Hydrochloric Acid → HCID 178516170, compound

HRID 2192952Notes

Reaction equation

[CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:32]\[C@H:33]3[CH2:53][CH2:52][C:35]4(O[C@H](C5C=CC=CC=5)[C@@H](C5C=CC=CC=5)[O:36]4)[CH2:34]3)/[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22](C(OC(C)(C)C)=O)[N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.Cl.[OH-].[Na+].ClCCl>O1CCOCC1.[Cl-].[Na+].O>[CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:32]\[C@H:33]3[CH2:53][CH2:52][C:35](=[O:36])[CH2:34]3)/[C:17]([NH:19][C:20]3[CH:24]=[CH:23][NH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:11])=[O:12])[CH2:2][CH2:3]1

Participants

Conditions

Temperature: 50 °C

Procedure

To a solution of triphenylphosphine (300 mg) in dichloromethane (4 mL) was added N-bromosuccinimide (200 mg) under ice-cooling, followed by stirring for 15 minutes under ice-cooling, and a solution of (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]acrylic acid (300 mg) in dichloromethane (3 mL) was then slowly added thereto, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added a solution of tert-butyl 3-amino-1H-pyrazole-1-carboxylate (190 mg) in dichloromethane (3 mL), and further added pyridine (0.1 mL), followed by stirring at room temperature for 3 hours. To the reaction mixture were added water (20 mL) and dichloromethane (20 mL), and the organic layer was sequentially washed with 1 M hydrochloric acid (20 mL) and saturated brine (20 mL), and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25→60:40) to obtain tert-butyl 3-({(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl] prop-2-enoyl}amino)-1H-pyrazole-1-carboxylate (338 mg) as a colorless amorphous substance. To a solution of tert-butyl 3-({(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]prop-2-enoyl}amino)-1H-pyrazole-1-carboxylate (330 mg) in 1,4-dioxane (3 mL) was added 4 M hydrochloric acid (3 mL), followed by stirring at 50° C. for 3 hours. After leaving it to be cooled at room temperature, 1 M sodium hydroxide (12 mL), saturated brine (20 mL), and dichloromethane (20 mL) were added thereto, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. To a solution of the residue in ethyl acetate (3 mL) was added 4 M hydrogen chloride/ethyl acetate (0.3 mL), followed by stirring at room temperature for a while, and the solvent was then evaporated under reduced pressure. The obtained colorless solid was purified by silica gel column chromatography (ethyl acetate→chloroform→chloroform/methanol (95/5)) and again purified by silica gel column chromatography (ethyl acetate/methanol 100/0→90/10) to obtain (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1S)-3-oxocyclopentyl]-N-1H-pyrazol-3-yl acrylamide (100 mg) as a colorless amorphous substance.

Workup

customAfter leaving it
temperatureto be cooled at room temperature
dry with materialthe organic layer was dried over anhydrous magnesium sulfate
customthe solvent was then evaporated under reduced pressure
additionTo a solution of the residue in ethyl acetate (3 mL) was added 4 M hydrogen chloride/ethyl acetate (0.3 mL)
stirringby stirring at room temperature for a while
customthe solvent was then evaporated under reduced pressure
customThe obtained colorless solid was purified by silica gel column chromatography (ethyl acetate→chloroform→chloroform/methanol (95/5))
customagain purified by silica gel column chromatography (ethyl acetate/methanol 100/0→90/10)

Sources & evidence

ORD record: ord-863b85929e5d43c9bc099d146d4f91b4
Source dataset: uspto-grants-2012_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08329707B2

Reaction notes

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