CN104803861B - Method for synthesizing tapentadol hydrochloride - Google Patents
Method for synthesizing tapentadol hydrochloride Download PDFInfo
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Abstract
The invention discloses a method for synthesizing tapentadol hydrochloride. The method comprises a reaction route shown in the specification. In the reaction route, R1 is one of halogens, -OH, -OR4, -NO2, -NH2, -NR5R6, -SH and -SR7. A required chiral isomer is directly obtained through a reaction under chiral catalysis, so the method has the advantages of avoiding of problems of a large amount of wastes and environmental protection due to chiral splitting, short route, simple operation, easy industrialization, high raw material utilization rate, great improvement of the yield, cost reduction, meeting of requirements of industrial production of tapentadol hydrochloride, and significant progress.
Description
Technical field
The present invention relates to a kind of method of synthetic hydrochloric acid tapentadol hydrochloride, belong to technical field of medicine synthesis.
Background technology
Tapentadol hydrochloride（Tapentadol Hydrochloride）Chemical name be (1R, 2R) -3- (3- dimethyl
Amino -1- Ethyl-2-Methyls propyl group) phenol hydrochloride, its chemical structural formula is as follows：
Tapentadol hydrochloride is to act on central nervous system by a kind of novelty of German Grunenthal companies research and development
Oral pain alleviating medicine.It in Initial Public Offering in 2008, for alleviating moderate and severe acute pain.It has opiate receptor
Exciting and norepinephrine reabsorption suppresses double action mechanism.
Reported according to pertinent literature, the synthetic route of tapentadol hydrochloride mainly has following several at present：
Route 1（See European patent document EP0693475）：
The route is with 1- (dimethylamino) -2- methyl-propione and Meta Bromo Anisole as initiation material, through grignard reaction
Obtain 4 chiral isomers, need chiral post separation to obtain the intermediate of desired single configuration, then through thionyl chloride chloro,
Zinc borohydride reduction, demethylation, the tapentadol hydrochloride that single configuration is obtained into salt, synthesis step are more long, operate cumbersome, receipts
Rate is low, and the especially separation of chiral isomer needs to use chiral column, it is difficult to realize industrialized production.
Route 2（See international patent documents WO2008016047, Chinese patent literature CN101495445 and European patent text
Offer EP2046724）：
The route is initiation material using meta-methoxy propiophenone, anti-with the Mannich of formaldehyde using dimethylamine hydrochloride
Should, 3- dimethylaminos -1- (3- methoxyphenyls) -2- methyl acetone intermediates of racemization are obtained, recycle chiral resolving agent to tear open
Get desired S-3- dimethylaminos -1- (3- methoxyphenyls) -2- methyl acetone intermediates, then by grignard reaction, disappear
Except, catalytic hydrogenation, methionine removing several steps such as methyl obtain final product tapentadol hydrochloride.Although the route can greatly improve institute
The ratio of the isomers wanted, but still there is route more long, high cost, easily produce many unexpected accessory substances and generation
The defect problems such as many discarded objects, it is also difficult to industrial applications.
Route 3（See Chinese patent literature CN102002065A）：
The route induces meta substituted benzaldehyde to be condensed with the asymmetric Aldol of propionic aldehyde using R- proline, and a step obtains 2
Individual chiral centre, grignard reaction after hydroxysulfonamide is replaced, and last deprotection base obtains desired product.Although the route
It is short, two chiral centres can be formed with a step, but raw material is relatively difficult to obtain, and grignard reaction requirement is high, is also unfavorable for industrialization.
Route 4（See international patent documents WO2011/080736A1）：
The route is raw material with alkyl phosphoric acid fat using meta-methoxy propiophenone, uses Horner-Wadsworth-
Emmons reacts, and is only just synthesized with four-step reaction and obtains target product.Although the route synthetic method is relatively new, route is short,
Implementation process requirement is harsher, is operated using precious metal catalyst, anhydrous and oxygen-free, ultralow temperature, column chromatography for separation etc., it is also not possible to use
In large-scale industrial production.
Route 5（See international patent documents WO2011/080756A1）：
The route is initiation material using m-methoxybenzaldehyde and cyan-acetic ester, is reacted by Knoevenagel
Generation 2- cyano group -3- m-methoxyphenyl ethyl acrylates, reuse the addition of ethyl RMgBr, methylate, decarboxylation, cyano group also
The 7 steps reaction such as former, amino pair methylates, dephenolize methyl ether, chiral resolution obtains final product.The route is more long, and reduction cyano group makes
Borane dimethylsulf iotade toxicity is big and inflammable, and operation is cumbersome, should not be used in a large amount of productions.
Route 6（See Chinese patent literature CN102557851）：
The route is reduced with the propiophenone that meta replaces, and the secondary alcohol for obtaining is replaced with halogen, then directly uses methyl-prop two
Diethyl phthalate nucleophilic displacement of fluorine, product hydrolysis decarboxylation obtains 2- methyl -3- phenylpentanoic acids, then passes through into acid amides, reduction, protection group and take off
Except and chiral resolution obtain final product.Although the route is simple to operate, low raw-material cost, synthetic route is long, produces
Journey can produce more discarded object, be also not suitable for industrialization production requirements.
Route 7（See Chinese patent literature CN102617501A）：
Or
The route after first forming acid amides with Chiral Amine, then carries out chirality with cinnamic acid or 2- penetenoic acids as initiation material
The benzene of the asymmetric Macheal additions of induction, upper ethyl or meta substitution, then after methyl on carbonyl alpha-position, take off Chiral Amine
Base, changes dimethylamine into, after taking off phenolic hydroxyl group protection, obtains tapentadol hydrochloride.Although this route raw material is cheap and easily-available, operate numerous
It is trivial.
