CN104803861A - Method for synthesizing tapentadol hydrochloride - Google Patents
Method for synthesizing tapentadol hydrochloride Download PDFInfo
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- CN104803861A CN104803861A CN201410038975.3A CN201410038975A CN104803861A CN 104803861 A CN104803861 A CN 104803861A CN 201410038975 A CN201410038975 A CN 201410038975A CN 104803861 A CN104803861 A CN 104803861A
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- 0 CCC(c1cccc(*)c1)=O Chemical compound CCC(c1cccc(*)c1)=O 0.000 description 3
- HZHARSIEQVMHOB-LLVKDONJSA-N CC[C@H](CCN(C)C)c1cccc(O)c1 Chemical compound CC[C@H](CCN(C)C)c1cccc(O)c1 HZHARSIEQVMHOB-LLVKDONJSA-N 0.000 description 1
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
The chemical name of tapentadol hydrochloride (Tapentadol Hydrochloride) is (1R, 2R)-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) phenol hydrochloride, and its chemical structural formula is as follows:
Tapentadol hydrochloride is the oral pain alleviating medicine acting on central nervous system of a kind of novelty researched and developed by German Grunenthal company.It was in Initial Public Offering in 2008, for alleviating moderate and severe acute pain.It has opiate receptor excitement and norepinephrine heavily absorbs suppression double action mechanism.
According to pertinent literature report, the synthetic route of tapentadol hydrochloride mainly contains following several at present:
Route 1(is shown in European patent document EP0693475):
This route is for starting raw material with 1-(dimethylin)-2-methyl-propione and Meta Bromo Anisole, 4 chiral isomers are obtained through grignard reaction, chiral post is needed to be separated the intermediate obtaining desired single configuration, the tapentadol hydrochloride of single configuration is obtained again through sulfur oxychloride chloro, zinc borohydride reduction, demethylation, salify, synthesis step is longer, and operate more loaded down with trivial details, yield is low, especially the separation of chiral isomer needs, with chiral column, to be difficult to realize suitability for industrialized production.
Route 2(is shown in international patent documents WO2008016047, Chinese patent literature CN101495445 and European patent document EP2046724):
This route uses meta-methoxy Propiophenone to be starting raw material, the Mannich of dimethylamine hydrochloride and formaldehyde is utilized to react, obtain 3-dimethylamino-1-(3-the p-methoxy-phenyl)-2-methylacetone intermediate of racemization, recycling chiral resolving agent splits and obtains desired S-3-dimethylamino-1-(3-p-methoxy-phenyl)-2-methylacetone intermediate, then removes several steps such as methyl obtain final product tapentadol hydrochloride through grignard reaction, elimination, shortening, methionine(Met).Although this route can improve the ratio of desired isomer greatly, but still have that route is longer, cost is high, a lot of beyond thought by product of easy generation and produce the defect problems such as a lot of wastes, be also difficult to industrial applications.
Route 3(is shown in Chinese patent literature CN102002065A):
This route uses the asymmetric Aldol condensation of position substituted benzaldehyde and propionic aldehyde between the induction of R-proline(Pro), and a step obtains 2 chiral centres, and replaced by grignard reaction after hydroxysulfonamide, last deprotection base obtains wanted product.Although this route is short, a step can form two chiral centres, raw material is comparatively difficult to obtain, and grignard reaction requires high, is also unfavorable for industrialization.
Route 4(is shown in international patent documents WO2011/080736A1):
This route uses meta-methoxy Propiophenone and alkylphosphonic acid carboxylic acid fat to be raw material, uses Horner-Wadsworth-Emmons reaction, only just synthesizes with four-step reaction and obtains target product.Although this route synthetic method is more novel, route is short, and implementation process requires harsher, uses the operations such as precious metal catalyst, anhydrous and oxygen-free, very low temperature, column chromatography for separation, also can not be used for large-scale industrial production.
Route 5(is shown in international patent documents WO2011/080756A1):
This route uses NSC 43794 and ethyl cyanacetate to be starting raw material, generate 2-cyano group-3-m-methoxyphenyl ethyl propenoate by Knoevenagel reaction, re-use the addition of ethyl Grignard reagent, methylate, decarboxylation, cyano reduction, aminoly twoly to methylate, 7 steps such as dephenolize methyl ether, chiral separation are obtained by reacting final product.This route is longer, and the borane dimethylsulf iotade toxicity that reduction cyano group uses is large and inflammable, and operation is loaded down with trivial details, should not be used for a large amount of production.
Route 6(is shown in Chinese patent literature CN102557851):
The Propiophenone reduction that this route replaces with a position; the secondary alcohol halogen substiuted obtained; then directly use methyl-malonic ester nucleophilic substitution, product hydrolysis decarboxylation obtains 2-methyl-3-phenylpentanoic acid, then pass through into acid amides, reduction, protecting group removes and chiral separation obtains final product.Although this route is simple to operate, low raw-material cost, synthetic route is long, and production process can produce more waste, is also not suitable for industrialization production requirements.
Route 7(is shown in Chinese patent literature CN102617501A):
or
This route with styracin or 2-pentenoic acid for starting raw material; after first forming acid amides with Chiral Amine; carry out the asymmetric Macheal addition of chiral induction again; the benzene that upper ethyl or a position replace; after methyl, take off chiral amino, change dimethylamine on carbonyl alpha-position again; after taking off phenolic hydroxyl group protection, obtain tapentadol hydrochloride.Although this route raw material is cheaply easy to get, complex operation.
