Benzonitrile, 4-bromo- → (R)-4-(3-(3-(bis(4-methoxyphenyl)(phenyl)methylamino)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenylamino)benzonitrile

HRID 403230Notes

Reaction equation

HRID 403230 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:42])=[C:6]([C@:8]2([CH3:41])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH:17][C:18]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:9]2)[CH:7]=1.Br[C:44]1[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:18]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)([NH:17][C:10]2[CH2:11][O:12][CH2:13][C:14]([F:16])([F:15])[C@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:44]4[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=4)[CH:3]=[CH:4][C:5]=3[F:42])([CH3:41])[N:9]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:26][CH:27]=1

Participants

7

Reactant 4

HCID 12162Benzonitrile, 4-bromo-HCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneHCID 23676156Sodium t-butoxideHCID 68227104[(R)-5-(5-amino-2-fluoro-phenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine

Product 1

HCID 68227192(R)-4-(3-(3-(bis(4-methoxyphenyl)(phenyl)methylamino)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenylamino)benzonitrileYield 49%

Reagents, catalysts & solvents 2

HCID 11029508Palladium, tris[mu-[(1,2-eta:4,5-eta)-(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one]]di-, compd. with trichloromethane (1:1)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
107.5 °C

Procedure

To a solution of [(R)-5-(5-amino-2-fluoro-phenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine (intermediate A12A) (40 mg, 69.5 μmol) in toluene (0.6 ml) in a sealable tube was added subsequently at 23° C. and under an argon atmosphere 4-bromobenzonitrile (25.3 mg, 139 μmol), sodium tert-butoxide (13.4 mg, 139 μmol), 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (2.95 mg, 6.95 μmol) and tris(dibenzylideneacetone) dipalladium chloroform adduct (2.16 mg, 2.08 μmol), the tube was sealed and heated to 105 to 110° C. for 17 h. The mixture was cooled to 23° C., partitioned between saturated aqueous NaHCO3 and ethyl acetate, the organic layer was dried and evaporated to give the crude product, which was purified by silica gel flash chromatography with n-heptane/ethyl acetate and trituration with diethyl ether/pentane to give the (R)-4-(3-(3-(bis(4-methoxyphenyl)(phenyl)methylamino)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenylamino)benzonitrile (23 mg, 49%) as a light yellow crystalline. MS (ISN): m/z=675.5 [M−H]−.

Workup

  1. customthe tube was sealed
  2. temperatureThe mixture was cooled to 23° C.
  3. custompartitioned between saturated aqueous NaHCO3 and ethyl acetate
  4. customthe organic layer was dried
  5. customevaporated
  6. customto give the crude product, which
  7. customwas purified by silica gel flash chromatography with n-heptane/ethyl acetate and trituration with diethyl ether/pentane

Sources & evidence

ORD record
ord-87efb567ae2d45af8898bc7baeb2c744
Source dataset
uspto-grants-2014_06
Patent number
US08748418B2

Reaction notes

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