Hydrochloric Acid → 2-Carboxy-7-chloro-4-methylthioquinoline

HRID 982967노트

반응식

HRID 982967 반응식
C[O:2][C:3]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[C:3]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[CH:10][CH:11]=2)[N:6]=1)([OH:4])=[O:2]

참가 물질

5

반응물 3

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 221848242-(Methoxycarbonyl)-7-chloro-4-methylthioquinoline

생성물 1

HCID 221847702-Carboxy-7-chloro-4-methylthioquinoline수율 76.5%

시약·촉매·용매 1

HCID 21881883Oxolane--water (1/1)용매

실험 절차

To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added Mel (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%-2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1 N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCI (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%-3% MeOH in CH2Cl2 afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4-3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm.

후처리

  1. extractionExtraction with ethyl acetate
  2. washwashing with brine
  3. dry with materialdrying over sodium sulfate and evaporation

출처 및 근거

ORD 기록
ord-53692720d3814c678aef413f219b1060
출처 데이터셋
uspto-grants-2005_03
특허 번호
US06861424B2

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