MXPA97000720A - Procedure for the preparation of a 2,5-diamino-3-hidroxihex - Google Patents

Abstract

The present invention relates to a process for the preparation of the substantially pure compound of the formula: wherein R6 and R7 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 lower alkyl trifluoromethyl, alkoxy, halogen and phenyl, and wherein the naphthyl ring is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy and halogen, R6 and R7 taken together with the nitrogen atom to which they are attached are, wherein Rf, Rg, Rh and Ri were independently selected from hydrogen, lower alkyl, alkoxy, halogen and trifluoromethyl, or an addition salt thereof, which comprises reacting an enaminoketone compound of the formula: wherein R6 and R7 are as defined before s with hydrogen gas in the presence of a hydrogenation catalyst and a

Description

PROCEDURE FOR THE PREPARATION OF A 2.5-DIAMINO-3- HYDROXYHEXANE Technical Field The present invention relates to intermediates and methods that are useful for the preparation of a 2,5-diamino-3-hydroxyhexane.

Background of the Invention Compounds that are inhibitors of HIV protease 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 2,5-diamino-3-hydroxyhexane. HIV protease inhibitors of particular interest are the compounds of formula 1: rf ^ wherein A is R2NHCH (R?) C (0) - and B is R2a or where A is R2a and B is R? NHCH? RCO) - wherein R, is a lower alkyl and R2 and R2a are independently selected from -C (0) -R3-R4 wherein in each occurrence R3 is independently selected from O, S and -N (R5) - wherein Rs is hydrogen or lower alkyl and in each occurrence R4 is independently selected from heterocyclic alkyl or alkyl (heterocyclic); or a pharmaceutically acceptable salt, prodrug or ester thereof. The compounds of formula 1 are described in European Patent Application No. EP0486948, published May 27, 1992. A preferred HIV protease inhibitor of formula 1 is a compound of formula a: 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 of formula 2b is described in PCT Patent Application No. W094 / 14436, published July 7, 1994, which is incorporated herein by reference. An intermediate that is especially useful for preparing the compounds of formula 1 and 2 is a substantially pure compound of formula 3: wherein R6 and R7 are independently selected from a group of N-protection; or an acid addition salt thereof. The preferred N-protection groups R6 and R7 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, halogen and phenyl; Y wherein the naphthyl ring is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy and halogen. Alternatively, R6 and R7 taken together with the nitrogen atom to which they are attached are wherein Rf, Rg, Rh and R, are independently selected from hydrogen, lower alkyl, alkoxy, halogen and trifluoromethyl. The most preferred N-protecting groups R6 and R7 are those wherein R6 and R are independently selected from benzyl and substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents selected independently from lower alkyl, trifluoromethyl, alkoxy, halogen and phenyl. The most preferred N-protection groups R6 and 7 are those in which R6 and R7 are each benzyl. Preferred intermediates of formula 3 are compounds wherein R6 and R are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy , halogen and phenyl. The most preferred intermediates of formula 3 are the compounds wherein R6 and R7 are benzyl.

Description of the Invention The present invention relates to a process for the preparation of a substantially pure compound of the formula 3.

A key intermediary in the process of the present invention is a substantially pure enaminoketone compound of the formula wherein R6 and R are independently selected from a group of N-protection; or an acid addition salt thereof. The preferred N-protection groups R6 and R7 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, lower alkyl, trifluoromethyl, alkoxy, halogen and phenyl; Y / CH2- (») wherein the naphthyl ring is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy and halogen. Alternatively, R6 and R7 taken together with the nitrogen atom to which they are attached are wherein Rf, Rg, Rh and Rj were independently selected from hydrogen, lower alkyl, alkoxy, halogen and trifluoromethyl. Preferred intermediates of formula 4 are the compounds wherein R6 and R7 are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy , halogen and phenyl. The most preferred intermediates of formula 4 are compounds wherein R6 and R7 are benzyl. The compounds of formula 4 and a process for their preparation are described in U.S. Pat. series 141,795, filed on October 22, 1993, which is incorporated herein by reference. A process for the preparation of 3 from 4 involves the catalytic hydrogenation of 3 in a solvent comprising (1) a protein solvent, (2) an ether solvent or (3) a mixture of a protein solvent and a hydrocarbon solvent in the presence of an acid.

