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Preparation method for hemihydrate lorcaserin hydrochloride

A technology of hemihydrate and aqueous solution, which is applied in the field of preparation of greencaserin hydrochloride hemihydrate, which can solve the problems of low substance content and unqualified ignition residue, and achieve good yield, suitable for industrial production, and stable crystal form Effect

Active Publication Date: 2017-03-08
科兴生物制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This method still has problems such as unqualified ignition residue of the final product and low content of related substances.

Method used

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  • Preparation method for hemihydrate lorcaserin hydrochloride
  • Preparation method for hemihydrate lorcaserin hydrochloride
  • Preparation method for hemihydrate lorcaserin hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1, preparation green caserin hydrochloride hemihydrate

[0050] The experimental parameter range of this embodiment is a pilot production batch, and the error range of the heating and cooling system in the workshop is ±5°C, which are the parameter range values ​​determined through the accumulation of a large number of experiments.

[0051] 1. Preparation method

[0052] according to figure 1 Process flow chart shown in prepares green caserin hydrochloride hemihydrate, concrete steps are as follows

[0053] (1) Intermediate (RS)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (code-named LCS-1, structural formula as shown in formula IV shown) preparation

[0054]

[0055] In a 20L reaction flask, under nitrogen protection, 4050.0g (15.08mol) SM-A (1-[(2-(4-chlorophenyl)ethyl)amino]-2-chloropropane hydrochloride was added successively under stirring, The structural formula is shown in Formula V), 3015.0g (22.61mol) of aluminum chloride, heated to 1...

Embodiment 2

[0163] Embodiment 2, preparation green caserin hydrochloride hemihydrate

[0164] Prepare green caserin hydrochloride hemihydrate according to the steps in Example 1, only the concentration of ammonia solution in step (3) is replaced by 10% (the mol ratio of LSC-2 and ammonia is the same as in Example 1), the resulting final The HPLC purity of the product was 99.066%.

Embodiment 3

[0165] Embodiment 3, preparation green caserin hydrochloride hemihydrate

[0166] Green caserin hydrochloride hemihydrate was prepared according to the steps in Example 1, only the isopropanol in step (4) was replaced with 1,4-dioxane, and the HPLC purity of the final product obtained was 99.116%.

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Abstract

The invention discloses a preparation method for hemihydrate lorcaserin hydrochloride. The preparation method comprises the following steps: (1) making a compound shown as a formula III react with ammonia to obtain a compound shown as a formula II; (2) under the protection of nitrogen gas, dissolving the compound shown as the formula II in an organic solvent, adding a hydrogen chloride solution of which the solvent is the organic solvent to salify, and adding water and cyclohexane to form a hemihydrate in order to obtain the compound shown as a formula I, wherein the organic solvent is isopropanol or 1,4-dioxane. In the preparation method disclosed by the invention, ammonium hydroxide substitutes for potassium carbonate in the prior art, so that unqualified ignition residues of a finial product caused by potassium chloride generated after salt removal can be avoided; an isopropoxide hydrochloride solution substitutes for the conventional hydrogen chloride gas, so that other impurities can be prevented from being introduced in a preparation process under the improper control of dosage and rate of the gas.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of green caserin hydrochloride hemihydrate. Background technique [0002] Greencaserin is an appetite-suppressing drug that acts on the central nervous system. It was developed by Alina Pharmaceuticals of the United States in 2005 and was approved for marketing in the United States on June 27, 2012. The trade name is Belviq. It is reported in CN102321023 that green caserin hydrochloride has three crystal forms. Forms I and II are anhydrous, hygroscopic forms, and both forms readily convert to the more stable form III upon exposure to moisture. The medicinal crystal form of this product is green caserin hydrochloride crystal form III, that is, green caserin hydrochloride hemihydrate. [0003] Green caserin hydrochloride hemihydrate, also known as green caserin hydrochloride hemihydrate, D-green caserin hydrochloride hemihydrate, D-green caserin hydrochloride he...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
CPCC07B2200/13C07D223/16
Inventor 崔宁董祥君郝志海
Owner 科兴生物制药股份有限公司
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