p-Toluenesulfonic acid monohydrate → 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide

HRID 2234325Notes

Reaction equation

HRID 2234325 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:37]([O:38][CH3:39])=[CH:36][C:26]([C:27]([NH:29][C@@H:30]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31]2)=[O:28])=[C:25]([F:40])[CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:37]([O:38][CH3:39])=[CH:36][C:26]([C:27]([NH:29][C@@H:30]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31]5)=[O:28])=[C:25]([F:40])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1

Participants

5

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 579699392-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropan]-6(7H)-one2×HCID 686817384-amino-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide2×

Product 1

HCID 686826364-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamideYield 46.5%

Reagents, catalysts & solvents 1

HCID 79104-Methyl-2-PentanolSolvent

Procedure

2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 100 mg, 0.32 mmol), 4-amino-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide (Intermediate 182; 87 mg, 0.32 mmol) and 4-toluenesulphonic acid monohydrate (154 mg, 0.81 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140° C. for 3 hours. The mixture was cooled and absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (80 mg, 46%).

Workup

  1. temperatureThe mixture was cooled
  2. customabsorbed on to an SCX column
  3. washwashed with methanol
  4. washeluted with ammonia in methanol
  5. additionProduct containing fractions
  6. concentrationwere concentrated
  7. custompurified by base modified reverse phase preparative HPLC

Sources & evidence

ORD record
ord-0ae1d41251ae4eafb827a878e3fb9d97
Source dataset
uspto-grants-2010_05
Patent number
US07709471B2

Reaction notes

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