Route 8(is shown in Chinese patent literature CN102936205):
This route is after being reduced with 1-(dimethylamino)-2-methyl-propione, carry out hydroxy halogeno, again gained halides and meta-methoxy borane reagent, silica reagent or tin reagent are carried out linked reaction under nickel catalysis, then demethylation obtains the tapentadol hydrochloride of racemization, and last chiral separation obtains optically active final product.This route cost is very high, and especially tin reagent has stronger toxicity, and splits an in the end step and carry out, and produces more waste, there is environmental pollution problem, therefore also unsuitable industrial applications.
Route 9(is shown in american documentation literature US20130150622A1, international patent documents WO2013090161):
This route utilizes the asymmetric Claisen of styryl carbinol propylene ether to reset, and generates 2-methyl-3-phenyl-4-pentenals, then obtains N through reduction amination, N, 2-trimethylammonium-3-phenyl-4-amylene ammonia, and last hydrogenating reduction double bond is also sloughed protecting group and obtained wanted product.Although this highway route design is ingenious, route is longer, and multistep employs expensive catalyzer, and reaction conditions requires harsh, also cannot be applicable to large-scale commercial production.
Route 10(is shown in international patent documents WO2012089177A1 and WO2012089181):
This route styryl carbinol propionic ester is starting raw material, resets and generates 2-methyl-3-phenyl-4-pentenoic acid, then obtain wanted product through steps such as diformazan amination, reduction, deprotections under the catalysis of alkali.This route need react under low temperature, anhydrous condition, and industrial application is more difficult, and it is larger to split loss.
Visible in sum, although the synthetic method bibliographical information of tapentadol hydrochloride is more, all there are the various defect problems being unfavorable for suitability for industrialized production: the route had is oversize, what have employs expensive or poisonous chemical reagent, some operations are loaded down with trivial details, and requiring conversion unit of having is higher; So that adopt the cost of prior art industry preparation tapentadol hydrochloride to remain high, large-scale production requirement can not be met.
Summary of the invention
The present invention is directed to the problems referred to above and the defect of prior art existence, aim to provide a kind of method directly being obtained the synthetic hydrochloric acid tapentadol hydrochloride of desired chiral isomer by reaction, to avoid producing a large amount of waste because of chiral separation, industrialization production requirements such as realizing improving yield, reduce costs, shorten reaction scheme, simplify the operation.
For achieving the above object, the technical solution used in the present invention is as follows:
A method for synthetic hydrochloric acid tapentadol hydrochloride, comprises following reaction scheme:
Wherein:
The Propiophenone that between reaction a makes shown in formula IV, position replaces is raw material, react under the catalysis of chiral catalyst is induced with paraformaldehyde and dimethylamine hydrochloride, obtain (the S)-3-dimethylamino-2-methyl isophthalic acid-m-phenylcnc-1-acetone shown in formula III;
Reaction b makes (the S)-3-dimethylamino-2-methyl isophthalic acid-m-phenylcnc-1-acetone shown in formula III and ethyl phosphonic acid ester or Ethyltriphenylphosphonium brimide or ethyltriphenyl phosphonium chloride phosphorus react under the effect of alkali, obtain (the S)-N shown in formula II, N, 2-trimethylammonium-3-m-phenylcnc-3-amylene ammonia;
Reaction c makes (S)-N, N, 2-trimethylammonium-3-m-phenylcnc-3-amylene ammonia shown in formula II at transition metal-catalyzed lower hydrogenation reduction, obtains the tapentadol hydrochloride shown in formula I;
R in formula
1for halogen ,-OH ,-OR
4,-NO
2,-NH
2,-NR
5r
6,-SH ,-SR
7in one.
Preferably, described R
4for the one in alkyl, cycloalkyl, alkylidene group phenyl, alkylidene group naphthyl, tetrahydropyrans, acyl group or silylation, described R
5and R
6respectively or be H simultaneously, benzyl, benzyloxymethyl, 2, 4-dimethoxy-benzyl, 2, 6-dimethoxy-benzyl, 4-methoxy-benzyl, adjacent nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2, 4-dichloro benzyl, 2, 6-dichloro benzyl, formyl radical, methoxyl group acyl group, ethanoyl, ethoxyacyl, trifluoroacetyl group, chloracetyl, tribromo-acetyl base, propionyl, cyclopropyl formyl radical, positive butyryl radicals, isobutyryl, positive pentanoyl, isovaleryl, positive caproyl, isocaproyl, positive oenanthyl, different oenanthyl, benzoyl, benzyloxy acyl group, dibenzoyl, benzenesulfonyl, to Methyl benzenesulfonyl base, the tertiary butyl, allyl group, described R7 is benzyl, benzyloxymethyl, 2, 4-dimethoxy-benzyl, 2, 6-dimethoxy-benzyl, 4-methoxy-benzyl, adjacent nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2, 4-dichloro benzyl, 2, 6-dichloro benzyl, 2,4,6-trimethoxy benzyls, 2, one in 4,6-trimethyl benzyl, diphenyl-methyl, trityl, the tertiary butyl, methoxymethyl, benzyloxymethyl, ethanoyl, benzoyl, trifluoroacetyl group.
