Pyridine → 4-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazine-1-carbonyl)-2,6-difluoro-phenyl]-amide

HRID 912168Notes

Reaction equation

HRID 912168 reaction equation
COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.N1C=CC=CC=1.ClC(Cl)(O[C:51](=O)[O:52][C:53](Cl)(Cl)Cl)Cl.NC1C(F)=CC(C(N2CCN(CC)CC2)=O)=CC=1F.[CH2:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]([C:88]2[CH:93]=[C:92]([F:94])[C:91]([NH:95][C:96]([N:98]3[C:102]4[N:103]=[C:104]([N:132]5[CH2:137]COC[CH2:133]5)[N:105]=[C:106]([C:107]5[CH:108]=[N:109][C:110]([N:113](CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=[N:111][CH:112]=5)[C:101]=4[CH2:100][CH2:99]3)=[O:97])=[C:90]([F:138])[CH:89]=2)=[O:87])[CH2:82][CH2:81]1)[CH3:79].C(N[C@H](C(O)=O)CS)(=O)C>ClCCl.C(O)(C(F)(F)F)=O>[CH2:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]([C:88]2[CH:89]=[C:90]([F:138])[C:91]([NH:95][C:96]([N:98]3[C:102]4[N:103]=[C:104]([N:132]5[CH2:137][CH2:51][O:52][CH2:53][CH2:133]5)[N:105]=[C:106]([C:107]5[CH:112]=[N:111][C:110]([NH2:113])=[N:109][CH:108]=5)[C:101]=4[CH2:100][CH2:99]3)=[O:97])=[C:92]([F:94])[CH:93]=2)=[O:87])[CH2:82][CH2:81]1)[CH3:79]

Participants

9

Reactant 6

HCID 1049PyridineHCID 12035N-Acetyl-L-CysteineHCID 94429TriphosgeneHCID 45258862Bis-(4-methoxybenzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amineHCID 55160008(4-Amino-3,5-difluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone2×HCID 673849544-{2-[Bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazine-1-carbonyl)-2,6-difluoro-phenyl]-amide

Product 1

HCID 592446784-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazine-1-carbonyl)-2,6-difluoro-phenyl]-amideYield 51%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

To a solution of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (2.50 g, 4.63 mmol) in dichloromethane (50 ml), pyridine (749 ml, 9.27 mmol) was added, and triphosgene (2.75 g, 9.27 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. To this, dichloroethane (100 ml) was added, and (4-amino-3,5-difluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (4.99 g, 18.5 mmol) obtained in Step D was added, followed by refluxing for 14 hours. The solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=50/1 to 10/1), to obtain a mixture of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazine-1-carbonyl)-2,6-difluoro-phenyl]-amide and (4-amino-3,5-difluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone. This was dissolved in TFA (40 ml), and N-acetylcysteine (1.13 g, 6.95 mmol) was added, followed by refluxing for 14 hours. The solvent was distilled off under reduced pressure. 5M-NaOH aqueous solution was added to adjust the pH to 8, and 500 ml of water was added, followed by extraction with dichloromethane (1 l×3). The solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=40/1 to 10/1), followed by further washing with methanol (100 ml), to obtain the desired compound as a yellow solid (1.31 g, 51%).

Workup

  1. distillationthe solvent was distilled off under reduced pressure
  2. additionTo this, dichloroethane (100 ml) was added
  3. temperatureby refluxing for 14 hours
  4. distillationThe solvent was distilled off under reduced pressure
  5. customfollowed by purification by silica gel column chromatography (dichloromethane/methanol=50/1 to 10/1)
  6. customto obtain
  7. temperatureby refluxing for 14 hours
  8. distillationThe solvent was distilled off under reduced pressure
  9. addition5M-NaOH aqueous solution was added
  10. additionwas added
  11. extractionfollowed by extraction with dichloromethane (1 l×3)
  12. distillationThe solvent was distilled off under reduced pressure
  13. customThis was purified by silica gel column chromatography (dichloromethane/methanol=40/1 to 10/1)
  14. washby further washing with methanol (100 ml)

Sources & evidence

ORD record
ord-408014cc492d41d6a811b54f673a8d6c
Source dataset
uspto-grants-2011_09
Patent number
US08022205B2

Reaction notes

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