Thionyl Chloride → HCID 178429380, compound

HRID 707372Notes

Reaction equation

HRID 707372 reaction equation
Cl[C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[F:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([NH:27][C@H:28]3[CH2:31][C@H:30]([NH2:32])[CH2:29]3)=[N:24][C:23]=2[CH:33]=1.C(N(C(C)C)CC)(C)C.CC(C)([O-])C.[Na+]>ClCCl.O1CCCC1.C(OCC)(=O)C.O>[F:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([NH:27][C@H:28]3[CH2:31][C@H:30]([N:32]4[C:2]5=[N:7][CH:6]=[CH:5][N:4]=[C:3]5[C:8]([CH3:13])([CH3:12])[C:9]4=[O:11])[CH2:29]3)=[N:24][C:23]=2[CH:33]=1

Participants

10

Reactant 5

HCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 23676156Sodium t-butoxideHCID 866941182-(3-Chloropyrazin-2-yl)-2-methylpropanoic acid2×HCID 178511740HCID 178511740, compound

Product 1

HCID 178429380HCID 178429380, compoundYield 34.1%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-(3-Chloropyrazin-2-yl)-2-methylpropanoic acid, INTERMEDIATE 29 (0.250 g, 1.246 mmol) was dissolved in a mixture of thionyl chloride (5 ml, 68.5 mmol) and dichloromethane (5 mL) and heated to reflux. After 20 minutes the solution was evaporated to dryness under reduced pressure. The crude was dissolved in carbon tetrachloride (20 mL) and evaporated to dryness once more. The crude was dried further under high vac then dissolved in dichloromethane (20 mL). The product was then added to an ice cooled solution of trans-N1-(5-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine, in the presence of INTERMEDIATE 73 (0.245 g, 1.032 mmol) and diisopropylethylamine (1.0 ml, 5.75 mmol) in dry tetrahydrofuran (30 mL). The mixture was stirred for 5 minutes then sodium tert-butoxide (0.50 g, 5.20 mmol) was added in one portion and the reaction stirred for an additional 20 minutes. Water (200 mL) and ethyl acetate (300 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired 5-(trans-3-((5-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.135 g, 0.352 mmol, 34.1% yield) m/z: 384.0 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 1.46 (s, 6 H) 2.45-2.55 (m, 2 H) 3.40-3.51 (m, 2 H) 4.53-4.63 (m, 1 H) 5.31 (quin, J=8.46 Hz, 1 H) 6.62 (br. s., 1 H) 6.84 (td, J=8.80, 2.15 Hz, 1 H) 7.27 (dd, J=9.98, 2.15 Hz, 1 H) 7.51 (dd, J=8.70, 5.38 Hz, 1 H) 8.11 (dd, J=13.99, 3.03 Hz, 2 H).

Workup

  1. temperatureheated to reflux
  2. customAfter 20 minutes the solution was evaporated to dryness under reduced pressure
  3. dissolutionThe crude was dissolved in carbon tetrachloride (20 mL)
  4. customevaporated to dryness once more
  5. customThe crude was dried further under high vac
  6. dissolutionthen dissolved in dichloromethane (20 mL)
  7. stirringthe reaction stirred for an additional 20 minutes
  8. additionthe phases mixed
  9. customseparated
  10. dry with materialThe organic was dried with magnesium sulfate
  11. customevaporated to dryness under reduced pressure
  12. customPurification

Sources & evidence

ORD record
ord-9b6c6ad3454d4321ad98b2356db66cd5
Source dataset
uspto-grants-2015_11
Patent number
US09174992B2

Reaction notes

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