CN105601522A - Method for industrially synthesizing desvenlafaxine - Google Patents
Method for industrially synthesizing desvenlafaxine Download PDFInfo
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07—ORGANIC CHEMISTRY
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Abstract
The invention provides a method for industrially synthesizing desvenlafaxine. The method is a new technology including the steps that 4-hydroxybenzyl cyanide serves as a starting raw material and is subjected to hydroxyl protection, a condensation reaction, pressurized hydrogenation and an Eschweiler-Clark reaction, and the desvenlafaxine is obtained. The method is small in step number, easy and convenient to operate, high in yield and low in cost, and the product is easy to separate and purify; adopted reagents are all common reagents, and the method is a new technology suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of desmethylvenlafaxine, the method is applicable to extensive, suitability for industrialized production, cost low andYield is high, belongs to chemosynthesis technical field.
Background technology
Desmethylvenlafaxine, chemical name is RS-4-[2-dimethylamino-1-(1-hydroxy-cyclohexyl) ethyl] phenol), structural formulaAs shown in (V), be the main metabolites of antidepressants desmethylvenlafaxine, for serotonin and norepinephrine are taken the photograph againGet inhibitor, be mainly used in treating various depression.
At present, the conventional method of synthetic desmethylvenlafaxine is mainly synthetic through a step demethylating reaction taking Venlafaxine as raw materialDesmethylvenlafaxine. But because the phenoxy group in Venlafaxine structure is highly stable group, therefore demethylation is anti-conventionallyShould often need violent reaction condition and special reagent, and this reagent must meet selective attack methoxyl group and to cyclohexaneHydroxyl nonrecognition reaction on ring.
WO00/32555, WO00/32556 disclose with diphenyl phosphatization lithium and have prepared desmethylvenlafaxine as demethylation reagent.But there are two deficiencies in the method: 1. used inflammable and have in irritating diphenylphosphine 2. solvents exist insoluble in a large numberVenlafaxine lithium.
WO03/48104, US03/105358 disclose use lauryl mercaptan sodium and have carried out demethylating reaction 200 DEG C of left and right.The method exists reaction substrate the risk of inevitably decomposing occurs under this high temperature; Simultaneously because reaction has generated thioether,Increase the difficulty of post processing.
WO2007/071404 discloses use vulcanized sodium and has prepared desmethylvenlafaxine as demethylation reagent. The method exists examinationThe problem of agent storage and product residue foul smelling smell.
Also all there is the expensive shortcoming of initiation material in the synthetic desmethylvenlafaxine of above one-step method except described shortcoming. Remove first literary compositionDaraf(reciprocal of farad) is pungent synthetic by other routes. But technique often exists severe reaction conditions, the shortcoming that yield is low cannot be carried outSuitability for industrialized production.
US2012/0157544 discloses the synthetic desmethylvenlafaxine taking p-hydroxyphenylaceticacid as initiation material. There is condensation in the methodReaction has been used grignard reagent, severe reaction conditions, and the problem of the strict anhydrous and oxygen-free of need, is not suitable for suitability for industrialized production.
WO2009084039 discloses the synthetic desmethylvenlafaxine taking p-hydroxybenzylcyanide as initiation material. There is reaction in the methodRoute is longer, and total recovery is lower, and approximately 34.7%.
Summary of the invention
Technical problem to be solved by this invention is for the deficiencies in the prior art, and provide, one is can industrialization synthetic goesThe method of first Venlafaxine. Taking p-hydroxybenzylcyanide as initiation material, through hydroxyl protection, condensation reaction, hydrogenation,Desmethylvenlafaxine is prepared in Eschweiler--Clark reaction. The method production cost is lower, reaction condition gentleness, does not existPotential safety hazard, post processing is simple to operation, and reactions steps is few, total recovery is high, is applicable to large-scale industrial production.
