盐酸奈必洛尔是一种具有降压活性的高选择性β1-受体阻滞剂，药用的奈必洛尔为(S, R, R, R)-和(R, S, S, S)-奈必洛尔的消旋体。本论文设计并完成了两条盐酸奈必洛尔的不对称合成路线。1. 采用(S)-2-氨基丁酰胺盐酸盐对消旋的6-氟色满-2-羧酸进行拆分得到(R)-和(S)-6-氟色满-2-羧酸。将(R)-6-氟色满-2-羧酸转化为硝基酮(R)-9，之后将其还原为氨基醇(R)-3的非对映异构体，重结晶分离可以得到(R, R)-3和(R, S)-3，并将(R, S)-3转化为环氧化合物(R, S)-2。(S)-6-氟色满-2-羧酸经过相同的步骤可以得到氨基醇(S, S)-3和环氧化合物(S, R)-2。最后将环氧化合物(S, R)-2与氨基醇(R, R)-3偶联得到(S, R, R, R)-奈必洛尔，将环氧化合物(R, S)-2与氨基醇(S, S)-3偶联，得到(R, S, S, S)-构型的奈必洛尔。该路线以(R)-和(S)-6-氟色满-2-羧酸为起始原料，经过5步反应分别得到(S, R, R, R)-奈必洛尔和(R, S, S, S)-奈必洛尔，总产率为24.5%。2. 以(R)-环氧氯丙烷为原料，先与苄胺反应得到(R)-12，再与CDI反应得到噁唑烷酮(R)-13，之后经过乙酰氧基取代、水解得到手性中心构型保持的噁唑烷酮 (R)-15。用DMP将(R)-15氧化成醛，再与Wittig试剂反应得到, -不饱和羰基化合物(S)-21。经过环化、催化氢化、水解得到苄基氨基醇(S, R)-4和(R, R)-4。(S, R)-4经过甲基化、环化得到环氧化合物(S, R)-2。将(S, R)-2与(R, R)-4偶联，再经过催化氢化脱去苄基得到(S, R, R, R)-奈必洛尔。仍以(R)-12为原料，先与(Boc)2O反应，再在碱性条件下发生分子内环化、酸性条件下发生分子内SN2取代反应，得到手性中心构型翻转的噁唑烷酮 (S)-15，再经过相同的反应得到苄基氨基醇(S, S)-4和环氧化合物(R, S)-2。将二者偶联、催化氢化脱去苄基得到(R, S, S, S)-奈必洛尔。该路线以同一手性化合物(R)-环氧氯丙烷为原料，经过两条不同的路线，均为13步反应，分别得到(S, R, R, R)-奈必洛尔和(R, S, S, S)-奈必洛尔，产率分别为12.9%和12.5%。两条路线所涉及的关键中间体化合物及目标产物均经过1H NMR、13C NMR、IR、HRMS、熔点、旋光分析表征，化合物36和(S, S)-22经过X-射线单晶衍射分析确认构型。

Nebivolol hydrochloride is a potent and selective β1-adrenergic blocker with antihypertensive properties. Nebivolol is marketed as hydrochloride and is manufactured as a racemate which consists of enantiomers (S, R, R, R)- and (R, S, S, S)- Nebivolol. Two asymmetric synthesis routes of Nebivolol have been designed and carried out in this article.1. Resolution of racemic 6-fluorochromane-2-carboxylic acid with (S)-2-aminobutanamide hydrochloride gave (R)- and (S)-enantiomer. Nitro ketone (R)-9, obtained from (R)-6- fluorochromane-2-carboxylic, was reduced to mixture of amino alcohols (R, R)-3 and (R, S)-3 that were separated by recrystallized. Then (R, S)-3 was converted to epoxide (R, S)-2. Amino alcohol (S, S)-3 and epoxide (S, R)-2 were obtained from (S)-6-fluorochromane -2-carboxylic in the same way. Finally, the epoxide (S, R)-2 coupled with amino alcohol (R, R)-3 to give (S, R, R, R)-nebivolol, similarly (R, S, S, S)-nebivolol was achieved by coupling of epoxide (R, S)-2 and amino alcohol (S, S)-3.(S, R, R, R)-nebivolol and (R, S, S, S)-nebivolol were prepared in 5 steps with 24.5% overall yield from (R)- and (S)-6-fluorochromane-2-carboxylic.2. The reaction of (R)-2-(chloromethyl)oxirane and benzylamine formed (R)-12. (R)-12 reacted with CDI to give oxazolidinone (R)-13. Oxazolidinone (R)-15 with same configuration at chiral carbon was obtained after (R)-13 was substituted by acetoxy group and then hydrolyzed. Aldehyde, from oxidation reaction of (R)-15 with DMP, reacted with Wittig regent to offer , -unsaturated carbonyl compound (S)-21. Benzyl amino alcohols (S, R)-4 and (R, R)-4 were furnished from (S)-21 by cyclization, catalytic hydrogenation and hydrolysis. (S, R)-4 was methylated and cyclized to give epoxide (S, R)-2. Then (S, R, R, R)-Nevolol was achieved after benzyl amino alcohols (R, R)-4 coupled with epoxide (S, R)-2, followed by deprotection of the N-benzyl. (S)-15 with inversion at the chiral carbon was obtained after the reaction of (R)-12 with (Boc)2O, intramolecular cyclization in basic condition and intra molecular SN2 substitution reaction in acidic condition,. Coupling of benzyl amino alcohols (S, S)-4 and epoxide (R, S)-2 both from (S)-15 in the same way, followed by removal of the N-benzyl, achieved (R, S, S, S)-Nevolol.(S, R, R, R)-nebivolol was prepared starting with (R)-2-(chloromethyl)oxirane as raw material in 13 steps with 12.9% overall yield, and (R, S, S, S)-nebivolol was obtained from the same raw material in 13 steps with 12.5% overall yield.The target products and key intermediate compounds involved in two synthesis routes have been characterized by 1H NMR、13C NMR、IR、HRMS、optical rotation、melting point. The configuration of compound 36 and (S, S)-22 have been further determined by X-ray crystallographic.