MXPA99011055A - Process for the preparation of substituted keto-enamines - Google Patents

Abstract

The present invention discloses a process for the preparation of a substantially pure compound having formula (4). The process comprises the step of reacting an enolate having formula (A) with a Grignard reagent. The enolate salt is formed in situ from the reaction of a protected ester wherein M is an alkali metal. R6 and R7 are each hydrogen or are independently selected from (i) wherein Ra and Rb are independently selected from hydrogen, lower alkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, lower alkyl, trifluoromethyl, alkoxy, halo and phenyl;and (ii) wherein the naphthyl ring is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy and halo. Alternatively, R6 is as defined above and R7 is R12OC(O)- wherein R12 is benzyl;or R6 and R7 taken together with the nitrogen atom to which they are bonded form (B) or (C), wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, lower alkyl, alkoxy, halogen and trifluoromethyl.

Description

PROCESS FOR THE PREPARATION OF SUBSTITUTE CETO-ENA INAS TECHNICAL FIELD The present invention relates to a process for the preparation of an intermediate enamine which is used for the preparation of substituted 2,5-diamino-3-hydroxyhexane. BACKGROUND OF THE INVENTION Compounds which are human immunodeficiency virus (HIV) protease inhibitors are useful for inhibiting HIV protease in vitro and in vivo and are useful for inhibiting HIV infection. Certain HIV protease inhibitors comprise a portion which is a substituted 2,5-diamino-3-hydroxyhexane. HIV protease inhibitors of particular interest are compounds having the formula 1: wherein A is R2NHCH (R1) C (O) - and B is R2a or wherein A is R2a and B is R2NHCH (R -?) C (O) - wherein Ri is a lower alkyl and R and R2a are sectioned independently of -C (O) -R3-R wherein each time it occurs, R3 is independently separated from O, S and -N (R5) - wherein R5 is hydrogen or lower alkyl and each time it occurs, R4 is independently selected from heterocyclic or heterocyclic alkyl; or a pharmaceutically acceptable salt, prodrug or ester thereof. The compounds of the formula 1_ are described in the patent of E.U.A. Do not.' 5,354,866, issued October 11, 1994, Patent of U.S.A. No. 5,541,206. issued on July 30, 1996, and the patent of E.U.A. No. 5,491,253, issued February 13, 1996. A preferred inhibitor of HIV protease having the formula 1_ is a compound of the formula 2a: 2a or a pharmaceutically acceptable salt, prodrug or ester thereof. Another preferred HIV protease inhibitor of formula 1 is a compound of formula 2b: The compound having the formula 2b_ is described is the patent of E.U.A. No. 5,421,206, issued July 30, 1996. An intermediate which is especially useful for preparing compounds having the formula 1_ and 2 is a substantially pure compound having the formula 3; Wherein R6, R7 and R8 are independently selected from hydrogen and N-protecting groups, such as, for example, t-butyloxycarbonyl (Boc), benzyl and the like; or an acid addition salt thereof. The preparation of compounds having the formula 3 have been described in the patent of E.U.A. 5,491,253, issued February 13, 1996 (the '253 patent).

The process described in the '253 patent begins with a protected benzyl L-phenylalanine ester. The ester is reacted with a -carbonion of acetonitrile in an inert solvent to provide a ketonitrile, shown below.

