Acetonitrile → 5-(1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-6-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one

HRID 2046229ノート

反応式

HRID 2046229 の反応式
FC(F)(F)C(O)=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH2:32][CH2:31][N:30]4[N:33]=[C:34]([CH2:36][O:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:35]=[C:29]4[C:28]3=[O:44])[N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>C(Cl)Cl.O>[NH4+:15].[OH-:4].[N:22]1[C:23]([N:27]2[CH2:32][CH2:31][N:30]3[N:33]=[C:34]([CH2:36][O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:35]=[C:29]3[C:28]2=[O:44])=[CH:24][CH:25]=[CH:26][C:21]=1[CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1

参加物

8

反応物 4

HCID 6342Acetonitrile2 回HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 679916106-(4-oxo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester

生成物 2

HCID 14923Ammonium HydroxideHCID 679738875-(1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-6-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one収率 24%

試薬・触媒・溶媒 2

HCID 962Water溶媒2 回HCID 6344Dichloromethane溶媒

実験手順

Trifluoroacetic acid (0.5 mL) was added to a stirred solution of 6-(4-oxo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (44 mg, 0.087 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 16 hours. The mixture was basified with a saturated solution of Na2CO3 and extracted with more DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 N solution of ammonia in MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by ion exchange chromatography using an ISOLUTE SCX2 cartridge and eluting with MeOH and 7 N solution of ammonia in MeOH. The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with DIPE and repurified by RP HPLC on (C18 XBridge 30×100 5 um). Mobile phase (Gradient from 80% 0.1% NH4CO3H/NH4OH pH 9 solution in H2O, 20% ACN to 0% 0.1% NH4CO3H/NH4OH pH 9 solution in H2O, 100% ACN) to yield 5-(1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (8 mg, 24% yield) as a white solid. 1H NMR (400 MHz, CDCl3d) δ ppm 1.66 (br. s., 1H), 1.70-1.83 (m, 2H), 1.89 (dd, J=12.0, 1.8 Hz, 2H), 2.76 (td, J=12.3, 2.8 Hz, 2H), 2.74-2.83 (m, 1H), 3.21 (dt, J=12.0, 2.8 Hz, 2H), 4.46-4.54 (m, 2H), 4.58-4.68 (m, 2H), 5.13 (s, 2H), 6.93-7.00 (m, 2H), 7.00-7.05 (m, 2H), 7.06 (s, 1H), 7.27-7.34 (m, 2H), 7.66 (t, J=8.0 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H).

後処理

  1. extractionextracted with more DCM
  2. customThe organic layer was separated
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. customthe solvents evaporated in vacuo
  6. customThe crude product was purified by flash column chromatography (silica; 7 N solution of ammonia in MeOH in DCM 0/100 to 10/90)
  7. customThe desired fractions were collected
  8. customthe solvents evaporated in vacuo
  9. customThe product was repurified by ion exchange chromatography
  10. washeluting with MeOH and 7 N solution of ammonia in MeOH
  11. customThe desired fractions were collected
  12. customthe solvents evaporated in vacuo
  13. customThe product was triturated with DIPE
  14. customrepurified by RP HPLC on (C18 XBridge 30×100 5 um)

出典と根拠

ORDレコード
ord-41c0541b26e44070951c6afbd4d9db42
出典データセット
uspto-grants-2013_11
特許番号
US08592422B2

反応ノート

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