Purification method of loratadine key intermediate

A technology of loratadine and a purification method, which is applied in the field of purification of key intermediates of loratadine, can solve the problems of difficult preparation of loratadine, many by-products, low purity, etc., to ensure process stability, Improvement of quality and yield, high yield and high purity effect

Active Publication Date: 2022-02-25
北京鑫开元医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] But the loratadine key intermediate with formula (1) structure that existing preparation technology makes has many by-products, low purity, it is difficult to prepare qualified loratadine

Method used

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  • Purification method of loratadine key intermediate
  • Purification method of loratadine key intermediate
  • Purification method of loratadine key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] A method for purifying the key intermediate of loratadine, comprising:

[0050]Add 10.00 g (0.029 mol) of the crude intermediate of loratadine into 60 mL of ethanol, heat to 60-70 °C and stir to dissolve, add 3.39 g (0.029 mol) of fumaric acid, keep stirring for 1 hour, cool down to 0-10 ℃, stirred for 1 hour, filtered the solid with suction, added the obtained solid to 200mL 5% sodium hydroxide aqueous solution, added 200mL ethyl acetate, extracted, separated liquids, dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure until no liquid was dropped, Add 45mL of isopropyl acetate, heat to dissolve, cool down and crystallize to obtain 5.42g of the purified loratadine key intermediate, with a yield of 54.2% and a purity of 99.07% as measured by HPLC. The HPLC chromatogram is as figure 2 Shown, NMR structure confirmation see image 3 shown.

[0051] Add 40.0g of concentrated sulfuric acid into the reaction flask, start stirring, coo...

Embodiment 2

[0053] A method for purifying the key intermediate of loratadine, comprising:

[0054] Add 10.00 g (0.029 mol) of the crude intermediate of loratadine into 60 mL of ethanol, heat to 60-70 °C and stir to dissolve, add 3.39 g (0.029 mol) of fumaric acid, keep stirring for 1 hour, cool down to 0-10 ℃, stirred for 1 hour; filtered the solid with suction, added 200mL of 5% sodium hydroxide aqueous solution to the obtained solid, added 200mL of ethyl acetate, extracted, separated liquids, dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure until no liquid was dropped, Add 45mL of ethyl acetate, heat to dissolve, cool down to crystallize, and obtain 3.46g of purified loratadine key intermediate, with a yield of 34.6% and a purity of 99.10% as measured by HPLC.

Embodiment 3

[0056] A method for purifying the key intermediate of loratadine, comprising:

[0057] Add 10.00 g (0.029 mol) of the crude intermediate of loratadine into 60 mL of ethanol, heat to 60-70 °C and stir to dissolve, add 3.39 g (0.029 mol) of fumaric acid, keep stirring for 1 hour, cool down to 0-10 ℃, stirred for 1 hour; filtered the solid with suction, added 200mL of 5% sodium hydroxide aqueous solution to the obtained solid, added 200mL of ethyl acetate, extracted, separated liquids, dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure until no liquid was dropped, Add 150 mL of methyl tert-butyl ether, heat, cool down and crystallize to obtain 7.01 g of the purified loratadine key intermediate, with a yield of 70.1% and a purity of 78.48% as measured by HPLC.

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Abstract

The invention belongs to the field of medicinal chemistry, and provides a purification method of a loratadine key intermediate with a structure as shown in a formula (1). The structure of the formula (1) is shown in the specification. The purification method comprises the following steps of adding a crude product of the loratadine key intermediate into an alcohol solvent, stirring and dissolving, adding acid to form salt, cooling and crystallizing, filtering, dissociating, drying and recrystallizing to obtain the purified loratadine key intermediate. The purification method of the loratadine key intermediate, provided by the invention, is good in purification effect, the yield and the purity of the purified target product are relatively high, the process stability of the next step is better ensured, and the quality of the loratadine product is favorably improved; the purification process is simple, the used solvent is common and easy to recover, the industrial operation is greatly simplified, and the method is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for purifying a key intermediate of loratadine. Background technique [0002] The chemical name of loratadine is 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cycloheptane[1,2-b]pyridine-11-ene base)-1-piperidinecarboxylic acid ethyl ester, the chemical structural formula is as follows: [0003] [0004] Loratadine, as a representative of the second-generation antihistamines, can competitively inhibit histamine H1 receptors and the allergy caused by histamine, and has no obvious anti-central and choline inhibitory effects. It has good clinical curative effect and is used Safety. [0005] The compound with the structure of formula (1) is a key intermediate in the preparation process of loratadine. Improving the synthesis process of the intermediate and improving the purity of the intermediate are of great significance to the production of loratadine. [0006]...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04C07B2200/13Y02P20/55
Inventor 孙学涛郭文君于凯苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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