CN114805097A - Green industrial synthesis method of desvenlafaxine and succinate thereof - Google Patents

Abstract

The invention provides a green industrial synthesis method of desvenlafaxine and succinate thereof, which comprises the steps of carrying out carbonyl nucleophilic addition reaction on 4-benzyloxy benzyl cyanide serving as a raw material and cyclohexanone, then carrying out benzyl deprotection and cyano reduction reaction, and then carrying out aminomethylation reaction to obtain the desvenlafaxine; and carrying out salt-forming reaction on desvenlafaxine and succinic acid to obtain desvenlafaxine succinate. The method of the invention overcomes the pollution problem of cyclohexanone, can realize high-yield synthesis of desvenlafaxine and succinate thereof by taking p-hydroxyphenylacetonitrile as a starting material, has the advantages of easily obtained raw materials, environment-friendly reaction reagents, no need of column chromatography separation and the like, and is beneficial to industrial production.

Description

Green industrial synthesis method of desvenlafaxine and succinate thereof

Technical Field

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

Background

Desvenlafaxine and succinate (namely desvenlafaxine succinate) thereof are used as the first metabolic activity product of venlafaxine entering a human body, and have good clinical advantages when being used for treating mental disorder diseases such as mild and severe depression, anxiety and the like. The developed pharmaceutical products (@ Pristq) have the advantages of Efficacy, Safety, and andmedicine of the nature, are more and more favored by patients, and are preferred as the first prescription drugs for treating depression and anxiety by psychiatrists. Therefore, the method has great practical significance and market value for improving the synthesis process and the quality standard of desvenlafaxine and desvenlafaxine succinate, and attracts more and more synthesizers to research.

At present, a plurality of synthesis routes of desvenlafaxine and desvenlafaxine succinate are reported, but all have certain improvement space in process. Hadfield AF et al report that p-hydroxyphenylacetonitrile is used as a starting material to produce p-methoxyphenylacetonitrile under the action of a methylating agent, lithium tri-sec-butylborohydride is used as a base to catalyze a condensation product of cyclohexanone and p-methoxyphenylacetonitrile, and a free amine product is obtained through reduction reaction of a cyano group. Finally obtaining the desvenlafaxine under the action of a demethylating kit aminomethyl reagent, wherein the synthetic route is as follows:

in the method, the adopted raw material is cyanide which is simple and easy to obtain but has higher price, and the used condensation reagent and lithium tri-sec-butylborohydride reduction reagent have higher risk coefficients and are difficult to operate; and the flammable irritant compound diphenylphosphine is used, and the reduction condition of the cyano group 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 p-hydroxyphenylacetic acid is used as a starting material, an amide compound is prepared by acid halogenation and aminolysis, then the amide compound is condensed with cyclohexanone, desvenlafaxine is prepared by reduction of an amide carbonyl group, and then desvenlafaxine succinate monohydrate crystal form I is prepared under the action of acetone/water, and the synthetic route is as follows:

in the method, an acyl chlorination kit dimethylamine aqueous solution is used in the condensation and amide reduction reaction steps respectively, n-butyl lithium and a low-temperature environment are used in the condensation step, the reaction conditions are harsh, and lithium aluminum hydride, which is a dangerous reagent, is used as a carbonyl reduction reagent in the last step, so that the method is not beneficial to industrial operation.

Plum dragon and nepheline, etc. report that p-hydroxyacetophenone is used as a starting material, reacts with benzyl bromide under the action of potassium carbonate to generate benzyl-protected p-anisyl acetophenone, and then halogenation is carried out under the action of copper dibromide, and dimethyl reagent is carried out on a 33% dimethylamine solution under the condition of hydrogen bromide to generate an intermediate; reducing carbonyl to hydroxyl alcohol by sodium borohydride/sodium hydroxide, and then performing thionyl chloride acyl chlorination to obtain a halogenated product; under the action of n-butyl, triethylamine is used as alkali, a condensation compound of cyclohexanone is carried out, and finally benzyl removal is carried out through hydrogenation of 10% Pd/C; desvenlafaxine is prepared by the method, and the desvenlafaxine succinate monohydrate crystal form I is generated by crystallization under the condition of 3:1 of succinic acid and acetone/water, and the synthetic route is as follows:

the method has the advantages of longer reaction steps, low yield, and great environmental pollution due to the use of dimethylamine aqueous solution and hydrogen bromide solution in the reaction process; the use of sodium borohydride greatly increases the danger coefficient of the reaction, and is not beneficial to industrial production; the n-butyl lithium needs to be in a low temperature condition, the reaction cost is improved, and the use of 10 percent Pd/C and the hydrogenation reaction have higher requirements on laboratories. The method is not beneficial to industrial production through comprehensive analysis.