Route 8（See Chinese patent literature CN102936205）：
The route is to carry out hydroxy halogeno after being reduced with 1- (dimethylamino) -2- methyl-propione, then by gained halogen
Coupling reaction is carried out under nickel catalysis for thing and meta-methoxy borane reagent, silica reagent or tin reagent, then demethylation obtains racemization
Tapentadol hydrochloride, last chiral resolution obtains optically active final product.The route cost is very high, and especially tin reagent has stronger
Toxicity, and fractionation carries out in final step, produces more discarded object, there are problems that environmental pollution, therefore should not also industrialize should
With.
Route 9（See american documentation literature US20130150622A1, international patent documents WO2013090161）：
The route is reset using the asymmetric Claisen of cinnamyl alcohol propylene ether, generates 2- methyl -3- phenyl -4- pentenals,
N is obtained by reduction amination, N, 2- trimethyl -3- phenyl -4- amylene ammonia, last hydrogenating reduction double bond are simultaneously sloughed protection group and obtained again
To desired product.Although the highway route design is ingenious, route is more long, and multistep has used the catalyst of costliness, and reaction condition
It is required that it is harsh, cannot also be applied to large-scale industrial production.
Route 10（See international patent documents WO2012089177A1 and WO2012089181）：
The route cinnamyl alcohol propionic ester is initiation material, and generation 2- methyl -3- phenyl -4- penta is reset under the catalysis of alkali
Olefin(e) acid, then obtain desired product by steps such as diformazan amination, reduction, deprotections.The route need to be anti-under low temperature, anhydrous condition
Should, commercial Application is more difficult, and it is larger to split loss.
It is visible in sum, although the synthetic method document report of tapentadol hydrochloride is more, but presence is unfavorable for work
The various defect problems that industry metaplasia is produced：Some routes are oversize, and what is had has used expensive or poisonous chemical reagent, some reaction behaviour
Make cumbersome, what is had is higher to consersion unit requirement；So that being occupied using the cost of the industrially prepared tapentadol hydrochloride of prior art high
Under not, it is impossible to meet large-scale production requirement.
The content of the invention
The present invention is in view of the above-mentioned problems existing in the prior art and defect, it is desirable to provide one kind directly obtains institute by reaction
The method of the synthetic hydrochloric acid tapentadol hydrochloride of the chiral isomer wanted, to avoid producing a large amount of discarded objects because of chiral resolution, realizes
Yield, reduces cost are improved, shortened reaction scheme, simplified the industrialization production requirements such as operation.
For achieving the above object, the technical solution adopted by the present invention is as follows：
A kind of method of synthetic hydrochloric acid tapentadol hydrochloride, including following reaction scheme：
Wherein：
Reaction a is that the propiophenone for replacing the meta shown in formula IV is raw material, is existed with paraformaldehyde and dimethylamine hydrochloride
The lower reaction of catalysis induction of chiral catalyst, obtains (the S) -3- dimethylaminos -2- methyl isophthalic acids-meta substituted benzene shown in formula III
Base -1- acetone；
Reaction b is to make (S) -3- dimethylaminos -2- methyl isophthalic acids-m-phenylcnc -1- acetone and the ethyl shown in formula III
Phosphate or Ethyltriphenylphosphonium brimide or ethyltriphenyl phosphonium chloride phosphorus react in the presence of alkali, obtain (S) shown in formula II-
N, N, 2- trimethyl -3- m-phenylcnc -3- amylene ammonia；
Reaction c is to make (S)-N, N, the 2- trimethyl -3- m-phenylcnc -3- amylene ammonia shown in formula II in transition metal
The lower hydrogenation reduction of catalysis, obtains the tapentadol hydrochloride shown in formula I；
R in formula1It is halogen ,-OH ,-OR4、-NO2、-NH2、-NR5R6、-SH、-SR7In one kind.
Preferably, described R4It is alkyl, cycloalkyl, alkylidene phenyl, alkylidene naphthyl, oxinane, acyl
One kind in base or silylation；Described R5And R6Separately or concurrently for H, benzyl, benzyloxymethyl, 2,4- dimethoxy-benzyls,
2,6- dimethoxy-benzyls, 4- methoxy-benzyls, adjacent nitro benzyl, 4- nitrobenzyls, 2- chlorobenzyls, 4- chlorobenzyls, 2,4- bis-
Chlorobenzyl, 2,6- dichloro benzyls, formoxyl, methoxyl group acyl group, acetyl group, ethoxyacyl, trifluoroacetyl group, chloracetyl,
Tribromo-acetyl base, propiono, cyclopropyl formoxyl, positive bytyry, isobutyryl, positive valeryl, isovaleryl, positive caproyl,
Isocaproyl, positive heptanoyl group, different heptanoyl group, benzoyl, benzyloxy acyl group, dibenzoyl, benzenesulfonyl, to methylbenzene sulphur
Acyl group, the tert-butyl group, pi-allyl；Described R7 is benzyl, benzyloxymethyl, 2,4- dimethoxy-benzyls, 2,6- dimethoxy benzyls
Base, 4- methoxy-benzyls, adjacent nitro benzyl, 4- nitrobenzyls, 2- chlorobenzyls, 4- chlorobenzyls, 2,4- dichloro benzyls, 2,6- dichloros
Benzyl, 2,4,6- trimethoxy benzyls, 2,4,6- trimethyl benzyls, benzhydryl, trityl, the tert-butyl group, methoxy,
One kind in benzyloxymethyl, acetyl group, benzoyl, trifluoroacetyl group.
