Cesium carbonate → (R)-5-chloro-2-fluoro-4-(9'-isopropyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-N-(1-methylpyrrolidin-3-yl)benzamide

HRID 2234307Notes

Reaction equation

HRID 2234307 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[C:8]3([CH2:17][CH2:16]3)[CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=2[N:12]=1.[NH2:20][C:21]1[C:35]([Cl:36])=[CH:34][C:24]([C:25]([NH:27][C@@H:28]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29]2)=[O:26])=[C:23]([F:37])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd+2].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>[Cl:36][C:35]1[C:21]([NH:20][C:2]2[N:3]=[CH:4][C:5]3[N:6]([CH3:19])[C:7](=[O:18])[C:8]4([CH2:17][CH2:16]4)[CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=3[N:12]=2)=[CH:22][C:23]([F:37])=[C:24]([CH:34]=1)[C:25]([NH:27][C@@H:28]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29]1)=[O:26]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 686875884-amino-5-chloro-2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide2×HCID 866175592'-chloro-9'-isopropyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepin]-6'(5'H)-one2×

Product 1

HCID 68682696(R)-5-chloro-2-fluoro-4-(9'-isopropyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-N-(1-methylpyrrolidin-3-yl)benzamideYield 90%

Reagents, catalysts & solvents 2

HCID 9897284tris(dibenzylideneacetone) palladium (II)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2′-chloro-9′-isopropyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 208; 88 mg, 0.32 mmol), 4-amino-5-chloro-2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide (Intermediate 207; 101 mg, 0.36 mmol) and XANTPHOS (17 mg, 0.03 mmol) were dissolved in 1,4-dioxane (7.5 mL). Caesium carbonate (229 mg, 0.65 mmol) was added and the system purged with a stream of nitrogen for 15 minutes before tris(dibenzylideneacetone) palladium (II) (18 mg, 0.02 mmol) was added. The apparatus was evacuated and backfilled with nitrogen (×3) and then heated at 100° C. for 3 hours. The mixture was cooled, filtered and the filtrate absorbed on to an SCX column, which was washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% 7N ammonia in MeOH/DCM) to yield the title compound as a pale yellow foam (148 mg, 90%).

Workup

  1. additionwas added
  2. customThe apparatus was evacuated
  3. temperatureThe mixture was cooled
  4. filtrationfiltered
  5. customthe filtrate absorbed on to an SCX column, which
  6. washwas washed with methanol
  7. washeluted with ammonia in methanol
  8. additionProduct containing fractions
  9. concentrationwere concentrated
  10. custompurified by column chromatography (2.5% 7N ammonia in MeOH/DCM)

Sources & evidence

ORD record
ord-ba1f5044f6df41228d2cb65bdc8df924
Source dataset
uspto-grants-2010_05
Patent number
US07709471B2

Reaction notes

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