Desvenlafaxine has also been reported to be prepared by dehydroxylating agents such as thiols, diphenylphosphine, hydrobromic acid, etc., starting with venlafaxine, and the synthetic route is as follows:

in the method, a toxic and easily-polluted air compound mercaptan, a flammable and irritant compound diphenylphosphine and a strong 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 in the background art, the invention provides a green industrial synthesis method of desvenlafaxine and succinate thereof, which overcomes the pollution problem of cyclohexanone, can realize high-yield synthesis of desvenlafaxine and succinate thereof by taking p-hydroxyphenylacetonitrile as a starting material, has the advantages of easily obtained raw materials, environment-friendly reaction reagents, no need of column chromatography separation and the like, and is beneficial to industrial production.

The invention provides a green industrial synthesis method of desvenlafaxine, which comprises the following steps:

4-benzyloxy benzyl cyanide is used as raw material, after the nucleophilic addition reaction of carbonyl with cyclohexanone, the benzyl deprotection and the reduction reaction of cyano are carried out, and then the aminomethylation reaction is carried out, thus obtaining the desvenlafaxine;

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

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-benzyloxyphenylacetonitrile to cyclohexanone is 1:1 to 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, during benzyl deprotection and cyano reduction, the intermediate I is added into a reaction solvent, and hydrogenation is performed under the conditions of a palladium reduction catalyst and an acid reagent to perform benzyl deprotection and cyano reduction, so as 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 capacity of the palladium carbon catalyst is preferably 10 wt%; 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, during the aminomethylation reaction, the intermediate II is added into a reaction solvent to carry out the aminomethylation reaction with formaldehyde and formic acid to obtain desvenlafaxine;

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

Preferably, the method further comprises the following steps: taking p-hydroxyphenylacetonitrile as an initial raw material, and carrying out hydroxyl protection reaction on the p-hydroxyphenylacetonitrile and benzyl bromide to obtain the 4-benzyloxy phenylacetonitrile.

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

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, and potassium carbonate is preferred;

preferably, the molar ratio of the p-hydroxyphenylacetonitrile to the benzyl bromide is 1:1.1-1.3, preferably 1: 1.2;

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

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

after the desvenlafaxine is obtained according to the method, carrying out a salt forming reaction with succinic acid to obtain desvenlafaxine succinate;

preferably, when carrying out salt-forming reaction with succinic acid, adding desvenlafaxine into a reaction solvent, and carrying out salt-forming reaction with succinic acid to obtain desvenlafaxine succinate;

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

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

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

Detailed Description

Hereinafter, the technical solution of the present invention will be described in detail by specific examples, but these examples should be explicitly proposed for illustration, but should not be construed as limiting the scope of the present invention.

Examples

Synthesis of 4-benzyloxyphenylacetonitrile:

as shown in the reaction formula, p-hydroxyphenylacetonitrile is added into a reaction solvent to be completely dissolved, benzyl bromide is slowly added under the stirring condition, an alkali reagent is slowly added in batches after the dissolution, the reaction is completely stirred by heating, the reaction solvent is removed by rotary evaporation after the reaction solvent is cooled to room temperature, a white solid is separated out, and then the mixture is filtered, washed and dried to obtain 4-benzyloxy phenylacetonitrile;

according to the above method, 16 parallel test groups were set, and different reaction solvents, different alkali reagents, and different molar equivalents of p-hydroxyphenylacetonitrile and benzyl bromide were used, and the reaction temperature and the reaction time were varied, so that the purity and yield of 4-benzyloxyphenylacetonitrile obtained were as shown in table 1 below:

TABLE 1 comparison table of reaction purity and yield of 4-benzyloxyphenylacetonitrile under different reaction conditions

