Potassium Carbonate → [bis-(4-methoxy-phenyl)-phenyl-methyl]-((R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-amine

HRID 331154Notes

Reaction equation

HRID 331154 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:10][C:11]2[CH2:12][O:13][C:14]([CH3:30])([CH3:29])[C:15]([F:28])([F:27])[C@:16]([C:19]3[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=3[F:26])([CH3:18])[N:17]=2)=[CH:5][CH:4]=1.[Cl:45][C:46]1[CH:47]=[C:48]([N:52]2[CH:56]=[C:55](B(O)O)[CH:54]=[N:53]2)[CH:49]=[CH:50][CH:51]=1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:10][C:11]2[CH2:12][O:13][C:14]([CH3:30])([CH3:29])[C:15]([F:28])([F:27])[C@:16]([C:19]3[CH:24]=[C:23]([C:55]4[CH:54]=[N:53][N:52]([C:48]5[CH:49]=[CH:50][CH:51]=[C:46]([Cl:45])[CH:47]=5)[CH:56]=4)[CH:22]=[CH:21][C:20]=3[F:26])([CH3:18])[N:17]=2)([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:5][CH:4]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 467386771-(3-Chlorophenyl)pyrazole-4-boronic acidHCID 68227452(R)-N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine

Product 1

HCID 68380365[bis-(4-methoxy-phenyl)-phenyl-methyl]-((R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-amineYield 77.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A dried pressure tube was consecutively charged with (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate B9.1) (199 mg, 299 μmol), 1,2-dimethoxyethane (4 ml), 1-(3-chlorophenyl)-1H-pyrazol-4-ylboronic acid (CAS 1072945-88-0) (102 mg, 448 μmol), and a solution of potassium carbonate (2M, 448·1). The tube was flushed with argon, thereafter tetrakistriphenylphosphinepalladium(0) (17.3 mg, 14.9 μmol) was added, the tube was sealed and the reaction mixture heated at 85° C. for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 80:20 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-((R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-amine (177 mg, 77% yield) was obtained as a white foam. MS (ISP): m/z=765.4 [M+H]+ and 767.4 [M+2+H]+.

Workup

  1. customThe tube was flushed with argon
  2. customthe tube was sealed
  3. customFor the workup, the reaction mixture was evaporated at reduced pressure
  4. customthe residue directly purified by chromatography on an amine-silica phase

Sources & evidence

ORD record
ord-a9ce1a4c3f26424bb762a1184c59639d
Source dataset
uspto-grants-2014_11
Patent number
US08877744B2

Reaction notes

Loading…