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Method for continuously preparing citalopram diol

A technology of cyanodiol and cyanophthalide, which is applied in the field of continuous preparation of 5-cyanodiol, can solve the problems of not being able to control the formation of main impurities, unsatisfactory yield, and low production yield, and achieve the production process Simple and controllable, reducing the risk of reaction, and easy to industrialize the effect of amplification

Active Publication Date: 2020-06-19
SHANGHAI AOBO PHARMTECH INC LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of the method of this patent is not ideal, not only the method of dropping Grignard reagents in batches is used, but also the post-treatment needs to be carried out twice, and the one-pot method is not used for synthesis, the operation is more complicated, the cycle is long, and the preparation cost Very high, there is no advantage in applying to industrial production
[0015] At present, the main method for preparing 5-cyanodiol is to add formula 3 to react with formula 2, and then add formula 4 to react. 2), resulting in low production yield, long production cycle and high cost of raw materials
[0016] At present, 5-cyanodiol is all prepared in a batch manner, especially by first adding Grignard reagent 3 for heat preservation reaction, and then adding Grignard reagent 4 for heat preservation reaction. This series of preparation processes leads to the main The amount of impurities generated is high, and the preparation yield is low
Since Grignard reagents are added to the reaction system by dropwise addition, it has a long production cycle, and the use of Grignard reagents also has certain safety risks

Method used

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  • Method for continuously preparing citalopram diol
  • Method for continuously preparing citalopram diol
  • Method for continuously preparing citalopram diol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (1) Prepare feed solution A: 5-cyanophthalide tetrahydrofuran solution, concentration 0.23mmol / g;

[0038] Preparation of material solution B: Grignard reagent tetrahydrofuran solution, the concentration of raw material 3 is 0.19mmol / g, and the concentration of raw material 4 is 0.20mmol / g;

[0039] (2) Control the temperature of the microreactor at 10°C, and continuously transport the feed liquid B of the feed liquid A in step (1) into the microreactor at 12.0g / min and 15g / min respectively, with a residence time of 2.6min, at the end of the reactor The outlet is quenched with a saturated ammonium chloride solution, and the sample is detected to obtain the HPLC detection result of the reaction solution, and the results are shown in Table 2;

[0040] (3) Concentrate, extract, acidify, crystallize the quenched reaction solution in step (2), and finally centrifuge and dry to obtain 5-cyanodiol hydrochloride with a yield of 89.38%.

Embodiment 2

[0042] (1) Prepare feed solution A: 2-methyltetrahydrofuran solution of 5-cyanophthalide, concentration 0.50mmol / g;

[0043] Prepare material solution B: Grignard reagent ether solution, raw material 3 concentration 0.33mmol / g, raw material 4 concentration 0.33mmol / g;

[0044] (2) control microreactor temperature 3 ℃, feed liquid B in step (1) feed liquid A enters microreactor continuously with 15.0g / min and 23.0g / min respectively, residence time 3.2min, in reactor The terminal outlet was quenched with a saturated ammonium chloride solution, and a sample was taken for detection to obtain the HPLC detection result of the reaction solution, and the results are shown in Table 2;

[0045] (3) Concentrate, extract, acidify, crystallize the quenched reaction solution in step (2), and finally centrifuge and dry to obtain 5-cyanodiol hydrochloride with a yield of 88.74%.

Embodiment 3

[0047] (1) Prepared material solution A: 5-cyanophthalide toluene solution, concentration 0.30mmol / g; prepared material solution B: Grignard reagent 2-methyltetrahydrofuran solution, raw material 3 concentration 0.36mmol / g, raw material 4 concentration 0.26 mmol / g;

[0048] (2) Control microreactor temperature 80 ℃, feed liquid B in step (1) feed liquid A enters microreactor continuously with 8.0g / min and 18.0g / min respectively, residence time 0.9min, in reactor The terminal outlet was quenched with a saturated ammonium chloride solution, and a sample was taken for detection to obtain the HPLC detection result of the reaction solution, and the results are shown in Table 2;

[0049] (3) Concentrate, extract, acidify, crystallize the quenched reaction solution in step (2), and finally centrifuge and dry to obtain 5-cyanodiol hydrochloride with a yield of 88.26%.

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Abstract

The invention provides a method for continuously preparing a citalopram intermediate citalopram diol. The method comprises the following steps: preferentially mixing two Grignard reagents required bya reaction, mixing the mixed Grignard reagent with a raw material 5-cyanophthalide in a micro-mixer to obtain a reaction solution, completing the reaction of the reaction solution through a reactor toobtain a citalopram diol reaction solution, quenching, concentrating, extracting, acidifying, crystallizing, and carrying out other operations to obtain a qualified product. The citalopram diol provided by the invention is good in selectivity, high in yield, high in safety, safe, reliable, less in pollution discharge and suitable for industrial production.

Description

technical field [0001] The invention relates to a method for continuously preparing 5-cyanodiol (citalopram diol), which belongs to the field of medicine and chemical industry. Background technique [0002] 5-cyanodiol (citalopram diol), 5-cyanodiol hydrochloride (citalopram diolhydrochloride) or 5-cyanodiol hydrobromide (citalopram diol hydrobromide) is an important intermediate for preparing citalopram (Citalopram). Citalopram and its isomers (S(+)citalopram) are serotonin selective inhibitors (SSRIs) that are clinically used for the treatment of anxiety and depression. The full name of 5-cyanodiol is 4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile, CAS number is 103146-25-4, Formula 1 is its structural formula: [0003] [0004] Generally, 5-cyanodiol is composed of 5-cyanophthalide (5-cyanophthalide, formula 2) and 4-fluorophenyl magnesium halide (4-flourophenyl magnesium halide, formula 3) and 3,3-dimethyl Aminopropylmagnesium hal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30C07C255/59
CPCC07C253/30C07C255/59Y02P20/55
Inventor 刘辰李星叶花香张继承黄鲁宁陶安平安建国顾虹
Owner SHANGHAI AOBO PHARMTECH INC LTD
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