CN114805097B

CN114805097B - Synthesis method of desmethylvenlafaxine and succinate thereof

Info

Publication number: CN114805097B
Application number: CN202210581505.6A
Authority: CN
Inventors: 杨士伟; 郑斌; 毕文杰; 王小红; 田恒; 胡星明; 朱金苗; 董华泽; 张佳乐; 王知闲; 许思喆; 王紫璇; 李新纪; 查安旭; 刘家成; 汪小艳; 方芳; 段萍
Original assignee: Hefei Normal University
Current assignee: Hefei Normal University
Priority date: 2022-05-26
Filing date: 2022-05-26
Publication date: 2024-07-16
Anticipated expiration: 2042-05-26
Also published as: CN114805097A

Abstract

The invention provides a synthesis method of desmethylvenlafaxine and succinate thereof, which comprises the steps of taking 4-benzyloxy benzyl cyanide as a raw material, carrying out carbonyl nucleophilic addition reaction with cyclohexanone, then carrying out benzyl deprotection and cyano reduction reaction, and then carrying out amino methylation reaction to obtain the desmethylvenlafaxine; and (3) carrying out salt formation reaction on the desmethylvenlafaxine and succinic acid to obtain the desmethylvenlafaxine succinate. The method of the invention overcomes the pollution problem of cyclohexanone, can realize the high-yield synthesis of the desmethylvenlafaxine and succinate thereof by taking the parahydroxyphenylacetonitrile as a starting material, has the advantages of easily obtained raw materials, environment-friendly reaction reagent, no need of column chromatography separation and the like, and is beneficial to industrial production.

Description

Synthesis method of desmethylvenlafaxine and succinate thereof

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of desvenlafaxine and succinate thereof.

Background

The desmethylvenlafaxine and its succinate (i.e. desmethylvenlafaxine succinate) are used as the first metabolic active product of venlafaxine after entering human body and have good clinical advantages for treating mental disorder diseases such as major depression and anxiety. The developed preparation medicine (@ Pristiq) has the advantages of efficiency, safety, and Tolerability of and the like, is favored by more and more patients, and is used as a first prescription medicine for treating depression and anxiety by psychiatrists. Therefore, the method has great practical significance and market value for improving the synthesis process and quality standard of the desmethylvenlafaxine and the desmethylvenlafaxine succinate, and attracts more and more synthesizers to study.

At present, various synthetic routes of the desmethylvenlafaxine and the desmethylvenlafaxine succinate are reported, but a certain improvement room exists in the process. HADFIELD A F et al report that p-methoxyphenylacetonitrile is produced from p-hydroxyphenylacetonitrile as a starting material under the action of a methylating agent, lithium tri-sec-butylborohydride is used as a base to catalyze the condensation product of cyclohexanone and p-methoxyphenylacetonitrile, and then the free amine product is obtained by reduction reaction of cyano groups. Finally, under the action of aminomethyl reagent of demethylating kit, the desmethylvenlafaxine is obtained, and the synthetic route is as follows:

In the method, cyanide is adopted as the raw material, although the cyanide is simple and easy to obtain, the price is slightly high, the danger coefficient of the used condensation reagent and the tri-sec-butyl lithium borohydride reducing reagent is high, and the operation is not easy; and the flammable and irritant compound diphenyl phosphine is used, and the cyano reduction condition is relatively harsh, so that the method does not meet the economical efficiency and is not suitable for industrial production.

It has also been reported that by using p-hydroxyphenylacetic acid as starting material, preparing an amide compound by halogenation and aminolysis of an acid, then condensing with cyclohexanone, preparing desvenlafaxine by reduction of an amide carbonyl group, and then preparing desvenlafaxine succinate monohydrate form I under the action of acetone/water, the synthetic route is as follows:

In the method, an acyl chloride kit dimethylamine aqueous solution is respectively used in the condensation and amide reduction reaction steps, n-butyllithium and a low-temperature environment are used in the condensation step, the requirements on reaction conditions are severe, and lithium aluminum hydride is used as a carbonyl reduction reagent in the last step, which is a dangerous reagent and is not beneficial to industrial operation.

Li Longxia et al report that p-hydroxyacetophenone is used as a starting material, reacted with benzyl bromide under the action of potassium carbonate to produce benzyl-protected p-benzyloxyacetophenone, then halogenated under the action of copper dibromide and a 33% dimethylamine solution are subjected to a dimethyl reagent under the condition of hydrogen bromide to produce an intermediate; then reducing carbonyl into hydroxyl alcohol by sodium borohydride/sodium hydroxide, and obtaining halogenated products by thionyl chloride; under the action of n-butyl, triethylamine is used as alkali, a condensate of cyclohexanone is carried out, and finally benzyl removal is carried out through 10% Pd/C hydrogenation; the preparation method comprises the steps of preparing the desvenlafaxine, and crystallizing under the conditions of succinic acid and acetone/water in a ratio of 3:1 to obtain a crystal form I of the succinic acid desvenlafaxine monohydrate, wherein the synthetic route is as follows:

The method has longer reaction steps and low yield, and the dimethylamine aqueous solution and the hydrogen bromide solution are used in the reaction process, so that the environmental pollution is high; the use of sodium borohydride greatly increases the dangerous coefficient of the reaction, and is not beneficial to industrial production; the n-butyllithium needs to be in a low-temperature condition, so that the reaction cost is increased, and the use of 10% Pd/C and hydrogenation reaction have high requirements on laboratories. The method is unfavorable for industrial production due to comprehensive analysis.

