Methanol → Trifluoroacetic acid

HRID 1506540노트

반응식

HRID 1506540 반응식
[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]3[O:21][N:20]=[C:19]4[C:22]5[C:27]([CH2:28][CH2:29][C:18]=34)=[CH:26][C:25]([CH:30]=O)=[CH:24][CH:23]=5)[CH:10]=[N:9]2)=[N:6][CH:7]=1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1.C1CCN2C(=NCCC2)CC1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:52])C.[Na+].[CH3:64][OH:65]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:14])[F:15])=[C:11]([C:17]3[O:21][N:20]=[C:19]4[C:22]5[C:27]([CH2:28][CH2:29][C:18]=34)=[CH:26][C:25]([CH2:30][N:32]3[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]3)=[CH:24][CH:23]=5)[CH:10]=[N:9]2)=[N:6][CH:7]=1.[C:64]([OH:52])([C:13]([F:16])([F:15])[F:14])=[O:65]

참가 물질

8

반응물 5

HCID 887MethanolHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 931923-azetidinecarboxylic AcidHCID 5049666Sodium triacetoxyborohydride2회HCID 866699373-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde

생성물 2

HCID 6422Trifluoroacetic acid수율 84%HCID 671696561-((3-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

To a stirred mixture of 3-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 122C, 40 mg, 0.093 mmol), dichloromethane (4 mL) and MeOH (1 mL) was added azetidine-3-carboxylic acid (28.3 mg, 0.280 mmol) at room temperature followed by DBU (0.028 mL, 0.187 mmol). The reaction mixture was stirred at room temperature for 5 min. before sodium triacetoxyborohydride (59.4 mg, 0.280 mmol) was added in one lot. The mixture was stirred at room temperature overnight. More sodium triacetoxyborohydride (30 mg) was added and the mixture was stirred at room temperature for 4 hr. The mixture was concentrated and dissolved in methanol and dichloromethane. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization gave 1-((3-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (51 mg, 0.079 mmol, 84% yield) as a white solid. The compound had an HPLC retention time=2.77 min. (condition C); LC/MS M+1=513.9; 1H NMR (400 MHz, MeOD) δ ppm 8.49 (1H, s), 8.18 (1H, s), 8.02 (1H, d, J=7.7 Hz), 7.89-7.93 (2H, m), 7.52 (1H, s), 7.49 (1H, d, J=7.7 Hz), 4.46 (2H, s), 4.31-4.42 (4H, m), 3.70 (1H, quin, J=8.3 Hz), 3.09 (2H, t, J=6.9 Hz), 2.93 (2H, t, J=7.0 Hz).

후처리

  1. additionwas added in one lot
  2. stirringthe mixture was stirred at room temperature for 4 hr
  3. concentrationThe mixture was concentrated
  4. dissolutiondissolved in methanol
  5. customPurification
  6. concentrationphase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization

출처 및 근거

ORD 기록
ord-438c8f088604473c8d750fe276baac7a
출처 데이터셋
uspto-grants-2015_12
특허 번호
US09216972B2

반응 노트

불러오는 중…