CN110498764B - Synthesis method of doxylamine succinate - Google Patents
Synthesis method of doxylamine succinate Download PDFInfo
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- CN110498764B CN110498764B CN201910909042.XA CN201910909042A CN110498764B CN 110498764 B CN110498764 B CN 110498764B CN 201910909042 A CN201910909042 A CN 201910909042A CN 110498764 B CN110498764 B CN 110498764B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The application discloses a method for synthesizing doxylamine succinate, which comprises (1) adding 2-pyridylphenyl methyl methanol into an organic solvent I, respectively adding a catalyst, strong alkali or alkali metal and 2-dimethylaminochloroethane, heating to 100-110 ℃ for reaction for 1-2 hours; then cooling and filtering; backwashing the water phase with an organic solvent I, heating to 70-80 ℃, adding activated carbon for decolorization, filtering, adding a low-boiling point organic solvent for extraction, drying the extracted organic solvent, and concentrating under reduced pressure at 50-56 ℃ to obtain doxylamine; (2) Dissolving doxylamine in an organic solvent II, adding succinic acid at 50-60 ℃ for reaction, adding medicinal active carbon for decolorization and filtration, cooling to below 5 ℃, stirring for crystallization, carrying out suction filtration, washing with a precooled organic solvent II, and finally carrying out vacuum drying to obtain doxylamine succinate. The synthesis method of the application simplifies the operation and reduces the energy consumption; and the reaction conversion rate and the yield are high.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a synthesis technology of doxylamine succinate.
Background
Doxylamine succinate is an ethanolamine type medicine, has the characteristics of antihistamine, anticholinergic effect and obvious sedative effect, has strong activity, low gastrointestinal side effect and the like, and is suitable for various allergic skin diseases, hay fever, allergic rhinitis, asthmatic bronchitis and the like. The route for the synthesis of doxylamine succinate in the prior published patent literature is as follows:
2-pyridylphenyl methyl methanol and 2-dimethylamino ethyl chloride generate doxylamine base under the action of organic base; and then salifying the doxylamine base and succinic acid to obtain doxylamine succinate.
The doxylamine synthesis method disclosed in patent CN 102108059B: 2-pyridylphenyl methyl methanol is adopted to react with sodium amide to generate 2-pyridylphenyl methyl sodium methoxide, the solvent is dimethylbenzene, after the reaction is refluxed for 5 hours, 2-dimethylaminochloroethane is added into the reaction solution dropwise, the reflux reaction is continued for 20 hours, and the water quenching reaction is used. The resulting mixture was eluted by column chromatography to separate 2-pyridylphenylmethyl methanol from doxylamine.
The salt forming method comprises the following steps: doxylamine and succinic acid were added to about 4 times acetone, heated and stirred until dissolved, and stirring was continued for half an hour. Cooled to room temperature and then frozen in a refrigerator at-20 ℃ for 24 hours. The crude product is heated, dissolved and recrystallized with acetone.
The doxylamine synthesis method disclosed in patent CN 103524403B: adding sodium amide and dimethylbenzene into a three-neck flask, and heating to 140 ℃; 2-pyridylphenyl methyl methanol mixed xylene is dripped into the reaction system, and reflux reaction is carried out for 5h under the condition; and slowly dripping the dimethyl amino ethyl chloride mixed xylene solution into a reaction system, and carrying out reflux reaction for 3-4 h. After the reaction is finished, saturated NH is added dropwise 4 Stirring the Cl aqueous solution for 0.5h, adding water, adjusting the pH value to 2-3, discarding the organic phase, retaining the aqueous phase, extracting the aqueous phase with ethyl acetate, and discarding the organic phase; regulating the pH value of the water phase to 5-6, adding ethyl acetate for extraction, and discarding an organic phase, wherein most of unreacted 2-pyridylphenyl methyl methanol and a part of impurities can be removed; regulating the pH value of the water phase to 9-10, adding ethyl acetate for extraction, reserving an organic phase, drying the organic phase, and spin-drying to obtain an oily crude product; the oily crude product is stirred with silica gel and is put on a column, and the eluent is collected and dried to obtain the doxylamine.