In particular, the process comprises dissolving the compound 3 in a suitable solvent, adding the acid, then adding the hydrogenation catalyst and, finally, pressurizing the reaction vessel with hydrogen gas. A preferred solvent for the process is (1) a protein solvent such as an alcohol (eg, isopropanol, methanol, ethanol, t-butanol, sec-butanol, n-butanol or propanol and the like), (2) ether solvent such such as dimethoxyethane, metrl-t-butyl ether or dioxane and the like or (3) a mixture of a protein solvent and a hydrocarbon solvent (e.g., pentane, hexane, heptane or toluene and the like). A more preferred solvent is ethanol. A preferred acid is an inorganic acid (for example, HCI, HBr, sulfuric acid, phosphoric acid, perchloric acid, fluorosulfonic acid, Me2SiOS03H and the like) or an organic acid selected from (i) R8-COOH wherein R8 is alkyl lower, haloalkyl, phenyl or halophenyl, (ii) R9-S03H wherein R9 is lower alkyl, haloalkyl, phenyl, phenyl substituted with lower alkyl, halophenyl or naphthyl and (iii) R-? 0-P? 3H2 wherein R10 is lower alkyl or phenyl; or a combination of such acids. Examples of R8-COOH acids include acetic acid, propionic acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, difluoroacetic acid, benzoic acid and pentafluorobenzoic acid. Examples of acids R9-S03H include methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, phenylsulfonic acid and p-toluenesulfonic acid. Examples of acids R10-PO3H2 include methylphosphonic acid, ethyllosophonic acid and phenylphosphonic acid. A more preferred acid for the process of this invention is methanesulfonic acid or sulfuric acid. A preferred amount of the acid is from about 2 molar equivalents to about 4 molar equivalents (based on the enaminoketone). A more preferred amount of the acid is from about 3 molar equivalents to about 4 molar equivalents. A preferred hydrogenation catalyst is a platinum catalyst (which includes platinum black or platinum oxide or the like). Preferably, the catalyst is supported on a support such as carbon, alumina, graphite, sulfided carbon, polyethyleneimine / SiO 2 (Royer, et al., J. Org. Chem. 22 2268 (1980)) or aminopolysiloxane (e.g., Deloxan® AP II, available from Degussa, 65 Challenger Road, Ridgefield Park, NJ 07660) and the like. Platinum on carbon can also be doped with Pd, Ru, Re or Rh. A more preferred catalyst is 5% platinum or a 5% carbon or platinum over aminopolysiloxane. The hydrogenation process is preferably carried out at a hydrogen pressure of about 4,218 kg / cm 2 to about 70.3 kg / cm 2. A more preferred hydrogen pressure is from about 17,575 kg / cm 2 to about 70.3 kg / cm 2.