Used as further preferred scheme, the alkyl is selected from methyl, ethyl, n-propyl, isopropyl, Cvclopropvlmethvl, alkene
It is propyl group, propargyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, isohesyl, n-heptyl, different
One kind in heptyl；The cycloalkyl is selected from the one kind in cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl；The Asia
Alkyl phenyl is selected from benzyl, benzyloxymethyl, 2,6- dimethyl benzyls, 4- methoxy-benzyls, 2,4- dimethoxy-benzyls, 2,6-
Dimethoxy-benzyl, adjacent nitro benzyl, 4- nitrobenzyls, 2- chlorobenzyls, 4- chlorobenzyls, 2,4- dichloro benzyls, 2,6- benzyl dichlorides
One kind in base；The acyl group is selected from formoxyl, methoxyl group acyl group, acetyl group, ethoxyacyl, trifluoroacetyl group, chloracetyl
Base, tribromo-acetyl base, propiono, cyclopropyl formoxyl, positive bytyry, isobutyryl, positive valeryl, isovaleryl, positive hexanoyl
Base, isocaproyl, positive heptanoyl group, different heptanoyl group, benzoyl, benzenesulfonyl, to the one kind in Methyl benzenesulfonyl base；The silicon
Alkyl is selected from the one kind in trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or triisopropylsilyl.
Used as a kind of preferred scheme, methods described includes following reaction scheme：
It is therein：
R is H, 4- methoxyl group, 2,4- dimethoxys, 2,6- dimethoxys, 2,6- dimethyl, 2- nitros, 4- nitros, 2-
One kind in chlorine, 4- chlorine, 2,4- dichloros, 2,6- dichloros；
The content of reaction a, reaction b and reaction c is same as above.
Used as a kind of preferred scheme, methods described includes following reaction scheme：
It is therein：
The content of reaction a and reaction b is same as above；
Reaction c1 is to make (S)-N, N, the 2- trimethyls -3- m-phenylcncs -3- amylenes ammonia and connection boric acid shown in formula II
Pinacol ester first reacts generation boric acid ester compound, then the phenolic hydroxyl group chemical combination under the oxidation of sodium perborate shown in production I '
Thing；
Reaction c2 is to make the phenolic hydroxyl-compounds shown in formula I ' in transition metal-catalyzed lower hydrogenation reduction, obtains formula I
Shown tapentadol hydrochloride.
Used as further preferred scheme, reaction c1 includes following operation：Halides shown in formula II are dissolved in suitable solvent
In, it is subsequently adding connection boric acid pinacol ester, catalyst and alkali, heating response；When detection reaction terminates, add molten equivalent to original
The water and sodium perborate of agent 1/4, are stirred at room temperature to reaction and terminate；PH value in regulation reaction system is to 9~10.
As still more preferably scheme, the suitable solvent be tetrahydrofuran, 2- methyltetrahydrofurans, toluene, 1,
One kind in 4- dioxane, DMF, DMSO, methyl tertiary butyl ether(MTBE), isopropyl ether, it is optimal with Isosorbide-5-Nitrae-dioxane.
Used as still more preferably scheme, described catalyst is palladium catalyst, may be selected from Pd [(PPh3)]4、Pd
[(PPh3)2]Cl2、Pd(dba)2、Pd2(dba)3、Pd(dppf)Cl2、Pd(dppp)Cl2、Pd[(CH3CN)2]Cl2、Pd
[(PCy3)2]Cl2Or Pd [P (t-Bu)3]2, with Pd [(PPh3)]4Or Pd (dppf) Cl2Most preferably.
As still more preferably scheme, described alkali be selected from triethylamine, diisopropyl ethyl amine, potassium carbonate, sodium carbonate,
At least one in potassium acetate, sodium acetate, cesium carbonate, potassium phosphate, sodium phosphate, it is optimal with potassium acetate, sodium acetate.
Used as still more preferably scheme, described sodium perborate is selected from a water sodium perborate, three water sodium perborate or four
Water sodium perborate.
Used as a kind of preferred scheme, methods described includes following reaction scheme：
It is therein：
The content of reaction a and reaction b is same as above；
Reaction c3 is to make (S)-N, N, the 2- trimethyls -3- m-phenylcncs -3- amylenes ammonia shown in formula II in transition gold
Amino-compound shown in category catalysis lower hydrogenation reduction, production I "；
Reaction c4 is to make formula I " shown in amino-compound in the presence of natrium nitrosum first diazotising, then hydrolyze again and obtain
Tapentadol hydrochloride shown in formula I.
As further preferred scheme, the chiral catalyst described in reaction a is chiral amino acid, chiral alkaloid or its
He contains the organic molecule of chiral centre, for example：Proline and the like, tartaric acid and its derivative, quinine and its similar
Thing etc..
Used as still more preferably scheme, described chiral catalyst is L-PROLINE or L-TARTARIC ACID.
Used as further preferred scheme, reaction a solvent for use is water, methyl alcohol, ethanol, normal propyl alcohol, isopropanol, tetrahydrochysene furan
Mutter, 2- methyltetrahydrofurans, acetonitrile, toluene, dichloromethane, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, diformazan it is sub-
At least one in sulfone.
Used as further preferred scheme, the general structure of the ethyl phosphonic acid ester described in reaction b is：Formula
In R2 and R3 be at the same time or separately the one kind in fatty alkyl, phenyl, naphthyl, benzyl, pi-allyl.