The salt forming method comprises the following steps: adding 2.5 times of acetone into doxylamine and succinic acid, heating and refluxing until the solid is dissolved, and continuously stirring for 1h; steaming out acetone, adding 2 times isopropyl ether, performing ultrasonic treatment for 10min, removing the isopropyl ether at the upper layer, spin-drying, adding 2 times acetone, stirring at 0 ℃ for crystallization, and performing suction filtration to obtain a crude product. The crude product was recrystallized twice from acetone.
The doxylamine synthesis method disclosed in patent CN 105237467B: 2-pyridylphenyl methyl methanol is dissolved in dimethylbenzene at 0-5 ℃ in ice bath, sodium amide is added under the protection of nitrogen, stirring is carried out for 15-30 minutes, dimethylaminochloroethane hydrochloride is added, stirring is carried out for 15-30 minutes at 0-5 ℃, the temperature is slowly increased to 140-150 ℃, reflux stirring is carried out for 50-70 minutes, and after the reaction is finished, the organic phase is quenched, extracted, dried, and the solvent is distilled under reduced pressure to obtain doxylamine;
the salifying method comprises dissolving doxylamine in mixed solution of isopropanol and ethyl acetate (without definite solvent mass multiple), adding succinic acid at a certain temperature, cooling for crystallization after salifying, suction filtering, and washing with organic solvent to obtain doxylamine succinate, wherein the volume ratio of isopropanol and ethyl acetate is (0.5-2): 1
The method for synthesizing doxylamine in patent CN107056685A comprises the following steps: adding 2-pyridylphenyl methyl methanol into toluene or xylene, heating and refluxing to make the water content of a reaction system less than 0.1%, cooling the reaction solution to room temperature, controlling the temperature of the reaction solution to be 30-50 ℃ under the protection of intense stirring and nitrogen, slowly adding phase strong base or alkali metal in batches, heating to 60 ℃ to react for 1 hour at 70 ℃ and then for 1 hour at 80 ℃, reacting for 1 hour at 90 ℃ and for 1 hour at 100 ℃, and refluxing and reacting for 1 hour at 110 ℃ until all the added alkali is reacted; the molar ratio of the strong alkali or alkali metal with phase to the 2-pyridylphenyl methyl methanol is 0.9-1.5:1, a step of; then cooling to 90-100 ℃, adding 2-dimethylamino ethyl chloride toluene or xylene solution for 5-6 hours, wherein the feeding mole ratio of 2-pyridyl phenyl methyl methanol to 2-dimethylamino ethyl chloride is 1: heating and refluxing for 18-28 hours at the temperature of 0.8-2, cooling, dropwise adding ice water at the temperature of 15-25 ℃ under the protection of nitrogen for quenching reaction, stirring for 1 hour, separating out an aqueous phase, continuously washing an organic phase with ice water, separating out an aqueous phase, adding 15-20% organic acid solution into the organic phase to ensure that the pH value of a reaction solution is=3-4, stirring for 30 minutes, separating out the aqueous phase, repeating the operation twice, backwashing all the aqueous phases with recycled toluene or xylene for 2-3 times, adding activated carbon at room temperature for decolorization, filtering, adding 10% sodium hydroxide into filtrate at the temperature of 15-25 ℃ to ensure that the pH value is 10-11, adding cyclohexane for extracting the aqueous phase for three times, washing the organic phase with 10-15% brine for two times, drying with anhydrous sodium sulfate, and concentrating under reduced pressure at the temperature of 45 ℃ to obtain the dry doxylamine;
the salt forming method comprises the following steps: dissolving the doxylamine obtained in the step (2) in an organic solvent with the weight of 2-10, adding medicinal active carbon for decolorization, adding succinic acid at 45-50 ℃, precipitating crystals, slowly cooling to 10 ℃, stirring for crystallization for 1 hour, carrying out suction filtration, washing with a precooled organic solvent, and carrying out vacuum drying to obtain doxylamine succinate crystals; the molar ratio of doxylamine to succinic acid is 1:0.8-1.2.
