Diisopropylethylamine → 7-(2-Butyn-1-yl)-8-[(3R)-3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-piperidinyl]-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione

HRID 44900Notes

Reaction equation

HRID 44900 reaction equation
[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[C:40]1(=[O:56])[N:44]([CH:45]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]2)[C:43](=[O:51])[C:42]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:41]12.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:47]4[CH2:48][CH2:49][CH2:50][C@@H:45]([N:44]5[C:43](=[O:51])[C:42]6=[CH:52][CH:53]=[CH:54][CH:55]=[C:41]6[C:40]5=[O:56])[CH2:46]4)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 247500498-Bromo-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dioneHCID 667041493-(Phthalimido)piperidine d-tartrate

Product 1

HCID 595225287-(2-Butyn-1-yl)-8-[(3R)-3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-piperidinyl]-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
140 °C

Procedure

10.00 kg (22.06 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 12.59 kg (33.09 mol) of 3-(phthalimido)piperidine D-tartrate and 17.5 liters of N-methyl-2-pyrrolidone are initially charged in the reactor. The reactor contents are heated to 140° C. After the temperature has been attained, 11.41 kg (88.24 mol) of diisopropylethylamine are metered in within 20 minutes. The feed vessel is flushed with 2.5 liters of N-methyl-2-pyrrolidone and the reaction mixture is subsequently stirred at 140° C. for 2 hours. After the reaction has ended, the reaction mixture is cooled to 60° C. and diluted with 80 liters of methanol. The resulting suspension is stirred at 50° C. for 30 minutes, then cooled to 23° C. and stirred for a further 30 minutes. Subsequently, the product is centrifuged off and washed 3 times with 20 liters each time of methanol. Drying is effected at 45° C. in a drying cabinet under inertization.

Workup

  1. customare metered in within 20 minutes
  2. customThe feed vessel is flushed with 2.5 liters of N-methyl-2-pyrrolidone
  3. temperaturethe reaction mixture is cooled to 60° C.
  4. additiondiluted with 80 liters of methanol
  5. stirringThe resulting suspension is stirred at 50° C. for 30 minutes
  6. temperaturecooled to 23° C.
  7. stirringstirred for a further 30 minutes
  8. washwashed 3 times with 20 liters each time of methanol
  9. customDrying
  10. customis effected at 45° C. in a drying cabinet under inertization

Sources & evidence

ORD record
ord-19cc520347484076bb791909116eb117
Source dataset
uspto-grants-2013_09
Patent number
US08541450B2

Reaction notes

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