Sodium Carbonate → N2-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide

HRID 2385907Notes

Reaction equation

HRID 2385907 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[C:23]([C:25](=[O:31])[NH:26][CH2:27][C@H:28]([OH:30])[CH3:29])[CH:22]=[CH:21][C:20]=4[Cl:32])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:33]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:55][C:37]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:76][S:77]([CH2:80][CH2:81][NH2:82])(=[O:79])=[O:78].Cl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:32][C:20]1[CH:21]=[CH:22][C:23]([C:25](=[O:31])[NH:26][CH2:27][C@H:28]([OH:30])[CH3:29])=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:37]([NH:82][CH2:81][CH2:80][S:77]([CH3:76])(=[O:79])=[O:78])=[O:55])=[CH:33][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 17749886Ethanamine, 2-(methylsulfonyl)-, hydrochloride (1:1)HCID 67050592HCID 67050592, compound

Product 1

HCID 67050604N2-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamideYield 179.9%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A suspension of 8-bromo-N-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (500 mg, 0.91 mmol), Pd(OAc)2 (10 mg, 0.045 mmol), Xantphos (53 mg, 0.091 mmol), MeSO2(CH2)2NH2.HCl (218 mg, 1.36 mmol) and Na2CO3 (289 mg, 2.73 mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphere of CO from balloon overnight. Then it was filtrated and concentrated, the crude product was purified by pre-TLC (DCM: MeOH=10:1 as eluted solvent) to give 387 (101.5 mg, yield 18%). 1H NMR (DMSO-d6, 400 MHz): δ8.73 (s, 1H, NH), 8.60 (s, 1H, NH), 8.12-7.45 (m, 6H, ArH), 6.61 (s, 1H, ═CH), 4.76 (d, J=4.8 Hz, 1H, OH), 4.20 (br s, 2H, CH2), 3.80-3.77 (m, 1H, CH), 3.67-2.98 (m, 14H, CH3, CH2), 1.06 (t, J=5.2 Hz, 3H, CH3). LC-MS: (ESI, m/z)=542 [M+Na]+

Workup

  1. filtrationThen it was filtrated
  2. concentrationconcentrated
  3. customthe crude product was purified by pre-TLC (DCM: MeOH=10:1 as eluted solvent)

Sources & evidence

ORD record
ord-356d01c593c8494e8ed90301e95d3594
Source dataset
uspto-grants-2012_09
Patent number
US08263633B2

Reaction notes

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