Isopropanol → 6'-[(3,3-Difluorocyclobutyl)methoxy]-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''(3''H)-thione

HRID 1468076Notes

Reaction equation

HRID 1468076 reaction equation
[F:1][C:2]1([F:25])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]4)[C:14]3=[NH:17])=[CH:10][CH:9]=2)[CH2:3]1.C(OC)(OC)OC.CC(O)C.O=[C:38]([CH3:42])[C:39](=[S:41])[NH2:40]>CO.CCCCCCC.CCOC(C)=O>[F:1][C:2]1([F:25])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([C:14]53[NH:40][C:39](=[S:41])[C:38]([CH3:42])=[N:17]5)[CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]4)=[CH:10][CH:9]=2)[CH2:3]1

Participants

8

Reactant 4

HCID 3776IsopropanolHCID 9005Trimethyl orthoformateHCID 207652372-Oxopropanethioamide2×HCID 867067236'-((3,3-difluorocyclobutyl)methoxy)-4-methoxyspiro[cyclohexane-1,2'-inden]-1'(3'H)-imine

Product 1

HCID 867067246'-[(3,3-Difluorocyclobutyl)methoxy]-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''(3''H)-thioneYield 12%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolventHCID 8900HeptaneSolvent

Conditions

Temperature
60 °C

Procedure

HCl (4 M in 1,4-dioxane, 4.13 mL, 16.5 mmol) was added to a solution of N-(5′-((3,3-difluorocyclobutyl)methoxy)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 18, 750 mg, 1.65 mmol) in anhydrous 1,4-dioxane (25 mL). A white precipitate formed immediately and the resulting cloudy mixture was stirred under a nitrogen atmosphere overnight. The mixture was diluted with NaHCO3 (aq.) and extracted with DCM. The organic phase was dried and concentrated, to yield 6′-((3,3-difluorocyclobutyl)methoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (672 mg, 1.92 mmol). The imine, trimethyl orthoformate (0.557 mL, 5.08 mmol) and 2-propanol (5 mL) was placed into a MW tube and the mixture was heated at 60° C. in an oil bath. 2-oxopropanethioamide (Intermediate 1, 397 mg, 3.85 mmol) in MeOH (15 mL) was added and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo. The product was isolated using column chromatography (0-50% EtOAc in heptane) to give 106 mg (12% yield) of the title compound. MS (ES+) m/z 435 [M+H]+.

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. customThe product was isolated

Sources & evidence

ORD record
ord-abbc71761ad84c3f854d55136a54d790
Source dataset
uspto-grants-2015_04
Patent number
US09000185B2

Reaction notes

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