 9: In a round bottom container equipped with mechanical stirrer, a Teflon outlet line, and a thermometer was added THF (500 ml) followed by aS- [Bis (phenylmethyl) amino] benzene-propanaldehyde (10 g, 30.4 mmol) under nitrogen. And then BrCH2CI (5 mL, 76.9 mmol) was charged into the reactor and the solution was stirred for 5 minutes at room temperature. The teflon outlet of reactor A was connected to a static mixer which was immersed in a cooling bath at a temperature of about -30 ° C. A separate vessel equipped with a mechanical stirrer, a Teflon inlet line, and a thermometer was connected to the output of the static mixer. The aldehyde / BrCH2CI / THF solution in the first vessel was pumped through the static mixer through the Teflon line at a rate of 21 ml / min. At the same time, n-BuLi (1.6 M) (approximately 42 ml) was introduced into the static mixer by a syringe pump at a rate of 1.8 ml / min. The reaction mixture of the static mixer was stirred in the second reactor and heated to room temperature immediately. After the chlorohydrin was converted to epoxide, the reaction mixture was quenched with 16% NH 4 Cl (aq) (150 ml). The organic layer was washed with H 0 (150ml) and then concentrated. The residue was then azeotroped with toluene (100 ml) to give 1.06 g of crude N, N, aS-tris (phenylmethyl) -2S-oxirane-green methanamine. HPLC analysis indicated 52.3% by weight of the desired epoxide of N, N, aS-tris (phenylmethyl) -2S-oxirane-methanamine (55.48% yield).

EXAMPLE 3A A solution of aldehyde 3 (190 kg, 576 mol) and chloroiodomethane (48.8 L; 751 mol) in tetrahydrofuran (1900 L) was cooled to -40 to -45 ° C in a stainless steel reactor. A solution of n-butyllithium in hexane (1.6 M, 244 kg) was then added at a rate that kept the temperature below -30 ° C. After the addition the mixture was stirred at -30 to -35 ° C for 10 minutes. Further additions of reagents were carried out as follows: (1) Additional chloroiodomethane (15.2 L) was added, followed by n-butyllithium (73.3 kg) at < -30 ° C. after the addition was complete, the mixture was stirred at -30 to -35 ° C for 10 minutes. This was repeated 3 times. A sample was taken for a process control by HPLC. The chlorohydrin reaction is considered complete when the aldehyde content is less than 5%. The reaction mixture was warmed to room temperature and stirred at room temperature for at least 2 hours until HPLC or TLC (silica gel, 20% ethyl acetate / hexane) indicated that the epoxidation reaction was complete. The reaction mixture was cooled to 5 ° C and quenched with 16% ammonium chloride solution (1092 L). After being kept stirring at the temperature below 25 ° C for 30 minutes, the layers were separated. The organic phase was extracted with water (825 L). After phase separation, the organic phase was concentrated at 60 ° C under vacuum to a minimum stirrable volume. Toluene (430 L) was then added to the reactor and evaporated to a minimum stirrable volume. This procedure was then repeated twice to give an oily brown residue 4 (the weight of the crude product was> 100% yield). The composition of this crude oily product mixture was analyzed by HPLC (column, Partisil 5 (manufacturer, Whatman), 250 mm x 4. 6 mmi.d., particle size 5 μm; mobile phase, hexane / tert-butylmethyl ether, 95: 5 (v / v); flow rate, 1.0 mL / min; UV detector at 215 nm; Alcohol retention time = 6.5 min; Unwanted epoxide retention time = 9. 5 min; desired epoxide retention time = 10.5 min). The crude product contained about 55% of the desired epoxide at this point. The optical purity of the product was determined to be > 99.9%. The other analytical data as RNM were consistent with the published literature. The oil obtained was used in the next step without purification.

EXAMPLE 4 3S-rN, N-Bis (phenylmethyl) amino1-1 - (2-methylpropyl) amino-4-phenylbutan-2R-ol To a solution of crude N, N, aS-tris (phenylmethyl) l-2S-oxiranemethanamine (388.5 g, 1.13 moles) from example 3 in isopropanol (2.7 L) (or ethyl acetate) was added isobutylamine (1.7 kgm, 23.1 g). moles) for 2 minutes. The temperature increased from 25 ° C to 30 ° C. The solution was heated to 82 ° C and stirred at this temperature for 1.5 hours. The warm solution was concentrated under reduced pressure at 65 ° C. The brown oil residue was transferred to a 3L vessel and dried in vacuo (0.8 mm Hg) for 16 hours to give 450 g of 3S- [N, N-bis (phenylmethyl) amino] -1- (2-methylpropyl. ) amino-4-phenylbutan-2R-ol as a crude oil. The product was used directly in the next step without purification. An analytical sample of the desired main diastomeric product was obtained by purifying a small sample of crude product by silica gel chromatography (40% ethyl acetate / hexane).

Tlc analysis: silica gel, 40% ethyl acetate / hexane; Rf = 0.28; analysis HPLC: ODS column of ultrasphere, 25% triethylamine / phosphate pH regulator, pH 3 / acetonitrile, flow rate 1 mL / min UV detector; retention time 7.49 min; HRMS calculated for C28H37N20 (M + 1) 417,616, discovered 417.2887. An analytical sample of the minor diastereomeric product 3S- [N, N-Bis (phenylmethyl) amino] -1- (2-methylpropyl) amino-4-phenylbutan-2S-ol was also obtained by purifying a small sample of crude product by silica gel (40% ethyl acetate / hexane).

EXAMPLE 5 3S-rN.N-B¡s (phenylmethyl-amino-1- (3-methylbutyamino-4-phenylbutan-2R-ol Example 4 was continued using isoamylamine instead of isobutylamine to prepare 3S- [N, N-Bis (phenylmethyl) amino] -1- (3-methylbutyl) amino-4-phenylbutan-2R-ol and 3S- [N, N -Bis (phenylmethyl) amino] -1- (3-methylbutyl) amino-4-phenylbutan-2S-ol in yields comparable to that of example 4. The crude amine was used in the next step without further purification.

