Sodium Carbonate → (5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

HRID 877536

Reaktionsgleichung

Reaktionsgleichung von HRID 877536
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([N:15]3[CH2:19][CH2:18][CH:17](CO)[CH2:16]3)=[O:14])=[N:10][N:9]=2)=[C:4]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:3]=1.[NH2:26][C:27]1[CH:35]=[CH:34][C:30]2[N:31]=[CH:32][S:33][C:29]=2[CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:57][C:39]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[S:33]1[C:29]2[CH:28]=[C:27]([NH:26][C:2]3[N:7]=[CH:6][C:5]([C:8]4[S:12][C:11]([C:13]([N:15]5[CH2:16][CH2:17][CH2:18][CH:19]5[CH2:39][OH:57])=[O:14])=[N:10][N:9]=4)=[C:4]([NH:22][CH:23]([CH3:24])[CH3:25])[CH:3]=3)[CH:35]=[CH:34][C:30]=2[N:31]=[CH:32]1

Komponenten

8

Edukt 4

HCID 10340Sodium CarbonateHCID 682886-AminobenzothiazoleHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 89691050(5-(6-Chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone

Produkt 1

HCID 71660460(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
115 °C

Versuchsvorschrift

To a solution of (5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone (27a) (50 mg, 0.15 mmol) in dioxane (5 mL): H2O (1 mL), 6-amino benzothiazole (0.18 mmol, 1.2 equiv.), xanthphos (0.07 mmol, 0.5 equiv.) and Na2CO3 (0.7 mmol, 3 equiv.) were added and degassed for 10 min. To the reaction mixture Pd2(dba)3 (0.07 mmol, 0.5 equiv.) was added and degassed again for 10 min then heated at 115° C., overnight. The reaction mixture was cooled and filtered through small pad of celite. The filtrate was concentrated and the crude material was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent. The material was further purified by prep HPLC to afford the title compound. 1H NMR: 400 MHz, CD3OD: δ 1.38 (d, J=6.40 Hz, 1H), 2.01-2.03 (m, 4H), 3.71-3.85 (m, 4H), 3.87-4.23 (m, 2H), 6.22 (s, 1H), 7.57 (dd, J=2.00, 8.80 Hz, 1H), 8.15 (d, J=8.80 Hz, 1H), 8.22 (m, 1H), 8.35 (bs, 1H), 9.28 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.809 min; LCMS (ES-API), m/z 496.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.317 min; Purity: 96.7%.

Aufarbeitung

  1. customdegassed for 10 min
  2. customdegassed again for 10 min
  3. temperatureThe reaction mixture was cooled
  4. filtrationfiltered through small pad of celite
  5. concentrationThe filtrate was concentrated
  6. customthe crude material was purified by column chromatography through silica gel and MeOH
  7. customThe material was further purified by prep HPLC

Quellen und Nachweise

ORD-Eintrag
ord-5c60ca2741c044109a53076e4ee63ec2
Quelldatensatz
uspto-grants-2015_03
Patentnummer
US08987311B2

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