Hydrochloric Acid → Azd-1656

HRID 418028Notes

Reaction equation

HRID 418028 reaction equation
[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=3)[C:17]([OH:19])=O)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:39][C:40]1[N:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(#N)C.C1(C)C=CC=CC=1>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=3)[C:17]([NH:46][C:43]3[CH:42]=[N:41][C:40]([CH3:39])=[CH:45][N:44]=3)=[O:19])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 10340Sodium CarbonateHCID 24386Thionyl ChlorideHCID 3132155-Methylpyrazin-2-amineHCID 591271113-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid

Product 1

HCID 16039797Azd-1656Yield 85%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6342AcetonitrileSolvent2×

Conditions

Temperature
45 °C

Procedure

To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid (1.0 eq), and acetonitrile (10 vols) followed by pyridine (3 eq) under a nitrogen atmosphere. Thionyl chloride (1.2 eq) as a solution in acetonitrile (0.225 vols) was added slowly, drop-wise via syringe pump over at least 2 hours. 5-Methylpyrazin-2-amine (1.2 eq) was added to the mixture as a solid. After 2.5 hours the reaction was quenched by adding toluene (10 vols) and 1.0M sodium carbonate solution (2.5 eq). The layers were separated. The organic layer was retained in the flask, then 1.0M hydrochloric acid (1.94 eq) was added. The mixture was agitated for 15 minutes then separated. The organic layer was washed with two aliquots of water (5 vols) then the solvent was removed on the rotary evaporator. Toluene (5 vols) was added to the residue, and warmed to 45° C. Isohexane (1.7 vols) was added, the mixture was seeded, and allowed to cool to ambient temperature overnight. The mixture was cooled to 0° C. for 4 hours, and then cooled to −10° C. for 3 hours. The solid was isolated by filtration then washed with isohexane (2.5 vols). After drying in the vacuum oven at 40° C. overnight, the desired product was obtained as a solid (corrected yield 85%).

Workup

  1. customTo a flask fitted with overhead stirrer, condenser
  2. customdrop-wise via syringe
  3. waitpump over at least 2 hours
  4. customAfter 2.5 hours the reaction was quenched
  5. customThe layers were separated
  6. customthen separated
  7. washThe organic layer was washed with two aliquots of water (5 vols)
  8. customthe solvent was removed on the rotary evaporator
  9. additionToluene (5 vols) was added to the residue
  10. additionIsohexane (1.7 vols) was added
  11. temperatureto cool to ambient temperature overnight
  12. temperatureThe mixture was cooled to 0° C. for 4 hours
  13. temperaturecooled to −10° C. for 3 hours
  14. customThe solid was isolated by filtration
  15. washthen washed with isohexane (2.5 vols)
  16. customAfter drying in the vacuum oven at 40° C. overnight

Sources & evidence

ORD record
ord-8b63cb487e034ce3bda39baee836996a
Source dataset
uspto-grants-2012_01
Patent number
US08093252B2

Reaction notes

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