It has also been reported that desmethylvenlafaxine is prepared from venlafaxine as starting material by dehydroxylation of demethylating reagents such as thiols, diphenylphosphines, hydrobromic acid and the like, and the synthetic route is as follows:

In the method, toxic and easily polluted air compound mercaptan, flammable and irritant compound diphenyl phosphine and stronger corrosive compound are used in the demethylation, so that the operation difficulty and the post-treatment process are increased, and the reaction is not suitable for industrial production.

Disclosure of Invention

Based on the technical problems existing in the background technology, the invention provides a method for synthesizing the desmethylvenlafaxine and the succinate thereof, which overcomes the pollution problem of cyclohexanone, can realize high-yield synthesis of the desmethylvenlafaxine and the succinate thereof by taking the parahydroxyphenylacetonitrile as a starting material, has the advantages of easily obtained raw materials, environment-friendly reaction reagent, no need of column chromatography separation and the like, and is beneficial to industrial production.

The invention provides a synthesis method of desmethylvenlafaxine, which comprises the following steps:

4-benzyloxy benzyl cyanide is used as a raw material, and is subjected to carbonyl nucleophilic addition reaction with cyclohexanone, benzyl deprotection and cyano reduction reaction, and amino methylation reaction to obtain the desmethylvenlafaxine;

When the intermediate I is subjected to carbonyl nucleophilic addition reaction with cyclohexanone, 4-benzyloxy benzyl cyanide is added into water, and the intermediate I is obtained through carbonyl nucleophilic addition reaction with cyclohexanone under the conditions of an alkali reagent and a phase transfer catalyst.

Preferably, the alkali agent is at least one of sodium hydroxide or potassium hydroxide, and the phase transfer catalyst is at least one of tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium chloride or tetrabutylammonium iodide.

Preferably, the molar ratio of 4-benzyloxyphenyl acetonitrile to cyclohexanone is 1:1-3, preferably 1:2; the molar ratio of the 4-benzyloxy benzyl cyanide to the phase transfer catalyst is 1:0.01-1, preferably 1:0.08; the molar ratio of the 4-benzyloxy benzyl cyanide to the alkali reagent is 1:0.5-1.5, preferably 1:1;

Preferably, the temperature of the addition reaction is 10-35 ℃, preferably 25 ℃.

Preferably, when benzyl deprotection and cyano reduction reaction are carried out, adding the intermediate I into a reaction solvent, and carrying out benzyl deprotection and cyano reduction reaction by hydrogenation under the conditions of palladium reduction catalyst and acid reagent to obtain an intermediate II;

Preferably, the reaction solvent is at least one of methanol or ethanol, preferably methanol; the palladium reduction catalyst is a palladium-carbon catalyst, and the palladium loading of the palladium-carbon catalyst is preferably 10wt%; preferably, the acid reagent is at least one of hydrochloric acid, nitric acid or sulfuric acid, preferably hydrochloric acid;

preferably, the temperature of the reduction reaction is 25-45 ℃, preferably 45 ℃;

preferably, the mass ratio of the intermediate I to the palladium reduction catalyst is 1:0.3-0.4, preferably 1:0.3.

Preferably, in the process of carrying out the aminomethylation reaction, adding the intermediate II into a reaction solvent to carry out the aminomethylation reaction with formaldehyde and formic acid to obtain the desmethylvenlafaxine;

Preferably, the reaction solvent is at least one of water, methanol or isopropanol, preferably isopropanol;

Preferably, the molar ratio of intermediate II to formaldehyde is from 1:2 to 6, preferably from 1:3, and the molar ratio of intermediate II to formic acid is from 1:5 to 10, preferably from 1:5.

Preferably, the method further comprises: and (3) taking p-hydroxyphenylacetonitrile as a starting material, and carrying out hydroxyl protection reaction with benzyl bromide to obtain 4-benzyloxy-phenylacetonitrile.

Preferably, when hydroxyl protection reaction is carried out with benzyl bromide, p-hydroxyphenylacetonitrile is added into a reaction solvent, and the reaction solvent and benzyl bromide are subjected to hydroxyl protection reaction under the condition of alkali reagent to obtain 4-benzyloxy-phenylacetonitrile;

preferably, the reaction solvent is at least one of acetone, methanol or ethyl acetate, preferably acetone; the alkali reagent is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, preferably potassium carbonate;

Preferably, the molar ratio of parahydroxyphenylacetonitrile to benzyl bromide is from 1:1.1 to 1.3, preferably 1:1.2;

preferably, the temperature of the hydroxyl protection reaction is 25-55 ℃, preferably 55 ℃.