The reaction of ketonitrile with a Grignard benzyl, usually more than three equivalents, provides the enamine product. The enamine can easily be transformed into the compound 3. An object of the present invention is to provide a simple method for the preparation of enamines, which can be converted into diaminoles having the formula 3. An object of the present invention is to provide a method for the preparation of enamines which provide enamines with high yield. COMPENDIUM OF THE INVENTION The present invention describes a process for the preparation of a substantially pure compound having the formula 4: The process comprises the step of reacting an enolate that has the formula: '' -R7 with a Grignard reagent. The enolate salt is formed in situ from an ester protected with an amide metal, MNH2, wherein M is a metal cation. R6 and R7 are each hydrogen or are independently selected from wherein Ra and R are independently separated from hydrogen, lower alkyl and phenyl and R0, Rd and Re are independently selected from hydrogen, lower alkyl, trifluoromethyl, alkoxy, halo and phenyl; Y ) Wherein the naphthyl ring is unsubstituted or substituted with one, two or three substituents independently selected from a lower alkyl, trifluoromethyl, alkoxy and halo. Alternatively, R6 is as defined above and R7 is R12OC (O) - wherein R12 is benzyl; or R6 and R7 taken together with the nitrogen atom to which they are attached wherein Rf, Rg, Rh, Rj are independently selected from hydrogen, lower alkyl, alkoxy, halogen and trifluoromethyl with the proviso that R6 and R7 can not both be hydrogen. R 4 is a hydrocarbyl group capable of forming a Grignard reagent. Preferred R groups are selected from the group consisting of alkyl, alkyl, substituted alkaryl, such as, benzyl, and substituted benzyl, aryl, such as, phenyl, substituted phenyl, naphthyl and substituted naphthyl. R15 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkaryl, such as, benzyl, and substituted benzyl, aryl, such as, phenyl, substituted phenyl, naphthiio and substituted naphthyl. The process of the invention also includes the preparation of acid addition salts of compound 4. DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications, and literature references cited in the specification, are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present description, including its definitions, will prevail.

The present invention relates to a process for the preparation of a compound having the formula 4.

In the process of the invention R6 and R7 are hydrogen or are independently selected from wherein Ra and Rb are independently selected from hydrogen, lower alkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, trifluoromethyl lower alkyl, alkoxy, halo and phenyl; Y (i) wherein the naphthyl ring is unsubstituted or substituted with one, two or three substituents independently selected from a lower alkyl, trifluoromethyl, alkoxy, and halo; or R6 is as defined above and R7 is R7aOC (O) - wherein R7 is a lower alkyl or benzyl; or R6 and R taken together with the nitrogen atom to which they are attached are wherein Rf, Rg, Rh and Rj are independently selected from hydrogen, lower alkyl. Alkoxy, halogen, and trifluoromethyl; with the proviso that R6 and R7 can not both be hydrogen. R-M is a hydrocarbyl group capable of forming a Grignard reagent. Preferred R1 groups are selected from the group consisting of alkyl, substituted alkyl, alkaryl, such as, benzyl, and substituted benzyl, aryl, such as, phenyl, substituted phenyl, naphthyl and substituted naphthyl. R15 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkaryl, such as, benzyl, and substituted benzyl, aryl, such as, phenyl, substituted phenyl, naphthyl and substituted naphthyl. The process of the invention also includes the preparation of acid addition salts of compound 4. Examples of substituents suitable for substitution in the alkyl, phenyl, benzyl, and naphthyl groups include, but are not limited to, lower alkyl, aryl , cycloalkyl, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino. Alkylarylamino, and the like. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl. The alkyl groups may be optionally interrupted by one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and phosphorus. The Grignard reagents which can be used practicing the present invention, are compounds having the formula R? 4MgX where R? it is as defined above and X is a halogen atom. Halogen atoms which are useful in the practice of this invention include chloride, bromide and iodide. Examples of metal cations which are useful in the practice of the present invention include, but are not limited to, Group I alkali metals, such as, for example, sodium, lithium, potassium, and the like. The preferred metals are sodium, and potassium. A preferred form of compound 4 is compound 4a: 4a where R6 and R7 are independently selected from benzyl and substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from the lower alkyl, trifluoromethyl, alkoxy, halo and phenyl and R8 is hydrogen, benzyl, substituted benzyl, or -C (O) R9 wherein R9 is lower alkyl, alkoxy, or phenyl, wherein the Phenyl ring is unsubstituted or substituted with one, two or three substituents independently selected from the lower alkyl, trifluoromethyl, alkoxy and halo. A more preferred form of compound 4a is a compound wherein R6 and R are benzyl and R8 is hydrogen or t-butyloxycarbonyl. The general process of the invention is illustrated in Scheme 1. The protection of the amino group in an L-amino acid and the esterification provides the compound III. The reaction of III with the form of about 1.05 to about 1.5 equivalents, preferably from about 1.1 to about 1.3 equivalents, of an α-carbanium of acetonitrile in a suitable solvent provides the intermediate enolate-nitrile II. The reaction is then concentrated and the ammonium is removed. The reaction of the enolate-nitrile II with about 1.0 to about 3.5 equivalents of Grignard reagent (ie, R1 MgX) provides enamine 4. The ratio of the preferred Grignard reagent is about 1.25 to about 3.0 equivalents and the more preferred is from about 1.5 to about 2.5 equivalents based on the number of equivalents of the protected L-amino acid.