To achieve these goals, the present invention adopts following technical scheme:
A commercial run for synthetic desmethylvenlafaxine, comprises the following steps:
(1) synthetic 4-benzyloxy benzene acetonitrile: by p-hydroxybenzylcyanide (I): be dissolved in organic solvent-acetone, at acid binding agentThe lower back flow reaction 4～10h that carries out under the condition of 55-59 DEG C with bromobenzyl of effect, removes organic through filtration, decompression distillation after reaction finishesSolvent acetone, recrystallization, purifying obtain 4-benzyloxy benzene acetonitrile (II);
Described acid binding agent is inorganic base; The mol ratio of described p-hydroxybenzylcyanide (I), acid binding agent, bromobenzyl is1:1.5～3.5:1.2；
(2) prepare 1-[cyano group (to benzyloxy phenyl) methyl] cyclohexanol (III): the 4-benzyloxy benzene second that step 1 is obtainedNitrile (II) is dissolved in organic solvent toluene, adds the phase transfer catalyst of alkali lye and catalytic amount, and stirring at room temperature is after 1～2 hourDrip cyclohexanone and react at 40～45 DEG C, react after 8～36 hours and to filter, filter cake is recrystallized after washing with distilled water again,Purifying obtains 1-[cyano group (to benzyloxy phenyl) methyl] cyclohexanol (III);
The mol ratio of described 4-benzyloxy benzene acetonitrile (II), cyclohexanone, alkali is 1:1.5～6:1.2～4; Described phase transfer catalysis (PTC)The mole dosage of agent is 0.01～0.015 times of 4-benzyloxy benzene acetonitrile;
(3) preparation (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol) (IV): the 1-[cyanogen that step 2 is obtainedBase (to benzyloxy phenyl) methyl] cyclohexanol (III) is dissolved in organic solvent methyl alcohol, adds palladium carbon and 45%, is forced into 0.8-3MPaAnd react 8-24 hour under this pressure condition, and reaction finishes rear filtration, and filter cake is with removing organic molten through decompression distillation after methanol washAgent methyl alcohol, recrystallization, purifying obtain (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol) (IV);
Described 1-[cyano group (to benzyloxy phenyl) methyl] mass ratio of cyclohexanol (III), palladium carbon, formic acid is1:0.05～0.4:1.6～1.8；
(4) prepare desmethylvenlafaxine (V): (1-[2-amino-1-(p-hydroxybenzene) second that step (3) is obtainedBase] cyclohexanol) (IV) add in formalin, at room temperature stirring reaction 1～1.5 hour, and then add aqueous formic acid,Back flow reaction is carried out in heating, reacts 8～20 hours, after reacting completely, is down to room temperature, adds NaOH water under ice-water bath conditionSolution is adjusted to 5.5～6.0 by system pH, filters, and filter cake is with obtaining desmethylvenlafaxine through recrystallization, purifying after distilled water washing;
The mol ratio of described (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol) (IV), formaldehyde, formic acid is1:2.5～8.4:4～12；
The W-response formula of above-mentioned synthetic method is:
In technique scheme, in step (1), described organic solvent-acetone and the weight ratio of p-hydroxybenzylcyanide are 15～18:1.
In technique scheme, in step (1), the mol ratio of described p-hydroxybenzylcyanide, acid binding agent, bromobenzyl is preferably1:2:1.2。
In technique scheme, in step (1), reflux time is preferably 6～8h.
In technique scheme, in step (1), described acid binding agent inorganic base, is preferably lithium hydroxide, NaOH, hydrogenThe inorganic bases such as potassium oxide, sodium carbonate, potash, cesium carbonate, more preferably potash.
In technique scheme, in step (2), described organic solvent toluene and 4-benzyloxy benzene acetonitrile weight ratio be20～25:1。
In technique scheme, in step (2), described alkali be lithium hydroxide in inorganic base, NaOH, potassium hydroxide,Any one in ammoniacal liquor, sodium carbonate, potash, cesium carbonate, or organic base sodium hydrogen, sodium methoxide, caustic alcohol, the tert-butyl alcoholAny one in potassium, DBU, triethylamine, pyridine, piperidines, nafoxidine.
