Separation and application background and overview of 2-tetrahydrofurancarboxylic acid[1][2]
2-Tetrahydrofuran-2-carboxylic acid (2-THFA), after separation, (R)-2-THFA and (S)-2-THFA can be obtained respectively. Chiral 2-tetrahydrofurancarboxylic acid is not Important ligand synthon in symmetric synthesis reactions. Among them, (R)-2-THFA is an important intermediate in the synthesis of the antibiotic furopenem. It can be used as an antagonist of the antigen VLA-4. It is also a chiral resolving agent for an important intermediate of the super influenza drug Xofluza; (S)-2- THFA is the main raw material for the preparation of chiral auxiliary (S)-acetyltetrahydrofuran, the raw material for the preparation of cephalosporin antibiotic intermediates, and an important intermediate for the preparation of the hormone LHRH that stimulates hormone release.
Resolution and application of 2-tetrahydrofurancarboxylic acid[1]
Add (RS)-2-THFA (0.638g, 5.5mmol) into a 50mL two-neck reaction flask, add L-phenylalaninol (0.38g, 2.5mmol, 99% ee), and add 5mL ethyl acetate Mixed solvent with 15 mL of acetone, react at 20°C for 1 hour, a white solid precipitates, filter, and weigh to obtain 0.366 g of diastereomeric salt. The obtained diastereomeric salt is recrystallized with ethyl acetate. First, heat it to about 77°C to obtain a clear and transparent liquid. Stop heating, slowly cool down naturally and stir at low speed until the temperature drops to 20°C. Stir at constant temperature and low speed to crystallize. After 1 hour, filter, dissolve the filter cake with 5mol/L sulfuric acid aqueous solution and adjust to pH<2, add DCM (3×10mL) to extract and separate the layers, combine the extracted organic phases, then dry with anhydrous Na2SO4, and then concentrate to recover the solvent to obtain (S)-2-THFA (0.136g), 99.5% ee, 42.6% yield.
Add D-phenylalaninol resolving agent (2.5 g, 16.5mmol, 98% ee) and 75mL acetone into a 250mL three-neck reaction flask. After stirring to dissolve the resolving agent, add 25mL ethyl acetate and (R) -2-THFA (2.tetramethylurea tetrafluoroborate 88g, 24.8mmol, 22.79% ee, recovered in Example 9), mechanically stirred for 1 hour at 20°C, a white solid precipitated, filtered quickly, and weighed 2.229 g of diastereomeric salts were recovered. The obtained diastereomeric salt is recrystallized with acetone. First, heat it to about 56°C to obtain a clear and transparent liquid. Stop heating, slowly cool down naturally and stir at low speed until the temperature drops to 20°C. Stir at constant temperature and low speed for 1 hour to crystallize. Filter, dissolve the filter cake with 5mol/L sulfuric acid aqueous solution and adjust to pH <2, add DCM (3×50mL) for extraction, separate the liquids to obtain the aqueous phase d1 and the first organic phase, combine the extracted first organic phase, and then use Dry over anhydrous Na2SO4, then concentrate to recover the solvent to obtain (R)-2-THFA (0.59g), 99.9% ee, yield 31.6%.
Separation and application of 2-tetrahydrofurancarboxylic acid[2]
Alfuzosin hydrochloride is a quinazoline derivative that can competitively bind to α1-receptors in the prostate, prostate capsule, proximal urethra and bladder base, and antagonize α1-receptor-mediated Smooth muscle contraction. Alfuzosin hydrochloride can significantly reduce urinary disorders in clinical patients with benign prostatic hyperplasia, increase urinary flow rate, and effectively improve the patient’s quality of life. Alfuzosin hydrochloride was developed by the German company Beiezsdozf. It was first launched in France in 1988 and has been widely used in the treatment of clinical symptoms of benign prostatic hyperplasia. CN200410080024.9 discloses a preparation method of alfuzosin hydrochloride, which uses N-methylpropylenediamine as raw material and undergoes a condensation reaction with 2-tetrahydrofurancarboxylic acid chloride or 2-tetrahydrofurancarboxylic acid. The resulting condensate is directly used without purification. Cerium carbonate reacts with 2-chloro-4-amino-6,7-dimethoxyquinazoline to undergo a condensation reaction to obtain alfuzosin, which is then salted with hydrochloric acid to obtain alfuzosin hydrochloride. The method has simple operation, low cost, high yield and easy realization of reaction conditions, and is suitable for large-scale industrial production.