EXAMPLE 6 N-r3S-rN.N-B1s (phenylmetinamino1-2R-hydroxyl-4-phenylbutyl-N '- (1,1-dimethylethyl) -N- (2-methylpropyl, urea A solution of the crude 3S- [N, N-Bis (phenylmethyl) amino] -1- (2-methylpropyl) amino-4-phenylbutan-2R-ol (446.0 g, 1.1 moles) of Example 4 in tetrahydrofuran (6 L) (or ethyl acetate) was cooled to 8 ° C. T-butyl isocyanate (109.5 g 1.1 mol) was then added to the amine solution from an addition funnel at a rate that maintained the temperature between 10-12 ° C (addition time was 10 min). The external cooling was stopped and the reaction was heated to 18 ° C after 30 min. The solution was transferred directly from the reactor to a rotary evaporator vessel (10 I) through a Teflon tube using vacuum and then concentrated. The vessel was heated in a 50 ° C water bath for 2 hours required for the distillation of the solvent. The brown residue was dissolved in ethyl acetate (3 L), washed with 5% aqueous solution of citric acid (1 x 1.2 L), water (2 x 500 mL), brine (1 x 400 mL), dried on magnesium sulfate (200 g) and filtered. The volume of product solution was reduced to 671 mL for 2 hours on a rotary evaporator at 50 ° C. The concentrate was stirred and diluted with 1.6 L of hexane. The mixture was cooled to 12 ° C and stirred for 15 hours. The product crystals were isolated by filtration, washed with 10% ethyl acetate / hexane (1 x 500 mL), hexane (1 x 200 mL) and dried in vacuo (2 mm) at 50 ° C for 1 hour. to give 248 g of N- [3S- [N, N-bis- (phenylimethyl) amino] -2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2-methylpropyl) -urea. The mother liquor and the washings were combined and concentrated on a rotary evaporator to give 270 g of a brown oil. This material was dissolved in ethyl acetate (140 mL) at 50 ° C and diluted with hexane (280 mL) and seeded with crystals of the first crop product (20 mg). The mixture was cooled on an ice bath and stirred for 1 hour. The solid was isolated by filtration, washed with 10% ethyl acetate / hexane (1 x 200 mL) and dried in vacuo (2 mm) at 50 ° C for 1 hour to give 55.7 g of 11 as the second crop. (total yield 49%). Mp 126 ° C; [a] -D25 = -59.0 ° (c = 1.0, CH2Cl2), TLC: Rf 0.31 (silica gel, 25% ethyl acetate / hexane). An analytical sample of the minor diasatereomer, N- [3S- [N, N-bis (phenylmethyl) amino] -2S-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2-methylpropyl) ) urea was isolated by silica gel chromatography (10-15% ethyl acetate / hexane in an initial experiment and characterized.

EXAMPLE 7 N-r3S-rN, N-Bis (phenylmethylamino1-2R-hydroxy-4-phenylbutyne-N '- (1,1-dimethylethyl) -N- (3-methylbutyl) urea The crude product of Example 5 was reacted with t-butyl isocyanate following the method of Example 6 to prepare N- [3S- [N, N-Bis (phenylmethyl) amino] -2R-hydroxy-4-phenylbutyl-N '- (1 , 1-d-methylethyl) -N- (3-methylbutyl) urea and N- [3S- [N, N-Bis (phenylmethyl) amino] -2S-hydroxy-4-phenylbutyl] -N'- (1,1-dimethylethyl) -N- (3-methylbutyl) -urea in yields comparable to that of Example 6.

EXAMPLE 8 N-rSS-Amino ^ R -hydroxy ^ -phenylbutyn-N'-d.l-dimethylethi-N-IZ-methylpropylurea From Example 6, N- [3S- [N, N-Bis (phenylmethyl) amino] -2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2-methylpropyl) was dissolved in ethanol. ) urea (125.77 g, 0.244 moles) (1.5 L) (or methanol) and 20% palladium hydroxide on carbon (18.87 g) (or 4% palladium on charcoal) was added to the solution under nitrogen. The mixture was stirred at room temperature under a nitrogen atmosphere at 60 psi for about 8 hours. The catalyst was removed by filtration and the filtrate was concentrated to give 85 g of N- [3S- [Amino-2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2-methylpropyl) ) urea as a colorless oil.

EXAMPLE 9 N-r3S-Amino-2R-hydroxy-4-phenylbutyn-N'-1,1-dimethylethyl-N- (3-methylbutyl) urea N- [3S- [N, N-Bis (phenylmethyl) amino] -2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (3-methylbutyl) urea of Example 7 was hydrogenated following the method of Example 8 to prepare N- [3S-Amino-2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (3-methylbutyl) urea in yields comparable to Example 8.

EXAMPLE 10 N-benzyl-L-phenylalaninol Method 1: L-phenylalaninol (89.51 g, 0.592 mol) was dissolved in 375 ml of methanol under inert atmosphere, 35.52 g (0.592 mol) of glacial acetic acid and 50 ml of methanol were added followed by a solution of 62.83 g (0.592). moles) of benzaldehyde in 100 ml of methanol. The mixture was cooled to about 15 ° C and a solution of 134.6 g (2.14 moles) of sodium cyanoborohydride in 700 ml of methanol was added in about 40 minutes, maintaining the temperature between 15 ° C and 25 ° C. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and partitioned between 1 L of 2M ammonium hydroxide solution and 2L of ether. The ether layer was washed with 1 L of 1 M ammonium hydroxide solution, twice with 500 mL of water, 500 mL of brine and dried over magnesium sulfate for 1 hour. The ether layer was filtered, concentrated under reduced pressure and the crude solid product was recrystallized from 110 ml of ethyl acetate and 1.3 L of hexane to give 115 g (81% yield) of N-benzyl-L-phenylalaninol as a white solid.

Method 2: L-phenylalaninol (5 g, 33 mmol) and 3.59 g (33.83 mmol) of benzaldehyde were dissolved in 55 ml of 3A ethanol under an inert atmosphere on a Parr shaker and the mixture was heated at 60 ° C for 2.7 hours. The mixture was cooled to about 25 ° C and 0.99 g of 5% platinum on carbon was added and the mixture was hydrogenated at 60 psi of hydrogen and 40 ° C for 10 hours. The catalyst was filtered, the product was concentrated under reduced pressure and the crude solid product was recrystallized from 150 ml of hetano to give 3.83 g (48% yield) of N-benzole-L-phenylalaninol as a white solid.

EXAMPLE 11 N- (t-Butoxycarbonyl) -N-benzyl-L-phenylalaninol N-benzyl-L-phenylalaninol (2.9 g, 12 mmol) of Example 10 was dissolved in 3 ml of triethylamine and 27 ml of methanol and 5.25 g (24.1 mole) of di-tert-butyl dicarbonate were added. The mixture was heated at 60 ° C for 35 minutes and concentrated under reduced pressure. The residue was dissolved in 150 ml of ethyl acetate and washed twice with 10 ml of cold diluted hydrochloric acid (0-5 ° C), (pH 2.5 to 3), 15 ml of water, 10 ml of brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The crude product oil was purified by silica gel chromatography (ethyl acetate: hexane, 12: 3 as elution solvent) to give 3. 98 g (97% yield) of colorless oil.