The invention also provides a synthesis method of the desmethylvenlafaxine succinate, which comprises the following steps:

after the desmethylvenlafaxine is obtained according to the method, carrying out salt formation reaction with succinic acid to obtain the desmethylvenlafaxine succinate;

Preferably, in the salt formation reaction with succinic acid, the desmethylvenlafaxine is added into a reaction solvent to perform the salt formation reaction with succinic acid to obtain the desmethylvenlafaxine succinate;

Preferably, the reaction solvent is a mixed solvent of water and acetone, and the molar ratio of water to acetone is preferably 1:3;

preferably, the molar ratio of desmethylvenlafaxine to succinic acid is 1:0.9-1.0, preferably 1:0.95; the molar volume ratio of the desmethylvenlafaxine to the reaction solvent is 1:3-10, preferably 1:5.

Compared with the prior literature and patent report, the synthesis method of the desmethylvenlafaxine and the succinate thereof provided by the invention avoids using pollution reagents in the whole process, obviously reduces the impurity content, improves the yield and the product purity, has simple operation, low cost and low environmental pollution, and is suitable for industrial production.

Detailed Description

The technical scheme of the present invention will be described in detail by means of specific examples, which should be explicitly set forth for illustration, but should not be construed as limiting the scope of the present invention.

Examples

Synthesis of 4-benzyloxyphenylacetonitrile:

adding p-hydroxyphenylacetonitrile into a reaction solvent to dissolve completely, slowly adding benzyl bromide under the stirring condition, slowly adding an alkali reagent in batches after the completion of the reaction, heating, stirring completely, cooling to room temperature, removing the reaction solvent by rotary evaporation, separating out a white solid, filtering, washing with water, and drying to obtain 4-benzyloxy-benzyl cyanide;

According to the method, 16 parallel test groups are set, and different reaction solvents, alkali reagents, and different molar equivalents of p-hydroxyphenylacetonitrile and benzyl bromide are respectively adopted, so that the reaction temperature and the reaction time are changed, and the purity and the yield of the obtained 4-benzyloxyphenylacetonitrile are shown in the following table 1:

TABLE 1 comparison of the reaction purity and yield of 4-benzyloxyphenylacetonitrile under various reaction conditions

Note that: n (p-hydroxyphenylacetonitrile) and n (benzyl bromide) are the molar equivalents of p-hydroxyphenylacetonitrile and benzyl bromide respectively; purity was obtained by HPLC measurement, wherein purity in No.4-6 was obtained by HPLC measurement of the reaction solution, and no solid was formed in No. 15; the yield is the product yield obtained after one recrystallization.

As is clear from Table 1, the molar equivalent ratio of p-hydroxyphenylacetonitrile to benzyl bromide has little effect on the product purity, but has some effect on the product yield, and the more the benzyl bromide equivalent, the more thorough the reaction. Under the premise of ensuring that the residual quantity of the benzyl bromide does not exceed the standard, 1.2 equivalents of benzyl bromide are selected for reaction, and 4-benzyloxy benzyl cyanide can be obtained with 99.83% purity and 90.10% yield (Table 1, no. 3). The optimization of the reaction time is from 2h to 4h, the reaction progress of different reaction times is tracked through high performance liquid chromatography, and the result shows that the reaction time is too short, which is unfavorable for the generation of 4-benzyloxyphenylacetonitrile, and the reaction progress of the reaction time of 4h reaches the highest (Table 1, no. 6). The reaction temperature mainly influences the yield of 4-benzyloxyphenyl acetonitrile, and the higher the temperature, the more favorable the nucleophilic attack of the phenoxyanion on benzyl positive ion and the departure of bromide ions (Table 1, no. 10). The reaction did not give a solid product in methylene chloride, acetone, ethyl acetate and methanol were similar in purity, and ethyl acetate was not dominant in yield (Table 1, no. 14). Under the condition that the yield and the purity are similar, from the viewpoints of atom economy and production cost of raw materials, acetone is the optimal reaction solvent (Table 1, no. 11). The alkali of the inorganic base has direct influence on the reaction, and too strong alkali can increase byproducts, influence related substances and impurity content (Table 1, no. 16) of 4-benzyloxy benzyl cyanide, and the alkali is too weak to carry out negative ionization on H of phenolic hydroxyl, so that nucleophilic attack activity of oxy anions on benzyl bromide benzyl is reduced, and the leaving of bromide ions is not facilitated.

Synthesis of intermediate I:

As shown in the reaction formula, adding 4-benzyloxyphenyl acetonitrile into a reaction solvent, uniformly stirring, slowly adding cyclohexanone, adding tetrabutylammonium bromide after finishing, cooling to room temperature, slowly adding sodium hydroxide aqueous solution, controlling the temperature of a reaction solution to be lower than 5 ℃, heating and stirring after finishing, completely reacting, precipitating a large amount of white solid, filtering, washing with water, and drying to obtain an intermediate I;

According to the method, 22 groups of parallel test groups are arranged, and different reaction solvents and different 4-benzyloxy benzyl cyanide, cyclohexanone, tetrabutylammonium bromide and sodium hydroxide molar equivalents are respectively adopted, so that the reaction temperature and the reaction time are changed, and the purity and the yield of the obtained intermediate I are shown in the following table 2:

TABLE 2 reaction purity and yield of intermediate I under various reaction conditions

Note that: n ₁、n₂、n₃、n₄ is the molar equivalent of 4-benzyloxyphenylacetonitrile, cyclohexanone, tetrabutylammonium bromide and sodium hydroxide, respectively, the purity is obtained by HPLC measurement, wherein, the purity in No.10-12 is obtained by HPLC measurement of the reaction solution; the yield is the yield of the product obtained after one recrystallization; the sodium hydroxide was replaced with equal molar equivalents of potassium carbonate and potassium hydroxide, respectively, in Nos. 21-22.

