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Preparation process of Rupatadine

A preparation process and solution technology, which is applied in the field of rupatadine preparation process, can solve the problems of low solubility, high cost, and low product yield, and achieve the effects of mild reaction conditions, low equipment requirements, and high product yield

Inactive Publication Date: 2017-04-12
HEFEI PINGGUANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method of synthesizing amides is mainly to carry out acid amine condensation under the conditions of DCC\HOBT\DMF, the required dehydrating agent DC and racemization inhibitor CHOBT are more expensive, the cost is higher, and the yield is lower; the by-product N, N-Dicyclohexylurea (DCU) has low solubility in most organic solvents and is difficult to remove
The method of reducing amide has: reported in the patent ES2087818 with POCl 3 / NaBH 4 As a method for reducing amides with a reducing agent, this method requires column chromatography to obtain qualified products. The product has high purity and good yield, but the operation is cumbersome, and product purification is difficult and requires a column chromatography. POCl 3 Strong corrosion, high requirements on equipment
Introduced in the U.S. Patent No.5407941 in tetrahydrofuran solution, the reduction method with lithium aluminum hydride as reductant, but product yield is low, and purity is relatively poor
In the Chinese patent CN1865259A, a reduction method using sodium dihydroaluminate as a reducing agent in tetrahydrofuran is introduced, but the product yield is low, the purity is poor, and the amount of a class of solvent is large

Method used

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  • Preparation process of Rupatadine
  • Preparation process of Rupatadine
  • Preparation process of Rupatadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] A preparation process for rupatadine, comprising the steps of:

[0054] S1. Preparation of methyl 5-methylnicotinate: mix 5-methylnicotinic acid and methanol evenly, add thionyl chloride dropwise, raise the temperature to 40°C, keep warm for 7.5h, keep stirring during the dropping and keeping warm, Adjust the temperature to 50°C, remove methanol and thionyl chloride by evaporation under reduced pressure, cool to room temperature, add ice water to obtain solution A; in an ice bath, adjust the pH of solution A to 9, add ethyl acetate for extraction, and obtain ethyl acetate Ester phase rotary evaporation obtains methyl 5-methylnicotinate;

[0055] S2. Preparation of 5-methyl-3-pyridinemethanol: mix magnesium chloride, potassium borohydride, and tetrahydrofuran, heat up to 65°C, reflux for 4.5 hours, and cool to room temperature to obtain solution B; Dissolve the methyl ester in tetrahydrofuran, adjust the temperature to 0°C, add solution B dropwise, keep warm for 1.5h, s...

Embodiment 2

[0059] A preparation process for rupatadine, comprising the steps of:

[0060] S1. Preparation of methyl 5-methylnicotinate: mix 5-methylnicotinic acid and methanol evenly, add thionyl chloride dropwise, heat up to 100°C, keep warm for 2.5h, and keep stirring during the process of dropping and keeping warm. Adjust the temperature to 60°C, remove methanol and thionyl chloride by evaporation under reduced pressure, cool to room temperature, add ice water to obtain solution A; in an ice bath, adjust the pH of solution A to 7, add ethyl acetate for extraction, and obtain ethyl acetate Ester phase rotary evaporation obtains methyl 5-methylnicotinate;

[0061] S2. Preparation of 5-methyl-3-pyridinemethanol: mix magnesium chloride, potassium borohydride, and tetrahydrofuran, heat up to 70°C, reflux for 0.5h, and cool to room temperature to obtain solution B; Dissolve the methyl ester in tetrahydrofuran, adjust the temperature to 80°C, add solution B dropwise, keep warm for 0.5h, sti...

Embodiment 3

[0065] A preparation process for rupatadine, comprising the steps of:

[0066] S1. Preparation of methyl 5-methylnicotinate: Mix 1 part of 5-methylnicotinic acid and 10 parts of methanol in molar parts, add 5 parts of thionyl chloride dropwise, and the addition of thionyl chloride is completed within 10 minutes , heat up to 90°C, keep warm for 3h, keep stirring during the dropwise addition and heat preservation, adjust the temperature to 58°C, remove methanol and thionyl chloride by evaporation under reduced pressure, cool to room temperature, add ice water to obtain solution A; , use ammonia water to adjust the pH of solution A to 7.5, add ethyl acetate to extract, add anhydrous sodium sulfate to the ethyl acetate phase to dry to a moisture content of 0.5wt%, filter, take the ethyl acetate phase and rotary evaporate to obtain 5-formaldehyde methyl nicotinate;

[0067] S2. Preparation of 5-methyl-3-pyridinemethanol: Mix 1 part of magnesium chloride, 1 part of potassium borohy...

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PUM

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Abstract

The invention discloses a rupatadine preparation process, which comprises: S1, preparing methyl 5-methylnicotinate; S2, preparing 5-methyl-3-pyridinemethanol; S3, preparing 3-methyl-5-chloromethylpyridine hydrochloride; and S4, preparing rupatadine. According to the present invention, the preparation process has advantages of low cost, mild reaction condition, simple operation, low requirement onequipment, good product purity and high yield, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of rupatadine preparation, in particular to a preparation process of rupatadine. Background technique [0002] Rupatadine is 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidinylidene]-5H-benzo[ 5,6]Cycloheptano[1,2-b]pyridine. Its molecular formula is C 26 h 26 ClN 3 , the molecular weight is 415.96, the CAS number is 158876-82-5, and the melting point is 58-61°C. Rupatadine has dual effects of antihistamine and platelet activating factor antagonism, and is mainly used in the treatment of allergic rhinitis and hay fever, and has broad market prospects. Its structural formula is as follows: [0003] [0004] At present, there are mainly two synthetic routes of rupatadine. Route 1 looks like this: [0005] [0006] Route 2 looks like this: [0007] [0008] Among the above two routes, route 1 is shorter than route 2, and saves the reduction step of synthetic amide and amide,...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 王康林汪祥黄志生柏春雷张成栋
Owner HEFEI PINGGUANG PHARMA
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