1. A synthesis method of desvenlafaxine is characterized in that the reaction route of the synthesis method comprises the following steps:

the synthesis method comprises the following steps:

1) selecting p-hydroxyphenylacetonitrile in a formula (1), adding an activating agent under an anhydrous condition, and reacting with cyclohexanone to obtain 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile in a formula (2);

2) adding 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile in the formula (2) into peroxyacetic acid for oxidation to obtain an epoxy compound in the formula (3);

3) adding Raney nickel and potassium hydroxide into the epoxy compound of the formula (3), and carrying out high-pressure hydrogenation to obtain an amino compound of the formula (4);

4) adding formic acid and formaldehyde into the amino compound of the formula (4) to obtain the desvenlafaxine of the formula (5).

2. The method for synthesizing desvenlafaxine according to claim 1, wherein in step 1), the activating agent is one of sodium methoxide, sodium ethoxide or potassium tert-butoxide; the mass ratio of the activating agent to the cyclohexanone to the p-hydroxyphenylacetonitrile is 0.6-1: 1: 1.22 to 1.25.

3. The synthesis method of desvenlafaxine according to claim 1 or 2, wherein in step 1), the activating agent and cyclohexanone are dissolved in absolute ethanol, the p-hydroxyphenylacetonitrile of the formula (1) is added at 25-30 ℃, and after the addition is finished, the mixture is stirred and reacted at 70-80 ℃ for 5-6 hours; after the reaction of the p-hydroxyphenylacetonitrile is finished, decompressing and concentrating absolute ethyl alcohol, adding water, stirring for 2-3 hours at 0-5 ℃, filtering, washing a filter cake with water, and drying the filter cake to obtain the 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile of the formula (2).

4. The synthesis method of desvenlafaxine as claimed in claim 1, wherein in step 2), 1-1.5 mL of sulfuric acid is added into 1-2L of acetic acid, the mixture is cooled to 0-5 ℃, stirred, and then 25% of hydrogen peroxide solution is slowly dropped at 0-5 ℃; after the dropwise addition is finished, stirring and reacting for 1-2 hours at 0-5 ℃; continuously stirring, and dropwise adding a dichloromethane solution of 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile at 0-5 ℃; after the dropwise addition is finished, stirring and reacting for 4-5 hours at the temperature of 5-10 ℃; after ensuring that the 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile completely reacts, standing for layering, taking out a lower dichloromethane layer, adding dichloromethane into an upper water layer for extraction, then combining with the taken dichloromethane layer, and washing with 20% sodium bisulfite aqueous solution and water; concentrating dichloromethane under reduced pressure, adding water, stirring for 3-4 hours at 0-5 ℃, filtering, washing a filter cake with water, and drying the filter cake to obtain the epoxy compound shown in the formula (3).

5. The method for synthesizing desvenlafaxine according to claim 1 or 4, wherein in step 2), the mass ratio of the peracetic acid to the 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile of formula (2) is 1: 3 to 4.

6. The synthesis method of desvenlafaxine according to claim 1, wherein in the step 3), the mass ratio of the epoxy compound of the formula (3) to raney nickel is 5-8: 1, the addition amount of the potassium hydroxide is 0.1-0.5 wt% of the mass of the epoxy compound.

7. The synthesis method of desvenlafaxine according to claim 1 or 6, wherein in the step 3), anhydrous ethanol is added into the autoclave to dissolve the epoxy compound of the formula (3) and raney nickel, nitrogen is introduced to replace the air in the autoclave, then hydrogen is introduced, the pressure is controlled to be 4-5 MPa, and hydrogenation reaction is carried out at 65-75 ℃ for 12-14 hours; after ensuring that the epoxy compound shown in the formula (3) completely has no residue in the reaction, filtering and recovering Raney nickel; and concentrating the ethanol under reduced pressure, adding a mixed solution of the ethanol and the water, recrystallizing, filtering, washing a filter cake with the water, and drying the filter cake to obtain the amino compound shown in the formula (4).

