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Triethylamine → (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-thiazol-4-ylethynyl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-one

HRID 331152
Notes
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Reaction equation

HRID 331152 reaction equation
[F:1][C:2]1([F:21])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[O:11])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17](I)[CH:16]=[CH:15][C:14]=1[F:20])[CH3:12].[CH3:22][C:23]1[S:24][CH:25]=[C:26]([C:28]#[C:29][Si](C)(C)C)[N:27]=1.C(N(CC)CC)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[F:1][C:2]1([F:21])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[O:11])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:29]#[C:28][C:26]2[N:27]=[C:23]([CH3:22])[S:24][CH:25]=2)[CH:16]=[CH:15][C:14]=1[F:20])[CH3:12]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 3

HCID 8471TriethylamineHCID 109214422-Methyl-4-(2-(trimethylsilyl)ethynyl)-1,3-thiazoleHCID 68380642(R)-6,6-difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-one

Product 1

HCID 68379907(R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-thiazol-4-ylethynyl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-oneYield 91%

Reagents, catalysts & solvents 5

HCID 11776
Triphenylphosphine
Catalyst
HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst
HCID 67553Tetrabutylammonium IodideCatalyst
HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalyst
HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
40 °C

Procedure

A dried pressure tube was charged with (R)-6,6-difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate B6″.1) (203 mg, 491 μmol), 2-methyl-4-((trimethylsilyl)ethynyl)thiazole (115 mg, 590 μmol), and N,N-dimethylformamide (3 ml) flushed with nitrogen (solution 1). Another dried pressure tube was flushed with argon, thereafter, successively N,N-dimethylformamide (3 ml), bis(triphenylphosphine) palladium(II)chloride (24.6 mg, 34.4 μmol), triphenylphoshine (5.2 mg, 19.7 μmol), copper(I)iodide (1.9 mg, 9.8 μmol), triethylamine (249 mg, 2.46 mmol), and tetrabutylammoniumiodide (185 mg, 491 μmol) were added. The mixture was heated to 40° C., and solution 1 was added dropwise. The temperature was raised to 60° C. and stirring was continued for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-thiazol-4-ylethynyl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-one (182 mg, 91% yield) was obtained as a white foam. MS (ISP): m/z=409.3 [M+H]+.

Workup

  1. customflushed with nitrogen (solution 1)
  2. customAnother dried pressure tube was flushed with argon
  3. temperatureThe temperature was raised to 60° C.
  4. customFor the workup, the reaction mixture was evaporated at reduced pressure
  5. customthe residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent

Sources & evidence

ORD record
ord-8e817188ba6840c3b1abcf874949eb57
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