Pyridine → 3-methoxy-2,2-dimethylpropionic acid 5-[(R)-[3-(2-acetoxyethoxy)-2-fluoro-5-methoxyphenyl]-(4-{amino[2-methylallyloxycarbonylimino]methyl}phenylamino)methyl]-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester

HRID 2089694

Reaktionsgleichung

Reaktionsgleichung von HRID 2089694
[CH3:1][C:2](=[CH2:43])[CH2:3][O:4][C:5](=[O:42])[N:6]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C@H:16]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH2:38][CH2:39][OH:40])[C:30]=2[F:41])[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)=[CH:11][CH:10]=1)[NH2:8].Cl[CH2:45][O:46][C:47](=[O:54])[C:48]([CH3:53])([CH3:52])[CH2:49][O:50][CH3:51].C(=O)([O-])[O-].[Rb+].[Rb+].N1C=CC=CC=1.[C:67](OC(=O)C)(=[O:69])[CH3:68]>CN(C)C1C=CN=CC=1.O.C(OCC)(=O)C.CN(C)C(=O)C>[C:67]([O:40][CH2:39][CH2:38][O:37][C:31]1[C:30]([F:41])=[C:29]([C@@H:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C:7]([NH2:8])=[N:6][C:5]([O:4][CH2:3][C:2]([CH3:1])=[CH2:43])=[O:42])=[CH:10][CH:11]=2)[C:17]2[N:21]=[C:20]([O:22][CH2:45][O:46][C:47](=[O:54])[C:48]([CH3:53])([CH3:52])[CH2:49][O:50][CH3:51])[N:19]([C:23]3[N:24]=[CH:25][CH:26]=[CH:27][N:28]=3)[N:18]=2)[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=1)(=[O:69])[CH3:68]

Komponenten

10

Edukt 5

HCID 1049PyridineHCID 7918Acetic AnhydrideHCID 11431Carbonic acid, rubidium salt (1:2)HCID 144596933-Methoxy-2,2-dimethylpropionic acid chloromethyl esterHCID 136334036[1-amino(4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl](5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]amino}phenyl)methylene]carbamic acid 2-methylallyl ester

Produkt 1

HCID 674711843-methoxy-2,2-dimethylpropionic acid 5-[(R)-[3-(2-acetoxyethoxy)-2-fluoro-5-methoxyphenyl]-(4-{amino[2-methylallyloxycarbonylimino]methyl}phenylamino)methyl]-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl esterAusbeute 46,3 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 142844-(Dimethylamino)pyridineKatalysatorHCID 962WaterLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 31374DimethylacetamideLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

Under nitrogen atmosphere, a mixture of [1-amino(4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl](5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]amino}phenyl)methylene]carbamic acid 2-methylallyl ester (1.0 g, 1.69 mmol), 3-methoxy-2,2-dimethylpropionic acid chloromethyl ester (641 mg, 3.55 mmol), rubidium carbonate (312 mg, 1.35 mmol), and N,N-dimethylacetamide (30 mL) was stirred at 85° C. for 115 minutes. After cooling to room temperature, pyridine (0.69 mL, 8.45 mmol), 4-dimethylaminopyridine (20.7 mg, 0.169 mmol), and acetic anhydride (0.32 mL, 3.39 mmol) were added to the reaction solution, and the resulting mixture was stirred at room temperature for 2 hours. Ethyl acetate (150 mL) and water (150 mL) were added to the reaction mixture, and the resulting mixture was extracted. The organic layer was collected, sequentially washed with water (100 mL) and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of ethyl acetate-methanol) to obtain the captioned compound (610 mg) as a solid.

Aufarbeitung

  1. temperatureAfter cooling to room temperature
  2. stirringthe resulting mixture was stirred at room temperature for 2 hours
  3. extractionthe resulting mixture was extracted
  4. customThe organic layer was collected
  5. washsequentially washed with water (100 mL) and saturated aqueous sodium chloride solution
  6. dry with materialdried over anhydrous magnesium sulfate
  7. filtrationThe desiccant was filtered off
  8. customthe filtrate obtained
  9. concentrationwas concentrated under reduced pressure
  10. customThe residue obtained
  11. customwas purified by silica gel column chromatography (mixed solvent of ethyl acetate-methanol)

Quellen und Nachweise

ORD-Eintrag
ord-c1e40e8f5fe34393ba8b09c765a0c457
Quelldatensatz
uspto-grants-2013_05
Patentnummer
US08436009B2

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