Methanol → methyl 3-[rel-(4aR,6R,8aS)-2-(benzoylamino)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzoate

HRID 1496779

반응식

HRID 1496779 반응식
Br[C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.C(OC[CH:43]1[CH2:45][O:44]1)C1C=CC=CC=1.C(N(CC)CC)C.C[OH:54]>CN1CCCC1=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][C@H:15]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[O:16][CH2:17][C@:8]2([C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[F:33])[C:45]([O:44][CH3:43])=[O:54])[N:9]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1

참가 물질

7

반응물 4

HCID 887MethanolHCID 8471TriethylamineHCID 94247Benzyl glycidyl etherHCID 86762665N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

생성물 1

HCID 90209264methyl 3-[rel-(4aR,6R,8aS)-2-(benzoylamino)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzoate

시약·촉매·용매 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 13387N-methyl-2-pyrrolidone용매

반응 조건

온도
120 °C

실험 절차

To a mixture of N-[rel-(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide [(+/−)-C46, which may be prepared in the same manner as C46, by using the chemistry described in Preparation 1 followed by Examples 10 and 12, but employing racemic 2-[(benzyloxy)methyl]oxirane as starting material](1.0 g, 1.9 mmol) and triethylamine (580 mg, 5.73 mmol) in methanol (20 mL) and 1-methylpyrrolidin-2-one (10 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg, 0.19 mmol) in one portion at room temperature. The reaction mixture was stirred under carbon monoxide (2.5 MPa) at 120° C. for 18 hours, whereupon it was concentrated in vacuo to remove methanol, and partitioned between water (500 mL) and ethyl acetate (500 mL). The organic layer was washed with saturated aqueous sodium chloride solution (2×400 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Eluent: ethyl acetate) afforded the product as a red solid. Yield: 570 mg, 1.12 mmol, 59%. LCMS m/z 509.1 [M+H+].

후처리

  1. custommay be prepared in the same manner as C46
  2. customdescribed in Preparation 1
  3. concentrationwas concentrated in vacuo
  4. customto remove methanol
  5. custompartitioned between water (500 mL) and ethyl acetate (500 mL)
  6. washThe organic layer was washed with saturated aqueous sodium chloride solution (2×400 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure

출처 및 근거

ORD 기록
ord-54b72bf762114ef3836924869553d573
출처 데이터셋
uspto-grants-2015_12
특허 번호
US09198917B2

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