EXAMPLE 12 N- (t-Butoxycarbonyl, -N-benzyl-L-phenylalaninol Method 1: To a solution of 0.32 g (0.94 moles) of N- (t-Butoxycarbonyl) -N-benzyl-L-phenylalaninol from Example 1 1 in 2.8 ml of toluene were added 2.4 mg (0.015 mmoles) of 2, 2 , 6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO), 0.1 g (0.97 mmoles) of sodium bromide, 2.8 ml of ethyl acetate and 0.34 ml of water. The mixture was cooled to 0 ° C and an aqueous solution of 4.2 ml of 5% household bleach containing 0.23 g (3.0 ml, 2.738 mmol) of sodium bicarbonate was slowly added over 30 minutes. The mixture was stirred at 0 ° C for 10 minutes. Three more additions (0.4 ml each) of bleach were added followed by shaking for 10 minutes after each addition to consume all the starting material. The mixture of two phases was allowed to stand to separate. The aqueous layer was extracted twice with 8 ml of toluene. The combined organic layer was washed with 1.25 ml of a solution containing 0.75 g of potassium iodide, sodium bisulfate (0.125 g) and water (1.1 ml), 1.25 ml of 10% aqueous sodium thiosulfate solution, 1.25 ml of phosphate pH regulator, pH 7 and 1.5 ml of brine solution. The organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.32 g (100% yield) of N- (t-Butoxycarbonyl) -N-benzyl-L-phenylalaninol.

Method 2: To a solution of 2.38 g (6.98 mmoles of N- (t-Butoxycarbonyl) -N-benzyl-L-phenylalaninol of Example 1 in 3.8 ml (27.2 mmoles) of triethylamine at 10 ° C was added a solution of 4.33. g (27.2 mmoles) of sulfur trioxide / pyridine complex in 17 ml of dimethyl sulfoxide The mixture was warmed to room temperature and stirred for 1 hour, water (16 ml) was added and the mixture was extracted with 20 ml. of ethyl acetate The organic layer was washed with 20 ml of 5% citric acid, 20 ml of water, 20 ml of brine, dried over magnesium sulfate and filtered The filtrate was concentrated under reduced pressure to give 2.37 g. g (100% yield) of N- (t-Butoxycarbonyl) -N-benzyl-L-phenylalaninol.

EXAMPLE 13 N, aS-Bis (phenylmethyl) -N- (t-b? Toxicarbonyl) -2S-oxiranemetnamnam Method 1: A solution of 2.5 g (7.37 mmoles) of N- (t-butoxycarbonyl) -N-benzyl-L-phenylalaninol from Example 12 and 0.72 ml of chloroiodomethane in 35 ml of THF was cooled to -78 ° C. About 4.64 ml of a solution of n-butyllithium (1.6 M in hexane, 7.42 mmoles) were added slowly, keeping the temperature below -70 ° C. The mixture was stirred for 10 minutes between -70 to -75 ° C. Two additional 0.22 ml portions of chloroiodomethane and 1.4 ml of n-butyl lithium were added sequentially and the mixture was stirred for 10 minutes between -70 to -75 ° C after each addition. Four additional 0.1 ml portions of chloroiodomethane and 0.7 ml of n-butyllithium were added sequentially and the mixture was stirred for 10 minutes between -70 to -75 ° C after each addition. The mixture was heated at room temperature for 3.5 hours. The product was turned off to below 5 ° C with 24 ml of ice-cooled water. The biphasic layers were separated and the aqueous layer was extracted twice with 30 ml of ethyl acetate. The combined organic layers were washed three times with 10 ml of water, then with 10 ml of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2.8 g of a crude yellow oil. This crude oil (> 100% yield) is a mixture of the diastomeric epoxides N, aS-Bis (phenylmethyl) -N- (t-butoxycarbonyl) -2S-oxiranemethanamine and N, aS-Bis (phenylmethyl) -N- (t-butoxycarbonyl) -2R-oxiranemethanamine. The crude mixture is used directly in the next step without purification.

Method 2: To a suspension of 2.92 g (13.28 mmol) of trimethylsulfoxonium iodide in 45 ml of acetonitrile was added 1.49 (13.28 mmol) of potassium t-butoxide. A solution of 3.0 g (8.85 mmol) of N- (t-butoxycarbonyl) -N-benzyl-L-phenylalaninal from Example 12 in 18 ml of acetonitrile were added and the mixture was stirred at room temperature for one hour. The mixture was diluted with 150 ml of water and extracted twice with 200 ml of ethyl acetate. The organic layers were combined and washed with 100 ml of water, 50 ml of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to 3.0 g of a crude yellow oil. The crude product was purified by silica gel chromatography (ethyl acetate / hexane: 1: 8 as eluent solvent) to give 1.02 g (32.7% yield) of a mixture of the two diastereomers N, aS-bis (phenylmethyl). l) N- (t-butoxycarbonyl) -2S-oxiranemethanamine and N, a S-bis (phenylmethyl) -N- (t-butoxycarbonyl) -2R-oxiranemethanamine.

Method 3: To a suspension of 0.90 g (4.42 mmol) of trimethylsulfonium iodide in 18 ml of acetonitrile was added 0.495 g (4.42 mmol) of potassium t-butoxide. A solution of 1.0 g (2.95 mmoles) of N- (t-butoxycarbonyl) -N-benzyl-L-phenylalaninal from Example 12 in 7 ml of acetonitrile was added and the mixture was stirred at room temperature for one hour.

The mixture was diluted with 80 ml of water and extracted twice with 80 ml of ethyl acetate. The organic layers were combined and washed with 100 ml of water, 30 ml of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.04 g of a crude yellow oil. The crude product was a mixture of the two diastereomers N, aS-bis (phenylmethyl) -N- (t-burtoxycarbonyl) -2S-oxiranemethanamine and N, aS-bis (phenylmethyl) -N- (t-butox Carbonyl) -2R-oxiranmetanamine.

EXAMPLE 14 3S-rN- (t-butoxycarbonyl) -N- (phenylmethylammono1-1- (2-methylpropyl) amino-4-phenylbutan-2R-ol To a solution of 500 mg (1.42 mmol) of the crude epoxide of Example 13 in 0.98 ml of isopropanol was added 0.71 ml (7.14 mmol) of isobutylamine. The mixture was heated to reflux at 85 ° C to 90 ° C for 1.5 hours. The mixture was concentrated under reduced pressure and the product oil was purified by silica gel chromatography (chloroform: methanol, 100: 6 as eluting solvents) to give 330 mg of 3S- [N- (t-butoxycarbonyl) -N- phenylmethyl) amino] -1- (2-methylpropyl) amino-4-phenylbutan-2R-ol as a colorless oil (yield 54.5%). 3S- [N- (t-butoxycarbonyl) -N- (phenylmethyl) amino] -1- (2-methylpropyl) amino-4-phenylbutan-2S-ol was also isolated.bis (phenylmethyl) -N- (t -butoxycarbonyl) -2S-oxiranemethanamine was also isolated. When purified N, aS-bis (phenylmethyl) -N- (t-butoxycarbonyl) -2S-oxiranmetanamine was used as starting material, 3S- [N- (t-burtoxycarbonyl) -N-phenylmethyl) amino-1- (2-methylpropiol) amino-4-phenylbutan-2R-ol was isolated after purification by chromatography in 86% yield.