SCHEME I NH2 Re- • N- R7 R15"C02H R15" C02R Groups R6 = R7 = protectors lll l R6 = R7 = Protective groups A preferred embodiment for preparing the enamine of the invention having the formula 4a is illustrated in Scheme II. The amino group in L-phenylalanine is protected as the benzyl amine, and the acid group is esterified simultaneously, ie, R, R6 and R7 are benzyl, to provide the compound 5. The reaction of 5. with the a-carbanipn of acetonitrile (about 2.2 equivalents) in an inert solvent, such as methyl tert-butyl ether (ETBM), provides nitrile. enolato, 6a_. Preferably the acetonitrile anion is prepared from the sodium or potassium amide (NaNH2 or KNH2). The most preferred is sodium amide. The reaction of the nitrile-enolate, 6a with about 1.5 equivalents of Grignard (eg, magnesium benzyl chloride hydrate) provides enamine, 6a. The ratio of acetonitrile carbanion required is from about 1.0 to about 2.0 equivalents, preferably from about 1.1 to about 1.5 equivalents. The proportion of Grignard reagent required is around 1.0 to about 3.5 equivalents. The preferred proportion of Grignard reagent is from about 1.35 to about 3.0 equivalents and the most preferred is from about 1.5 to about 2.5 equivalents, based on the number of equivalents of the protected L-amino acid. Inert solvents suitable for use in the process of the invention include dialkyl ether solvents, such as, for example, methyl ether, ethyl ether, propyl ether, n-butyl ether, n-butyl methyl ether, ether of tert-butyl methyl (ETBM, for its acronym in English). Pentyl ether, hexyl ether, dimethoxyhexane and the like; a mixture of a solvent such as, for example, tetrahydrofuran (THF), dioxane and the like with an alkyl or cycloalkyl solvent such as, for example, pentane, cyclopentane, hexane, cyclohexane, heptane and the like. The preferred solvents are the alkyl ethers. A preferred solvent is ETBM.

SCHEME II NH2 RR = R7 = R = Bencil L-Phenylalanine R6 = R7 = Benzyl R6 = R7 = Benzyl 4a Various processes for the conversion of compounds having the formula 4a to the hydroxy diamine, compounds having the formula 3, are described in the patent of E.U.A. No. 5,354,866, The U.S. Patent. No. 5,541,206, and the U.S. Patent. No. 5,491,253. Processes for the preparation of compounds having formula 4a described in these patents describe the purification and isolation of cyano-ketone 6 prior to conversion to enamine, 4a. This process is illustrated in Scheme III. The elimination of the additional step of nitrile insulation increases production by about 20% and reduces the proportion of reagents necessary to conduct the reaction, particularly the proportion of the required Grignard reagent, by about 50%. SCHEME lll NH2 R6 = R7 = R = Benzyl L- Phenylalanine 4a The term "alkyl," as used herein, refers to straight or branched chain alkyl radicals containing from 1 to 12 carbon atoms.The term "lower alkyl" refers to branched or straight chain alkyl radicals. containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, - methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like Alkyl groups may be optionally interrupted by one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus. The term "aryl", as used herein, refers to an unsubstituted carbocyclic aromatic radical including, for example, phenyl and 1- or 2-naphthyl The term "cycloalkyl", as used herein, is refers to saturated monocyclic hydrocarbon radicals having from three to eight atoms d carbon in the ring and optionally substituted with one to three optional radicals selected from alkaryl, alkoxy, lower alkyl, halo, alkylamino, hydroxy-substituted alkyl, hydroxy, alkoxy, halogen and amino, dialkylamino and the like. Cycloalkyl radicals include, groups such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloethyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2-amino-cyclopropyl and the like.

