Study On Total Synthesis Of Nebivolol

In this thesis, the total synthesis of Nebivolol was stdudied.Nebivolol is a new kind of drug for lowering blood pressure with additional effect for dilatating cardiovasculars. There are several filed synthetic methods for Nebivolol, among which the one invented by Janssen Pharmaceutica Institution via the optical resolution of a chroman carboxylic acid is the most suitable one to be industrialized. But it is still restricted by synthetic routes and high cost ,which makes Nebivolol difficult to be widely used. In this thesis, the synthesis of the main intermediates and the whole synthetic system of Nebivolol were studied, aiming to optimize the industrialized conditions . Following are the contents and results:1) The key intermediate 6-fluro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (6), which was the raw material in the Janssen's, was synthesized from 4-fluoro phenol as follows:Maleic anhydride method: 6-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (5) was synthesized from 4-fluoro phenol, via methylization, Friedel-Crafts reaction with Maleic anhydride and then Michael addition at basic condition to be cyclized . 5 was hydrogenolysised in catalyst to give 6 . Conditions were studied, and the optimized one was achieved. The key step was cyclization, whose yield was found best in condition of 10% NaHCO₃ catalyzing and refluxing for 15 min. The yield overall was 67.0%.Diethyl oxalate method: It involves 6 steps including esterification, rearrangment, acylation, cyclization, hydrolyzation and hydrogenation with an overall yield of 27.3%. First, 4-fluoro phenol(2) was esterified with acetic anhydride to give 4-fluorophenyl acetate(3), then 3 was rearranged in the presence of anhydrous AlCl₃ to afford 4-fluoro-2-acetyl phenol (35) , these two steps yielded 61.0%. 35 was transformed into 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (34) bytreatment with diethyloxalate via acylation, cyclization and then hydrolyzation, using a single reagent to finish three steps. The title product, 6 was finally obtained by reducing 34 with hydrogen and 10% Pd/C in acetic acid.Both the two methods upon have the potential perspective to be industrialized due to the mild conditions and readily available reagents. The former is better when in small scale, and the latter will have a better plant environment . In this thesis, the former was selected.2) A practical process for the resolution of racemic 6 was studied as follows: (+)-dehydroabietylamine, the chiral resolving reagent, was separated from rosin amine with a purity of 98.8% and the optical purity 98.3%. Dehydroabietylamine and racemic 6 in ratio of 1 :l(mol) were used to form the diastereomeric amides; the pure diastereomer 40a was got from ethanol by fractional crystallization in a yield of 31.3%; and 40b from methanol in 30.0% , totally yielding 61.3%; the optical acid 6a was got by hydrolysis of 40a under a 40-h-refluxing with amide:acetic acid: concentrated HCl/g=0.15:2:1, and so was 6b by hydrolysis of 40b. The total yield of resolution was raised from 20.1% to 29.7% . For a first time, the spectral and physical properties of the diastereomers were given, and the racemization of 6 was studied. The diastereomeric amides were found hydrolyzed to give racemic 6 in boiling glycol with KOH. Based on this, 6 was recovered from the mother liquor in resolution in a yield of 51.6%. This resolving process is more suitable to be industrialized with easier gained chiral reagent, higher yield and recyclable mother liquor.3) The key intermediate 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehy-de (8) was prepared at room temperature and normal pressure as follows:6 was reacted with ClCOOCH₂CH₃ to afford a mixed anhydride, and then the anhydride was directly used without purification to give the acohol 7 via NaBH₄, the yield of 7 was 90.2%; and so was 6a to 7a and 6b to 7b. A coated PCC oxidant was invented by a selected inorganic absorber with PCC, which was more reactive andconvenient to be used than uncoated one. 7 was oxidized to give 8 by this oxidant with a yield of more than 80%, and so was 7a to 8a and 7b to 8b. The two steps were both done at room temperature and normal pressure without any changes in the stereo structures, totally yield to 75%. (Janssen's method: expensive and unstable DIBAL-H as reductant, -78℃, yielding 50%.)4) Racemic 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (9) was prepared by 8, via dimethylsulfonium methylide instead of dimethyloxosulfonium methylide, yielding 99.5%; and so was (R,R)-9 (9a) by 8a, yielding 20.5%; and (S,R)-9 (9b) by 8b, yielding 38.8%.5) (S,R,R,R)-Nebivolol was got as follows:9a was reacted with benzylamine to give (R,R)-6-fluoro-3,4-dihydro -α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanol (10a), 10a was coupled with 9b to give 42, and then 42 was desamidizated via hydrogenlysis to give the goal product.The corresponding spectra of all the main intermediates and the goal product were given, which identified the structures of the products.