1-(4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine → tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-6-methoxy-1,4-diazepane-1-carboxylate

HRID 1915891노트

반응식

HRID 1915891 반응식
[N+](C1C=NNC=1N1CC=C(O[Si](C)(C)C)CC1)([O-])=O.[CH3:20][O:21][CH:22]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][N:24]([C:36]2[N:40]([CH3:41])[N:39]=[CH:38][C:37]=2[N+:42]([O-])=O)[CH2:23]1>CO.[Pd]>[NH2:42][C:37]1[CH:38]=[N:39][N:40]([CH3:41])[C:36]=1[N:24]1[CH2:23][CH:22]([O:21][CH3:20])[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:26][CH2:25]1

참가 물질

5

반응물 2

HCID 866800961-(4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridineHCID 86680097tert-butyl 6-methoxy-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate

생성물 1

HCID 86680095tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-6-methoxy-1,4-diazepane-1-carboxylate수율 96%

시약·촉매·용매 2

HCID 23938Palladium촉매HCID 887Methanol용매

실험 절차

A solution of Intermediate 47, tert-butyl 6-methoxy-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (114 mg, 0.32 mmol) in MeOH (15 mL) was passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-6-methoxy-1,4-diazepane-1-carboxylate as a pink solid (100 mg). To a solution of this solid in DCM (5 mL) was added DIPEA (0.84 mL, 48 mmol), PyBOP (219 mg, 0.42 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (118 mg, 0.33 mmol) and the mixture was stirred at room temperature for 65 hr. The mixture was diluted with DCM (50 mL) and washed with water (10 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave tert-butyl 4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6-methoxy-1,4-diazepane-1-carboxylate as a pink solid (160 mg). This solid (159 mg, 0.24 mmol) was dissolved in HCl in 1,4-dioxane (4 M, 3 mL, 12.0 mmol) and MeOH (3 mL) and heated in a sealed pressure vessel behind a blast shield at 60° C. for 16 hr. The solvents were removed under reduced pressure and the crude residue re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 0-10% 7 N ammonia in MeOH/DCM to give 194 as a pale brown solid (53 mg, 36% over three steps). 1H NMR (400 MHz, CDCl3) δ 11.35 (s, 1H), 8.13 (s, 1H), 7.39-7.29 (m, 1H), 7.04 (t, J=8.6 Hz, 2H), 6.33 (s, 2H), 3.74 (s, 3H), 3.41-3.28 (m, 4H), 3.36-3.00 (m, 6H), 2.88-2.77 (m, 1H), 2.69 (dd, J=12.7, 7.6 Hz, 1H). Alkyl NH not observed. LCMS (ES+) m/z 464 (M+1).

후처리

  1. customThe solvent was removed under reduced pressure

출처 및 근거

ORD 기록
ord-79ac9b2455f0413697452ad0499264f2
출처 데이터셋
uspto-grants-2013_12
특허 번호
US08614206B2

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