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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
Notes
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Reaction equation

HRID 331139 reaction equation
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
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 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

Product 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-oneYield 50%

Reagents, catalysts & solvents 2

HCID 1542701,5-Diphenylpenta-1,4-dien-3-one;palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

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]+.

Workup

  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

Sources & evidence

ORD record
ord-b968e67a63a442f4ba55a97bccde5267
Source dataset
uspto-grants-2014_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08877744B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes