Tris(hydroxymethyl)aminomethane → HCID 135537670, compound

HRID 2111184Notes

Reaction equation

HRID 2111184 reaction equation
[OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[C:13]3[S:19][C:18]([C:20](O)=[O:21])=[CH:17][C:14]=3[NH:15][N:16]=1)=[CH:6]2.ON1C2C=CC=CC=2N=N1.N=C=N.[CH2:36]([O:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH3:37].C(O)C(N)(CO)CO>ClCCl.CO.CN(C)C=O>[CH2:36]([O:38][CH2:39][CH2:40][CH2:41][NH:42][C:20]([C:18]1[S:19][C:13]2[C:12]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([CH2:2][OH:1])=[CH:11][CH:10]=4)=[N:16][NH:15][C:14]=2[CH:17]=1)=[O:21])[CH3:37]

Participants

9

Reactant 5

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 22720Propanolamine ethyl etherHCID 757711-HydroxybenzotriazoleHCID 160435CarbodiimideHCID 135442621HCID 135442621, compound

Product 1

HCID 135537670HCID 135537670, compoundYield 17.3%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a mixture of 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid [159 mg, 0.507 mmol, Example 37], 1-hydroxybenzotriazole (116 mg, 0.858 mmol), PS-carbodiimide (1.2 mmol/g, 845 mg) in Dichioromethane (8 mL) and dimethyl formamide (2 mL) is stirred at room temperature for 25 minutes before addition of 3-ethoxypropylamine (45 mg, 0.436 mmol). After 4 h, PS-trisamine (4.03 mmol/g, 500 mg) is added and stirred for 6 hours. The reaction mixture is filtered and the resin washed under suction with Dichloromethane (3×15 mL). The filtrate is evaporated in vacuo. The crude is purified by chromatography on 10 g silica gel cartridge (ethyl acetate then 1% methanol in ethyl acetate) to give thick semi solid. It is redissolved in methanol and triturated with water to give 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid (3-ethoxy-propyl)-amide [30 mg, Example 39] as pale yellow solid; 1H NMR [(CD3)2SO)]: δ 13.490 (1H, s, NH), 11.56 (1H, NH, s), 8.70 (1H, t), 7.88 (1H, s), 7.51 (1H, s), 7.38 (1H, d), 7.10 (1H, s), 6.66 (1H, s), 5.01 (1H, t, OH), 4.55 (2H, HOCH2—), 3.44 (6H, m), 1.80 (2H), 1.12 (3H, t); LC/MS: 399 (M+H).

Workup

  1. filtrationThe reaction mixture is filtered
  2. washthe resin washed under suction with Dichloromethane (3×15 mL)
  3. customThe filtrate is evaporated in vacuo
  4. customThe crude is purified by chromatography on 10 g silica gel cartridge (ethyl acetate
  5. custom1% methanol in ethyl acetate) to give thick semi solid
  6. customtriturated with water

Sources & evidence

ORD record
ord-e9d08eeb9fef4d03a34b76390be2836a
Source dataset
uspto-grants-2009_04
Patent number
US07518000B2

Reaction notes

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