As further preferred version, described alkyl is selected from the one in methyl, ethyl, n-propyl, sec.-propyl, Cvclopropvlmethvl, allyl group, propargyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, different heptyl; Described cycloalkyl is selected from the one in cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl; Described alkylidene group phenyl is selected from benzyl, benzyloxymethyl, 2,6-dimethyl benzyl, 4-methoxy-benzyl, 2,4-dimethoxy-benzyl, 2,6-dimethoxy-benzyl, adjacent nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2, one in 4-dichloro benzyl, 2,6-dichloro benzyls; Described acyl group be selected from formyl radical, methoxyl group acyl group, ethanoyl, ethoxyacyl, trifluoroacetyl group, chloracetyl, tribromo-acetyl base, propionyl, cyclopropyl formyl radical, positive butyryl radicals, isobutyryl, positive pentanoyl, isovaleryl, positive caproyl, isocaproyl, positive oenanthyl, different oenanthyl, benzoyl, benzenesulfonyl, to the one in Methyl benzenesulfonyl base; Described silylation be selected from trimethyl silicon based, t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based or one in triisopropylsilyl.
As a kind of preferred version, described method comprises following reaction scheme:
Wherein:
R is the one in H, 4-methoxyl group, 2,4-dimethoxys, 2,6-dimethoxys, 2,6-dimethyl, 2-nitro, 4-nitro, 2-chlorine, 4-chlorine, 2,4-dichloros, 2,6-dichloros;
The content of reaction a, reaction b and reaction c is same as above.
As a kind of preferred version, described method comprises following reaction scheme:
Wherein:
The content of reaction a and reaction b is same as above;
Reaction c1 makes (S)-N, N, 2-trimethylammonium-3-m-phenylcnc-3-amylene ammonia shown in formula II first react generation boric acid ester compound with connection boric acid pinacol ester, then under the oxidation of sodium perborate the phenolic hydroxyl-compounds shown in production I ';
Reaction c2 makes the phenolic hydroxyl-compounds shown in formula I ' at transition metal-catalyzed lower hydrogenation reduction, obtains the tapentadol hydrochloride shown in formula I.
As further preferred version, reaction c1 comprises following operation: be dissolved in suitable solvent by halides shown in formula II, then adds connection boric acid pinacol ester, catalyzer and alkali, reacting by heating; When detection reaction terminates, then add the water and sodium perborate that are equivalent to former solvent 1/4, stirring at room temperature is to reacting end; Regulate pH value to 9 ~ 10 in reaction system.
As further preferred version, described suitable solvent is the one in tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, Isosorbide-5-Nitrae-dioxane, DMF, DMSO, methyl tertiary butyl ether, isopropyl ether, best with Isosorbide-5-Nitrae-dioxane.
As further preferred version, described catalyzer is palladium catalyst, can be selected from Pd [(PPh
3)]
4, Pd [(PPh
3)
2] Cl
2, Pd (dba)
2, Pd
2(dba)
3, Pd (dppf) Cl
2, Pd (dppp) Cl
2, Pd [(CH
3cN)
2] Cl
2, Pd [(PCy
3)
2] Cl
2or Pd [P (t-Bu)
3]
2, with Pd [(PPh
3)]
4or Pd (dppf) Cl
2best.
As further preferred version, described alkali is selected from least one in triethylamine, diisopropyl ethyl amine, salt of wormwood, sodium carbonate, potassium acetate, sodium acetate, cesium carbonate, potassiumphosphate, sodium phosphate, best with potassium acetate, sodium acetate.
As further preferred version, described sodium perborate is selected from a water sodium perborate, three water sodium perborate or four water sodium perborate.
As a kind of preferred version, described method comprises following reaction scheme:
Wherein:
The content of reaction a and reaction b is same as above;
Reaction c3 make (S)-N, N, 2-trimethylammonium-3-m-phenylcnc-3-amylene ammonia shown in formula II at transition metal-catalyzed lower hydrogenation reduction, production I " shown in aminocompound;
Reaction c4 make formula I " shown in aminocompound Sodium Nitrite exist under first diazotization, and then hydrolysis obtain the tapentadol hydrochloride shown in formula I.
As further preferred version, the chiral catalyst of reaction described in a is chiral amino acid, chiral alkaloid or other organic molecules containing chiral centre, such as: proline(Pro) and analogue, tartrate and derivative thereof, quinine and analogue thereof etc.
As further preferred version, described chiral catalyst is L-PROLINE or L-TARTARIC ACID.
As further preferred version, reaction a solvent for use is water, methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, acetonitrile, toluene, methylene dichloride, N, at least one in dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide.
As further preferred version, the general structure of the ethyl phosphonic acid ester of reaction described in b is:
r2 and R3 in formula is the one in fatty alkyl, phenyl, naphthyl, benzyl, allyl group at the same time or separately.
As further preferred version, described fatty alkyl is selected from the one in methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, different heptyl; Described benzyl is selected from phenylbenzyl, benzyloxymethyl, 2,6-dimethyl benzyl, 4-methoxy-benzyl, 2,4-dimethoxy-benzyl, 2,6-dimethoxy-benzyl, adjacent nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2, one in 4-dichloro benzyl, 2,6-dichloro benzyls.
As further preferred version, reaction b solvent for use is selected from least one in tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, methyl tertiary butyl ether, isopropyl ether, toluene, normal hexane, normal heptane.
As further preferred version, the alkali of reaction described in b is selected from least one in sodium methylate, sodium ethylate, sodium hydride, sodium tert-butoxide, potassium tert.-butoxide, n-Butyl Lithium.
