3-AMINO-3-METHYL-BUTYRIC ACID ETHYL ESTER HCL

A solution of ethyl 3-methylbut-2-enoate (1 g, 7.8 MMOL) in anhydrous ethanol (12 mL) was cooled to-20 °C and saturated with gaseous ammonia. The tube was sealed and kept at 90°C for 24 hours. The reaction was cooled to room temperature, bubbled with nitrogen to eliminate the residual ammonia and treated with a 4 N solution of HCI in dioxane (1. 9 mL). After 30 minute stirring, the mixture was evaporated under reduced pressure to give ethyl 3- amino-3-methylbutanoate hydrochloride as a grey solid (1.19 G, Y=84percent). 'H NMR (CI3/400 MHz) 5 ppm 1.2 (t, 3H), 1.26 (s, 6H), 2. 65 (s, 2H), 4.1 (q, 2H), 8.27 (BS, 3H).Example 5 Preparation of 6, 6-DIMETHYL-2, 4-DIOXOPIPERIDINE A solution of ethyl 3-METHYLBUT-2-ENOATE (1 g, 7.8 MMOL) in anhydrous ethanol (12 mL) was cooled to-20 °C and saturated with gaseous ammonia. The tube was sealed and kept at 90°C for 24 hours. The reaction was cooled to room temperature, bubbled with nitrogen to eliminate the residual ammonia and treated with a 4 N solution of HCI in dioxane (1.9 mL). After 30 minute stirring, the mixture was evaporated under reduced pressure to give ethyl 3- AMINO-3-METHYLBUTANOATE HYDROCHLORIDE as a grey solid (1.19 g, Y=84percent).EXAMPLE 7 INTERMEDIATE 49Ethyl 3-ammo-3-methylbutanoate hydrochloride; To a stirred solution of ethyl 3, 3-dimethylacrylate (5.0 g, 39.1 mmol) in EtOH (20 mL) in a Parr.(R). reactor at OINTERMEDIATE 1Ethyl 3-amino-3-methylbutanoate hydrochlorideTo a stirred solution of ethyl 3, 3-dimethylacrylate (5.0 g, 39.1 mmol) in EtOH (20 mL) in a ParrINTERMEDIATE 1Ethyl 3-amino-3-methylbutanoate hydrochlorideTo a stirred solution of ethyl 3, 3-dimethylacrylate (5.0 g, 39.1 mmol) in EtOH (20 mL) in a Parr.(R). reactor at OTo a stirred solution of ethyl 3, 3-dimethylacrylate (5.0 g, 39.1 mmol) in EtOH (20 mL) in a PARR.(R). reactor was added liquid NHStep II-I-a: Ethyl 3-amino-3-methylbutanoate hydrochloride salt (11-I-a)To a solution of ethyl 3-methylbut-2-enoate (15 g, 117 mmol) in EtOH (40 mL) was added liquid ammonia (80 mL) at -70° C. and the reaction mixture stirred in a autoclave (200 Psi) at 45° C. for 16 h. After completion of the reaction (monitored by TLC), excess ammonia was removed by flashing NStep 5-I-a: A solution of ethyl 3-methylbut-2-enoate (1 g, 7.8 MMOL) in anhydrous ethanol (12 mL) was cooled to-20 °C and saturated with gaseous ammonia. The tube was sealed and kept at 90°C for 24 hours. The reaction was cooled to room temperature, bubbled with nitrogen to eliminate the residual ammonia and treated with a 4 N solution of HCI in dioxane (1. 9 mL). After 30 minute stirring, the mixture was evaporated under reduced pressure to give ethyl 3- amino-3-methylbutanoate hydrochloride as a grey solid (1.19 G, Y=84percent). 'H NMR (CI3/400 MHz) 5 ppm 1.2 (t, 3H), 1.26 (s, 6H), 2. 65 (s, 2H), 4.1 (q, 2H), 8.27 (BS, 3H).Example 5 Preparation of 6, 6-DIMETHYL-2, 4-DIOXOPIPERIDINE A solution of ethyl 3-METHYLBUT-2-ENOATE (1 g, 7.8 MMOL) in anhydrous ethanol (12 mL) was cooled to-20 °C and saturated with gaseous ammonia. The tube was sealed and kept at 90°C for 24 hours. The reaction was cooled to room temperature, bubbled with nitrogen to eliminate the residual ammonia and treated with a 4 N solution of HCI in dioxane (1.9 mL). After 30 minute stirring, the mixture was evaporated under reduced pressure to give ethyl 3- AMINO-3-METHYLBUTANOATE HYDROCHLORIDE as a grey solid (1.19 g, Y=84percent).EXAMPLE 7 INTERMEDIATE 49Ethyl 3-ammo-3-methylbutanoate hydrochloride; To a stirred solution of ethyl 3, 3-dimethylacrylate (5.0 g, 39.1 mmol) in EtOH (20 mL) in a Parr.(R). reactor at OINTERMEDIATE 1Ethyl 3-amino-3-methylbutanoate hydrochlorideTo a stirred solution of ethyl 3, 3-dimethylacrylate (5.0 g, 39.1 mmol) in EtOH (20 mL) in a ParrINTERMEDIATE 1Ethyl 3-amino-3-methylbutanoate hydrochlorideTo a stirred solution of ethyl 3, 3-dimethylacrylate (5.0 g, 39.1 mmol) in EtOH (20 mL) in a Parr.(R). reactor at OTo a stirred solution of ethyl 3, 3-dimethylacrylate (5.0 g, 39.1 mmol) in EtOH (20 mL) in a PARR.