Hydrochloric Acid → 4-(4-chloro-6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-3,5-dimethyl-1H-indazole-1-carbaldehyde

HRID 80857Notes

Reaction equation

HRID 80857 reaction equation
[Cl:1][C:2]1[C:3]([CH:41]2[CH2:43][CH2:42]2)=[N:4][N:5]([CH3:40])[C:6]=1[N:7]1[CH2:39][CH2:38][C:10]2[N:11]=[C:12]([C:17]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]4[C:18]=3[C:19]([CH3:37])=[N:20][N:21]4S(C3C=CC(C)=CC=3)(=O)=O)[N:13]=[C:14](OC)[C:9]=2[CH2:8]1.[ClH:44].[OH-:45].[Na+].[CH3:47][N+](C)=C[Cl:50].[Cl-:52]>CCO.CN(C=O)C.CCOCC.O.CCOC(C)=O>[Cl:50][C:14]1[C:9]2[CH2:8][N:7]([C:6]3[N:5]([CH3:40])[N:4]=[C:3]([CH:41]4[CH2:43][CH2:42]4)[C:2]=3[Cl:1])[CH2:39][CH2:38][C:10]=2[N:11]=[C:12]([C:17]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19]([CH3:37])=[N:20][NH:21]3)[N:13]=1.[Cl:44][C:14]1[C:9]2[CH2:8][N:7]([C:6]3[N:5]([CH3:40])[N:4]=[C:3]([CH:41]4[CH2:42][CH2:43]4)[C:2]=3[Cl:52])[CH2:39][CH2:38][C:10]=2[N:11]=[C:12]([C:17]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19]([CH3:37])=[N:20][N:21]3[CH:47]=[O:45])[N:13]=1

Participants

11

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 77311Chloro-N,N-dimethylformiminium chlorideHCID 712388626-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Product 2

HCID 866902914-(4-chloro-6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-3,5-dimethyl-1H-indazole-1-carbaldehydeHCID 178423507HCID 178423507, compound

Reagents, catalysts & solvents 5

HCID 702EthanolSolventHCID 962WaterSolvent2×HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (5.4 g, 8.74 mmol) in EtOH (50 mL) was added concentrated HCl (21.2 mL, 699 mmol) at room temperature, and the reaction mixture was then heated to 100° C. for 24 h. The mixture was then cooled to room temperature and 200 mL of water was added. Then, solid NaOH was added until the pH of the solution reached pH 10. EtOAc was added to the reaction mixture and the resulting layers were separated and the aqueous layers were extracted with EtOAc (3×). The organic layers were combined and the combined organics were dried (Na2SO4), filtered and concentrated to a light yellow solid and used without further purification. The yellow solid (2.47 g, 5.49 mmol) was dissolved in DMF (55 mL) and Vilsmeier reagent (3.51 g, 27.4 mmol) was added to the mixture at room temperature, and the reaction mixture was stirred for 15 min. Then, the reaction mixture was poured into water, and Et2O added. The layers were separated and the aqueous layer was extracted with Et2O. The organics were combined and washed with 5% aqueous LiCl. The organics were then dried (Na2SO4), filtered and concentrated to a yellow oil. The residue was purified by FCC (20-100% EtOAc/heptane) to provide 4-chloro-6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine and 4-(4-chloro-6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-3,5-dimethyl-1H-indazole-1-carbaldehyde, MS (ESI+) m/z 468.1 (M+H)+ and MS (ESI+) m/z 496.1 (M+H)+, respectively.

Workup

  1. temperatureThe mixture was then cooled to room temperature
  2. customthe resulting layers were separated
  3. extractionthe aqueous layers were extracted with EtOAc (3×)
  4. dry with materialthe combined organics were dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated to a light yellow solid
  7. customused without further purification
  8. additionadded
  9. customThe layers were separated
  10. extractionthe aqueous layer was extracted with Et2O
  11. washwashed with 5% aqueous LiCl
  12. dry with materialThe organics were then dried (Na2SO4)
  13. filtrationfiltered
  14. concentrationconcentrated to a yellow oil
  15. customThe residue was purified by FCC (20-100% EtOAc/heptane)

Sources & evidence

ORD record
ord-ef3ddb439fb643e3ac4c534ffbc87054
Source dataset
uspto-grants-2014_09
Patent number
US08846656B2

Reaction notes

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