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1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) → 5-chloro-4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide

HRID 2234340
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 2234340
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:41]([Cl:42])=[CH:40][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]2)=[O:29])=[C:26]([F:43])[CH:25]=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>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:42][C:41]1[C:24]([NH:23][C:2]2[N:3]=[CH:4][C:5]3[N:6]([CH3:22])[C:7](=[O:21])[C:8]4([CH2:19][CH2:20]4)[CH2:9][N:10]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:11]=3[N:12]=2)=[CH:25][C:26]([F:43])=[C:27]([CH:40]=1)[C:28]([NH:30][CH:31]1[CH2:32][CH2:33][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:35][CH2:36]1)=[O:29]
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Komponenten

6

Edukt 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 579698842'-chloro-9'-cyclohexyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepin]-6'(5'H)-one2×HCID 686828744-amino-5-chloro-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide2×

Produkt 1

HCID 68682573
5-chloro-4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide
Ausbeute 28,2 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9897284tris(dibenzylideneacetone) palladium (II)KatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

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-5-chloro-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide (Intermediate 175; 92 mg, 0.29 mmol), and XANTPHOS (16 mg, 0.03 mmol) were dissolved in 1,4-dioxane (7.5 mL). Caesium 10 carbonate (210 mg, 0.59 mmol) was added and the system purged with a stream of nitrogen for 15 minutes before tris(dibenzylideneacetone) palladium (II) (17 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, and the column then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (49 mg, 28%).

Aufarbeitung

  1. additionwas added
  2. customThe apparatus was evacuated
  3. temperatureThe mixture was cooled
  4. filtrationfiltered
  5. customthe filtrate absorbed on to an SCX column
  6. washthe column then washed with methanol
  7. washeluted with ammonia in methanol
  8. additionProduct containing fractions
  9. customevaporated
  10. customthe residue purified by base modified reverse phase preparative HPLC

Quellen und Nachweise

ORD-Eintrag
ord-3855e6edb4d44478aa36662672d8eb8f
Quelldatensatz
uspto-grants-2010_05
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US07709471B2

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