Used as still more preferably scheme, described fatty alkyl is selected from methyl, ethyl, n-propyl, isopropyl, positive fourth
One kind in base, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, isohesyl, n-heptyl, different heptyl；Institute
The benzyl stated be selected from phenylbenzyl, benzyloxymethyl, 2,6- dimethyl benzyls, 4- methoxy-benzyls, 2,4- dimethoxy-benzyls,
2,6- dimethoxy-benzyls, adjacent nitro benzyl, 4- nitrobenzyls, 2- chlorobenzyls, 4- chlorobenzyls, 2,4- dichloro benzyls, 2,6- bis-
One kind in chlorobenzyl.
Used as further preferred scheme, reaction b solvent for use is selected from tetrahydrofuran, 2- methyltetrahydrofurans, ether, methyl
At least one in tertbutyl ether, isopropyl ether, toluene, n-hexane, normal heptane.
As further preferred scheme, the alkali described in reaction b be selected from sodium methoxide, caustic alcohol, sodium hydride, sodium tert-butoxide,
At least one in potassium tert-butoxide, n-BuLi.
As further preferred scheme, the compound of formula III and ethyl phosphonic acid ester or Ethyltriphenylphosphonium brimide in reaction b
Or the mol ratio between ethyltriphenyl phosphonium chloride phosphorus and alkali three is 1:(1~2):(1~2), with 1:(1.4~1.6):(1.4~
1.6) it is optimal.
Used as further preferred scheme, the reaction temperature for reacting b is 0~100 DEG C, optimal with 40~70 DEG C.
Used as further preferred scheme, the transition-metal catalyst described in reaction c is selected from palladium, palladium on carbon, nickel, platinum, carbon
Carry one kind that platinum, carbon are carried during ruthenium, carbon carry rhodium.
Used as further preferred scheme, the solvent used by reaction c is selected from water, methyl alcohol, ethanol, normal propyl alcohol, isopropanol, tertiary fourth
At least one in alcohol, tetrahydrofuran, 2- methyltetrahydrofurans, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.
Relative to prior art, it is different that the present invention directly obtains desired chirality by way of chiral catalysis, by reaction
Structure body, it is to avoid a large amount of discarded objects and environmental issue produced by chiral resolution, not only whole route is short, and operation letter
It is single, it is easy to industrialize, and raw material availability is high, substantially increases yield, reduces cost, meet industrialized production hydrochloric acid he
The requirement more than him is sprayed, with conspicuousness progress.
Specific embodiment
With reference to embodiment, the present invention is described in further detail and completely.
Embodiment 1：(S) -3- dimethylaminos -2- methyl isophthalic acids-m-methoxyphenyl -1- acetone（The compound of formula III）Synthesis
By 164.2g meta-methoxy propiophenones（The compound of formula IV）, 244.6g dimethylamine hydrochlorides, 90g paraformaldehydes and
9.9g mass fractions are that 37% aqueous hydrochloric acid solution is dissolved in 200mL ethanol, add 34.5g L-PROLINEs, mixed reactant
Backflow is heated under nitrogen protection, back flow reaction is cooled to room temperature after 16 hours, first decompression evaporates most of solvent, remaining
Thing is dissolved in water, then enriching ammonia spirit adjusts pH value to alkalescence, and dichloromethane is extracted 3 times, and after merging organic layer, weak aqua ammonia is washed
Wash 1 time, anhydrous Na2SO4Dry, filter, be spin-dried for obtaining pale yellow oil：(S) -3- dimethylaminos -2- methyl isophthalic acids-meta-methoxy
Phenyl -1- acetone（172.6g, molar yield is that 78%, HPLC purity is 98%, ee=95%）；It is directly used in next step reaction.MS-
ESI(m/z)：222.1(M+H)+.
Embodiment 2：(S) -3- dimethylaminos -2- methyl isophthalic acids-benzyloxy-phenyl -1- acetone（The compound of formula III）Synthesis
By benzyloxy propiophenone between 240.3g（The compound of formula IV）, 244.6g dimethylamine hydrochlorides, 90g paraformaldehydes and
9.9g mass fractions are that 37% aqueous hydrochloric acid solution is dissolved in 200mL ethanol, add 34.5g L-PROLINEs, mixed reactant
Backflow is heated under nitrogen protection, back flow reaction is cooled to room temperature after 16 hours, first decompression evaporates most of solvent, remaining
Thing is dissolved in water, then enriching ammonia spirit adjusts pH value to alkalescence, and dichloromethane is extracted 3 times, and after merging organic layer, weak aqua ammonia is washed
Wash 1 time, anhydrous Na2SO4Dry, filter, be spin-dried for obtaining pale yellow oil：(S) -3- dimethylaminos -2- methyl isophthalic acids-benzyloxy
Phenyl -1- acetone（252g, molar yield is that 85%, HPLC purity is 98%, ee=97%）；It is directly used in next step reaction.MS-
ESI(m/z)：298.2(M+H)+.