The above synthesis methods have the following problems: patent CN102108059B disadvantages: 1. the super alkali and dimethylbenzene are adopted for reflux reaction for more than 25 hours, so that the reaction time is long, the temperature is high, and the damage to reaction equipment is extremely large; 2. the reaction is quenched by water directly, so that the reaction is extremely dangerous, and the sodium amide is subjected to severe and rapid reaction when meeting water, so that the dangers of spraying, explosion and the like are easily generated. 3. The obtained doxylamine has low purity, needs column passing and is not suitable for industrial production at all. 4. The salification needs to be carried out at the temperature of minus 20 ℃ for 24 hours, so that the energy consumption is high, and the industrial production is not easy to realize. 5. The melting point of the final product is 101-103 ℃, which does not meet the requirements of 103-108 in USP 41.
The doxylamine synthesis in CN103524403B is the same as the basic route in CN102108059B, except that the reaction time is slightly shortened. Post-treatment also requires column passing, and industrialization cannot be realized. The salt forming method is complex in operation, is not beneficial to industrial production, and the final product does not give data such as melting point, and the like, and the final product is found to be yellow in appearance and the melting point does not meet the USP standard through repeating the process.
CN105237467B doxylamine synthesis: the dosage of the sodium amide is 5.6 times of the molar quantity of the 2-pyridylphenyl methyl methanol, and the dosage of the dimethylaminochloroethane hydrochloride is 7.4 times of the molar quantity of the 2-pyridylphenyl methyl methanol. In the method, the raw materials of the sodium amide and the dimethylaminoethyl chloride hydrochloride are expensive, so that the large dosage inevitably leads to the extra high cost of doxylamine, and the method has no industrial significance.
The synthesis of CN107056685A doxylamine takes super-strong alkali such as sodium amide and the like as raw materials, the reaction time is over 30 hours, the disadvantage is equivalent to that of patent CN102108059B, and a large amount of strongly alkaline wastewater is brought by post-treatment, so that great environmental protection pressure exists in industrialization.
In conclusion, the existing doxylamine synthesis technology has the problems of high energy consumption, high cost, potential safety hazard and the like, and is not suitable for industrial production.
Disclosure of Invention
The technical problems to be solved by the application are as follows: aiming at the defects existing in the prior art, the synthesis method of doxylamine succinate is provided, which has the advantages of safe production, low energy consumption, high reaction conversion rate and high yield, and is suitable for industrial production.
In order to solve the technical problems, the technical scheme of the application is as follows:
a method for synthesizing doxylamine succinate, comprising the following steps:
(1) Synthesis of doxylamine base:
the reaction formula:
adding 2-pyridylphenyl methyl methanol into an organic solvent I, respectively adding an onium salt catalyst, strong alkali or alkali metal and 2-dimethylaminoethyl chloride, heating to 100-110 ℃ and reacting for 1-2 hours; then cooling, filtering out solids and collecting filtrate; adding 1-20% acid solution into the filtrate to adjust the pH value of the filtrate to be 3-4, and separating out an aqueous phase and an organic phase after stirring for 30 minutes; repeatedly separating the organic phases for 1 time, merging water phases obtained by the two separation, backwashing for 2-3 times by using an organic solvent I, heating to 70-80 ℃, adding active carbon for decolorization, filtering, adding 40wt% of sodium hydroxide into filtrate at 10-25 ℃ to adjust pH to 11-12, adding a low boiling point organic solvent to extract the water phases for three times, washing the extracted organic phases with 15-25 wt% of salt water for two times, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure at 50-56 ℃ until the yellow oily matter is obtained, namely doxylamine; the chemical name is N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine;
(2) Synthesis of doxylamine succinate:
the reaction formula:
dissolving the doxylamine obtained in the step (1) in an organic solvent II, adding succinic acid at 50-60 ℃ for reaction, adding medicinal active carbon for decolorization and filtration, slowly cooling to below 5 ℃, stirring and crystallizing for 0.5-1 hour, then carrying out suction filtration, washing with a precooled organic solvent II, and finally carrying out vacuum drying to obtain the doxylamine succinate.
