CN102557851B - New method for synthesizing tapentadol hydrochloride and analogue of tapentadol hydrochloride - Google Patents

New method for synthesizing tapentadol hydrochloride and analogue of tapentadol hydrochloride Download PDF

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CN102557851B
CN102557851B CN201110413051.3A CN201110413051A CN102557851B CN 102557851 B CN102557851 B CN 102557851B CN 201110413051 A CN201110413051 A CN 201110413051A CN 102557851 B CN102557851 B CN 102557851B
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徐自奥
赵永海
李晓祥
李德刚
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XINXING MEDICAMENT DEVELOPMENT Co Ltd ANHUI PROV
Anhui New Star Pharmaceutical Dev Co Ltd
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Abstract

The invention provides a new method for synthesizing tapentadol hydrochloride and analogue of the tapentadol hydrochloride, and particularly provides a method for synthesizing a compound with the formula shown as a formula (1). Groups of the compound are defined in the specification. The invention also particularly provides a method for synthesizing the tapentadol hydrochloride and the analogue compound of the tapentadol hydrochloride by using 1-(3-substituted phenyl)-1-ketone compound as an initial raw material. According to the method, the raw materials are easy to obtain, and reaction conditions are mild; and the method is easy to control and operate, reduces production cost and is particularly suitable for industrial production.

Description

The synthetic method of a kind of tapentadol hydrochloride and analogue thereof
Technical field
The invention provides the synthetic method of a kind of tapentadol hydrochloride and analogue thereof, specifically, the method of a kind of synthetic following formula (I) compound is provided, especially adopting 1-(3-substituted-phenyl)-1-ketone compounds is the method that starting raw material is prepared tapentadol hydrochloride and analogue activeconstituents thereof, particularly the synthetic method of tapentadol hydrochloride, belongs to pharmaceutical chemistry field.
Figure DEST_PATH_GSB0000116606300000011
Wherein:
Described R1, R2, R3, R4 are identical or different, are selected from independently of one another hydrogen, C 1～4alkyl (preferable methyl, ethyl);
Described R is selected from hydrogen, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted alkoxyl group, halogen, nitro, replacement or unsubstituted amino, sulfur-containing group (as sulfydryl, sulfonic group, sulphonamide etc.).
background technology
Tapentadol hydrochloride (Tapentadol Hydrochloride) is the hydrochloride of tapentadol hydrochloride, a kind of novel maincenter type anodyne with double action mechanism of Shi You U.S. Johnson & Johnson company research and development.It is to be used as medicine with the individual isomer form of (1R, 2R), molecular formula C 14h 23nO.HCl, chemistry is by name:
3-[(1R,2R)-3-(Dimethylamino)-1-ethyl-2-methylpropyl]phenol?hydrochloride。
Its structural formula is as follows:
Figure DEST_PATH_GSB0000116606300000012
Tapentadol hydrochloride belongs to 1-phenyl-3-dimethylin propane compounds, this compounds has multiple pharmacologically active, can be for alleviating pain (EP0693475), also can be used for the treatment of psychosis (DE102007012165), dysthymia disorders (DE10233048), the urinary incontinence (WO2002043715) etc.
Tapentadol hydrochloride (Tapentadol) is a kind of novel mu opioid receptor (MOR) excitement and norepinephrine (Norepinephrine of having concurrently, NE) heavily absorb persistent erection pivot anodyne (the Tzschentke TM that suppresses dual function mode, et al., J.Pharm.Exper.Therap., 2007,323,265).On January 23rd, 2008, FDA Food and Drug Administration (FDA) has accepted the new drug application that tapentadol hydrochloride releases sheet, on November 21st, 2008 is by U.S. FDA approval listing, clinically for removing the treatment of the severe acute pain of adult's central nervous system.Result of study shows, tapentadol hydrochloride does not rely on metabolism activation, there is no active metabolite, to acute, inflammatory and chronic neuropathic pain model model have good result, its usefulness is between morphine (Morphine) and U-26225A (Tramadol), intravenous injection or the oral equal Plasma Concentration that can obtain satisfaction, and than morphine more difficult generation analgesia tolerance and drug dependence, and more can improve side effect (especially gastrointestinal side-effect is as nausea and vomiting) than the strong opioid drug of equivalent analgesic dose, be expected acute and chronic in better to prospect in severe pain treatment.
The chemical structure of tapentadol hydrochloride and analogue thereof is at EP0, 693, in 475B1 (CN1077566C has 1-phenyl-3-dimethylaminopropanecompounds compounds of pharmacological effect), be disclosed, this patent adopts that to take 3-bromoanisole and 1-dimethylin-2-methylpent-2-ketone be starting raw material, to after the two reaction, obtain racemization intermediate 1-dimethylin-3-(3-p-methoxy-phenyl)-2-methylpent-3-alcohol, through high performance liquid phase separator column, split and obtain chirality (2S, 3R)-1-dimethylin-3-(3-p-methoxy-phenyl)-2-methylpent-3-alcohol, then by (2S, 3R)-1-dimethylin-3-(3-p-methoxy-phenyl)-2-methylpent-3-alcohol and sulfur oxychloride effect obtain corresponding chloro-product, through eliminating, reduction reaction obtains (2R, 3R)-[3-(3-p-methoxy-phenyl)-2-methyl amyl]-dimethylamine, finally with Hydrogen bromide demethylation, obtain tapentadol hydrochloride.The drawback of this method maximum has adopted Chiral liquid chromatography method to carry out chiral separation to key intermediate exactly, and this is difficult to realize when commercial scale production, directly causes this technique can not carry out industrialization.Its reaction scheme is shown in reaction formula I:
Figure BSA00000634373000031
Reaction formula I
WO2008/012047[CN 101495445A, (1R, the preparation method of 2R)-3-(3-dimethylin-1-Ethyl-2-Methyl propyl group) phenol)] adopting 1-(3-p-methoxy-phenyl) third-1-ketone is starting raw material, through Mannich reaction, obtain 3-(dimethylin)-1-(3-p-methoxy-phenyl)-2-methyl-prop-1-ketone, then after chiral separation, obtain (S)-3-(dimethylin)-1-(3-p-methoxy-phenyl)-2-methyl-prop-1-ketone, through grignard reaction, obtain (2S, 3R)-1-dimethylin-3-(3-p-methoxy-phenyl)-2-methylpent-3-alcohol, then through elimination and hydrogenation reduction, obtain (2R, 3R)-[3-(3-p-methoxy-phenyl)-2-methyl amyl]-dimethylamine, finally by obtaining tapentadol hydrochloride after Hydrogen bromide demethylation.The drawback of this method is harsher in Grignard reaction conditions, need to definitely under anhydrous condition, carry out, simultaneously at (2R, 3R)-[3-(3-p-methoxy-phenyl)-2-methyl amyl] in-dimethylamine preparation process, need high pressure catalytic hydrogenation, in production, operator are had relatively high expectations, danger is larger, brings safely hidden danger to industrial production.Its reaction scheme is shown in reaction formula II:
Figure BSA00000634373000032
Reaction formula II
WO2008/012046[CN 101495446A, 3-[(1R, 2R)-3-(dimethylin)-1-Ethyl-2-Methyl propyl group] preparation of phenol] to adopt 1-(3-(benzyloxy) phenyl) third-1-ketone be after starting raw material and N-methyl-N-methylene radical-methane chlorination ammonium and Acetyl Chloride 98Min. effect, to obtain 3-(dimethylamino)-1-(3-(benzyloxy) phenyl)-2-methyl isophthalic acid-acetone, this compound obtains (2S)-3-(dimethylamino)-1-(3-(benzyloxy) phenyl)-2-methyl isophthalic acid-acetone after chiral separation.Through grignard reaction, obtain (2S, 3R)-1-(dimethylamino)-3-(3-(benzyloxy) phenyl)-2-methyl-3-amylalcohol again, through trifluoroacetic anhydride trifluoroacetylation again high pressure catalytic hydrogenation reduction obtain target product tapentadol hydrochloride.This method has been used industrial more unmanageable grignard reaction and high pressure catalytic hydrogenation, suitability for industrialized production poor stability equally.Its reaction scheme is shown in reaction formula III:
Figure BSA00000634373000041
Reaction formula III
CN102002065A (Preparation Method And Their Intermediate of tapentadol hydrochloride) has provided a kind of new method of preparing tapentadol hydrochloride, it is starting raw material that the method adopts 3-tertiary butyl dimethyl Si benzaldehyde, under R-Proline-Catalyzed, there is Aldol condensation reaction with propionic aldehyde, obtain (2R, 3S)-3-hydroxy-2-methyl-3-(3-tertiary butyl dimethyl Si base phenyl) propionic aldehyde, this compound and dimethylamine hydrochloride effect obtain (1S, 2S)-3-(dimethyl amido)-2-methyl isophthalic acid-(3-tertiary butyl dimethyl Si base phenyl)-1-propyl alcohol, after gained compound and Tosyl chloride effect, obtain (1S, 2S)-3-(dimethyl amido)-2-methyl isophthalic acid-(3-tertiary butyl dimethyl Si base phenyl) propyl group-4-tosylate, through grignard reaction, obtain (2R again, 3R)-3-(3-tertiary butyl dimethyl Si base phenyl)-N, N, 2-tri-methyl-amyl-1-amine, finally by trifluoroacetic acid Deprotection, obtain tapentadol hydrochloride, this reaction starting raw material 3-tertiary butyl dimethyl Si benzaldehyde does not have commercially available at present, in reaction process, adopted the harsher reaction of the conditions such as grignard reaction simultaneously, increased the difficulty of suitability for industrialized production.Its reaction scheme is shown in reaction formula IV:
Figure BSA00000634373000051
Reaction formula IV
CN 101948397A (preparation method of anodyne tapentadol hydrochloride important intermediate) has set forth the synthetic method of another tapentadol hydrochloride, the method is with 1-N, N-dimethyl-2-methyl-3-ketone is starting raw material, this raw material obtains (S)-1-N after splitting with L-DBTA, N-dimethyl-2-methyl-3-ketone, and a bromophenyl ether obtains (2S)-1-dimethylamino-3-(3-p-methoxy-phenyl)-2-methylpent-3-alcohol hydrochloride again through chloro after grignard reaction, reduction obtains (2R, 3R)-1-dimethylamino-2-methyl-3-(3-p-methoxy-phenyl)-propane, last demethylation, hcl acidifying obtains tapentadol hydrochloride.Its reaction scheme is shown in reaction formula V:
Figure BSA00000634373000052
Reaction formula V
WO2011/080736A1 (Intermediate compounds and processes for the preparation of tapentadol and related compounds) has disclosed the method for another synthetic hydrochloric acid tapentadol hydrochloride, it is starting raw material that the method has adopted 1-(3-p-methoxy-phenyl) third-1-ketone, through Huo Naer-Wordsworth-Ai Mengsi reaction, obtain (Z)-3-(3-p-methoxy-phenyl)-N with organo phosphorous compounds, N, 2-trimethylammonium penta-2-alkene acid amides, then obtain tapentadol hydrochloride after reduction, demethylation.This technique is a more novel tapentadol hydrochloride synthetic route, synthetic route is shorter, but this technique adopts a lot of harsher reaction conditionss in implementation process, for example noble metal catalysis, anhydrous and oxygen-free, very low temperature reaction, column chromatography for separation etc., this is difficult to control in commercial process, having relatively high expectations of production operation is unfavorable for the carrying out of course of industrialization very much, and these unfavorable factors have limited the use of this technique greatly.Its reaction scheme reaction formula VI:
Figure BSA00000634373000061
Reaction formula VI
WO2011/080756A1 (Processes for the preparation of 1-phenyl-3-dimethylaminopropane derivatives) has disclosed the another kind of synthetic method of tapentadol hydrochloride, the method is that the m-aubepine of employing is starting raw material, under the effect of DBU He after ethyl cyanacetate condensation, generate 2-cyano group-3-(3-methoxyl group-phenyl)-ethyl propenoate, then react with ethylmagnesium bromide and generate 2-cyano group-3-(3-methoxyl group-phenyl)-Valeric acid ethylester, this compound generates 2-cyano group-3-(3-methoxyl group-phenyl)-2-methyl-Valeric acid ethylester with methyl iodide effect again, after hydrolysis, obtain 2-cyano group-3-(3-methoxyl group-phenyl)-2-methyl-valeric acid, through high temperature decarboxylation, generate 3-(3-methoxyl group-phenyl)-2-methyl-valeronitrile again, 3-(3-methoxyl group-phenyl)-2-methyl-valeronitrile obtains 3-(3-p-methoxy-phenyl)-2-methyl amyl amine after the reduction of borine dimethyl sulphide, 3-(3-p-methoxy-phenyl)-2-methyl amyl amine generates [3-(3-p-methoxy-phenyl)-2-methyl amyl]-dimethylamine after methylating, after fractionation, obtain tapentadol hydrochloride.This reaction process has been agreed to adopt grignard reaction, has been used more expensive chemical reagent as reaction reagent, in the process that cyano reduction is become to amine, used the larger borine dimethyl sulphide of environmental hazard as reductive agent, this reductive agent is very easily burning in air, need definitely under anhydrous and oxygen-free condition, carry out, this product toxicity is larger in addition, higher to production requirement.This reaction scheme is shown in reaction formula VII:
Figure BSA00000634373000062
Reaction formula VII
WO2011/067714A1 (New processes for the preparation of tapentadol and intermediates thereof), the method is to take m-nitrobenzaldehyde as starting raw material, after Mannich reaction, obtain 3-(dimethylin)-1-(3-nitrophenyl)-2-methyl-prop-1-ketone, after splitting, L-(-)-DBTA obtains (S)-3-(dimethylin)-1-(3-nitrophenyl)-2-methyl-prop-1-ketone again, reduction obtains (S)-3-(dimethylin)-1-(3-aminophenyl)-2-methyl-prop-1-ketone, (S)-3-(dimethylin)-1-(3-aminophenyl)-2-methyl-prop-1-ketone and Grignard reagent reaction obtain (2S, 3R)-1-dimethylin-3-(3-aminophenyl)-2-methylpent-3-alcohol, by (2S, 3R)-1-dimethylin-3-(3-aminophenyl)-2-methylpent-3-alcohol after trifluoroacetylation again by obtaining (2R after Pd/C catalytic hydrogenation, 3R)-[3-(3-aminophenyl)-2-methyl amyl]-dimethylamine, finally by obtaining target product tapentadol hydrochloride after diazotization, in this operating process, used Grignard reagent, expensive acylating reagent trifluoroacetic anhydride, and employing Pd-C high pressure catalytic hydrogenation etc., these are all unfavorable for suitability for industrialized production, to actually operating, bring difficulty.This reaction scheme is shown in reaction formula VIII:
Figure BSA00000634373000071
Reaction formula VIII
Summary of the invention
In order to overcome the deficiency of above-mentioned existing tapentadol hydrochloride and analogue synthetic method thereof, the invention provides a kind of employing 1-(3-substituted-phenyl)-1-ketone compounds is the method that starting raw material is prepared tapentadol hydrochloride and analogue thereof, by enforcement of the present invention, can obviously improve yield and the quality product of tapentadol hydrochloride and analogue thereof, greatly reduced production cost, simplified production stage (multistep product directly can react for next step without refining), synthesis technique environmental protection (react the reagent using and all meet the requirement of ICH residual solvent governing principle), requirement (the reaction conditions gentleness that is more applicable to suitability for industrialized production, without specific installation).
