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 529777Notes

Reaction equation

HRID 529777 reaction equation
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

Participants

9

Reactant 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

Product 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]-amideYield 8%

Reagents, catalysts & solvents 3

HCID 98885Molybdenum carbonyl (Mo(CO)6)CatalystHCID 11104995trans-Bis(acetato)bis[2-[bis(2-methylphenyl)phosphino]benzyl]dipalladium(II)CatalystHCID 887MethanolSolvent4×

Conditions

Temperature
125 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-f138fbb4fdda4dcf882c367c53ad3469
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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