1-(2-Hydroxyethyl)piperazine → 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 {3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenyl}-methyl-amide

HRID 912267Notes

Reaction equation

HRID 912267 reaction equation
Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:51])[C:9]([N:11]2[C:15]3[N:16]=[C:17]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:18]=[C:19]([C:20]4[CH:21]=[N:22][C:23]([N:26]([CH2:36][C:37]5[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=5)[CH2:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)=[N:24][CH:25]=4)[C:14]=3[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N:89]1([CH2:95][CH2:96][OH:97])[CH2:94][CH2:93][NH:92][CH2:91][CH2:90]1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CN(C=O)C>[OH:97][CH2:96][CH2:95][N:89]1[CH2:94][CH2:93][N:92]([C:2]2[CH:3]=[C:4]([N:8]([CH3:51])[C:9]([N:11]3[C:15]4[N:16]=[C:17]([N:45]5[CH2:50][CH2:49][O:48][CH2:47][CH2:46]5)[N:18]=[C:19]([C:20]5[CH:21]=[N:22][C:23]([N:26]([CH2:36][C:37]6[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=6)[CH2:27][C:28]6[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=6)=[N:24][CH:25]=5)[C:14]=4[CH2:13][CH2:12]3)=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:91][CH2:90]1

Participants

7

Reactant 4

HCID 76771-(2-Hydroxyethyl)piperazineHCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 592449624-{2-[Bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-bromo-phenyl)-methyl-amide

Product 1

HCID 673856414-{2-[Bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenyl}-methyl-amide

Reagents, catalysts & solvents 2

HCID 9832798Tris(dibenzylideneacetone) dipalladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a DMF solution (2.0 ml) 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 (3-bromo-phenyl)-methyl-amide (70.5 mg) obtained in Step B, tris(dibenzylideneacetone) dipalladium (4.3 mg), S-Phos (3.8 mg) and potassium phosphate (39.8 mg), 2-piperazin-1-yl-ethanol (23 μl) was added, and degassed under ultrasonic irradiation. After this was stirred at 100° C. for 4 hours, water (10 ml) was added, followed by extraction with ethyl acetate (10 ml×2), and the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography, to obtain 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 {3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenyl}-methyl-amide. The PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-153) as a colorless solid (7.2 mg, 14%).

Workup

  1. customdegassed under ultrasonic irradiation
  2. additionwater (10 ml) was added
  3. extractionfollowed by extraction with ethyl acetate (10 ml×2)
  4. dry with materialthe organic layer was dried over sodium sulfate
  5. filtrationAfter the sodium sulfate was filtered off
  6. distillationthe solvent was distilled off under reduced pressure
  7. customfollowed by purification by silica gel column chromatography

Sources & evidence

ORD record
ord-a170a361c1d5429093cf3d8d99eec501
Source dataset
uspto-grants-2011_09
Patent number
US08022205B2

Reaction notes

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