Triethylamine → 5-(3-{(3R,4R)-1-tert-butoxycarbonyl-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-ureido)-indazole-1-carboxylic acid t-butyl ester

HRID 497461노트

반응식

HRID 497461 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([O:42][C:43]([N:45]1[C:53]2[C:48](=[CH:49][C:50]([NH:54][C:55](OC3C=CC=CC=3)=[O:56])=[CH:51][CH:52]=2)[CH:47]=[N:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(#N)C.C(OCC)(=O)C>[C:38]([O:42][C:43]([N:45]1[C:53]2[C:48](=[CH:49][C:50]([NH:54][C:55]([NH:14][C@@H:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]3[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:18]3)=[O:16])=[O:56])=[CH:51][CH:52]=2)[CH:47]=[N:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]

참가 물질

6

반응물 3

HCID 8471TriethylamineHCID 69747061HCID 69747061, 화합물HCID 69748878(3R,4R)-4-amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester

생성물 1

HCID 697487235-(3-{(3R,4R)-1-tert-butoxycarbonyl-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-ureido)-indazole-1-carboxylic acid t-butyl ester수율 61.2%

시약·촉매·용매 2

HCID 6342Acetonitrile용매HCID 8857Ethyl Acetate용매

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온도
60 °C

실험 절차

In a dry flask (3R,4R)-4-Amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (72 mg, 0.171 mmol) was dissolved in acetonitrile (2 mL) and triethylamine (25 μL, 0.179 mmol) and 5-(phenoxycarbonylamino)-1-indazolecarboxylic acid 1-tert-butyl ester (72 mg, 0.204 mmol) were added. The reaction mixture was stirred for 64 hours while heating to 60° C. The reaction mixture was cooled, diluted with ethyl acetate, washed twice with water and once with brine. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (71 mg, 61%). 1H NMR (300 MHz, CDCl3), δ: 8.09 (m, 2H), 7.90 (2s, 1H), 7.44 (m, 1H), 7.10 (m, 1H), 6.99 (m, 1H), 6.83 (m, 2H), 4.90 (bs, 1H), 4.43 (bd, 1H, J=11), 4.22 (bs, 2H), 3.98 (bm, 2H), 3.14 (t, 1H, J=13), 2.75 (bm, 4H), 2.45 (bm, 3H), 1.94 (bm, 3H), 1.73 (2s, 9H), 1.48 (m, 9H), 1.45 (bm, 3H), 1.22 (bm, 1H). HRMS (ESI), C36H48FN6O6 m+/z: calc.=679.3619, found=679.3621.

후처리

  1. temperatureThe reaction mixture was cooled
  2. washwashed twice with water and once with brine
  3. dry with materialThe organic layer was dried with magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid)

출처 및 근거

ORD 기록
ord-3d2925c7232742309d160a0482634c56
출처 데이터셋
uspto-grants-2005_09
특허 번호
US06949546B2

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