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

As can be seen from Table 1 above, the molar equivalent ratio of p-hydroxyphenylacetonitrile to benzyl bromide has little influence on the product purity, but has some influence on the product yield, and the more equivalents of benzyl bromide, the more thorough the reaction. Under the premise of ensuring that the excess benzyl bromide residue does not exceed the standard, 1.2 equivalents of benzyl bromide are selected for reaction, so that 4-benzyloxy benzyl cyanide with the purity of 99.83 percent and the yield of 90.10 percent can be obtained (Table 1, No. 3). The reaction time is optimized from 2h to 4h, the progress of the reaction is tracked by high performance liquid chromatography for different reaction times, the result shows that the time is too short to be beneficial to the generation of the 4-benzyloxy benzyl cyanide, and the reaction progress reaches the highest after the reaction time is 4h (Table 1, No. 6). The reaction temperature mainly influences the yield of the 4-benzyloxy benzyl cyanide, and the higher the temperature is, the more favorable the nucleophilic attack of the phenoxy negative ion on the benzyl positive ion is, and the more favorable the bromide ion is removed (Table 1, No. 10). The reaction did not yield a solid product in dichloromethane, acetone, ethyl acetate and methanol were of similar purity, and ethyl acetate yield was not predominant (table 1, No. 14). Under the conditions of similar yield and purity, acetone is the best reaction solvent from the viewpoint of atom economy and production cost of crude drug (table 1, No. 11). The alkalinity of the inorganic base directly influences the reaction, the alkalinity is too strong, the byproducts are increased, the contents of related substances and impurities of 4-benzyloxy benzyl cyanide (table 1 and No.16) are influenced, the alkalinity is too weak, and the H of phenolic hydroxyl cannot be negatively ionized, so that the nucleophilic attack activity of oxygen anions on benzyl methyl of benzyl bromide is reduced, and the leaving of bromide ions is not facilitated.

Synthesis of intermediate I:

adding 4-benzyloxy benzyl cyanide into a reaction solvent, uniformly stirring, slowly adding cyclohexanone, adding tetrabutyl ammonium bromide after the cyclohexanone is completely added, cooling to room temperature, slowly adding a sodium hydroxide aqueous solution, controlling the temperature of the reaction solution to be lower than 5 ℃, heating, stirring and completely reacting after the reaction is completely finished, separating out a large amount of white solids, filtering, washing with water, and drying to obtain an intermediate I;

according to the above method, 22 parallel test sets were set, and the reaction temperature and reaction time were varied using different reaction solvents and different molar equivalents of 4-benzyloxyphenylacetonitrile, cyclohexanone, tetrabutylammonium bromide and sodium hydroxide, respectively, to obtain the intermediate I having the purity and yield shown in table 2 below:

TABLE 2 comparison of the reaction purities and yields of intermediate I under different reaction conditions

Note: n is ₁ 、n ₂ 、n ₃ 、n ₄ The molar equivalents of 4-benzyloxy benzyl cyanide, cyclohexanone, tetrabutylammonium bromide and sodium hydroxide respectively, and the purity is measured by HPLC, wherein the purity in No.10-12 is measured by HPLC of the reaction solution; the yield is the product yield obtained after primary recrystallization; in Nos. 21 to 22, potassium carbonate and potassium hydroxide were used in place of sodium hydroxide in the same molar equivalents, respectively.

From the above table 2, it can be seen that, when the intermediate I is prepared by the condensation reaction of 4-benzyloxyphenylacetonitrile and cyclohexanone under the catalysis of an inorganic base, the condensation reaction has better yield and purity in the reaction solvent of water under the action of a phase transfer catalyst tetrabutylammonium bromide. When the molar equivalent ratio of the cyclohexanone to the 4-benzyloxyphenylacetonitrile is 2.0, the 1, 2-nucleophilic addition reaction of the 4-benzyloxyphenylacetonitrile to the unsaturated carbonyl group on the cyclohexanone is facilitated, the yield is high, and the cyclohexanone residue can be removed in the subsequent process (Table 2, No. 2). Tetrabutylammonium bromide belongs to genotoxic impurities, so the requirement on the catalytic dosage is strict, the overproof risk cannot be brought to the residue under the condition of ensuring that benzyl negative ions of 4-benzyloxy phenylacetonitrile and cyclohexanone undergo a homogeneous reaction through phase transfer catalysis, and the high-yield and low-residue result can be obtained when the equivalent ratio of the tetrabutylammonium bromide to the 4-benzyloxy phenylacetonitrile is 0.08 (Table 2, No. 5). Carbanionic action on 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, so the choice of the base reagent and the equivalent of the base reagent is also important. The results showed that when sodium hydroxide was used as the inorganic base, the amount of by-products increased at 1.5 equivalents (tables 2 and 9), and that when the amount was 0.5 equivalents, the reactivity decreased and the reaction was incomplete (tables 2 and 7). And the inorganic base is weaker in alkalinity and is not beneficial to the generation of benzyl methyl carbanion (Table 2, No.21), when the alkalinity is stronger, the generated carbanion continuously performs 1, 2-nucleophilic addition on unsaturated carbonyl to generate an intermediate I, the yield is higher (Table 2, No.22), the reaction is completed after 4h, and the reaction progress of the reaction liquid is 95.66% (Table 2, No. 12). The 1, 2-nucleophilic addition reaction activity of carbanions to unsaturated carbonyls obtained by the benzyl group reaction of sodium hydroxide and 4-benzyloxyphenylacetonitrile is high, and the reaction temperature at the start of the condensation reaction should not be too high, thereby reducing the formation of by-products (Table 2, No. 14). Compared with organic solvent as 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 the organic solvents, toluene (high boiling point) is particularly difficult to remove. And the detection results of tetrabutylammonium bromide and cyclohexanone show that cyclohexanone is not detected, and the residual content of tetrabutylammonium bromide is below the standard, namely 0.7ppm at least, which has important significance for improving the quality of the bulk drugs.