Embodiment 3：(S) -3- dimethylaminos -2- methyl isophthalic acids-m-bromophenyl -1- acetone（The compound of formula III）Synthesis
By brom-acetophenone between 213.1g（The compound of formula IV）, 244.6g dimethylamine hydrochlorides, 90g paraformaldehydes and 9.9g matter
Measure the aqueous hydrochloric acid solution that fraction is 37% to be dissolved in 200mL ethanol, add 34.5g L-PROLINEs；Mixed reactant is in nitrogen
Backflow is heated under protection, back flow reaction is cooled to room temperature after 16 hours, first decompression evaporates most of solvent, and residue adds water
Dissolving, then enriching ammonia spirit adjusts pH value to alkalescence, and dichloromethane is extracted 3 times, and after merging organic layer, weak aqua ammonia is washed 1 time,
Anhydrous Na2SO4Dry, filter, be spin-dried for obtaining pale yellow oil：(S) -3- dimethylaminos -2- methyl isophthalic acids-m-bromophenyl -1- acetone
（229.7g, molar yield is that 85%, HPLC purity is 95%, ee=96%）；It is directly used in next step reaction.MS-ESI(m/z)：
270.0,272.0 (M+H)+.
Embodiment 4：(S) -3- dimethylaminos -2- methyl isophthalic acids-m-nitro base -1- acetone（The compound of formula III）Synthesis
By 179.17g m-nitro acetone（The compound of formula IV）, 244.6g dimethylamine hydrochlorides, 90g paraformaldehydes and
9.9g mass fractions are that 37% aqueous hydrochloric acid solution is dissolved in ethanol 200mL, add 34.5g L-PROLINEs；Mixed reactant
Backflow is heated under nitrogen protection, back flow reaction is cooled to room temperature after 16 hours, first decompression evaporates most of solvent, remaining
Thing is dissolved in water, then enriching ammonia spirit adjusts pH value to alkalescence, and dichloromethane is extracted 3 times, and after merging organic layer, weak aqua ammonia is washed
Wash 1 time, anhydrous Na2SO4Dry, filter, be spin-dried for obtaining pale yellow oil：(S) -3- dimethylaminos -2- methyl isophthalic acids-m-nitro
Base -1- acetone（160.6g, molar yield is that 68%, HPLC purity is 93%, ee=97%）；It is directly used in next step reaction.MS-
ESI(m/z)：237.2(M+H)+.
Embodiment 5：(S) -3- dimethylaminos -2- methyl isophthalic acids-[3- (4- methoxy-benzyls) phenyl] -1- acetone（Formula III is changed
Compound）Synthesis
By 179.17g3- (4- methoxybenzyls epoxide) propiophenone（The compound of formula IV）, 244.6g dimethylamine hydrochlorides, 90g
Paraformaldehyde and the aqueous hydrochloric acid solution that 9.9g mass fractions are 37% are dissolved in 200mL ethanol, add 34.5g L-PROLINEs；
Mixed reactant is heated to backflow under nitrogen protection, and back flow reaction is cooled to room temperature after 16 hours, and first decompression evaporates major part
Solvent, residue is dissolved in water, then enriching ammonia spirit adjusts pH value to alkalescence, and dichloromethane is extracted 3 times, merges organic layer
Afterwards, weak aqua ammonia is washed 1 time, anhydrous Na2SO4Dry, filter, be spin-dried for obtaining pale yellow oil：(S) -3- dimethylaminos -2- methyl -
1- [3- (4- methoxybenzyls epoxide) phenyl] -1- acetone（288.1g, molar yield is that 88%, HPLC purity is 99%, ee=99%）；
It is directly used in next step reaction.MS-ESI(m/z)：328.2(M+H)+.
Embodiment 6：(R) -3- (3- benzyloxy-phenyls)-N, the amyl- 3- alkene -1- amine of N, 2- trimethyl（The compound of formula II）Conjunction
Into
Under room temperature condition, 278.4g ethyltriphenylphosphonium bromides are suspended in 500mL toluene, stirring is lower to add 72.1g
Sodium tert-butoxide, continues to stir 1 hour, and reaction solution is in orange red, and ice bath is cooled to less than 20 DEG C, and the compound of formula III is slowly added dropwise：
(S) -3- dimethylaminos -2- methyl isophthalic acids-benzyloxy-phenyl -1- acetone（148.6g,0.5mol）Toluene solution（300mL）,
After completion of dropping, it is warming up to 60 DEG C and reacts 3 hours, is slowly down to room temperature；Reaction solution is washed twice with water, every time 200mL, then
With 200mL saturated common salt water washings, dry, filtering；To the ethyl acetate solution that HCl is added in the solution being filtrated to get, there is white
Color solid is separated out, and after stirring and crystallizing 30min, filtering, solid is washed with 50mL ethyl acetate, is vacuum dried, and is obtained：(R)-3-
(3- benzyloxy-phenyls)-N, the amyl- 3- alkene -1- amine hydrochlorates of N, 2- trimethyl（148.7g, molar yield is that 86%, HPLC purity is
99%）；It is directly used in next step reaction.MS-ESI(m/z)：310.2(M+H)+.
Embodiment 7：(R) -3- m-bromophenyls-N, the amyl- 3- alkene -1- amine of N, 2- trimethyl（The compound of formula II）Synthesis
Under room temperature condition, 278.4g ethyltriphenylphosphonium bromides are suspended in 500mL toluene, stirring is lower to add 72.1g
Sodium tert-butoxide continues to stir 1 hour, and reaction solution is in orange red, and ice bath is cooled to less than 20 DEG C, and the compound of formula III is slowly added dropwise：
(S) -3- dimethylaminos -2- methyl isophthalic acids-m-bromophenyl -1- acetone（135.1g,0.5mol）Toluene solution（300mL）, it is added dropwise
After finishing, it is warming up to 60 DEG C and reacts 3 hours, is slowly down to room temperature；Reaction solution is washed twice with water, and 200mL is used every time, then use
200mL saturated common salt water washings, dry, filtering；To the ethyl acetate solution that HCl is added in the solution being filtrated to get, there is white
Solid is separated out, and after stirring and crystallizing 30min, filtering, solid is washed with 50mL ethyl acetate, is vacuum dried, and is obtained：(R) bromine between -3-
The amyl- 3- alkene -1- amine hydrochlorates of phenyl-N, N, 2- trimethyl（114.3g, molar yield is that 81%, HPLC purity is 98%）；Directly
For next step reaction.MS-ESI(m/z)：282.0,284.0(M+H)+.