Preferably, more preferably potassium hydroxide aqueous solution of described alkali, wherein the mass fraction of potassium hydroxide is preferably10～40%, more preferably 20～25%.
In technique scheme, in step (2), described phase transfer catalyst be tetrabutyl ammonium fluoride, tetramethyl ammonium chloride,Etamon chloride, tetrabutylammonium chloride, TBAB, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, tetrabutyl sulphurAny one in acid hydrogen ammonium, is preferably tetrabutylammonium iodide.
In technique scheme, in step (2), the mol ratio of described 4-benzyloxy benzene acetonitrile, cyclohexanone, alkali is preferably 1:2.5～3:1.5～2。
In technique scheme, in step (3), described reaction pressure is preferably 1.2～1.5MPa, and the reaction time is preferably10～12h。
In technique scheme, in step (3), described 1-[cyano group (to benzyloxy phenyl) methyl] cyclohexanol and organicThe weight ratio of solvent methanol is 1:18.
In technique scheme, in step (3), described 1-[cyano group (to benzyloxy phenyl) methyl] cyclohexanol, palladium carbon,The weight ratio of formic acid is preferably 1:0.1～0.15:1.6～1.8;
In technique scheme, in step (3), described palladium carbon is that mass fraction is 10% wet palladium carbon, and described hydrochloric acid isMass fraction is 10～35% aqueous hydrochloric acid solution, described formic acid be mass fraction be 50～99.9% aqueous formic acid or100% pure formic acid.
In technique scheme, in step (4), described reflux time is preferably 12～15h.
In technique scheme, in step (4), in described formalin, the mass fraction of formaldehyde is 37%; Described firstIn aqueous acid, the mass fraction of formic acid is 5～45%, is preferably 10～15%.
In technique scheme, in step (4), described (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol),The mol ratio of formaldehyde, formic acid is preferably 1:3.5～4:6～7.5.
The advantage of technical solution of the present invention is, taking p-hydroxybenzylcyanide as initiation material, by hydroxyl protection, condensation reaction,Desmethylvenlafaxine is prepared in hydrogenation, Eschweiler – Clarke reaction. Compared to the side of the above synthetic desmethylvenlafaxineMethod, it is lower that this method has production cost, reaction condition gentleness, do not have potential safety hazard, and post processing is simple to operation, reactionStep is few, total recovery is up to 60.4%, is applicable to large-scale industrial production.
Detailed description of the invention
Below the detailed description of the invention of technical solution of the present invention is described in detail, but the present invention is not limited to following description content:
Embodiment 1:
(1) in 50L still, add 20L acetone, open and stir, to add in still 1.01kg potash (18.02mol) and1.2kg (9.01mol) p-hydroxybenzylcyanide; At room temperature drip 1.85kg bromobenzyl (10.82mol), dropwise rear unlatching heating,Back flow reaction reaction in 4.5 hours is complete, filters, and filtrate, is recrystallized through ethyl acetate and n-hexane except desolventizing through decompression distillationObtain 4-benzyloxy benzene acetonitrile 1.45kg, yield 86.7%;
(2) in 50L reactor, add 25L toluene, cool to-5～0 DEG C of left and right, open and stir, in still, add 4-benzyloxyBase benzene acetonitrile 1.2kg (5.37mol); 2580ml (20%) potassium hydroxide aqueous solution is slowly dropped in above-mentioned system, stirMix after 1 hour and drip cyclohexanone 790g (8.06ml), keep-20～25 DEG C of reactions 5 hours, after reacting completely, add water 5LCancellation reaction, filters and obtains white solid, and 45 DEG C are dried 18 hours, obtain 1-[cyano group (to benzyloxy phenyl) methyl] hexamethyleneAlcohol 1.4kg, yield 98%;
(3) by 6L methyl alcohol, 1-[cyano group (to benzyloxy phenyl) methyl] cyclohexanol 500g with, 45% formic acid 30ml, 50g10% wet palladium carbon adds 10L autoclave, after displacement gas 3 times, passes into hydrogen, and keeping the pressure of still is 1.2MPa, reacts 10 hoursRear sampling detects, and reaction raw materials has reacted, and 0～5 DEG C of reactant liquor cooling adds sodium hydrate aqueous solution to regulate PH to reactant liquor≈ 9～10, filters, and 45 DEG C are dried 18 hours, (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol) 290g, receivesRate 89.2%;
(4) 250g (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol) and 20g37% formalin are addedIn 10L reactor, add water 350ml, under room temperature, stir after 1 hour and add 30g anhydrous formic acid, add hot reflux 12 hours anti-Should be complete. Cooling, sodium hydrate aqueous solution regulates pH=5.5～6.0, has a large amount of solids to separate out, and filters, and 45 DEG C are dried 18 hours,Filter cake through recrystallization ethanol water be recrystallized in desmethylvenlafaxine 208g, yield 79.8%.