Synthesis of intermediate II:

adding the intermediate I into a reaction solvent, slowly adding a 10% palladium carbon reducing agent, adding concentrated hydrochloric acid in batches after the reaction is finished, introducing hydrogen, keeping the hydrogen pressure at 2.5MPa, heating, stirring, reacting completely, cooling to room temperature, removing the reaction solvent by rotary evaporation, separating out a white solid, filtering, recrystallizing and drying to obtain an intermediate II;

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

TABLE 3 comparison of the reaction purities and yields of intermediate II under different reaction conditions

Note: 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, HCl (m/v) is the weight volume equivalent of concentrated hydrochloric acid relative to intermediate I; the purity was measured by HPLC, wherein the purity in Nos. 13 to 15 was measured by HPLC of the reaction solution; the yield is the product yield obtained after one recrystallization.

From table 3 above, it can be seen that deprotection of benzyl group and reduction of cyano group can be achieved simultaneously by palladium on carbon hydrogenation, we have made process optimization for the equivalent of palladium on carbon catalyst and recycling jacket from the perspective of saving cost, and when the catalytic equivalent of 10% palladium on carbon reducing agent is 0.30, 87% yield can be obtained (table 3, No.3), and 0.60 equivalent of recycled palladium on carbon reducing agent has the same reduction effect. The addition of hydrochloric acid favoured the formation of a salt with the amine group in the product, allowing the cyano group to be reduced continuously to the amine group, and gave 94.20% yield at an equivalent of 0.3, 94.44% purity (table 3, No. 4). The equivalent of hydrochloric acid increases, and the by-products increase, and the isomerization of the tertiary alcohol in an unstable state under acidic conditions occurs (table 3, No. 6). Deprotection of the benzyl group and reduction of the cyano group the reaction proceeds favourably by increasing the temperature during the hydrogenation pressure reduction (Table 3, Nos. 7, 8, 9). When isopropanol, a protic solvent, was used as a reaction solvent, the amount of the starting material remained was large (Table 3, No.12), and methanol was more advantageous in the yield than ethanol (Table 3, No.10, 11). The reaction time is not less than 5h, and the result of HPLC tracing the reaction progress of the reaction solution (T table 3, Nos. 13, 14 and 15) shows that the reaction time is short, and the byproduct desvenlafaxine impurity E which is not fully reduced is obtained, and the structural formula is shown as follows:

synthesis of desvenlafaxine:

adding the intermediate II into a reaction solvent, slowly adding a 37% formaldehyde solution under stirring, stirring for reacting for 2 hours at 20 ℃, then slowly adding an 85% formic acid solution, heating to 103 ℃ under the protection of nitrogen, completely reacting, cooling to room temperature, then removing the reaction solvent by rotary evaporation until syrup is formed, adding water, washing with ethyl acetate for three times, combining water phases, adjusting the pH value to 9-10 with a 50% sodium hydroxide solution, separating out solids, filtering, washing with water, recrystallizing and drying to obtain the desvenlafaxine;

according to the above method, 18 parallel test groups were set, and the reaction temperature and reaction time were varied using different reaction solvents and different molar equivalents of intermediate II, formaldehyde and formic acid, respectively, to obtain desvenlafaxine with the purity and yield as shown in table 4 below:

TABLE 4 comparison of desvenlafaxine reaction purity and yield under different reaction conditions

Note: n (intermediate II), n (formaldehyde) and n (formic acid) are the molar equivalents of intermediate II, formaldehyde and formic acid, respectively; the purity was measured by HPLC, wherein the purity in Nos. 14 to 17 was measured by HPLC of the reaction solution; the yield is the product yield obtained after one recrystallization.