The term "lower alkyl" as used herein refers to straight or branched 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, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. The term "alkoxy" as used herein refers to -OR10 wherein Rio is a lower alkyl group. The term "halogen" as used herein refers to F, Cl, Br or I. The term "haloalkyl" as used herein refers to a lower alkyl group in which one or more hydrogen atoms have 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-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,5-trichlorophenyl, 2,4,6 -trichlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenol, 2,4-dichloro-5-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-diflurophenyl, 2 , 6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trifluorophenyl, 2,3,6-trifluorophenyl, 2 , 4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2,3,4,5-tetraflurophenyl, 2,3,5,6-tetraflurophenyl. Pentaflurophenyl and the like. The acid addition salts of the compounds of the invention can be derived from the reaction of an amine-containing compound of the invention with an inorganic or organic acid. These salts include but are not limited to the following: acetate, adopate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, cyclopentanpropionate, dodecyl sulfate, ethanesulfonate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate , hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, malonate, glutarate, malate, mandelate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Examples of acids that can be used to form the acid addition salts include organic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid as well as the other aforementioned acids. The term "substantially pure" as used herein refers to a compound that is contaminated by not more than 10% of any other stereoisomer (enantiomer or diastereomer), preferably by not more than 5% of any stereoisomer and more preferably by no more than 3% of any other stereoisomer. As used herein, the terms "S" and "Y" configuration "R" are as defined by the 1974 IUPAC Recommendations for Section E, Fundamental Stoichiometry, "Puré Appl. Chem. (1976) 45, 13-30". The following examples will serve to further illustrate the compounds and methods of the invention.

Example 1 Benzyl ester of (L) -NN-Dibenzylphenylalanine A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L) and Benzyl chloride (415 kg, 3275 moles) was heated to 90 ± 15 ° C for 10-24 hours. The reaction 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 components, stirred and the layers were separated. The organic components were washed once with a water / methanol mixture (150L / 150L). The organic components were deprotected to give the desired product as an oil, which was taken to the next step without purification.

IR (net) 3090, 3050, 3030, 1730, 1495, 1450, 1160 cm - "11,? NMR (300 MHZ, CDCI3) d 7.5-7.0 (m, 20H), 5.3 (d, 1H, J = 13.5 Hz ), 4.0 (d, "H, 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) d 172.0, 139.2, 138.0, 135.9, 129.4, 128.6, 128.5, 128.4, 128.2, 128.1, 128.1, 126.9, 126.2, 66.0, 62.3, 54.3, 35.6. [a] D -79 ° (c = 0.9, DMF) Example 2a 4-S-N1N-Dibenzylamino-3-oxo-5-phenyl-pentanenitrile A solution containing the product of Example 1 (ie, benzyl ester) (about 0.45 mol) in 520 mL of tetrahydrofuran and 420 mL of acetonitrile they were cooled to -40 ° C under nitrogen. A second solution containing sodium amide (48.7 g, 1.25 moles) in 850 mL of tetrahydrofuran was cooled to -40 ° C. To the sodium amide solution, 75 mL of acetonitrile was slowly added and the resulting solution was stirred at -40 ° C for more than 15 minutes. The sodium / acetonitrile amide solution was slowly added to the benzyl ester solution at -40 ° C. The combined solution was stirred at -40 ° C for one hour and then quenched with 1150 mL of a 25% citric acid solution. % (p / v). The resulting paste was heated to room temperature and the organic components were separated. The organic components were then washed with 350 ml of a 25% (w / v) sodium chloride solution, then diluted with 900 ml of heptane. The organic components were washed three times with 900 ml of a 5% (w / v) sodium chloride solution, 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 components were deprotected and the resulting material was dissolved in 700 mL of hot ethanol. Upon cooling to room temperature, the desired product was precipitated. Filtration gave the desired product in 59% yield from L-phenylalanine. IR (CHCl3) 3090, 3050, 3030, 2250, 1735, 1600, 1490, 1450, 1370, 1215 cm "1, 1 H NMR (CDCl 3) d 7.3 (m, 15 H), 3.9 (d, 1 H, J = 19.5 Hz ), 3.8 (d, 2H, J = 13.5 Hz), 3.6 (d, 2H, J = 13.5 Hz), 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) d 197.0, 138.4, 138.0, 129.5, 129.0, 128.8, 128.6, 127.8, 126.4, 68.6, 54.8, 30.0, 28.4 .. [a] D -95 ° (c = 0.5, DMF) EXAMPLE 2B Alternative preparation of 4-S-N, N-Dibenzylamino-3-oxo-5-phenyl-pentanenitrile To a flask, sodium amide (5.8 g, 134 mmol) was charged under nitrogen followed by 100 ml of methyl t-butyl ether (MTBE). The stirred solution was cooled to 10 ° C. Acetonitoplo (8.6 mL, 165 mmol) was added during 1 minute. This solution was stirred at 5 ± 5aC for 30 minutes. A solution of benzyl ester of (L) -N, N-dibenzylphenylalanine (25 g, 90% pure, 51.6 mmol) in 125 mL of MTBE was added over 15 minutes and the resulting heterogeneous mixture was stirred at 5 ± 5aC until it was completed the reaction (about 3 hours). The reaction was quenched with 100 mL of 25% w / v citric acid and heated to > t at 25 ° C before separating the layers. The organic components were then washed with 100 mL of H20. The aqueous layer was separated and the organic components were filtered and concentrated in vacuo. The residue was crystallized from 50 mL of ethanol to obtain 13.8 g of the desired product as a white solid.

