CN104803861B - Method for synthesizing tapentadol hydrochloride - Google Patents

Abstract

The invention discloses a method for synthesizing tapentadol hydrochloride, which comprises the following reaction scheme: Wherein R ₁ is one of halogen, -OH, -OR ₄ , -NO ₂ , -NH ₂ , -NR ₅ R ₆ , -SH, -SR ₇ . The present invention directly obtains the desired chiral isomer through reaction through chiral catalysis, avoiding a large amount of waste and environmental protection problems caused by chiral resolution, not only the whole route is short, but also simple to operate and easy to industrialize. Moreover, the raw material utilization rate is high, the yield is greatly improved, and the cost is reduced, which meets the requirements of industrial production of tapentadol hydrochloride, and has significant progress.

Description

A method for synthesizing tapentadol hydrochloride

technical field

The invention relates to a method for synthesizing tapentadol hydrochloride, which belongs to the technical field of medicine synthesis.

Background technique

The chemical name of Tapentadol Hydrochloride is (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol hydrochloride, and its chemical structure is as follows :

Tapentadol hydrochloride is a novel oral analgesic drug that acts on the central nervous system developed by the German company Grunenthal. It was first marketed in 2008 for the relief of moderate and severe acute pain. It has dual mechanisms of opioid μ receptor agonism and norepinephrine reuptake inhibition.

According to relevant literature reports, the synthetic routes of tapentadol hydrochloride mainly contain the following types at present:

Route 1 (see European patent document EP0693475):

This route takes 1-(dimethylamino)-2-methyl-3-pentanone and m-bromoanisole as starting materials, and obtains 4 chiral isomers through the Grignard reaction, which need to pass through a chiral column. Separation of the desired single-configuration intermediate, and then chlorination by thionyl chloride, reduction by zinc borohydride, demethylation, and salt formation to obtain tapentadol hydrochloride of a single configuration. The synthesis steps are long and the operation is cumbersome. , the yield is low, especially the separation of chiral isomers requires a chiral column, which is difficult to achieve industrial production.

Route 2 (see international patent document WO2008016047, Chinese patent document CN101495445 and European patent document EP2046724):

This route uses m-methoxypropiophenone as a starting material, and utilizes the Mannich reaction of dimethylamine hydrochloride and formaldehyde to obtain racemic 3-dimethylamino-1-(3-methoxyphenyl)-2 -Methyl acetone intermediate, then use chiral resolving agent to resolve to obtain the desired S-3-dimethylamino-1-(3-methoxyphenyl)-2-methyl acetone intermediate, and then pass through grid The final product, tapentadol, is obtained through several steps such as reaction, elimination, catalytic hydrogenation, and demethylation of methionine. Although this route can greatly increase the ratio of the desired isomer, it still has defects such as long route, high cost, easy to produce many unexpected by-products and a lot of waste, and it is also difficult for industrial application.

Route 3 (see Chinese patent document CN102002065A):

This route uses R-proline to induce the asymmetric Aldol condensation of meta-substituted benzaldehyde and propionaldehyde, and obtains two chiral centers in one step, and replaces the hydroxyl group with Grignard reaction after sulfonylation, and finally removes the protecting group to obtain the desired product . Although the route is short and two chiral centers can be formed in one step, the raw materials are difficult to obtain, and the Grignard reaction requires high requirements, which is not conducive to industrialization.

Route 4 (see international patent document WO2011/080736A1):

This route uses m-methoxypropiophenone and alkyl phosphate as raw materials, and uses Horner-Wadsworth-Emmons reaction to synthesize the target product in only four steps. Although the synthesis method of this route is relatively novel and the route is short, the implementation process requires more stringent requirements, and it is impossible to use in large-scale industrial production by using noble metal catalysis, anhydrous and oxygen-free, ultra-low temperature, column chromatography separation and other operations.

Route 5 (see international patent document WO2011/080756A1):

This route uses m-methoxybenzaldehyde and ethyl cyanoacetate as starting materials, generates 2-cyano-3-m-methoxyphenyl acrylate ethyl ester through Knoevenagel reaction, and then uses ethyl Grignard reagent addition , methylation, decarboxylation, cyano group reduction, amino dimethylation, dephenol methyl ether, chiral resolution and other 7-step reactions to obtain the final product. This route is long, and the borane dimethyl sulfide used for reducing cyano groups is highly toxic and flammable, and the reaction operation is cumbersome, so it is not suitable for mass production.