As can be seen from table 4 above, the methylation reaction of the amine group is achieved by forming an imine intermediate from the formaldehyde solution and the intermediate II, and reducing the imine intermediate with formic acid as a hydrogen source to form an aminomethyl group. Of these, the equivalent of formaldehyde is not so large that it is preferably 2 to 3 equivalents (Table 4, Nos. 1, 2 and 3), and when the equivalent of formaldehyde exceeds 4 equivalents, the formed imine intermediate becomes more stable and less likely to be destroyed, and the yield becomes lower (Table 4, No. 6). Similarly, the equivalent of formic acid is optimized to 5 equivalents, and by continuing to increase the equivalent of formic acid, the product yield is not significantly increased, while the material cost is increased (Table 4, Nos. 7, 8, 9). Surprisingly, it was found that this reaction gave unexpectedly good results with isopropanol as the reaction solvent (Table 4, No.12, 18), giving a maximum yield of 84.77% and a maximum purity of 99.20%, the reaction progress, product yield, purity being much higher than those obtained with water or methanol as the solvent (Table 4, No.10, 11). The compound is also a protic solvent, and methanol and water have higher polarity than isopropanol, are easier to form solvation effect with the intermediate II and are not beneficial to the generation of the imine intermediate of formaldehyde. When formic acid was used as a reaction solvent, little product was produced and the yield was low when the reaction was carried out under the solventless condition, and this also proves that the more polar the protic solvent is, the more unfavorable the reaction is (Table 4, No. 13).

Synthesis of desvenlafaxine succinate (i.e. desvenlafaxine succinate monohydrate form I):

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

according to the method, 18 parallel test groups are set, different desvenlafaxine, succinic acid molar equivalents and different solvents are respectively adopted to change the reaction time relative to desvenlafaxine volume mass equivalents, and the purity and yield of the desvenlafaxine succinate monohydrate crystal form I obtained by the method are shown in the following table 5:

TABLE 5 comparison of the reaction purity and yield of desvenlafaxine succinate under different reaction conditions

Note: n (desvenlafaxine) and n (succinic acid) are the molar equivalents of desvenlafaxine and succinic acid; purity is measured by HPLC; the yield is the product yield obtained after primary recrystallization; in nos. 13 to 15, acetone was replaced with a mixed solvent of ethyl acetate and isopropyl alcohol having volume mass equivalents of 5(v/m), 10(v/m), and 15(v/m) (v/v ═ 1:1), respectively, as a washing solvent; in No.16, the crystals were crystallized from a mixed solvent of ethyl acetate and isopropyl alcohol (v/v ═ 1:1) having a volume-mass equivalent of 10 (v/m); in Nos. 17 to 18, the mixed solvent of ethyl acetate and isopropyl alcohol was heated to 50 ℃ or room temperature, respectively, using a volume mass equivalent of 10 (v/m).

From the above table 5, it can be seen that the synthesis process of desvenlafaxine succinate monohydrate crystal form I adopts the complete dissolution reaction under the condition of mixed solvent of acetone and water and the natural cooling crystallization preparation, and then the acetone cleaning is carried out to achieve the purpose of refining to obtain the qualified product. When the volume-to-mass ratio of the reaction solvent was 10 times, 99.72% purity and 59.47% yield were obtained from 0.5 equivalents of succinic acid (Table 5, No. 2). The results of the reaction time of 2 to 4 hours show (Table 5, No.4, 5, 6), that the longer the reaction time, the more favorable the crystallization, and the highest purity of 99.90% and yield of 90.27% were obtained (Table 5, No. 12). Since desvenlafaxine succinate monohydrate has a certain solubility in water, the more the solvent amount, the less product is precipitated, and reducing the solvent amount has a good effect on the product yield (table 5, No. 8). The cleaning solvent acetone is replaced by the mixed solvent of ethyl acetate and isopropanol to achieve the content control of the maximum single impurity, and the result shows that the product purity is 99.90-99.91% with the increase of the mixed solvent amount, and the yield is inversely proportional to the solvent amount, which indicates that the refining effect of the mixed solvent under the room temperature condition is not obvious (Table 5, No.13, 14 and 15), the maximum refining effect of the mixed solvent under the heating condition is 99.92%, the content of the single impurity is 0.08%, the yield is low (Table 5, No.16, 17 and 18), and the influence on the yield is large. XRD powder diffraction and DSC-TGA detection are carried out on the crystal form and the crystal water of the product prepared by the mixed solvent, and the crystal form is converted compared with the crystal form and the crystal water of the acetone refining process.