Embodiment 2:
(1) in 50L still, add 20L acetone, open and stir, to add in still 720g NaOH (18.00mol) and1.3kg (9.02mol) p-hydroxybenzylcyanide; At room temperature drip 1.85kg bromobenzyl (10.82mol), dropwise rear unlatching heating,Back flow reaction reaction in 4.5 hours is complete, filters, and filtrate, is recrystallized through ethyl acetate and n-hexane except desolventizing through decompression distillationObtain 4-benzyloxy benzene acetonitrile 725g, yield 82.3%;
(2) in 50L reactor, add 25L toluene, cool to-5～0 DEG C of left and right, open and stir, in still, add 4-benzyloxyBase benzene acetonitrile 1.2kg (5.37mol); 2580ml (25%) potassium hydroxide aqueous solution is slowly dropped in above-mentioned system, stirMix after 1 hour and drip cyclohexanone 790g (8.06ml), keep 20～25 DEG C of reactions 5 hours, after reacting completely, add water 5LCancellation reaction, filters and obtains white solid, and 45 DEG C are dried 18 hours, obtain 1-[cyano group (to benzyloxy phenyl) methyl] hexamethyleneAlcohol 1.4kg, yield 98%;
(3) by 4000ml methyl alcohol, 1-[cyano group (to benzyloxy phenyl) methyl] cyclohexanol 300g, 65% formic acid and 20g10%Wet palladium carbon adds 10L autoclave, after displacement gas 3 times, passes into hydrogen, and keeping the pressure of still is 1.5MPa, reacts and gets after 12 hoursSample detects, and reacts completely, and 0～5 DEG C of reactant liquor cooling, adds sodium hydrate aqueous solution to regulate PH ≈ 9～10 to reactant liquor, filter,45 DEG C are dried 15 hours, (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol) 180g, yield 78.5%;
(4) 250g (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol) and 20g37% formalin are addedIn 10L reactor, add water 300ml, under room temperature, stir after 1 hour and add 30g anhydrous formic acid, add hot reflux 15 hours anti-Should be complete, cooling, sodium hydrate aqueous solution regulates pH=5.5～6.0, filters, and 45 DEG C are dried 15 hours, and filter cake is through recrystallization secondThe alcohol water desmethylvenlafaxine 180g that is recrystallized to obtain, yield 81.2%.
Compared to the method for the above synthetic desmethylvenlafaxine, this method has the following advantages: 1. condensation reaction is with hydroxidePotassium is as alkali, and reaction condition gentleness, has not only reduced production cost, and reaction yield is up to 98%, the purity of the crude product of generationUp to 98%. 2. pressurization hydrogenation carries out cyano group hydrogenation and debenzylation one step, has shortened synthetic route, makes overall process succinct,Post processing is simple to operation. 3. used the formaldehyde that concentration is suitable only to make to react and carry out with formic acid (the especially concentration of formic acid)Eschweiler – Clarke methylation reaction, and in product, phenolic hydroxyl group does not react. 4. reactions steps is few, total recovery is highReach 60.4%, be applicable to large-scale industrial production.