For realizing this goal of the invention, technical scheme of the present invention is as follows:
The invention provides the synthetic method of a kind of tapentadol hydrochloride or its analogue, be characterised in that it is that employing 1-(3-substituted-phenyl)-1-ketone compounds (II) is starting raw material, after reduction, halo, nucleophilic substitution, hydrolysis, decarboxylation, amidation, reduction, fractionation and hydrochloric acid salify, obtain Compound I.
Specifically, the invention provides a kind of method of preparing Compound I, the method by Compound I I through comprising following steps prepares Compound I:
(1) Compound I I obtains compound III through reduction;
Figure BSA00000634373000081
(2) compound III obtains compound IV through halo;
Figure BSA00000634373000082
(3) compound IV obtains compound V through nucleophilic substitution;
(4) compound V obtains compound VI through hydrolysis;
Figure BSA00000634373000091
(5) compound VI obtains compound VI I through decarboxylation;
Figure BSA00000634373000092
(6) compound VI I obtains compound VI II through acidylate;
Figure BSA00000634373000093
(7) compound VI II obtains Compound I X through amination;
Figure BSA00000634373000094
(8) Compound I X obtains compounds X through reduction;
Figure BSA00000634373000101
(9) compounds X obtains Compound I through chiral separation;
Figure BSA00000634373000102
Wherein:
Described R1, R2, R3, R4 are identical or different, are selected from independently of one another hydrogen, C 1-4alkyl (preferable methyl or ethyl);
Described R is selected from hydrogen, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted alkoxyl group, halogen, nitro, replacement or unsubstituted amino, sulfur-containing group (as sulfydryl, sulfonic group, sulphonamide etc.);
Described R5 is for replacing or unsubstituted C 1～4alkyl;
Described X, Y are identical or different, are selected from independently of one another halogen atom.
Wherein, method described above, is characterized in that described step (1) is that Compound I I and reductive agent carry out reduction reaction and obtain compound III under organic solvent or alkaline aqueous solution existence.
Wherein, method described above, is characterized in that described step (2) is that compound III and halogenating agent carry out halogenating reaction and obtain compound IV under organic solvent exists; Preferably, described halogenating agent is selected from sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, tribromo oxygen phosphorus or iodination reagent etc.
Wherein, method described above, is characterized in that described step (3) is that compound IV and beta-dicarbonyl compound carry out nucleophilic substitution reaction and obtain compound V under organic solvent and catalytic condition; Preferably, described beta-dicarbonyl compound is selected from dimethyl malonate, diethyl malonate, Methylpropanedioic acid dimethyl ester, methyl-malonic ester, ethyl malonic acid dimethyl ester, ethyl malonic acid diethylester, propylmalonic acid dimethyl ester, propylmalonic acid diethyl ester, butyl malonic acid dimethyl ester and diethyl butylmalonate etc.; Preferably, described catalyzer be selected from sodium alkoxide (as sodium methylate, sodium ethylate, sodium isopropylate or sodium tert-butoxide etc.), potassium alcoholate (as potassium methylate, potassium ethylate, potassium isopropoxide or potassium tert.-butoxide etc.), metal hydride (as sodium hydride, potassium hydride KH etc.), phase-transfer catalyst (as polyethers, cyclic crown ether class, quaternary ammonium salt, tertiary amine, quaternary amine alkali or season phosphonium salt etc.) or mineral alkali (as sodium carbonate, salt of wormwood, sodium hydroxide or potassium hydroxide etc.).
Wherein, method described above, is characterized in that described step (4) is compound V under the catalytic condition of alkali or acid, is hydrolyzed reaction and obtains compound VI in the aqueous solution, preferably, described alkali or acid are selected from mineral acid or inorganic base (example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium pyrosulfate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, Sodium phosphate dibasic or dipotassium hydrogen phosphate etc.) or organic acid or organic bases (as formic acid, acetic acid, propionic acid, butyric acid, Citric Acid, tartrate, oxysuccinic acid, oxalic acid, fumaric acid, diethylamine, triethylamine, TERTIARY BUTYL AMINE, propylamine, sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide, potassium methylate, potassium ethylate, potassium isopropoxide or potassium tert.-butoxide etc.).
Wherein, method described above, it is characterized in that described step (5) be compound VI have or the existence of anhydrous or organic solvent under, under highly basic condition, heating, obtains compound VI I after decarboxylation; Preferably, described highly basic is selected from sodium hydroxide, potassium hydroxide, soda-lime (CaO), or its mixture, as soda-lime sodium hydroxide (CaO+NaOH) or soda-lime potassium hydroxide (CaO+KOH) etc.
Wherein, method described above, is characterized in that described step (6) is compound VI I under having or organic solvent-free exists, and reacts with halogenating agent and obtains compound VI II; Preferably, described halogenating agent is selected from sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, tribromo oxygen phosphorus or iodination reagent etc.
Wherein, method described above, is characterized in that described step (7) is compound VI II under water or organic solvent exist, and reacts with amination reagent and obtains Compound I X; Preferably, described amination reagent is selected from ammoniacal liquor, methylamine, dimethylamine etc.
