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US 12,466,802 B2Granted
Nebivolol synthesis method and intermediate compound thereof
AssigneeZhejiang Ausun Pharmaceutical Co., Ltd.
InventorZhiguo Zheng
Life of this patent
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Abstract
The present invention relates to a nebivolol synthesis method and intermediate compound thereof. Specifically, the present invention relates to a method for synthesizing nebivolol, intermediate compound thereof, and a method for preparing the intermediate compound.
Claims17
A process for preparation of (A) the compound of formula VII (S*/R*),
- wherein VII (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIa (S/R) and the enantiomer VIIb (R/S),
- the process comprising the following steps:
- 1) epoxidation of the compound of formula IV1 in trans-configuration in the presence of epoxidating reagent to give epoxide intermediate V,
- wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or silyl protective group,
- wherein the compound V is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Va and the enantiomer Vb, the relative configuration of which is represented as V (2R*,3R*)
- and 2) deprotecting the compound of formula V (2R*,3R*), followed by cyclization reaction, to give the intermediate compounds of formula VII (S*/R*), wherein R is defined as above,
- wherein VII (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIa (S/R) and the enantiomer VIIb (R/S),
- or (B) the compound of formula VIII (R*/R*),
- wherein VIII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIIa (R/R) and the enantiomer VIIIb (S/S),
- the process comprising the following steps:
- 1) epoxidation of the compound of formula IV2 in cis-configuration in the presence of epoxidating reagent to give epoxide intermediate VI,
- wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or silyl protective group,
- wherein the compound VI is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIa and the enantiomer VIb, the relative configuration of which is represented as VI (2R*,3S*)
- and 2) deprotecting the compound of formula VI (2R*,3S*), followed by cyclization reaction, to give the intermediate compounds of formula VIII (R*/R*), wherein R is defined as above,
- wherein VIII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIIa (R/R) and the enantiomer VIIIb (S/S),
12 more elements
A compound of formula V′ (2R*,3R*)
- wherein Rc is hydrogen or Rc is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group,
- wherein the compound V′ is racemate, the relative configuration of which is represented by V′ (2R*,3R*), which is a racemic mixture consisting of equimolar amounts of Va′(2R,3R) and the enantiomer Vb′(2S,3S);
- or
- a compound of formula VI′ (2R*,3S*)
- wherein Rd is hydrogen or Rd is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group,
- wherein the compound VI′ is racemate, the relative configuration of which is represented by VI′ (2R*,3S*), which is a racemic mixture consisting of equimolar amounts of VIa′(2R,3S) and the enantiomer VIb′ (2S,3R).
3 more elements
Dependencies are inferred from the claim text.