EXAMPLE 15 N-r3S-rN-ft-butoxycarbonyl) -N-phenylmethyl-amino-2-R-hydroxy-4-phenylbutyl-N '- (1,1-dimethylethyl-N- (2-methylpropyl, urea To a solution of 309 mg (0.7265 mmoles) of 3S- [N- (t-butoxycarbonyl) -N- (phenylmethyl) amino] -1- (2-methylpropyl) amino-4-phenylbutan-2R-ol of Example 14 in 5 ml of THF was added 0.174 ml (1.5 mmol) of t-butyl isocyanate. The mixture was stirred at room temperature for 1.5 hours. The product was concentrated under reduced pressure to give 350 mg (92% yield) of a white solid crude product. The crude product was purified by silica gel chromatography (ethyl acetate / ethane: 1: 4 as eluting solvents) to give 324 mg of N- [3S- [N- (t-butoxycarbonyl) -N- (phenolmethyl ) amino] -2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2-methylpropyl) -urea as a white solid (yield of 85.3%).

EXAMPLE 16 3S-rN- (t-butoxycarbonyl) -N- (phenylmethyl) amino1-2S-hydroxy-4-phenylbutyronitrile A solution of 7.0 g (20.65 mmol) of N- (t-butoxycarbonyl) -N-benzyl-L-phenylalanine from Example 12 in 125 mL of THF was cooled to -5 ° C. A solution of 12.96 g of sodium bisulfite in 68 ml of water was added for 40 minutes, keeping the temperature below 5 ° C. The mixture was stirred for 3 hours at 0 to 5 ° C. An additional 1.4 g of sodium bisulfite was added and the mixture was stirred for another two hours. Sodium cyanide (3.3 g, 82.56 moles) was added to the bisulfite product at 0 to 5 ° C and the mixture was stirred at room temperature for 16 hours. The biphasic mixture was extracted with 150 ml of ethyl acetate. The aqueous layer was extracted twice each with 100 ml of ethyl acetate. The combined organic layers were washed twice with 30 ml of water, twice with 25 ml of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 7.5 g (crude yield of 100% of both diastereomers ) of crude oil. The crude oil was purified by silica gel chromatography (ethyl acetate: hexane, 1: 4 as eluting solvents) to give 5.725 g (76% yield) of 3S- [N- (t-butoxycarbonyl) -N- ( phenylmethyl) amino] -2S-hydroxy-4-phenylbutyronitrile as the last major eluting diastereomer and 0.73 g (9.6% yield) of 3S- [N- (t-butoxycarbonyl) -N- (phenylmethyl) amino] -2R-hydroxy -4-phenylbutyronitrile as the minor diastereomer. The combined yields of both isomers of cyanohydrins is yield of 85.6%.

EXAMPLE 17 3S-rN- (t-butoxycarbonyl) -N- (phenylmethyl) amino1-1 -amino-4-phenylbutan-2R-ol To a solution of 205.5 mg (0.56 mmoles) of 3S- [N- (t-butoxycarbonyl) -N- (phenylmethyl) amino] -2S-hydroxy-4-phenylbutyronitrile of example 16 in 4 ml of THF 2.4 ml of a borane solution in THF (1.0 M, 4 mmol) was added. The mixture was stirred at room temperature for 30 minutes. An additional 1.4 ml of borane in THF was added and the mixture was stirred for another 30 minutes. The mixture was cooled to 0 ° C and 2.0 ml of cold water (0-5 ° C) were added slowly. The mixture was warmed to room temperature and stirred for 30 minutes. The product was extracted twice with 30 ml of ethyl acetate. The organic layers were combined and washed with 4 ml of water, 4 ml of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 200 mg of 3S- [N- (t-butoxycarbonyl) -N- (phenylmethyl) amino] -1-amino-4 phenylbutan-2R-ol as a white solid (96.4% yield).

EXAMPLE 18 3S-rN- (t-butoxycarbonyl) -N- (phenylmethyl) amino1-1- (2-methy1propyl) amino-4-phenylbutan-2R-ol To a solution of 2.41 g (6,522 mmol) of 3S- [N- (t-butoxycarbonyl) -N- (phenylmethyl) amino] -1-amino-4-phenylbutan-2R-ol of Example 17 in 40 mL of methanol was added. they added 0.592 ml (6.522 mmol) of isobutyraldehyde and 0.373 ml (6.522 mmol) of acetic acid. The mixture was stirred for 10 minutes. Sodium cyanoborohydride (1639 g, 26 mmol) was added and the mixture was stirred for 16 hours at room temperature. The product mixture was concentrated under reduced pressure and partitioned between 150 ml of ethyl acetate and 50 ml of 1.5 M ammonium hydroxide. The organic layer was washed twice with 20 ml of water, twice with 20 ml of brine, dried over sodium sulfate, filtered and concentrated to a yellow oil. The crude product was purified by silica gel chromatography (chloroform: methanol, 100: 6 as eluting solvents) to give 2.326 g of 3S- [N- (t-butoxycarbonyl) -N- (phenylmethyl) amino] -1- ( 2-methylpropyl) amino-4-phenylbutan-2R-ol as a colorless oil (88.8% yield).

EXAMPLE 19 N-r3S-ÍN- (t-butoxycarbonyl) - (phenylmetnamnamyl) -2R-hydroxy-4-phenylbutyl-N '- (1,1-dimethylethyl) -N- (2-methylpropiDurea) To a solution of 309 mg (0.7265 mmoles) of 3S- [N- (t-butoxycarbonyl) -N- (phenylmethyl) amino-1- (2-methylpropyl) amino-4-phenylbutan-2R-ol of the Example 18 in 5 ml of THF was added 0.174 ml (1.5 mmol) of t-butyl isocyanate. The mixture was stirred at room temperature for 1.5 hours. The product was concentrated under reduced pressure to give 350 mg (92% yield) of a white solid crude product. The crude product was purified by silica gel chromatography (ethyl acetate / hexane: 1: 4 as eluting solvents) to give 324 mg of N- [3S- [N- (t-tuboxycarbonyl) -N- (phenylmethyl) amino] ] - 2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2-methylpropyl) urea as a white solid (85.3% yield).

