Tert-butyl cis-(3-carbamoylcyclohexyl)carbamate → tert-butyl N-[(1R,3S)-3-[[4-(5,5-dimethyl-4,6-dihydropyrrolo[2,1-e]pyrazol-3-yl)-5-fluoro-2-pyridinyl]carbamoyl]cyclohexyl]carbamate

HRID 567

Reaction equation

HRID 567 reaction equation
CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](C(N)=O)C1.CC1(C)Cc2c(-c3cc(Cl)ncc3F)cnn2C1>C1COCCO1.CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21.O=C([O-])[O-].[Cs+].[Cs+].[Pd].c1ccc(P(c2ccccc2)c2ccccc2)cc1.c1ccc(P(c2ccccc2)c2ccccc2)cc1.c1ccc(P(c2ccccc2)c2ccccc2)cc1.c1ccc(P(c2ccccc2)c2ccccc2)cc1>CC1(C)Cc2c(-c3cc(NC(=O)[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)ncc3F)cnn2C1

Participants

7

Reactant 2

HCID 71279992Tert-butyl cis-(3-carbamoylcyclohexyl)carbamateHCID 1241553193-(2-Chloro-5-fluoro-4-pyridinyl)-5,5-dimethyl-4,6-dihydropyrrolo[2,1-e]pyrazole

Product 1

HCID 124164051tert-butyl N-[(1R,3S)-3-[[4-(5,5-dimethyl-4,6-dihydropyrrolo[2,1-e]pyrazol-3-yl)-5-fluoro-2-pyridinyl]carbamoyl]cyclohexyl]carbamateYield 35.11%

Reagents, catalysts & solvents 4

HCID 10796Cesium carbonateReagentHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

Tetrakis(triphenylphosphine)palladium(0) (56.5 mg, 0.05 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (130 mg, 0.49 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (119 mg, 0.49 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (56.6 mg, 0.10 mmol) and Cesium carbonate (478 mg, 1.47 mmol) in 1,4-dioxane (5.98 ml). Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 °C for 2 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and DCM (40ml) and separated using a phase separation cartridge. The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate (81 mg, 35.1 %) as a pale yellow solid.

Sources & evidence

ORD record
ord-8563d32d81ef4e67b37807469f34e85c
Source dataset
750 AstraZeneca ELN dataset
Original link
View source

Linked notes

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