8. The synthesis method of desvenlafaxine as claimed in claim 1, wherein in step 4), the mixed solution of acetic acid and formic acid and formaldehyde aqueous solution are added, then the amino compound of formula (4) is added, the mixture is stirred and reacted for 15-16 hours at 110-115 ℃, after the amino compound of formula (4) is completely reacted, the mixture is concentrated, the mixed solution of acetic acid and formic acid is recovered, the obtained concentrate is dissolved by dichloromethane and transferred to a separating funnel, and then the mixture is washed by 10% sodium bicarbonate aqueous solution and water; concentrating dichloromethane under reduced pressure, adding water for recrystallization, filtering, washing a filter cake with water, and drying the filter cake to obtain the desvenlafaxine of the formula (5).

Background

Desmethylvenlafaxine (1, chemical name is 1-2-N, N- — methylamino-1-4-hydroxyphenyl) ethyl cyclohexanol, a novel phenethylamine antidepressant developed by American Whitman, is approved by FDA to be marketed in the United states 2.29 days after 2008.

The existing methods for synthesizing desvenlafaxine include four methods: 1. the desvenlafaxine succinate is synthesized by benzylation, halogenation, ammonolysis, reduction, hydroxyl halogenation, condensation, debenzylation reaction and hydration salt synthesis with succinic acid/water by taking p-hydroxyacetophenone as a raw material. 2. P-hydroxyphenylacetonitrile is used as an initial raw material, and is subjected to benzyl protection on hydroxyl, condensation reaction with cyclohexanone, pressurized palladium-carbon catalytic hydrogenation and Eschweiler-Clark reaction to obtain the desvenlafaxine. Although the method has few steps, the step of palladium carbon catalytic hydrogenation reduction of cyano and debenzylation is very difficult to realize. Because the palladium carbon reduces cyano by-products to a large extent, palladium carbon is not used as a catalyst for reducing cyano in general, and raney nickel is used as a catalyst. Therefore, this process cannot be realized at all. 3. Taking a compound 1- [2, amido-1- (4-methoxyphenyl) ethyl ] cyclohexanol as a raw material, demethylating under the catalysis of thiolate anion, cobalt or lithium diphenylphosphinate to obtain l- [ 2-amido-1- (4-hydroxyphenyl) ethyl ] cyclohexanol, performing cyclodextrin inclusion, and performing N-methylation reaction with formaldehyde or paraformaldehyde and formic acid to obtain a target product 1, wherein the total yield is about 70%. The initial raw material 1- [ 2-amido-1- (4-methoxyphenyl) ethyl ] cyclohexanol is demethylated and then N-methylated on amino to obtain the target product. The reaction in the N-methylation step is not complete for more than 20 hours, and the method also has the defects of severe demethylation reaction conditions, difficult obtainment of starting materials, high price and the like, and is not suitable for industrial production. 4. Desvenlafaxine is synthesized through the reaction of venlafaxine and aluminum trihalide thiol system at 0-25 deg.c. The specific process comprises the steps of adopting an aluminum trihalide (aluminum trichloride, aluminum tribromide), mercaptan or an aluminum trihalide (aluminum trichloride, aluminum tribromide) mercaptan dichloromethane system, adjusting the pH to acidity with inorganic acid after reaction, washing with an organic solvent, adjusting the pH to 9.5-10 with alkali to precipitate, filtering, washing, and drying in vacuum to obtain the desvenlafaxine. In fact, desvenlafaxine is extremely unstable under acidic conditions, and in particular, it decomposes rapidly under strong acid conditions such as aluminum trichloride, so that desvenlafaxine is not obtained.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide a synthesis method of desvenlafaxine, which does not adopt raw materials taking phenolic hydroxyl as a protective group, so that the protective group of phenolic hydroxyl is removed without adding unpleasant and toxic thiol, and the environmental pollution is avoided; the method also has the advantages of mild conditions, no need of high-temperature treatment, high yield and high purity, and is suitable for industrial large-scale production.