Embodiment 8：(R) the amyl- 3- alkene -1- amine of -3- m-nitros base-N, N, 2- trimethyls（The compound of formula II）Synthesis
Under room temperature condition, 278.4g ethyltriphenylphosphonium bromides are suspended in 500mL toluene, stirring is lower to add 72.1g
Sodium tert-butoxide continues to stir 1 hour, and reaction solution is in orange red, and ice bath is cooled to less than 20 DEG C, and the compound of formula III is slowly added dropwise：
(S) -3- dimethylaminos -2- methyl isophthalic acids-m-nitro base -1- acetone（118.1g,0.5mol）Toluene solution（300mL）, drop
Add after finishing, be warming up to 60 DEG C and react 3 hours, be slowly down to room temperature；Reaction solution is washed twice with water, and 200mL is used every time, then
With 200mL saturated common salt water washings, dry, filtering；To the ethyl acetate solution that HCl is added in the solution being filtrated to get, there is white
Color solid is separated out, and after stirring and crystallizing 30min, filtering, solid is washed with 50mL ethyl acetate, is vacuum dried, and is obtained：(R) between -3-
The amyl- 3- alkene -1- amine hydrochlorates of nitrobenzophenone-N, N, 2- trimethyl（95.5g, molar yield is that 77%, HPLC purity is 93%）；Directly
Connect for next step reaction.MS-ESI(m/z)：249.1(M+H)+.
Embodiment 9：(R) -3- [3- (4- methoxybenzyls epoxide) phenyl]-N, the amyl- 3- alkene -1- amine of N, 2- trimethyl（Formula II
Compound）Synthesis
Under room temperature condition, 278.4g ethyltriphenylphosphonium bromides are suspended in 500mL toluene, stirring is lower to add 72.1g
Sodium tert-butoxide continues to stir 1 hour, and reaction solution is in orange red, and ice bath is cooled to less than 20 DEG C, and the compound of formula III is slowly added dropwise：
(S) -3- dimethylaminos -2- methyl isophthalic acids-[3- (4- methoxybenzyls epoxide) phenyl] -1- acetone（163.7g,0.5mol）Toluene
Solution（300mL）, after completion of dropping, it is warming up to 60 DEG C and reacts 3 hours, slowly it is down to room temperature；Reaction solution is washed twice with water, often
It is secondary to use 200mL, then with 200mL saturated common salt water washings, dry, filtering；To the acetic acid that HCl is added in the solution being filtrated to get
Ethyl ester solution, has white solid to separate out, and after stirring and crystallizing 30min, filtering, solid is washed with 50mL ethyl acetate, is vacuum dried,
Obtain：(R) -3- [3- (4- methoxybenzyls epoxide) phenyl]-N, the amyl- 3- alkene -1- amine hydrochlorates of N, 2- trimethyl（170.7g, rubs
Your yield is that 91%, HPLC purity is 99%）；It is directly used in next step reaction.MS-ESI(m/z)：340.2(M+H)+.
Embodiment 10：Tapentadol hydrochloride（Type I compound）Synthesis
By the compound of 6.9g formulas II：(R) -3- (3- benzyloxy-phenyls)-N, the amyl- 3- alkene -1- amine of N, 2- trimethyl is dissolved in
In 20mL methyl alcohol, after adding the Pd/C that 350mg palladium contents are 10%, hydrogen to replace 3 times, it is placed in and is stirred overnight at room temperature；Use diatom
Soil filtering, removes Pd/C solids, is washed with 5mL methyl alcohol, and filtrate decompression is evaporated, and obtains off-white powder 5.1g；This solid acetic acid
Ethyl ester is recrystallized, and obtains final product white solid product tapentadol hydrochloride（4.2g, molar yield is 82%, ee=100%）；MS-ESI(m/
z)：222.1(M+H)+.
Embodiment 11：Tapentadol hydrochloride（Type I compound）Synthesis
By the compound of 7.5g formulas II：(R) -3- [3- (4- methoxybenzyls epoxide) phenyl]-N, the amyl- 3- alkene of N, 2- trimethyl -
1- amine is dissolved in 20mL methyl alcohol, after adding the Pd/C that 350mg palladium contents are 10%, hydrogen to replace 3 times, is placed in stirred at room temperature
Night；Filtered with diatomite, remove Pd/C solids, washed with 5mL methyl alcohol, filtrate decompression is evaporated, and obtains off-white powder 5.0g；This consolidates
Body re-crystallizing in ethyl acetate, obtains final product white solid product tapentadol hydrochloride（4.1g, molar yield is 80%, ee=100%）；
MS-ESI(m/z)：222.1(M+H)+.