As further preferred version, mol ratio between formula III compound in reaction b and ethyl phosphonic acid ester or Ethyltriphenylphosphonium brimide or ethyltriphenyl phosphonium chloride phosphorus and alkali three is 1:(1 ~ 2): (1 ~ 2), with 1:(1.4 ~ 1.6): (1.4 ~ 1.6) are best.
As further preferred version, the temperature of reaction of reaction b is 0 ~ 100 DEG C, with 40 ~ 70 DEG C of the bests.
As further preferred version, the transition-metal catalyst described in c is selected from palladium, carbon carries palladium, nickel, platinum, carbon carry platinum, carbon carries ruthenium in reaction, carbon carries one in rhodium.
As further preferred version, reaction c solvent used is selected from least one in water, methyl alcohol, ethanol, n-propyl alcohol, Virahol, the trimethyl carbinol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, DMF, N,N-dimethylacetamide.
Relative to prior art, the present invention, by the mode of chiral catalysis, directly obtains desired chiral isomer by reacting, and avoids a large amount of waste and environmental issue that produce because of chiral separation, not only whole route is short, and simple to operate, be easy to industrialization, and raw material availability is high, substantially increase yield, reduce cost, meet the requirement of suitability for industrialized production tapentadol hydrochloride, there is significance progress.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail and completely.
Embodiment 1:(S) synthesis of-3-dimethylamino-2-methyl isophthalic acid-m-methoxyphenyl-1-acetone (formula III compound)
By 164.2g meta-methoxy Propiophenone (formula IV compound), 244.6g dimethylamine hydrochloride, 90g paraformaldehyde and 9.9g massfraction be 37% aqueous hydrochloric acid be dissolved in 200mL ethanol; add 34.5g L-PROLINE again; mixed reactant is heated to backflow under nitrogen protection; back flow reaction is after 16 hours; be cooled to room temperature; first decompression evaporates most of solvent; resistates is dissolved in water; add concentrated ammonia solution adjust ph again to alkalescence; dichloromethane extraction 3 times; after merging organic layer, weak ammonia washs 1 time, anhydrous Na
2sO
4drying, filters, is spin-dried for obtain pale yellow oil: (S)-3-dimethylamino-2-methyl isophthalic acid-m-methoxyphenyl-1-acetone (172.6g, molar yield is 78%, HPLC purity is 98%, ee=95%); Be directly used in next step reaction.MS-ESI(m/z)：222.1(M+H)+。
Embodiment 2:(S) synthesis of-3-dimethylamino-2-methyl isophthalic acid-benzyloxy-phenyl-1-acetone (formula III compound)
By benzyloxy Propiophenone between 240.3g (formula IV compound), 244.6g dimethylamine hydrochloride, 90g paraformaldehyde and 9.9g massfraction be 37% aqueous hydrochloric acid be dissolved in 200mL ethanol; add 34.5g L-PROLINE again; mixed reactant is heated to backflow under nitrogen protection; back flow reaction is after 16 hours; be cooled to room temperature; first decompression evaporates most of solvent; resistates is dissolved in water; add concentrated ammonia solution adjust ph again to alkalescence; dichloromethane extraction 3 times; after merging organic layer, weak ammonia washs 1 time, anhydrous Na
2sO
4drying, filters, is spin-dried for obtain pale yellow oil: (S)-3-dimethylamino-2-methyl isophthalic acid-benzyloxy-phenyl-1-acetone (252g, molar yield is 85%, HPLC purity is 98%, ee=97%); Be directly used in next step reaction.MS-ESI(m/z)：298.2(M+H)+。
Embodiment 3:(S) synthesis of-3-dimethylamino-2-methyl isophthalic acid-bromophenyl-1-acetone (formula III compound)
By brom-acetophenone between 213.1g (formula IV compound), 244.6g dimethylamine hydrochloride, 90g paraformaldehyde and 9.9g massfraction be 37% aqueous hydrochloric acid be dissolved in 200mL ethanol, then add 34.5g L-PROLINE; Mixed reactant is heated to backflow under nitrogen protection, and back flow reaction, after 16 hours, is cooled to room temperature, and first decompression evaporates most of solvent; resistates is dissolved in water, then adds concentrated ammonia solution adjust ph to alkalescence, dichloromethane extraction 3 times; after merging organic layer, weak ammonia washs 1 time, anhydrous Na
2sO
4drying, filters, is spin-dried for obtain pale yellow oil: (S)-3-dimethylamino-2-methyl isophthalic acid-bromophenyl-1-acetone (229.7g, molar yield is 85%, HPLC purity is 95%, ee=96%); Be directly used in next step reaction.MS-ESI(m/z)：270.0，272.0(M+H)+。
Embodiment 4:(S) synthesis of-3-dimethylamino-2-methyl isophthalic acid-m-nitro base-1-acetone (formula III compound)
By 179.17g m-nitro acetone (formula IV compound), 244.6g dimethylamine hydrochloride, 90g paraformaldehyde and 9.9g massfraction be 37% aqueous hydrochloric acid be dissolved in ethanol 200mL, then add 34.5g L-PROLINE; Mixed reactant is heated to backflow under nitrogen protection, and back flow reaction, after 16 hours, is cooled to room temperature, and first decompression evaporates most of solvent; resistates is dissolved in water, then adds concentrated ammonia solution adjust ph to alkalescence, dichloromethane extraction 3 times; after merging organic layer, weak ammonia washs 1 time, anhydrous Na