EXAMPLE 20 N-r3S-rN- (Phenylmethylamino1-2R-hydroxy-4-phenyl] -N '- (1,1-dimethylethyl-N- (2-methylpropyl) urea To a solution of 210 mg (0.4 mmoles) of N- [3S- [N- (t-Butoxycarbonyl) -N- (phenylmethyl) amino] -2R-hydroxy-4-phenylbutyl] -N '- ( 1,1-dimethylethyl) -N- (2-methylpropyl) urea of example 19 in 5.0 ml of THF was added 5 ml of 4N hydrochloric acid. The mixture was stirred at room temperature for 2 hours. The solvents were removed under reduced pressure to give 200 mg (100%) of N- [3S- [N- (phenylmethyl) amino] -2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2-methylpropyl) urea as a white solid.

EXAMPLE 21 N-r3S-Amino-2R-hydroxyl-4-phenylbutyl) -N- '- (1,1-dithomethyl-N- (2-methylpropiPurea) To a solution of 200 mg (0.433 mmoles) of N- [3S- [N- (phenylmethyl) amino] -2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2 -methylpropyl) urea of Example 20 in 7 ml of 3A ethanol was added 0.05 g of palladium on charcoal 20%. The mixture was hydrogenated at 40 ° C for 1.8 hours at 5 psi followed by hydrogenation at 60 psi at room temperature for 22 hours. The filter catalyst and the solvent and the by-product were removed under reduced pressure to give 150 mg (93.4% yield) of N- [3S-amino-2R-hydroxy-4-phenylbutyl] -N '- (1, 1-dimethylethyl) -N- (2-methylpropyl) urea as a white solid.

EXAMPLE 22 3S- (N-t-Butoxycarbonyl, amino-4-phenylbutan-1,2R-diol) To a solution of 1 g (3.39 mmol) of 2S- (Nt-butoxycarbonyl) amino-1S-hydroxy-3-phenylbutanoic (commercially available from Nippon Karyaku, Japan) in 50 ml of THF at 0 ° C was added 50 ml of borane-THF complex (liquid, 1.0 M in THF), keeping the temperature below 5 ° C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was cooled to 0 ° C and 20 ml of water were added slowly to destroy excess BH3 and to quench the product mixture, keeping the temperature below 12 ° C. The paid mixture was stirred for 20 minutes and concentrated under reduced pressure. The product mixture was extracted 3 times with 60 ml of ethyl acetate. The organic layers were combined and washed with 20 ml of water, 25 ml of saturated sodium chloride solution and concentrated under reduced pressure to give 1.1 g of crude oil. The crude product was purified by silica gel chromatography (chloroform / methanol, 10: 6 as eluting solvents) to give 900 mg (94.4% yield) of 3s- (Nt-butoxycarbonyl) amino-4-phenylbutan-1, 2R -diol as a white solid.

EXAMPLE 23 3S- (N-t-Butoxycarbonyl) amino-2R-hydroxy-4-phenylbut-1-yl Toluenesulfonate To a solution of 744.8 mg (2.65 mmol) of 3S- (Nt-butoxycarbonyl) amino-4-phenylbutan-1,2R-diol from Example 22 in 13 ml of pyridine at 0 ° C was added 914 mg of toluene sulfonium chloride in a portion. The mixture was stirred at 0 ° C to 5 ° C for 5 hours. A mixture of 6.5 ml of ethyl acetate and 15 ml of 5% aqueous sodium bicarbonate solution was added to the reaction mixture and stirred for 5 minutes. The product mixture was extracted 3 times with 50 ml of ethyl acetate. The organic layers were combined and washed with 15 ml of water, 10 ml of saturated sodium chloride solution and concentrated under reduced pressure to give 1.1 g of a yellow bulky solid. The crude product was purified by silica gel chromatography (ethyl acetate / hexane 1: 3 as eluting solvents) to give 850 mg (yield 74%) of 3S- (Nt-butoxycarbonyl) amino-2R-hydroxy-4-phen. L-butyl-l-toluenesulfonate as a white solid.

EXAMPLE 24 3S-rN- (t-butoxycarbonyl) aminol-1 - (2-methylpropyl) amino-4-phenylbutan-2R-ol To a solution of 90 mg (0.207 mmol) of 3S- (Nt-butoxycarbonyl) amino-2R-hydroxy-4-phenylbut-1-yl toluenesulfonate from Example 23 in 0.143 ml of isopropanol and 0.5 ml of toluene were added 0.103 ml ( 1034 mmoles) of isobutylamine. The mixture was heated to 80 to 85 ° C and stirred for 1.5 hours. The product mixture was concentrated under reduced pressure at 40 to 50 ° C and purified by silica gel chromatography (chloroform / methanol, 10: 1 as eluting solvents) to give 54.9 mg (76.8% yield) of 3S- [ N- (t-Butoxycarbonyl) amino] -1- (2-methylpropyl) amino-4-phenylbutan-2R-ol as a white solid.

EXAMPLE 25 N-r3S-rN- (t-Butoxycarbonnamnamol-2R-hydroxy-4-phenylbutyl-N '- (1,1-dimethylethyl) -N- (2-methylpropyl) urea To a solution of 0.1732 g (0.516 mmol) of 3S- [N- (t-butoxycarbonyl) amino] -1- (2-methylpropyl) amino-4-phenylbutan-2R-ol of Example 24 in 5 mL of ethyl acetate at 0 ° C, 1.62 ml (12.77 mmoles) of t-butyl isocyanate were added and the mixture was stirred for 1 hour. The product was concentrated under reduced pressure and purified by silica gel chromatography (chloroform / methanol, 100: 1.5 as eluting solvents) to give 96 mg (42.9% yield) of N- [3s- [N- (t- butoxycarbonyl) amino] -2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2-methylpropyl) urea as a white solid.

EXAMPLE 26 methylpropiDurea To a solution of 10 mg (0.023 mmoles) of N- [3S- [N- (t-butoxycarbonylamino] -2R-hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2- methyl-propyl) urea of example 27 in 1 ml of methanol at 0 ° C was added 1.05 ml of 4 m hydrogen chloride in methanol and the mixture was stirred at room temperature for 45 minutes.The product was concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol and concentrated under reduced pressure.This operation was repeated 3 times to remove water from the product, after which 8.09 mg (95.2% yield) of N- [3S-amino-2R- hydroxy-4-phenylbutyl] -N '- (1,1-dimethylethyl) -N- (2-methylpropyl) urea was obtained as a white solid.

EXAMPLE 27 3S- (N-N-Dibenzy-Dano-2S-hydroxy-4-phenylbutyronitrile) ether, O-trimethylsilyl To a solution of 24.33 g (73.86 mmol) of 2S- (N, N-dibenzyl) amino-3-phenylpropaanl in 740 ml of methylene chloride anhydride at -20 ° C under a nitrogen atmosphere, 1.8 ml was added ( 8.8 g, 88.6 mmol) of trimethylsilylcyanide, then 19.96 g (88.6 mmol) of anhydrous zinc bromide. After 4 hours at -15 ° C, and 18 hours at room temperature, the solvent was removed under reduced pressure, ethyl acetate was added, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to provide 31.3 g of a brown oil, which was identified as a 95: 5 mixture of 3S- (N, N-dibenzyl) amino-2S-hydroxy-4-phenylbutyronitrile, O-trimethylsilyl ether, m / e = 429 (M + H) and 3S- (N, N-dibenzyl) amino-2R-hydroxy-4-phenylbutyronitrile, O-trimethylsilyl ether, respectively.

