METHYL 3-METHYLAMINOCROTONATE

white crystalline powder

1.2 g Silicagel was added to 11.6 g (100 mmol, 1 eq.) methyl acetoacetate. To this, 9.25 g (120 mmol, 1.2 eq.) methylamine solution (aqueous; 40percent) was added and the mixture stirred overnight. The reaction mixture was extracted with DCM, dried with MgSOMethylamine solution in MeOH (45 g, 517 mmol, 37percentw/w) was added into compound I-la (30 g, 258.6 mmol) at rt, then the mixture was heated to 45 °C for 18 hrs. After being cooled to rt, the mixture was extracted with DCM (250 mLX3), the combined organic layer a washed with water, dried over NaGeneral procedure: 1195 mg (9.25 mmol 1 eq.) 1 and 1000 mg (9.25 mmol 1 eq.) 1, 4-benzoquinone is solved in 12 mL nitromethane. The mixture is left for 24 hrs (no stirring). Crystals of product precipitate. They were filtered, washed with nitromethane and recrystallized from EtOAc. Rf in PE+EtOAc 2+1: 0.2. Yellow solid, yield: 1300 mg, 64 %. Compound described in 2.1.2 g Silicagel was added to 11.6 g (100 mmol, 1 eq.) methyl acetoacetate. To this, 9.25 g (120 mmol, 1.2 eq.) methylamine solution (aqueous; 40%) was added and the mixture stirred overnight. The reaction mixture was extracted with DCM, dried with MgSO4, filtered and evaporated. Yellow oil, yield: 12.21 g, 95 %. H1-NMR: [CDCl3] delta = [ppm] 8.47 (s, NH, 1H), 4.47 (s, CH, 1H), 3.61 (s, OCH3, 3H), 2.91 (d, NHCH3, J = 5.22 Hz, 3H), 1.92 (s, CH3, 3H). Compound described in1.Methylamine solution in MeOH (45 g, 517 mmol, 37%w/w) was added into compound I-la (30 g, 258.6 mmol) at rt, then the mixture was heated to 45 C for 18 hrs. After being cooled to rt, the mixture was extracted with DCM (250 mLX3), the combined organic layer a washed with water, dried over Na2S04, and concentrated in vacuo to give compound I-2a (29 g, yield 88%).Synthesis of 5-(4-{4-[l-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl- isoxazol-5-yl}-phenyl)-pent-4-ynoic acid (Compound 1-1); Step 1: 3-Methylamino-but-2-enoic acid methyl ester; [00438] To a solution of methyl acetoacetate (29.4g, 253mmol) in MeOH (3OmL) was added methylamine (33 wt% in EtOH; 48mL, 385mmol) dropwise at room temperature. The reaction was stirred for 1 hour, and then concentrated and dried to give the title compound as a white crystalline solid.Step 1: 3-Methylamino-but-2-enoic acid methyl esterTo a solution of methyl acetoacetate (29.4 g, 253 mmol) in methanol (30 mL) was added methylamine (33 wt % in EtOH; 48 mL, 385 mmol) dropwise at room temperature. The reaction was stirred for 1 hour, and then concentrated and dried to give the title compound as a white crystalline solid.To a solution of methyl acetoacetate (29.4g, 253mmol) in MeOH (3OmL) was added methylamine (33 wt% in EtOH; 48mL, 385mmol) dropwise at room temperature. The reaction was stirred for 1 hour, and then concentrated and dried to give the title compound as a white crystalline solid.Step 1: 3-Methylamino-but-2-enoic acid methyl ester To a solution of methyl acetoacetate (29.4 g, 253 mmol) in MeOH (30 mL) was added methylamine (33 wt % in EtOH; 48 mL, 385 mmol) dropwise at room temperature. The reaction was stirred for 1 hour, and then concentrated and dried to give the title compound as a white crystalline solid.Step 1: 3-Methylamino-but-2-enoic acid methyl ester To a solution of methyl acetoacetate (29.4 g, 253 mmol) in MeOH (30 mL) was added methylamine (33% w/w in EtOH, 48 mL, 385 mmol) dropwise at room temperature. The reaction was stirred for 1 hour then concentrated and dried to give the title compound as a white crystalline solid.Synthesis of 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acidStep 1: 3-Methylamino-but-2-enoic acid methyl ester [00473] To a solution of methyl acetoacetate (29.4g, 253mmol) in Methanol (30mL) was added methylamine (33 wt% in EtOH; 48mL, 385mmol) dropwise at room temperature. The reaction was stirred for 1 hour, and then concentrated and dried to give the title compound as a white crystalline solid.To a mixture of methyl acetoacetate (23.2 g, 0.2 mol) in water (15 mL) at 10 C was added dropwise methylamine (40% aqueous solution, 18.6 g, 0.24 mol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting solid precipitate was collected by filtration and washed with ice water (2x), and then dried in a vacuum oven at 55 C overnight to provide the title compound as a white solid (20.9 g). lH NMR (CDCI3): delta 