2sO
4drying, filters, is spin-dried for obtain pale yellow oil: (S)-3-dimethylamino-2-methyl isophthalic acid-m-nitro base-1-acetone (160.6g, molar yield is 68%, HPLC purity is 93%, ee=97%); Be directly used in next step reaction.MS-ESI(m/z)：237.2(M+H)+。
Embodiment 5:(S) synthesis of-3-dimethylamino-2-methyl isophthalic acid-[3-(4-methoxy-benzyl) phenyl]-1-acetone (formula III compound)
By 179.17g3-(4-methoxyl group benzyloxy) Propiophenone (formula IV compound), 244.6g dimethylamine hydrochloride, 90g paraformaldehyde and 9.9g massfraction be 37% aqueous hydrochloric acid be dissolved in 200mL ethanol, then add 34.5g L-PROLINE; Mixed reactant is heated to backflow under nitrogen protection, and back flow reaction, after 16 hours, is cooled to room temperature, and first decompression evaporates most of solvent; resistates is dissolved in water, then adds concentrated ammonia solution adjust ph to alkalescence, dichloromethane extraction 3 times; after merging organic layer, weak ammonia washs 1 time, anhydrous Na
2sO
4drying, filters, is spin-dried for obtain pale yellow oil: (S)-3-dimethylamino-2-methyl isophthalic acid-[3-(4-methoxyl group benzyloxy) phenyl]-1-acetone (288.1g, molar yield is 88%, HPLC purity is 99%, ee=99%); Be directly used in next step reaction.MS-ESI(m/z)：328.2(M+H)+。
Embodiment 6:(R) synthesis of-3-(3-benzyloxy-phenyl)-N, N, 2-trimethylammonium penta-3-alkene-1-amine (formula II compound)
Under room temperature condition, 278.4g ethyltriphenylphosphonium bromide is suspended in 500mL toluene, add 72.1g sodium tert-butoxide under stirring, continue stirring 1 hour, reaction solution is orange red, ice bath is cooled to less than 20 DEG C, slowly drip formula III compound: the toluene solution (300mL) of (S)-3-dimethylamino-2-methyl isophthalic acid-benzyloxy-phenyl-1-acetone (148.6g, 0.5mol), after dropwising, be warming up to 60 DEG C of reactions 3 hours, be slowly down to room temperature; Reaction solution washes twice with water, each all 200mL, then uses the water washing of 200mL saturated common salt, dry, filters; The ethyl acetate solution of HCl is added in the solution that filtration obtains, adularescent solid is separated out, after stirring and crystallizing 30min, filter, solid 50mL ethyl acetate is washed, vacuum-drying, obtain: (R)-3-(3-benzyloxy-phenyl)-N, N, 2-trimethylammonium penta-3-alkene-1-amine hydrochlorate (148.7g, molar yield is 86%, HPLC purity is 99%); Be directly used in next step reaction.MS-ESI(m/z)：310.2(M+H)+。
Embodiment 7:(R) synthesis of bromophenyl-N, N, 2-trimethylammonium penta-3-alkene-1-amine (formula II compound) between-3-
Under room temperature condition, 278.4g ethyltriphenylphosphonium bromide is suspended in 500mL toluene, add 72.1g sodium tert-butoxide under stirring and continue stirring 1 hour, reaction solution is orange red, and ice bath is cooled to less than 20 DEG C, slowly drips formula III compound: (S)-3-dimethylamino-2-methyl isophthalic acid-bromophenyl-1-acetone (135.1g, toluene solution (300mL) 0.5mol), after dropwising, be warming up to 60 DEG C of reactions 3 hours, be slowly down to room temperature; Reaction solution washes twice with water, all uses 200mL at every turn, then uses the water washing of 200mL saturated common salt, dry, filters; The ethyl acetate solution of HCl is added in the solution that filtration obtains, adularescent solid is separated out, after stirring and crystallizing 30min, filter, solid 50mL ethyl acetate is washed, vacuum-drying, obtain: bromophenyl-N between (R)-3-, N, 2-trimethylammonium penta-3-alkene-1-amine hydrochlorate (114.3g, molar yield is 81%, HPLC purity is 98%); Be directly used in next step reaction.MS-ESI(m/z)：282.0,284.0(M+H)+。
Embodiment 8:(R) synthesis of-3-m-nitro base-N, N, 2-trimethylammonium penta-3-alkene-1-amine (formula II compound)
Under room temperature condition, 278.4g ethyltriphenylphosphonium bromide is suspended in 500mL toluene, add 72.1g sodium tert-butoxide under stirring and continue stirring 1 hour, reaction solution is orange red, and ice bath is cooled to less than 20 DEG C, slowly drips formula III compound: (S)-3-dimethylamino-2-methyl isophthalic acid-m-nitro base-1-acetone (118.1g, toluene solution (300mL) 0.5mol), after dropwising, be warming up to 60 DEG C of reactions 3 hours, be slowly down to room temperature; Reaction solution washes twice with water, all uses 200mL at every turn, then uses the water washing of 200mL saturated common salt, dry, filters; The ethyl acetate solution of HCl is added in the solution that filtration obtains, adularescent solid is separated out, after stirring and crystallizing 30min, filter, solid 50mL ethyl acetate is washed, vacuum-drying, obtain: (R)-3-m-nitro base-N, N, 2-trimethylammonium penta-3-alkene-1-amine hydrochlorate (95.5g, molar yield is 77%, HPLC purity is 93%); Be directly used in next step reaction.MS-ESI(m/z)：249.1(M+H)+。
