Diisopropylethylamine → 1-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)thiourea

HRID 868895Notes

Reaction equation

HRID 868895 reaction equation
C([C@@H](O)[C@H](O)C([O-])=O)(O)=O.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C@H:16]([NH3+:26])[CH2:17][C:18]([CH2:24][F:25])([CH2:22][F:23])[O:19]2)=[CH:14][CH:13]=1.[N:27]([C:30]1[CH:39]=[C:38]2[C:33]([CH2:34][CH2:35][C:36](=[O:40])[NH:37]2)=[CH:32][CH:31]=1)=[C:28]=[S:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C@H:16]([NH:26][C:28]([NH:27][C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][C:36](=[O:40])[NH:37]4)=[CH:32][CH:31]=3)=[S:29])[CH2:17][C:18]([CH2:24][F:25])([CH2:22][F:23])[O:19]2)=[CH:14][CH:13]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 157190197-isothiocyanato-3,4-dihydroquinolin-2(1H)-oneHCID 86689141(R)-7-chloro-2,2-bis(fluoromethyl)chroman-4-aminium (2S,3S)-3-carboxy-2,3-dihydroxypropanoate

Product 1

HCID 866891401-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-3-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)thioureaYield 78.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a slurry of (R)-7-chloro-2,2-bis(fluoromethyl)chroman-4-aminium (2S,3S)-3-carboxy-2,3-dihydroxypropanoate (0.20 g, 0.51 mmol) in CH2Cl2 (1.3 mL) was added the product of Example 252A (0.10 g, 0.51 mmol) and diisopropylethyl amine (0.088 mL, 0.51 mmol). The mixture was stirred at ambient temperature overnight then placed directly onto a silica gel column. Elution with a 20-60% EtOAc/hexane gradient afforded the title compound (0.18 g, 76% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.12 (s, 1H), 9.63 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.03 (dd, J=8.3, 2.1 Hz, 1H), 6.99-6.92 (m, 2H), 6.90 (d, J=1.9 Hz, 1H), 5.84-5.73 (m, 1H), 4.77-4.62 (m, 2H), 4.58-4.50 (m, 2H), 2.83 (dd, J=8.4, 6.6 Hz, 2H), 2.43 (dd, J=8.4, 6.7 Hz, 2H), 2.34 (dd, J=13.5, 5.8 Hz, 1H), 2.12-2.00 (m, 1H); MS (ESI) m/z: 451.9 (M+H)+.

Workup

  1. washElution with a 20-60% EtOAc/hexane

Sources & evidence

ORD record
ord-f3ef5d53c1f94351a6b3e34edd952ca0
Source dataset
uspto-grants-2015_03
Patent number
US08969325B2

Reaction notes

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