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Synthesis method of doxylamine succinate

A technology of doxylamine succinate and synthesis method, which is applied in the field of synthesis of doxylamine succinate, can solve the problems of reaction equipment damage, long reaction time, and high cost of doxylamine, and achieve anticholinergic sedation effect, low gastrointestinal side effects, significant sedative effect

Pending Publication Date: 2019-11-26
深圳沃兰德药业有限公司
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In the above synthesis method, the problems that exist respectively are: patent CN102108059B shortcoming: 1, adopt super strong alkali and xylene to reflux reaction for over 25 hours, the reaction time is long, the temperature is high, and the reaction equipment is greatly damaged; 2, directly quenching with water The extinguishing reaction is extremely dangerous. Sodium amide reacts violently and quickly when it meets water, which is prone to dangers such as spraying and explosion.
3. The obtained doxylamine has low purity and needs to be passed through the column, so it is not suitable for industrial production at all
4. It needs to be frozen at -20°C for 24 hours to form salt, which consumes a lot of energy and is difficult to realize industrial production
5. The melting point of the final product is 101-103°C, which does not meet the requirements of 103-108 in USP41
In this method, the raw materials of sodium amide and dimethylaminoethyl chloride hydrochloride are expensive, and such a large amount will inevitably cause the cost of doxylamine to be extremely high, and there is no industrial significance
[0015] CN107056685A also uses super strong bases such as sodium amide as raw materials for the synthesis of doxylamine, and the reaction time exceeds 30 hours. The disadvantages are equivalent to those of the patent CN102108059B, and the post-treatment brings a large amount of strong alkaline wastewater. Industrialization has great environmental protection pressure
[0016] In summary, the existing doxylamine synthesis technologies all have problems such as high energy consumption, high cost, and potential safety hazards, and are not suitable for industrial production

Method used

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  • Synthesis method of doxylamine succinate
  • Synthesis method of doxylamine succinate
  • Synthesis method of doxylamine succinate

Examples

Experimental program
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Effect test

Embodiment 1

[0057] (1) Put 500g of xylene into a 2000ml three-necked flask, add 100g (0.5mmol) of 2-pyridylphenylmethylmethanol, add catalyst tetrabutylammonium bromide 1g, sodium hydride 24.1g (0.6mmol) and 2 -Dimethylaminoethyl chloride 81g (0.75mmol), warming up to 108 ° C for reflux reaction for 2 hours, the reaction is complete; then cool down, filter, filter out the solid and collect the filtrate, add 20wt% hydrochloric acid aqueous solution to make the filtrate pH=3.5, stir After 30 minutes, separate the aqueous phase and the organic phase, continue to add 50g of 20wt% hydrochloric acid aqueous solution to the organic phase, stir after 30 minutes, separate the aqueous phase, merge the aqueous phase twice, and backwash twice with xylene 50g each time. Add activated carbon and raise the temperature to 75°C for decolorization for 1 hour and then filter the filtrate. Cool the filtrate to 15°C and add 40wt% sodium hydroxide to make the pH 11.5, then add 100 g of n-hexane each time to ext...

Embodiment 2

[0060] (1) Add 700g of toluene into a 2000ml three-necked flask, add 100g (0.5mmol) of 2-pyridylphenylmethylmethanol, and add 2g of catalyst tetrabutylammonium iodide, 1.2mmol of sodium tert-butoxide and 2-dimethyl Aminochloroethane 64.8g (0.6mmol), heat up to 105°C for reflux reaction for 1.8 hours, the reaction is complete; then cool down, filter, filter out the solid and collect the filtrate, add 15wt% hydrochloric acid aqueous solution to make the filtrate pH = 3, stir for 30 minutes Finally, separate the water phase and the organic phase, continue to add 15wt% hydrochloric acid aqueous solution to the organic phase to make pH=3, after stirring for 30 minutes, separate the water phase, combine the water phase twice, and then backwash twice with toluene 50g each time, add Activated carbon was heated up to 78°C for decolorization for 1 hour and then filtered, and the filtrate was cooled to 20°C and added with 40wt% sodium hydroxide to make the pH 11, then 100 g of ether was a...

Embodiment 3

[0063] (1) Add 600g of toluene into a 2000ml three-necked flask, add 100g (0.5mmol) of 2-pyridylphenylmethylmethanol, add catalyst tetrabutylammonium bromide 3g, metal potassium 0.6mmol and 2-dimethylamino Ethyl chloride (1mmol), warming up to 110°C for reflux reaction for 1.6 hours, the reaction is complete; then cool down, filter, filter out the solid and collect the filtrate, add 25wt% hydrochloric acid aqueous solution to make the filtrate pH=4, after stirring for 30 minutes, separate the water phase And the organic phase, continue to add 25wt% hydrochloric acid aqueous solution to the organic phase, after stirring for 30 minutes, separate the water phase, combine the water phase twice, and then backwash twice with toluene 80g each time, add activated carbon and heat up to 76 ° C for 1 hour decolorization Filtrate, cool the filtrate to 22°C and add 45wt% sodium hydroxide to make the pH 12, add 100g of dichloromethane each time to extract the aqueous phase 3 times, combine t...

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Abstract

The invention discloses a synthesis method of doxylamine succinate. The method includes: (1) adding 2-pyridylphenylmethylcarbinol into an organic solvent I, adding a catalyst, strong base or alkali metal and 2-dimethylaminochloroethane respectively, performing heating to 100-110DEG C and carrying out reaction for 1-2h; then conducting cooling and filtering; subjecting an aqueous phase to backwashing with the organic solvent I, then performing heating to 70-80DEG C, adding activated carbon for decolorization, then performing filtering, then adding a low-boiling-point organic solvent for extraction, drying the extracted organic phase, and finally conducting reduced pressure concentration at 50-60DEG C to dryness to obtain doxylamine; and (2) dissolving the doxylamine in an organic solvent II, adding succinic acid at 50-60DEG C for reaction, then employing medicinal activated carbon for decolorization and filtering, conducting cooling to a temperature at or below 5DEG C, carrying out stirring crystallization, then performing pumping filtering, and conducting washing with the precooled organic solvent II, and finally performing vacuum drying to obtain the doxylamine succinate. The synthesis method provided by the invention simplifies operation, lowers energy consumption, and has high reaction conversion rate and high yield.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a synthesis technology of doxylamine succinate. Background technique [0002] Doxylamine succinate is a kind of ethanolamine drug, which has antihistamine effect, anticholinergic effect and significant sedative effect. It has the characteristics of strong activity and low gastrointestinal side effects, and is suitable for a variety of allergic skin diseases. Hay fever, allergic rhinitis, asthmatic bronchitis, etc. The route of synthesizing doxylamine succinate in the existing published patent literature is as follows: [0003] 2-Pyridylphenylmethylmethanol and 2-dimethylaminoethyl chloride generate doxylamine base under the action of an organic base; then doxylamine base and succinic acid are salified to obtain doxylamine succinate. [0004] The synthesis method of doxylamine disclosed in patent CN102108059B: 2-pyridylphenylmethylmethanol is reacted with sodium amide ...

Claims

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Application Information

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IPC IPC(8): C07D213/30C07C51/41C07C55/10
CPCC07D213/30C07C51/412C07C55/10Y02P20/584
Inventor 高宇潘晶晶
Owner 深圳沃兰德药业有限公司
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