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

HRID 912155Notes

Reaction equation

HRID 912155 reaction equation
COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.N1C=CC=CC=1.[C:47](Cl)(Cl)=[S:48].[CH2:51]([N:53]1[CH2:58][CH2:57][N:56]([C:59]([C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[C:63]([NH2:68])[CH:62]=2)=[O:60])[CH2:55][CH2:54]1)[CH3:52]>ClCCl>[CH2:51]([N:53]1[CH2:54][CH2:55][N:56]([C:59]([C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[C:63]([NH:68][C:47]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)[N:20]=[C:15]([C:12]5[CH:13]=[N:14][C:9]([NH2:8])=[N:10][CH:11]=5)[C:16]=4[CH2:29][CH2:28]3)=[S:48])[CH:62]=2)=[O:60])[CH2:57][CH2:58]1)[CH3:52]

Participants

6

Reactant 4

HCID 1049PyridineHCID 10040ThiophosgeneHCID 167887345-[(4-Ethylpiperazin-1-YL)carbonyl]-2-methylanilineHCID 45258862Bis-(4-methoxybenzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine

Product 1

HCID 592444334-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid [5-(4-ethyl-piperazine-1-carbonyl)-2-methyl-phenyl]-amideYield 39%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
80 °C

Procedure

A dichloromethane solution (3 ml) 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 (100 mg, 0.185 mmol), pyridine (30 μl, 0.37 mmol) and thiophosgene (28 μl, 0.37 mmol) was stirred for 40 minutes. This was concentrated and dried under reduced pressure, and subsequently (4-ethyl-piperazin-1-yl)-(3-amino-4-methyl-phenyl)-methanone (90 mg, 0.390 mmol) obtained in Step B was added, followed by stirring in dichloromethane (3 ml) for 16 hours. The reaction mixture was washed with aqueous ammonium chloride solution, and subsequently dried over sodium sulfate. The drying agent was removed, followed by concentration and drying. To this, TFA (2 ml) was added, followed by stirring at 80° C. for 4 hours. After TFA was removed under reduced pressure, dichloromethane was added, followed by washing with sodium hydrogencarbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered and concentrated, to obtain a crude product. Purification by silica gel column chromatography (dichloromethane/methanol=10/1) afforded 4-(2-amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid [5-(4-ethyl-piperazine-1-carbonyl)-2-methyl-phenyl]-amide (42 mg, 39%) as a pale yellow powder.

Workup

  1. concentrationThis was concentrated
  2. additionwas added
  3. washThe reaction mixture was washed with aqueous ammonium chloride solution
  4. dry with materialsubsequently dried over sodium sulfate
  5. customThe drying agent was removed
  6. concentrationfollowed by concentration
  7. customdrying
  8. additionTo this, TFA (2 ml) was added
  9. customAfter TFA was removed under reduced pressure, dichloromethane
  10. additionwas added
  11. washby washing with sodium hydrogencarbonate aqueous solution
  12. dry with materialThe organic layer was dried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customto obtain a crude product
  16. customPurification by silica gel column chromatography (dichloromethane/methanol=10/1)

Sources & evidence

ORD record
ord-36b68e72510a41398bd4c2fdd4bb213b
Source dataset
uspto-grants-2011_09
Patent number
US08022205B2

Reaction notes

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