Preparation method of S-3-aminoquinuclidine dihydrochloride

A technology of aminoquinine dihydrochloride and S-3-, applied in the field of preparation of S-3-aminoquinine dihydrochloride, can solve the problem of affecting yield and cost, affecting yield and cost, and inconvenient operation and other problems, to achieve the effect of low cost, high yield and simple method

Inactive Publication Date: 2011-08-03
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In the method reported by literature (Chemical Industry Times, 2005, 19 (2), 12-13; and patent CN101161651A), quinine hydrochloride is used as raw material, and (R)-phenylethylamine is aminated, and the reaction is carried out by NaBH 4 Reduction, followed by 10% Pd / C hydrogenolysis and debenzylation to obtain the product (S)-3-aminoquinine dihydrochloride, the synthetic imine yield of this route is not high, separation and purification are troublesome, and NaBH is required in the subsequent reaction process 4 Reduction and high-pressure reaction debenzylation, complex operation, long route, affecting yield and cost
In addition, in the method reported in the literature (US5290938A1), 3-aminoquinine dihydrochloride is used as a raw material to generate an amide, which is then resolved with chiral acid, and the resulting salt is hydrolyzed and extracted to prepare S-3-aminoquinine dihydrochloride. Hydrochloride, acylation is used in the route, the hydrolysis process is inconvenient to operate, and the hydrolysis extraction rate is not high, which affects the yield and cost

Method used

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  • Preparation method of S-3-aminoquinuclidine dihydrochloride
  • Preparation method of S-3-aminoquinuclidine dihydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0029] The preparation method of S-3-aminoquinine dihydrochloride is realized through the following steps:

[0030] 1) Preparation of S-3-aminoquinine-D-tartrate

[0031] Add 10g of 3-aminoquinine dihydrochloride and 150ml of methanol to a 250ml single-necked bottle, cool in an ice-water bath to 0-5°C, add 6.9g of potassium carbonate, stir at room temperature for 1 hour after the addition, and filter to remove the inorganic salt potassium chloride. Under stirring at 50°C, 7.3 g of D-tartaric acid was added to the mother liquor, stirred for 1 hour to form a salt, a large amount of solids precipitated, the solids were filtered, washed with a small amount of solvent, and dried to obtain 7.2 g.

[0032] Mp: 213-215°C, [α] D 20 =-35.0 0 (C=1, H 2 O).

[0033] 2) recrystallization of S-3-aminoquinine-D-tartrate,

[0034] Measure 50ml of methanol into a 250ml single-mouth bottle, add the salt obtained in step 1), raise the temperature to 50°C, stop heating after the salt is com...

Embodiment 2

[0044] The preparation method of S-3-aminoquinine dihydrochloride is realized through the following steps:

[0045] 1) Preparation of S-3-aminoquinine-D-camphorsulfonate

[0046] Add 10g of 3-aminoquinine dihydrochloride and 150ml of absolute ethanol to a 250ml single-necked bottle, cool in an ice-water bath to 0-5°C, slowly add 8.5g of sodium bicarbonate, the whole addition process lasts for 1 hour, and stir at room temperature after the addition is complete 1.5h, filter to remove the inorganic salt sodium chloride, add 12.8g of D-camphorsulfonic acid to the mother liquor under stirring at 30°C, stir to form a salt for 2h, a solid precipitates, filter the solid, wash the solid with a small amount of solvent, and dry to obtain 9.9 g

[0047] Mp: >300°C, [α] D 20=-49.5 0 (C=1, H 2 O).

[0048] 2) recrystallization of S-3-aminoquinine-D-camphorsulfonate,

[0049] Measure 60ml of absolute ethanol and place it in a 250ml single-mouth bottle, add the salt obtained in step 1)...

Embodiment 3

[0059] The preparation method of S-3-aminoquinine dihydrochloride is realized through the following steps:

[0060] 1) Preparation of S-3-aminoquinine-L-dibenzoyl tartrate

[0061] Add 10g of 3-aminoquinine dihydrochloride and 150ml of isopropanol to a 250ml single-necked bottle, cool in an ice-water bath to 0-5°C, slowly add 8.3g of sodium acetate, the whole adding process lasts for 1h, and stir at room temperature for 2h after the addition , filter to remove the inorganic salt sodium chloride, add 18.9 g of L-dibenzoyl tartaric acid to the mother liquor under stirring at 20°C, stir to form a salt for 3 hours, a large amount of solids precipitate, filter the solids, wash the solids with a small amount of solvent, and dry to obtain 14.0g

[0062] Mp: 179-181°C, [α] D 25 =+135 0 (C=1, H 2 O).

[0063] 2) Recrystallization of S-3-aminoquinine-D-dibenzoyl tartrate,

[0064] Measure 70ml of isopropanol into a 250ml single-mouth bottle, add the salt obtained in step 1), rais...

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Abstract

The invention relates to a preparation method of S-3-aminoquinuclidine dihydrochloride which is obtained by taking 3-aminoquinuclidine dihydrochloride as a raw material and carrying out resolving, salifying by resolving, recrystallizing, resolving, salifying, decoloring and crystallizing by concentration. The S-3-aminoquinuclidine dihydrochloride serves as an important raw material for preparing palonosetron. In the method, the 3-aminoquinuclidine dihydrochloride is taken as the raw material and is directly subjected to chiral acid resolution in proper solvent without derivation, with resolution ratio over 40% and optical purity over 98%. The method has simple synthetic method and low production cost, has total product yield over 35% and can be used for industrial production.

Description

technical field [0001] The invention relates to a preparation method of S-3-aminoquinine dihydrochloride, which belongs to the technical field of organic chemistry and also belongs to the technical field of medicinal chemistry. Background technique [0002] S-3-Aminoquinine dihydrochloride is the precursor of chiral ligands, from which chiral ligands can be synthesized for asymmetric catalysis; it is also an important raw material for the synthesis of antiemetic drugs. Since the 1970s, the synthesis of antiemetics has been the focus of attention and research hotspot in the pharmaceutical industry at home and abroad. [0003] In the method reported in the literature (Chemical Industry Times, 2005, 19 (2), 12-13; and patent CN101161651A), quinine hydrochloride is used as a raw material, and (R)-phenylethylamine is used for amination reaction, and after NaBH 4 Reduction, followed by 10% Pd / C hydrogenolysis and debenzylation to obtain the product (S)-3-aminoquinine dihydrochlor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D453/02
Inventor 申永存李学超徐维赟
Owner WUHAN UNIV OF TECH
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