Route 6 (see Chinese patent document CN102557851):

This route is reduced with meta-substituted propiophenone, and the obtained secondary alcohol is substituted with halogen, and then directly nucleophilicly substituted with diethyl methylmalonate, and the product is hydrolyzed and decarboxylated to obtain 2-methyl-3-phenylpentanoic acid, The final product was obtained through amide formation, reduction, removal of protecting groups and chiral resolution. Although the route is simple to operate and the cost of raw materials is low, the synthesis route is long and the production process will generate more waste, which is not suitable for industrial production requirements.

Route 7 (see Chinese patent document CN102617501A):

or

The route uses cinnamic acid or 2-pentenoic acid as the starting material, first forms an amide with a chiral amine, and then performs chiral-induced asymmetric Macheal addition, adding ethyl or meta-substituted benzene, and then adding carbonyl After the methyl group is attached to the α-position, the chiral amino group is removed and replaced with dimethylamine, and after the protection of the phenolic hydroxyl group is removed, tapentadol is obtained. Although the raw materials of this route are cheap and easy to obtain, the operation is cumbersome.

Route 8 (see Chinese patent document CN102936205):

This route is after 1-(dimethylamino)-2-methyl-3-pentanone is reduced, carries out hydroxyhalogenation, and then the gained halide is reacted with m-methoxy boron reagent, silicon reagent or tin reagent in nickel A coupling reaction is carried out under catalysis, followed by demethylation to obtain racemized tapentadol, and finally chiral resolution to obtain an optically active final product. The cost of this route is very high, especially the tin reagent is highly toxic, and the splitting is carried out in the last step, which generates more waste and has environmental pollution problems, so it is not suitable for industrial application.

Route 9 (see US patent document US20130150622A1, international patent document WO2013090161):

This route utilizes the asymmetric Claisen rearrangement of cinnamyl alcohol propylene ether to generate 2-methyl-3-phenyl-4-pentenal, which is then reductively aminated to give N,N,2-trimethyl-3-benzene Base-4-pentenylamine, and finally hydrogenation to reduce the double bond and remove the protecting group to obtain the desired product. Although the route is ingeniously designed, the route is long, expensive catalysts are used in multiple steps, and the reaction conditions are harsh, and it is not suitable for large-scale industrial production.

Route 10 (see international patent documents WO2012089177A1 and WO2012089181):

This route uses cinnamyl alcohol propionate as the starting material, rearranges under the catalysis of alkali to generate 2-methyl-3-phenyl-4-pentenoic acid, and then undergoes steps such as dimethylamination, reduction, and deprotection The desired product was obtained. This route needs to be reacted under low temperature and anhydrous conditions, and the industrial application is relatively difficult, and the resolution loss is relatively large.

In summary, although there are many synthetic methods of tapentadol hydrochloride reported in the literature, there are various defects that are unfavorable for industrialized production: some routes are too long, some use expensive or toxic chemical reagents, Some reaction operations are cumbersome, and some have higher requirements on reaction equipment; as a result, the cost of industrially preparing tapentadol hydrochloride using the prior art remains high, which cannot meet the requirements of large-scale production.

Contents of the invention

The present invention aims at the above-mentioned problems and defects in the prior art, and aims to provide a method for synthesizing tapentadol hydrochloride that directly obtains the desired chiral isomer through reaction, so as to avoid a large amount of waste due to chiral resolution. material, to achieve industrial production requirements such as increasing yield, reducing cost, shortening reaction route, and simplifying operation.

For realizing above-mentioned purpose of the invention, the technical scheme that the present invention adopts is as follows:

A method for synthesizing tapentadol hydrochloride, comprising the following reaction scheme:

in:

Reaction a is to make meta-substituted propiophenone shown in formula IV as raw material, and react with paraformaldehyde and dimethylamine hydrochloride under the catalytic induction of chiral catalyst to obtain (S)-3 shown in formula III -Dimethylamino-2-methyl-1-meta-substituted phenyl-1-propanone;

Reaction b is to make (S)-3-dimethylamino-2-methyl-1-meta-substituted phenyl-1-acetone shown in formula III with ethyl phosphoric acid ester or ethyl triphenylphosphine bromide or Ethyltriphenylphosphorous chloride is reacted under the action of a base to obtain (S)-N,N,2-trimethyl-3-meta-substituted phenyl-3-pentenylamine shown in formula II;

Reaction c is the hydrogenation reduction reaction of (S)-N,N,2-trimethyl-3-substituted phenyl-3-pentenylamine shown in formula II under transition metal catalysis to obtain the The indicated tapentadol hydrochloride;

In the formula, R ₁ is one of halogen, -OH, -OR ₄ , -NO ₂ , -NH ₂ , -NR ₅ R ₆ , -SH, -SR ₇ .

