Aniline → 2-[4-(2-Allyloxy-6-fluoro-4-morpholin-4-yl-phenylamino)-5-chloro-pyrimidin-2-ylamino]-5-methyl-8,9-dihydro-5h-7-oxa-5-aza-benzocyclohepten-6-one

HRID 1041673Notes

Reaction equation

HRID 1041673 reaction equation
C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]([CH3:27])[C:25](=[O:28])[O:24][CH2:23][CH2:22][C:21]=2[CH:29]=1.[CH2:30]([O:33][C:34]1[CH:39]=[C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:37]=[C:36]([F:46])[C:35]=1[NH:47][C:48]1[C:53]([Cl:54])=[CH:52][N:51]=[C:50](Cl)[N:49]=1)[CH:31]=[CH2:32].C(=O)([O-])[O-].C(=O)(O)[O-].[Na+].ClC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.NC1C=CC=CC=1>C(O)(C)C.O1CCOCC1.CCOC(C)=O.O>[CH2:30]([O:33][C:34]1[CH:39]=[C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:37]=[C:36]([F:46])[C:35]=1[NH:47][C:48]1[C:53]([Cl:54])=[CH:52][N:51]=[C:50]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[N:26]([CH3:27])[C:25](=[O:28])[O:24][CH2:23][CH2:22][C:21]=3[CH:29]=2)[N:49]=1)[CH:31]=[CH2:32]

Participants

12

Reactant 7

HCID 6115AnilineHCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 19660Carbonate IonHCID 343679-Fluorenylmethyl chloroformate2×HCID 516892Sodium BicarbonateHCID 580154687-amino-1-methyl-4,5-dihydro-3,1-benzoxazepin-2(1H)-one3×HCID 87330208(2-Allyloxy-6-fluoro-4-morpholin-4-yl-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine

Product 1

HCID 668305312-[4-(2-Allyloxy-6-fluoro-4-morpholin-4-yl-phenylamino)-5-chloro-pyrimidin-2-ylamino]-5-methyl-8,9-dihydro-5h-7-oxa-5-aza-benzocyclohepten-6-one

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

10-Camphorsulfonic acid (3.4 mg, 0.015 mmol), 2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (28 mg, 0.15 mmol), and (2-Allyloxy-6-fluoro-4-morpholin-4-yl-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine (59 mg, 0.15 mmol) in Isopropyl alcohol (3 mL) was irradiated in a CEM microwave (120° C., 30 min). The solution was neutralized by the addition of MP-Carbonate (2.69 mmol/g loading; 0.10 g, 0.269 mmol), filtered and conc. in vacuo. The resultant oil was chromatographed (ISCO, 12 g SiO2, 0-100% EtOAc:Hex) to afford the product as the second eluting peak. The isolated product was contaminated in a 1:1 ratio with remaining 2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one as determined by 1H-NMR. The mixture of product and 2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (32 mg) was dissolved in dioxane (5 mL) and aq. satd. sodium bicarbonate (1 mL) was added. 9-Fluorenylmethyl chloroformate (21 mg, 0.081 mmol) was added, and the mixture was stirred under an atmosphere of Nitrogen. HPLC/LCMS showed FMOC-incorporation onto the impurity aniline. A second aliquot of 9-Fluorenylmethyl chloroformate (42 mg, 0.16 mmol) was added and stirred for an additional 48 h. The solution was diluted with EtOAc (10 mL) and water (5 mL). The layers were separated, the aq. extracted with 5 mL DCM, and the combined organics dried over sodium sulfate, then conc. onto 1.5 g SiO2. Chromatography (ISCO, 12 g, 0-85% EtOAc:Hex) afforded 4 major peaks, the last eluting at 80% being 2-[4-(2-Allyloxy-6-fluoro-4-morpholin-4-yl-phenylamino)-5-chloro-pyrimidin-2-ylamino]-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one as a beige foam (14 mg, 17%). LCMS: 555 (M+H); 1H-NMR (CDCl3): 8.01 (s, 1H), 7.50 (s, 1H), 7.15 (d, 1H, J=8.9 Hz), 6.93 (d, 1H, J=8.1 Hz), 6.86 (s, 1H), 5.92 (m, 1H), 5.30 (d, 1H, J=17.0 Hz), 5.21 (d, 1H, J=10.6 Hz), 4.52 (m, 2H), 4.41 (t, 2H, J=6.3 Hz), 3.86 (m, 4H), 3.34 (s, 3H), 3.16 (m, 4H), 2.78 (t, 2H, J=6.3 Hz).

Workup

  1. filtrationfiltered and conc. in vacuo
  2. customThe resultant oil was chromatographed (ISCO, 12 g SiO2, 0-100% EtOAc:Hex)
  3. customto afford the product as the second eluting peak
  4. stirringstirred for an additional 48 h
  5. customThe layers were separated
  6. extractionthe aq. extracted with 5 mL DCM
  7. dry with materialthe combined organics dried over sodium sulfate
  8. customChromatography (ISCO, 12 g, 0-85% EtOAc:Hex) afforded 4 major peaks
  9. washthe last eluting at 80%

Sources & evidence

ORD record
ord-7593b2f6b3524a90b40a7b20fc1124a3
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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