Tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate → Tert-butyl 4-(3-(4-(3,4-difluoro-2-(trifluoro-methyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate

HRID 58505

Reaktionsgleichung

Reaktionsgleichung von HRID 58505
Cl.[F:2][C:3]1[C:4]([C:26]([F:29])([F:28])[F:27])=[C:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:19]4[CH2:25][NH:24][CH2:23][C:20]=4[NH:21][N:22]=3)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9].Cl[C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:2][C:3]1[C:4]([C:26]([F:27])([F:28])[F:29])=[C:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:19]4[CH2:25][N:24]([C:31]([N:33]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]5)=[O:32])[CH2:23][C:20]=4[NH:21][N:22]=3)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9]

Komponenten

5

Edukt 2

HCID 11334154Tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylateHCID 118483352(4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) methanone hydrochloride salt

Produkt 1

HCID 118483472Tert-butyl 4-(3-(4-(3,4-difluoro-2-(trifluoro-methyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylateAusbeute 71,2 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 142844-(Dimethylamino)pyridineKatalysatorHCID 6344DichloromethaneLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

A solution of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) methanone hydrochloride salt (50 mg, 0.11 mmol), N,N,N-diisopropylethylamine (0.05 mL, 0.3 mmol) and DMAP (0.5 mg, 0.004 mmol) in anhydrous CH2Cl2 (1 mL) was cooled to 0° C. under an atmosphere of N2, treated with tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (30 mg, 0.12 mmol) and stirred at 0° C. for 1 h. The cooling bath was then removed and the reaction stirred at room temperature for a further 4 h. After this time, the mixture was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep gold column, 0% to 10% CH3OH in CH2Cl2) to provide tert-butyl 4-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate as a white solid (48 mg, 71%): 1H NMR (500 MHz, CDCl3) δ 10.76 (br s, 1H), 7.33 (dd, J=17.0, 9.0 Hz, 1H), 7.11 (dd, J=9.0, 4.0 Hz, 1H), 4.88-4.52 (m, 2H), 4.69 (br s, 2H), 4.62 (s, 2H), 3.49 (apparent t, J=4.5 Hz, 4H), 3.32 (apparent t, J=4.5 Hz, 4H), 3.25 (apparent t, J=12.5 Hz, 1H), 3.14-2.88 (m, 2H), 1.94 (d, J=12.5 Hz, 2H), 1.72-1.66 (m, 2H), 1.48 (s, 9H).

Aufarbeitung

  1. customThe cooling bath was then removed
  2. stirringthe reaction stirred at room temperature for a further 4 h
  3. customAfter this time, the mixture was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep gold column, 0% to 10% CH3OH in CH2Cl2)

Quellen und Nachweise

ORD-Eintrag
ord-46de99d459294938a40ea8502401c6d6
Quelldatensatz
uspto-grants-2016_09
Patentnummer
US09434727B2

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