As a preferred embodiment, the organic solvent I has a water content of < 0.5% by weight.
The organic solvent I is toluene or xylene and a mixture thereof.
As a preferred technical scheme, the strong base or alkali metal is any one of sodium hydride, potassium hydride, sodium tert-butoxide, sodium potassium tert-butoxide, sodium amide, potassium amide or metal simple substance lithium, sodium or potassium or a combination thereof.
As a preferable technical scheme, the acid for adjusting the pH value of the filtrate is one or more of organic acids such as hydrochloric acid, formic acid, acetic acid, propionic acid, butyric acid and the like.
As a preferred embodiment, the onium salt catalyst is any one of tetrabutylammonium bromide (TBAB) and tetrabutylammonium iodide (TBAI).
As a preferable technical scheme, the low-boiling-point organic solvent is one or more of diethyl ether, isopropyl ether, petroleum ether, n-hexane, cyclohexane, dichloromethane and ethyl acetate.
As a preferable technical scheme, the feeding mole ratio of the 2-pyridylphenyl methyl methanol to the alkali or alkali metal and the 2-dimethylamino chloroethane is 1:1.1 to 3:1 to 2.
As a preferable technical scheme, the mass ratio of the 2-pyridylphenyl methyl methanol to the organic solvent I is 1:4-8; the mass ratio of the 2-pyridylphenyl methyl methanol to the onium salt catalyst is 1:0.01 to 0.05.
As a preferable technical scheme, the organic solvent II is one or more of ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran and ethyl acetate.
As a preferable technical scheme, the molar ratio of the doxylamine to the succinic acid is 1:0.85 to 1; the mass ratio of the doxylamine to the organic solvent II is 1:1.5-5.
Due to the adoption of the technical scheme, the application has the beneficial effects that:
in the synthesis method of doxylamine succinate, the required raw materials and auxiliary materials are added into a reaction kettle at one time before reaction, and a two-phase catalyst is added, so that compared with the prior art, the 2-dimethylamino chloroethane is required to be added dropwise, the operation is simplified, the equipment investment is simplified, and the reaction can be completed after heating and refluxing for 2 hours; compared with the prior art, the reaction time of more than 25-30 hours is greatly shortened, the energy consumption is greatly reduced, and the damage to equipment is also reduced to the minimum; and the reaction conversion rate and the yield are high.
The post-treatment process of doxylamine succinate is more concise, efficient and environment-friendly. The operation that silica gel is needed to pass through a column and impurities are extracted by adjusting the pH value for a plurality of times in the prior art is not beneficial to industrial production. And after the reaction is finished, inorganic salts are directly filtered, so that compared with the prior art, the operation steps are reduced, and the pollution discharge of alkaline wastewater is reduced.
The finished product doxylamine succinate obtained by salifying can reach the USP standard only by one-time crystallization, avoids the conditions of repeated crystallization and low yield and purity in the prior art, and is an economic and reasonable industrial mass production line.
The catalyst tetrabutylammonium bromide or tetrabutylammonium iodide used in the application belongs to an onium salt phase transfer catalyst, and the reaction process of doxylamine alkali is that 2-pyridine phenylmethyl methanol reacts with strong alkali or alkali metal to generate corresponding alkoxide and then reacts with dimethylaminochloroethane to form doxylamine, while 2-pyridine phenylmethyl methanol is in a liquid phase, alkali metal is solid, two-phase reaction is generally difficult, and the reaction rate is low. After the phase transfer catalyst is added, the catalyst is combined with ions in strong alkali or alkali metal to enter a liquid phase, so that the catalyst and 2-pyridine phenyl methyl methanol are in the liquid phase, and the reaction rate is accelerated.
Drawings
The application will be further described with reference to the drawings and examples.
FIG. 1 is a GC spectrum of doxylamine base of example 1 of the present application;
FIG. 2 is a GC spectrum of doxylamine succinate of example 1 of the present application;
FIG. 3 is a HPLC chromatogram of doxylamine succinate of example 1 of the present application.