As can be seen from the above Table 2, when 4-benzyloxyphenylacetonitrile and cyclohexanone are subjected to condensation reaction under the catalysis of inorganic base to prepare the intermediate I, the condensation reaction has better yield and purity in a reaction solvent of water through the action of tetrabutylammonium bromide serving as a phase transfer catalyst. When the molar equivalent ratio of cyclohexanone to 4-benzyloxyphenylacetonitrile is 2.0, the method is favorable for 1, 2-nucleophilic addition reaction of 4-benzyloxyphenylacetonitrile to unsaturated carbonyl on cyclohexanone, the yield is high, and cyclohexanone residues can be removed in the subsequent process (Table 2, no. 2). Tetrabutylammonium bromide belongs to genotoxic impurities, so that the requirement on the catalytic dosage is strict, under the condition that the homogeneous reaction of benzyl anion of 4-benzyloxyphenylacetonitrile and cyclohexanone is ensured by the phase transfer catalysis, the excessive risk cannot be brought to residue, and when the equivalent ratio of tetrabutylammonium bromide to 4-benzyloxyphenylacetonitrile is 0.08, the high-yield and low-residue result can be obtained (Table 2, no. 5). The carbanionization of the benzyl group of 4-benzyloxyphenylacetonitrile is also a crucial step, which directly determines the 1, 2-nucleophilic addition reactivity to the unsaturated carbonyl group on cyclohexanone, and so the choice of base reagent and base reagent equivalents is also important. As a result, it was found that when sodium hydroxide was used as an inorganic base, the amount of by-products was increased at 1.5 equivalents (Table 2, no. 9), and the reactivity was decreased at 0.5 equivalents, and the reaction was incomplete (Table 2, no. 7). And the inorganic base has weaker alkalinity, which is unfavorable for the generation of benzyl carbanion (Table 2, no. 21), when the alkalinity is stronger, the generated carbanion continuously adds to the 1, 2-nucleophilic of the unsaturated carbonyl to generate an intermediate I, the yield is higher (Table 2, no. 22), the reaction is carried out for 4 hours, the reaction is complete, and the reaction progress of the reaction liquid is 95.66% (Table 2, no. 12). The carbanion obtained by the benzyl reaction of sodium hydroxide and 4-benzyloxyphenylacetonitrile has higher 1, 2-nucleophilic addition reaction activity to unsaturated carbonyl, and the reaction temperature at the beginning of the condensation reaction should not be excessively high, so that the generation of byproducts is reduced (Table 2, no. 14). Compared with the organic solvent used as the reaction solvent (Table 2, no.16, 17, 18 and 19), the method can obtain higher yield and purity in water, has no organic waste liquid, and is more green and economic; among organic solvents, toluene in particular (high boiling point) is difficult to remove with solvent residues. And the detection results of tetrabutylammonium bromide and cyclohexanone show that the cyclohexanone is not detected, the residual content of the tetrabutylammonium bromide is below the standard, and the minimum content is 0.7ppm, thereby having important significance for improving the quality of the bulk drug.

Synthesis of intermediate II:

Adding the intermediate I into a reaction solvent, slowly adding 10% palladium-carbon reducer, adding concentrated hydrochloric acid in batches after the completion of the reaction, introducing hydrogen, keeping the hydrogen pressure at 2.5MPa, heating and stirring the mixture to react completely, cooling the mixture to room temperature, removing the reaction solvent by rotary evaporation, precipitating white solid, filtering the white solid, recrystallizing, and drying the white solid to obtain an intermediate II;

According to the method, 15 groups of parallel test groups are arranged, different reaction solvents, and different equivalent weights of an intermediate I, a palladium-carbon reducing agent and concentrated hydrochloric acid are respectively adopted, the reaction temperature and the reaction time are changed, and the purity and the yield of the obtained intermediate II are shown in the following table 3:

TABLE 3 reaction purity and yield of intermediate II under various reaction conditions

Note that: n (intermediate I) is the molar equivalent of intermediate I, 10% Pd/C (m/m) is the weight equivalent of palladium on carbon reducing agent relative to intermediate I, and HCl (m/v) is the weight volume equivalent of concentrated hydrochloric acid relative to intermediate I; purity was measured by HPLC, wherein purity in No.13-15 was obtained by HPLC measurement of the reaction solution; the yield is the product yield obtained after one recrystallization.

