CN110240564B - Preparation method of 9-hydroxymethyl-9, 10-dihydroacridine - Google Patents
Preparation method of 9-hydroxymethyl-9, 10-dihydroacridine Download PDFInfo
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- CN110240564B CN110240564B CN201910604968.8A CN201910604968A CN110240564B CN 110240564 B CN110240564 B CN 110240564B CN 201910604968 A CN201910604968 A CN 201910604968A CN 110240564 B CN110240564 B CN 110240564B
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- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/02—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with only hydrogen, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
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Abstract
The invention relates to a preparation method of 9-hydroxymethyl-9, 10-dihydroacridine. The preparation method comprises the following steps: the acridine ester shown in the formula (I) is subjected to reduction reaction in a solvent containing Lewis acid and a reducing agentTo generate 9-hydroxymethyl-9, 10-dihydroacridine; formula (I) is
Wherein R is C1‑3Alkyl group of (1). According to the preparation method of 9-hydroxymethyl-9, 10-dihydroacridine, the acridine ester is used as an initial raw material, and ester groups and carbon-nitrogen double bonds with considerable reduction difficulty participate in reduction reaction through selection of the raw material, so that the selectivity of the reduction reaction is improved, the occurrence of side reactions is favorably reduced, and the reaction yield is improved.
Description
Technical Field
The invention belongs to the field of preparation of acridine derivatives, and particularly relates to a preparation method of 9-hydroxymethyl-9, 10-dihydroacridine.
Background
9-hydroxymethyl-9, 10-dihydroacridine is an important starting material for the preparation of 5H-dibenzo [ b, f ] azepine and 10, 11-dihydro-5H-dibenzo [ b, f ] azepine intermediates. The 5H-dibenzo [ b, f ] azepine compounds have high therapeutic activity and are useful as antiemetics, sedatives, antihistamines, spasmolytics, anti-shock agents, antidepressants and potentiators of analgesics or anesthetics.
Although 9-hydroxymethyl-9, 10-dihydroacridine has high application value, the existing synthetic method is limited and has the problems of dangerous reaction process, difficult post-treatment, expensive reducing agent and low yield.
A document published in J.org.chem.,1960,25,827 discloses a method for preparing 9-hydroxymethyl-9, 10-dihydroacridine, which is prepared by using 9-carboxy acridine as a raw material and performing a reduction reaction under the action of a reducing agent lithium aluminum hydride. The synthesis method obtains the final product through one-step reduction, the preparation process is simple, but the yield of the product is only 80%, and a strong reducing agent lithium aluminum hydride is needed due to the reduction of hydroxymethyl and carbon-nitrogen double bonds.
Lithium aluminum hydride is very easy to absorb water and catch fire to cause danger in the using process, and the lithium aluminum hydride has strong reducibility, so that side reaction is easy to occur, the reaction yield is low, and the post-treatment difficulty is high. In a comprehensive view, the existing preparation method of 9-hydroxymethyl-9, 10-dihydroacridine has the disadvantages of low yield, violent reaction process, large difficulty in post-treatment and unsuitability for large-scale production.
Disclosure of Invention
The invention aims to provide a preparation method of 9-hydroxymethyl-9, 10-dihydroacridine, which aims to solve the problems of harsh reaction conditions, low reaction yield and unsuitability for industrial production of the existing preparation method.
In order to realize the purpose, the technical scheme of the preparation method of the 9-hydroxymethyl-9, 10-dihydroacridine is as follows:
a preparation method of 9-hydroxymethyl-9, 10-dihydroacridine comprises the following steps: performing reduction reaction on the acridine ester shown in the formula (I) in a solvent containing Lewis acid and a reducing agent to generate 9-hydroxymethyl-9, 10-dihydroacridine;
in the formula (I), R is C1-3Alkyl group of (1).