As a preferred version, the R ₄ is one of alkyl, cycloalkyl, alkylene phenyl, alkylene naphthyl, tetrahydropyran, acyl or silyl; the R ₅ and R ₆ are H, benzyl, benzyloxymethyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, 4-methoxybenzyl, o-nitrobenzyl, respectively or simultaneously Base, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2,6-dichlorobenzyl, formyl, methoxyacyl, acetyl, Ethoxyacyl, trifluoroacetyl, chloroacetyl, trichloroacetyl, propionyl, cyclopropylformyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, n-hexanoyl, isohexanoyl, N-heptanoyl, isoheptanoyl, benzoyl, benzyloxyacyl, dibenzoyl, benzenesulfonyl, p-toluenesulfonyl, tert-butyl, allyl; the R7 is benzyl, benzyl Oxymethyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, 4-methoxybenzyl, o-nitrobenzyl, 4-nitrobenzyl, 2- Chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2,6-dichlorobenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl One of group, benzhydryl, trityl, tert-butyl, methoxymethyl, benzyloxymethyl, acetyl, benzoyl, trifluoroacetyl.

As a further preferred version, the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl, allyl, propargyl, n-butyl, isobutyl, tert-butyl , n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl; the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, One of cyclohexyl and cycloheptyl; the alkylene phenyl is selected from benzyl, benzyloxymethyl, 2,6-dimethylbenzyl, 4-methoxybenzyl, 2,4 -Dimethoxybenzyl, 2,6-dimethoxybenzyl, o-nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl One of benzyl and 2,6-dichlorobenzyl; the acyl group is selected from formyl, methoxyacyl, acetyl, ethoxyacyl, trifluoroacetyl, chloroacetyl, trichloroacetyl , propionyl, cyclopropylformyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, n-hexanoyl, isohexanoyl, n-heptanoyl, isoheptanoyl, benzoyl, benzenesulfonyl, p-methyl One of phenylsulfonyl groups; the silyl group is selected from one of trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl.

As a preferred version, the method includes the following reaction scheme:

one of them:

R is H, 4-methoxy, 2,4-dimethoxy, 2,6-dimethoxy, 2,6-dimethyl, 2-nitro, 4-nitro, 2-chloro, One of 4-chloro, 2,4-dichloro, 2,6-dichloro;

The contents of reaction a, reaction b and reaction c are the same as above.

As a preferred version, the method includes the following reaction scheme:

one of them:

The contents of reaction a and reaction b are the same as above;

Reaction c1 is to first react (S)-N,N,2-trimethyl-3-substituted phenyl-3-pentenylamine shown in formula II with biboronic acid pinacol ester to generate a borate compound , and then generate the phenolic hydroxyl compound shown in formula I' under the oxidation of sodium perborate;

Reaction c2 is to make the phenolic hydroxyl compound shown in formula I' undergo a hydrogenation reduction reaction under transition metal catalysis to obtain tapentadol hydrochloride shown in formula I.

As a further preferred solution, reaction c1 includes the following operations: dissolving the halogenated compound shown in formula II in a suitable solvent, then adding biboronic acid pinacol ester, catalyst and base, and heating the reaction; when the detection reaction is over, adding the equivalent 1/4 of the original solvent water and sodium perborate, stirred at room temperature until the reaction is completed; adjust the pH value in the reaction system to 9-10.

As a further preferred solution, the suitable solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, 1,4-dioxane, DMF, DMSO, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane is the best.

As a further preferred solution, the catalyst is a palladium catalyst, which 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 ₃ CN) ₂ ]Cl ₂ , Pd[(PCy ₃ ) ₂ ]Cl ₂ or Pd[P(t-Bu) ₃ ] ₂ , with Pd[(PPh ₃ )] ₄ or Pd(dppf)Cl ₂ are the best.

As a further preferred version, the base is selected from at least one of triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, potassium acetate, sodium acetate, cesium carbonate, potassium phosphate, sodium phosphate, Potassium acetate and sodium acetate are the best.