From table 3 above, it is clear that the deprotection of benzyl group and the reduction of cyano group can be simultaneously achieved by palladium carbon hydrogenation method, from the viewpoint of saving cost, we can optimize the equivalent of palladium carbon catalyst and recovery sleeve as process, the yield of 87% can be obtained when the catalytic equivalent of 10% palladium carbon reducing agent is 0.30 (table 3, no. 3), and the recovery palladium carbon reducing agent of 0.60 equivalent has the same reduction effect. The addition of hydrochloric acid favors the formation of salts with amine groups in the product, allowing the cyano group to be continuously reduced to amine groups, and gives a 94.20% yield, 94.44% purity at equivalent weight of 0.3 (Table 3, no. 4). The cause of isomerization of tertiary alcohol in an unstable state under acidic conditions is the increase in the equivalent of hydrochloric acid, which increases the amount of by-products (Table 3, no. 6). Deprotection of the benzyl group and reduction of the cyano group at the time of hydrogenation pressure reduction, the reaction proceeds with an increase in temperature (Table 3, no.7, 8, 9). When isopropanol was used as the reaction solvent, the raw materials remained in a large amount (Table 3, no. 12), and methanol was more advantageous than ethanol in terms of yield (Table 3, no.10, 11). The reaction time is not less than 5 hours, and as can be seen from the reaction progress results of the HPLC tracking reaction solution (T table 3, no.13, 14, 15), the reaction time is short to obtain the unreduced and fully byproduct, namely, the desmethylvenlafaxine Xin Zazhi E, the structural formula is shown as follows:

Synthesis of desmethylvenlafaxine:

As shown in the reaction formula, adding the intermediate II into a reaction solvent, slowly adding 37% formaldehyde solution under stirring, stirring at 20 ℃ for reaction for 2 hours, slowly adding 85% formic acid solution under nitrogen protection, heating to 103 ℃ for complete reaction, cooling to room temperature, removing the reaction solvent by rotary evaporation until a syrup is formed, adding water, washing with ethyl acetate for three times, combining water phases, regulating the pH value to 9-10 with 50% sodium hydroxide solution, filtering, washing with water, recrystallizing, and drying to obtain the desmethylvenlafaxine;

According to the above method, 18 parallel test groups are set, and different reaction solvents and different molar equivalents of intermediate II, formaldehyde and formic acid are respectively adopted, so that the reaction temperature and reaction time are changed, and the purity and yield of the obtained desmethylvenlafaxine are shown in the following table 4:

TABLE 4 reaction purity and yield of desvenlafaxine under various reaction conditions

Note that: n (intermediate II), n (formaldehyde) and n (formic acid) are the molar equivalents of intermediate II, formaldehyde and formic acid, respectively; purity was measured by HPLC, wherein purity in No.14-17 was obtained by HPLC measurement of the reaction solution; the yield is the product yield obtained after one recrystallization.

As is clear from Table 4, the methylation reaction of amine groups was carried out by reducing the imine intermediate with formic acid as a hydrogen source to form an aminomethyl group by using a formaldehyde solution and the intermediate II to form an imine intermediate. Among them, the equivalent of formaldehyde is not easily excessive, and 2 to 3 equivalents are preferable (Table 4, no.1, 2, 3), and when the equivalent of formaldehyde exceeds 4 equivalents, the formed imine intermediate is more stable and less likely to be destroyed, and the yield is lower (Table 4, no. 6). Similarly, the equivalent of formic acid was preferably 5 equivalents, and the increase in the equivalent of formic acid was continued, with no significant increase in the product yield, and with an increase in the material cost (Table 4, no.7, 8, 9). Surprisingly, we found that the reaction gave unexpectedly good results with isopropanol as the reaction solvent (Table 4, no.12, 18) with a maximum yield of 84.77% and a maximum purity of 99.20%, the progress of the reaction, the product yield, and the purity were much higher than those with water or methanol as the solvent (Table 4, no.10, 11). The solvent is also a proton solvent, the polarity of methanol and water is larger than that of isopropanol, and the solvent effect is formed with an intermediate II more easily, so that the imine intermediate of formaldehyde is not favored to be generated. With formic acid as the reaction solvent, the reaction proceeds under no solvation conditions with little product formation and low yields, which also proves that the more polar the protic solvent is, the more detrimental the reaction proceeds (Table 4, no. 13).

Synthesis of desvenlafaxine Xin Hubo acid salt (i.e., desvenlafaxine succinate monohydrate form I):

As shown in the reaction formula, adding the desvenlafaxine into a mixed solvent of acetone and water in a volume ratio of 3:1, adding succinic acid, heating to 90 ℃, stirring to react completely, cooling to 60 ℃, filtering to remove trace insoluble substances, continuously cooling to 35 ℃, stirring for 6 hours, cooling and filtering in an ice water bath, washing a filter cake with acetone, draining, and drying at 60 ℃ for 3 hours to obtain a crystal form I of the desvenlafaxine succinate monohydrate;

According to the above method, 18 parallel test groups were set up, and the reaction time was varied using different molar equivalents of desvenlafaxine, succinic acid and different solvent to volume mass equivalents of desvenlafaxine, respectively, whereby the purity and yield of the resulting crystalline form I of desvenlafaxine succinate monohydrate were as shown in table 5 below:

TABLE 5 comparison of reaction purity and yield of the salt of desvenlafaxine Xin Hubo under various reaction conditions

Note that: n (desmethylvenlafaxine) and n (succinic acid) are molar equivalents of desmethylvenlafaxine and succinic acid; purity was measured by HPLC; the yield is the yield of the product obtained after one recrystallization; the acetone was replaced in nos. 13-15 with a mixed solvent of ethyl acetate and isopropyl alcohol (v/v=1:1) having volume mass equivalent weights of 5 (v/m), 10 (v/m), 15 (v/m), respectively, as a washing solvent; crystallization was carried out in No.16 using a mixed solvent of ethyl acetate and isopropyl alcohol (v/v=1:1) having a volume mass equivalent of 10 (v/m); no.17-18 was prepared by heating a mixed solvent of ethyl acetate and isopropyl alcohol having a volume mass equivalent of 10 (v/m) to 50℃or room temperature, respectively.