The purpose of the invention is realized by adopting the following technical scheme:

a synthesis method of desvenlafaxine, wherein the reaction route of the synthesis method comprises the following steps:

the synthesis method comprises the following steps:

1) selecting p-hydroxyphenylacetonitrile in a formula (1), adding an activating agent under an anhydrous condition, and reacting with cyclohexanone to obtain 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile in a formula (2); the structural formula is as follows:

2) adding 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile in the formula (2) into peroxyacetic acid for oxidation to obtain an epoxy compound in the formula (3); the structural formula is as follows:

3) adding Raney nickel and potassium hydroxide into the epoxy compound of the formula (3), and carrying out high-pressure hydrogenation to obtain an amino compound of the formula (4); the structural formula is as follows:

4) adding formic acid and formaldehyde into the amino compound of the formula (4) to obtain the desvenlafaxine of the formula (5). The structural formula is as follows:

further, in the step 1), the activating agent is one of sodium methoxide, sodium ethoxide or potassium tert-butoxide; the mass ratio of the activating agent to the cyclohexanone to the p-hydroxyphenylacetonitrile is 0.6-1: 1: 1.22 to 1.25.

Further, in the step 1), dissolving the activating agent and the cyclohexanone in absolute ethyl alcohol, adding the p-hydroxyphenylacetonitrile shown in the formula (1) at 25-30 ℃, and after the addition is finished, stirring and reacting for 5-6 hours at 70-80 ℃; after the reaction of the p-hydroxyphenylacetonitrile is finished, decompressing and concentrating absolute ethyl alcohol, adding water, stirring for 2-3 hours at 0-5 ℃, filtering, washing a filter cake with water, and drying the filter cake to obtain the 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile of the formula (2).

Further, in the step 2), 1-1.5 mL of sulfuric acid is added into 1-2L of acetic acid, the mixture is cooled to 0-5 ℃, stirred, and then 25% hydrogen peroxide is slowly dripped at 0-5 ℃; after the dropwise addition is finished, stirring and reacting for 1-2 hours at 0-5 ℃; continuously stirring, and dropwise adding a dichloromethane solution of 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile at 0-5 ℃; after the dropwise addition is finished, stirring and reacting for 4-5 hours at the temperature of 5-10 ℃; after ensuring that the 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile completely reacts, standing for layering, taking out a lower dichloromethane layer, adding dichloromethane into an upper water layer for extraction, then combining with the taken dichloromethane layer, and washing with 20% sodium bisulfite aqueous solution and water; concentrating dichloromethane under reduced pressure, adding water, stirring for 3-4 hours at 0-5 ℃, filtering, washing a filter cake with water, and drying the filter cake to obtain the epoxy compound shown in the formula (3).

Still further, in the step 2), the mass ratio of the peroxyacetic acid to the 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile of the formula (2) is 1: 3 to 4.

Further, in the step 3), the mass ratio of the epoxy compound of the formula (3) to the raney nickel is 5-8: 1, the addition amount of the potassium hydroxide is 0.1-0.5 wt% of the mass of the epoxy compound.

Further, in the step 3), adding absolute ethyl alcohol to dissolve the epoxy compound and the raney nickel in the formula (3) into the high-pressure kettle, introducing nitrogen to replace air in the high-pressure kettle, introducing hydrogen, controlling the pressure to be 4-5 MPa, and performing hydrogenation reaction for 12-14 hours at 65-75 ℃; after ensuring that the epoxy compound shown in the formula (3) completely has no residue in the reaction, filtering and recovering Raney nickel; and concentrating the ethanol under reduced pressure, adding a mixed solution of the ethanol and the water, recrystallizing, filtering, washing a filter cake with the water, and drying the filter cake to obtain the amino compound shown in the formula (4).

Further, in the step 4), adding a mixed solution of acetic acid and formic acid and a formaldehyde aqueous solution, adding the amino compound of the formula (4), stirring and reacting at 110-115 ℃ for 15-16 hours, concentrating after ensuring that the amino compound of the formula (4) completely reacts, recovering the mixed solution of acetic acid and formic acid, dissolving the obtained concentrate with dichloromethane, transferring the dissolved concentrate into a separating funnel, and washing with a 10% sodium bicarbonate aqueous solution and water; concentrating dichloromethane under reduced pressure, adding water for recrystallization, filtering, washing a filter cake with water, and drying the filter cake to obtain the desvenlafaxine of the formula (5).