EXAMPLE 2C Alternative preparation of 4-S-N, N-Dibenzylamino-3-oxo-5-phenyl-pentanenitrile To a solution containing sodium amide (120 kg, 3077 mols), heptane (1194 L) and tetrahydrofuran (590 L) cooled to 0 ° C, a solution containing the product of Example 1 (ie benzyl ester) was added. (approximately 975 mols), tetrahydrofuran (290 L), heptane (570 L), and acetonitrile (114 L). The addition was made keeping the temperature below 5 ° C. The combined solution was stirred at 0 ± 5 ° C for approximately 1 hour before extinguishing with 25% citric acid solution (1540 L) to adjust the pH to 5.0-7.0. The upper organic layer was separated and washed with 25% aqueous sodium chloride (715 kg), treated with activated carbon (2 kg) and deprotected. The resulting residue was crystallized from an ethanol / water solution at 55 ° C (809 kg / 404 kg). The solution was cooled to 0 ° C before crystallization to give approximately 215 kg of the desired product.

EXAMPLE 3 Alternative preparation of 4-S-N, N-Dibenzylamino-3-oxo-5-phenyl-penta nitrile A solution of potassium t-butoxide (32 g, 0.289 mol, 3.0 equiv.) In tetrahydrofuran was charged to a 1-liter jacketed reaction flask equipped with a thermometer, nitrogen inlet, equalized pressure addition funnel and mechanical stirrer. 350 mL) and cooled to an internal temperature of -10 ° C. To this was added a solution of the product of Example 1 (ie, benzyl ester) (42.0 g, 0.0964 mol, 1.0 equiv.) In tetrahydrofuran (10 mL) and acetonitrile (15 mL, 0.289 mol, 3.0 equiv.) By of an equalized pressure addition funnel for a period of 20 minutes. During the addition, the internal temperature was increased to -5 ° C. The reaction mixture (now orange and clear) was stirred for an additional 30 minutes at -10 ° C An aliquot removed from the reaction mixture after the addition of the benzyl ester solution was quenched in 10% aqueous citric acid and partitioned between heptane and analyzed by HPLC and it was found that no material remained and the presence of the desired nitrile in 93% in favor of the S isomer, Chiralpak AD column, 1 mL / min, 10% / propanol in heptane, monitored T205 nm). The contents of the reactor were allowed to warm to 0 ° C for 30 minutes. The citric acid (10% aqueous, 200 ml) was charged followed by Heptane (100 ml) and the reaction contents were allowed to warm to 20 ° C. The aqueous phase was separated and the organic phase was washed with 10% aqueous sodium chloride solution (200 mL) and the aqueous phase was separated. The organic phase was concentrated in vacuo using a bath at 45 ° C. The n-butanol (100 mL) was then charged and the distillation was conducted in vacuo until the contents were reduced to approximately 10% by volume. The resulting solution was allowed to cool to 20 ° C with mechanical stirring and was maintained at that temperature for 18 hours. The solid was dried and filtered in vacuo at 45 ° C. The yield of the first crop was 20.5 g (57%). The material was > 98% pure by HPLC.