According to the preparation method of 9-hydroxymethyl-9, 10-dihydroacridine, the acridine ester is used as an initial raw material, and ester groups and carbon-nitrogen double bonds with considerable reduction difficulty participate in reduction reaction through selection of the raw material, so that the selectivity of the reduction reaction is improved, the occurrence of side reactions is favorably reduced, and the reaction yield is improved. Meanwhile, due to the reduction of the reduction difficulty, the conventional reducing agent can be utilized to carry out reaction under a mild reaction condition, so that the production cost is favorably reduced, and the safe and large-scale production is realized.
In order to promote the sufficient conversion of the raw materials and improve the reaction efficiency, the ratio of the amount of the acridine ester, the reducing agent and the Lewis acid is preferably 1: (1-5): (0.2-2).
The reduction reaction can ensure that the raw materials are fully converted, and in order to further improve the reaction efficiency and reduce the occurrence of side reactions, the temperature of the reduction reaction is preferably 30-75 ℃ and the time is preferably 1-5 h.
Preferably, the reducing agent is borohydride, in view of the cost of raw materials, the reaction yield and the reduction effect. In order to further reduce the cost of the reducing agent, preferably, the borohydride is at least one of potassium borohydride and sodium borohydride.
The Lewis acid can activate the ester carbonyl in the raw material and increase the electrophilic capacity of the carbonyl to negative hydrogen. Preferably, the Lewis acid is at least one of lithium chloride, zinc chloride, aluminum chloride, copper chloride, and cobalt chloride hexahydrate, in view of both the cost of raw materials and the activation effect.
The solvent for the reduction reaction is not particularly limited, and may be at least one of tetrahydrofuran, ethanol, methanol, and diethyl ether, considering the cost of the solvent and the reaction effect.
After the reduction reaction is finished, a final product can be obtained by utilizing conventional post-treatment means such as column separation, recrystallization and the like, and preferably, after the reduction reaction, the reaction is quenched, the reaction solvent is recovered, extracted and dried to obtain the catalyst for the reduction reaction. The target product with the purity of about 98 percent and the yield of about 95 percent can be obtained by a simple extraction method, and the synthesis method of the method has the advantages of reaction selectivity and reaction cost reduction.
The acridine ester shown in the formula (I) can be directly used as a commercial raw material, and in order to further reduce the cost of the raw material and make the synthesis of a target product more suitable for industrial implementation, the acridine ester shown in the formula (I) is preferably prepared by a method comprising the following steps: mixing 9-carboxyl acridine, thionyl chloride and alcohol, and carrying out reflux reaction to obtain the compound.
Drawings
FIG. 1 is a nuclear magnetic diagram of a product obtained by the method for producing 9-hydroxymethyl-9, 10-dihydroacridine according to example 1 of the present invention.
Detailed Description
The invention provides a preparation method of 9-hydroxymethyl-9, 10-dihydroacridine, which is simple and easy to implement and convenient for industrial implementation, mainly through selection of reaction raw materials, the preparation method avoids violent reaction, has mild reaction conditions, mild and easily-controlled process, high product purity and yield, simple post-treatment and high equipment utilization rate, and has good industrial application value.
Under the condition of using 9-carboxyl acridine as an initial raw material, the reaction route is as follows:
wherein R is C1-3Alkyl group of (1).
In the process of preparing the acridine ester by using 9-carboxyl acridine, in order to further reduce the industrial manufacturing cost of the acridine ester, the molar ratio of the 9-carboxyl acridine to the thionyl chloride can be controlled to be 1 (2-4). The alcohol can be selected from low molecular weight alcohol with carbon number of 1-3, such as methanol, n-propanol, etc. The amount of 9-carboxyacridine per liter of low molecular alcohol may be set to 1 to 3 mol. The time for the reflux reaction can be set to 3 hours or more.
In the process of adding borohydride and Lewis Acid (Lewis Acid) for reaction, the borohydride and the Lewis Acid can be added at the same time for reaction, and in order to further improve the selectivity of the reaction, preferably, the Lewis Acid is added for activation, and then the borohydride is added for reaction. The activation can be carried out at room temperature for 0.5-3 h.