Compared with the prior art, the invention has the beneficial effects that:

the preparation method comprises the following steps: the first step is as follows: adopting p-hydroxyphenylacetonitrile as a raw material, adding an activating agent under an anhydrous condition, and reacting with cyclohexanone to obtain 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile; the second step is that: oxidizing 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile with peroxyacetic acid to obtain an epoxy compound; the third step: adding catalyst Raney nickel and potassium hydroxide into the epoxy compound for catalysis, and performing high-pressure hydrogenation to obtain an amino compound; the fourth step: and (3) carrying out Eschweiler-Clarke reaction on the amino substance, namely reacting the amino substance in a formic acid-formaldehyde system to obtain the desvenlafaxine. The desvenlafaxine is prepared without adopting a raw material of a phenolic hydroxyl protecting group, and thiol is not required to be added to remove the phenolic hydroxyl protecting group, so that the desvenlafaxine is safe, non-toxic and environment-friendly. The method has the advantages of low cost and easy obtainment of the used reaction materials, simple steps of the synthesis method, mild reaction conditions and high total yield of more than 87 percent, thereby being suitable for large-scale industrial production.

Detailed Description

The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment.

A synthesis method of desvenlafaxine, wherein the reaction route of the synthesis method comprises the following steps:

the synthesis method comprises the following steps:

1) selecting p-hydroxyphenylacetonitrile in a formula (1), adding an activating agent under an anhydrous condition, and reacting with cyclohexanone to obtain 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile in a formula (2);

2) adding 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile in the formula (2) into peroxyacetic acid for oxidation to obtain an epoxy compound in the formula (3);

3) adding Raney nickel and potassium hydroxide into the epoxy compound of the formula (3), and carrying out high-pressure hydrogenation to obtain an amino compound of the formula (4);

4) adding formic acid and formaldehyde into the amino compound of the formula (4) to obtain the desvenlafaxine of the formula (5).

Example 1

1) 3L of absolute ethyl alcohol, 240g of sodium methoxide and 400g of cyclohexanone are added into a 5L three-neck flask, stirred and slowly added with 500g of p-hydroxy-phenylacetonitrile at 25-30 ℃. After the addition, stirring and reacting for 6 hours at 70-80 ℃. Detecting by thin layer chromatography (wherein the adsorbent is petroleum ether and ethyl acetate solution with the mixing ratio of 3: 1), and finishing the reaction after ensuring that the reaction of the p-hydroxyphenylacetonitrile is complete. Concentrating the ethanol under reduced pressure, adding 3L of water, stirring for 3 hours at 0-5 ℃, filtering, and washing the filter cake with 200ml of water. The filter cake was dried to obtain 750g of 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile of the formula (2). Purity: 98.6% (HPLC normalization method). Yield: 92.3 percent.

2) Adding 1L of acetic acid and 2mL of sulfuric acid into a 5L three-neck flask, cooling to below 5 ℃, stirring, and slowly dropwise adding 500g of 25% hydrogen peroxide at 0-5 ℃. And after the dropwise addition, stirring and reacting for 1 hour at the temperature of 0-5 ℃. And slowly dripping a solution prepared from 600g of 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile and 2L of dichloromethane at the temperature of 0-5 ℃. And after the dropwise addition, stirring and reacting for 4 hours at the temperature of 5-10 ℃. Detecting by thin layer chromatography (wherein, the adsorbent adopts petroleum ether and ethyl acetate solution with the mixing ratio of 3: 1), ensuring that the 2-cyclohexylidene-2- (4 hydroxyphenyl) acetonitrile completely reacts, and finishing the reaction. Transfer to 5L separatory funnel and separate the layers. The lower methylene chloride layer was transferred to a 5L three-necked flask, the upper acid aqueous layer was extracted once with 500ml of methylene chloride, and the methylene chloride layers were combined and put into the 5L three-necked flask. Then, 1L of a 20% aqueous solution of sodium hydrogen sulfite was added and washed twice, and 1L of water was added and washed once. The dichloromethane was concentrated under reduced pressure, 3L of water was added, stirred at 0-5 ℃ for 3 hours, filtered and the filter cake was washed with 200ml of water. The filter cake was dried to obtain 610g of the epoxy compound of the formula (3). Purity: 99.1% (HPLC normalization method). Yield: 93.7 percent.

