(2S)-3-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[N-[N-(4-(piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl]-L-β-cyclohexyl alanine amide ##STR17##A. N-BOC-β-cyclohexylalanine (2.0 g.) and triethyl amine (1.03 ml) aredissolved together in THF (100 ml) and the solution cooled to -20° C. Isobutyl chloroformate (1.06 ml) is added and the solution stirred at -20° C. for about 30 minutes. A saturated solution of ammonia in methanol (20 ml) is added and the solution allowed to warm to room temperature and stirred at room temperature for about 18 hours. The solution is evaporated in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution is washed with water, 5% HCl, saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate, filtered and evaporated in vacuo to give N-BOC-β-cyclohexylalanine amide. to warm to room temperature stirred at room temperature for about 18 hours The solution is evaporated in vacuo the residue dissolved in ethyl acetate The ethyl acetate solution is washed with water, 5% HCl, saturated sodium bicarbonate solution, water, brine dried over sodium sulfate filtered evaporated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropanoic acid (5.0 g, 18 mmol) in tetrahydrofuran (50 mL) at 0° C. was added 1.0 M borane-THF complex in THF (55.3 mL, 55.3 mmol). After addition, the reaction mixture was stirred at room temperature for 3 hours, then cooled down with an ice-bath, and quenched by the slow addition of AcOH:MeOH (1:5, 40 mL). Then the mixture was warmed to room temperature for 2 hours. The THF volume was reduced by ½ and the product was partitioned between saturated aqueous NaHCO3 and DCM. The combined organic fractions were dried over Na2SO4 and concentrated under reduced pressure to give an oil residue which was used directly in the next reaction without further purification. LC-MS found: 168.1 (M−Boc)+. After addition cooled down with an ice-bath quenched by the slow addition of AcOH:MeOH (1:5, 40 mL) Then the mixture was warmed to room temperature for 2 hours the product was partitioned between saturated aqueous NaHCO3 and DCM The combined organic fractions were dried over Na2SO4 concentrated under reduced pressure to give an oil residue which was used directly in the next reaction without further purification

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropanoic acid (37 g, 0.136 mmol) in anhydrous THF (300 mL) cooled to −20° C. was added dropwise N-methylmorpholine (16.6 mL, 0.15 mmol), followed by isobutyl chloroformate (20 mL, 0.15 mmol) and the reaction mixture was stirred at −20° C. for 30 min. The mixture was warmed to 0° C., and an etheral solution of CH2N2 (0.8 mol) was added. Stirring was continued overnight at rt. Excess diazomethane was decomposed by addition of acetic acid. The mixture was diluted with ether, washed with brine, satd aq NaHCO3 and brine to give a solution of crude (S)-tert-butyl 1-cyclohexyl-4-diazo-3-oxobutan-2-ylcarbamate (48 g, 100%), which was used without isolation. The mixture was warmed to 0° C. Stirring was continued overnight at rt washed with brine

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropanoic acid (37 g, 0.136 mmol) in anhydrous THF (300 mL) cooled to −20° C. was added dropwise N-methylmorpholine (16.6 mL, 0.15 mmol), followed by isobutyl chloroformate (20 mL, 0.15 mmol) and the reaction mixture was stirred at −20° C. for 30 min. The mixture was warmed to 0° C., and an etheral solution of CH2N2 (0.8 mol) was added. Stirring was continued overnight at rt. Excess diazomethane was decomposed by addition of acetic acid. The mixture was diluted with ether, washed with brine, satd aq NaHCO3 and brine to give a solution of crude (S)-tert-butyl 1-cyclohexyl-4-diazo-3-oxobutan-2-ylcarbamate (48 g, 100%), which was used without isolation. The mixture was warmed to 0° C. Stirring was continued overnight at rt washed with brine

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]cyclohexanepropanoic acid (93 g., 343 mmole) in dry tetrahydrofuran (1 l.) was added a 20% molar excess of 1,1'-carbonyldiimidazole over a period of less than 10 minutes with very efficient stirring to keep the internal temperature below 30°. After stirring for 30 minutes, N,O-dimethylhydroxylamine hydrochloride (36.8 g., 377 mmole) was added, followed by triethylamine (38.2 g., 377 mmole). After stirring at room temperature for 4 hours, the reaction mixture was filtered and the resulting filtrate was concentrated in vacuo. The amber colored residue (100 g.) was dissolved in ether (900 ml.) and poured into 1N HCl (1 l.). The acidic aqueous phase was separated, further extracted with ether and the combined ethereal solutions were washed with water, saturated sodium bicarbonate, water, and brine, then dried (MgSO4) to give (S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-N-methoxy-N-methylcyclohexanepropanamide as a colorless oil. [α]D =-12.9° (c=1, methanol). TLC (silica gel; 1:1, ethyl acetate:hexanes) Rf =0.58. the internal temperature below 30° After stirring for 30 minutes After stirring at room temperature for 4 hours the reaction mixture was filtered the resulting filtrate was concentrated in vacuo The amber colored residue (100 g.) was dissolved in ether (900 ml.) poured into 1N HCl (1 l.) The acidic aqueous phase was separated further extracted with ether the combined ethereal solutions were washed with water, saturated sodium bicarbonate, water, and brine dried (MgSO4)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-BOC-b-cyclohexylalanine (2.0 g.) and triethyl amine (1.03 ml) are dissolved together in THF (100 ml) and the solution cooled to −20° C. Isobutyl chloroformate (1.06 ml) is added and the solution stirred at −20° C. for about 30 minutes. A saturated solution of ammonia in methanol (20 ml) is added and the solution allowed to warm to room temperature and stirred at room temperature for about 18 hours. The solution is evaporated in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution is washed with water, 5% HCl, saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate, filtered and evaporated in vacuo to give N-BOC-b-cyclohexylalanine amide. to warm to room temperature stirred at room temperature for about 18 hours The solution is evaporated in vacuo the residue dissolved in ethyl acetate The ethyl acetate solution is washed with water, 5% HCl, saturated sodium bicarbonate solution, water, brine dried over sodium sulfate filtered evaporated in vacuo

