Sodium Bicarbonate → (R)-5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one

HRID 331139

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HRID 331139 반응식
Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.CC1C=CC(S(NN=[C:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)(=O)=O)=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Li+].C(=O)([O-])O.[Na+]>O1CCOCC1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[O:37]1[CH2:36][CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]3)[CH:7]=2)[CH2:39][CH2:38]1

참가 물질

8

반응물 5

HCID 516892Sodium BicarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 236647642-Propanol, 2-methyl-, lithium salt (1:1)HCID 58562968(R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-oneHCID 68380128N'-(dihydro-2H-pyran-4(3H)-ylidene)-4-methylbenzenesulfonohydrazide

생성물 1

HCID 68380032(R)-5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one수율 50%

시약·촉매·용매 2

HCID 1542701,5-Diphenylpenta-1,4-dien-3-one;palladium촉매HCID 312751,4-Dioxane용매

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온도
110 °C

실험 절차

A solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (151 mg, 412 μmol) and 4-methyl-N′-(2H-pyran-4(3H,5H,6H)-ylidene)benzenesulfonohydrazide (CAS1240042-12-9) (122 mg, 454 μmol) in dioxane (5 ml) was treated under argon with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS) (19.7 mg, 41.2 μmol), bis(dibenzylideneacetone) palladium (11.9 mg, 20.6 μmol) and finally lithium tert-butoxide (72.6 mg, 907 μmol). The reaction mixture was stirred in a sealed microwave tube at 110° C. for 16 hours. For the workup, the reaction mixture was poured on a saturated solution of sodium hydrogencarbonate followed by 2 extractions with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and evaporated at reduced pressure to give brown oil. The residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 20:80 as the eluent. The (R)-5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (76 mg, 50% yield) was obtained as an off-white foam. MS (ISP): m/z=370.2 [M+H]+.

후처리

  1. extractionfollowed by 2 extractions with ethyl acetate
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over sodium sulphate
  4. filtrationfiltered
  5. customevaporated at reduced pressure
  6. customto give brown oil
  7. customThe residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 20:80 as the eluent

출처 및 근거

ORD 기록
ord-b968e67a63a442f4ba55a97bccde5267
출처 데이터셋
uspto-grants-2014_11
특허 번호
US08877744B2

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