4-Methylmorpholine → (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(3-(pyrrolidin-1-yl)propyl)acetamide

HRID 77145

反応式

HRID 77145 の反応式
[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:5]

参加物

6

反応物 4

HCID 79724-MethylmorpholineHCID 316701-PyrrolidinepropanamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 674589572-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid

生成物 1

HCID 53496990(R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(3-(pyrrolidin-1-yl)propyl)acetamide収率 54.3%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

実験手順

(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), 1-(3-aminopropyl)pyrrolidine (11.89 mg, 0.093 mmol), and BOP (41.0 mg, 0.093 mmol). The reaction mixture was stirred overnight and was then concentrated. The resulting residue was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(3-(pyrrolidin-1-yl)propyl)acetamide (13.7 mg, 0.025 mmol, 53.5% yield): LCMS=542.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.28 Hz), 7.50-7.81 (7 H, m), 5.14 (1 H, s), 3.33-3.41 (2 H, m), 2.90 (4 H, br. s.), 2.78 (2 H, t, J=7.65 Hz), 1.74-2.01 (6 H, m); Analytical LC/MS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.2 min.

後処理

  1. concentrationwas then concentrated
  2. customThe resulting residue was purified via preparative LCMS with the following conditions
  3. waitGradient: 15-100% B over 25 minutes
  4. customa 5-minute hold
  5. additionFractions containing the desired product
  6. customdried via centrifugal evaporation

出典と根拠

ORDレコード
ord-08b61ac0dccb4652bad1b220a808a173
出典データセット
uspto-grants-2014_09
特許番号
US08835470B2

関連ノート

読み込み中…