3) Adding 1L of absolute ethyl alcohol, 400g of epoxy compound, 50g of Raney nickel and 0.4g of potassium hydroxide into a 2L high-pressure autoclave, replacing three times with nitrogen, completely discharging air, introducing hydrogen, controlling the pressure of the hydrogen to be 4-5 MPa, and carrying out hydrogenation reaction for 10 hours at the temperature of 55-70 ℃. Detecting by thin layer chromatography (wherein, the adsorbent is petroleum ether and ethyl acetate solution with the mixing ratio of 3: 1), and finishing the reaction after the epoxy compound reaction is ensured. Filtering and recovering the Raney nickel catalyst. The ethanol was concentrated under reduced pressure and 3L of a mixture of 1: 1, recrystallizing the mixed solution of ethanol and water, filtering, and washing the filter cake by 100ml of water. The filter cake was dried to give 406g of an amino compound of the formula (4). Purity: 99.6% (HPLC normalization method). Yield: 98.6 percent. Repeating the step 3) for three times until 1kg of amino substance is collected;

4) in a 10L three-necked flask, 5L of acetic acid, 1ml of formic acid, and 1L of 37% aqueous formaldehyde solution were placed, and 1kg of the amino compound of the formula (4) was added thereto. The reaction was stirred at 110 ℃ and 115 ℃ for 15 hours. Detecting by thin layer chromatography (wherein, the adsorbent is petroleum ether and ethyl acetate solution with the mixing ratio of 1: 1), and finishing the reaction after the amino compound reaction is ensured. Concentrating, and recovering acetic acid and formic acid for the next reaction. The concentrate was dissolved in 6L of dichloromethane, transferred to a 10L separatory funnel, washed twice with 2L of 10% aqueous sodium bicarbonate solution and once with 2L of water. The dichloromethane was concentrated under reduced pressure, 6L of water was added for recrystallization, filtration was performed, and the filter cake was washed with 500ml of water. And drying the filter cake to obtain 1kg of desvenlafaxine. Purity: 99.9% (HPLC external standard, with 99.9% purity of desmethylvenlafaxine from mcelin as control). Yield: 89.2 percent.

Example 2

1) 3L of absolute ethyl alcohol, 330g of sodium ethoxide and 410g of cyclohexanone are added into a 5L three-neck flask, stirred, and 500g of p-hydroxyphenylacetonitrile is slowly added at 25-30 ℃. After the addition, stirring and reacting for 5 hours at 70-80 ℃. Detecting by thin layer chromatography (wherein the adsorbent is petroleum ether and ethyl acetate solution with the mixing ratio of 3: 1), and finishing the reaction after ensuring that the reaction of the p-hydroxyphenylacetonitrile is complete. Concentrating the ethanol under reduced pressure, adding 3L of water, stirring for 3 hours at 0-5 ℃, filtering, and washing the filter cake with 200ml of water. The filter cake was dried to obtain 761g of 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile of the formula (2). Purity: 98.1% (HPLC normalization method). Yield: 93.2 percent.

