Potassium Carbonate → 2-chloro-4,4-difluoro-1'-[[1-[3-(methoxymethyl)-2-pyridyl]-3-methyl-pyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]

HRID 1517608노트

반응식

HRID 1517608 반응식
[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-].[K+].[K+].Br[C:32]1[C:37]([CH2:38][O:39][CH3:40])=[CH:36][CH:35]=[CH:34][N:33]=1.CN[C@@H]1CCCC[C@H]1NC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:23])([F:24])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][N:17]([C:32]2[C:37]([CH2:38][O:39][CH3:40])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:18]=1)[CH2:9][CH2:8]3

참가 물질

8

반응물 4

HCID 11430Potassium CarbonateHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 197015792-Bromo-3-(methoxymethyl)pyridineHCID 178434546HCID 178434546, 화합물

생성물 1

HCID 582685912-chloro-4,4-difluoro-1'-[[1-[3-(methoxymethyl)-2-pyridyl]-3-methyl-pyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]수율 65.5%

시약·촉매·용매 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)촉매HCID 1140Toluene용매HCID 8857Ethyl Acetate용매

실험 절차

To a screw-cap test tube is added copper (I) iodide (1.15 g, 6.02 mmol), 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (15 g, 40.12 mmol), potassium carbonate (11.76 g, 84.26 mmol), 15 mL of toluene (previously bubbled with nitrogen for 20 minutes) and a stir bar. The reaction mixture is bubbled with nitrogen for additional 10 min and then 2-bromo-3-methoxymethyl-pyridine (10.54 g, 52.16 mmol), and trans-N,N′-dimethylcyclohexane-1,2-diamine (1.90 mL, 12.04 mmol) are added. The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield), stirred at room temperature for 5 min and immersed in a preheated oil bath at 115° C. for 24 h. The sample is cooled down to room temperature, diluted with ethyl acetate and filtered through celite. The solvent is evaporated in vacuo. The residue is purified by normal phase Isco chromatography using hexane/ethyl acetate (30-70%). The desired fractions are collected and evaporated. Some impure fractions (<2 g) are repurified by normal phase Isco chromatography using hexane/ethyl acetate (20-60% in ethyl acetate) as eluent. All the fractions containing final compound are combined and evaporated to dryness in vacuo. The residue is dissolved in dichloromethane and washed with 10% aqueous solution of ammonium hydroxide to remove copper residues. The organic solvent is evaporated and the compound is dried overnight to yield 13 g of 2-chloro-4,4-difluoro-1′-[[1-[3-(methoxymethyl)-2-pyridyl]-3-methyl-pyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]. MS (m/z): 495 (M+1).

후처리

  1. custompreviously bubbled with nitrogen for 20 minutes) and a stir bar
  2. customThe reaction mixture is bubbled with nitrogen for additional 10 min
  3. customThe reaction tube is quickly sealed (caution
  4. waitimmersed in a preheated oil bath at 115° C. for 24 h
  5. temperatureThe sample is cooled down to room temperature
  6. filtrationfiltered through celite
  7. customThe solvent is evaporated in vacuo
  8. customThe residue is purified by normal phase Isco chromatography
  9. customThe desired fractions are collected
  10. customevaporated
  11. customSome impure fractions (<2 g) are repurified by normal phase Isco chromatography
  12. additionAll the fractions containing final compound
  13. customevaporated to dryness in vacuo
  14. dissolutionThe residue is dissolved in dichloromethane
  15. washwashed with 10% aqueous solution of ammonium hydroxide
  16. customto remove copper residues
  17. customThe organic solvent is evaporated
  18. customthe compound is dried overnight

출처 및 근거

ORD 기록
ord-72347b5613bd4d86949c9de7450abad6
출처 데이터셋
uspto-grants-2012_07
특허 번호
US08232289B2

반응 노트

불러오는 중…