The term "alkoxy" as used herein, refers to groups having formula -OR10 wherein R10 is a lower alkyl group The term "thioalkoxy" as used herein, refers to groups having formula - SRn wherein Rn is a lower alkyl group The term "alkoxyalkoxy" as used herein, refers to groups having the formula -OR-ie-OR-io wherein R16 is a lower alkylene group R10 is a group lower alkyl The term "alkaryl" refers to a lower alkyl radical having attached thereto an aromatic hydrocarbon group, such as benzyl and phenylethyl.The term "alkylamino" as used herein, refers to groups have the formula -NHR17 wherein R17 is a lower alkyl group The term "dialkylamino" as used herein, refers to groups having the formula -N (R?) 2 wherein each R17 is independently an alkyl group The term "arylamino" as used in the present, refers to groups having the formula -NHR? 8 wherein R18 is an aryl group.

The term "diaryioamino" as used herein, refers to groups having the formula -N (R18) 2 wherein each R18 is independently an aryl group.

The term "alkylaryloamino" as used herein refers to groups having the formula -N (R 17 R 18) 2 wherein one R 17 is an alkyl group and the other R 8 is an aryl group. The term "halo", as used herein, refers to F, Cl, Br or l. The term "acid addition salts", as used herein, refers to salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, and the like, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, and the like, or using other methods used in the art such as ion exchange. The term "haloalkyl", as used herein, refers to a lower alkyl group in which one or more hydrogen atoms have been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl and the like. The term "halophenyl", as used herein, refers to a phenyl group in which one, two, three, four or five hydrogen atoms have been replaced with a halogen including, but not limited to, chlorophenyl , bromophenyl, fluorophenyl, iodophenyl, 2,3-dichlorophenyl, 2,4-cyclochlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenium, 2,3,5-trichlorophenyl , 2,4,6-trichlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 2,4-dichloro-5-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5 -difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl, 2,3, 4-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5,6-tetrafluorophenyl, pentafluorophenyl and the like. The term "N-protected" or "N-protected" group, as used herein, refers to those groups that attempt to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. . Commonly the N-protecting groups used are described in T.H. Greene and P.G.M. Wuts, Protective Groups ¡n Orqanic Synthesis, 2nd edition, John Wiley & Sons, New York (1991) N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, f? I o, o-nitrophenoxyacetyl, a-chlorobutryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesufonyl and the like; carbamate forming groups such as beziloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxy-benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy-benzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-Notro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenyl) -1-methoxy-ethoxycarbonyl, α, α-dimethyl-3,5-dimethoxy-benzyloxycarbonyl, benzyldyloxycarbonyl, t-butyloxy carbonyl, diisopropyl-methoxycarbonyl, isopro piloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluoroenyl-9-methoxycarbonyl, ciciopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as methyl trimethyls and the like. Preferred N-protecting groups are formyl, acetyl, bezoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). As used herein, the configuration of the terms "S" and "R" are as defined by the recommendations of lUPAC 1974 for Section E, Fundamental Stereochemistry, Puré Appl. Chem. (1976) 45, 13-30. The reagents required by the synthesis of the compounds of the invention and readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York 14652-3512); Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz and Bauer (Waterbury, CT 06708). Compounds which are not commercially available can be prepared using methods known from the chemical literature. The following examples illustrate the process of the invention without limitation. Example 1 (L) -N, N-Dibenzylphenylalanine benzyl ester. A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride hydrate (415 kg, 3275 moles) ) was heated at 90 ± 15 ° C for 24 hours. The reaction of the mixture was cooled to 60 ° C and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organic layer, stirred and the layers separated. The organic layer was washed once with a water / methanol mixture (150 L / 150 L). The organic layer was removed to provide the title product as an oil. This was carried out in the next step without purification. The results are illustrated below- NMR 1H (300MHz, CDCl3) 67.5-7.0 (m, 20H), 5.3 (d, 1H, J = 13.5 Hz), 5.2 (d, 1H, J = 13.5 Hz), 4.0 (d, 2H, J = 15 Hz), 3.8 (t, 2H, J = 8.4 Hz), 3.6 (d, 2H, J = 15 Hz), 3.2 (dd, 1H, J = 8.4, 14.4 Hz). 13 C NMR (300 MHz, CDCl 3) 6172.0, 139.2, 138.0, 135.9, 129.4, 128.6, 128.5, 128.4, 128.2, 128.1, 126.9, 126.2, 66.0, 62.3, 54.3, 35.6. IR (pure) 3090, 3050, 3030, 1730, 1495, 1450, 1160 cm "1. [A] D -79 ° (c = o.9, CMF).

