Trimethylaluminum → HCID 178489779, compound

HRID 16803Notes

Reaction equation

HRID 16803 reaction equation
C[Al](C)C.CO[C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)=[O:8].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][CH2:38][C:39]2[CH:40]=[C:41]([NH2:44])[NH:42][N:43]=2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH3:36][O:35][C:33]1[CH:32]=[C:31]([CH2:37][CH2:38][C:39]2[CH:40]=[C:41]([NH:44][C:7]([C:9]3[S:13][C:12]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]4)=[CH:11][CH:10]=3)=[O:8])[NH:42][N:43]=2)[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=1

Participants

6

Reactant 3

HCID 16682925TrimethylaluminumHCID 57440414Tert-butyl 4-(5-(methoxycarbonyl)thiophen-2-yl)piperazine-1-carboxylateHCID 178489815HCID 178489815, compound

Product 1

HCID 178489779HCID 178489779, compoundYield 50.2%

Reagents, catalysts & solvents 2

HCID 180AcetoneSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
20 °C

Procedure

2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was added dropwise to a stirred solution of tert-butyl 4-(5-(methoxycarbonyl)thiophen-2-yl)piperazine-1-carboxylate (0.326 g, 1 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1.00 mmol) in toluene (7.14 ml) at 20° C. under nitrogen. The reaction mixture was stirred at 20° C. for 20 h. The temperature was increased to 60° C. and the reaction mixture was stirred for 20 h and then allowed to cool. The reaction mixture was diluted with acetone (10 ml) and quenched with damp solid sodium sulphite. The mixture was stirred for 30 mins, and then a solution of 10% methanol in DCM (10 mL) was added and the mixture stirred for a further 30 mins. The suspension was filtered and the solid washed with 10% methanol in DCM (20 mL); the combined filtrates were evaporated to give a yellow foam. The crude product was purified by silica column chromatography, eluting with a gradient of 1 to 10% 2M ammonia/methanol in DCM. Pure fractions were evaporated to dryness to afford the crude product. This was further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl 4-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]thiophen-2-yl]piperazine-1-carboxylate (0.272 g, 50.2%) as a white dry film.

Workup

  1. temperatureThe temperature was increased to 60° C.
  2. stirringthe reaction mixture was stirred for 20 h
  3. temperatureto cool
  4. customquenched with damp solid sodium sulphite
  5. stirringThe mixture was stirred for 30 mins
  6. additiona solution of 10% methanol in DCM (10 mL) was added
  7. stirringthe mixture stirred for a further 30 mins
  8. filtrationThe suspension was filtered
  9. washthe solid washed with 10% methanol in DCM (20 mL)
  10. customthe combined filtrates were evaporated
  11. customto give a yellow foam
  12. customThe crude product was purified by silica column chromatography
  13. washeluting with a gradient of 1 to 10% 2M ammonia/methanol in DCM
  14. customPure fractions were evaporated to dryness
  15. customto afford the crude product
  16. customThis was further purified by preparative HPLC
  17. additionFractions containing the desired compound
  18. customwere evaporated to dryness

Sources & evidence

ORD record
ord-17dfbaf7861a4d658a65b4ff63b188b6
Source dataset
uspto-grants-2010_06
Patent number
US07737149B2

Reaction notes

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