2) Adding 2.2L of acetic acid and 1ml of sulfuric acid into a 10L three-neck flask, cooling to below 5 ℃, stirring, and slowly dropwise adding 1.5kg of 25% hydrogen peroxide at 0-5 ℃. And after the dropwise addition, stirring and reacting for 1 hour at the temperature of 0-5 ℃. Stirring, and slowly dripping 1.5kg of 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile and 4L of dichloromethane solution at the temperature of 0-5 ℃. And after the dropwise addition, stirring and reacting for 4 hours at the temperature of 5-10 ℃. Detecting by thin layer chromatography (wherein, the adsorbent adopts petroleum ether and ethyl acetate solution with the mixing ratio of 3: 1), ensuring that the 2-cyclohexylidene-2- (4 hydroxyphenyl) acetonitrile completely reacts, and finishing the reaction. Transfer to 10L separatory funnel and separate the layers. The lower methylene chloride layer was transferred to a 10L three-necked flask, the upper acid aqueous layer was extracted once with 1.5L methylene chloride, and the methylene chloride layers were combined and put into the 10L three-necked flask. The reaction mixture was washed twice with 2L of a 20% aqueous sodium bisulfite solution and once with 2L of water. Concentrating dichloromethane under reduced pressure, adding 6L of water, stirring for 3 hours at 0-5 ℃, filtering, and washing a filter cake with 500ml of water. The filter cake was dried to obtain 1.51kg of the epoxy compound of the formula (3). Purity: 99.5% (HPLC normalization method). Yield: 93.2 percent.

3) Adding 3L of absolute ethyl alcohol, 1000g of epoxy compound shown in the formula (3), 200g of Raney nickel and 2g of potassium hydroxide into a 5L high-pressure autoclave, replacing three times with nitrogen, introducing hydrogen after air is completely discharged, and controlling the hydrogen pressure to be 4-5 MPa and the temperature to be 65-75 ℃ for hydrogenation reaction for 12 hours. Detecting by thin layer chromatography (wherein, the adsorbent is petroleum ether and ethyl acetate solution with the mixing ratio of 3: 1), and finishing the reaction after the epoxy compound reaction is ensured. Filtering and recovering the Raney nickel catalyst. The ethanol was concentrated under reduced pressure using 8L of a mixture ratio of 1: 1, recrystallizing the mixed solution of ethanol and water, filtering, and washing the filter cake by 100ml of water. The filter cake was dried to obtain 1005g of an amino compound of the formula (4). Purity: 99.3% (HPLC normalization method). Yield: 97.3 percent.

4) In a 10L three-necked flask, 5L of acetic acid, 1ml of formic acid and 1L of a 37% aqueous formaldehyde solution were placed, and 1kg of an amino compound was added thereto. Stirring and reacting for 15 hours at 110-115 ℃. Detecting by thin layer chromatography (wherein, the adsorbent is petroleum ether and ethyl acetate solution with the mixing ratio of 1: 1), and finishing the reaction after the amino compound reaction is ensured. Concentrating, recovering acetic acid and formic acid, and recycling. The concentrate was dissolved in 6L of dichloromethane, transferred to a 10L separatory funnel, washed twice with 2L of 10% aqueous sodium bicarbonate solution and once with 2L of water. The dichloromethane was concentrated under reduced pressure, 6L of water was added for recrystallization, filtration was performed, and the filter cake was washed with 500ml of water. And drying the filter cake to obtain 1kg of desvenlafaxine. Purity: 99.3% (HPLC external standard, with 99.9% purity of desmethylvenlafaxine from Michael as control). Yield: 87.4 percent.

Example 3

1) In a 5L three-necked flask, 7L of absolute ethanol, 800g of potassium tert-butoxide and 810g of cyclohexanone were added, and 1kg of p-hydroxyphenylacetonitrile was slowly added thereto with stirring at 30 ℃. After the addition, the reaction was stirred at 80 ℃ for 4 hours. Detecting by thin layer chromatography (wherein the adsorbent is petroleum ether and ethyl acetate solution with the mixing ratio of 3: 1), and finishing the reaction after ensuring that the reaction of the p-hydroxyphenylacetonitrile is complete. Concentrating the ethanol under reduced pressure, adding 6L of water, stirring for 3 hours at 0-5 ℃, filtering, and washing the filter cake with 500ml of water. The filter cake was dried to give 1.53g of 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile of the formula (2). Purity: 98.9% (HPLC normalization method). Yield: 95.0 percent.