(R). reactor was added liquid NHStep II-I-a: Ethyl 3-amino-3-methylbutanoate hydrochloride salt (11-I-a)To a solution of ethyl 3-methylbut-2-enoate (15 g, 117 mmol) in EtOH (40 mL) was added liquid ammonia (80 mL) at -70° C. and the reaction mixture stirred in a autoclave (200 Psi) at 45° C. for 16 h. After completion of the reaction (monitored by TLC), excess ammonia was removed by flashing NStep 5-I-a: Example 151 Synthesis of N-(6, 6-dimethyl-4-oxo-1, 4, 5, 6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide hydrochloride Ethyl-3-amino-3-methylbutanoate hydrochloride (0.20 g, 1.12 mmol) was dissolved in ethanol (20 mL) at room temperature. Piperidine cyanoguanidine (0.17 g, 1.12 mmol) was added thereto and stirred under reflux for 15 hours. The reaction mixture was concentrated under reduced pressure, and separated and purified using a chromatography in a condition where the ratio of methylene chloride to methyl alcohol was 9:1 and the target compound was obtained as a white solid (0.32 g, 10.0%). 1H NMR (600 MHz, CD3OD) delta3.16 (m, 4H), 2.51 (m, 2H), 1.58 (m, 6H), 1.29 (s, 6H) LCMS: 252.2 [M+H]+(3) Synthesis of the titled compound To a solution of To an acetonitrile (55 mL) suspension of the hydrochloride salt of ethyl 3-amino- 3-methylbutanoate (5.00 g, 27.5 mmol) was added potassium carbonate (3.80 g, 27.5 mmol, 1.0 equiv.), followed by 2-(chloromethyl)oxirane (4.31 mL, 55.0 mmol, 1.0 equiv.). After 60 hours, the reaction mixture was filtered and concentrated in vacuo. Chromatography over silica gel, eluting with methanol/ethyl acetate, afforded the title compound as a clear oil. LC/MS = 202 [M+l].General procedure: Liquid ammonia (5 ml) condensed ammonia gas was added to a stirred solution of ethyl 2-(oxan-4-ylidene)acetate (1 .0 g, 5.88 mmol) in ethanol (10 ml) in autoclave. The mixture was heated at 90C for 24 hours. Reaction was stopped and the autoclave cooled to -78C and the mixture was removed. The mixture was allowed to warm to RT and N2-gas was bubbled for 30 minutes into the reaction mixture to remove the excess of the ammonia gas. The reaction mixture was made acidic by purging HCI-gas at 0C and the solvent was removed under reduced pressure. The residue was washed with n- pentane and the compound was dried under reduced pressure. The yield of ethyl 2-(4-aminooxan-4-yl)acetate hydrochloride was 1 .1 g.To 4-bromo-2-methylbenzene-l-sulfonyl chloride (2.00 g, 7.42 mmol) in dichloromethane (40 mL) was added ethyl 3 -amino-3 -methylbutanoate hydrochloride (1.62 g, 8.92 mmol) and triethylamine (1.88 g, 18.6 mmol). The resulting solution was stirred for 4 h at ambient temperature, then concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/ petroleum ether: 1/1) to afford the title compound.To 4-bromo-2-methylbenzene-1-sulfonyl chloride (2.00 g, 7.42 mmol) indichloromethane (40 mL) was added (Step 1) Ethyl 3-(tert-butoxycarbonylamino)-3-methylbutanoate Ethyl 3-amino-3-methylbutanoate hydrochloride (10.5 g, 57.5 mmol) was dissolved in methylene chloride (100 mL). To the solution, triethylamine (8.19 mL, 5.95 g, 58.8 mmol) and di-tert-butyl dicarbonate (9.41 g, 43.1 mmol) were added, and the mixture was stirred at room temperature for 71.7 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Biotage Japan Ltd., eluting solvent: hexane/ethyl acetate = 98/2 to 50/50) to obtain the title compound (10.4 g, yield: 73.7%) as an oil substance. 1H-NMR (CDCl3) delta: 4.91 (1H, br s), 4.14 (2H, q, J = 7.1 Hz), 2.67 (2H, s), 1.43 (9H, s), 1.38 (6H, s), 1.26 (3H, t, J = 7.1 Hz).To a solution of Step 5 A mixture of 5-{[3-(1-bromopropyl)-6-chloro-2-fluorophenyl]carbonyl}pyridin-2-amine(300mg, 0.81 mmol), Step 5-I-b: Ethyl 3-(ethyl 2-carbamoylacetyl)-3-methylbutanoate (5-I-b) To a solution of compound 5-I-a (11 g, 68.9 mmol) in DCM (150 mL) was added TEA (38.1 mL, 275 mmol) and ethyl malonoyl chloride (8.8 mL, 68.9 mmol) at 0 C. The reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction was quenched water and extracted with DCM (2*200 mL). The combined organic layer was washed with 1N HCl (100 mL), saturated NaHCO3 (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford 5-I-b (11 g, 62%) as brown syrup. TLC: 30% EtOAc/Hexane (Rf: 0.3); 1H-NMR (CDCl3, 200 MHz): delta 4.28-4.07 (m, 4H), 3.24 (s, 2H), 2.74 (s, 2H), 1.45 (s, 6H), 1.35-1.20 (m, 6H); Mass: 260 [M++1].

Molecular Weight:181.66
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:181.0869564
Monoisotopic Mass:181.0869564
Topological Polar Surface Area:52.3
Heavy Atom Count:11
Complexity:121
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes