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Oxalyl chloride → (1-(4-[(1-ethyl-5-fluoro-1H-indole-2-carbonyl)amino]-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester

HRID 409398
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반응식

HRID 409398 반응식
[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:13]([OH:15])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:22][O:23][C:24](=[O:42])[CH2:25][C:26]1[C:27]([CH3:41])=[N:28][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][C:34]=2[F:40])[C:30]=1[CH3:31].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:22][O:23][C:24](=[O:42])[CH2:25][C:26]1[C:27]([CH3:41])=[N:28][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:13]([C:4]3[N:3]([CH2:1][CH3:2])[C:11]4[C:6]([CH:5]=3)=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)=[O:15])=[CH:35][C:34]=2[F:40])[C:30]=1[CH3:31]
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참가 물질

8

반응물 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 178868281-ethyl-5-fluoro-1H-indole-2-carboxylic acidHCID 66707516[1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester

생성물 1

HCID 68276522(1-(4-[(1-ethyl-5-fluoro-1H-indole-2-carbonyl)amino]-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester수율 54.6%

시약·촉매·용매 3

HCID 142844-(Dimethylamino)pyridine촉매HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매2회

실험 절차

To a solution of 1-ethyl-5-fluoro-1H-indole-2-carboxylic acid (140 mg, 0.68 mmol) in 6 mL dichloromethane is added oxalyl chloride (0.094 mL, 0.68 mmol) and a drop dimethylformamide. After stirring at room temperature for 1 hour the solvent is removed by evaporation in vacuo. The residue is dissolved in dichloromethane (5 mL) and dropped to a solution of [1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (177 mg, 0.61 mmol) and diisopropylethylamine (0.23 mL, 1.35 mmol) in dichloromethane (5 mL). After addition of 4-dimethylaminopyridine (8.255 mg, 0.069 mmol) the solution is stirred at room temperature for 12 hours. The solution is extracted twice with hydrochloric acid (1 M), twice with water, twice with an aqueous solution of NaOH (1 M) and twice with water. The organic layer is dried over MgSO4, filtered and the solvent is evaporated in vacuo. The residue is purified by MPLC (dichloromethane/methanol 95:5) to yield 160 mg of (1-(4-[(1-ethyl-5-fluoro-1H-indole-2-carbonyl)amino]-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=481; Retention time HPLC: 0.93 min (method D)). b) To a solution of (1-(4-[(1-ethyl-5-fluoro-1H-indole-2-carbonyl)amino]-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (160 mg, 0.33 mmol) in dioxane (2 mL) is added an aqueous solution of NaOH (1 M, 0.66 mL) and the mixture is stirred at 60° C. for 1 hour. The solvent is evaporated in vacuo, and the residue is suspended in water and treated with acetic acid (2 M). The precipitate is freeze dried, dissolved in methanol and a little dimethylformamide, and the product is precipitated with a little water, filtered and dried to yield 137 mg of the title compound (ESI mass spectrum: [M+H]+=467; Retention time HPLC: 0.89 min (method D)).

후처리

  1. customis removed by evaporation in vacuo
  2. dissolutionThe residue is dissolved in dichloromethane (5 mL)
  3. stirringis stirred at room temperature for 12 hours
  4. extractionThe solution is extracted twice with hydrochloric acid (1 M), twice with water, twice with an aqueous solution of NaOH (1 M) and twice with water
  5. dry with materialThe organic layer is dried over MgSO4
  6. filtrationfiltered
  7. customthe solvent is evaporated in vacuo
  8. customThe residue is purified by MPLC (dichloromethane/methanol 95:5)

출처 및 근거

ORD 기록
ord-cf49bdf62d4c4f029ca8e30ee12855ec
출처 데이터셋
uspto-grants-2014_06
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08759386B2

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