Above-mentioned example just, for explanation technical conceive of the present invention and technical characterstic, can not limit protection model of the present invention with thisEnclose. Equivalent transformation or modification that all essence according to the present invention is done, within all should being encompassed in protection scope of the present invention.
Claims (10)
1. an industrial method for synthetic desmethylvenlafaxine, is characterized in that, comprises the following steps:
(1) synthetic 4-benzyloxy benzene acetonitrile: p-hydroxybenzylcyanide is dissolved in organic solvent-acetone, under acid binding agent effect, under the condition of 55-59 DEG C, carry out back flow reaction 4～10 hours with bromobenzyl, after reaction finishes through filtering, decompression distillation obtains intermediate 4-benzyloxy benzene acetonitrile except organic solvent-acetone, recrystallization, purifying;
Described acid binding agent is inorganic base; The mol ratio of described p-hydroxybenzylcyanide, acid binding agent, bromobenzyl is 1:1.5～3.5:1.2;
(2) prepare 1-[cyano group (to benzyloxy phenyl) methyl] cyclohexanol: the 4-benzyloxy benzene acetonitrile that step 1 is obtained is dissolved in organic solvent toluene, add the phase transfer catalyst of alkali lye and catalytic amount, stirring at room temperature drips cyclohexanone and reacts at 40～45 DEG C after 1～2 hour, react after 8～36 hours and to filter, filter cake with being recrystallized again after distilled water washing, purifying obtains 1-[cyano group (to benzyloxy phenyl) methyl] cyclohexanol;
The mol ratio of described 4-benzyloxy benzene acetonitrile, cyclohexanone, alkali is 1:1.5～6:1.2～4; The mole dosage of described phase transfer catalyst is 0.01～0.015 times of 4-benzyloxy benzene acetonitrile;
(3) preparation (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol): 1-[cyano group (to the benzyloxy phenyl) methyl that step 2 is obtained] cyclohexanol is dissolved in organic solvent methyl alcohol, add palladium carbon and hydrochloric acid/formic acid, be forced into 0.8～3MPa and under this pressure condition, react 8～24 hours, reaction finishes rear filtration, and filter cake is with obtaining (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol) through decompression distillation except organic solvent methanol, recrystallization, purifying after methanol wash;
Described 1-[cyano group (to benzyloxy phenyl) methyl] mass ratio of cyclohexanol, palladium carbon, formic acid is 1:0.05～0.4:1.6～1.8;
(4) prepare desmethylvenlafaxine: step (3) is obtained (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol) add in formalin, at room temperature stirring reaction adds aqueous formic acid again after 1～1.5 hour, back flow reaction is carried out in heating, after reaction 8～20h finishes, be down to room temperature, under ice-water bath condition, add sodium hydrate aqueous solution that system pH is adjusted to 5.5～6.0, filter, filter cake is with obtaining desmethylvenlafaxine through recrystallization, purifying after distilled water washing;
The mol ratio of described (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol), formaldehyde, formic acid is 1:2.5～8.4:4～12.
2. method according to claim 1, is characterized in that, in step (1), described organic solvent-acetone and the weight ratio of p-hydroxybenzylcyanide are 15～18:1; The mol ratio of p-hydroxybenzylcyanide, acid binding agent, bromobenzyl is 1:2:1.2; Reflux time is preferably 6～8 hours, and wherein said acid binding agent is inorganic base lithium hydroxide, NaOH, potassium hydroxide, sodium carbonate, potash, cesium carbonate.
3. method according to claim 2, is characterized in that, described inorganic base is potash.
4. method according to claim 1, is characterized in that, the weight ratio of the organic solvent toluene described in step (2) and 4-benzyloxy benzene acetonitrile is 20～25:1; The mol ratio of 4-benzyloxy benzene acetonitrile, cyclohexanone, alkali and phase transfer catalyst is 1:2.5～3:1.5～2:0.01～0.015; Reaction time is preferably 15～18 hours. Wherein alkali is any one in lithium hydroxide in inorganic base, NaOH, potassium hydroxide, ammoniacal liquor, sodium carbonate, potash, cesium carbonate, or any one in organic base sodium hydrogen, sodium methoxide, caustic alcohol, potassium tert-butoxide, DBU, triethylamine, pyridine, piperidines, nafoxidine.