Embodiment 9:(R) synthesis of-3-[3-(4-methoxyl group benzyloxy) phenyl]-N, N, 2-trimethylammonium penta-3-alkene-1-amine (formula II compound)
Under room temperature condition, 278.4g ethyltriphenylphosphonium bromide is suspended in 500mL toluene, add 72.1g sodium tert-butoxide under stirring and continue stirring 1 hour, reaction solution is orange red, ice bath is cooled to less than 20 DEG C, slowly drip formula III compound: (S)-3-dimethylamino-2-methyl isophthalic acid-[3-(4-methoxyl group benzyloxy) phenyl]-1-acetone (163.7g, toluene solution (300mL) 0.5mol), after dropwising, be warming up to 60 DEG C of reactions 3 hours, be slowly down to room temperature; Reaction solution washes twice with water, all uses 200mL at every turn, then uses the water washing of 200mL saturated common salt, dry, filters; The ethyl acetate solution of HCl is added in the solution that filtration obtains, adularescent solid is separated out, after stirring and crystallizing 30min, filter, solid 50mL ethyl acetate is washed, vacuum-drying, obtain: (R)-3-[3-(4-methoxyl group benzyloxy) phenyl]-N, N, 2-trimethylammonium penta-3-alkene-1-amine hydrochlorate (170.7g, molar yield is 91%, HPLC purity is 99%); Be directly used in next step reaction.MS-ESI(m/z)：340.2(M+H)+。
Embodiment 10: the synthesis of tapentadol hydrochloride (type I compound)
By 6.9g formula II compound: (R)-3-(3-benzyloxy-phenyl)-N, N, 2-trimethylammonium penta-3-alkene-1-amine is dissolved in 20mL methyl alcohol, adds the Pd/C that 350mg palladium content is 10%, after hydrogen exchange 3 times, be placed in room temperature for overnight; With diatomite filtration, removing Pd/C solid, uses 5mL methanol wash, filtrate decompression evaporate to dryness, obtains off-white color solid 5.1g; This solid with ethyl acetate recrystallization, obtains white solid product tapentadol hydrochloride (4.2g, molar yield is 82%, ee=100%); MS-ESI (m/z): 222.1 (M+H)+.
Embodiment 11: the synthesis of tapentadol hydrochloride (type I compound)
By 7.5g formula II compound: (R)-3-[3-(4-methoxyl group benzyloxy) phenyl]-N, N, 2-trimethylammonium penta-3-alkene-1-amine is dissolved in 20mL methyl alcohol, adds the Pd/C that 350mg palladium content is 10%, after hydrogen exchange 3 times, be placed in room temperature for overnight; With diatomite filtration, removing Pd/C solid, uses 5mL methanol wash, filtrate decompression evaporate to dryness, obtains off-white color solid 5.0g; This solid with ethyl acetate recrystallization, obtains white solid product tapentadol hydrochloride (4.1g, molar yield is 80%, ee=100%); MS-ESI (m/z): 222.1 (M+H)+.
Embodiment 12:(R) synthesis of the synthesis (formula I ' compound) of hydroxy phenyl-N, N, 2-trimethylammonium penta-3-alkene-1-amine between-3-
By formula II compound: bromophenyl-N between (R)-3-, N, 2-trimethylammonium penta-3-alkene-1-amine (5.6g, 20mmol), connection boric acid pinacol ester (5.6g, 22mmol), Pd (PPh
3)
4(1.16g, 1mmol), Glacial acetic acid potassium (0.39g, 40mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (20mL), are warming up to 80 DEG C of reactions and spend the night, be cooled to room temperature under nitrogen protection; Add water (5mL), NaBO
33H
2o (6.8g, 50mmol), stirred at ambient temperature 8 hours; Cross and filter insolubles, filtrate adds water (100mL), adds NaOH aqueous solution adjust ph to 9-10, extraction into ethyl acetate (30mL*3), merges organic layer, dry, filters; Organic layer instillation HCl ethyl acetate solution, adularescent solid is separated out, and filters, obtains: hydroxy phenyl-N between (R)-3-, N, 2-trimethylammonium penta-3-alkene-1-amine hydrochlorate (3.33g, molar yield is 65%, HPLC purity is 92%); MS-ESI (m/z): 220.1 (M+H)+.
Embodiment 13: the synthesis of tapentadol hydrochloride (type I compound)
By 3.33g formula I ' compound: hydroxy phenyl-N between (R)-3-, N, 2-trimethylammonium penta-3-alkene-1-amine hydrochlorate is dissolved in 15mL methyl alcohol, and adding 150mg palladium content is 10%Pd/C, after hydrogen exchange 3 times, is placed in room temperature for overnight; With diatomite filtration, removing Pd/C solid, uses 5mL methanol wash, filtrate decompression evaporate to dryness, obtains off-white color solid 3.20g; This solid with ethyl acetate recrystallization, obtains 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) synthesis of-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) anilinechloride (formula I " compound)
By 5.70g formula II compound: (R)-3-m-nitro base-N, N, 2-trimethylammonium penta-3-alkene-1-amine is dissolved in 20mL methyl alcohol, adds the Pd/C that 350mg palladium content is 10%, after hydrogen exchange 3 times, be placed in room temperature for overnight; With diatomite filtration, removing Pd/C solid, uses 5mL methanol wash, filtrate decompression evaporate to dryness, obtains off-white color solid 4.72g; This solid with ethyl acetate recrystallization, obtains white solid product: (1R, 2R)-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) anilinechloride (3.78g, molar yield is 73.6%, ee=100%); MS-ESI (m/z): 221.2 (M+H)+.
