Ammonia → HCID 58851449, compound

HRID 1696579Notes

Reaction equation

HRID 1696579 reaction equation
[CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[Cl:22])=[O:13])[N:8]([C:23]3[CH:31]=[C:30]4[C:26]([CH2:27][CH2:28][CH:29]4[C:32](O)=[O:33])=[CH:25][CH:24]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=[N:41]C=2C=1.CCN=C=NCCCN(C)C.N.O1CCOCC1>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[C:32]([CH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([N:8]3[C:9]([NH:11][C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[Cl:22])=[O:13])=[CH:10][C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[N:7]3)[CH:31]=2)[CH2:27][CH2:28]1)(=[O:33])[NH2:41]

Participants

9

Reactant 5

HCID 222AmmoniaHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 312751,4-DioxaneHCID 757711-HydroxybenzotriazoleHCID 67271746HCID 67271746, compound

Product 1

HCID 58851449HCID 58851449, compound

Reagents, catalysts & solvents 3

HCID 311Citric AcidSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a 1:1:1 mix of EtOH:H2O:dioxane (6 mL) was placed ethyl 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylate (520 mg, 0.986 mmol) and lithium hydroxide (71 mg, 2.96 mmol). The solution warmed to 40 C and stirred, ON. LC shows complete reaction. The solution cooled to RT and diluted with 5% citric acid (20 mL) and Ethyl acetate (20 mL). The organic phase separated, washed with brine and dried over sodium sulfate. The solvents were evaporated at reduced pressure to give 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid as a foam, 474 mg (96%), used as is. In DMF (5 mL) was placed 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid (474 mg, 0.949 mmol), HOBt (196 mg, 1.09 mmol) and EDAC (218 mg, 1.42 mmol). The mixture was stirred at RT for 1 hr and then treated with a solution of 0.5N ammonia in dioxane (7.59 mL, 3.80 mmol). The mixture was stirred at RT, ON. LC shows complete reaction. The mixture was diluted with 5% citric acid (20 mL) and Ethyl acetate (20 mL). The organic phase separated, washed with saturated sodium bicarbonate (20 mL), brine (20 mL) and dried over sodium sulfate. The solvents evaporated at reduced pressure to give a foam, dried on high vacuum line at RT for 2 hrs. The foam was then purified by Biotage chromatography (S1-25 column, 65-95% Ethyl acetate/Hex). Fractions 10-19 were combined and evaporated at reduced pressure to give 1-(1-(3-carbamoyl-2,3-dihydro-1H-inden-5-yl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea as a white solid. The solid was dried on the high vacuum line at 65 C in the abderhalden for 3 hrs, 210 mg (44%). 1H NMR (DMSO-d6) 1.59-1.73 (m, 6H), 1.95-1.99 (m, 2H), 2.23-2.33 (m, 2H), 2.88-3.06 (m, 3H), 3.90-4.04 (m, 1H), 6.31 (s, 1H), 6.98 (s, 1H), 7.26-7.42 (m, 5H), 7.63 (br s, 1H), 8.07-8.09 (m, 1H), 8.77 (s, 1H), 9.21 (s, 1H). LC-MS (EI) m/z: 500.0 (M+H+).

Workup

  1. stirringThe mixture was stirred at RT
  2. customreaction
  3. customThe organic phase separated
  4. washwashed with saturated sodium bicarbonate (20 mL), brine (20 mL)
  5. dry with materialdried over sodium sulfate
  6. customThe solvents evaporated at reduced pressure
  7. customto give a foam
  8. customdried on high vacuum line at RT for 2 hrs
  9. customThe foam was then purified by Biotage chromatography (S1-25 column, 65-95% Ethyl acetate/Hex)
  10. customevaporated at reduced pressure

Sources & evidence

ORD record
ord-230e26db721947fba8cd269b8094ae8d
Source dataset
uspto-grants-2012_04
Patent number
US08163756B2

Reaction notes

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