8.45 (br s, 1H, NH), 4.47 (s, 1H), 3.62 (s, 3H), 2.91 (d, 3H), 1.92 (s, 3H).Synthesis of l-{4'-[3-Methyl-4-((R)-l-phenyl-ethoxycarbonylamino)-isoxazol-5-yll- biphenyl-4-v -cvclopropanecarboxylic acid (Compound 1)[00498] Step 1: 3-Methylamino-but-2-enoic acid methyl ester: To a solution of methyl acetoacetate (29.4g, 253mmol) in MeOH (30mL) was added methylamine (33 wt% in EtOH; 48mL, 385mmol) dropwise at room temperature. The reaction was stirred for 1 hour, and then concentrated and dried to give the title compound as a white crystalline solid.Example 1Synthesis of 1-[4'-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester Step 1: 3-Methylamino-but-2-enoic acid methyl esterTo a solution of methyl acetoacetate (29.4 g, 253 mmol) in MeOH (30 mL) was added methylamine (33 wt % in EtOH; 48 mL, 385 mmol) dropwise at room temperature. The reaction was stirred for 1 hour, and then concentrated and dried to give the title compound as a white crystalline solid.General procedure: A mixture of a N-hydroxybenzimidoyl chloride 1 (0.22 mmol) and an enamino carbonyl compound 2 (0.2 mmol) was added to a stainless-steel jar (5 mL, 12 mm x 50 mm, 61.556 g) containing two stainless-steel balls (2 x 0.519 g, 5 mm in diameter). The mass ratio of the reaction mixture to balls were from 1:12.5 to 1:15.8. The same mixture was also added to a second parallel jar. The two reaction vessels were vibrated in Spex SamplePrep 8000 mixer mill at a frequency of 875 cycles per minute at room temperature for 20-60 min. The combined reaction mixtures from two vessels were collected and dissolved in ethyl acetate. The solution was filtrated to remove the residue and then evaporated to dryness under reduced pressure. Finally, the resulting product 3 was purified by column chromatography over silica gel using ethyl acetate/petroleum ether as the eluent. 4.2.1. Methyl 3-(4-chlorophenyl)-5-methylisoxazole-4-carboxylate (3a) Yield 86% (86.7'mg). 1H NMR (400'MHz, CDCl3) delta 7.58 (d, J?=?8.5'Hz, 2H), 7.42 (d, J?=?8.5'Hz, 2H), 3.79 (s, 3H), 2.73 (s, 3H); 13C NMR (100'MHz, CDCl3) delta 176.2, 162.3, 161.7, 136.1, 130.7, 128.4, 126.9, 108.2, 51.7, 13.7; HRMS (EI-TOF) m/z [M]+ calcd for C12H1035ClNO3, 251.0349; found, 251.0346.General procedure: The following procedure for the synthesis of methyl 3-amino-2-((E)-2-nitrovinyl)but-2-enoate (6a) is representative. Methyl 3-aminobut-2-enoate (1a, 1.15g, 10mmol) and nitroacetaldehyde potassium salt (2, 1.53g, 12mmol) in a mixture of dry methanol (3.00mL), 17 glacial acetic acid (3.00mL) were stirred at rt under argon atmosphere for 24h, after which the precipitate was filtered off giving 6a (1.66g, 89%) as a yellow powderGeneral procedure: To a vigorously stirred solution of N-(chlorosulfonyl)trichloroacetimidoyl chloride 15a (2.80 g, 10.0 mmol) in dichloromethane (250 mL) a solution of respective enamine 23 (10 mmol) in dichloromethane (50 mL) was added dropwise within 1 h. A solution of i-Pr2NEt (2.84 g, 22.0 mmol) in dichloromethane (50 mL) was added dropwise within 2 h and the resulting mixture was left overnight. The volatiles were evaporated at reduced pressure. The residue was triturated with 5% HCl (30 mL), the resulting solid was washed with water (4 × 50 mL) and isolated by filtrationMethyl 3-(methylamino)but-2-enoate 12 (15 mg, 0.1 mmol) was added to a solution of imine 7a (20 mg, 0.1 mmol) in ether (2 mL). After 30 min the solvent was removed in vacuo, the residue triturated with petroleum ether. Yield 71%. 1H NMR (DMSO-d6): delta = 1.15 (t, 3JHH = 7 Hz, 6H, CH3), 2.19 (s, 3H, =CCH3), 2.95 (d, 3JHH = 5 Hz, 3H, NHCH3), 3.21 (q, 3JHH = 7 Hz, 2H, CH2), 3.31 (q, 3JHH = 7 Hz, 2H, CH2), 3.72 (s, 3H, OCH3), 5.61 (dq, 3JHH ' 3JHF ' 9 Hz, 1H, CH), 6.18 (d, 3JHH = 9.5 Hz, 1H, NHCO), 9.76 (br, 1H, NHMe). 19F NMR (DMSO-d6): delta = -75.2. 13C NMR (CDCl3): delta = 13.33 (CH3-CH2), 15.00 (CH3C=), 29.98 (CH3N), 40.99 (CH2N), 49.91 (CH3O), 50.23 (q, 2JCF = 33 Hz, CHCF3), 85.11 (=CCH), 125.48 (q, 1JCF = 283 Hz, CF3), 155.96 (NHC=O), 164.97 (=C-NH), 169.51 (COO). Anal. calc. for C13H22F3N3O3: C, 47.99; H, 6.82; N, 12.92. Found: C, 48.34; H, 6.49; N, 12.62.

Molecular Weight:129.16
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:129.078978594
Monoisotopic Mass:129.078978594
Topological Polar Surface Area:38.3
Heavy Atom Count:9
Complexity:129
Undefined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes