Preparation and application background of (R)-tetrahydrofurancarboxylic acid
(R)-Tetrahydrofurancarboxylic acid is an important pharmaceutical intermediate, and the effectiveness of its stereoisomers has attracted people’s attention. P.C. Belanger et al. “(Can.J.Chem.61, 1383 (1983)” first reported an effective separation method for this compound. However, this method used extremely toxic and expensive strychnine ( Brucinedihydrate) as the resolving agent. In addition, this method also has problems such as low product yield and low recovery rate of the resolving agent. In order to solve these problems and make this separation process adapt to the needs of industrial production, Researchers have done a lot of research on resolving agents, reaction solvents, etc.
(R)-Tetrahydrofurancarboxylic acid
Preparation and application of (R)-tetrahydrofurancarboxylic acid
(R)-Tetrahydrofurancarboxylic acid can be used to prepare azosin-based drugs for the treatment of hypertension, alfuzosin, terazosin, drugs for the treatment of prostate cancer, as well as the synthesis of cephalosporin antibiotic intermediates and chiral auxiliaries (R)- Acetyl tetrahydrofuran. At present, only furancarboxylic acid is produced in China, and (R)-tetrahydrofurancarboxylic acid is not produced. The price of imported products is as high as 4,500 yuan/kg, and the price of split R-tetrahydrofurancarboxylic acid is as high as 1,500 US dollars/b. Now domestic Research on azosin-based products is active and there are many manufacturers, so there will be a greater demand for (R)-tetrahydrofurancarboxylic acid.
Preparation and application of (R)-tetrahydrofurancarboxylic acid to prepare N-3-chloropropyl-2-tetrahydrofurancarboxamide
Under the conditions of organic base, 3-halopropylamine and (R)-tetrahydrofurancarboxylic acid undergo a condensation reaction in a solvent to obtain N-3-chloropropyl-2-tetrahydrofurancarboxamide (II). The reaction temperature is -10℃～100℃, reaction time is 6～28 hours.
Preparation and application of (R)-tetrahydrofurancarboxylic acid
Preparation of resolving agent (+)-dimethylchloramphenicol
Add 35g (0.165mol) D-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol into 40ml 85% formic acid in batches under cooling and stirring. Then 35 ml of 37% formaldehyde was added dropwise, and the reaction mixture was stirred and reacted at a bath temperature of 100°C for 6 hours. After natural cooling, add 40ml of 4NHCI and concentrate under reduced pressure until the formaldehyde is evaporated. The residual liquid was adjusted to pH=9 with 30% NaOH, and a large amount of yellow crystals precipitated. It was suction filtered, and the solid was washed twice with water, dried in vacuum, and recrystallized with benzene (1g/ml) to obtain (+)-dimethylchloramphenicol. The amine is a light yellow needle-shaped crystal, with a yield of 36 to 38 grams, a yield of 91 to 96%, m.p=97 to 98°C, [α]25°=+27° (C=1, CH3OH).
Preparation and application of (R)-tetrahydrofurancarboxylic acid Preparation of (R)-tetrahydrofurancarboxylic acid
Dissolve 24g (0.1mol)(+)-dimethylchloramphenicol into 105ml of a mixed solvent of formic acid and ethyl acetate (1:2), and stir at a bath temperature of 60 to 70°C. A solution of 11.6g (0.1mol) (±)-2-tetrahydrofurancarboxylic acid in 15ml of the above mixed solvent was added dropwise. After the dripping was completed, the reaction was continued to stir for 0.5 hours and left to stand. The light yellow square crystals generated by filtration are (+) amine·(-) acid salt, weighing 14 grams. The mother liquor is concentrated to 80 ml, left to stand, cooled, and filtered, and 2 grams of crystals are obtained (the mother liquor is collected and used as (R )-Tetrahydrofurancarboxylic acid, yield 90%, [&alpisopropylpyridine ha;] 25°=+16.5° (C=1, CH3OH).
Dissolve the above crystals into a mixed solvent of 10 ml water and 20 ml ethyl acetate, and add 40% NaOH aqueous solution dropwise with stirring until the pH is about 9. The organic layer was separated, and the aqueous layer was extracted four times with ethyl acetate (20 ml/time). The organic layers were combined and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the remaining solid was recrystallized from benzene. 10 grams (92%) of the resolving agent (+)-dimethylchloramphenicol was recovered. After the aqueous layer was adjusted to pH=1~2 with 6NHCI, it was extracted with ethyl acetate 5 times (30ml/time). The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated, and then distilled under reduced pressure. The 99-100°C/300Pa fraction was collected to obtain 4.4 grams of colorless (R)-tetrahydrofurancarboxylic acid, with a yield of 85%.