Example 2 (2S) -5-amino-2- (N, N.dibenzyl) amino-3-oxo-1,6-diphenylohex-4-ene. A solution comprising benzyl ester of (L) -N, N-dibenzyl-phenylalanine (0.24 mol) in 85 mL methyl tertiary butyl ether (MTBE) and 13.9 mL, 270 mmol, of acetonitrile was added slowly to a slurry of 90% sodium amide (22.9 g, 0.53 mol) in 185 mL of MTBE, maintaining the subsequent temperature 0 ° C. This was stirred for 6 hours. The excess of benzyl magnesium chloride was removed with a solution of 120 g of citric acid in 630 mL of water. The aqueous layer was separated and the organic layer was concentrated. The resulting product was crystallized from ethanol to provide 90 g (80%) of (2S) -5-amino-2- (N, N-dibenzyl) amino-3-oxo-1,6-diphenyle-4-ene (enamine ). The results are illustrated below. 1 H NMR (CDCl 3) 9.80 (br s, 1H), 7.45-7.05 (m, 20H), 5.10 (s, 1H), 4.90 (br s, 1H), 3.75 (d, J = 15Hz, 2H), 3.55-3.45 (m, 3H), 3.15 (dd, J = 7.2, 13.2Hz, 1H), 2.97 (dd, J = 7.2, 13.2Hz, 1H). 13 C NMR (CDCl 3) 198.2, 162.8, 140.2, 140.1, 135.7, 129.5, 129.3, 128.9, 128.7, 128.1, 128.0, 127.3, 126.7, 125.6, 96.9, 66.5, 54.3, 42.3, 32.4. IR (film) 3620, 3480, 3030, 1615, 1595, 1520, 1495, 1455 cm "1 MS (CI) m / e (rel.int.) 461 ((M + H) +, 100), 196 ( 10). CLAR is 100% (Chiracel OD column, 10% PrOH / Hexanes).

Example 3. (2S) -5-Amino-2- (N, N-dibenzyl) amino-3-oxo-1-phenylhex-4-ene. The title compound was prepared from benzyl ester of (L) -N, N-dibenzyl-phenylalanine, 46.0 mmoles, and 2.6 mL, 50 mmoles, of acetonitrile. Following the procedure described in Example 2 the ester and the nitrile mixture were added the 4.4 g, 101 mmol sodium amide in MTBE. Methyl Grignard (CH3MgCI 150 mmol) was replaced by magnesium benzyl chloride. The resulting enamine was crystallized from heptane. The enamine production was 17 g (43 mmol, 93%). The results are illustrated below. 1 H NMR (CDCl 3); 9.87 (br s, 1H, NH), 7.32-7.08 (m, 15H), 5.03 (s, 1H), 5.00 (br s, 1H), 3.87 (d, J = 13.5Hz, 2H), 3.67 (d, J = 13.5Hz, 2H), 3.52 (t, J = 7.1Hz, 1H), 3.12 (dd, J = 13, 7.1Hz, 1H), 3.01 (dd, J = 13, 7.1Hz, 1H), 1.94 ( s, 3H). 13 C NMR (CDCl 3); 197.6, 161.1, 140.2, 140.1, 129.5, 128.7, 128.1, 128.0, 126.7, 125.6, 96.7, 66.3, 54.3, 33.1, 22.6. IR (KBr); 3340.3260, 3190, 3020, 1620, 1600, 1525, 745, 700 cm -1 CLAR; 100% ee (Chiracel OD column, 10% PrOH / Hexanes). Example 4 (4S) -1-Amino-4- (N, N-dibenzyl) amino-1,5-diphenyl-3-oxo-pent-1-ene.

