Diisopropylethylamine → N-(2-tert-butoxycarbonylamino-5-trifluoromethyl-phenyl)-malonamic acid benzyl ester

HRID 1591724Notes

Reaction equation

[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:29]([O:36][C:37](=[O:42])[CH2:38][C:39](O)=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:29]([O:36][C:37](=[O:42])[CH2:38][C:39]([NH:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1

Participants

Conditions

Temperature: 0 °C

Procedure

(2-Amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (570 mg) was dissolved in CH2Cl2 (15 ml) and DMF (5 ml) prior to the addition of DIEA (2.3 ml) and malonic acid monobenzyl ester (400 mg). After cooling to 0° C., HATU (940 mg) was added. The resulting mixture was warmed to rt and stirred overnight before being concentrated. Flash chromatography of the resulting residue gave N-(2-tert-butoxycarbonylamino-5-trifluoromethyl-phenyl)-malonamic acid benzyl ester (570 mg), MS found: (M−H)−=451.2. (20b) The above derivative (20a) (860 mg) was dissolved in THF (9.5 ml) prior to the addition of HOAc (28.5 ml). The resulting solution was heated in an oil bath at 65° C. for 3 h. After cooling, the solution was concentrated. Flash chromatography of the resulting residue gave (5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid benzyl ester (343.3 mg). MS found: (M+H)+=335.2. (20c) A portion (142 mg) of the above derivative (20b) was dissolved in THF (1 ml) prior to the addition of a solution of LiOH (10 mg) in H2O (1 ml) and several drops of MeOH. After stirring at rt for 0.5 h, the reaction was concentrated. The resulting residue was dissolved in water and this was extracted with EtOAc to remove BnOH. The water layer was freeze-dried to give (5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid lithium salt. 1H NMR (CD3OD, δ ppm, 300 mHz) 3.3 (s, 2H), 7.43 (d, 1H), 7.61 (d, 1H), 7.79 (s, 1H). (20d) (±)(1S*,2R*,4R*)—N4-Isopropyl-N4-methyl-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexane-1,4-diamine TFA salt, from example (19g), (34 mg) was dissolved in DMF (2 ml) prior to the addition of DIEA (61 μl) and example (20c) (19 mg). After cooling to 0° C., HATU (53 mg) was added. The resulting mixture was warmed to rt and stirred overnight before being concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (15 mg). MS found: (M+H)+=597.3

Workup

temperatureThe resulting mixture was warmed to rt
concentrationbefore being concentrated

Sources & evidence

ORD record: ord-0a6001f6292549e88358d06f4f2695d7
Source dataset: uspto-grants-2007_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07291615B2

Reaction notes

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