Sodium bis(trimethylsilyl)amide → HCID 178489770, compound

HRID 16792Notes

Reaction equation

HRID 16792 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH2:36]1[CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][N:40]2[CH2:39][CH2:38][N:37]1[C:46]1[CH:55]=[CH:54][C:49]([C:50](OC)=[O:51])=[CH:48][CH:47]=1>C1COCC1>[CH2:36]1[CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][N:40]2[CH2:39][CH2:38][N:37]1[C:46]1[CH:55]=[CH:54][C:49]([C:50]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=3)[CH:13]=2)=[O:51])=[CH:48][CH:47]=1

Participants

5

Reactant 3

HCID 2724254Sodium bis(trimethylsilyl)amide2×HCID 57440371Tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate2×HCID 66589873Methyl 4-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)benzoate

Product 1

HCID 178489770HCID 178489770, compoundYield 9.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

A 1M solution of NaHMDS in THF (1.13 ml, 1.05 mmol) was added to a stirred solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and methyl 4-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)benzoate (231 mg, 0.84 mmol) in THF (5 ml) at 0° C. under nitrogen, over 5 minutes. The reaction mixture was stirred for an additional 5 minutes at 0° C., then stirred at 20° C. for 18 h. An additional amount of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (80 mg, 0.23 mmol ) was added with 1M NaHMDS in THF (1.13 ml, 1.13 mmol). The reaction mixture was stirred for an additional 3 h. The reaction mixture was quenched with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3×20 ml). The extracts were washed with saturated brine solution (15 ml), dried (MgSO4) and evaporated to give crude product. The crude product was purified by reverse phase prep. HPLC (basic) using a 38-58% gradient of acetonitrile in water containing 1% 0.880 ammonium hydroxide. The clean fractions were taken and evaporated to afford the title compound as a white solid (32 mg, 9%); 1H NMR (500.13 MHz, DMSO-d6) δ 1.25 (1H, s), 1.62 (2H, t), 1.72 (1H, d), 1.93-1.95 (2H, m), 2.19-2.20 (1H, m), 2.44 (1H, s), 2.81 (3H, q), 2.87 (4H, s), 3.28 (1H, s), 3.69 (1H, s), 3.72 (6H, s), 3.77 (1H, d), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 6.96 (2H, d), 7.89 (2H, d), 10.29 (1H, s), 12.07 (1H, s). MS: m/z 490 (MH+).

Workup

  1. stirringstirred at 20° C. for 18 h
  2. stirringThe reaction mixture was stirred for an additional 3 h
  3. customThe reaction mixture was quenched with saturated ammonium chloride (20 ml)
  4. extractionextracted with ethyl acetate (3×20 ml)
  5. washThe extracts were washed with saturated brine solution (15 ml)
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customto give crude product
  9. customThe crude product was purified by reverse phase prep
  10. customevaporated

Sources & evidence

ORD record
ord-fb4ca531aaa64bfea5d390756d6ceace
Source dataset
uspto-grants-2010_06
Patent number
US07737149B2

Reaction notes

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