CN110407737B - Preparation method of cyproheptadine hydrochloride - Google Patents
Preparation method of cyproheptadine hydrochloride Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of cyproheptadine hydrochloride. The invention improves the existing preparation method of cyproheptadine hydrochloride, greatly simplifies the whole synthesis steps, has higher purity and yield of the prepared cyproheptadine hydrochloride, reduces the use of organic solvents and dangerous chemicals, simplifies the operation steps, reduces the operation difficulty, reduces the cost, lightens the environmental burden, and is more beneficial to large-scale industrial production.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a preparation method of cyproheptadine hydrochloride.
Background
Aiming at the current few related preparation methods of cyproheptadine hydrochloride, patent US3014911 discloses that 1-methyl-4-chloropiperidine reacts with magnesium in tetrahydrofuran to generate 1-methyl-4-chloropiperidine magnesium chloride, then the 1-methyl-4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatriene) piperidine is generated by reacting with dibenzo [ a, e ] cycloheptatriene-5-ketone, during the process, toluene is used for extraction, ethanol aqueous solution is crystallized, separated and purified to obtain 1-methyl-4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatriene) piperidine, then glacial acetic acid, hydrogen chloride gas and acetic anhydride are used for treating the 1-methyl-4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine to produce 1-methyl-4- (5H-dibenzo [ a, e ] cycloheptatrien-5-ylidene) piperidine, treating the 1-methyl-4- (5H-dibenzo [ a, e ] cycloheptatrien-5-ylidene) piperidine with water, sodium hydroxide, toluene, hydrogen chloride gas to produce cyproheptadine hydrochloride, and purifying the cyproheptadine hydrochloride by: the hydrochloride was dissolved in water and the solution was adjusted to basic pH and extracted with toluene and dried over sodium sulfate, evaporated to remove benzene and reduced pressure to give the hydrochloride with a purity of 97%.
Although the method can prepare hydrochloride with high purity, a large amount of toluene is used as an extraction solvent in the synthesis process, the actual extraction effect is difficult to control, a large amount of glacial acetic acid and controlled acetic anhydride are used in the synthesis process, the production cost is increased, the environmental pollution is increased, the staff health is not facilitated, a large amount of hydrogen chloride gas is used in the reaction and the post-treatment, the requirements on transportation, equipment, use and management are high, the cost is increased invisibly, the refined post-treatment method is very complex, the enterprise is difficult to obtain profit, and the large-scale industrial production is also very difficult to achieve.
Therefore, aiming at the defects that the existing cyproheptadine hydrochloride synthesis method is complex, high in energy consumption, difficult to repeat in practical application and not suitable for industrial mass production, a synthesis method which is simpler, easy to operate and suitable for industrial mass production is needed.
Disclosure of Invention
The invention aims to provide a preparation method of cyproheptadine hydrochloride.
The technical scheme adopted by the invention is as follows:
the invention aims to provide a preparation method of cyproheptadine hydrochloride, which comprises the following steps:
1) dissolving 1-methyl-4-chloropiperidine in tetrahydrofuran, and adding magnesium chips to obtain a 1-methyl-4-chloropiperidine magnesium solution;
2) adding dibenzo [ a, e ] cycloheptatriene-5-ketone for reaction to obtain 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatriene) piperidine solution;
3) concentrating under reduced pressure, cooling, adjusting pH, and crystallizing to obtain 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatriene) piperidine crude product;
4) dissolving the 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product, adding concentrated hydrochloric acid solution for reaction, filtering and crystallizing to obtain cyproheptadine hydrochloride;
the synthetic route is as follows:
in order to further obtain cyproheptadine hydrochloride with higher purity, it is preferable to further include a step of refining the cyproheptadine hydrochloride obtained in the step 4).
Preferably, the refining is carried out by dissolving cyproheptadine hydrochloride in ethanol or methanol solution and then recrystallizing.
Preferably, the ethanol or methanol solution accounts for 10-95% by mass; more preferably 15 to 35%.
Preferably, the ethanol or methanol solution is an aqueous solution of ethanol or methanol.
The purity of the refined cyproheptadine hydrochloride can reach more than 99.8 percent, and the yield reaches 60-75 percent.
