Lithium Hydroxide → 6-(6-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

HRID 1047111노트

반응식

HRID 1047111 반응식
I[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[CH:7]=[C:6]([C:20]([O:22]CC)=[O:21])[C:5]2=[O:25].[CH2:26]([NH:28][C:29](=[O:49])[NH:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[C:33]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH:32]=1)[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([NH:28][C:29](=[O:49])[NH:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[N:10][CH:11]=2)[N:8]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]3=[O:25])=[C:33]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH:32]=1)[CH3:27]

참가 물질

8

반응물 4

HCID 3939Lithium HydroxideHCID 10796Cesium carbonateHCID 594161896-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid2회HCID 68750415Ethyl 6-iodo-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate2회

생성물 1

HCID 498334426-(6-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid수율 7.4%

시약·촉매·용매 3

HCID 178418397HCID 178418397, 화합물촉매HCID 962Water용매2회HCID 312751,4-Dioxane용매

반응 조건

온도
100 °C

실험 절차

To a solution of ethyl 6-iodo-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 1, 952 mg, 2.32 mmol) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 834 mg, 2.32 mmol) in 1,4-dioxane (7.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (268 mg, 0.23 mmol) followed by a solution of cesium carbonate (1.51 g, 4.63 mmol) in water (2 mL). The reaction mixture was stirred at 100° C. for 2 h. 2 M lithium hydroxide (2.32 mL, 4.63 mmol) was then added and the mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water, and the precipitate was washed with water and hexanes and then dried. The compound was purified via reverse phase HPLC (C18, 0-95% acetonitrile/water, gradient) and concentrated under reduced pressure to give 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid as a light yellow solid (106.1 mg, 7%).

후처리

  1. stirringthe mixture was stirred at 100° C. for 12 h
  2. washthe precipitate was washed with water and hexanes
  3. customdried
  4. customThe compound was purified via reverse phase HPLC (C18, 0-95% acetonitrile/water, gradient)
  5. concentrationconcentrated under reduced pressure

출처 및 근거

ORD 기록
ord-6ba1a98aaaa44881b266f1a53fa1f30b
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08569484B2

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