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

HRID 1987051ノート

反応式

HRID 1987051 の反応式
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]

参加物

7

反応物 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

生成物 1

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

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒

実験手順

{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).

後処理

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

出典と根拠

ORDレコード
ord-fc92b009393545ceb7542bbd1c3e2f26
出典データセット
uspto-grants-2009_06
特許番号
US07550474B2

反応ノート

読み込み中…