The cyproheptadine hydrochloride prepared by the preparation method disclosed by the application does not need to be subjected to a complicated refining process of US3014911 to obtain cyproheptadine hydrochloride with higher purity (97%), the reaction mode, intermediate post-treatment and cyproheptadine refining of the cyproheptadine hydrochloride preparation method disclosed by the application are simple, the production cost and production consumption are greatly reduced, and the cyproheptadine hydrochloride with higher purity (99.8%) can be obtained through a simple refining process.
Preferably, the reaction temperature in the step 4) is 80-90 ℃.
Preferably, the reaction time in the step 4) is 1-2 h.
Preferably, the mass percent of the concentrated hydrochloric acid solution in the step 4) is 30-36%.
Preferably, the step 4) of adding concentrated hydrochloric acid for reaction further comprises a step of adding activated carbon, wherein the purpose of adding activated carbon is decolorization.
Preferably, the mass ratio of the activated carbon to the 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product is 0.01-0.05: 1.
Preferably, the solvent for dissolving the crude 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine in step 4) is selected from lower alcohol solutions or water.
Preferably, the lower alcohol is selected from methanol and/or ethanol.
Preferably, the lower alcohol solution is 70 to 99 percent by mass; more preferably 90 to 99%.
Preferably, the lower alcohol solution is an aqueous solution of a lower alcohol.
And 4) filtering, and then obtaining the cyproheptadine hydrochloride only by simple operation of standing for crystallization.
The purity of the cyproheptadine hydrochloride prepared in the step 4) is over 90 percent, and the yield is 70-75 percent.
Compared with the prior art that acetic anhydride and hydrogen chloride gas are added, the hydrochloric acid solution is directly added into the 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product for reaction, so that the production cost is reduced, the operation difficulty and the danger are reduced, the post-treatment operation steps are reduced, the purity of the obtained cyproheptadine hydrochloride can reach more than 90%, and the yield is high.
Preferably, the temperature is reduced to less than or equal to 10 ℃ after the concentration under reduced pressure in the step 3), and the temperature is reduced to the temperature so as to facilitate the subsequent purification operation.
Preferably, the pH is adjusted to neutral in step 3).
Preferably, strong acid and weak base salt solution such as ammonium chloride and ammonium sulfate can be used for adjusting the pH in the step 3), and dilute acid solution can also be used.
The purpose of adjusting the pH in step 3) is to remove part of the by-products such as magnesium oxide, magnesium hydroxide, excess magnesium chips, etc.
Preferably, step 3) further comprises a step of centrifugation before obtaining crude 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine; preferably, the rotation speed of the centrifugation is 1000-4000 r/min.
Preferably, the pH value is adjusted after adding distilled water in step 3).
Because a part of the raw materials of the previous step which are not completely reacted remain in the reaction mixture and generate a large amount of heat when meeting water, so that the local temperature rise is too high, the distilled water is required to be slowly added under stirring, and preferably, the temperature of a speed control system for adding the distilled water in the step 3) is not more than 1-2 ℃/min.
According to the method, a plurality of steps such as extraction of 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine are not needed, so that the reaction steps are effectively reduced, the cost is reduced, the environmental burden is reduced, more importantly, the purity and yield of the hydrochloric acid suncured heptidine prepared in the step 4) are not negatively affected, the industrial large-scale production is facilitated, the step of toluene extraction is not needed, and the yield of the hydrochloric acid suncured heptidine obtained subsequently is higher.
Preferably, the reaction temperature in the step 2) is 0-25 ℃; more preferably 0 to 10 ℃.
Preferably, the reaction time in the step 2) is 1-2 h.
Preferably, the speed of adding dibenzo [ a, e ] cycloheptatriene-5-ketone in the step 2) is controlled to control the temperature of the system to rise by 1-5 ℃ in the whole reaction.
Preferably, the reaction temperature in the step 1) is 60-65 ℃.
Preferably, the reaction time in the step 1) is 1-2 h.
Preferably, the magnesium chips in the step 1) are magnesium chips after fresh grinding treatment, and there is no special requirement on how to grind the magnesium chips, and the oxide film on the surface of the magnesium chips can be treated by mechanical grinding, or the oxide film on the surface of the magnesium chips can be treated by a chemical method.