EXAMPLE 28 3S- (N, N-D-benzyl-amino-2S-hydroxy-4-phenylbutronitrile) To a solution of 10.4 g (24.3 mmol) of the crude 95: 5 mixture of 3S- (N, N-dibenzyl) amino-2S-hydroxy-4-phenylbutyronitrile, O-trimethylsilyl, and 3S ether - (N, Nd-benzyl) amino-2R-hydroxy-4-phenylbutyronitrile, O-trimethylsilyl of example 27 in 40 ml of methanol were added to 220 ml of 1 N hydrochloric acid with vigorous stirring. The resulting solid was combined, dissolved in ethyl acetate, washed with acidic sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to provide 8.04 g of crude product. This was recrystallized from ethyl acetate and hexane to provide 3S- (N, N-dibenzyl) amino-2S-hydroxy-4-phenylbutyronitrile, m / e = 357 (M + H).

EXAMPLE 29 3s- (N, N-Dibenzyl) amino-2-hydroxy-4-phenylbutylamine Method 1: A solution of 20.3 g (47.3 mmol) of the crude 95: 5 mixture of 3S- (N, N-dibenzyl) amino-2S-hydroxy-4-phenylbutyronitrile, O-trimethylsilyl ether, and ether of 3S- (N, N-dibenzyl) amino-2R-hydroxy-4-phenylbutyronitrile, O-trimethylsilyl of example 27 in 20 ml of anhydrous diethyl ether was added to 71 ml (71 mmol) of a solution of 1M lithium aluminum hydride in diethyl ether at reflux. After the addition, the reaction was refluxed for 1 hour, cooled to 0 ° C, and quenched by the careful addition of 2.7 ml of water, 2.7 ml of 15% aqueous sodium hydroxide, and 8.1 ml of water . The resulting solids were removed by filtration and the filtrate was washed with water, brine, dried over magnesium sulfate, filtered and concentrated to provide 13.8 g of crude material, which was recrystallized from tetrahydrofuran and isooctane to provide 10.6 g. g of 3S- (N, N-dibenzyl) amino-2R-hydroxy-4-phenylbutylamine, mp 46-49 C, m / e = 361 (M + H), which was contaminated by approximately 2% of 3S- ( N, N-dibenzyl) amino-2S-hydroxy-4-phenylbutylamine.

Method 2: To 15.6 ml (60.4 mmoles) of 70% sodium bis (methoxyethoxy) aluminum hydride in toluene, 15 ml of anhydrous toluene was added, and after cooling to 0 ° C, a solution of 20.0 g (46 g) mmoles) of the crude 95: 5 mixture of 3S- (N, N-dibenzyl) amino-2R-hydroxy-4-phenylbutyronitrile, O-trimethylsilyl ether and 3S- (N, N-dibenzyl) amino-2R- ether hydroxy-4-phenyl butyric acid, O-trimethylsilyl of example 27 in 10 ml of anhydrous toluene, at a rate such as to maintain the temperature below 15 ° C. After 2.5 hours at room temperature, the reaction was quenched by the careful addition of 200 ml of 5% aqueous sodium hydroxide. The solution was dissolved with ethyl acetate, washed with 5% sodium hydroxide, sodium tartrate solution, brine, dried over magnesium sulfate, filtered and concentrated to provide 16.6 g of crude product, which was tested by HPLC and shown to contain 87% of 3S- (N, N-dibenzyl) amino-2R-hydroxy-4-phenylbutylamine.

EXAMPLE 30 N-r3S-rN, N-dibenzyl, amino-2R-hydroxy-4-phenylbuty-N'-f1.1 -dimethylethyl) -N- (3-methylbutylDurea) Step 1: To a solution of 1.0 g (2.77 mmoles) of 3S- (N, N-dibenzyl) amino-2R-hydroxy-4-phenylbutylamine from Example 29 in 4.6 ml of ethanol, 0.3 ml (0.24 g, 2.77 g. mmoles) of isovaleraldehyde. After 1 hour at room temperature, the ethanol was removed under reduced pressure, 4 ml of ethyl acetate were added and the solution was purged with nitrogen. To the solution, 360 mg of 5% platinum on carbon was added as a catalyst, the solution was purged with 40 psig of hydrogen and then kept under 40 psig of hydrogen for 20 hours. The solution was purged with nitrogen, the catalyst was removed by filtration and the solvent was removed under reduced pressure to provide 473 mg of the crude product. Step 2: The crude product of step A was dissolved directly in 5.4 ml of ethyl acetate and 109 mg (1.1 mmmoles) of tertiary butyl isocylate was added. After 1 hour at room temperature, the solution was washed with 5% citric acid, brine, dried over magnesium sulfate, filtered and concentrated to give 470 mg of crude product. The crude product was recrystallized from ethyl acetate and isooctane to provide 160 mg of 3S- (N, N-dibenzyl) amino-2R-hydroxy-4-phenylbutyl] N '- (1,1-dimethylethyl) -N- (3 -methylbutyl) urea, mp 120.4-121.7 ° C, m / e = 530 (M + H).

EXAMPLE 31 Preparation of 1,3-benzodioxol-5-sulfonyl chloride Method 1: To a solution of 4.25 g of anhydrous N, N-dimethylformamide at 0 ° C under nitrogen was added 7.84 g sulfuryl chloride, whereby a solid formed. After stirring for 15 minutes, 6.45 g of 1,3-benzodioxol were added, and the mixture was heated at 100 ° C for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated to give 7.32 g of crude material as a black oil. This was chromatographed on silica gel using 20% methylene chloride / hexane to provide 1.9 g of (1,3-benzodioxol-5-yl) sulfonyl chloride.