EXAMPLE 4 2-amino-5-S-N, N-dibenzylamino-4-oxo-1,6-diphenylhex-2-ene To a solution of the nitrile product of Example 2 (90 Kg, 244 mols) in tetrahydrofuran (288 L), benzylmagnesium chloride (378 kg, 2M in THF, 7089 mols) was added. The solution was warmed to room temperature and stirred until the analysis showed no starting material. The solution was again cooled to 5 ° C and slowly transferred to a 15% citric acid solution (465 kg). Additional tetrahydrofuran (85L) was used to rinse the original vessel and the rinse was added to the citric acid quench vessel. The organic components were separated and washed with 10% sodium chloride (235 kg) and deprotected to a solid. The product was again deprotected from ethanol (289 L) and then dissolved in ethanol at 80 ° C (581 L)). After cooling to room temperature and stirring for 12 hours, the resulting product was filtered and dried in a vacuum oven at 30 ° C to give approximately 95 kg of the desired product. Mp 101-102 ° C, IR (CDCl 3) 3630, 3500, 33110, 3060, 3030, 2230, 1620, 1595, 1520, 1495, 1450 cm "1, 1 H NMR (300 MHz, CDCl 3) d 9.8 (brs, 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, 14.4Hz), 13C NMR (CDCI3) d 198.0, 162.8, 140.2, 140 1, 136.0, 129.5, 1293, 128.9, 128.7, 128.1, 128.0, 127.3, 126.7, 125.6, 96.9, 66.5, 54.3, 42.3, 32.4. [A] D -147 ° (c = 0.5, DMF) EXAMPLE 5 (2S.3S, 5S) -5-amino-2- (dibenzylamino) -3-hydroxy-1,6-diphenyl-hexane A solution of 2-amino-5-SN, N-dibenzylamino-4-oxo-1,6-diphenylhex-2-ene (30 g, 65 mmol), methanesulfonic acid (24 g, 248 mmol), ethanol (240 mL) ), and 4 grams of 5% platinum supported on carbon was pressurized at 17,575 kg / cm with hydrogen and stirred at 50 ° C for 14 hours followed by stirring at 23 ° C for 10 hours. The pressure was released and the catalyst was removed by filtration over celite. The filtrate was diluted with 1N sodium hydroxide (250 mL) and the product was extracted with MTBE (300 mL). The organics were washed with brine (100 mL) and concentrated in vacuo to provide the desired product as a yellow oil: IR (CHCl3) 3510, 3400, 3110, 3060, 3030, 1630, 1 H NMR (300 MHz, CDCl 3) d 7.2 (m, 20 H), 4.1 (d, 2 H, J = 13.5 Hz), 3.65 (m, 1 H), 3.5 (d, 2H, J = 13.5 Hz), 3.1 (m, 2H), 2.8 (m, 1H), 2.65 (m, 3H), 1.55 (m, 1H), 1.30 (m, 1H), 13C NMR (300 MHz, CDCI3 ) d 140.8, 140.1, 138.2, 129.4, 129.4, 128.6, 128.4, 128.3, 128.2, 126.8, 126.3, 125.7, 72.0, 63.6, 54.9, 53.3, 46.2, 40.1, 30.2.

EXAMPLE 6 Alternative preparation of (2S.3S.5S) -5-amino-2- (dibenzylamino) -3-hydroxy-1,6-diphenyl-hexane To a solution of 2-amino-5-SN, N-dibenzylamino-4-oxo-1,6-diphenylhex-2-ene (30 g, 65 mmol), methanesulfonic acid (24 g, 248 mmol), ethanol (240 mL), and 4 grams of 5% platinum supported on Deloxan® AP II was pressurized at 70.3 kg / cm with hydrogen and stirred at 0-5 ° C for 15 hours followed by stirring at 23 ° C for 32 hours. The pressure was released and the catalyst was removed by filtration over celite. The filtrate was diluted with 1N sodium hydroxide (250 mL) and the product was extracted with ethyl acetate (300 mL). The organic components were washed with brine (100 mL) and concentrated in vacuo to provide the desired product. The foregoing is only illustrative of the invention and is not intended to limit the invention to the described embodiments. It is intended that the variations and changes that are apparent to those skilled in the art are within the scope and nature of the invention that are defined in the appended claims.