The invention has the beneficial effects that:
the invention improves the existing preparation method of cyproheptadine hydrochloride, greatly simplifies the whole synthesis steps, has higher purity and yield of the prepared cyproheptadine hydrochloride, reduces the use of organic solvents and dangerous chemicals, simplifies the operation steps, reduces the operation difficulty, reduces the cost, lightens the environmental burden, and is more beneficial to large-scale industrial production.
Detailed Description
The present invention will be described in further detail with reference to examples. It will also be understood that the following examples are included merely for purposes of further illustrating the invention and are not to be construed as limiting the scope of the invention, as the invention extends to insubstantial modifications and adaptations of the invention following in the light of the principles set forth herein. The specific process parameters and the like of the following examples are also only one example of suitable ranges, and the skilled person can make a selection within the suitable ranges through the description herein, and are not limited to the specific data of the following examples.
Example 1
A preparation method of cyproheptadine hydrochloride comprises the following steps:
1) adding 0.89g of newly polished magnesium strip into a 500mL reaction bottle, introducing nitrogen for protection, adding 50mL of tetrahydrofuran, heating to 60-65 ℃, then dropwise adding a solution of 3.80g of 1-methyl-4-chloropiperidine dissolved in 10mL of tetrahydrofuran, keeping the reaction slightly boiling during dropwise adding, and carrying out reflux reaction for 1h after dropwise adding is finished to obtain a 1-methyl-4-chloropiperidine magnesium solution;
2) cooling the 1-methyl-4-chloropiperidine magnesium solution to 0 ℃, then slowly adding 5.38g dibenzo [ a, e ] cycloheptatriene-5-ketone, and reacting for 1h at room temperature to obtain 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatriene) piperidine solution;
3) distilling a solution of 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine at 40-50 ℃ under reduced pressure to obtain tetrahydrofuran, stirring, cooling to 0 ℃, slowly adding 250mL of distilled water, adjusting the temperature of the mixed solution to be not more than 1-2 ℃/min at a speed of adding the distilled water, adjusting the mixed solution to be neutral by using dilute hydrochloric acid, standing overnight to separate out a precipitate, filtering out the precipitate, centrifuging and drying in the air to obtain 7.1g of a crude product of the 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine;
4) adding 6.1g of 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product into a 500mL round-bottom bottle, adding 40mL of 95% ethanol water solution by mass, heating for dissolving, adding 10mL of 35% concentrated hydrochloric acid by mass, continuously heating to 90 ℃, stirring for reacting for 1h, slightly cooling, adding 0.12g of active carbon, keeping the temperature and stirring for 20min, filtering while hot, washing filter residues with a small amount of hot water, combining the filtrate, standing at room temperature for crystallization, filtering, and drying at 80-100 ℃ to obtain 6.4g of cyproheptadine hydrochloride white crystalline powder with the purity of 92.2% and the yield of 70.6%, further dissolving the obtained cyproheptadine hydrochloride into 20% ethanol water solution by mass for recrystallization to obtain refined cyproheptadine hydrochloride with the purity of 99.9% and the yield of 63%.
The molecular weight is 287.17 through mass spectrum detection, and is consistent with the molecular weight of the target cyproheptadine hydrochloride.
Example 2
A preparation method of cyproheptadine hydrochloride comprises the following steps:
1) adding 9.0g of newly polished magnesium chips into a 2L reaction bottle, introducing nitrogen for protection, adding 350mL of tetrahydrofuran, heating to 60-65 ℃, then adding 300mL of tetrahydrofuran solution of 38g of 1-methyl-4-chloropiperidine, keeping reaction slight boiling during dropwise addition, and carrying out reflux reaction for 1h after dropwise addition is finished to obtain 1-methyl-4-chloropiperidine magnesium solution;
2) cooling the 1-methyl-4-chloropiperidine magnesium solution to 5 ℃, then slowly adding 52g dibenzo [ a, e ] cycloheptatriene-5-ketone, and reacting for 1h at room temperature to obtain 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatriene) piperidine solution;
3) distilling 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine solution at 40-50 ℃ under reduced pressure to remove tetrahydrofuran, stirring, cooling to 4 ℃, slowly adding 1000mL of distilled water, adjusting the temperature of the mixed solution to be not more than 1-2 ℃/min at a speed of adding distilled water, adjusting the mixed solution to be neutral by using dilute hydrochloric acid, standing overnight to separate out a precipitate, filtering out the precipitate, centrifuging and drying in the air to obtain 74.2g of 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product;
4) 74.0g of 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product is put into a 2000mL round-bottomed bottle, 500mL of 95% ethanol water solution is added and heated to be dissolved, 100mL of 35% concentrated hydrochloric acid is added, the mixture is continuously heated to 90 ℃ and stirred to react for 1 hour, the mixture is slightly cooled, 2.2g of activated carbon is added, the mixture is kept warm and stirred for 20 minutes, the mixture is filtered while the mixture is hot, filter residues are washed by a small amount of hot water, the filtrate is combined and stood at room temperature for crystallization, the filtrate is filtered and dried at 80-100 ℃ to obtain 63.5g of cyproheptadine hydrochloride white crystalline powder, the purity is 90.6%, the yield is 72.5%, and further, the obtained cyproheptadine hydrochloride is dissolved in 20% ethanol water solution for recrystallization, and the purity is 99.8%, and the yield is 65%.