Method 2: To a 22 liter round-bottomed vessel equipped with a magnetic stirrer, a cooling condenser, a heating mantle and a pressure equalization dropping funnel were added DMF sulfur trioxide compound (2778 g, 18.1 mol). Dichloromethane (4 liters) was then added and stirring started. 1, 3-benzodioxol (1905 g, 15.6 moles) was then added through the dropping funnel over a period of 5 minutes. The temperature then rose to 751 ° C and it was maintained for 22 hours (NMR indicated that the reaction was done after 9 hours). The reaction was cooled to 26 ° C and oxalyl chloride (2290 g, 18.3 moles) was added at a rate such as to maintain the temperature below 40 ° C (1.5 hours). The mixture was heated at 67 ° C for 5 hours followed by cooling to 16 ° C with an ice bath. The reaction was quenched with water (5 I) at a rate that maintained the temperature below 20 ° C. After the addition of water was complete, the mixture was stirred for 10 minutes. The layers were separated and the organic layer was washed twice again with water (5 I). The organic layer was dried with magnesium sulfate (500 g) and filtered to remove the drying agent. The solvent was removed under vacuum at 50 ° C. The resulting warm liquid was allowed to cool down at which time a solid began to form. After 1 hour, the solid was washed with hexane (400 ml), filtered and dried to provide the desired sulfonyl chloride (2823 g). The hexane wash was concentrated and the resulting solid was washed with 400 ml of hexane to provide additional sulfonyl chloride (464 g). The total yield was 3287 g (95.5% based on 1, 3-benzoidioxol).

Method 3: 1,4-Benzodioxan-6-sulfonyl chloride was prepared according to the procedure described in EP 583960 incorporated herein by reference.

EXAMPLE 32 Preparation of 1-IN-H .3-benzodioxol-5-yl.sulfonyl-N- (2-methylpropyl) amino-1-3 (S.-rbis (phenylmethyl-amino-4-phenyl-2 (R) -butanol Method 1: N- [3 (S) - [N, N-bis (phenylmethyl) amino] -2- (R) -hydroxy- acid salt was added to a 3-neck container of 5000 ml equipped with a mechanical stirrer. 4-Phenylbutyl] -N-isobutylamine-oxalic acid (WO 96/22275) (354.7 g, 0.7 mol) and 1,4-dioxane (2000 ml). A solution of potassium carbonate (241 g, 1.75 mol) in water (250 ml) was then added. The resulting heterogeneous mixture was stirred for 2 hours at room temperature followed by the addition of 1,3-benzodioxole-5-sulfonyl chloride (162.2 g, 0.735 moles) dissolved in 1,4-dioxane (250 ml) for 15 minutes. The reaction mixture was stirred at room temperature for 18 hours. Ethyl acetate (1000 ml) and water (500 ml) were charged to the reactor and stirring continued for another hour. The aqueous layer was separated and extracted further with ethyl acetate (200 ml). The combined layers of ethyl acetate were washed with 25% brine solution (500 ml) and dried over anhydrous magnesium sulfate. After filtering and washing the magnesium sulfate with ethyl acetate (200 ml) the solvent in the filtrate was removed under reduced pressure yielding the desired sulfonamide as a viscous yellow foamy oil (440.2 g, yield 105%). HPLC / MS (electroaspersion) m / z 601 [M + H] +].

EXAMPLE 33 Preparation of salt of 1-rN-r (1-.3-benzodioxol-5-yl) sulfonyl-N- (2-methylpropM) amino-3- (S) -amino-4-phenyl-2 (R) - methanesulfonic butanol Method 1: 1 - [N - [(1 -, 3-benzodioxol-5-yl) sulfonyl] -N- (2-methylpropyl) amino] -3 (S) - [bis (phenylmethyl) amino-4- crude phenyl-2 (R) -butanoI (6.2g, 0.010 mol) was dissolved in methanol (40 mL). Methanesulfonic acid (0.969 g, 0.010 mol) and water (5 mL) were then added to the solution. The mixture was placed in a 500 mL Parr hydrogenation bottle containing 20% Pd (OH) 2 on charcoal 255 mg, 50% water content). The bottle was placed in the hydrogenator and purged 5 times with nitrogen and 5 times with hydrogen. The reaction was allowed to proceed at 35 ° C with a pressure of 63 PSI of hydrogen for 18 hours. Additional catalyst (125 mg) was added and, after purging, the hydrogenation was continued for an additional 20 hours. The mixture was filtered through celite which was washed with methanol (2 x 10 mL). Approximately one third of methanol was removed under reduced pressure. The remaining methanol was removed by azeotropic distillation with toluene at 80 torr. Toluene was added in portions of 15, 10, 10 and 10 mL. The product was crystallized from the mixture and filtered and washed twice with 10 mL portions of toluene. The solid was dried at room temperature at 1 torr for 6 hours to yield the amino salt (4.5 g, 84%). HPLC / MS (electroasperption) was consistent with the desired product (m / z 421 [M + H] +).

Method 2: Part A: N- [3 (S) - [N, N-bis (phenylmethyl) amino] -2 (R) -hydroxy-4-phenylbutyl] -N-isobutyl amine oxalic acid salt 2800 g, 5.53 moles) and THF (4L) were added to a 22L round bottom vessel equipped with a mechanical stirrer. Potassium carbonate (1921g, 13.9 moles) was dissolved in water (2.8L) and added to the THF paste. The mixture was then stirred for one hour. 1,3-Benzodioxole-5-sulfonyl chloride (1281g, 5.8 moles) was dissolved in THF (1.4L) and added to the reaction mixture for 25 minutes. An additional 200 mL of THF was used to rinse the addition funnel. The reaction was allowed to stir for 14 hours and then water (4 L) was added. This mixture was stirred for 30 minutes and the layers were allowed to separate. The layers were removed and the aqueous layer was washed twice with THF (500 mL). The combined THF layers were dried with magnesium sulfate (500 g) for 1 hour. This solution was then filtered to remove the drying agent and used in subsequent reactions. Part B: to the THF solution of 1- [N - [(1-, 3-benzodioxol-5-yl) sulfonyl] -N- (2-methylpropyl) amino] -3 (S) - [b] s (phenylmethyl) ) amino] -4-phenyl-2 (R) -butanol was added water (500 mL) followed by methanesulfonic acid (531 g, 5.5 moles). The solution was stirred to ensure a complete mixture and added to an 18.925 liter autoclave. The Pearlman catalyst (200g of 20% Pd (OH) 2 on C / 50% water) was added to the autoclave with the help of THF (500 mL). The reactor was purged four times with nitrogen and four times with hydrogen. The reactor was charged with 60 psig of hydrogen and agitation at 450 rpm started. After 16 hours, HPLC analysis indicated that a small amount of the mono-benzyl intermediate was still present. Additional catalyst (50 g) was added and the reaction allowed to run overnight. The solution was then filtered through celite (500g) to remove the catalyst and concentrated in vacuo in five portions. To each portion toluene (500 mL) was added and it was removed under vacuum to residual water azeotropically removed. The resulting solid was divided into three portions and each was washed with methyl t-butyl ether (2 L) and filtered. The residual solvent was stirred at room temperature in a vacuum oven to less than 1 torr to yield 2714 g of the expected salt. If desired, the product can be further purified by the following procedure. A total of 500 mL of methanol and 170 g of previous material were heated to reflux until everything dissolved. The solution cooled, 200 mL of isopropanol and then 1000-1300 mL of hexane were added, whereupon a white solid precipitated. After cooling to 0 ° C, this precipitate was combined and washed with hexane to provide 123 g of the desired material. Through this procedure, the original material that was a mixture of 95: 5 diastereomers of alcohol was greater than 99: 1 of the desired diastereomer.