Wherein, method described above, it is characterized in that described step (8) be Compound I X in organic solvent, under reductive agent exists, carry out reduction reaction and obtain compounds X.
Wherein, method described above, it is characterized in that described step (9) is that Compound I X is under organic solvent exists, react with chiral selectors, hcl acidifying salify again, obtain Compound I, preferably, described chiral selectors is selected from chiral organic acid compounds (as D or L MALIC ACID, Pfansteihl), D or L-type amino acids are (as 1B, L-PROLINE, D-Cys, D-phenylalanine, D-trp, D-Val etc., D or L-TARTARIC ACID), replace D or L-type tartrate (as D-(+)-to methyldiphenyl formyl tartrate, L-(-)-to methyldiphenyl formyl tartrate, D-(+)-dibenzoyl tartaric acid, L-(-)-dibenzoyl tartaric acid, D-to methoxy dibenzoyl tartrate or L-to methoxy dibenzoyl tartrate etc.), D or L-type camphorsulfonic acid and D or L-type amygdalic acid etc.
Wherein, method described above, is characterized in that wherein said organic solvent is selected from one or more in methyl alcohol, ethanol, Virahol, butanols, the trimethyl carbinol, acetone, butanone, mibk, benzene,toluene,xylene, methylene dichloride, chloroform, tetracol phenixin, ether, tetrahydrofuran (THF), dioxane, light sherwood oil, sherwood oil, methyl acetate, ethyl acetate, acetonitrile, ether, isopropyl ether, ethane, dimethyl formamide, methyl-sulphoxide etc.
Wherein, method described above, is characterized in that wherein said reductive agent is selected from hydrogen, sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, lithium aluminum hydride, amino lithium borohydride, sodium triacetoxy borohydride, three tert.-butoxy lithium aluminum hydrides, borine or borane complex etc.
Preferably, wherein, in aforesaid method, step (1) be by II and suitable reductive agent under organic solvent or alkaline aqueous solution exist, temperature of reaction is-50～50 ℃, the reaction times is 0～24 hour, carries out reduction reaction and obtains compound III.Described reductive agent is hydrogen, sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, lithium aluminum hydride, amino lithium borohydride, sodium triacetoxy borohydride, three tert.-butoxy lithium aluminum hydrides, borine and borane complex etc.; Described organic solvent is one or more in methyl alcohol, ethanol, Virahol, benzene,toluene,xylene, ether, isopropyl ether and tetrahydrofuran (THF) etc. preferably.
Preferably, wherein, in aforesaid method, step (2) be by III and suitable halogenating agent under organic solvent exists, temperature of reaction is-50～50 ℃, the reaction times is 0～24 hour, carries out halogenating reaction and obtains compound IV.Described halogenating agent is sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, tribromo oxygen phosphorus and iodination reagent etc.; Described organic solvent is one or more in benzene,toluene,xylene, methylene dichloride, chloroform, tetracol phenixin, ether, tetrahydrofuran (THF), dioxane, light sherwood oil, sherwood oil, methyl acetate, ethyl acetate, acetone, butanone, acetonitrile etc. preferably.
Preferably, wherein, in aforesaid method, step (3) be by IV and suitable beta-dicarbonyl compound under organic solvent and catalytic condition, temperature of reaction is 0～150 ℃, the reaction times is 1～72 hour, carries out nucleophilic substitution reaction and obtains compound V.Described beta-dicarbonyl compound is dimethyl malonate, diethyl malonate, Methylpropanedioic acid dimethyl ester, methyl-malonic ester, ethyl malonic acid dimethyl ester, ethyl malonic acid diethylester, propylmalonic acid dimethyl ester, propylmalonic acid diethyl ester, butyl malonic acid dimethyl ester and diethyl butylmalonate etc.; Described organic solvent is one or more in benzene,toluene,xylene, methyl alcohol, ethanol, Virahol, butanols, the trimethyl carbinol, tetrahydrofuran (THF), dioxane, dimethyl formamide and methyl-sulphoxide etc. preferably; Described catalyzer be sodium alkoxide (as sodium methylate, sodium ethylate, sodium isopropylate and sodium tert-butoxide etc.), potassium alcoholate (as potassium methylate, potassium ethylate, potassium isopropoxide and potassium tert.-butoxide etc.), metal hydride (as sodium hydride, potassium hydride KH etc.), phase-transfer catalyst (as polyethers, cyclic crown ether class, quaternary ammonium salt, tertiary amine, quaternary amine alkali and season phosphonium salt etc.) and mineral alkali (sodium carbonate, salt of wormwood, sodium hydroxide and potassium hydroxide etc.).
Preferably, wherein, in aforesaid method, step (4) be by V under suitable alkali or acid catalysis condition, temperature of reaction is 0～120 ℃, the reaction times is 0～48 hour, is hydrolyzed reaction and obtains compound VI in the aqueous solution.Described catalyzer is mineral acid, alkali and salt (example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium pyrosulfate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, Sodium phosphate dibasic and dipotassium hydrogen phosphate etc.) and organic acid, alkali and salt (formic acid, acetic acid, propionic acid, butyric acid, Citric Acid, tartrate, oxysuccinic acid, oxalic acid, fumaric acid, diethylamine, triethylamine, TERTIARY BUTYL AMINE, propylamine, sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide, potassium methylate, potassium ethylate, potassium isopropoxide and potassium tert.-butoxide etc.).
Preferably, wherein, in aforesaid method, step (5) be by VI have or solvent-free existence condition under, intense heating or heat under highly basic condition.Temperature of reaction is 0～250 ℃, and the reaction times is 0～48 hour, obtains compound VI I after decarboxylation.Described highly basic is that sodium hydroxide, potassium hydroxide, sodium salt are as soda-lime (CaO+NaOH) or sylvite or soda-lime (CaO+KOH) etc.
Preferably, wherein, in aforesaid method, step (6) be by VII have or solvent-free existence condition under, react with halogenating agent.Temperature of reaction is 0～150 ℃, and the reaction times is 0～24 hour, and compound VI I obtains acetyl halide compound VIII after by halo.Described solvent is one or more in benzene,toluene,xylene, methylene dichloride, chloroform, tetracol phenixin, ether, tetrahydrofuran (THF), dioxane, light sherwood oil, ethane, sherwood oil, methyl acetate, ethyl acetate, acetone, butanone, acetonitrile etc.Described halogenating agent is sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, tribromo oxygen phosphorus and iodination reagent etc.
Preferably, wherein, in aforesaid method, step (7) be by VIII under solvent existence condition, react with amination reagent.Temperature of reaction is-50～100 ℃, and the reaction times is 0～48 hour, and compound VI II obtains amide compound IX after by amination.Described solvent is one or more in water, dioxane, acetone, butanone, acetonitrile and tetrahydrofuran (THF) etc.