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-BOC-b-cyclohexylalanine (2.0 g.) and triethyl amine (1.03 ml) are dissolved together in THF (100 ml) and the solution cooled to −20° C. Isobutyl chloroformate (1.06 ml) is added and the solution stirred at −20° C. for about 30 minutes. A saturated solution of ammonia in methanol (20 ml) is added and the solution allowed to warm to room temperature and stirred at room temperature for about 18 hours. The solution is evaporated in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution is washed with water, 5% HCl, saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate, filtered and evaporated in vacuo to give N-BOC-b-cyclohexylalanine amide. to warm to room temperature stirred at room temperature for about 18 hours The solution is evaporated in vacuo the residue dissolved in ethyl acetate The ethyl acetate solution is washed with water, 5% HCl, saturated sodium bicarbonate solution, water, brine dried over sodium sulfate filtered evaporated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid (5 g, 19.4 mmol) in DMF (50 mL) at 0° C. was added cyclopentanol (8.8 ml, 97.15 mmol), EDC (4.09 g, 21.37 mmol) and finally DMAP (237 mg, 1.94 mmol). The reaction mixture was warmed to RT and stirred for 18 h. The DMF was removed in vacuo to give a clear oil. This was separated between water and EtOAc. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude extract was purified by column chromatography (25% EtOAC in heptane) to yield the desired product as a clear oil (14.87 g, 55%). 1H NMR (300 MHz, d6-DMSO) δ: 7.09 (1H, d), 5.08 (1H, t), 3.76 (1H, t), 1.50-1.85 (10H, br m), 1.39 (9H, s), 1.00-1.25 (9H, br m). The DMF was removed in vacuo to give a clear oil This was separated between water and EtOAc The organic phase was dried (MgSO4) concentrated in vacuo The crude extract was purified by column chromatography (25% EtOAC in heptane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid (5 g, 19.4 mmol) in DMF (50 mL) at 0° C. was added cyclopentanol (8.8 ml, 97.15 mmol), EDC (4.09 g, 21.37 mmol) and finally DMAP (237 mg, 1.94 mmol). The reaction mixture was warmed to RT and stirred for 18 h. The DMF was removed in vacuo to give a clear oil. This was separated between water and EtOAc. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude extract was purified by column chromatography (25% EtOAC in heptane) to yield the desired product as a clear oil (14.87 g, 55%). 1H NMR (300 MHz, d6-DMSO) δ: 7.09 (1H, d), 5.08 (1H, t), 3.76 (1H, t), 1.50-1.85 (10H, br m), 1.39 (9H, s), 1.00-1.25 (9H, br m). The DMF was removed in vacuo to give a clear oil This was separated between water and EtOAc The organic phase was dried (MgSO4) concentrated in vacuo The crude extract was purified by column chromatography (25% EtOAC in heptane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After preparing N-(6-methoxy-6-oxohexyl)-3-cyclohexyl-L-alaninamide monohydrochloride from the title product of Example 36 by the methods of Examples 1 and 3, the title compound was prepared by coupling this material with the title product of Example 99 using the general mixed anhydride procedure of Example 1. Structure assignment of the product isolated by chromotography was supported by elemental analysis. Structure assignment of the product isolated by chromotography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After preparing N-(6-methoxy-6-oxohexyl)-3-cyclohexyl-L-alaninamide monohydrochloride from the title product of Example 36 by the methods of Examples 1 and 3, the title compound was prepared by coupling this material with the title product of Example 99 using the general mixed anhydride procedure of Example 1. Structure assignment of the product isolated by chromotography was supported by elemental analysis. Structure assignment of the product isolated by chromotography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 30.0 g (0.11 mole) of t-butoxycarbonylphenylalanine in 750 ml of tetrahydrofuran was hydrogenated at 60° for 24 hours using 50 psi hydrogen gas and 5% rhodium on carbon. The mixture was filtered and the filtrate concentrated to give the title compound (30.7 g) as a colorless oil. The oil was used without further purification. Structure assignment was supported by the nmr spectrum (loss of aromatic protons and appearance of cyclohexyl protons). The mixture was filtered the filtrate concentrated