1,2-Dichloroethane → Tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoate

HRID 77144

반응식

HRID 77144 반응식
[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.Cl.[NH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(Cl)CCl>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:4]

참가 물질

8

반응물 4

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 16218890Tert-butyl 3-aminopropanoate hydrochlorideHCID 674589572-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid

생성물 1

HCID 67459034Tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoate수율 25.7%

시약·촉매·용매 3

HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매HCID 57417360Sodium chloride; water용매

실험 절차

(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of N-methylmorpholine (0.031 mL, 0.278 mmol), tert-butyl 3-aminopropanoate-HCl (16.43 mg, 0.090 mmol), and EDC (17.33 mg, 0.090 mmol). This was stirred overnight before EtOAc and brine were added. The organic layer was washed with brine, 1N HCl, and sat NaHCO3. The organic layer was then dried (MgSO4), filtered, and concentrated. The resulting residue was dissolved in CH2Cl2 (1 mL) and TFA (2.0 mL). After 1 h, this was concentrated and then was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, retention time for product=12.4 min) (R/S)-tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoate (10 mg, 0.018 mmol, 25.7% yield): LCMS=559.1 [M+H]+. This material was dissolved in CH2Cl2 (0.5 mL) prior to the addition of TFA (1 mL). After stirring for lh, the solution was concentrated to give (R/S)-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (10 mg, 0.018 mmol, 98% yield): LCMS=503.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.35 Hz), 7.69 (4 H, d, J=7.91 Hz), 7.52-7.65 (3H, m), 5.11 (1 H, s), 3.50 (2 H, t, J=6.59 Hz), 2.54 (2 H, t, J=6.81 Hz); HPLC Peak RT=8.8 min (Analytical Method A).

후처리

  1. additionwere added
  2. washThe organic layer was washed with brine, 1N HCl
  3. dry with materialThe organic layer was then dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe resulting residue was dissolved in CH2Cl2 (1 mL)
  7. concentrationthis was concentrated
  8. customwas purified by preparative HPLC (PHENOMENEX® Luna 5u
  9. washC18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid
  10. customover 10 min
  11. customfor product=12.4 min

출처 및 근거

ORD 기록
ord-2c4ef722dcc44d0fb00b90de477c33c2
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08835470B2

연결된 노트

불러오는 중…