As shown in the table 5, the synthesis process of the crystal form I of the desmethylvenlafaxine succinate monohydrate adopts the full-dissolution reaction and natural cooling crystallization under the condition of a mixed solvent of acetone and water to prepare the crystal form I, and the crystal form I is cleaned by the acetone to achieve the purpose of obtaining a qualified product. When the volume/mass ratio of the reaction solvent was 10 times, 99.72% purity and 59.47% yield were obtained from 0.5 equivalent succinic acid (Table 5, no. 2). The results of the reaction time in the range of 2 to 4 hours showed that the longer the reaction time, the more advantageous the crystallization was, and the highest 99.90% purity and 90.27% yield were obtained (Table 5, no. 12). Since desmethylvenlafaxine succinate monohydrate has a certain solubility in water, the more the solvent amount, the less the product precipitated, the lower the solvent amount has a good effect on the product yield (Table 5, no. 8). As a result of changing the cleaning solvent acetone into a mixed solvent of ethyl acetate and isopropanol to control the content of the maximum single impurity, the product purity was found to be 99.90% -99.91% with the increase of the amount of the mixed solvent, and the yield was inversely proportional to the amount of the solvent, which indicates that the refining effect of the mixed solvent under the room temperature condition is not obvious (tables 5, no.13, 14, 15), the refining effect of the mixed solvent under the heating condition was the highest purity of 99.92%, the single impurity content was 0.08%, and the yield was lower (tables 5, no.16, 17, 18), and the influence on the yield was great. XRD powder diffraction and DSC-TGA detection are carried out on the products prepared by the mixed solvent to detect the crystal forms and the crystal water of the products, and the crystal forms are converted compared with the refining process of acetone.

According to the optimized conditions, the synthesis method of the desmethylvenlafaxine and the succinate thereof provided by the invention comprises the following steps:

(1) 200.0g of p-hydroxyphenylacetonitrile (1.5 mol) and 1000mL of acetone are added into a 3L reaction bottle, 282.56g of benzyl bromide (1.65 mol) is slowly added under stirring, 320.28g of anhydrous potassium carbonate (2.32 mol) is slowly added in batches after the addition is finished, the reaction is stirred overnight at 55 ℃, TLC monitors the reaction (developing agent: ethyl acetate: n-hexane=5:1) until the reaction is complete, the solvent is directly distilled off, a large amount of white solid is separated out, the solution is filtered, a filter cake is leached by a large amount of water and dried, and 331.19g of 4-benzyloxyphenylacetonitrile is obtained, and the yield is 99.13%;

4-Benzyloxyphenyl acetonitrile (C₁₅H₁₃NO),¹H NMR(400MHz,Chloroform-d)δ7.45–7.28(m,5H),7.25–7.18(m,2H),6.96(d,J＝8.7Hz,2H),5.05(s,2H),3.65(s,2H).¹³CNMR(101MHz,Chloroform-d)δ158.57,136.72,129.17,128.69,128.13,127.50,122.14,118.24,115.53,70.14,22.85.

(2) 250.0G of 4-benzyloxyphenylacetonitrile (1.12 mol) and 500mL of water are added into a 1L three-port reaction bottle, 176.02g of cyclohexanone (1.80 mol) is slowly added under stirring, 22.0g of tetrabutylammonium bromide (0.07 mol) is further added after the addition is finished, 100mL of 36.0g of sodium hydroxide (0.90 mol) aqueous solution with cooling room temperature is slowly added, the temperature of the reaction solution is lower than 5 ℃, the reaction is stirred for 4 hours at the temperature lower than 20 ℃ after the addition is finished, TLC monitors the reaction (developing agent: ethyl acetate: n-hexane=5:1) until the reaction is complete, a large amount of white solid is precipitated, the reaction solution is filtered, and a filter cake is rinsed with a large amount of water and dried to obtain 359.69g of an intermediate I with the yield of 99.94%.

Intermediate products I(C₂₁H₂₃NO₂),¹H NMR(400MHz,Chloroform-d)δ7.46–7.35(m,4H),7.33(dd,J＝8.3,5.5Hz,1H),7.26(d,J＝8.7Hz,2H),6.97(d,J＝8.7Hz,2H),5.06(s,2H),3.72(s,1H),1.71(d,J＝13.1Hz,1H),1.67–1.43(m,9H),1.18(dd,J＝12.7,6.2Hz,1H).¹³C NMR(101MHz,Chloroform-d)δ158.97,136.68,130.72,128.69,128.15,127.52,123.98,119.88,115.00,72.77,70.14,49.38,34.98,34.90,25.22,21.59,21.51.

