Tetrahydrofuran → 2-chloro-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino) pyrimidine-5-carboxamide

HRID 2201981Notes

Reaction equation

Cl.[NH2:2][C@H:3]1[CH2:8][C@@H:7]([OH:9])[C@H:6]([CH3:10])[CH2:5][CH2:4]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([C:19]([NH2:21])=[O:20])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>O>[Cl:11][C:12]1[N:17]=[C:16]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@@H:6]([CH3:10])[C@H:7]([OH:9])[CH2:8]2)[C:15]([C:19]([NH2:21])=[O:20])=[CH:14][N:13]=1

Participants

Conditions

Temperature: 0 °C

Procedure

To a reactor was added (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (16.0 kg), 2,4-dichloropyrimidine-5-carboxamide (19.0 kg), K2CO3 (14.9 kg) and THF (160 L) at 25° C. The batch was cooled to 0° C., and water (160 L) was added. The batch was stirred for an additional 1 h at 0° C., warmed to 25° C. and held for 16 h. Water (288 L) was added to the batch while keeping the batch at 25° C., and the batch was cooled to 15° C. and agitated for an additional 4 hs. The batch was filtered, rinsed twice with water (2×80 L), and dried in a vacuum oven at 40° C. with nitrogen bleed for 24 h to give 2-chloro-4-{[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide as white powder (23.3 kg, 86% yield). 1H NMR (DMSO-d6) δ 0.93 (d, J=5.7 Hz, 3H), 0.97-1.29 (m, 4H), 1.63-1.68 (m, 1H), 1.75-1.88 (m, 1H), 2.09-2.13 (m, 1H), 3.00-3.08 (m, 1H), 3.80-3.95 (m, 1H), 4.65 (d, J=5.1 Hz, 1H), 7.69 (br. s., 1H), 8.20 (br. s., 1H), 8.53 (s, 1H), 9.22 (d, J=7.5 Hz, 1H).

Workup

temperaturewarmed to 25° C.
waitheld for 16 h
customat 25° C.
temperaturethe batch was cooled to 15° C.
stirringagitated for an additional 4 hs
filtrationThe batch was filtered
washrinsed twice with water (2×80 L)
customdried in a vacuum oven at 40° C. with nitrogen
waitbleed for 24 h

Sources & evidence

ORD record: ord-dd33c63cc5734528b70671b6fae2a15c
Source dataset: uspto-grants-2016_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09365524B2

Reaction notes

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