Embodiment 12：(R) hydroxy phenyl-N between -3-, the synthesis of the amyl- 3- alkene -1- amine of N, 2- trimethyl（The compound of formula I '）
Synthesis
By the compound of formula II：(R) -3- m-bromophenyls-N, the amyl- 3- alkene -1- amine of N, 2- trimethyl（5.6g,20mmol）, connection
Boric acid pinacol ester（5.6g, 22mmol）、Pd(PPh3)4(1.16g, 1mmol), acetic anhydride potassium（0.39g,40mmol）It is dissolved in
1,4- dioxane（20mL）In, 80 DEG C of reactions are warming up under nitrogen protection overnight, it is cooled to room temperature；Add water（5mL）、
NaBO3·3H2O (6.8g, 50mmol), stirs 8 hours at room temperature；Insoluble matter is filtered to remove, filtrate adds water（100mL）, plus NaOH
The aqueous solution adjusts pH value to 9-10, ethyl acetate extraction（30mL*3）, merge organic layer, dry, filtering；Organic layer instills HCl
Ethyl acetate solution, has white solid to separate out, filtering, obtains：(R) hydroxy phenyl-N between -3-, the amyl- 3- alkene -1- of N, 2- trimethyl
Amine hydrochlorate（3.33g, molar yield is that 65%, HPLC purity is 92%）；MS-ESI(m/z)：220.1(M+H)+.
Embodiment 13：Tapentadol hydrochloride（Type I compound）Synthesis
By the compound of 3.33g formulas I '：(R) hydroxy phenyl-N between -3-, the amyl- 3- alkene -1- amine hydrochlorates of N, 2- trimethyl are dissolved in
In 15mL methyl alcohol, it is 10%Pd/C to add 150mg palladium contents, after hydrogen replaces 3 times, is placed in and is stirred overnight at room temperature；Use diatomite
Filtering, removes Pd/C solids, is washed with 5mL methyl alcohol, and filtrate decompression is evaporated, and obtains off-white powder 3.20g；This solid acetic acid second
Ester is recrystallized, and obtains final product white solid product tapentadol hydrochloride（2.70g, molar yield is 81%, ee=100%）；MS-ESI(m/
z)：222.1(M+H)+.
Embodiment 14：(1R, 2R) -3- (3- dimethylamino -1- Ethyl-2-Methyls propyl group) anilinechloride（Formula I " is changed
Compound）Synthesis
By the compound of 5.70g formulas II：(R) the amyl- 3- alkene -1- amine of -3- m-nitros base-N, N, 2- trimethyls is dissolved in 20mL first
In alcohol, after adding the Pd/C that 350mg palladium contents are 10%, hydrogen to replace 3 times, it is placed in and is stirred overnight at room temperature；Use diatomite mistake
Filter, removes Pd/C solids, is washed with 5mL methyl alcohol, and filtrate decompression is evaporated, and obtains off-white powder 4.72g；This solid ethyl acetate
Recrystallization, obtains white solid product：(1R, 2R) -3- (3- dimethylamino -1- Ethyl-2-Methyls propyl group) anilinechloride
（3.78g, molar yield is 73.6%, ee=100%）；MS-ESI(m/z)：221.2(M+H)+.
Embodiment 15：Tapentadol hydrochloride（Type I compound）Synthesis
By 20mL mass fractions for 30-35% aqueous sulfuric acid add 100mL flasks in, ice-water bath is cooled to 0~5 DEG C,
It is subsequently adding 3.78g formulas I " compound：(1R, 2R) -3- (3- dimethylamino -1- Ethyl-2-Methyls propyl group) anilinechloride,
Again by the NaNO of 5mL0.304g/mL2The aqueous solution is slowly instilled；Drop finished insulated and stirred after 1 hour, obtained diazol reaction solution；
The aqueous sulfuric acid that 20mL mass fractions are 10~15% is added in another round-bottomed flask, 110 DEG C is heated to, by foregoing diazonium
Reactant salt liquid is slowly added into, and control foam should not be overflowed, and addition is finished, and in 100 DEG C of insulation reaction 15min, is subsequently cooled to room
Temperature；NaOH solution is added to adjust pH value to 10~11, ethyl acetate is extracted 3 times, and 30mL is used every time；Collected organic layer is dried
Afterwards, filter, add the ethyl acetate solution of HCl, produce a large amount of white solids；Filtering, he sprays to obtain final product white solid product hydrochloric acid
He is more（2.85g, molar yield is 75%, ee=100%）；MS-ESI(m/z)：222.1(M+H)+.
Finally be necessary described herein be：Above example is served only for making further in detail technical scheme
Ground explanation, it is impossible to be interpreted as limiting the scope of the invention, those skilled in the art's the above of the invention
Some the nonessential modifications and adaptations made belong to protection scope of the present invention.
Claims (11)
1. a kind of method of synthetic hydrochloric acid tapentadol hydrochloride, including following reaction scheme：
Wherein：
Step b is to make (S) -3- dimethylaminos -2- methyl isophthalic acids-m-phenylcnc -1- acetone and the ethyl phosphonic acid shown in formula III
Ester or Ethyltriphenylphosphonium brimide or ethyltriphenyl phosphonium chloride phosphorus react in the presence of alkali, obtain (S)-N, the N shown in formula II,
2- trimethyl -3- m-phenylcnc -3- amylene ammonia；
Step c is to make (S)-N, N, the 2- trimethyl -3- m-phenylcnc -3- amylene ammonia shown in formula II transition metal-catalyzed
Lower hydrogenation reduction, obtains the tapentadol hydrochloride shown in formula I；It is characterized in that：
Step a is the propiophenone and paraformaldehyde and dimethylamine hydrochloride for replacing the meta shown in formula IV in L-PROLINE or L-
The lower reaction of catalysis induction of tartaric acid, directly obtains (the S) -3- dimethylaminos -2- methyl isophthalic acids-meta substituted benzene shown in formula III
Base -1- acetone；
R in formula1It is halogen ,-OH ,-OR4、-NH2In one kind, described R4Selected from methyl, ethyl, n-propyl, isopropyl, ring
Hydroxypropyl methyl, pi-allyl, propargyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, dissident
Base, n-heptyl, different heptyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, benzyl, benzyloxymethyl, 2,6- diformazans
Base benzyl, 4- methoxy-benzyls, 2,4- dimethoxy-benzyls, 2,6- dimethoxy-benzyls, adjacent nitro benzyl, 4- nitrobenzyls,
2- chlorobenzyls, 4- chlorobenzyls, 2,4- dichloro benzyls, 2,6- dichloro benzyls, formoxyl, methoxyl group acyl group, acetyl group, ethyoxyl acyl
Base, trifluoroacetyl group, chloracetyl, tribromo-acetyl base, propiono, cyclopropyl formoxyl, positive bytyry, isobutyryl, positive penta
Acyl group, isovaleryl, positive caproyl, isocaproyl, positive heptanoyl group, different heptanoyl group, benzoyl, benzenesulfonyl, to methylbenzene
One kind in sulfonyl, trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or triisopropylsilyl.
