Triisopropyl borate → 3-{5-[2-Methoxy-5-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyridazin-3-ylamide

HRID 1469374

반응식

HRID 1469374 반응식
Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].B(OC(C)C)(OC(C)C)OC(C)C.C([Li])CCC.B(O)O.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43]([N:45]2[CH2:48][CH:47]([O:49][C:50]3[CH:55]=[CH:54][C:53](I)=[CH:52][N:51]=3)[CH2:46]2)=[O:44])[N:37]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(Cl)Cl.CN(C=O)C>[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43]([N:45]2[CH2:46][CH:47]([O:49][C:50]3[CH:55]=[CH:54][C:53]([C:2]4[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][C:3]=4[O:13][CH3:14])=[CH:52][N:51]=3)[CH2:48]2)=[O:44])[N:37]=1

참가 물질

10

반응물 6

HCID 21531Triisopropyl borateHCID 61668Boronic AcidHCID 516892Sodium BicarbonateHCID 580730982-Bromo-1-methoxy-4-(2-methoxy-ethoxy)-benzeneHCID 66710496US10918640, Example 14HCID 178418339Butyllithium

생성물 1

HCID 442190563-{5-[2-Methoxy-5-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyridazin-3-ylamide수율 44.9%

시약·촉매·용매 3

HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매HCID 8028Tetrahydrofuran용매

실험 절차

A solution of 2-bromo-1-methoxy-4-(2-methoxy-ethoxy)-benzene (110 mg, 0.42 mmol) in anhydrous THF (2 mL) was cooled to −78° C. with a CO2— acetone bath under a nitrogen atmosphere. Triisopropyl borate (0.19 mL, 0.842 mmol) was added, followed by n-butyl lithium solution (2.5M in hexanes, 0.22 mL, 0.55 mmol). The mixture was allowed to warm to ambient temperature the solvents were removed in vacuo to afford a colourless solid. To the crude boronic acid was added 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (Example 7, step 1) (150 mg, 0.38 mmol), 1N aqueous sodium bicarbonate solution (1.26 mL), DMF (7 mL) and 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (15 mg). Nitrogen gas bubbled through mix for 5 minutes and reaction mixture heated at 80° C. for 2 hr. Mix was allowed to cool, partitioned between ethyl acetate (30 mL) and water (30 mL). Organic phase was separated then washed with sat. aqueous sodium chloride solution (60 mL) and dried over sodium sulphate. Solvents were removed in vacuo to afford a crude oil which was purified by flash chromatography on silica gel, eluting with a gradient of 0-10% ethyl acetate in hexane to afford the title compound (77 mg, 41%) as a pale yellow foam.

후처리

  1. customwere removed in vacuo
  2. customto afford a colourless solid
  3. customNitrogen gas bubbled
  4. additionthrough mix for 5 minutes
  5. customreaction mixture
  6. temperatureheated at 80° C. for 2 hr
  7. additionMix
  8. temperatureto cool
  9. custompartitioned between ethyl acetate (30 mL) and water (30 mL)
  10. customOrganic phase was separated
  11. washthen washed with sat. aqueous sodium chloride solution (60 mL)
  12. dry with materialdried over sodium sulphate
  13. customSolvents were removed in vacuo
  14. customto afford a crude oil which
  15. customwas purified by flash chromatography on silica gel
  16. washeluting with a gradient of 0-10% ethyl acetate in hexane

출처 및 근거

ORD 기록
ord-5efd098085c94941b1e81c308e2a529a
출처 데이터셋
uspto-grants-2015_04
특허 번호
US09006269B2

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