Preferably, wherein, in aforesaid method, step (8) be by IX under solvent existence condition, with reduction reagent react.Temperature of reaction is-100～50 ℃, and the reaction times is 0～24 hour, carries out reduction reaction and obtains compounds X.Described reductive agent is hydrogen, sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, lithium aluminum hydride, amino lithium borohydride, sodium triacetoxy borohydride, three tert.-butoxy lithium aluminum hydrides, borine and borane complex etc.; Described organic solvent is one or more in methyl alcohol, ethanol, Virahol, benzene,toluene,xylene, ether, isopropyl ether and tetrahydrofuran (THF) etc. preferably.
Preferably, wherein, in aforesaid method, step (9) be by IX under solvent existence condition, react with chiral selectors.Temperature of reaction is-20～100 ℃, reaction times is 0～72 hour, described chiral selectors is that chiral organic acid compounds is as D or L MALIC ACID, Pfansteihl, D or L-type amino acids are as 1B, L-PROLINE, D-Cys, D-phenylalanine, D-trp, D-Val etc., D or L-TARTARIC ACID, replace D or L-type tartrate as D-(+)-to methyldiphenyl formyl tartrate, L-(-)-to methyldiphenyl formyl tartrate, D-(+)-dibenzoyl tartaric acid, L-(-)-dibenzoyl tartaric acid, D-to methoxy dibenzoyl tartrate or L-to methoxy dibenzoyl tartrate etc., D or L-type camphorsulfonic acid and D or L-type amygdalic acid etc., described organic solvent is one or more in methyl alcohol, ethanol, Virahol, acetone, butanone, mibk, benzene,toluene,xylene, methylene dichloride, chloroform, tetracol phenixin, ether, tetrahydrofuran (THF), dioxane, light sherwood oil, sherwood oil, methyl acetate, ethyl acetate and acetonitrile etc. preferably.
As a specific embodiment of the present invention, in method described above, wherein, R1 is that ethyl, R2, R3 and R4 are that methyl, R are hydroxyl, and described Compound I is the Compound I a of following formula structure:
Figure BSA00000634373000141
Compare with the tapentadol hydrochloride of prior art and the synthetic method of similar compound thereof, tool of the present invention has the following advantages:
1. process costs of the present invention is cheap, is easy to industrialization.This technique be take 1-(3-p-methoxy-phenyl) third-1-ketone as reaction starting raw material, and this raw material is common domestic raw material, cheap and easy to get.
2. this reaction conditions is gentle, easily controls, and easy and simple to handle, separating step is few, is applicable to industrialization production requirements.
3. the end product of this reaction fractionation means are simple, avoided the fractionation means of some more complicated.Improve product yield (total recovery of tapentadol hydrochloride is more than 10%) and quality and (through raceme chemical purity of sample after twice chiral separation, be greater than 99.5% (HPLC), the production cost reducing, has met the needs of commercial scale production.
The method of synthetic hydrochloric acid tapentadol hydrochloride of the present invention or its analogue, with respect to existing tapentadol hydrochloride synthetic method, the present invention is intended to find a kind of raw material and is easy to get, safety is controlled, environmental protection and synthetic hydrochloric acid tapentadol hydrochloride novel method with low cost, enforcement by the method can obviously improve this product yield and quality product, greatly reduced production cost, safety is controlled, easy and simple to handle, the solvent adopting meets International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH) residual solvent governing principle requirement, meet environment protection, more be applicable to the requirement of suitability for industrialized production.
Embodiment
Below by embodiment, further illustrate the present invention.Described embodiment should not be understood to be the perhaps restriction of purport in the present invention.
The preparation of embodiment 1 1-(3-p-methoxy-phenyl)-propyl-1-alcohol
Under condition of ice bath, methyl alcohol 1.5L, 1-(3-p-methoxy-phenyl) third-1-ketone 700g (4.26mol) is joined in reaction flask, stir and pass into N 2when system is down to 5 ℃ of left and right, divide and add 96% sodium borohydride 201.7g (5.34mol) for 4 times, finish follow-up continuous insulation reaction 30 minutes, it is complete that TLC follows the tracks of reaction, underpressure distillation goes out solvent, reactant is poured in 2L water, be extracted with ethyl acetate, anhydrous magnesium sulfate drying, after concentrating under reduced pressure, obtain 700g 1-(3-p-methoxy-phenyl)-propyl-1-alcohol, yield 98.9%.
Molecular formula: C 10h 14o 2, molecular weight: 166.22, MS (m/z): 167.21 (M ++ H).
1HNMR(CDCl 3，400MH Z)δ：7.12(t，1H，J＝8.0Hz，Ar-H)，6.81(d，1H，J＝8.0Hz，Ar-H)，6.67(m，2H，Ar-H)，4.62(t，1H，J＝5.2Hz，CH-O)，3.75(s，3H，-OCH 3)，1.81(m，2H，CH-CH 2-CH 3)，1.01(t，3H，J＝5.8Hz，CH-CH 2-CH 3)。
The preparation of embodiment 2 1-(3-nitrophenyl)-propyl-1-alcohol
With 1-(3-p-methoxy-phenyl) third-1-ketone in 1-(3-nitrophenyl) third-1-ketone alternate embodiment 1, obtain compound 1-(3-nitrophenyl)-propyl-1-alcohol.Yield 97.1%.
Molecular formula: C 9h 11nO 3, molecular weight: 181.2, MS (m/z): 182.18 (M ++ H).
The preparation of embodiment 3 3-(1-bromopropyl) methyl-phenoxide
At N 2under protection, 3-(3-p-methoxy-phenyl)-2-amylalcohol 700g (4.21mol), methylene dichloride 2L joined in reaction flask, when ice bath is cooled to 5 ℃ of left and right, drip 1.14Kg (4.21mol) PBr 3keep temperature, finish follow-up continuation of insurance temperature stirring reaction 1h, it is complete that TLC follows the tracks of reaction, and reactant is poured in frozen water, with dichloromethane extraction, organic layer washs with sodium bicarbonate aqueous solution, then washing, anhydrous magnesium sulfate drying, after concentrating under reduced pressure, obtain 3-(1-bromopropyl) methyl-phenoxide 920g, yield 95.4%.
Molecular formula: C 10h 13brO, molecular weight: 229.11, MS (m/z): 230.10 (M ++ H).
1HNMR(CDCl 3，400MH Z)δ：7.27(t，1H，J＝8.4Hz，，Ar-H)，6.68(m，2H，Ar-H)，6.51(s，1H，Ar-H)，4.67(t，1H，J＝4.8Hz，CH-Br)，3.73(s，3H，-OCH 3)，2.11(m，2H，CH-CH 2-CH 3)，0.96(t，3H，J＝5.8Hz，CH-CH 2-CH 3)。
The preparation of embodiment 4 3-(1-chloropropyl) methyl-phenoxide
3-(3-p-methoxy-phenyl)-2-amylalcohol 50g (0.3mol), methylene dichloride 20ml joined in reaction flask, add 100ml thionyl chloride, stirring at room reaction 8h, it is complete that TLC follows the tracks of reaction, after concentrating under reduced pressure, obtain 3-(1-chloropropyl) methyl-phenoxide 38g, yield 68.4%.