Claims (15)

1. A process for the preparation of the substantially pure compound of the formula: where R6 and R7 are independently selected from wherein 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, halogen and phenyl; Y wherein the naphthyl ring is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy and halogen; R6 and R7 taken together with the nitrogen atom to which they are attached are wherein Rf, Rg, Rh and Rj were independently selected from hydrogen, lower alkyl, alkoxy, halogen and trifluoromethyl; or an acid addition salt thereof, which comprises reacting an enaminoketone compound of the formula: wherein R6 and are as defined above with hydrogen gas in the presence of a hydrogenation catalyst and an acid.

2. The process of claim 1, wherein R6 and R7 are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy , halogen and phenyl.

3. The process of claim 1, wherein the reaction is carried out in a solvent comprising (1) a protic solvent or (2) an ether solvent.

4. The method of claim 1, wherein the catalyst is platinum.

5. The process of claim 1, wherein the acid is sulfuric acid or methanesulfonic acid.

6. A process for the preparation of the substantially pure compound of the formula: where R6 and R7 are independently selected from wherein 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, halogen and phenyl; Y wherein the naphthyl ring is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy and halogen; R6 and R7 taken together with the nitrogen atom to which they are attached are wherein Rf, Rg, Rh and Rj were independently selected from hydrogen, lower alkyl, alkoxy, halogen and trifluoromethyl; or an acid addition salt thereof, which comprises reacting an enaminoketone compound of the formula: wherein R6 and R are as defined above with hydrogen gas in the presence of a hydrogenation catalyst and from about 2 molar equivalents to about 4 molar equivalents (based on enaminoketone) of an acid.

The process of claim 6, wherein R6 and R7 are each substituted benzyl or benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from lower alkyl, trifluoromethyl, alkoxy , halogen and phenyl.

The method of claim 6, wherein the reaction is carried out in a solvent comprising (1) a protic solvent or (2) an ether solvent.

9. The process of claim 6, wherein the catalyst is platinum.

10. The process of claim 6, wherein the acid is sulfuric acid or methanesulfonic acid.

11. The process of claim 6 for the preparation of the substantially pure compound of the formula: where R6 and R are independently selected from wherein 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, halogen and phenyl; or an acid addition salt thereof, which comprises reacting an enaminoketone compound of the formula: wherein R6 and 7 are as defined above with hydrogen gas in the presence of a hydrogenation catalyst and from about 2 molar equivalents to about 4 molar equivalents (based on enaminoketone) of an acid.

The process of claim 11 for the preparation of the substantially pure compound of the formula: wherein R6 and R7 are each benzyl or an acid addition salt thereof, which comprises reacting an enaminoketone compound of the formula: wherein R6 and R7 are as defined above with hydrogen gas in the presence of a hydrogenation catalyst and from about 2 molar equivalents to about 4 molar equivalents (based on enaminoketone) of an acid.

13. A process for the preparation of the substantially pure compound of the formula: wherein R6 and R7 are each benzyl or an acid addition salt thereof, which comprises reacting an alcohol solution of the enaminoketone compound of the formula: wherein R6 and R7 are as defined above with hydrogen gas at a pressure from about 4,218 kg / cm to about 70.3 kg / cm in the presence of a platinum catalyst and from about 2 molar equivalents to about 4 molar equivalents (based on to the enaminoketone) or methanesulfonic acid.

The method of claim 13, wherein the alcohol is ethanol.

15. The process of claim 13, wherein the catalyst is platinum on carbon or platinum on aminopol isiloxane.