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Synthesis process of solifenacin succinate

A technology of solifenacin succinate and a synthesis process, applied in the field of medicine, can solve the problems of unstable tetrahydroisoquinoline carbamoyl chloride, complicated operation of solifenacin, and low conversion rate of transesterification, and the like. The effect of reducing reversible reactions, simple operation, and reducing operating procedures

Pending Publication Date: 2021-08-03
上海予君生物科技发展有限公司
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The low conversion rate of this type of transesterification reaction is related to the by-product ethanol generated by its condensation; ethanol can form sodium ethylate especially under the strong action, such as the presence of sodium hydride, which also has a strong nucleophilic ability to make the product back to the starting material
[0004] And in CN102875544, by (S)-1-phenyl-1,2,3,4- tetraradon isoquinoline carbamoyl chloride, with (S)-1-phenyl-1,2,3 , 4-tetrahydroisoquinoline carbamoyl chloride reacts with (R)-3-quinuclidinol metal salt to generate solifenacin base, and then solifenacin base is synthesized into solifenacin succinate, although the reaction The problem of low conversion rate of transesterification has been avoided, but the preparation of solifenacin base is complicated and the (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carbamoyl chloride prepared is not Stablize

Method used

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  • Synthesis process of solifenacin succinate
  • Synthesis process of solifenacin succinate
  • Synthesis process of solifenacin succinate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] see Figure 4 As shown, the technical solution adopted in this embodiment is:

[0028] 1. First add 10.0g (R)-3-quinuclidinol to 800.0ml acetonitrile, after it dissolves, add 20.0g diphosgene dropwise to the above system in an ice-water bath, sprinkle Remove from the ice-water bath, react at room temperature for 16 hours, and concentrate to obtain 13.4 g of chloroformic acid-(R)-3-quinuclidinyl ester.

[0029] 2. Add 11.3g (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 8.2g triethylamine to 100.0ml dichloromethane, add dropwise to the 13.4g of chloroformic acid-(R)-3-quinuclidinine solution diluted with 60.0ml of dichloromethane, stirred for 3~10min after adding, removed the ice-water bath, continued to stir the reaction, and concentrated solifenacin crude product, Dissolve with 100.0 ml of dichloromethane, wash the organic phase with water, and concentrate to obtain 17.6 g of abdozofenacin.

[0030] 3. Add 17.6g of solifenacin oil to 20.0mL of ethyl acetate, then a...

Embodiment 2

[0032] see Figure 5 As shown, the technical solution adopted in this embodiment is:

[0033] 1. First add 10.0g (R)-3-quinuclidinol to 600.0ml THF, after it dissolves, add 20.0g diphosgene dropwise to the above system in an ice-water bath, sprinkle it after the dropwise addition In an ice-water bath, react at room temperature for 16 hours, and concentrate to obtain 13.8 g of chloroformic acid-(R)-3-quinuclidinyl ester.

[0034] 2. Add 11.3g (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 6.4g pyridine to 100.0ml dichloromethane, add dropwise with 62.0ml 13.8g of chloroformic acid-(R)-3-quinuclidinine solution diluted with dichloromethane, stirred for 3~10min after adding, removed the ice-water bath, continued to stir the reaction, concentrated solifenacin crude product, and then used 100.0ml of dichloromethane was dissolved, the organic phase was washed with water, and concentrated to obtain 18.0g of solifenacin.

[0035] 3. Add 18.0g of solifenacin oil to 23.0mL of ethyl ...

Embodiment 3

[0038] see Figure 4As shown, the difference from Example 1 is: replace the reaction solvent therein for experiments, and change one of the solvent components each time.

[0039] 1 (R)-3-quinuclidinol is added to the solvent and diphosgene to generate the reaction solvent of chloroformic acid-(R)-3-quinuclidinate respectively using acetonitrile, tetrahydrofuran, dioxane, dichloro Methane, the chloroformic acid-(R)-3-quinuclidin ester that obtains, the total yield that final preparation obtains solifenacin succinate is respectively acetonitrile (63%), tetrahydrofuran (61%), dioxane ( 47%), dichloromethane (29%).

[0040] 2 (R)-3-quinuclidinol is dissolved in acetonitrile and reacts with phosgene, diphosgene or triphosgene respectively to generate chloroformate-(R)-3-quinuclidinate, and finally prepares solifena succinate The new total yields are all about 60%.

[0041] 3 Use morpholine, N- Methylmorpholine, triethylamine, pyridine, 4-picoline are used as base, and tetrahydr...

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Abstract

The invention discloses a synthesis process of solifenacin succinate, and relates to the technical field of medicines. The preparation method comprises the following steps: step 1, reacting (R)-quinuclidin-3-ol (B) with a reaction substance to generate (R)-quinuclidin-3-yl carbonochloridate (C); step 2, enabling (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (A) to react with (R)-quinuclidin-3-yl carbonochloridate (C) to generate solifenacin (D); and step 3, using the solifenacin (D) to prepare the solifenacin succinate. After the technical scheme is adopted, the method has the beneficial effects that in the synthesis process, the problem of low conversion rate caused by direct ester exchange reaction is avoided, meanwhile, the probability of reversible reaction caused by nucleophilic intermediate products generated in the condensation process is also reduced, and the reaction is greatly promoted, so that the yield of solifenacin succinate is increased, the reaction conditions are mild, the operation is simple, the operation procedures are reduced, and the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a synthesis process of solifenacin succinate. Background technique [0002] Solifenacin succinate, chemical name (3R)-1-azabicyclo[2.2.2]octane-3-yl(1S)-1-phenyl-3,4-dihydro Isoquinoline-2-(1H)-carboxylate succinate is a selective muscarinic M3 receptor antagonist developed by Japan Astellas Company. This product can selectively relax the detrusor muscle of the bladder and reduce the systemic adverse reactions of anticholinergic drugs in the past, such as dry mouth, constipation, dilated pupils and tachycardia. [0003] EP0801067 uses (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline to condense with ethyl chloroformate, and then with (R)-3-quinuclidinol under sodium hydride as base catalysis A transesterification reaction is carried out to synthesize Solifenacin; the reaction is carried out under reflux in toluene, and ethanol is produced by azeotropic distillation. WO2008 / 077357 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02C07C55/10C07C51/41C07C51/43
CPCC07D453/02C07C55/10C07C51/412C07C51/43
Inventor 罗维
Owner 上海予君生物科技发展有限公司
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