Benzaldehyde → 1-[5-(Benzylidene-amino)-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester

HRID 1521445Notes

Reaction equation

HRID 1521445 reaction equation
[CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]3[CH:30]=[C:31]([Cl:35])[C:32]([NH2:34])=[CH:33][C:21]=3[N:20]=2)[CH:18]=1)=[O:13])[CH3:10].NC1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2C=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]3[CH:30]=[C:31]([Cl:35])[C:32]([N:34]=[CH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:33][C:21]=3[N:20]=2)[CH:18]=1)=[O:13])[CH3:10]

Participants

6

Reactant 4

HCID 240BenzaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 444790641-(5-Amino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidHCID 669373191-[5-Amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester

Product 1

HCID 669371281-[5-(Benzylidene-amino)-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl esterYield 78.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
23 °C

Procedure

Benzaldehyde (93.0 mg, 0.876 mmol), 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.300 g, 0.762 mmol), THF (3 mL), and 4 Å molecular sieves (0.910 g) were combined and stirred for 18 h at 23° C. Sodium triacetoxyborohydride (0.242 g, 1.14 mmol) was added and stirring was continued for 4 days. The reaction was quenched with saturated aqueous sodium bicarbonate (15 mL) and stirred with dichloromethane (25 mL). This mixture was filtered and the layers were separated. The aqueous layer was extracted with dichlormethane (2×25 mL) and the combined organic layers were washed with brine (20 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound (0.288 g, 78% yield) as a 4:3 mixture of regioisomers. The titled compound was not stable enough to obtain a mass spectrum. 1H NMR (400 MHz, CDCl3): 8.87 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 8.03-7.94 (m, 2H), 7.73 (s, 1H), 7.58-7.48 (m, 3H), 7.39 (s, 1H), 6.12 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.7-3.6 (m, 2H), 3.5-3.4 (m, 2H), 3.32 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).

Workup

  1. stirringstirring
  2. waitwas continued for 4 days
  3. customThe reaction was quenched with saturated aqueous sodium bicarbonate (15 mL)
  4. stirringstirred with dichloromethane (25 mL)
  5. filtrationThis mixture was filtered
  6. customthe layers were separated
  7. extractionThe aqueous layer was extracted with dichlormethane (2×25 mL)
  8. washthe combined organic layers were washed with brine (20 mL)
  9. customdried
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified (FCC) (10-45% EtOAc/hexanes)

Sources & evidence

ORD record
ord-1c430c6888b04aec8548f46b7fd12477
Source dataset
uspto-grants-2015_07
Patent number
US09073923B2

Reaction notes

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