Hydrochloric Acid → {6-Cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid

HRID 1987051Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1987051
C([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]([NH:14][CH2:15][C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[C:7]=1[F:26])C.CO.[Li+].[OH-].Cl>O.C1COCC1>[C:12]([C:11]1[C:6]([CH2:5][C:4]([OH:27])=[O:3])=[C:7]([F:26])[C:8]([NH:14][CH2:15][C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)=[CH:9][CH:10]=1)#[N:13]

Komponenten

7

Edukt 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 3939Lithium HydroxideHCID 57722723{6-Cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid ethyl ester

Produkt 1

HCID 68828124{6-Cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

{6-Cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid ethyl ester (968 mg, 2.57 mmol), prepared as described in the previous step, was dissolved into MeOH:THF:H2O (51 mL, 1:2:1) and treated with LiOH (92 mg, 3.85 mmol, 1.5×). After 1.5 h, the reaction was neutralized with 428 μL, 12N HCl and concentrated in vacuo. The crude material was diluted with toluene and concentrated (3×25 mL) to afford the saponification product {6-cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid. {6-cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid, HCl salt of [N,N′-di(tert-butoxycarbonyl)]-2-aminoethoxyguanidine (1.8 g, 5.13 mmol, 2×) (prepared as described in Example 1d), and BOP (1.8 g, 4.16 mmol, 1.6×) were dissolved into CH3CN/CH2Cl2 (12 mL, 1:1) and cooled to 0° C. DIEA (2.7 mL, 15.6 mmol, 6×) was added dropwise and the reaction continued for 12 h, allowing the ice bath to warm to rt. The reaction was partitioned between EtOAc (50 mL) and H2O (50 mL), the organic phase dried over Na2SO4, and concentrated to afford the crude product as a white amorphous solid. Purification via flash chromatography (20% EtOAc/CH2Cl2) afforded the product as a white solid (832 mg, 1.28 mmol, 50% yield). 1H NMR (300 Hz, CDCl3) δ 9.14 (s, 1H), 8.49 (s, 1H), 7.61, m, 2H), 6.75 (t, J=8.2 Hz, 1H), 4.13 (m, 4H), 3.83 (s, 2H), 3.61 (m, 2H), 2.41 (s, 3H), 1.51 (s, 9H), 1.47 (s, 9H); LC/MS (m/z) [M+1]+ 650.3 (calculated for C30H39F3N7O6, 650.7).

Aufarbeitung

  1. concentrationconcentrated in vacuo
  2. additionThe crude material was diluted with toluene
  3. concentrationconcentrated (3×25 mL)

Quellen und Nachweise

ORD-Eintrag
ord-fc92b009393545ceb7542bbd1c3e2f26
Quelldatensatz
uspto-grants-2009_06
Patentnummer
US07550474B2

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