EXAMPLE 34 Preparation of 2R-hydroxy-3-IT.1-, 3-benzodioxol-5-yl, sulfonip (2- methylpropyl, amino1-1S-, phenylmethylpropylamine Part A: Preparation of phenylmethyl ester of 2R-hydroxy-3 - [[(1,3-benzodioxol-5-yl) sulfonyl] (2-methylpropyl) amino] -1 S (phenylmethyl) propylcarbamic acid To a solution of 3.19 g (8.6 mmoles) of N- [3S-benzyloxy carbonylamino-2R-hydroxy-4-phenyl] -N-isobutylamine in 40 mL of anhydrous methylene chloride, 0.87 g of triethylamine was added. The solution was cooled to 0 ° C and 1.90 g of (1,3-benzodioxol-5-yl) sulfonyl chloride were added, stirred for 15 minutes at 0 ° C, then for 17 hours at room temperature. Ethyl acetate was added, washed with 5% citric acid, saturated with sodium bicarbonate, brine, dried and concentrated to yield crude material. This was recrystallized from diethyl ether / hexane to provide 4.77 g of phenylmethyl 2R-hydroxy-3 - [[(1,3-benzodioxol-5-yl) sulfonyl] (2-methylpropyl) amino] -1S- pure (phenylmethyl) propylcarbamic acid. Part B: Preparation of 2R-hydroxy-3 - [[(1,3-benzodioxol-5-yl) sulfonyl] (2-methylpropyl) amino] -1 S- (phenylmethyl) propylamine A solution of 4.1 1 g of carbamic acid, phenylmethyl ester of 2R-hydroxy-3 - [[(1,3-benzodixol-5-yl) sulfonyl] (2-methyIpropyl) amino] -1S- (phenylmethyl) propyl- in 45 ml of tetrahydrofuran and 25 ml of methanol were hydrogenated about 1.1 g of 10% palladium on charcoal under 50 psig of hydrogen for 16 hours. The catalyst was removed by filtration and the filtrate was concentrated to provide 1.82 g of 2R-hydroxy-3 - [[(1,3-benzodioxol-5-yl) sulfonyl] (2-methylpropyl) amino] -1S- ( phenylmethyl) propylamine desired. From the detailed description mentioned above, a person skilled in the art can easily calculate the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make several changes and modifications to the invention to adapt it to various uses and terms. As described above, the present invention, referred to above as continuous synthesis in situ, involves several key features. According to the process, a protected aminoaldehyde, as can be protected by oxidation of a protected amino alcohol, is flowed into a mixing zone maintained at a temperature below 0 ° C, at the same time an organometallic halogenomethyl reagent, either separately added or created in situ from the reaction between an organometallic reagent and a dihalogenomethane (or a mixture of dihalogenomethanes), it also flows into the mixing zone in a molar excess relative to said protected aminoaldehyde to contact in the mixing zone with the said protected aminoaldehyde. At the same time, the reaction product (S) of said protected aminoaldehyde and the halogenomethyl organometallic reagent is (are) removed from the mixing zone, and with the heating of the reaction product (s), the amino epoxide is formed. Additional specific details of the procedure can be obtained from Liu, et al., Organic Process Research & Development, 1 (1): 45-54 (1997), which is incorporated herein by reference. Advancing the protected aminoaldehyde to a mixing zone with a suitable molar amount (excess) of the halogenomethyl organometallic reagent the length of time necessary to complete the reaction with the protected aminoalcohol is significantly decreased while the degree of unwanted side reactions is surprisingly limited . The method of the invention allows the scale of the mixing zone to be divorced from the amount of protected aminoaldehyde to be reacted. Therefore, the process allows the use of small mixing zones, the temperature of which can be controlled easily and carefully, even for the synthesis of multi-kilogram quantities of aminoepoxide.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - In a method for preparing an aminoepoxide characterized in that a protected aminoaldehyde is reacted with an organometallic halogenomethyl reagent in a suitable solvent at a temperature above -80 ° C, further characterized in that said organometallic halogenomethyl reagent is formed by reaction between a organometallic reagent and a dihalogenomethane, the improvement consisting in: flowing said protected aminoaldehyde into a first mixing zone, and also flowing the dihalogenomethane into the first mixing zone to contact in the first mixing zone with the protected aminoaldehyde to form a first mixture, flushing the organometallic reagent into a second mixing zone maintained at a temperature below 0 ° C and also flowing the first mixture into the second mixing zone to contact in the second mixing zone the dihalogenomethane from the first mixing zone. mix with the organometallic reagent to form a mixture of The reaction containing the organometallic reagent halogenomethyl; flow the reaction mixture into a third mixing zone, and remove from the third mixing zone, the reaction products of the protected aminoaldehyde and the organometallic reagent halogenomethyl.

2. - The method according to claim 1 further characterized in that the organometallic reagent is an organolithium reagent provided in a molar excess relative to the protected aminoaldehyde.

3. The method according to claim 2 further characterized in that the organolithium reagent is n-butyllithium.

4. The method according to claim 2 further characterized in that the dihalogenomethane is selected from bromochloromethane, chloroiodomethane, iodobromomethane, dibromomethane, and diiodomethane and bromofluoromethane.

5. The method according to claim 4 further characterized in that the second mixing zone is maintained at a temperature in the range of -80 ° C and 0 ° C.

6. The method according to claim 4 further characterized in that the second mixing zone is maintained at a temperature on a scale of -40 ° C and -15 ° C.

7. The method according to claim 1 further characterized in that separate streams of protected aminoaldehyde and dihalogenomethane are flowed into the first mixing zone, and separate streams of organometallic reagent and the first mixture are flowed into the second mixing zone .

8. The method according to claim 7 further characterized in that the organometallic reagent is a lithium organ reagent provided in a molar excess relative to the protected aminoaldehyde.

9. The method according to claim 8 further characterized in that the dihalogenomethane is selected from bromochloromethane, chloroiodomethane, iodobromomethane, dibromomethane, diiodomethane and bromofluoromethane.

10. The method according to claim 9 further characterized in that the second mixing zone is maintained at a temperature on a scale of -80 ° C and 0 ° C. 1. The method according to claim 9 further characterized in that the second mixing zone is maintained at a temperature on a scale of -40 ° C and -15 ° C. 12. The method according to claim 1 further characterized in that the halogenomethyl organometallic reagent is a halogenomethylitium provided in a molar excess relative to the protected aminoaldehyde. 13. The method according to claim 12 further characterized in that the dihalogenomethane is selected from bromochloromethane, chloroiodomethane, iodobromethane, dibromomethane, diiodomethane and bromofluoromethane.