Lithium Hydroxide → (+/-)-4-[1-(5-Cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid methylamide

HRID 45169Notes

Reaction equation

HRID 45169 reaction equation
C([O:3][C:4]([CH:6]1[N:36](C(OC(C)(C)C)=O)[CH2:35][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24](=[O:34])[NH:25][C:26]3[CH:30]=[C:29]([CH:31]5[CH2:33][CH2:32]5)[O:28][N:27]=3)[CH:19]=[CH:18]4)[C:8]=2[CH2:7]1)=O)C.[Li+].[OH-].C(Cl)(=O)C(Cl)=O.[CH3:52][NH2:53]>C1COCC1.CCO.O.CN(C=O)C>[CH3:52][NH:53][C:4]([CH:6]1[NH:36][CH2:35][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24](=[O:34])[NH:25][C:26]3[CH:30]=[C:29]([CH:31]5[CH2:32][CH2:33]5)[O:28][N:27]=3)[CH:19]=[CH:18]4)[C:8]=2[CH2:7]1)=[O:3]

Participants

7

Reactant 4

HCID 3939Lithium HydroxideHCID 6329MethylamineHCID 65578Oxalyl chlorideHCID 593941034-[1-(5-cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester

Product 1

HCID 59394042(+/-)-4-[1-(5-Cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid methylamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 18504229Ethanol tetrahydrofuran waterSolvent

Procedure

To a solution of 4-[1-(5-cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester (110 mg, 0.196 mmol) in THF/EtOH/H2O (3:1:1 mL) LiOH (0.016 g, 0.392 mmol) is added and the reaction stirred until starting material is consumed. At this point the reaction is quenched with 1N HCl (2 mL) and extracted with EtOAc. After drying and evaporation, the crude product is dissolved in DCM (3 mL) at 0° C., oxalyl chloride (0.026 mL, 0.294 mmol) and DMF (2 drops) are added. At this point Methylamine (2 M in THF) (0.49 mL, 0.981 mmol) is added and the reaction stirred for 1 h at rt. After work up with water and extraction with EtOAc the crude product is dissolved in DCM (2 mL) and TFA (1 mL) is added. After removing the solvent in vacuo, and basifying with NH4OH, the product is separated using FCC eluting with DCM:MeOH:NH4OH 100:0:0 to 90:8:2. MS (ESI) m/z 474.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.21 (s, 1 H)8.43 (s, 1 H)8.21-8.33 (m, 1 H)8.15 (d, J=3.79 Hz, 1 H)7.94 (d, J=5.81 Hz, 1 H)7.44 (d, J=2.27 Hz, 1 H)7.12 (d, J=9.09 Hz, 1 H)6.75 (d, J=3.03 Hz, 1 H)6.65 (s, 1 H) 3.91-4.15 (m, 2 H)3.61 (br. s, 1 H)2.83-2.95 (m, 2 H)2.66 (d, J=4.80 Hz, 3 H)2.12-2.24 (m, 1 H) 1.03-1.17 (m, 2 H)0.94 (dd, J=4.80, 2.53 Hz, 2 H).

Workup

  1. customis consumed
  2. customAt this point the reaction is quenched with 1N HCl (2 mL)
  3. extractionextracted with EtOAc
  4. customAfter drying
  5. customevaporation
  6. dissolutionthe crude product is dissolved in DCM (3 mL) at 0° C.
  7. stirringthe reaction stirred for 1 h at rt
  8. extractionAfter work up with water and extraction with EtOAc the crude product
  9. dissolutionis dissolved in DCM (2 mL)
  10. additionTFA (1 mL) is added
  11. customAfter removing the solvent in vacuo
  12. customthe product is separated
  13. washeluting with DCM:MeOH:NH4OH 100:0:0 to 90:8:2

Sources & evidence

ORD record
ord-ef08000580a44926811d20e5a7e25092
Source dataset
uspto-grants-2013_09
Patent number
US08541432B2

Reaction notes

Loading…