According to the optimized conditions, the green industrial synthesis method of desvenlafaxine and succinate thereof provided by the invention specifically comprises the following steps:

(1) adding 200.0g of p-hydroxyphenylacetonitrile (1.5mol) and 1000mL of acetone into a 3L reaction bottle, slowly adding 282.56g of benzyl bromide (1.65mol) under stirring, slowly adding 320.28g of anhydrous potassium carbonate (2.32mol) in batches after the addition is finished, stirring at 55 ℃ for reaction overnight, monitoring the reaction by TLC (a developing agent: ethyl acetate: n-hexane: 5:1) until the reaction is complete, directly performing rotary evaporation to remove the solvent and separate out a large amount of white solid, filtering, leaching a filter cake by using a large amount of water, and drying to obtain 331.19g of 4-benzyloxy phenylacetonitrile with the yield of 99.13%;

4-Benzyloxybenzeneacetonitrile (C) ₁₅ H ₁₃ NO)， ¹ H 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). ¹³ CNMR(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-benzyloxy benzyl cyanide (1.12mol) and 500mL of water are added into a 1L three-mouth reaction bottle, 176.02g of cyclohexanone (1.80mol) is slowly added under stirring, 22.0g of tetrabutylammonium bromide (0.07mol) is added after the addition is finished, 100mL of 36.0g of sodium hydroxide (0.90mol) aqueous solution which is cooled to room temperature is slowly added, the temperature of the reaction solution is kept below 5 ℃, the reaction is stirred for 4 hours under the temperature of 20 ℃ after the addition is finished, the reaction is monitored by TLC (developing agent: ethyl acetate: n-hexane: 5:1) until the reaction is complete, a large amount of white solid is separated out, the filtration is carried out, a filter cake is rinsed by a large amount of water and dried, and 359.69g of intermediate I is obtained, and the yield is 99.94%.

Intermediate I (C) ₂₁ H ₂₃ NO ₂ )， ¹ H 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). ¹³ C 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 (0.93mol) and 3000mL of industrial methanol are added into a 3L three-mouth reaction bottle, 99.99g of 10% Pd/C is slowly added under stirring, and after the addition is finished, 90.00mL of concentrated hydrochloric acid and H are slowly added in batches ₂ Balloon, stirring at 45 ℃ for reaction overnight, monitoring the reaction by TLC (developing agent: ethyl acetate: n-hexane: 2.5:1) until the reaction is complete, directly performing rotary evaporation to remove the solvent and separate out a large amount of white solid, recrystallizing the solid twice by ethyl acetate, and drying to obtain 179.90g of an intermediate II with yield of 82.52%;

(4) 150g of intermediate II (0.64mol), 100mL of water were added to a 250mL single-neck reaction flask, 38.60g of 37% formaldehyde solution was slowly added with stirring, the mixture was stirred at 20 ℃ for 2h, and 68.40g of 85% formic acid solution, N, were slowly added ₂ Balloon, stirring and reacting at 103 ℃ overnight, monitoring the reaction by TLC (developing agent: dichloromethane: methanol: triethylamine: 2.5:10drops:1drop) until the reaction is complete, directly performing rotary evaporation to remove the solvent to obtain a syrup, adding 50mL of water, washing with ethyl acetate for three times, combining water phases, adjusting the pH to about 9.5 by using 50% sodium hydroxide solution, separating out a solid, filtering to obtain a crude solid, recrystallizing once by using 20mL of water at 70 ℃, recrystallizing the filtered residue twice by using 15mL of methanol at 60 ℃, and drying to obtain 146.47g of desvenlafaxine with the yield of 87.70%.