The preparation of embodiment 5 3-(1-bromopropyl) oil of mirbane
According to embodiment 3 method operations, obtain 3-(1-bromopropyl) oil of mirbane.Yield 94.7%.
Molecular formula: C 9h 10nO 2, molecular weight: 244.1, MS (m/z): 245.0 (M ++ H).
Embodiment 6 2-[1-(3-p-methoxy-phenyl) propyl group] preparation of-2-methyl-malonic ester
Methyl-malonic ester 751g (4.31mol) and dry DMF 1.5L are joined in reaction flask, after stirring, be warming up to 40 ℃, add 130g (5.2mol) NaH, continue after reaction 1h, stir and drip the DMF solution of 3-(1-bromopropyl) methyl-phenoxide 900g (3.92mol), after finishing, 85 ℃ are continued stirring reaction 8 hours, and TLC follows the tracks of reaction and carries out completely, reactant being poured into water, be extracted with ethyl acetate to water layer without fluorescence, then wash organic layer 2 times, without dry, after concentrating under reduced pressure, be directly used in next step.
Embodiment 7 2-ethyl-2-[1-(3-p-methoxy-phenyl) propyl group] preparation of diethyl malonate
With the methyl-malonic ester of propylmalonic acid diethyl ester alternate embodiment 6, obtain compound 2-ethyl-2-[1-(3-p-methoxy-phenyl) propyl group] diethyl malonate, yield 62%.
Molecular formula: C 19h 28nO 5, molecular weight: 336.4, MS (m/z): 237.3 (M ++ H).
The preparation of embodiment 8 2-methyl-3-(3-p-methoxy-phenyl) valeric acids (VII)
The oily matter of embodiment 6 gained, ethanol 1L and water 1L are joined in reaction flask to the back end hydrogenation sodium oxide 200g that stirs, heating reflux reaction, TLC follows the tracks of reaction, and to keep pH be 14, and decompression steams ethanol, be extracted with ethyl acetate 2 times, separate organic layer.Water layer extracts by sour condition pH value to 2～3, ethyl acetate, separates organic layer, and anhydrous magnesium sulfate drying obtains yellow oil after concentrating under reduced pressure.Yellow oil is joined in three-necked flask, and 150 ℃ of oil bath reflux 5h, pour in aqueous sodium hydroxide solution, and making pH is alkalescence, is extracted with ethyl acetate insolubles.Water layer is adjusted pH to 3 with hydrochloric acid, ethyl acetate extraction, and dry, decompression steams solvent, obtains yellow liquid and is 2-methyl-3-(3-p-methoxy-phenyl) valeric acid 566g, yield 65%.
Molecular formula: C 13h 18o 3, molecular weight: 222.28, MS (m/z): 223.39 (M ++ H).
1HNMR(CDCl 3，400MH Z)：11.8(brs，1H，-COOH)，7.18(t，1H，J＝8.0Hz，Ar-H)，6.70(m，2H，Ar-H)，6.55(s，1H，Ar-H)，3.75(s，3H，-OCH 3)，3.09(q，1H，J＝12.8Hz，CH-Ar)，2.91(m，1H，COOH-CH-CH 3)，1.69(m，2H，CH-CH 2-CH 3)，0.81(d，3H，J＝6.0Hz，COOH-CH-CH 3)，0.64(t，3H，J＝12.8Hz，CH-CH 2-CH 3). 13C-NMR(CDCl 3，100MHz)δ：176.0，160.1，139.6，127.3，123.1，116.3，113.1，60.3，56.8，55.8，44.5，26.5，14.3，11.2。
The preparation of embodiment 9 2-methyl-3-(3-nitrophenyl) valeric acid
According to embodiment 6,8 method operations, can obtain 2-methyl-3-(3-nitrophenyl) valeric acid.Yield 58.9%.
Molecular formula: C 12h 15nO 4, molecular weight: 237.2, MS (m/z): 238.3 (M ++ H).
The preparation of embodiment 10 3-(3-p-methoxy-phenyl)-2-methylpent acyl chlorides
2-methyl-3-(3-p-methoxy-phenyl) valeric acid 550g (2.47mol) is joined in three-necked flask, add sulfur oxychloride 500ml, back flow reaction 4h, TLC detection reaction is substantially complete.Decompression steams sulfur oxychloride, obtains 3-(3-p-methoxy-phenyl)-2-methylpent acyl chlorides, is directly used in next step.
The preparation of embodiment 11 3-(3-p-methoxy-phenyl)-2-methyl-dimethyl-penten acid amides
506g (3.71mol) dimethylamine agueous solution (33%) is joined in three-necked flask, when ice bath is cooled to 5 ℃ of left and right, drip embodiment 10 gained 3-(3-p-methoxy-phenyl)-2-methylpent acyl chlorides, drip 30%NaOH solution simultaneously, make pH=12～14 of system.The temperature of maintenance system is no more than 20 ℃, and after dropwising, room temperature continues reaction 2h.Be extracted with ethyl acetate 2 times, merge organic phase, and with 10% salt acid elution 2 times, anhydrous magnesium sulfate drying.Decompression and solvent recovery, obtains the faint yellow oily matter of 495g and is 3-(3-p-methoxy-phenyl)-2-methyl-dimethyl-penten acid amides, yield 80.4%.
Molecular formula: C 15h 23nO 2, molecular weight: 249.4, MS (m/z): 250.3 (M ++ H).
1HNMR(CDCl 3，400MH Z)δ：7.13(t，1H，J＝8.0Hz，Ar-H)，6.72(m，2H，Ar-H)，6.62(s，1H，Ar-H)，3.75(s，3H，-OCH 3)，3.46(m，1H，CH-Ar)，3.16(m，1H，CH-CH 3)，2.97(s，6H，CH 2-N(CH 3) 2)，1.66(m，2H，CH-CH 2-CH 3)，1.37(d，3H，J＝5.6Hz，CH-CH 3)，0.91(t，3H，J＝10.4Hz，CH-CH 2-CH 3).
Embodiment 12 N, the preparation of N-diethyl-2-methyl-3-(3-p-methoxy-phenyl) valeramide
With the dimethylamine of diethylamine alternate embodiment 11, operation can obtain compound N, N-diethyl-2-methyl-3-(3-p-methoxy-phenyl) valeramide, yield 75% in accordance with the law.
Molecular formula: C 17h 27nO 2, molecular weight: 277.4, MS (m/z): 278.3 (M ++ H).
The preparation of embodiment 13 3-(3-nitrophenyl)-2-methyl-dimethyl-penten acid amides
According to embodiment 11 method operations, can obtain 3-(3-nitrophenyl)-2-methyl-dimethyl-penten acid amides.Yield 77.5%.
