p-Toluenesulfonic acid monohydrate → 4-(9'-cyclohexyl-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 2234341Notes

Reaction equation

HRID 2234341 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[C:38]([O:39][CH3:40])=[CH:37][C:27]([C:28]([NH:30][C@@H:31]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]2)=[O:29])=[C:26]([F:41])[CH:25]=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([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:38]([O:39][CH3:40])=[CH:37][C:27]([C:28]([NH:30][C@@H:31]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]5)=[O:29])=[C:26]([F:41])[CH:25]=4)=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1

Participants

5

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 579698842'-chloro-9'-cyclohexyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepin]-6'(5'H)-one2×HCID 686817384-amino-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide2×

Product 1

HCID 686819934-(9'-cyclohexyl-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 40%

Reagents, catalysts & solvents 1

HCID 79104-Methyl-2-PentanolSolvent

Procedure

2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 103 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 p-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, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (70 mg, 40%).

Workup

  1. temperatureThe mixture was cooled
  2. customabsorbed on to an SCX column, which
  3. washwas then washed with methanol
  4. washeluted with ammonia in methanol
  5. additionProduct containing fractions
  6. customevaporated
  7. custompurified by base modified reverse phase preparative HPLC

Sources & evidence

ORD record
ord-ac9a939207be4d55862ac10e560b484c
Source dataset
uspto-grants-2010_05
Patent number
US07709471B2

Reaction notes

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