The solvent for the reduction reaction is not particularly limited, and may be at least one of tetrahydrofuran, ethanol, methanol, and diethyl ether, considering the cost of the solvent and the reaction effect. The dosage of borohydride per liter of solvent is 1-6 mol.
In the post-treatment process, the extraction solvent used for extraction may be one of chloroform, dichloromethane, ethyl acetate, toluene, diethyl ether and 1, 2-dichloroethane.
The following examples are provided to further illustrate the practice of the invention.
Specific examples of the preparation method of 9-hydroxymethyl-9, 10-dihydroacridine according to the present invention
Example 1
The preparation method of 9-hydroxymethyl-9, 10-dihydroacridine of the embodiment has the following synthetic route:
the method specifically comprises the following steps: 0.78kg (3.5mol) of 9-carboxyacridine, 1.25kg (10.5mol) of thionyl chloride and 1.6L of methanol are added into a reactor with a thermometer and a reflux device, reflux reaction is carried out for 4h, evaporation is carried out, 2.3L of Tetrahydrofuran (THF) and 0.15kg (3.5mol) of lithium chloride are added, stirring is carried out for 1h at room temperature, 0.19kg (3.5mol) of potassium borohydride is slowly added at-10 ℃ under the protection of inert gas, and reaction is carried out for 1h at 30 ℃. After 1.4L of saturated ammonium chloride solution was added to quench the reaction, THF was recovered at 25 ℃ in a vacuum rotary evaporator, and about 1.4L of water remained (containing a small amount of tetrahydrofuran), 1.5L of chloroform was added to the remaining aqueous mother liquor to extract, and then the aqueous phase was re-extracted with 500mL of chloroform, dried, and the chloroform was recovered to obtain 0.72kg of a white solid with a purity of 98% and a yield of 95.0%.
The results of nuclear magnetic characterization of the product are shown in FIG. 1, which demonstrates the successful preparation of 9-hydroxymethyl-9, 10-dihydroacridine.
Example 2
The preparation method of 9-hydroxymethyl-9, 10-dihydroacridine of the embodiment has the following synthetic route:
446g (2mol) of 9-carboxyl acridine, 714g (6mol) of thionyl chloride and 800ml of ethanol are added into a reactor with a thermometer and a reflux device, reflux reaction is carried out for 4h, evaporation is carried out, 700ml of ethanol and 85g (2mol) of lithium chloride are added, stirring is carried out for 1h at room temperature, 95g (2.5mol) of sodium borohydride is slowly added at 0 ℃ under the protection of inert gas, and reaction is carried out for 3h at 45 ℃. Adding 900mL of saturated ammonium chloride solution to quench the reaction, spin-drying the ethanol, then adding chloroform to extract, drying, and recovering the chloroform to obtain 404g of white solid with the purity of 99% and the yield of 94.6%.
The nuclear magnetic characterization of the product was consistent with example 1.
Example 3
The preparation method of 9-hydroxymethyl-9, 10-dihydroacridine of the embodiment has the following synthetic route:
379g (11.7mol) of 9-carboxyl acridine, 607g (5.1mol) of thionyl chloride and 1140ml of methanol are added into a reactor with a thermometer and a reflux device, reflux reaction is carried out for 4h, evaporation is carried out, 760ml of THF and 232g (1.7mol) of zinc chloride are added, stirring is carried out for 1h at room temperature, 140g (2.6mol) of potassium borohydride is slowly added at-5 ℃ under the protection of inert gas, and reaction is carried out for 2h at 50 ℃. The reaction was quenched by the addition of 700mL of saturated ammonium chloride solution, THF was recovered, and then ethyl acetate was added for extraction, drying, and ethyl acetate was recovered to give 351g of a white solid with a purity of 98% and a yield of 95.8%.
The nuclear magnetic characterization of the product was consistent with example 1.