The title compound was prepared from benzyl ester of (L) -N, N-dibenzyl-phenylalanine, 150 mmol, and 8.6 mL, 165 mmol, of acetonitrile. Following the procedure described in Example 2 the ester and the nitrile mixture was added to 14.4 g, 330 mmol sodium amide in MTBE. Grignard phenyl (PhMgCI 300 mmole) was replaced by magnesium benzyl chloride. The resulting enamine was purified by column chromatography using silica gel, 240/400 mesh and 2: 1 heptane / ethyl acetate as the mobile phase. The enamine production was 53 g (119 mmol, 79%). The results are illustrated below. 1 H NMR (CDCl 3) 10.0 (br s, 1H, NH), 7.3 (m, 20H), 5.5 (s, 1H), 5.4 (br s, 1H, NH), 3.95 (d, J = 15Hz, 2H), 3.7 (dd, J = 7, 8Hz, 1), 3.3 (dd, J = 8, 15Hz, 1H), 3.1 (d, J = 7, 15Hz). 13 C NMR (CDCl 3) 198.7, 160.9, 140.1, 137.2, 131.0, 129.5, 128.9, 128.7, 128.1, 128.0, 126.7, 126.2, 125.7, 95.8, 66.9, 54.4, 32.8. IR (film) 3450, 3350, 3070, 3030, 1600, 1560, 1520, 1490, 1450 cm "1. MS (Cl) m / e (Int.R.) 447 (M +, 100), 300 (55) CLAR ee 97% (Chiracel OD column, 10% PrOH / Hexanes) Example 5. 4-Amino-1- (N, N-dibenzyl) amino-2-oxo-5-phenyl-pent-3-ene. The title compound was prepared from N, N-dibenzyl glycine benzyl ester, 54 mmole, and 3.3 mL, 64 mmole acetonitrile.