Embodiment 15: the synthesis of tapentadol hydrochloride (type I compound)
Be that the aqueous sulfuric acid of 30-35% adds in 100mL flask by 20mL massfraction, ice-water bath is cooled to 0 ~ 5 DEG C, then 3.78g formula I is added " compound: (1R; 2R)-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) anilinechloride, then by the NaNO of 5mL0.304g/mL
2the aqueous solution slowly instills; Drip complete insulated and stirred after 1 hour, obtain diazonium salt reaction solution; In another round-bottomed flask, add the aqueous sulfuric acid that 20mL massfraction is 10 ~ 15%, be heated to 110 DEG C, aforementioned diazonium salt reaction solution is slowly added, control foam and do not overflow, add complete, at 100 DEG C of insulation reaction 15min, be then cooled to room temperature; Add NaOH solution adjust ph to 10 ~ 11, extraction into ethyl acetate 3 times, uses 30mL at every turn; After collected organic layer carries out drying, filter, add the ethyl acetate solution of HCl, produce a large amount of white solid; Filter, obtain white solid product tapentadol hydrochloride (2.85g, molar yield is 75%, ee=100%); MS-ESI (m/z): 222.1 (M+H)+.
Finally be necessary described herein: above embodiment is only for being described in more detail technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (16)
1. a method for synthetic hydrochloric acid tapentadol hydrochloride, is characterized in that, comprises following reaction scheme:
wherein:
The Propiophenone that between reaction a makes shown in formula IV, position replaces is raw material, react under the catalysis of chiral catalyst is induced with paraformaldehyde and dimethylamine hydrochloride, obtain (the S)-3-dimethylamino-2-methyl isophthalic acid-m-phenylcnc-1-acetone shown in formula III;
Reaction b makes (the S)-3-dimethylamino-2-methyl isophthalic acid-m-phenylcnc-1-acetone shown in formula III and ethyl phosphonic acid ester or Ethyltriphenylphosphonium brimide or ethyltriphenyl phosphonium chloride phosphorus react under the effect of alkali, obtain (the S)-N shown in formula II, N, 2-trimethylammonium-3-m-phenylcnc-3-amylene ammonia;
Reaction c makes (S)-N, N, 2-trimethylammonium-3-m-phenylcnc-3-amylene ammonia shown in formula II at transition metal-catalyzed lower hydrogenation reduction, obtains the tapentadol hydrochloride shown in formula I;
R in formula
1for halogen ,-OH ,-OR
4,-NO
2,-NH
2,-NR
5r
6,-SH ,-SR
7in one.
2. the method for synthetic hydrochloric acid tapentadol hydrochloride as claimed in claim 1, is characterized in that: described R
4for the one in alkyl, cycloalkyl, alkylidene group phenyl, alkylidene group naphthyl, tetrahydropyrans, acyl group or silylation, described R
5and R
6respectively or be H simultaneously, benzyl, benzyloxymethyl, 2, 4-dimethoxy-benzyl, 2, 6-dimethoxy-benzyl, 4-methoxy-benzyl, adjacent nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2, 4-dichloro benzyl, 2, 6-dichloro benzyl, formyl radical, methoxyl group acyl group, ethanoyl, ethoxyacyl, trifluoroacetyl group, chloracetyl, tribromo-acetyl base, propionyl, cyclopropyl formyl radical, positive butyryl radicals, isobutyryl, positive pentanoyl, isovaleryl, positive caproyl, isocaproyl, positive oenanthyl, different oenanthyl, benzoyl, benzyloxy acyl group, dibenzoyl, benzenesulfonyl, to Methyl benzenesulfonyl base, the tertiary butyl, allyl group, described R7 is benzyl, benzyloxymethyl, 2, 4-dimethoxy-benzyl, 2, 6-dimethoxy-benzyl, 4-methoxy-benzyl, adjacent nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2, 4-dichloro benzyl, 2, 6-dichloro benzyl, 2,4,6-trimethoxy benzyls, 2, one in 4,6-trimethyl benzyl, diphenyl-methyl, trityl, the tertiary butyl, methoxymethyl, benzyloxymethyl, ethanoyl, benzoyl, trifluoroacetyl group.
3. the method for synthetic hydrochloric acid tapentadol hydrochloride as claimed in claim 2, is characterized in that: described alkyl is selected from the one in methyl, ethyl, n-propyl, sec.-propyl, Cvclopropvlmethvl, allyl group, propargyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, different heptyl; Described cycloalkyl is selected from the one in cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl; Described alkylidene group phenyl is selected from benzyl, benzyloxymethyl, 2,6-dimethyl benzyl, 4-methoxy-benzyl, 2,4-dimethoxy-benzyl, 2,6-dimethoxy-benzyl, adjacent nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2, one in 4-dichloro benzyl, 2,6-dichloro benzyls; Described acyl group be selected from formyl radical, methoxyl group acyl group, ethanoyl, ethoxyacyl, trifluoroacetyl group, chloracetyl, tribromo-acetyl base, propionyl, cyclopropyl formyl radical, positive butyryl radicals, isobutyryl, positive pentanoyl, isovaleryl, positive caproyl, isocaproyl, positive oenanthyl, different oenanthyl, benzoyl, benzenesulfonyl, to the one in Methyl benzenesulfonyl base; Described silylation be selected from trimethyl silicon based, t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based or one in triisopropylsilyl.