The molecular weight is 287.18 through mass spectrum detection, and is consistent with the molecular weight of the target cyproheptadine hydrochloride.
Example 3
A preparation method of cyproheptadine hydrochloride comprises the following steps:
1) adding 1.96kg of newly polished magnesium chips into a 300L reaction bottle, filling nitrogen for protection, adding 30kg of tetrahydrofuran, heating to 60-65 ℃, then adding 70kg of tetrahydrofuran solution containing 7.5kg of 1-methyl-4-chloropiperidine, keeping the reaction slightly boiling during dropwise adding, and carrying out reflux reaction for 1h after dropwise adding is finished to obtain 1-methyl-4-chloropiperidine magnesium solution;
2) cooling the 1-methyl-4-chloropiperidine magnesium solution to 5 ℃, then slowly adding 10.2kg dibenzo [ a, e ] cycloheptatriene-5-ketone, and reacting for 1h at room temperature to obtain 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatriene) piperidine solution;
3) distilling 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine solution at 40-50 ℃ under reduced pressure to obtain tetrahydrofuran, stirring, cooling to 2 ℃, slowly adding 80L of distilled water, adjusting the temperature of the mixed solution to be not more than 1-2 ℃/min at a speed of adding the distilled water, adjusting the mixed solution to be neutral by using dilute hydrochloric acid, standing overnight to separate out a precipitate, filtering out the precipitate, centrifuging and drying in the air to obtain 16.4kg of a crude product of 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine;
4) 16.4kg of 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product is put into a 2000mL round-bottomed bottle, 38L of 95 mass percent ethanol water solution is added and heated to be dissolved, 1.2L of 35 mass percent concentrated hydrochloric acid is added, the mixture is continuously heated to 90 ℃ and stirred to react for 1 hour, the mixture is slightly cooled, 180g of activated carbon is added, the mixture is kept warm and stirred for 20 minutes, the mixture is filtered while hot, filter residues are washed by a small amount of hot water, the filtrate is combined and stood at room temperature for crystallization, the filtrate is filtered and dried at 80-100 ℃ to obtain 12.7kg of cyproheptadine hydrochloride white crystalline powder, the purity is 93.3 percent, the yield is 74.2 percent, and further, the obtained cyproheptadine hydrochloride is dissolved in 20 mass percent ethanol water solution for recrystallization to obtain refined cyproheptadine hydrochloride, the purity is 99.9 percent, and the yield is 68 percent.
The molecular weight is 287.19 through mass spectrum detection, and is consistent with the molecular weight of the target cyproheptadine hydrochloride.