(3) 300G of intermediate I (0.93 mol) is added into a 3L three-port reaction bottle, 3000mL of industrial methanol is added slowly, 99.99g of 10% Pd/C is added slowly and batchwise after the addition is finished, 90.00mL of concentrated hydrochloric acid is added slowly, an H ₂ balloon is added, the reaction is stirred overnight at 45 ℃, TLC monitors the reaction (developing agent: ethyl acetate: n-hexane=2.5:1) until the reaction is complete, the solvent is directly distilled off in a rotary way, a large amount of white solid is separated out, the solid is recrystallized twice by ethyl acetate, and the obtained intermediate II is dried, so that 179.90g of intermediate II is obtained, and the yield is 82.52%;

(4) 150g of intermediate II (0.64 mol), 100mL of water are added into a 250mL single-port reaction bottle, 38.60g of 37% formaldehyde solution is slowly added under stirring, the mixture is stirred for 2 hours at 20 ℃, 68.40g of 85% formic acid solution is slowly added, N ₂ balloon is slowly added, the mixture is stirred at 103 ℃ for overnight, TLC monitors the reaction (developing agent: dichloromethane: methanol: triethylamine=2.5: 10drops:1 drop) until the reaction is complete, the solvent is directly removed by rotary evaporation until the reaction is complete, 50mL of water is added, the mixture is washed three times with ethyl acetate, the water phase is combined, the pH is regulated to about 9.5 by 50% sodium hydroxide solution, solids are separated out, the mixture is filtered to obtain crude solid, the crude solid is recrystallized once by 20mL of water at 70 ℃, the filtered filter residue is recrystallized twice by 15mL of methanol at 60 ℃, and the mixture is dried to obtain 146.47g of desmethylvenlafaxine with the yield of 87.70%.

Desmethylvenlafaxine (C₁₆H₂₅NO₂),¹H NMR(400MHz,DMSO-d6)δ9.11(s,1H),6.96(d,J＝6.9Hz,2H),6.64(d,J＝6.9Hz,2H),5.41(s,1H),3.12–2.86(m,1H),2.72(s,1H),2.40–2.25(m,1H),2.14(s,6H),1.61–1.25(m,8H),1.19–0.81(m,3H).¹³CNMR(101MHz,DMSO-d6)δ156.04,132.18,130.55,114.87,73.03,60.92,52.10,45.77,37.64,32.86,26.18,21.74,21.69.

(5) 64G of desvenlafaxine (0.24 mol), 27.30g of succinic acid (0.23 mol), 300mL of acetone and 100mL of purified water are added into a 1000mL round bottom flask, the mixture is stirred uniformly and then heated to 90 ℃ slowly, the mixture is stirred for 1h, all the mixture is dissolved into colorless and transparent, the mixture is cooled to 60 ℃ and filtered to remove trace insoluble substances, the temperature is reduced to 35 ℃ continuously, the mixture is stirred for 6h, the product is fully discharged, the ice water bath is used for cooling and filtering, a filter cake is washed by 100mL of ethyl acetate and 100mL of isopropanol, the filter cake is drained, and the mixture is dried for 3h at 60 ℃ to obtain finished product desvenlafaxine succinate monohydrate, the total content is 82.40g, and the yield is 85.83%.

Desmethylvenlafaxine succinate monohydrate (C₂₀H₃₂NO₇),¹H NMR(400MHz,Deuterium Oxide)δ7.19(d,J＝8.3Hz,2H),6.83(d,J＝8.7Hz,2H),3.64(t,J＝12.5Hz,1H),3.51(dd,J＝13.1,4.0Hz,1H),2.97(dd,J＝12.0,4.0Hz,1H),2.76(s,3H),2.70(s,3H),2.44(s,4H),1.60(d,J＝13.4Hz,1H),1.48–1.38(m,3H),1.35(dt,J＝7.3,4.2Hz,1H),1.33–1.23(m,2H),1.19(dd,J＝10.3,4.5Hz,2H),1.06–0.98(m,1H).¹³CNMR(101MHz,Deuterium Oxide)δ179.65,155.41,127.44,115.69,73.31,58.36,50.32,45.04,41.37,35.00,33.87,31.31,24.85,21.23,20.99.

In the invention, the existing process is continuously optimized to obtain the high-yield and high-purity desmethylvenlafaxine and succinate thereof for synthesis and preparation, the process of the intermediate I is more green, and no organic waste liquid is used for eliminating the pollution influence on the environment. Meanwhile, the residues of benzyl bromide and tetrabutylammonium bromide with genotoxic impurities are below the standard limit, so that the quality of the raw material medicine is improved, and the medicine is more safe to market. The preparation of the intermediate II adopts low-pressure, normal-temperature and dilute-acid process conditions, reduces the high-pressure and high-temperature safety risk of the reduction hydrogenation of the difunctional groups to a certain extent, simplifies post-treatment and refining operations, and is more beneficial to industrial mass production. The process for preparing desvenlafaxine has surprisingly been found to show the particular advantage of isopropanol as a protic solvent in the double methylation step, which isopropanol can also be recycled by recycling. The method can prepare the desmethylvenlafaxine succinate with high yield and high purity, and different new crystal forms can be obtained by adopting different refining conditions, thereby having important reference significance for the prescription process development in the research and development of the preparation.

The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should make equivalent substitutions or modifications according to the technical scheme of the present invention and the inventive concept thereof, and should be covered by the scope of the present invention.