As a further preferred solution, the sodium perborate is selected from sodium perborate monohydrate, sodium perborate trihydrate or sodium perborate tetrahydrate.

As a preferred version, the method includes the following reaction scheme:

one of them:

The contents of reaction a and reaction b are the same as above;

Reaction c3 is the hydrogenation reduction reaction of (S)-N,N,2-trimethyl-3-substituted phenyl-3-pentenylamine shown in formula II under transition metal catalysis to generate formula I" the indicated amino compound;

Reaction c4 is to make the amino compound shown in formula I" be diazotized in the presence of sodium nitrite, and then hydrolyzed to obtain tapentadol hydrochloride shown in formula I".

As a further preferred option, the chiral catalyst described in reaction a is a chiral amino acid, a chiral alkaloid or other small organic molecules containing a chiral center, such as: proline and its analogs, tartaric acid and its derivatives, Quinine and its analogues, etc.

As a further preferred solution, the chiral catalyst is L-proline or L-tartaric acid.

As a further preferred version, the solvent used in reaction a is water, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, toluene, methylene chloride, N,N-dimethylformamide, At least one of N,N-dimethylacetamide and dimethyl sulfoxide.

As a further preferred version, the general structural formula of the ethyl phosphate described in the reaction b is: R2 and R3 in the formula are simultaneously or respectively one of aliphatic alkyl, phenyl, naphthyl, benzyl and allyl.

As a further preferred version, the fatty alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl one of base, n-hexyl, isohexyl, n-heptyl, and isoheptyl; the benzyl is selected from phenylbenzyl, benzyloxymethyl, 2,6-dimethylbenzyl, 4- Methoxybenzyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, o-nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl One of benzyl, 2,4-dichlorobenzyl, and 2,6-dichlorobenzyl.

As a further preferred solution, the solvent used in reaction b is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, toluene, n-hexane, and n-heptane.

As a further preferred solution, the base in reaction b is at least one selected from sodium methoxide, sodium ethoxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, and n-butyllithium.

As a further preferred version, the mol ratio between the compound of formula III in reaction b and ethyl phosphoric acid ester or ethyl triphenyl phosphorus bromide or ethyl triphenyl phosphorus chloride and alkali is 1:(1～ 2):(1～2), 1:(1.4～1.6):(1.4～1.6) is the best.

As a further preferred solution, the reaction temperature of reaction b is 0-100°C, most preferably 40-70°C.

As a further preferred solution, the transition metal catalyst described in reaction c is selected from one of palladium, palladium on carbon, nickel, platinum, platinum on carbon, ruthenium on carbon, and rhodium on carbon.

As a further preferred version, the solvent used in reaction c is selected from water, methanol, ethanol, n-propanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N, At least one of N-dimethylacetamides.

Compared with the prior art, the present invention directly obtains the desired chiral isomer through reaction through chiral catalysis, avoids a large amount of waste and environmental protection problems caused by chiral resolution, not only the whole route is short, but also The method is simple in operation, easy in industrialization, high in raw material utilization rate, greatly improved in yield, lowered in cost, meets the requirements of industrialized production of tapentadol hydrochloride, and has significant progress.

detailed description

The present invention will be described in further detail and completely below in conjunction with the embodiments.

Example 1: Synthesis of (S)-3-dimethylamino-2-methyl-1-m-methoxyphenyl-1-propanone (compound of formula III)

Dissolve 164.2g of m-methoxypropiophenone (compound of formula IV), 244.6g of dimethylamine hydrochloride, 90g of paraformaldehyde and 9.9g of 37% aqueous hydrochloric acid in 200mL of ethanol, and then add 34.5g of L -Proline, the mixed reactant was heated to reflux under the protection of nitrogen, and after 16 hours of reflux reaction, it was cooled to room temperature, and most of the solvent was evaporated under reduced pressure, and the residue was dissolved in water, and then concentrated ammonia solution was added to adjust the pH value to alkali properties, extracted 3 times with dichloromethane, combined the organic layers, washed 1 time with dilute ammonia water, dried over anhydrous Na ₂ SO ₄ , filtered, and spin-dried to obtain a light yellow oil: (S)-3-dimethylamino-2- Methyl-1-m-methoxyphenyl-1-propanone (172.6 g, molar yield 78%, HPLC purity 98%, ee=95%); directly used in the next reaction. MS-ESI (m/z): 222.1 (M+H)+.

