Dimethylformamide → (R,R)-N-[4-bromo-3-(4-ethoxyphenyl)isothiazol-5-yl]-2-methylcyclopropane-carboxamide

HRID 2422715Notes

Reaction equation

Br[C:2]1[C:6]([Br:7])=[C:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH3:14])=[O:10])[S:4][N:3]=1.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH3:16].CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:7][C:6]1[C:2]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:15][CH3:16])=[CH:19][CH:20]=2)=[N:3][S:4][C:5]=1[NH:8][C:9]([C@@H:11]1[CH2:13][C@H:12]1[CH3:14])=[O:10]

Participants

Conditions

Temperature: 60 °C

Procedure

Degas a solution of (R,R)—N-[3,4-dibromoisothiazol-5-yl]-2-methylcyclopropane-carboxamide (0.500 g, 1.471 mmol), (4-ethoxyphenyl)boronic acid (0.485 g, 2.941 mmol), DMF (3 mL) and toluene (29 mL) with nitrogen. Add sodium carbonate (2 M) (4.41 mmol) and Pd(PPh3)4 (0.255 g, 0.221 mmol); then seal under nitrogen. Heat at 60° C. overnight. Add 100 mg of Pd(PPh3)4 and heat for 1 more day. Dilute with EtOAc and wash with brine. Separate and evaporate. Chromatography on silica gel, eluting with 15-50% EtOAc in hexane, followed by crystallization from EtOAc and hexane affords (R,R)—N-[4-bromo-3-(4-ethoxyphenyl)isothiazol-5-yl]-2-methylcyclopropane-carboxamide. Yield: 53.5% ES-MS: 380.0 (m+1).

Workup

customthen seal under nitrogen
temperatureheat for 1 more day
washwash with brine
customSeparate
customevaporate
washChromatography on silica gel, eluting with 15-50% EtOAc in hexane
customfollowed by crystallization from EtOAc and hexane

Sources & evidence

ORD record: ord-b12b384f02dd440bba74c536cb8a0cff
Source dataset: uspto-grants-2011_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07960419B2

Reaction notes

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