Detailed Description
The application is further illustrated in the following, in conjunction with the accompanying drawings and examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
As shown in fig. 1-3, the analysis maps corresponding to fig. 1, 2 and 3, respectively, are shown in tables 1, 2 and 3 below.
Table 1:
table 2:
table 3:
example 1
(1) 500g of dimethylbenzene is added into a 2000ml three-necked flask, 100g (0.5 mol) of 2-pyridylphenylmethylmethylmethylmethanol is added, 1g of tetrabutylammonium bromide, 24.1g (0.6 mol) of sodium hydride and 81g (0.75 mol) of 2-dimethylaminochloroethane are respectively added as catalysts, the temperature is raised to 108 ℃ and reflux reaction is carried out for 2 hours, and the reaction is completed; then cooling, filtering out solids, collecting filtrate, adding 20wt% hydrochloric acid aqueous solution to enable the pH value of the filtrate to be=3.5, stirring for 30 minutes, separating out aqueous phase and organic phase, sequentially adding 50g of 20wt% hydrochloric acid aqueous solution into the organic phase, stirring for 30 minutes, separating out aqueous phase, combining the aqueous phases twice, backwashing with 50g of dimethylbenzene for 2 times each time, adding active carbon to heat up to 75 ℃ for decoloring for 1 hour, filtering, cooling the filtrate to 15 ℃ and adding 40wt% sodium hydroxide to enable the pH value to be 11.5, adding 100g of normal hexane for extracting the aqueous phase for 3 times each time, combining the extracted organic phase, washing with 20g of 18wt% saline for two times each time, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness at 55 ℃ to obtain 122.1g of yellow oily substance, namely doxylamine. GC purity was 99.68% in 89.7% yield.
(2) In a 1000ml three-mouth bottle, 122.1g (0.45 mol) of doxylamine obtained in the step (1) is dissolved in 244.2g of acetone, 53.1g (0.45 mol) of succinic acid is added when the temperature is raised to 55 ℃, medicinal active carbon is added for decoloration and filtration, then the temperature is slowly reduced to 5 ℃ to separate out a large amount of white solid, the mixture is stirred and crystallized for 0.6 hour and then is subjected to suction filtration, pre-cooled acetone is used for leaching, and the mixture is dried in vacuum at 60 ℃ to obtain 162.4g of doxylamine succinate, the yield is 92.9%, and the melting point is 103.8-104.9 ℃. HPLC purity 99.83%, GC purity 99.84%.
Example 2
(1) 700g of toluene is added into a 2000ml three-necked flask, 100g (0.5 mol) of 2-pyridylphenyl methyl methanol is added, 2g of tetrabutylammonium iodide, 1.2mol of sodium tert-butoxide and 64.8g (0.6 mol) of 2-dimethylaminoethyl chloride are respectively added, the temperature is raised to 105 ℃ and the reflux reaction is carried out for 1.8 hours, and the reaction is completed; then cooling, filtering out solids, collecting filtrate, adding 15wt% hydrochloric acid aqueous solution to enable the pH value of the filtrate to be=3, stirring for 30 minutes, separating out aqueous phase and organic phase, sequentially adding 15wt% hydrochloric acid aqueous solution to enable the pH value to be=3, stirring for 30 minutes, separating out aqueous phase, combining aqueous phases twice, backwashing with 50g of toluene for 2 times each time, adding active carbon to heat to 78 ℃ for decoloration for 1 hour, filtering, cooling the filtrate to 20 ℃ and adding 40wt% sodium hydroxide to enable the pH value to be 11, adding 100g of diethyl ether to extract the aqueous phase for 3 times each time, combining the extracted organic phase, washing with 20g of 20wt% saline for two times each time, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness at 55 ℃ to obtain 123.1g of yellow oily matter, namely doxylamine. GC purity 99.4% yield 90.2%.
