Isopropanol → tert-Butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

HRID 2173047Notes

Reaction equation

[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:16][C:17]1[C:22]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:21]=2[C:20]([F:34])=[C:19](Cl)[N:18]=1.CC(O)C.CCN(C(C)C)C(C)C>CS(C)=O>[C:11]([O:10][C:9]([NH:8][C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][C:19]1[N:18]=[C:17]([Cl:16])[C:22]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:25][C:21]=2[C:20]=1[F:34])=[O:15])([CH3:12])([CH3:14])[CH3:13]

Participants

Conditions

Temperature: 78 °C

Procedure

To the 5-L RBF containing tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (STEP A) was added tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (400.0 g, 1.246 mol, 1 eq). To this mixture was added IPA (400 mL), DMSO (400 mL) and DIPEA (282 mL, 1.3 eq). The resulting pink slurry was heated up to 78° C. and was stirred for 34 hours. The mixture was then cooled to room temperature and was stirred over the weekend. HPLC analysis indicated the presence of 1.6% of the starting material, 4.63% of the des-Boc side product, 72.38% of the desired product, and 11.23% of an isomer. 1H NMR analysis indicated a ratio of 5.49 of the IPA/DMSO. Isopropanol (200 mL) was added to the mixture to adjust the ratio to 6. The slurry was heated up to 78° C. Water (1.6 L) was added over a period of 1 hour at a rate which kept the temperature of the mixture above 64° C. The mixture was then cooled to room temperature and was stirred overnight. The slurry was filtered the next morning through a fritted glass funnel. The filter cake was washed with IPA/water/DMSO (800 mL, 6:4:1) and IPA/water (2×800 mL, 3:2) to give the title compound, which was dried under high vacuum at 40-45° C. until a constant weight was obtained (299.27 g, 48% yield with a 96.6% purity). 1H NMR (300 MHz, CDCl3) δ ppm 1.80-1.30 (m, 26H), 4.04 (m, 1H), 4.21 (m, 1H), 4.64 (d, J=0.9 Hz, 1H), 4.85 (br, 1H), 6.08 (br, 1H).

Workup

temperatureThe mixture was then cooled to room temperature
stirringwas stirred over the weekend

Sources & evidence

ORD record: ord-cb769dfe6a534bbbbf18546dd2524b1d
Source dataset: uspto-grants-2015_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09056873B2

Reaction notes

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