Hydrochloric Acid → 3'-(2,5-Difluoro-phenyl)-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazine hydrochloride

HRID 220535

反応式

HRID 220535 の反応式
[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1B(O)O.Cl>CN(C)C(=O)C.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[ClH:1].[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1

参加物

9

反応物 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 2734335(2,5-Difluorophenyl)boronic acidHCID 594382163'-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl

生成物 1

HCID 685961223'-(2,5-Difluoro-phenyl)-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazine hydrochloride収率 12%

試薬・触媒・溶媒 4

HCID 178418397HCID 178418397、化合物触媒HCID 962Water溶媒2 回HCID 6342Acetonitrile溶媒HCID 31374Dimethylacetamide溶媒

反応条件

温度
115 °C

実験手順

Dissolve 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (153 mg, 0.50 mmol) in N,N-dimethylacetamide (2 mL, nitrogen purged) under nitrogen. Add potassium carbonate (166 mg, 1.20 mmol) then 2,5-difluorobenzeneboronic acid (95 mg, 0.60 mmol) and purge with nitrogen for 10 min. Add deoxygenated water (1 mL) and tetrakis(triphenylphosphine)palladium(0) (0.003 g, 0.003 mmol) then purge with nitrogen for 10 min. Heat at 115° C. for between 24 and 42 hr. Cool to room temperature, add water (5 mL) and extract with DCM (4×5 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®. Concentrate the filtrate and purify by SCX-2® chromatography washing with methanol then eluting with approximately 2 M ammonia in methanol. Purify (silica gel chromatography, eluting with 0:100 to 10:90 methanol:DCM). Further purify by low pH reverse phase HPLC, followed by passage through an SCX-2® ion exchange cartridge (wash with methanol, elute with 7M ammonia in methanol). Concentrate to provide the free base. Dissolve the free base in acetonitrile and add 2M aqueous HCl solution. Add water and lyophilize to give the title compound as a yellow solid (25 mg, 12%). MS (ES): m/z=385 [M+H]+.

後処理

  1. additionAdd
  2. customthen purge with nitrogen for 10 min
  3. temperatureCool to room temperature
  4. additionadd water (5 mL)
  5. extractionextract with DCM (4×5 mL)
  6. concentrationConcentrate the filtrate
  7. custompurify by SCX-2® chromatography
  8. washwashing with methanol
  9. washthen eluting with approximately 2 M ammonia in methanol
  10. customPurify
  11. wash(silica gel chromatography, eluting with 0:100 to 10:90 methanol:DCM)
  12. customFurther purify by low pH reverse phase HPLC
  13. washfollowed by passage through an SCX-2® ion exchange cartridge (wash with methanol, elute with 7M ammonia in methanol)
  14. concentrationConcentrate
  15. customto provide the free base

出典と根拠

ORDレコード
ord-07b47806108b4222998e09edc2a8f84e
出典データセット
uspto-grants-2012_06
特許番号
US08202873B2

関連ノート

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