Tetrahydrofuran → Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(5-chloro-2-difluoromethoxy-phenyl)-2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-thiazol-5-yl]-amide

HRID 529777Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 529777
Br[C:2]1[S:3][C:4]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:15]([F:17])[F:16])[N:6]=1.CN1CC2C(CNC2)C1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH2:52]1[CH2:62][CH2:61][N:60]2[C:55](=[N:56][CH2:57][CH2:58][CH2:59]2)CC1.C1C[O:66][CH2:65]C1>CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd].CO.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH:15]([F:17])[F:16])=[C:7]([C:5]2[N:6]=[C:2]([C:65]([N:56]3[CH2:57][CH:58]4[CH:62]([CH2:61][N:60]([CH3:55])[CH2:59]4)[CH2:52]3)=[O:66])[S:3][C:4]=2[NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[CH:12]=1

Komponenten

9

Edukt 5

HCID 8028TetrahydrofuranHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 83681Tris(1,1-dimethylethyl)phosphineHCID 129585332-Methyloctahydropyrrolo(3,4-c)pyrroleHCID 118531712Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide

Produkt 1

HCID 123842147Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(5-chloro-2-difluoromethoxy-phenyl)-2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-thiazol-5-yl]-amideAusbeute 8 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 98885Molybdenum carbonyl (Mo(CO)6)KatalysatorHCID 11104995trans-Bis(acetato)bis[2-[bis(2-methylphenyl)phosphino]benzyl]dipalladium(II)KatalysatorHCID 887MethanolLösungsmittel4×

Reaktionsbedingungen

Temperatur
125 °C

Versuchsvorschrift

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (200 mg, 0.4 mmol), 2-methyl-octahydro-pyrrolo[3,4-c]pyrrole (70 mg, 0.56 mmol), Herrmann's catalyst (4.5 mg, 0.0048 mmol), tri-tert-butyl phosphine hydrofluoroborate (3.5 mg, 0.011 mmol), molybdenum hexacarbonyl (53 mg, 0.2 mmol) and DBU (40 μl, 0.27 mmol) were dissolved in THF (2 ml) and heated in a microwave at 125° C. for 15 mins. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The resulting yellow glass was purified by HPLC (MDAP, Method 1). Appropriate fractions were combined and evaporated to afford a yellow solid. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH to give the title compound as a pale yellow solid (18 mg, 8%). LCMS (Method 5) [M+H]+=574.1, RT=3.06 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.88 (s, 1H), 9.42 (dd, 1H, J=1.6, 7.0 Hz), 8.81 (s, 1H), 8.61 (dd, 1H, J=1.5, 4.3 Hz), 7.84 (d, 1H, J=2.6 Hz), 7.73 (dd, 1H, J=2.6, 8.8 Hz), 7.54 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=4.3, 7.0 Hz), 7.22 (t, 1H, J=73.1 Hz), 4.24 (dd, 1H, J=8.6, 12.3 Hz), 4.09 (dd, 1H, J=3.9, 12.3 Hz), 3.80 (dd, 1H, J=8.9, 12.6 Hz), 3.59-3.47 (m, 1H), 3.02-2.92 (m, 1H), 2.88-2.80 (m, 1H), 2.65-2.48 (m, 4H), 2.29 (s, 3H).

Aufarbeitung

  1. customAfter flushing with MeOH
  2. washthe product was eluted with 2M ammonia in MeOH
  3. customThe resulting yellow glass was purified by HPLC (MDAP, Method 1)
  4. customevaporated
  5. customto afford a yellow solid
  6. customAfter flushing with MeOH
  7. washthe product was eluted with 2M ammonia in MeOH

Quellen und Nachweise

ORD-Eintrag
ord-f138fbb4fdda4dcf882c367c53ad3469
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09346815B2

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