Following the procedure described in Example 2 the ester and the nitrile mixture was added to 5.5 g, 127 mmol of sodium amide in MTBE. After removing the solvent, the magnesium benzyl chloride (PhCH2MgCI, 145 mmol) was added following the procedure in Example 2. The resulting enamine was purified by chromatography, following the procedure described in Example 4. The enamine production was of 22.3 g (50 mmol, 78%). The results are illustrated below. 1 H NMR (CDCl 3); 9.8 (br s, 1H), NH), 7.3 (m, 15H), 5.6 (s, 1H), . 0 (br s, 1H, NH), 3.6 (s, 4H), 3.5 (s, 2H), 3.1 (s, 2H). 13 C NMR (CDCl 3); 198.4, 163.5, 139.2, 135.6, 138.8, 128.7, 128.6, 128.2, 127.3, 126.9, 93.5, 76.6, 62.3, 58.4, 42.2. IR (KBr); 3300, 3150, 2810, 1600, 1530, 1580, 1420 cm "1. Elemental Analysis: Calculated C25H26N2O: C, 81.1; H, 7.1; N, 7.6; O, 4.3% Found: C, 81.3; H, 7.1 N, 7.3, 0.4.1%, Example 6 (+) - 4-Amino-1- (N, N-dibenzyl ') amino-1,5-diphenyl-2-oxo-pent-3-ene. The title compound was prepared from N, N-dibenzyl-benzylic glycine ether, 113 mmol, and 6.5 mL, 125 mmol acetonitrile Following the procedure described in Example 2 the ester and the nitrile mixture was added at 9.8. g, 225 mmole of sodium amide in MTBE. After removing the solvent, benzyl magnesium chloride (PhCH2MgCl 250 mmole) was added following the procedure in Example 2. The resulting enamine was purified by chromatography, following the procedure described in Example 4. The enamine production was 41 g (102 mmol, 90%) The results are illustrated below. 1 H NMR (CDCl 3); 9-8 (br s, 1H, NH), 7.4 (m, 20H), 5.6 (s, 1H), 5.2 (br s, 1H, NH), 4.5 (s, 1H), 3.9 (d, 2H, J = 15Hz), 3.7 (d, 2H, J = 15Hz), 3.5 (s, 2H). 13 C NMR (CDCl 3); 198.2, 163.9, 140.9, 139.3, 137.5, 135.6, 129.6, 129.1, 128.8, 128.7, 128.3, 128.0, 127.9, 127.3, 127.2, 126.8, 95.02, 71.9, 53.9, 42.1. IR (film); 3450, 3360, 2970, 2950, 2920, 1610, 1520, 1495, 1450 cm-1. MS (Cl); m / e (Int. Re.) 447 (M +, 100), 340 (15), 222 (45). Comparative example (2S) -5-Amino-2- (N, N-dibenzyl) amino-3-oxo-1,6-diphenyle-4-ene a. 4-S-N, N-dibenzylamino-3-oxo-5-phenyl-pentanonitriio. A solution containing the product of Example 1 (ie, benzyl ester of) (0.45 moles approx.) In 520 mL tetrahydrofuran and 420 mL acetonitrile was cooled to -40 ° C under nitrogen. A second solution containing sodium amide (48.7 g, 1.25 moles) in 850 mL tetrahydrofuran was cooled to -40 ° C. To the sodium amide solution was slowly added 75 mL of acetonitrile and the resulting solution was stirred at -40 ° C more than 15 minutes. The sodium amide / acetonitrile solution was then added to the benzyl ester solution at -40CC. The combined solution was stirred at -40 ° C one hour and then removed with 1150 mL of a 25% (w / v) citric acid solution. The resulting slurry was moistened at room temperature and the organic layer was separated. The organic layer was then washed with 350 mL of a 25% (w / v) sodium chloride solution, then diluted with 900 mL of heptane. The organic layer was then washed three times with 900 mL of a 5% sodium chloride solution (/ v), twice with 900 mL of a 10% methanolic water solution, once with 900 mL of a solution of methanolic water at 15%, and then once with 900 mL of a 20% methanolic water solution. The organic layer was removed and the resulting material was dissolved in 700 mL of hot ethanol. Upon cooling to room temperature, the desired product is precipitated. Filtration provides the title product in 59% production of L-phenylalanine. The results are illustrated below. 1 H NMR (CDCl 3); 6 7.3 (m, 15H), 3.9 (d, 1H, J = 19.5 Hz), 3.8 (d, 2H, J = 13.5 Hz), 3.6 (d, 2H, J = 13.5), 3.5 (dd, 1H, J = 4.0, 10.5 Hz), 3.2 (dd, 1H, J = 10.5, 13.5 Hz), 3.0 (dd, 1H, J = 4.0, 13.5 Hz), 3.0 (d, 1H, J = 19.5 Hz), 13C NMR ( 300 MHz, CDCI3); 6197.0, 138.4, 138.0, 129.5, 129.0, 128.8, 128.6, 127.8, 126.4, 68.6, 54.8, 30.0, 28.4. [] D-953 (c = 0.5, DMF). IR (CHCl3); 3090, 3050, 3030, 2250, 1735, 1600, 1490, 1450, 1370, 1300, 1215, cm "1, b, 2-Amino-5-SN, N-dibenzylamine-4-oxo-1, 6 diphenylex-2-ene To a solution at -5 ° C of the nitrile product of Comparative Example 2a (90 Kg, 244 moles) in tetrahydrofuran (288 L), magnesium benzyl chloride (378 Kg, 2M in THF, 708 was added moles) The solution was moistened at room temperature and stirred until the analysis shows no nitrile starting material. The solution was then cooled to 5 ° C and transferred slowly to a solution of 15% citric acid (456 kg). Additional tetrahydrofuran (85 mL) was used to rinse out of the original container and the rinse was added to the container retted with citric acid. The organic layer was separated and washed with 10% sodium chloride (235 kg). The solvent was removed to provide a solid. The crude solid was dissolved in ethanol (289 mL) and separated again. The product was redissolved in warm ethanol (80 ° C) (581 L) and cooled to room temperature and stirred for 12 hours. The resulting product was filtered and dried in a vacuum oven at 30 ° C to provide the title compound, p.f. 101-102 ° C, 95 kg, 85% yield, based on N, N-dibenzyl-phenylalanine benzyl ester. The results are illustrated below. 1 H NMR (300 MHz, CDCl 3); d 9.8 (br s, 1H), 7.2 (m, 20H), 5.1 (s, 1H), 4.9 (br s, 1H), 3.8 (d, 2H, J = 14.7 Hz), 3.6 (d, 2H, J = 14.7 Hz), 3.5 (m, 3H), 3.2 (dd, 1H, J = 7.5, 14.4 Hz), 3.0 (dd, 1H, J = 6.6, 14.4 Hz). 13 C NMR (CDCl 3); d 198.0, 162.8, 140.2, 140.1, 136.0, 129.5, 129.3, 12879, 128.7, 128.1, 128.0, 127.3, 126.7, 125.6, 96.9, 66.5, 54.3, 42.3, 32.4. IR (CDCI3); 3630, 3500, 3110, 3060, 3030, 2230, 1620, 1595, 1520, 1495, 1450, cm "1. [A] D; -147 ° (c = 0.5, DMF).