2) In a 10L three-neck flask, 2L of acetic acid and 0.5ml of sulfuric acid are added, cooled to below 5 ℃, stirred, and 1.5kg of 25 percent hydrogen peroxide solution is slowly dripped at the temperature of 5 ℃. And after the dropwise addition, stirring and reacting for 1 hour at the temperature of 0-5 ℃. Stirring, slowly adding dropwise a solution prepared from 1.5kg of 2-cyclohexylidene-2- (4-hydroxyphenyl) acetonitrile and 4L of dichloromethane at 5 ℃. And after the dropwise addition, stirring and reacting for 4 hours at the temperature of 5-10 ℃. Detecting by thin layer chromatography (wherein, the adsorbent adopts petroleum ether and ethyl acetate solution with the mixing ratio of 3: 1), ensuring that the 2-cyclohexylidene-2- (4 hydroxyphenyl) acetonitrile completely reacts, and finishing the reaction. Transfer to 10L separatory funnel and separate the layers. The lower methylene chloride layer was transferred to a 10L three-necked flask, the upper acid aqueous layer was extracted once with 1.5L methylene chloride, and the methylene chloride layers were combined and put into the 10L three-necked flask. The reaction mixture was washed twice with 2L of a 20% aqueous sodium bisulfite solution and once with 2L of water. The dichloromethane was concentrated under reduced pressure, 6L of water was added, stirred at 5 ℃ for 3 hours, filtered and the filter cake was washed with 500ml of water. The filter cake was dried to obtain 1.52kg of the epoxy compound of the formula (3). Purity: 99.2% (HPLC normalization method). Yield: 94.1 percent.

3) Adding 3L of absolute ethyl alcohol, 1000g of epoxy compound shown in the formula (3), 200g of Raney nickel and 5g of potassium hydroxide into a 5L high-pressure autoclave, replacing three times with nitrogen, introducing hydrogen after air is completely discharged, and controlling the pressure of the hydrogen to be 4-5 MPa and the temperature to be 75 ℃ for hydrogenation reaction for 10 hours. Detecting by thin layer chromatography (wherein, the adsorbent is petroleum ether and ethyl acetate solution with the mixing ratio of 3: 1), and finishing the reaction after the epoxy compound reaction is ensured. Filtering and recovering the Raney nickel catalyst. The ethanol was concentrated under reduced pressure using 8L of a mixture ratio of 1: 1, recrystallizing the mixed solution of ethanol and water, filtering, and washing the filter cake by 100ml of water. The filter cake was dried to give 1013g of an amino compound of the formula (4). Purity: 99.6% (HPLC normalization method). Yield: 98.1 percent.

4) In a 10L three-necked flask, 5L of acetic acid, 1ml of formic acid and 1L of a 37% aqueous formaldehyde solution were placed, and 1kg of an amino compound was added thereto. The reaction was stirred at 115 ℃ for 16 hours. Detecting by thin layer chromatography (wherein, the adsorbent is petroleum ether and ethyl acetate solution with the mixing ratio of 1: 1), and finishing the reaction after the amino compound reaction is ensured. Concentrating, recovering acetic acid and formic acid, and recycling. The concentrate was dissolved in 6L of dichloromethane, transferred to a 10L separatory funnel, washed twice with 2L of 10% aqueous sodium bicarbonate solution and once with 2L of water. The dichloromethane was concentrated under reduced pressure, 6L of water was added for recrystallization, filtration was performed, and the filter cake was washed with 500ml of water. And drying a filter cake to obtain 993.2g of desvenlafaxine. Purity: 99.5% (HPLC external standard, with 99.9% purity of desmethylvenlafaxine from Michael as control). Yield: 88.6 percent.

A combination of the above examples 1 to 3 gives the data shown in Table 1:

TABLE 1 purity and yield of desvenlafaxine prepared by the preparation method of examples 1-3

As shown in Table 1, the desvenlafaxine prepared by the methods of examples 1 to 3 has a purity of 99% or more and a yield of 87%. The yield of the desvenlafaxine prepared by the method is only 70%, and the method can improve the yield of the desvenlafaxine and is suitable for large-scale production.

The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.