Triphenylphosphine → (2S)-2-tert-butoxy-2-[4-(4,4-dimethyl-1-piperidyl)-5-[4-[(2,4-dimethylthiazol-5-yl)methoxy]phenyl]-2,6-dimethyl-3-pyridyl]acetic acid

HRID 718450노트

반응식

HRID 718450 반응식
[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[S:37][C:38]([CH2:42]O)=[C:39]([CH3:41])[N:40]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:42][C:38]3[S:37][C:36]([CH3:35])=[N:40][C:39]=3[CH3:41])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:24])([CH3:25])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]

참가 물질

8

반응물 5

HCID 11776TriphenylphosphineHCID 14798Sodium HydroxideHCID 2776250(Dimethyl-1,3-thiazol-5-yl)methanolHCID 5462977Diethyl azodicarboxylateHCID 118314205(S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate

생성물 1

HCID 118307792(2S)-2-tert-butoxy-2-[4-(4,4-dimethyl-1-piperidyl)-5-[4-[(2,4-dimethylthiazol-5-yl)methoxy]phenyl]-2,6-dimethyl-3-pyridyl]acetic acid수율 58.6%

시약·촉매·용매 2

HCID 887Methanol용매HCID 8028Tetrahydrofuran용매

실험 절차

To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), (2,4-dimethylthiazol-5-yl)methanol (22.92 mg, 0.160 mmol) and Ph3P-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DEAD (0.025 mL, 0.160 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (1.067 mL, 1.067 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((2,4-dimethylthiazol-5-yl)methoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (17.7 mg, 0.031 mmol, 58.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.29-7.21 (m, 1H), 7.14-7.01 (m, 3H), 5.84 (s, 1H), 5.36-5.15 (m, 2H), 3.27 (d, J=7.7 Hz, 1H), 2.79 (t, J=11.9 Hz, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H), 2.18 (d, J=12.5 Hz, 1H), 2.06 (s, 3H), 1.96-1.87 (m, 1H), 1.49 (br. s., 1H), 1.36-1.25 (m, 1H), 1.18 (d, J=12.8 Hz, 1H), 1.13 (s, 9H), 1.01 (d, J=11.7 Hz, 1H), 0.85 (br. s., 3H), 0.59 (br. s., 3H). LCMS (M+H)=566.6.

후처리

  1. filtrationmixture was filtered
  2. customto remove polymer
  3. concentrationconcentrated
  4. temperatureMixture was then cooled
  5. custompurified by prep-HPLC

출처 및 근거

ORD 기록
ord-bcee8cdbabc948eb9dc2d6b6f1313cfa
출처 데이터셋
uspto-grants-2015_11
특허 번호
US09193720B2

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