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Preparation method of solifenacin intermediate

A solifenacin and intermediate technology, applied in the field of drug synthesis, can solve the problems of stricter requirements for heavy metal impurities and heavy metal residues, and achieve the effects of easy availability of reagents, high recovery rate, and reduced risk of heavy metal residues

Active Publication Date: 2020-07-28
ENANTIOTECH CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the (R)-(-)-3-quinine alcohol synthesized by the above-mentioned method has the risk of heavy metal residue, and (R)-(-)-3-quinine alcohol is the last step in the preparation of solifenacin bulk drug Raw materials, the quality standards, especially the heavy metal impurities, are becoming stricter

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  • Preparation method of solifenacin intermediate
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  • Preparation method of solifenacin intermediate

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preparation example Construction

[0038] The invention provides a kind of preparation method of solifenacin intermediate, described preparation method comprises the following steps:

[0039] Dissolve 3-quinuclidone hydrochloride in a solvent to obtain 3-quinuclidone hydrochloride solution;

[0040] Adding a basic compound and a catalyst to the 3-quinuclidone hydrochloride solution, feeding hydrogen, stirring and reacting to obtain a reactant;

[0041] The catalyst in the reactant is recovered by filtration, and the obtained filtrate is concentrated under reduced pressure and then recrystallized;

[0042] Described catalyst has the structure shown in formula I:

[0043]

[0044] The degree of polymerization of the PEG is 60-400.

[0045] The above method adopts the asymmetric catalytic hydrogenation reduction method to prepare the solifenacin intermediate—(R)-(-)-3-quinine alcohol. In the catalyst structure, macromolecular structure polyethylene glycol (PEG) is introduced on the benzene ring of the nitrog...

Embodiment 1

[0071] This embodiment provides a preparation method of solifenacin intermediate [(R)-(-)-3-quinine alcohol], comprising the following steps:

[0072] Step 1: In a 5L autoclave, under an argon atmosphere, add 100g of 3-quinuclidinone hydrochloride from the feeding port, then add 1L of absolute ethanol to fully dissolve the raw materials, and cool down with cooling water Add 76 g of potassium tert-butoxide, stir well and continue to blow in argon gas for degassing by bubbling. The bubbling is continued for 1 hour, and the degassing is completed.

[0073] Step 2: Add 0.2 g of PEG having a structure shown in formula I through the feeding port, wherein the degree of polymerization of PEG is 180-220, and quickly close the feeding port. Replace the argon with hydrogen, slowly introduce hydrogen to 3.0Mpa, and close the inflation valve. Stir rapidly and set the temperature to 30 °C. When the pressure drops to remain constant, the reaction is considered to stop.

[0074]

[0075...

Embodiment 2

[0078] This embodiment provides a preparation method of Solifenacin intermediate [(R)-3-quinine alcohol], which is basically the same as Example 1, the difference is that the degree of polymerization of PEG in the catalyst is different, specifically comprising the following steps:

[0079] Step 1: In a 5L autoclave, under an argon atmosphere, add 100g of 3-quinuclidinone hydrochloride from the feeding port, then add 1L of absolute ethanol to fully dissolve the raw materials, and cool down with cooling water Add 76 g of potassium tert-butoxide, stir well and continue to blow in argon gas for degassing by bubbling. The bubbling is continued for 1 hour, and the degassing is completed.

[0080] Step 2: Add 0.2 g of PEG having a structure shown in formula I through the feeding port, wherein the degree of polymerization of PEG is 100-180, and quickly close the feeding port. Replace the argon with hydrogen, slowly introduce hydrogen to 3.0Mpa, and close the inflation valve. Stir rap...

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Abstract

The invention relates to a preparation method of a solifenacin intermediate. The preparation method comprises the following steps: dissolving 3-quinuclidinone hydrochloride to obtain a 3-quinuclidinone hydrochloride solution; adding an alkaline compound and a catalyst into the 3-quinuclidinone hydrochloride solution, introducing hydrogen, stirring to carry out reactions to obtain a reactant; filtering and recovering the catalyst in the reactant, concentrating the obtained filtrate under reduced pressure, and re-crystallizing. The catalyst has a structure shown as a formula I, wherein the polymerization degree of PEG is 60 to 400. According to the preparation method, the catalyst is easy to separate, the risk of heavy metal residues is reduced, the reaction operation is simple, convenient and safe, the three-waste treatment is simple and feasible, the preparation method is environment-friendly and is a green synthesis process, meanwhile, the yield of the preparation method is high and stable, the production cost is low, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of a solifenacin intermediate. Background technique [0002] Solifenacin, 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate-3-(R)quinuclidinate, is a selective toxin Alkaline M3 receptor antagonist, clinically used to treat overactive bladder with symptoms of urgency and frequent urination, and is a urinary system antispasmodic. (R)-(-)-3-quinine alcohol is an important intermediate in its synthesis. [0003] (R)-(-)-3-quinine alcohol, chemical name (R)-(-)-1-azabicyclo[2.2.2]octan-3-ol, its chemical structure is shown in the following formula: [0004] [0005] At present, the preparation methods of (R)-(-)-3-quinine alcohol mainly include chemical synthesis and biosynthesis. [0006] The biosynthesis method mainly uses microorganisms or enzymes to reduce 3-quinuclidinone to (R)-(-)-3-quinicol, or split quinuclidin-3-ol to obtain (R)-(-)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02B01J31/24
CPCB01J31/2409B01J2231/643B01J2531/0258B01J2531/821C07B2200/07C07D453/02
Inventor 李彦雄蒙发明梁鹏程谢昌玖刘育培邹俊文
Owner ENANTIOTECH CORP
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