Lithium Hydroxide → 2-Tert-butoxy-2-[4-chroman-6-yl-1-[(4-fluorophenyl)methyl]-6-methyl-pyrrolo[2,3-b]pyridin-5-yl]acetic acid

HRID 1912549노트

반응식

HRID 1912549 반응식
[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1.[Li+].[OH-]>CN(C)C=O.CO.C1COCC1.O>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]

참가 물질

7

반응물 4

HCID 3939Lithium HydroxideHCID 10796Cesium carbonateHCID 680214-Fluorobenzyl bromideHCID 71209024methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate

생성물 1

HCID 712094272-Tert-butoxy-2-[4-chroman-6-yl-1-[(4-fluorophenyl)methyl]-6-methyl-pyrrolo[2,3-b]pyridin-5-yl]acetic acid수율 91.8%

시약·촉매·용매 2

HCID 6228Dimethylformamide용매HCID 21892291Methanol tetrahydrofuran water용매

반응 조건

온도
80 °C

실험 절차

A mixture of methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (20 mg, 0.049 mmol) in N,N-dimethylformamide (DMF) (0.5 mL) was treated with cesium carbonate (32 mg, 0.098 mmol) followed by 1-(bromomethyl)-4-fluorobenzene (13.88 mg, 0.073 mmol) and the mixture was heated to 80° C. for 80 minutes after which time the reaction was judged complete by LCMS and TLC. The mixture was concentrated and used in the next step without further purification. LC/MS (m/z) ES+=517.41 (M+1). A solution of crude methyl ester in MeOH/THF/water (2:2:1, 0.5 mL) was treated with LiOH (18 mg, 0.735 mmol) and the mixture was heated at 70° C. until the reaction was judged complete. The mixture was concentrated; water was added and then adjusted to pH 2 with 1N HCl. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC to afford the purified desired product (22.5 mg, 0.045 mmol, 91%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.44 (m, 1 H), 7.29-7.25 (m, 2 H), 7.23-7.16 (m, 1 H), 7.08-6.98 (m, 3 H), 6.94 (dd, J=5.8, 8.3 Hz, 1 H), 6.30 (dd, J=3.5, 10.7 Hz, 1 H), 5.66-5.54 (m, 2 H), 5.53-5.44 (m, 1 H), 4.29 (t, J=4.9 Hz, 2 H), 2.97-2.80 (m, 2 H), 2.79 (s, 3 H), 2.15-2.03 (m, 2 H), 1.05-0.87 (s, 9 H); LC/MS (m/z) ES+=503.32 (M+1).

후처리

  1. concentrationThe mixture was concentrated
  2. customused in the next step without further purification
  3. temperaturethe mixture was heated at 70° C. until the reaction
  4. concentrationThe mixture was concentrated
  5. additionwater was added
  6. extractionThe mixture was extracted with ethyl acetate
  7. washThe extracts were washed with brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified by reverse phase HPLC
  12. customto afford the

출처 및 근거

ORD 기록
ord-6745942b7b1a4c15bde31961e27a55b1
출처 데이터셋
uspto-grants-2013_12
특허 번호
US08609653B2

반응 노트

불러오는 중…