(2) In a 1000ml three-mouth bottle, 123.1g (0.45 mol) of doxylamine obtained in the step (1) is dissolved in 400g of ethanol, 50.7g (0.43 mol) of succinic acid is added when the temperature is raised to 58 ℃, medicinal active carbon is added for decoloration and filtration, a large amount of white solid is separated out after slow cooling to 5 ℃, stirring and crystallization are carried out for 1 hour, suction filtration is carried out, pre-cooled ethanol is used for leaching, vacuum drying is carried out at 60 ℃, 158.6g of doxylamine succinate is obtained, the yield is 90.2%, and the melting point is 103.4-104.6 ℃. HPLC purity 99.7%, GC purity 99.8%.
Example 3
(1) 600g of toluene is added into a 2000ml three-necked flask, 100g (0.5 mol) of 2-pyridylphenylmethylmethylmethylmethanol is added, 3g of tetrabutylammonium bromide, 0.6mol of metallic potassium and 1mol of 2-dimethylaminochloroethane are respectively added as catalysts, the temperature is raised to 110 ℃ for reflux reaction for 1.6 hours, and the reaction is completed; then cooling, filtering out solids, collecting filtrate, adding 25wt% hydrochloric acid aqueous solution to enable the pH value of the filtrate to be=4, stirring for 30 minutes, separating out aqueous phase and organic phase, sequentially adding 25wt% hydrochloric acid aqueous solution into the organic phase, stirring for 30 minutes, separating out aqueous phase, combining aqueous phase twice, backwashing with 80g of toluene for 2 times each time, adding active carbon to heat up to 76 ℃ for decoloration for 1 hour, filtering, cooling filtrate to 22 ℃ and adding 45wt% sodium hydroxide to enable the pH value to be 12, adding 100g of dichloromethane for extracting aqueous phase for 3 times each time, combining organic phase obtained by extraction, washing with 30g of 20wt% saline for two times each time, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness at 56 ℃ to obtain 124.5g of yellow oily substance, namely doxylamine. GC purity 99.2% yield 91%.
(2) In a 1000ml three-mouth bottle, 124.5g (0.46 mol) of doxylamine obtained in the step (1) is dissolved in 300g of ethyl acetate, 54.3g (0.46 mol) of succinic acid is added when the temperature is raised to 60 ℃, medicinal active carbon is added for decoloration and filtration, a large amount of white solid is separated out after slow cooling to 5 ℃, stirring and crystallization are carried out for 1 hour, suction filtration is carried out, pre-cooled ethyl acetate is used for leaching, and vacuum drying is carried out at 60 ℃ to obtain 166g of doxylamine succinate, the yield is 93.5%, and the melting point is 103.7-104.8 ℃. HPLC purity 99.85%, GC purity 99.86%.
Comparative example 1
Comparative example 1 was different from example 1 in that tetrabutylammonium bromide was not added as a catalyst, 2-dimethylaminoethyl chloride was added dropwise, the reaction time of dropwise and reflux was 16 hours, and the rest was the same, and in the synthesis of doramesine in step (1), concentration under reduced pressure was carried out until it was dried to obtain 101.2g of yellow oily substance. GC purity 98.8% yield 73.7%. 129.3g of doxylamine succinate is obtained in the step (2), the yield is 90%, and the melting point is 103.3-104.3 ℃. HPLC purity 98.57%, GC purity 98.5%.
Comparative example 2
Comparative example 2 was different from example 1 in that tetrabutylammonium bromide was not added as a catalyst, and the rest was the same, and in the synthesis of doramectin base in step (1), concentration under reduced pressure was performed to dryness to give 81g of yellow oil. GC purity 97% yield 57.9%. In the step (2), 95.8g of doxylamine succinate is obtained, the yield is 85%, and the melting point is 102.3-103.4 ℃. HPLC purity 97.5%, GC purity 97.4%.