Embodiment 2: Synthesis of (S)-3-dimethylamino-2-methyl-1-m-benzyloxyphenyl-1-propanone (compound of formula III)

Dissolve 240.3g of m-benzyloxypropiophenone (compound of formula IV), 244.6g of dimethylamine hydrochloride, 90g of paraformaldehyde and 9.9g of 37% hydrochloric acid aqueous solution in 200mL of ethanol, and then add 34.5g of L -Proline, the mixed reactant was heated to reflux under the protection of nitrogen, and after 16 hours of reflux reaction, it was cooled to room temperature, and most of the solvent was evaporated under reduced pressure, and the residue was dissolved in water, and then concentrated ammonia solution was added to adjust the pH value to alkali properties, extracted 3 times with dichloromethane, combined the organic layers, washed 1 time with dilute ammonia water, dried over anhydrous Na ₂ SO ₄ , filtered, and spin-dried to obtain a light yellow oil: (S)-3-dimethylamino-2- Methyl-1-m-benzyloxyphenyl-1-propanone (252 g, molar yield 85%, HPLC purity 98%, ee=97%); directly used in the next reaction. MS-ESI (m/z): 298.2 (M+H)+.

Example 3: Synthesis of (S)-3-dimethylamino-2-methyl-1-m-bromophenyl-1-propanone (compound of formula III)

Dissolve 213.1g of m-bromopropiophenone (compound of formula IV), 244.6g of dimethylamine hydrochloride, 90g of paraformaldehyde and 9.9g of 37% aqueous hydrochloric acid in 200mL of ethanol, and then add 34.5g of L-proline Acid; the mixed reactant was heated to reflux under the protection of nitrogen, and after 16 hours of reflux reaction, it was cooled to room temperature, and most of the solvent was evaporated under reduced pressure first, and the residue was dissolved in water, and then concentrated ammonia solution was added to adjust the pH value to alkaline, Dichloromethane extracted 3 times, combined the organic layers, washed 1 time with dilute ammonia water, dried over anhydrous Na ₂ SO ₄ , filtered, and spin-dried to obtain a light yellow oil: (S)-3-dimethylamino-2-methyl - 1-m-bromophenyl-1-propanone (229.7g, molar yield 85%, HPLC purity 95%, ee=96%); directly used in the next reaction. MS-ESI (m/z): 270.0, 272.0 (M+H)+.

Example 4: Synthesis of (S)-3-dimethylamino-2-methyl-1-m-nitrophenyl-1-propanone (compound of formula III)

Dissolve 179.17g of m-nitropropiophenone (compound of formula IV), 244.6g of dimethylamine hydrochloride, 90g of paraformaldehyde and 9.9g of 37% hydrochloric acid aqueous solution in 200mL of ethanol, and then add 34.5g of L- Proline; the mixed reactant was heated to reflux under the protection of nitrogen, and after 16 hours of reflux reaction, it was cooled to room temperature, and most of the solvent was evaporated under reduced pressure, and the residue was dissolved in water, and then concentrated ammonia solution was added to adjust the pH value to alkaline , extracted 3 times with dichloromethane, combined the organic layers, washed once with dilute ammonia water, dried over anhydrous Na ₂ SO ₄ , filtered, and spin-dried to obtain a pale yellow oil: (S)-3-dimethylamino-2-methanol Base-1-m-nitrophenyl-1-propanone (160.6g, molar yield 68%, HPLC purity 93%, ee=97%); directly used in the next reaction. MS-ESI (m/z): 237.2 (M+H)+.

Example 5: Synthesis of (S)-3-dimethylamino-2-methyl-1-[3-(4-methoxybenzyl)phenyl]-1-propanone (compound of formula III)

Dissolve 179.17g of 3-(4-methoxybenzyloxy)propiophenone (compound of formula IV), 244.6g of dimethylamine hydrochloride, 90g of paraformaldehyde and 9.9g of 37% hydrochloric acid aqueous solution in 200mL of ethanol 34.5g of L-proline was added; the mixed reactant was heated to reflux under the protection of nitrogen, and after 16 hours of reflux reaction, it was cooled to room temperature, most of the solvent was distilled off under reduced pressure, the residue was dissolved in water, and concentrated Ammonia solution was used to adjust the pH value to alkaline, dichloromethane extracted 3 times, combined organic layers, washed 1 time with dilute ammonia water, dried over anhydrous Na ₂ SO ₄ , filtered, and spin-dried to obtain a light yellow oil: (S)-3 -Dimethylamino-2-methyl-1-[3-(4-methoxybenzyloxy)phenyl]-1-propanone (288.1 g, 88% molar yield, 99% purity by HPLC, ee =99%); directly used in the next reaction. MS-ESI (m/z): 328.2 (M+H)+.