Claims

1. A method of synthesizing desmethylvenlafaxine, comprising:

When the intermediate I is subjected to carbonyl nucleophilic addition reaction with cyclohexanone, adding 4-benzyloxy-benzyl cyanide into water, and under the conditions of an alkali reagent and a phase transfer catalyst, carrying out carbonyl nucleophilic addition reaction with cyclohexanone to obtain the intermediate I;

When an aminomethylation reaction is carried out, adding the intermediate II into a reaction solvent, and carrying out an aminomethylation reaction with formaldehyde and formic acid to obtain the desmethylvenlafaxine, wherein the reaction solvent is isopropanol, the molar ratio of the intermediate II to the formaldehyde is 1:3, and the molar ratio of the intermediate II to the formic acid is 1:5;

the aminomethylation reaction specifically comprises the following steps: adding the intermediate II into isopropanol, adding 37% formaldehyde solution, stirring at 20 ℃ for reaction for 2 hours, adding 85% formic acid solution, heating to 103 ℃ under the protection of nitrogen, and reacting for 24 hours to obtain the desmethylvenlafaxine.

2. The method for synthesizing desvenlafaxine according to claim 1, wherein the alkaline agent is at least one of sodium hydroxide or potassium hydroxide and the phase transfer catalyst is at least one of tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium chloride or tetrabutylammonium iodide.

3. The method for synthesizing desmethylvenlafaxine according to claim 1 or 2, wherein the molar ratio of 4-benzyloxyphenylacetonitrile to cyclohexanone is 1:1 to 3; the molar ratio of the 4-benzyloxy benzyl cyanide to the phase transfer catalyst is 1:0.01-1; the molar ratio of the 4-benzyloxy benzyl cyanide to the alkali reagent is 1:0.5-1.5.

4. The method for synthesizing desmethylvenlafaxine according to claim 1 or 2, wherein the molar ratio of 4-benzyloxyphenylacetonitrile to cyclohexanone is 1:2; the molar ratio of the 4-benzyloxy benzyl cyanide to the phase transfer catalyst is 1:0.08; the molar ratio of the 4-benzyloxy benzyl cyanide to the alkali reagent is 1:1.

5. The method for synthesizing desvenlafaxine according to claim 1 or 2, wherein the temperature of the addition reaction is 10 to 35 ℃.

6. The method for synthesizing the desmethylvenlafaxine according to claim 1 or 2, wherein in the process of benzyl deprotection and cyano reduction reaction, an intermediate I is added into a reaction solvent, and hydrogenation is carried out under the conditions of a palladium reduction catalyst and an acid reagent to obtain an intermediate II.

7. The method for synthesizing desvenlafaxine according to claim 6, wherein the reaction solvent is at least one of methanol or ethanol; the palladium reduction catalyst is a palladium-carbon catalyst, and the palladium loading of the palladium-carbon catalyst is 10wt%.

8. The method for synthesizing desvenlafaxine according to claim 6, wherein the acid reagent is at least one of hydrochloric acid, nitric acid or sulfuric acid.

9. The method for synthesizing desvenlafaxine according to claim 6, wherein the temperature of the reduction reaction is 25 to 45 ℃.

10. The method for synthesizing desmethylvenlafaxine according to claim 6, wherein the mass ratio of the intermediate I to the palladium reduction catalyst is 1:0.3-0.4.

11. The method for synthesizing desvenlafaxine according to claim 1 or 2, further comprising: and (3) taking p-hydroxyphenylacetonitrile as a starting material, and carrying out hydroxyl protection reaction with benzyl bromide to obtain 4-benzyloxy-phenylacetonitrile.

12. The method for synthesizing desvenlafaxine according to claim 11, wherein the hydroxy protection reaction with benzyl bromide is performed by adding p-hydroxyphenylacetonitrile to a reaction solvent and reacting with benzyl bromide in the presence of an alkaline reagent to obtain 4-benzyloxyphenylacetonitrile.

13. The method for synthesizing desvenlafaxine according to claim 12, wherein the reaction solvent is at least one of acetone, methanol or ethyl acetate; the alkali reagent is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

14. The method for synthesizing desvenlafaxine according to claim 12, wherein the molar ratio of parahydroxyphenylacetonitrile to benzyl bromide is 1:1.1 to 1.3.

15. The method for synthesizing desvenlafaxine according to claim 12, wherein the temperature of the hydroxy protection reaction is 25 to 55 ℃.

16. A method for synthesizing desmethylvenlafaxine succinate, comprising:

after obtaining desvenlafaxine according to any one of claims 1 to 15, salifying with succinic acid to obtain desvenlafaxine succinate;

17. The method for synthesizing desvenlafaxine succinate according to claim 16, wherein the desvenlafaxine succinate is obtained by adding the desvenlafaxine to a reaction solvent and performing a salt formation reaction with succinic acid.

18. The method for synthesizing desvenlafaxine succinate according to claim 17, wherein the reaction solvent is a mixture of water and acetone in a molar ratio of 1:3.

19. The method for synthesizing desvenlafaxine succinate according to claim 17, wherein the molar ratio of desvenlafaxine to succinic acid is 1:0.9 to 1.0; the molar volume ratio of the desmethylvenlafaxine to the reaction solvent is 1:3-10.