Claims (7)
1. The synthesis method of doxylamine succinate is characterized by comprising the following steps:
(1) Synthesis of doxylamine base: adding 2-pyridylphenyl methyl methanol into an organic solvent I, and respectively adding an onium salt catalyst, strong alkali or alkali metal and 2-dimethylaminoethyl chloride, wherein the strong alkali or alkali metal is any one of sodium hydride, potassium hydride, sodium tert-butoxide, sodium amide, potassium amide or metal simple substance lithium, sodium or potassium or a combination thereof; the onium salt catalyst is any one of tetrabutylammonium bromide and tetrabutylammonium iodide; the feeding mole ratio of the 2-pyridylphenyl methyl methanol to the alkali or alkali metal and the 2-dimethylamino chloroethane is 1:1.1 to 3:1 to 2; heating to 100-110 ℃ to react for 1-2 hours; then cooling, filtering out solids and collecting filtrate; adjusting the pH value of the filtrate to be 3-4, and stirring to separate an aqueous phase and an organic phase; repeatedly separating the organic phases for 1 time, merging water phases obtained by the two separation, washing for 2-3 times by using an organic solvent I, heating to 70-80 ℃, adding active carbon for decolorization, filtering, adjusting the pH of filtrate to 11-12 at 10-25 ℃, adding a low-boiling organic solvent for extracting the water phase for three times, washing the extracted organic phase with brine for two times, drying, and concentrating under reduced pressure at 50-56 ℃ until the yellow oily matter is obtained, namely doxylamine;
(2) Synthesis of doxylamine succinate: dissolving the doxylamine obtained in the step (1) in an organic solvent II, adding succinic acid at 50-60 ℃ for reaction, adding medicinal active carbon for decolorization and filtration, slowly cooling to below 5 ℃, stirring and crystallizing for 0.5-1 hour, then carrying out suction filtration, washing with a precooled organic solvent II, and finally carrying out vacuum drying to obtain the doxylamine succinate.
2. The method for synthesizing doxylamine succinate as claimed in claim 1, wherein: the water content of the organic solvent I is <0.5wt%.
3. The method for synthesizing doxylamine succinate as claimed in claim 1, wherein: the organic solvent I is toluene or xylene and a mixture thereof.
4. The method for synthesizing doxylamine succinate as claimed in claim 1, wherein: the low-boiling organic solvent is one or more of diethyl ether, isopropyl ether, petroleum ether, n-hexane, cyclohexane, dichloromethane and ethyl acetate.
5. The method for synthesizing doxylamine succinate as claimed in claim 1, wherein: the mass ratio of the 2-pyridylphenyl methyl methanol to the organic solvent I is 1:4-8; the mass ratio of the 2-pyridylphenyl methyl methanol to the onium salt catalyst is 1:0.01 to 0.05.
6. The method for synthesizing doxylamine succinate as claimed in claim 1, wherein: the organic solvent II is one or more of ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran and ethyl acetate.
7. The method for synthesizing doxylamine succinate as claimed in claim 1, wherein: the molar ratio of doxylamine to succinic acid is 1:0.85 to 1; the mass ratio of the doxylamine to the organic solvent II is 1:1.5-5.
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| CN102108059A (en) * | 2010-09-03 | 2011-06-29 | 合肥工业大学 | Method for synthesizing doxylamine succinate |
| CN103524403A (en) * | 2013-09-30 | 2014-01-22 | 江苏礼华生物技术有限公司 | Preparation method of doxylamine succinate |
| CN105237467A (en) * | 2015-09-23 | 2016-01-13 | 南京济群医药科技有限公司 | Preparation method of doxylamine succinate |
| CN107056685A (en) * | 2017-01-23 | 2017-08-18 | 珠海市海瑞德生物科技有限公司 | A kind of synthetic method of doxylamine succinate |
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| CN102108059A (en) * | 2010-09-03 | 2011-06-29 | 合肥工业大学 | Method for synthesizing doxylamine succinate |
| CN103524403A (en) * | 2013-09-30 | 2014-01-22 | 江苏礼华生物技术有限公司 | Preparation method of doxylamine succinate |
| CN105237467A (en) * | 2015-09-23 | 2016-01-13 | 南京济群医药科技有限公司 | Preparation method of doxylamine succinate |
| CN107056685A (en) * | 2017-01-23 | 2017-08-18 | 珠海市海瑞德生物科技有限公司 | A kind of synthetic method of doxylamine succinate |
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