5. method according to claim 4, is characterized in that, described alkali is potassium hydroxide aqueous solution, and wherein the mass fraction of potassium hydroxide aqueous solution is 20～25%.
6. method according to claim 1, it is characterized in that, in step (2), described phase transfer catalyst is any one in tetrabutyl ammonium fluoride, tetramethyl ammonium chloride, etamon chloride, tetrabutylammonium chloride, TBAB, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, 4-butyl ammonium hydrogen sulfate.
7. method according to claim 6, is characterized in that, described phase transfer catalyst is tetrabutylammonium iodide.
8. method according to claim 1, is characterized in that, in step (3), described reaction pressure is 1.2～1.5MPa, and the reaction time is 10～12 hours; 1-[cyano group (to benzyloxy phenyl) methyl] weight ratio of cyclohexanol and organic solvent methyl alcohol is 1:18; 1-[cyano group (to benzyloxy phenyl) methyl] weight ratio of cyclohexanol, palladium carbon, formic acid is preferably 1:0.1～0.15:1.6～1.8; Wherein palladium carbon is that mass fraction is 10% wet palladium carbon, and described formic acid is that mass fraction is 50～99.9% aqueous formic acid or 100% pure formic acid.
9. method according to claim 1, is characterized in that, in step (4), the mol ratio of described (1-[2-amino-1-(p-hydroxybenzene) ethyl] cyclohexanol), formaldehyde, formic acid is 1:3.5～4:6～7.5; Described reflux time is preferably 12～15 hours; In formalin, the mass fraction of formaldehyde is 37%; In described aqueous formic acid, the mass fraction of formic acid is 5～45%.
10. method according to claim 9, is characterized in that, in described aqueous formic acid, the mass fraction of formic acid is 10～15%.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440315A (en) * | 2018-03-12 | 2018-08-24 | 钦州学院 | Deuterated O-DMV and its preparation method and application |
| CN109012737A (en) * | 2018-06-19 | 2018-12-18 | 马学英 | A kind of process for catalytic synthesis of antidepressant intermediate |
| CN113402400A (en) * | 2021-04-29 | 2021-09-17 | 深圳市新浩瑞医药科技有限公司 | Synthesis method of desvenlafaxine |
| CN114805097A (en) * | 2022-05-26 | 2022-07-29 | 合肥师范学院 | Green industrial synthesis method of desvenlafaxine and succinate thereof |
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2016
- 2016-01-27 CN CN201610052918.XA patent/CN105601522A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440315A (en) * | 2018-03-12 | 2018-08-24 | 钦州学院 | Deuterated O-DMV and its preparation method and application |
| CN109012737A (en) * | 2018-06-19 | 2018-12-18 | 马学英 | A kind of process for catalytic synthesis of antidepressant intermediate |
| CN109012737B (en) * | 2018-06-19 | 2021-09-17 | 陕西蒲城万德科技有限公司 | Catalytic synthesis method of antidepressant drug intermediate |
| CN113402400A (en) * | 2021-04-29 | 2021-09-17 | 深圳市新浩瑞医药科技有限公司 | Synthesis method of desvenlafaxine |
| CN113402400B (en) * | 2021-04-29 | 2023-12-08 | 深圳市新浩瑞医药科技有限公司 | Synthesis method of desmethylvenlafaxine |
| CN114805097A (en) * | 2022-05-26 | 2022-07-29 | 合肥师范学院 | Green industrial synthesis method of desvenlafaxine and succinate thereof |
| CN114805097B (en) * | 2022-05-26 | 2024-07-16 | 合肥师范学院 | Synthesis method of desmethylvenlafaxine and succinate thereof |
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