Methylamine → (2R)-4-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-N-methylmorpholine-2-carboxamide

HRID 1435521노트

반응식

HRID 1435521 반응식
[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH:28]([C:32]([OH:34])=O)[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:35]([N:38](CC)C(C)C)(C)C.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][C@@H:28]([C:32]([NH:38][CH3:35])=[O:34])[CH2:27]3)(=[O:24])=[O:25])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]

참가 물질

6

반응물 4

HCID 6329MethylamineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 579373664-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)morpholine-2-carboxylic acid

생성물 1

HCID 57937334(2R)-4-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-N-methylmorpholine-2-carboxamide수율 78%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

실험 절차

Following the same procedure in Example 112, Step A, using 4-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)morpholine-2-carboxylic acid (500 mg, 1 mmol), N,N-diisopropylethylamine (1 mL, 5 mmol), methylamine (0.75 mL, 2.0M in THF, 1.5 mmol) and HATU (456 mg, 1.2 mmol) in DMF (10 mL). The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 400 mg (78% yield) as white solid racemic mixture of the title compound. The two enantiomers were separated on a chiral OD 5 microns column using 20% ethanol:hexane. [α]D: +37.4 (c=1.00, MeOH). 1H NMR (400 MHz, METHANOL-D4) δ 1.37-1.46 (m, 2 H), 1.48 (s, 9 H), 1.53-1.73 (m, 4 H), 1.88-2.01 (m, 2 H), 2.04-2.18 (m, 2 H), 2.29 (m, 1 H), 2.59 (s, 3 H), 3.43-3.49 (m, 1 H), 3.59 (m, 1 H), 3.77-3.85 (m, 1 H), 3.87-3.96 (m, 2 H), 4.30 (d, J=7.62 Hz, 2 H), 7.54 (dd, J=8.69, 1.66 Hz, 1 H), 7.67 (d, J=8.59 Hz, 1 H), 7.93 (d, J=1.76 Hz, 1 H); MS (APPI) (M+H)+=513.3; Anal. Calc. for C24H34F2N4O4S+1.5 TFA: C, 47.44; H, 5.23; N, 8.20. Found: C, 47.54; H, 4.91; N, 8.00.

후처리

  1. customThe crude product was purified by LCMS
  2. customto give 400 mg (78% yield)

출처 및 근거

ORD 기록
ord-5f57cfbeff164ac9bcf53a8b8c38867b
출처 데이터셋
uspto-grants-2009_11
특허 번호
US07615642B2

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