Ammonia → 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone

HRID 51567Notes

Reaction equation

HRID 51567 reaction equation
N.O1CCOCC1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:34][CH2:33][C:28]4(OCC[O:29]4)[CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][C:10]=1[O:35][CH3:36].Cl>CC(C)=O>[NH2:24][C:22]1[C:23]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([O:35][CH3:36])[CH:11]=3)=[CH:16][N:17]([CH:25]3[CH2:34][CH2:33][C:28](=[O:29])[CH2:27][CH2:26]3)[C:18]=2[N:19]=[CH:20][N:21]=1

Participants

6

Reactant 4

HCID 222AmmoniaHCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 227364215-(4-Amino-3-methoxyphenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine

Product 1

HCID 227363904-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanoneYield 78%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Procedure

tert-Butyl N-4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenylcarbamate (5.7 g, 0.011 mol), conc. ammonia solution (100 mL) and dioxan (100 mL) were heated in a pressure vessel for 20 hr at 120° C. The solvent was evaporated and the residue reconstituted in EtOAc/water (250 mL/100 mL). The organic layer was separated , dried (sodium sulphate), filtered and evaporated to give a solid which by HPLC (conditions: 5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) was observed to be a 2:1 mixture of tert-butyl N-4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenylcarbamate and 5-(4-amino-3-methoxyphenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. The mixture was dissolved in acetone (200 mL) and HCl (SN, 100 mL) was added dropwise over 0.5 hr. The resulting solution was stirred at room temperature overnight and the solvent was then evaporated. The acidic solution was basified with 2N NaOH (ice-cooling) and extracted with EtOAc (3×150 mL). The combined organics were washed with water (2×100 mL). During the extraction process a solid precipitated. This solid was filtered and triturated in hot EtOAc/MeOH. The insolubles were filtered, the filtrate evaporated and then resulting solid triturated with diethylether/ethyl acetate to give a yellow solid. The organic layers from the original extraction were dried (sodium sulphate), filtered and evaporated. The resulting solid was triturated with diethyl ether/ethyl acetate (5:1) and filtered to give 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone as a yellow solid. (2.3 g, combined yield=78%). 1H NMR (d6 DMSO, 400 MHz): 8.17(1H, s), 7.32(1H, s), 6.88(1H, s), 6.77(1H, m), 6.73(1H, m), 6.71(1H, m), 6.07(2H, bs), 5.14(1H, m), 3.81 (3H, s), 2.72(2H, m), 2.35(4H, m), 2.18 (2H, m). HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=11.24 min, 95%

Workup

  1. customThe solvent was evaporated
  2. customThe organic layer was separated
  3. dry with materialdried (sodium sulphate)
  4. filtrationfiltered
  5. customevaporated
  6. customto give a solid which by HPLC (conditions: 5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.)
  7. customthe solvent was then evaporated
  8. extractionextracted with EtOAc (3×150 mL)
  9. washThe combined organics were washed with water (2×100 mL)
  10. customDuring the extraction process a solid precipitated
  11. filtrationThis solid was filtered
  12. customtriturated in hot EtOAc/MeOH
  13. filtrationThe insolubles were filtered
  14. customthe filtrate evaporated
  15. customresulting solid
  16. customtriturated with diethylether/ethyl acetate
  17. customto give a yellow solid
  18. extractionThe organic layers from the original extraction
  19. dry with materialwere dried (sodium sulphate)
  20. filtrationfiltered
  21. customevaporated
  22. customThe resulting solid was triturated with diethyl ether/ethyl acetate (5:1)
  23. filtrationfiltered

Sources & evidence

ORD record
ord-e81fe03e478b4d3bbbaee2372386b2f7
Source dataset
uspto-grants-2004_03
Patent number
US06713474B2

Reaction notes

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