Tetrahydrofuran → 7-(2-aminoethyl)-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine

HRID 1910037

반응식

HRID 1910037 반응식
C1(COC(=O)[NH:10][CH2:11][CH2:12][C:13]2[C:14]3[O:22][CH:21]=[C:20]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([C:32](=[O:42])[CH2:33][C:34]4[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=4[F:41])[CH2:27][CH2:26]5)[C:15]=3[C:16]([NH2:19])=[N:17][CH:18]=2)C=CC=CC=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.O1CCCC1>C(O)C.[Pd].O.CN(C)C=O>[NH2:10][CH2:11][CH2:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:42])[CH2:33][C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[F:41])[CH2:27][CH2:26]4)[C:15]=2[C:16]([NH2:19])=[N:17][CH:18]=1

참가 물질

8

반응물 3

HCID 8028TetrahydrofuranHCID 493570Riboflavin2회HCID 69939762phenylmethyl [2-(4-amino-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-7-yl)ethyl]carbamate

생성물 1

HCID 668237087-(2-aminoethyl)-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine수율 25.7%

시약·촉매·용매 4

HCID 23938Palladium촉매2회HCID 702Ethanol용매HCID 962Water용매2회HCID 6228Dimethylformamide용매

반응 조건

온도
50 °C

실험 절차

A suspension of phenylmethyl[2-(4-amino-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-7-yl)ethyl]carbamate (91 mg, 0.156 mmol) and Pd/C (10 wt. % dry basis), wet (ca. 50% water), Degussa type E101 NE/W (27 mg, 0.013 mmol) in Ethanol (1 mL) and Tetrahydrofuran (THF) (5 mL) was stirred under an atmosphere of hydrogen for 3 hours. LCMS showed no conversion, and it appeared that the starting material was not very soluble in the reaction mixture. Some N,N-Dimethylformamide (DMF) (2 mL) was added along with another portion of Pd/C (10 wt. % dry basis), wet (ca. 50% water), Degussa type E101 NE/W (65 mg, 0.031 mmol), and the mixture was stirred under an atmosphere of hydrogen for another 19 hours. LCMS showed a mixture of product and a byproduct. The mixture was filtered and the filtrate was concentrated in vacuo. An attempt was made to convert the byproduct to the desired product by taking the mixture up in MeOH (ca. 10 mL), adding 2 M HCl (ca. 1 mL), and stirring at room temperature for 5 hours. No reaction was observed, so it was heated to 50° C. for another 16 hours. HPLC still showed no conversion, so the mixture was concentrated in vacuo. The residue was taken up in MeOH (1.5 mL) and purified by reverse phase HPLC (Gilson, C18, 20% to 27% CH3CN in water with 0.1% TFA, 8 minute gradient). The product fractions were concentrated in vacuo and azeotroped with acetonitrile three times. The residue was then taken up in DCM and passed through a Varian PL-HCO3 MP-resin cartridge, rinsing with more DCM. The filtrate was then concentrated in vacuo and dried in the vacuum oven overnight to give the free base of 7-(2-aminoethyl)-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (18 mg, 24.41% yield) as a white solid. LC/MS (ES) m/z=449 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d 1.53 (br. s., 2H), 2.72-2.79 (m, 2H), 2.79-2.86 (m, 2H), 3.28 (t, J=8.34 Hz, 2H), 3.96 (s, 2H), 4.30 (t, J=8.59 Hz, 2H), 5.33 (s, 2H), 7.14-7.33 (m, 4H), 7.41 (s, 1H), 7.69 (s, 1H), 7.93 (s, 1H), 8.12 (d, J=8.34 Hz, 1H).

후처리

  1. additiona mixture of product
  2. filtrationThe mixture was filtered
  3. concentrationthe filtrate was concentrated in vacuo
  4. additionadding 2 M HCl (ca. 1 mL)
  5. stirringstirring at room temperature for 5 hours
  6. concentrationso the mixture was concentrated in vacuo
  7. custompurified by reverse phase HPLC (Gilson
  8. customwith 0.1% TFA, 8 minute gradient
  9. concentrationThe product fractions were concentrated in vacuo
  10. customazeotroped with acetonitrile three times
  11. washrinsing with more DCM
  12. concentrationThe filtrate was then concentrated in vacuo
  13. customdried in the vacuum oven overnight

출처 및 근거

ORD 기록
ord-21ca3102fd304a41a5a46afbc28ce629
출처 데이터셋
uspto-grants-2013_12
특허 번호
US08598156B2

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