Desvenlafaxine (C) ₁₆ H ₂₅ NO ₂ )， ¹ H 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). ¹³ C NMR(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) Adding 64g of desmethylvenlafaxine (0.24mol), 27.30g of succinic acid (0.23mol), 300mL of acetone and 100mL of purified water into a 1000mL round-bottom flask, stirring uniformly, slowly heating to 90 ℃, stirring for 1h, completely dissolving into colorless transparent state, cooling to 60 ℃, filtering to remove trace insoluble substances, continuously cooling to 35 ℃, stirring for 6h, fully discharging the product, cooling in an ice-water bath, filtering, washing a filter cake with 100mL of ethyl acetate and 100mL of isopropanol, draining, drying at 60 ℃ for 3h to obtain the finished product of the desmethylvenlafaxine succinate monohydrate, wherein the total amount of 82.40g is 85.83 percent.

Desvenlafaxine succinate monohydrate (C) ₂₀ H ₃₂ NO ₇ )， ¹ H 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). ¹³ C NMR(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 high-yield and high-purity desvenlafaxine and the synthetic preparation of succinate thereof, the process of the intermediate I is greener, and no organic waste liquid is used to eliminate 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 medicines is improved, and the medicines are safer to market. The preparation of the intermediate II adopts the process conditions of low pressure, normal temperature and dilute acid, reduces the safety risk of high pressure and high temperature of the reduction hydrogenation of bifunctional groups to a certain extent, simplifies the post-treatment and refining operation, and is more beneficial to industrial mass production. The process for the preparation of desvenlafaxine is surprisingly found to show the particular advantage of isopropanol as protic solvent in the double methylation step, which can also be recycled. The method can prepare desvenlafaxine 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 prescription process development in preparation research and development.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims (9)

1. A green industrial synthesis method of desvenlafaxine is characterized by comprising the following steps:

4-benzyloxy benzyl cyanide is used as raw material, after the nucleophilic addition reaction of carbonyl with cyclohexanone, the benzyl deprotection and the reduction reaction of cyano are carried out, and then the aminomethylation reaction is carried out, thus obtaining the desvenlafaxine;

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

2. The green industrial synthesis method of desvenlafaxine according to claim 1, wherein 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.

3. The green industrial synthesis method of desvenlafaxine according to claim 1 or 2, wherein the molar ratio of 4-benzyloxyphenylacetonitrile 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 ℃.

4. The industrial synthesis method of green desmethylvenlafaxine according to any one of claims 1 to 3, wherein during the benzylde-protection and cyano reduction reaction, the intermediate I is added into a reaction solvent, and under the conditions of a palladium reduction catalyst and an acid reagent, the benzylde-protection and cyano reduction reaction are performed by hydrogenation 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 capacity of the palladium carbon catalyst is preferably 10 wt%; 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.

5. The green industrial synthesis method of desvenlafaxine according to any one of claims 1 to 4, wherein during the aminomethylation reaction, the intermediate II is added into a reaction solvent, and is subjected to aminomethylation reaction with formaldehyde and formic acid to obtain desvenlafaxine;

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

6. The green industrial synthesis method of desvenlafaxine according to any one of claims 1 to 5, further comprising: taking p-hydroxyphenylacetonitrile as an initial raw material, and carrying out hydroxyl protection reaction on the p-hydroxyphenylacetonitrile and benzyl bromide to obtain the 4-benzyloxy phenylacetonitrile.

7. The green industrial synthesis method of desvenlafaxine according to claim 6, wherein, during the hydroxyl protection reaction with benzyl bromide, p-hydroxyphenylacetonitrile is added into a reaction solvent and undergoes the hydroxyl protection reaction with benzyl bromide under the condition of an alkali reagent to obtain 4-benzyloxyphenylacetonitrile;

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, and potassium carbonate is preferred;

preferably, the molar ratio of the p-hydroxyphenylacetonitrile to the benzyl bromide is 1:1.1-1.3, preferably 1: 1.2;

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

8. A green industrial synthesis method of desvenlafaxine succinate is characterized by comprising the following steps:

obtaining desvenlafaxine according to any one of claims 1 to 7, and then carrying out a salt-forming reaction with succinic acid to obtain desvenlafaxine succinate;

9. the green industrial synthesis method of desvenlafaxine succinate as claimed in claim 8, wherein the desvenlafaxine is added into a reaction solvent during the salt-forming reaction with succinic acid, and then the desvenlafaxine is subjected to the salt-forming reaction with succinic acid to obtain desvenlafaxine succinate;

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

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