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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
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 409398
[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]
KomponentenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

8

Edukt 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

Produkt 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 ester
Ausbeute 54,6 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 142844-(Dimethylamino)pyridineKatalysatorHCID 6228DimethylformamideLösungsmittelHCID 6344DichloromethaneLösungsmittel2×

Versuchsvorschrift

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)).

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-cf49bdf62d4c4f029ca8e30ee12855ec
Quelldatensatz
uspto-grants-2014_06
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08759386B2

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