Molecular formula: C 14h 20n 2o 3, molecular weight: 264.3, MS (m/z): 265.2 (M ++ H).
The preparation of embodiment 14 [3-(3-p-methoxy-phenyl)-2-methyl amyl]-dimethyl amine
Anhydrous diethyl ether 2L is joined in four-hole boiling flask, and nitrogen protection, adds drying tube, prolong.Cryosel is bathed and is made interior temperature lower than 0 ℃, and gradation adds lithium aluminum hydride 102g (2.58mol), obtains the suspension liquid of lithium aluminum hydride.Slowly drip the diethyl ether solution of 495g (1.98mol) 3-(3-p-methoxy-phenyl)-2-methyl-dimethyl-penten acid amides, after dropwising, reflux 1h.Under cryosel bath condition, slowly drip and the equimolar water of lithium aluminum hydride, equimolar 15%NaOH, then add the water of 3 times of amounts.After stable, suction filtration, ethyl acetate extraction 2 times, water washing 1 time, dry.Decompression and solvent recovery, obtains weak yellow liquid [3-(3-p-methoxy-phenyl)-2-methyl amyl]-dimethyl amine 360g, yield 77%.
Molecular formula: C 15h 25nO, molecular weight: 235.4, MS (m/z): 236.2 (M ++ H).
1HNMR(CDCl 3，400MH Z)：7.24(t，1H，J＝8.0Hz，Ar-H)，7.11(m，2H，Ar-H)，6.76(s，1H，Ar-H)，3.73(s，3H，-OCH 3)，3.17(q，1H，J＝12.0Hz，CH-Ar)，2.79(s，6H，CH 2-N(CH 3) 2)，2.65(d，2H，J＝6.8Hz，CH 2-N(CH 3) 2)，2.33(t，1H，J＝4.8Hz，CH-CH 3)，1.74(m，2H，CH 2-CH 3)，0.98(d，?3H，J＝6.0Hz，CH-CH 3)，0.69(t，3H，J＝5.8Hz，CH 2-CH 3)。
The preparation of embodiment 15 3-(3-dimethylin-1-Ethyl-2-Methyl-propyl group)-aniline
According to embodiment 14 method operations, can obtain 3-(3-dimethylin-1-Ethyl-2-Methyl-propyl group)-aniline, yield 62%.
Embodiment 16 3-[3-(dimethylin)-1-Ethyl-2-Methyl propyl group] preparation of phenol
The sulfuric acid that adds 200ml 40% in 2L reaction flask, ice bath is cooled to 0 ℃.Slowly 87g (0.395mol) 3-(3-dimethylin-1-Ethyl-2-Methyl-propyl group)-aniline is joined in reaction flask, interior temperature is no more than 5 ℃.Sodium Nitrite 32.7g (0.474mol) is dissolved in 80ml water, is slowly added drop-wise in reaction flask.Keep temperature to be no more than 5 ℃.Continue reaction 30min.The sulfuric acid that adds 100ml 20% in another reaction flask, is warming up to 85 ℃, upper step is made to diazonium salt and be slowly added drop-wise in reaction flask.After dropwising, after insulation reaction 30min, be cooled to 5 ℃, the sodium hydroxide with 15% regulates the pH to 10 of reaction solution.Ethyl acetate extraction 2 times, merges organic layer, and dry, decompression and solvent recovery, obtains yellow oil 62g, is 3-[3-(dimethylin)-1-Ethyl-2-Methyl propyl group] phenol, yield 71%.
Molecular formula: C 14h 23nO, molecular weight: 221.34, MS (m/z): 222.30 (M ++ H).
Embodiment 17 3-[3-(dimethylin)-1-Ethyl-2-Methyl propyl group] preparation of phenol
[3-(3-p-methoxy-phenyl)-2-methyl amyl]-dimethyl amine 360g (1.53mol) is joined in reaction flask, add 45% hydroiodic acid HI 1.75L (6.15mol), reflux 5h.TLC detection reaction process.After reaction substantially completely, be cooled to room temperature, be poured in alkali lye, regulating pH is 10, and ethyl acetate extraction 3 times, washes 2 times.Decompression and solvent recovery after dry, obtains weak yellow liquid 3-[3-(dimethylin)-1-Ethyl-2-Methyl propyl group] phenol 279g, yield 82%.
Molecular formula: C 14h 23nO, molecular weight: 221.34, MS (m/z): 222.21 (M ++ H).
1H-NMR(CDCl 3，400MHz)δ：7.22(t，1H，J＝8.0Hz，Ar-H)，6.75(m，2H，Ar-H)，6.65(d，J＝8.0Hz，1H，Ar-H)，2.71(m，2H，-CH 2)，2.62(s，6H，N(CH 3) 2)，2.20(m，1H，-CH-CH 3)，2.04(m，1H，-CH-)，1.73，1.42(m，2H，-CH 2CH 3)，0.96(d，3H，J＝5.6Hz，-CHCH 3)，0.54(t，3H，J＝6.0Hz，-CH 2CH 3)。
Embodiment 18 3-[3-(dimethylin)-1-Ethyl-2-Methyl propyl group] preparation of phenol
With 45%HI in 48%HBr alternate embodiment 18, can obtain compound N, N-diethyl-2-methyl-3-(3-p-methoxy-phenyl) valeramide, yield 79%.
The preparation of embodiment 19 tapentadol hydrochlorides
L-(-)-dibenzoyl tartaric acid (a water thing) 376g (1.0mol), 1.5L acetone are joined in reaction flask, after stirring and dissolving, add 3-[3-(dimethylin)-1-Ethyl-2-Methyl propyl group] phenol 221g (1.0mol), after 60 ℃ of reaction 1h, naturally cool to room temperature, adularescent solid is separated out, suction filtration, and filter cake dissolves with 15%NaOH.Ethyl acetate extraction 2 times, organic layer is dry, after decompression and solvent recovery, again uses L-(-)-dibenzoyl tartaric acid (a water thing) to split, suction filtration, filter cake dissolves with 15%NaOH.Ethyl acetate extraction 2 times, organic layer is dry, decompression and solvent recovery.After hcl acidifying salify, obtain tapentadol hydrochloride 30.7g, yield 11.9%, m.p:201～202 ℃.HPLC：99.56％，ee％＜0.5％。
Molecular formula: C 14h 23nO.HCl, molecular weight: 257.8, MS (m/z): 222.18 (M +-HCl).
Ultimate analysis: theoretical value: C:65.23%, H:9.38%, N:5.43%; Measured value: C:65.13%, H:9.32%, N:5.38%.
1HNMR(D 2O，400MH Z)δ：7.15(t，1H，J＝7.6Hz，Ar-H)，6.99(m，2H，Ar-H)，6.54(s，1H，Ar-H)，3.08(q，1H，J＝12.8Hz，CH-Ar)，2.77(m，7H，CH 2-N(CH 3) 2)，2.37(t，1H，J＝5.2Hz，CH-CH 2-N(CH 3) 2)，2.11(d，1H，J＝6.8Hz，CH 2-N(CH 3) 2)，1.61(m，2H，CH 2-CH 3)，0.76(d，3H，J＝6.4Hz，CH-CH 3)，0.64(t，3H，J＝6.4Hz，CH 2-CH 3).
