N-(Methoxycarbonyl)-3-methyl-L-valine

Step 1: Synthesis of (S)-2-(methoxycarbonylaniino)-3, 3-dimethylb tanoic acid:A stirred solution of (S)-2-amino-3, 3-dimethylbutanoic acid (about 5.0 g, 38. 16 mmol) in Dioxane (about 20 ml) and sodium hydroxide (2N, 62 ml, Pmethyl (1S)-1-( (12- [ (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyl]-2- [4- (2- pyridinyl) benzyl] hydrazino} carbonyl)-2, 2-dimethylpropylcarbamate; Example 1A; (2S)-2-[(methoxycarbonyl) amino] -3, 3-dimethylbutanoic acid; (L)-tert-Leucine (10 g, 0.076 mol) was dissolved in 1, 4-dioxane (40 mL) and treated with 2M NaOH (125 mL, 3.2 equivalents) followed by dropwise addition of methyl chlorofonnate (11.2 mL, 1.9 equivalents) at 25°C. The mixture was heated at 60°C for 22 hrs, cooled, and extracted twice with dichloromethane. The aqueous layer was separated, cooled in ice bath, and acidified with 4N HC1 (60 mL). The mixture was extracted three times with ethyl acetate, and the organic layer was separated, dried with sodium sulfate, filtered, and the solvents were evaporated to give 14.1 g (98percent) of the title compound A 15percent by weight sodium hydroxide aqueous solution was added to the aqueous solution (72.4 g) containing L-tert-leucine (13.2 g, 0.10 mol), to adjust the pH to 13.0. Then, methyl chloroformate (9.52 g, 0.10 mol, 1.00 equivalent) was slowly added thereto with maintaining the temperature of the mixture below 25°C. At the time, the pH was decreased by adding methyl chloroformate; however, the pH of the solution was maintained at 10.0-12.8 by simultaneously adding a 15percent by weight of sodium hydroxide aqueous solution. After the addition of methyl chloroformate, the mixture was stirred for 2 hours. Then, the yield and quality were analyzed by HPLC. Yield: 98percent, Reaction selectivity: 100percentA solution of L-tert-Leucine (25 g, 190.58 mmol) in a mixture of dioxane (100 mL) and aqueous NaOH solution (315 mL, 2N) was treated dropwise with methyl chloroformate (29.3 mL, 379.19 mmol), keeping the internal temperature below 50° C. The mixture was warmed to 60° C. and stirred for 18 hours, cooled to 25° C. and extracted with dichloromethane. The aqueous phase was cooled to 0° C. and the pH was adjusted to about 1-2 with concentrated HCl. The mixture was partitioned between ethyl acetate and water. The combined organic extracts were washed with brine, dried over MgSOEXAMPLE 1F 2-Methoxycarbonylamino-3, 3-dimethyl-butyric acid (3) (0136) Into a 250 mL flask was placed L-tert-Leucine (5.0 gm, 38 mmol), 2N NaOH (66 mL), and methyl chloroformate (5.86 mL, 76 mmol, 2.0 equivalents). The reaction mixture was heated to 60° C., turning light-yellow. After approximately 20 hours, the heat was removed and the mixture cooled to room temperature, and then to 0° C. The reaction mixture was quenched at 0° C. with 2 N HCl (40 mL) to pH 1. The acidified mixture was transferred to a separatory funnel and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×150 mL), and saturated NaCl (150 mL), and then dried over NaCompound 1; L-tert-leucine (12.251 g, 93.4 mmol) was dissolved in a mixture of NaOH (2N, 154 mL) and dioxane (50.5 mL). Methyl chloroformate (14.30 mL, 185.84 mmol) was added slowly (e.g., dropwise) to the solution at room temperature (r.t.). The resulting reaction mixture was heated to 60General procedure: NaGeneral procedure: A suspended mixture of N-substituted amino acid (2.2 equiv)and hydroxybenzotriazole monohydrate (HOBt*H2O, 2.2 equiv) inDMF was stirred at room temperature for 10 min. Then, EDC (2.2equiv) was added and the clear solution was continuously stirredfor 30 min. To the former solution, compound 6 (1 equiv) wasadded. The resulting mixture was stirred at room temperatureovernight and then partitioned between ethyl acetate and water.The organic layer was dried over MgSO4, filtered, and concentrated.The residue was purified by column chromatography (methanol:CH2Cl2 1: 20) to afford the desired product.: Preparation of atazanavir using 1 equivalent of compound (II), 3.5 equivalents of compound (III), 3.5 equivalents of DIC, and 6.6 equivalents of NMM97.5 g of 1 -[4-(piridyn-2-yl)phenyl-4(S)-hydroxy]-5-(S)-2, 5-diamino-6-phenyl- 2-azahexane trihydrochloride (trihydrochloride of compound (II) with a 10%wt content of isopropanol, 185.97mmol) were suspended into 683 ml of dichloromethane under nitrogen atmosphere at -10 0C. 135 ml_ (1227.40 mmol) of /V-methylmorpholine were added maintaining the temperature at -10 0C.Separately, 100.8 ml_ (650.90 mmol) of N, N-diisopropylcarbodiimide were added to a suspension of 123.2 g (650.90 mmol) of N-(methoxycarbonyl)-L- tert-leucine (compound (III)) into 975 ml of dichloromethane.Then, the first suspension was quickly transferred over the second one. The resulting mixture was warmed up to room temperature and was maintained at such temperature until the reaction was completed (93% atazanavir by HPLC, monoimpurity content: 1.2%). The reaction mixture was filtered off and was washed with 800 ml_ of water. Then, the organic phase was concentrated up to half volume and 500 ml_ of tert-butylmethylether were added. The mixture was concentrated again up to half volume. This operation was repeated three times up to a dichloromethane content equal or less to 20%. The precipitated product was recovered by filtration. 125.4 g of atazanavir were obtained (Yield =96%). Purity by High Performance Liquid Chromatography (HPLC) = 98.2%, with 4% of N, N-diisopropylurea (DIU) and free of the other probable diastereomers. Molar yield =92%. Recrystallization in ethanol/water 45:55 yielded 105.34 g of atazanavir (149.5 mmol). Recrystallization yield: 84%. Purity HPLC = 99.4%, free of DIU, and free of the other probable diastereomers.The formula of the three probable diastereomers and the HPLC conditions to detect their presence are included below:d-ld-ll d-lHPLC conditions:Liquid chromatograph with UV detector equipped with automatic injector, and integration systemColumn: ZORBAX Eclipse XDB-C18 150x4.6 mm, 5mum.Mobile phase: A (0.05% formic acid in water) and B (ACN)Gradient elution:Detection: 254 nmFlow: 1 mL/minColumn temperature: 25 0CInjection: 2 muLTime injection and chromatogram: 20 minRelative retention time of the diastereomers (RRT):

Molecular Weight:189.21
XLogP3:1.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:189.10010796
Monoisotopic Mass:189.10010796
Topological Polar Surface Area:75.6
Heavy Atom Count:13
Complexity:207
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes