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Synthesis of 6-(3-Chloro-2-fluorobenzyl)-1- [1(S)-(hydroxymethyl)-2-methylpropyl] -7- methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

IP.com Disclosure Number: IPCOM000236466D
Publication Date: 2014-Apr-29
Document File: 3 page(s) / 30K

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Synthesis of 6-(3-Chloro-2-fluorobenzyl)-1- [1(S)-(hydroxymethyl)-2-methylpropyl] -7- methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
  6-(3-Chloro-2-fluorobenzyl)-1- [1(S)-(hydroxymethyl)-2-methylpropyl] -7-methoxy- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid referred to as Compound I, has the following chemical structure:

F

Cl

Provided herein are processes for preparing Compound I and intermediates thereof.

Example 1: Process for preparing 5-bromo-2,4-dimethoxybenzoic acid (2)

2,4-dimethoxybenzoic acid (10.0g; 45,89 mmol) was dissolved in acetic acid (80 ml) at room temperature. Into the obtained clear solution bromine (3.96 ml; 76,79 mmol) was added dropwise. The obtained suspension was stirred at room temperature for 1h, filtered off and washed with acetic acid. The obtained crystals were dissolved in dichloromethan (600 ml) and the solution was washed with 1% Na2SO3 solution (50 mL). The organic layer was concentrated to half volume and precipitated white crystals were filtered off (8,81 g; 61,5%).

Example 2: Process for preparing 5-bromo-2,4-dimethoxybenzoyl chloride (3)

To a suspension of 2 (80,76 g; 2,80 mmol) in methyl-t-butyl ether (10 ml) and DMF (0,1 eq) thionyl chloride (0,24 ml; 3,20 mmol) at 55 °C was added. The reaction mixture was stirred for 0,5 h, cooled to room temperature and white crystalls of 3 were filtered off (0,70 g; 89,7%).

Example 3: Process for preparing 3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropanenitrile (4)

Cyanoacetic acid (3,06 g;36mmol) and MgCl2 were suspended in THF (abs., 35 ml), NEt3 (9 ml; 64.6 mmol) was added dropwise, and reaction mixture was stirred at 60°C for 2 h. After cooling to room temperature 3 (3.6 g; 12.9 mmol) was added at once. The reaction mixture was stirred at 60°C for 1 h, cooled to room temperature and EtOAc (100 ml) and H3PO4 (dill.; 15ml conc./135 ml H2O) were added. After extraction, the organic layer was washed with water (2x100 ml), KHCO3 (dill.), water (2x100 ml), and dried over Na2SO4. After evaporation of the solvent, 1.24 g of crude product was obtained. The crude product was purified by flash

O

O N

O

OH

OH


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chromatography using dichloromethane as eluent and pure product (1.14 g; 31.0%) in form of light yellow solid was obtained.

Example 4: Process for preparing (S,E)-2-(5-bromo-2,4-dimethoxybenzoyl)-3-(1-hydroxy-3-

methylbutan-2-ylamino)acrylonitrile (6)

Compound 4 (0.5 g; 1.8 mmol) was suspended in DMF (2,5 ml) and DMF-dimethylacetal
(0.28 ml; 2.1 mmol) and HOAc (2.5 µl; 0.04 mmol) were added. The reaction mixture was stirred at 80°C for 2 h and L-valinol (0.274 g; 2.7 mmol) was added. The reaction mixture was stirred at 80 °C for 2.5 h and cooled to room temperature. EtOAc (35 ml) was added and the mixture was washed with NaCl solution (sat.; 5x30 ml), organic extract dried over Na2SO4 and solvent was evaporated at reduced pressure. Crude product was purified by flash chromatography using diisopropyl ether/methanol (9:1) mixture as eluen...