Example 4
The preparation method of 9-hydroxymethyl-9, 10-dihydroacridine of the embodiment has the following synthetic route:
536g (2.4mol) of 9-carboxyl acridine, 857g (7.2mol) of thionyl chloride and 1290ml of methanol are added into a reactor with a thermometer and a reflux device, reflux reaction is carried out for 4h, evaporation is carried out, 1500ml of THF and 341g (2.5mol) of zinc chloride are added, stirring is carried out for 1h at room temperature, 118g (3.1mol) of sodium borohydride is slowly added at 10 ℃ under the protection of inert gas, and reaction is carried out for 5h at 40 ℃. Adding saturated ammonium chloride solution 1L to quench reaction, recovering THF, adding 1, 2-dichloroethane to extract, drying, and recovering 1, 2-dichloroethane to obtain 493g white solid with purity of 97% and yield of 94.4%.
The nuclear magnetic characterization of the product was consistent with example 1.
Example 5
The preparation method of 9-hydroxymethyl-9, 10-dihydroacridine of the embodiment has the following synthetic route:
223g (1mol) of 9-carboxyl acridine, 357g (3mol) of thionyl chloride and 700ml of n-propanol are added into a reactor with a thermometer and a reflux device, reflux reaction is carried out for 4h, evaporation is carried out, 500ml of methanol and 476g (2mol) of cobalt chloride hexahydrate are added, stirring is carried out for 1h at room temperature, 106g (2.8mol) of sodium borohydride is slowly added at 25 ℃ under the protection of inert gas, and reaction is carried out for 4.5h at 50 ℃. The reaction was quenched by adding 450mL of saturated ammonium chloride solution, methanol was recovered, and then dichloromethane was added for extraction, drying, and dichloromethane was recovered to give 205g of white solid with 98% purity and 95.1% yield.
The nuclear magnetic characterization of the product was consistent with example 1.
In other embodiments of the process for preparing 9-hydroxymethyl-9, 10-dihydroacridine of the invention, zinc borohydride, calcium borohydride and the like can be used as the reducing agent, which has the disadvantage of high price; the solvent, the specific reaction conditions, the raw material ratio and the like can be adaptively adjusted according to the actual conditions such as production scale, reaction yield and the like, and all the solvents can achieve the test effect equivalent to that of the examples.
Claims (5)
1. A preparation method of 9-hydroxymethyl-9, 10-dihydroacridine is characterized by comprising the following steps: performing reduction reaction on the acridine ester shown in the formula (I) in a solvent containing Lewis acid and a reducing agent to generate 9-hydroxymethyl-9, 10-dihydroacridine;
in the formula (I), R is C1-3Alkyl groups of (a); the reducing agent is borohydride; the Lewis acid is at least one of lithium chloride, zinc chloride, aluminum chloride, copper chloride and cobalt chloride hexahydrate; the borohydride is at least one of potassium borohydride and sodium borohydride; the solvent is at least one of tetrahydrofuran, ethanol, methanol and diethyl ether.
2. The method for producing 9-hydroxymethyl-9, 10-dihydroacridine as claimed in claim 1, wherein the ratio of the amount of the acridine ester, the reducing agent and the Lewis acid is 1: (1-5): (0.2-2).
3. The method for producing 9-hydroxymethyl-9, 10-dihydroacridine as claimed in claim 1, wherein the temperature of the reduction reaction is 30-75 ℃ and the time is 1-5 hours.
4. The method for producing 9-hydroxymethyl-9, 10-dihydroacridine as claimed in any one of claims 1 to 3, wherein the reaction is quenched after the reduction reaction, and the reaction solvent is recovered, extracted and dried to obtain the compound.
5. The method for producing 9-hydroxymethyl-9, 10-dihydroacridine as claimed in any one of claims 1 to 3, wherein the acridine ester represented by formula (i) is produced by a method comprising the steps of: mixing 9-carboxyl acridine, thionyl chloride and alcohol, and carrying out reflux reaction to obtain the compound.
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