Dichloromethane → 10-[5-Fluoro-2-(acetoxymethyl)-3-[1-methyl-6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]-pyridin-2-yl}amino)-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one

HRID 1919042Notes

Reaction equation

HRID 1919042 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.[K+].C(Cl)Cl.[C:34]([O:37][CH2:38][C:39]1[C:44]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[CH:43][C:42]([F:60])=[CH:41][C:40]=1Br)(=[O:36])[CH3:35].C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[F:60][C:42]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:39]([CH2:38][O:37][C:34](=[O:36])[CH3:35])=[C:44]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:57])([CH3:58])[CH2:52][C:53]=43)[C:46]2=[O:59])[CH:43]=1

Participants

8

Reactant 5

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 580437585-Bromo-3-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-oneHCID 670163042-Bromo-4-fluoro-6-(9-oxo-4,4-dimethyl-1,10diazatricyclo[6.4.0.02,6]-dodeca-2(6),7-dien-10-yl)benzyl Acetate

Product 1

HCID 8666125010-[5-Fluoro-2-(acetoxymethyl)-3-[1-methyl-6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]-pyridin-2-yl}amino)-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-oneYield 49%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
105 °C

Procedure

A 44-mL sealed tube equipped with a magnetic stirrer was charged with 220a (400 mg, 1.0 mmol), 7 (508 mg, 2.0 mmol), potassium acetate (392 mg, 4.0 mmol) and 1,4-dioxane (10 mL). After the mixture was degassed for 30 minutes, Pd(dppf)Cl2.CH2Cl2 (82 mg, 0.10 mmol) was added. The resulting reaction mixture was stirred at 105° C. for 6 h. Then, it was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated, and the crude mixture was redissolved in DME (2 mL) and transferred into a 10-mL microwave reaction vessel. To this solution was added 10-[2-(acetoxymethyl)-3-bromo-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo-[6.4.0.02,6]dodeca-2(6),7-dien-9-one (189a) (270 mg, 0.60 mmol), Pd(PPh3)4 (50 mg, 0.050 mmol), and 2 N Na2CO3 (2 mL). Then, the reaction mixture was degassed for 5 minutes and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:methanol, 85:15) to give 49% (150 mg) of 245a.

Workup

  1. customA 44-mL sealed tube
  2. customequipped with a magnetic stirrer
  3. customAfter the mixture was degassed for 30 minutes
  4. customThe resulting reaction mixture
  5. temperatureThen, it was cooled to room temperature
  6. filtrationfiltered through a pad of Celite
  7. concentrationThe filtrate was concentrated
  8. dissolutionthe crude mixture was redissolved in DME (2 mL)
  9. customtransferred into a 10-mL microwave reaction vessel
  10. customThen, the reaction mixture was degassed for 5 minutes
  11. stirringAfter the reaction mixture was stirred at 125° C. for 7 min.
  12. customit was purified by flash chromatography (dichloromethane:methanol, 85:15)

Sources & evidence

ORD record
ord-7e384b74755345e6b1af7fb77e3f36a9
Source dataset
uspto-grants-2013_12
Patent number
US08618107B2

Reaction notes

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