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

HRID 1987051노트

반응식

HRID 1987051 반응식
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]

참가 물질

7

반응물 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

생성물 1

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

시약·촉매·용매 2

HCID 962Water용매HCID 8028Tetrahydrofuran용매

실험 절차

{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).

후처리

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

출처 및 근거

ORD 기록
ord-fc92b009393545ceb7542bbd1c3e2f26
출처 데이터셋
uspto-grants-2009_06
특허 번호
US07550474B2

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