2. the method for claim 1, it is characterised in that methods described includes following reaction scheme：
It is therein：
R is H, 4- methoxyl group, 2,4- dimethoxys, 2,6- dimethoxys, 2,6- dimethyl, 2- nitros, 4- nitros, 2- chlorine, 4-
One kind in chlorine, 2,4- dichloros, 2,6- dichloros；The content of step a, step b and step c is with described in claim 1.
3. the method for claim 1, it is characterised in that methods described includes following reaction scheme：
It is therein：
The content of step a and step b is with described in claim 1；
Step c1 be make (S)-N, N, 2- trimethyls -3- m-phenylcncs -3- amylenes ammonia shown in formula II and connection boric acid frequency that
Alcohol ester first reacts generation boric acid ester compound, then the phenolic hydroxyl-compounds under the oxidation of sodium perborate shown in production I '；
Step c2 is to make the phenolic hydroxyl-compounds shown in formula I ' in transition metal-catalyzed lower hydrogenation reduction, is obtained shown in formula I
Tapentadol hydrochloride.
4. method as claimed in claim 3, it is characterised in that step c1 includes following operation：Halides shown in formula II are molten
In suitable solvent, connection boric acid pinacol ester, catalyst and alkali, heating response are subsequently adding；When detection reaction terminates, then add
Enter the water and sodium perborate equivalent to former solvent 1/4, be stirred at room temperature to reaction and terminate；PH value in regulation reaction system to 9~
10。
5. method as claimed in claim 4, it is characterised in that：The suitable solvent is tetrahydrofuran, 2- methyl tetrahydrochysene furans
Mutter, the one kind in toluene, 1,4- dioxane, DMF, DMSO, methyl tertiary butyl ether(MTBE), isopropyl ether；Described catalyst is urged for palladium
Agent；Described alkali is selected from triethylamine, diisopropyl ethyl amine, potassium carbonate, sodium carbonate, potassium acetate, sodium acetate, cesium carbonate, phosphorus
At least one in sour potassium, sodium phosphate；Described sodium perborate is selected from a water sodium perborate, three water sodium perborate or four water boron high
Sour sodium.
6. the method for claim 1, it is characterised in that methods described includes following reaction scheme：
It is therein：
The content of step a and step b is with described in claim 1；
Step c3 is (S)-N, N, the 2- trimethyl -3- m-phenylcnc -3- amylene ammonia shown in formula II is urged in transition metal
Amino-compound shown in hydrogenation reduction under changing, production I "；
Step c4 is to make formula I " shown in amino-compound in the presence of natrium nitrosum first diazotising, the formula of obtaining I is then hydrolyzed again
Shown tapentadol hydrochloride.
7. the method for claim 1, it is characterised in that：Step a solvent for use is water, methyl alcohol, ethanol, normal propyl alcohol, different
Propyl alcohol, tetrahydrofuran, 2- methyltetrahydrofurans, acetonitrile, toluene, dichloromethane, N,N-dimethylformamide, N, N- dimethyl second
At least one in acid amides, dimethyl sulfoxide.
8. the method for claim 1, it is characterised in that：The general structure of the ethyl phosphonic acid ester described in step b is：R2 and R3 in formula are selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, uncle at the same time or separately
Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohesyl, n-heptyl, different heptyl, phenylbenzyl, benzyloxymethyl, 2,
6- dimethyl benzyls, 2,4- dimethyl benzyls, 4- methoxy-benzyls, adjacent nitro benzyl, 4- nitrobenzyls, 2- chlorobenzyls, 4- chlorine
One kind in benzyl, 2,4- dichloro benzyls, 2,6- dichloro benzyls.
9. the method for claim 1, it is characterised in that：Step b solvent for use is selected from tetrahydrofuran, 2- methyl tetrahydrochysene furans
Mutter, at least one in ether, methyl tertiary butyl ether(MTBE), isopropyl ether, toluene, n-hexane, normal heptane；Alkali choosing described in step b
At least one from sodium methoxide, caustic alcohol, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, n-BuLi.
10. the method for claim 1, it is characterised in that：Transition-metal catalyst described in step c is selected from palladium, carbon
Carry one kind that palladium, nickel, platinum, pallium-on-carbon, carbon are carried during ruthenium, carbon carry rhodium.
11. the method for claim 1, it is characterised in that：Solvent used by step c is selected from water, methyl alcohol, ethanol, positive third
In alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran, 2- methyltetrahydrofurans, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide
At least one.
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