4. the method for synthetic hydrochloric acid tapentadol hydrochloride as claimed in claim 1, it is characterized in that, described method comprises following reaction scheme:
Wherein:
R is the one in H, 4-methoxyl group, 2,4-dimethoxys, 2,6-dimethoxys, 2,6-dimethyl, 2-nitro, 4-nitro, 2-chlorine, 4-chlorine, 2,4-dichloros, 2,6-dichloros; The content of reaction a, reaction b and reaction c is with described in claim 1.
5. the method for synthetic hydrochloric acid tapentadol hydrochloride as claimed in claim 1, it is characterized in that, described method comprises following reaction scheme:
Wherein:
The content of reaction a and reaction b is with described in claim 1;
Reaction c1 makes (S)-N, N, 2-trimethylammonium-3-m-phenylcnc-3-amylene ammonia shown in formula II first react generation boric acid ester compound with connection boric acid pinacol ester, then under the oxidation of sodium perborate the phenolic hydroxyl-compounds shown in production I ';
Reaction c2 makes the phenolic hydroxyl-compounds shown in formula I ' at transition metal-catalyzed lower hydrogenation reduction, obtains the tapentadol hydrochloride shown in formula I.
6. the method for synthetic hydrochloric acid tapentadol hydrochloride as claimed in claim 5, is characterized in that, reaction c1 comprises following operation: be dissolved in suitable solvent by halides shown in formula II, then adds connection boric acid pinacol ester, catalyzer and alkali, reacting by heating; When detection reaction terminates, then add the water and sodium perborate that are equivalent to former solvent 1/4, stirring at room temperature is to reacting end; Regulate pH value to 9 ~ 10 in reaction system.
7. the method for synthetic hydrochloric acid tapentadol hydrochloride as claimed in claim 6, is characterized in that: described suitable solvent is the one in tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, Isosorbide-5-Nitrae-dioxane, DMF, DMSO, methyl tertiary butyl ether, isopropyl ether; Described catalyzer is palladium catalyst; Described alkali is selected from least one in triethylamine, diisopropyl ethyl amine, salt of wormwood, sodium carbonate, potassium acetate, sodium acetate, cesium carbonate, potassiumphosphate, sodium phosphate; Described sodium perborate is selected from a water sodium perborate, three water sodium perborate or four water sodium perborate.
8. the method for synthetic hydrochloric acid tapentadol hydrochloride as claimed in claim 1, it is characterized in that, described method comprises following reaction scheme:
Wherein:
The content of reaction a and reaction b is with described in claim 1;
Reaction c3 make (S)-N, N, 2-trimethylammonium-3-m-phenylcnc-3-amylene ammonia shown in formula II at transition metal-catalyzed lower hydrogenation reduction, production I " shown in aminocompound;
Reaction c4 make formula I " shown in aminocompound Sodium Nitrite exist under first diazotization, and then hydrolysis obtain the tapentadol hydrochloride shown in formula I.
9. the method for the synthetic hydrochloric acid tapentadol hydrochloride as described in claim 1 or 4 or 5 or 8, is characterized in that: the chiral catalyst of reaction described in a is chiral amino acid or chiral alkaloid.
10. the method for synthetic hydrochloric acid tapentadol hydrochloride as claimed in claim 9, is characterized in that: described chiral catalyst is L-PROLINE or L-TARTARIC ACID.
The method of 11. synthetic hydrochloric acid tapentadol hydrochlorides as described in claim 1 or 4 or 5 or 8, it is characterized in that: reaction a solvent for use is water, methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, acetonitrile, toluene, methylene dichloride, N, at least one in dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide.
The method of 12. synthetic hydrochloric acid tapentadol hydrochlorides as described in claim 1 or 4 or 5 or 8, is characterized in that: the general structure of the ethyl phosphonic acid ester of reaction described in b is:
r2 and R3 in formula is the one in fatty alkyl, phenyl, naphthyl, benzyl, allyl group at the same time or separately.
The method of 13. synthetic hydrochloric acid tapentadol hydrochlorides as claimed in claim 12, is characterized in that: described fatty alkyl is selected from the one in methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, different heptyl; Described benzyl is selected from phenylbenzyl, benzyloxymethyl, 2,6-dimethyl benzyl, 2, one in 4-dimethyl benzyl, 4-methoxy-benzyl, adjacent nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichloro benzyls, 2,6-dichloro benzyls.
The method of 14. synthetic hydrochloric acid tapentadol hydrochlorides as described in claim 1 or 4 or 5 or 8, is characterized in that: reaction b solvent for use is selected from least one in tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, methyl tertiary butyl ether, isopropyl ether, toluene, normal hexane, normal heptane; The alkali of reaction described in b is selected from least one in sodium methylate, sodium ethylate, sodium hydride, sodium tert-butoxide, potassium tert.-butoxide, n-Butyl Lithium.
15. the method for the synthetic hydrochloric acid tapentadol hydrochloride as described in claim 1 or 4 or 5 or 8, is characterized in that: the transition-metal catalyst described in c is selected from palladium, carbon carries palladium, nickel, platinum, carbon carry platinum, carbon carries ruthenium in reaction, carbon carries one in rhodium.
The method of 16. synthetic hydrochloric acid tapentadol hydrochlorides as described in claim 1 or 4 or 5 or 8, it is characterized in that: the solvent reacting c used is selected from water, methyl alcohol, ethanol, n-propyl alcohol, Virahol, the trimethyl carbinol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, at least one in dinethylformamide, N,N-dimethylacetamide.
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