Piperidine → N-(3-bromophenyl)-7-(1-piperidinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine

HRID 1292954Notes

Reaction equation

HRID 1292954 reaction equation
C[Al](C)C.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:20]3[C:27]4[CH2:28][CH2:29][CH:30]([C:32](OCC)=[O:33])[CH2:31][C:26]=4[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:16][CH:17]=1>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:20]3[C:27]4[CH2:28][CH2:29][CH:30]([C:32]([N:5]5[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]5)=[O:33])[CH2:31][C:26]=4[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:16][CH:17]=1

Participants

5

Reactant 3

HCID 8082PiperidineHCID 16682925TrimethylaluminumHCID 17990000Ethyl 4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate

Product 1

HCID 58774553N-(3-bromophenyl)-7-(1-piperidinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
0 °C

Procedure

Anhydrous toluene (2 mL) was added to a 50 mL round bottom flask previously evacuated and refilled with argon or nitrogen gas (3×). This was cooled to 0° C. in an ice-water bath for 5 min. Trimethylaluminum, 0.2 mL (1.8 equiv, 2.0M solution in hexanes) was added and the reaction was stirred at 0° C. for 15 min before piperidine (1.1 equiv, 0.25 mmol) was added to the above solution. It was allowed to stir at 0° C. for 10 min before warming to rt for 20 min. A 3 mL toluene solution of 100 mg (0.23 mmol, 1 equiv) of ethyl 4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate, 14, was added and the reaction mixture was heated at 100° C. until reaction was complete by TLC. The reaction mixture was cooled to 0° C. and quenched with 1N HCl. The reaction was adjusted to pH 9.0 with 1N NaOH and extracted with EtOAc (3×5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give a crude oil which was purified via flash column chromatography MeOH/CH2Cl2 1:9 to provide the required product, 27, as a white solid (100 mg, 92%). 1H-NMR (CD2Cl2-d4) δ 8.49 (s, 1H), 8.05 (d, 1H), 7.62–7.59 (m, 1H), 7.23–7.26 (m, 2H), 7.12 (s, 1H), 3.59 (q, 2H), 3.52 (t, 2H), 3.23–3.10 (m, 3H), 2.94 (dd, 1H), 2.20–2.19 (m, 1H), 2.10–2.08 (m, 1H), 1.71–1.58 (m, 7H); LCMS RT=3.28 min; [M+H]+=473.3.

Workup

  1. custompreviously evacuated
  2. additionrefilled with argon or nitrogen gas (3×)
  3. additionwas added to the above solution
  4. temperaturebefore warming to rt for 20 min
  5. temperaturethe reaction mixture was heated at 100° C. until reaction
  6. temperatureThe reaction mixture was cooled to 0° C.
  7. customquenched with 1N HCl
  8. extractionextracted with EtOAc (3×5 mL)
  9. dry with materialThe organic layer was dried over anhydrous Na2SO4
  10. concentrationconcentrated
  11. customto give a crude oil which
  12. customwas purified via flash column chromatography MeOH/CH2Cl2 1:9

Sources & evidence

ORD record
ord-98778ed3d585447fb454429493a3fa12
Source dataset
uspto-grants-2007_07
Patent number
US07238701B2

Reaction notes

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