13C-NMR(D 2O，100MH Z)δ：155.5，143.9，129.7，129.4，121.2，120.9，115.7，113.4，62.8，50.1，44.9，41.5，33.4，33.3，24.6，13.8，11.6。

Claims (20)

1. a method of preparing Compound I, is characterized in that the method through comprising following steps prepares by Compound I I: (1) Compound I I obtains compound III through reduction;
(2) compound III obtains compounds Ⅳ through halo;
Figure FSB0000119759150000012
(3) compounds Ⅳ obtains compound V through nucleophilic substitution;
Figure FSB0000119759150000013
(4) compound V obtains compound VI through hydrolysis;
Figure FSB0000119759150000014
(5) compound VI obtains compound VII through decarboxylation;
Figure FSB0000119759150000021
(6) compound VII obtains compound VIII through acidylate;
(7) compound VIII obtains compound IX through amination;
(8) compound IX obtains compounds X through reduction;
Figure FSB0000119759150000024
(9) compounds X makes Compound I after chiral separation and hydrochloric acid salify;
Figure FSB0000119759150000025
Wherein:
Described R1, R2, R3, R4 are identical or different, are selected from independently of one another hydrogen, C 1～4alkyl;
Described R is selected from hydrogen, hydroxyl, replacement or unsubstituted alkyl, replacement or unsubstituted alkoxyl group, halogen, nitro, replacement or unsubstituted amino, sulfur-containing group, described sulfur-containing group selected from mercapto, sulfonic group, sulphonamide;
Described R5 is for replacing or unsubstituted C 1～4alkyl;
Described X, Y are identical or different, are selected from independently of one another halogen atom.
2. method according to claim 1, is characterized in that described step (1) is that Compound I I and reductive agent carry out reduction reaction and obtain compound III under organic solvent or alkaline aqueous solution existence.
3. method according to claim 1, is characterized in that described step (2) is that compound III and halogenating agent carry out halogenating reaction and obtain compounds Ⅳ under organic solvent exists.
4. method according to claim 3, wherein said halogenating agent is selected from sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, tribromo oxygen phosphorus or iodination reagent.
5. method according to claim 1, is characterized in that described step (3) is that compounds Ⅳ and beta-dicarbonyl compound carry out nucleophilic substitution reaction and obtain compound V under organic solvent and catalytic condition.
6. method according to claim 5, wherein said beta-dicarbonyl compound is selected from dimethyl malonate, diethyl malonate, Methylpropanedioic acid dimethyl ester, methyl-malonic ester, ethyl malonic acid dimethyl ester, ethyl malonic acid diethylester, propylmalonic acid dimethyl ester, propylmalonic acid diethyl ester, butyl malonic acid dimethyl ester and diethyl butylmalonate.
7. method according to claim 5, wherein said catalyzer is selected from sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide, potassium methylate, potassium ethylate, potassium isopropoxide, potassium tert.-butoxide, sodium hydride, potassium hydride KH, polyethers, cyclic crown ether class, quaternary ammonium salt, tertiary amine, quaternary amine alkali, season phosphonium salt, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide.
8. method according to claim 1, it is characterized in that described step (4) be compound V under the catalytic condition of alkali or acid, in the aqueous solution, be hydrolyzed reaction and obtain compound VI.
9. method according to claim 8, wherein said alkali or acid are selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium pyrosulfate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, Sodium phosphate dibasic, dipotassium hydrogen phosphate, formic acid, acetic acid, propionic acid, butyric acid, Citric Acid, tartrate, oxysuccinic acid, oxalic acid, fumaric acid, diethylamine, triethylamine, TERTIARY BUTYL AMINE, propylamine, sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide, potassium methylate, potassium ethylate, potassium isopropoxide or potassium tert.-butoxide.
10. method according to claim 1, it is characterized in that described step (5) be compound VI under the existence of the optional water existing or the optional organic solvent existing, under highly basic condition, heating, obtains compound VII after decarboxylation.
11. methods according to claim 10, wherein said highly basic is selected from sodium hydroxide, potassium hydroxide, soda-lime or its mixture.
12. methods according to claim 1, is characterized in that described step (6) is compound VII under the optional organic solvent existing exists, and reacts with halogenating agent and obtains compound VIII.
13. methods according to claim 12, wherein said halogenating agent is selected from sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, tribromo oxygen phosphorus or iodination reagent.
14. methods according to claim 1, is characterized in that described step (7) is compound VIII under water or organic solvent exist, and reacts with amination reagent and obtains compound IX.
15. methods according to claim 14, wherein said amination reagent is selected from ammoniacal liquor, methylamine, dimethylamine.
16. methods according to claim 1, it is characterized in that described step (8) be compound IX in organic solvent, under reductive agent exists, carry out reduction reaction and obtain compounds X.
17. methods according to claim 1, it is characterized in that described step (9) is that Compound I X is under organic solvent exists, react with chiral selectors, hcl acidifying salify again, obtain Compound I, wherein said chiral selectors is selected from D or L MALIC ACID, Pfansteihl, 1B, L-PROLINE, D-Cys, D-phenylalanine, D-trp, D-Val, D or L-TARTARIC ACID, D-(+)-to methyldiphenyl formyl tartrate, L-(-)-to methyldiphenyl formyl tartrate, D-(+)-dibenzoyl tartaric acid, L-(-)-dibenzoyl tartaric acid, D-is to methoxy dibenzoyl tartrate, L-is to methoxy dibenzoyl tartrate, D or L-type camphorsulfonic acid, D or L-type amygdalic acid.
18. according to the method described in claim 2,3,5,10,12,14,16 or 17, it is characterized in that wherein said organic solvent is selected from one or more in methyl alcohol, ethanol, Virahol, butanols, the trimethyl carbinol, acetone, butanone, mibk, benzene,toluene,xylene, methylene dichloride, chloroform, tetracol phenixin, tetrahydrofuran (THF), dioxane, sherwood oil, methyl acetate, ethyl acetate, acetonitrile, ether, isopropyl ether, dimethyl formamide, methyl-sulphoxide.
19. according to the method described in claim 2 or 16, it is characterized in that wherein said reductive agent is selected from hydrogen, sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, lithium aluminum hydride, amino lithium borohydride, sodium triacetoxy borohydride, three tert.-butoxy lithium aluminum hydrides, borine or borane complex.
20. according to the method described in claim 1-17 any one, it is characterized in that wherein said R1 is ethyl, and R2, R3 and R4 are respectively methyl, and R is hydroxyl, and described Compound I is the Compound I a of following formula structure, is tapentadol hydrochloride:
Figure FSB0000119759150000041
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