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the embodiments described. Variations and changes, which are obvious to a person skilled in the art, can be made within the scope and nature of the invention which are defined in the appended claims.

Claims (19)

1. CLAIMS 1. A process for the preparation of a pure compound that substantially has the formula 4: said process comprising the step of reacting an enolate having the formula: e \ -R7 N ' with a Grignard reagent having the formula R? 4MgX; wherein R14 is a hydrocarbyl group capable of forming a Grignard reagent selected from the group consisting of alkyl, alkaryl, and aryl; R15 is selected from the group consisting of hydrogen, alkyl, alkaryl and aryl; M is an alkaline metal; and X is a halogen atom selected from the group consisting of chloride, bromide and iodide; wherein R6 and R7 are independently selected from the group consisting of hydrogen, the group: wherein Ra and Rb is independently selected from hydrogen, lower alkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, lower alkyl, trifluoromethyl, alkoxy, halo and phenyl; and the group: wherein the naphthyl ring is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy and halo; or R6 is as defined above and R7 is R12OC (0) - wherein R12 is benzyl; or R6 and R7 taken together with the hydrogen atom to which they are attached are wherein Rf, Rg, Rh and Rj are independently selected from hydrogen, lower alkyl, alkoxy, halogen and trifluoromethyl with the proviso that R6 and R7 can not be hydrogen.
2. 2. The process according to claim 1, wherein R14 and Ri5 are independently alkyl, benzyl or phenyl.
3. 3. The process according to claim 2, wherein R6 and R7 are each benzyl.
4. 4. The process according to claim 2, wherein R1 and R15 are independently methyl, benzyl or phenyl.
5. 5. The process according to claim 4, wherein R6 and R7 are each benzyl.
6. 6. The process according to claim 4, wherein R14 and R15 are independently benzyl or phenyl.
7. 7. The process according to claim 6, wherein R6 and R7 are each benzyl.
8. 8. The process according to claim 6, wherein R1 and R15 are each benzyl.
9. 9. The process according to claim 8, wherein R6 and R7 are each benzyl.
10. 10. The process according to claim 4, wherein R14 is methyl and R15 is benzyl.
11. The process according to claim 10, wherein R6 and R7 are each benzyl
12. 12. The process according to claim 6, wherein R1 is phenyl and R15 is benzyl.
13. 13. The process according to claim 12, wherein R6 and R7 are each benzyl.
14. 14. The process according to claim 4, wherein R1 is phenyl and R15 is methyl.
15. 15. The process according to claim 14, wherein R6 and R7 are each benzyl.
16. 16. The process according to claim 1, wherein R14 is benzyl and R-? 5 is phenyl.
17. 17. The process according to claim 1, wherein R6 and R are each benzyl.
18. 18. The process according to claim 1, wherein the metal ion is selected from the group consisting of sodium, potassium and lithium.
19. 19. The process according to claim 18, wherein the metal ion is sodium.