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Diisopropylethylamine → 2-[3-[(2,2-Difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl]-N-({6-[(tert-butoxy)carbonylamino]-2-methyl(3-pyridyl)}methyl) Acetamide

HRID 2184195
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Reaktionsgleichung

Reaktionsgleichung von HRID 2184195
[F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([OH:15])=O)[C:8]([Cl:11])=[CH:9][CH:10]=1.[NH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:30][C:31]=1[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:24][CH2:25][C:26]2[C:31]([CH3:32])=[N:30][C:29]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[CH:28][CH:27]=2)=[O:15])[C:8]([Cl:11])=[CH:9][CH:10]=1
KomponentenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

6

Edukt 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 10681361tert-Butyl 5-(aminomethyl)-6-methylpyridin-2-ylcarbamateHCID 224753482-{3-[(2,2-Difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic Acid

Produkt 1

HCID 22475329
2-[3-[(2,2-Difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl]-N-({6-[(tert-butoxy)carbonylamino]-2-methyl(3-pyridyl)}methyl) Acetamide
Ausbeute 91,2 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

To a solution of 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic acid (516 mg, 1.5 mmol), as prepared in step 15 of Example 1, in DMF (8.0 mL) was added N-[5-(aminomethyl)-6-methyl (2-pyridyl)](tert-butoxy) carboxamide (498 mg, 2.1 mmol) (Sanderson, P. E., et al., WO 97/01338 (1997)), BOP (1.06 g, 2.4 mmol), and DIEA (0.78 mL, 4.5 mmol). After stirring for 18 hours, additional amine (107 mg, 450 μmol) was added, and the mixture continued to stir for 18 hours. The solvents were evaporated, and the reaction mixture was partitioned between DCM and saturated NaHCO3. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with 10% KHSO4 (2 times), H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0, 1.5, and 2.5%) to give the title compound (770 mg, 91% yield) as a pale brown foam. 1H-NMR (400 MHz, CDCl3)δ 7.66 (d, J=8.4 Hz, 1H), 7.51-7.41 (m, 6H), 7.23 (bs, 1H), 7.01 (dd, J=8.8, 1.5 Hz, 1H), 6.57 (t, J=9.0 Hz, 1H), 5.64 (br s, 1H), 4.37 (d, J=5.6 Hz, 2H), 4.26-4.22 (m, 1H), 3.79-3.70 (m, 4H), 2.35 (s, 3H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calc'd for C28H31ClF3N4O3 (M+H): 563.2. Found: 562.9.

Aufarbeitung

  1. stirringto stir for 18 hours
  2. customThe solvents were evaporated
  3. customthe reaction mixture was partitioned between DCM and saturated NaHCO3
  4. customThe organic layer was separated
  5. extractionthe aqueous layer extracted with DCM
  6. washwashed with 10% KHSO4 (2 times), H2O, and brine
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated
  9. customflash chromatographed on silica gel eluting with MeOH/DCM (0, 1.5, and 2.5%)

Quellen und Nachweise

ORD-Eintrag
ord-067ca30d36b44ad3b23f5272746a7366
Quelldatensatz
uspto-grants-2005_05
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US06900231B2

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