Comparative example 1
A preparation method of cyproheptadine hydrochloride comprises the following steps:
1) adding 1.96kg of newly polished magnesium strips into a 300L reaction kettle, introducing nitrogen for protection, adding 30kg of tetrahydrofuran, heating to 60-65 ℃, then adding 70kg of tetrahydrofuran solution containing 7.5kg of 1-methyl-4-chloropiperidine, keeping reaction slight boiling during dropwise adding, and carrying out reflux reaction for 1h after dropwise adding is finished to obtain 1-methyl-4-chloropiperidine magnesium solution;
2) cooling the 1-methyl-4-chloropiperidine magnesium solution to 7 ℃, adding 10.2kg of dibenzo [ a, e ] cycloheptatriene-5-ketone in batches, and reacting at room temperature for 1h to obtain 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatriene) piperidine solution;
3) distilling 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine solution at 40-50 ℃ under reduced pressure to remove tetrahydrofuran, stirring, cooling to 0 ℃, slowly adding 15L of distilled water, adjusting the temperature of the mixed solution to be not more than 1-2 ℃/min, adjusting the mixed solution to be neutral by using dilute hydrochloric acid, extracting for 4 times by using 120kg of toluene, combining toluene phases by using 30kg of toluene each time, and concentrating under reduced pressure until the mixed solution is dry to obtain 6.25kg of 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product;
4) 6.25kg of 1-methyl 4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product is put into a 100L reaction tank, 20L of 95% ethanol water solution is added and heated to be dissolved, 1.4L of 35% concentrated hydrochloric acid is added, the mixture is continuously heated to 90 ℃ and stirred to react for 1 hour, the mixture is slightly cooled, 200g of activated carbon is added, the mixture is kept warm and stirred for 20 minutes, the mixture is filtered while hot, filter residues are washed by a small amount of hot water, the combined filtrate is kept at room temperature for standing and crystallizing, the mixture is filtered and dried at 80-100 ℃ to obtain 4.61kg of cyproheptadine hydrochloride white crystalline powder, the purity is 93.5%, the yield is 36.2%, and further, the obtained cyproheptadine hydrochloride is dissolved in 20% ethanol water solution for recrystallization, and the refined cyproheptadine hydrochloride is obtained, the purity is 99.8%, and the yield is 33%.
The molecular weight is 287.19 through mass spectrum detection, and is consistent with the molecular weight of the target cyproheptadine hydrochloride.
Claims (9)
1. A preparation method of cyproheptadine hydrochloride is characterized in that: the method comprises the following steps:
1) dissolving 1-methyl-4-chloropiperidine in tetrahydrofuran, and adding magnesium chips to obtain a 1-methyl-4-chloropiperidine magnesium solution;
2) adding dibenzo [ a, e ] cycloheptatriene-5-ketone for reaction to obtain 1-methyl-4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatriene) piperidine solution;
3) concentrating under reduced pressure, cooling, adjusting pH, and crystallizing to obtain 1-methyl-4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatriene) piperidine crude product;
4) dissolving the 1-methyl-4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product, adding concentrated hydrochloric acid solution for reaction, filtering and crystallizing to obtain cyproheptadine hydrochloride;
step 2), controlling the speed of adding dibenzo [ a, e ] cycloheptatriene-5-ketone to be 1-5 ℃ of the temperature of the system in the whole reaction; adding distilled water in the step 3), adjusting the pH value to be neutral, and controlling the temperature of a speed control system for adding the distilled water to be not more than 1-2 ℃/min.
2. The method of claim 1, wherein: further comprising a step of refining the cyproheptadine hydrochloride obtained in the step 4); the refining is that the cyproheptadine hydrochloride is dissolved in ethanol or methanol solution for recrystallization refining.
3. The method of claim 2, wherein: the mass percentage of the ethanol or methanol solution is 10-95%.
4. The method of claim 1, wherein: the reaction temperature in the step 4) is 80-90 ℃; the reaction time is 1-2 h.
5. The method of claim 1, wherein: the mass percentage of the concentrated hydrochloric acid solution in the step 4) is 30-36%.
6. The method of claim 1, wherein: step 4) adding concentrated hydrochloric acid solution and then adding activated carbon; the mass ratio of the activated carbon to the 1-methyl-4- (5-hydroxy-5-dibenzo [ a, e ] cycloheptatrienyl) piperidine crude product is 0.01-0.05: 1.
7. The method of claim 1, wherein: after the vacuum concentration in the step 3), the temperature is reduced to be less than or equal to 10 ℃.
8. The production method according to any one of claims 1 to 7, characterized in that: the reaction temperature in the step 2) is 0-25 ℃; the reaction time is 1-2 h.
9. The production method according to any one of claims 1 to 7, characterized in that: the reaction temperature in the step 1) is 60-65 ℃; the reaction time is 1-2 h.
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