Example 6: Synthesis of (R)-3-(3-benzyloxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (compound of formula II)

At room temperature, suspend 278.4 g of ethyltriphenylphosphine bromide in 500 mL of toluene, add 72.1 g of sodium tert-butoxide under stirring, and continue stirring for 1 hour. Slowly add the compound of formula Ⅲ: (S)-3-dimethylamino-2-methyl-1-m-benzyloxyphenyl-1-propanone (148.6g, 0.5mol) in toluene solution (300mL), drop After the addition, the temperature was raised to 60°C for 3 hours, and then slowly lowered to room temperature; the reaction solution was washed twice with water, 200 mL each time, and then washed with 200 mL saturated saline, dried, and filtered; HCl was added to the filtered solution A white solid was precipitated, stirred and crystallized for 30 min, filtered, the solid was washed with 50 mL of ethyl acetate, and dried in vacuo to obtain: (R)-3-(3-benzyloxyphenyl)-N, N,2-trimethylpent-3-en-1-amine hydrochloride (148.7 g, molar yield 86%, HPLC purity 99%); directly used in the next reaction. MS-ESI (m/z): 310.2 (M+H)+.

Example 7: Synthesis of (R)-3-m-bromophenyl-N,N,2-trimethylpent-3-en-1-amine (compound of formula II)

At room temperature, suspend 278.4g of ethyltriphenylphosphine bromide in 500mL of toluene, add 72.1g of sodium tert-butoxide under stirring and continue to stir for 1 hour, the reaction solution is orange-red, cooled to below 20°C in an ice bath, slowly Slowly add the compound of formula Ⅲ: (S)-3-dimethylamino-2-methyl-1-m-bromophenyl-1-propanone (135.1g, 0.5mol) in toluene solution (300mL), after the dropwise addition , heated to 60°C for 3 hours, then slowly lowered to room temperature; the reaction solution was washed twice with water, each time with 200mL, and then washed with 200mL saturated saline, dried, and filtered; to the filtered solution was added HCl acetic acid Ethyl solution, a white solid precipitated, stirred and crystallized for 30min, filtered, the solid was washed with 50mL ethyl acetate, and dried in vacuo to obtain: (R)-3-m-bromophenyl-N,N,2-trimethyl Pent-3-en-1-amine hydrochloride (114.3 g, molar yield 81%, HPLC purity 98%); directly used in the next reaction. MS-ESI (m/z): 282.0, 284.0 (M+H)+.

Example 8: Synthesis of (R)-3-m-nitrophenyl-N,N,2-trimethylpent-3-en-1-amine (compound of formula II)

At room temperature, suspend 278.4g of ethyltriphenylphosphine bromide in 500mL of toluene, add 72.1g of sodium tert-butoxide under stirring and continue to stir for 1 hour, the reaction solution is orange-red, cooled to below 20°C in an ice bath, slowly Slowly add the compound of formula Ⅲ: (S)-3-dimethylamino-2-methyl-1-m-nitrophenyl-1-propanone (118.1g, 0.5mol) in toluene solution (300mL), the dropwise addition is complete Afterwards, the temperature was raised to 60°C for 3 hours, and then slowly lowered to room temperature; the reaction solution was washed twice with water, each time with 200 mL, and then washed with 200 mL of saturated saline, dried, and filtered; added HCl to the filtered solution Ethyl acetate solution, a white solid precipitated, stirred and crystallized for 30min, filtered, the solid was washed with 50mL ethyl acetate, and dried in vacuo to obtain: (R)-3-m-nitrophenyl-N,N,2-tri Methylpent-3-en-1-amine hydrochloride (95.5 g, molar yield 77%, HPLC purity 93%); used directly in the next reaction. MS-ESI (m/z): 249.1 (M+H)+.

Example 9: (R)-3-[3-(4-methoxybenzyloxy)phenyl]-N,N,2-trimethylpent-3-en-1-amine (compound of formula II) Synthesis

At room temperature, suspend 278.4g of ethyltriphenylphosphine bromide in 500mL of toluene, add 72.1g of sodium tert-butoxide under stirring and continue to stir for 1 hour, the reaction solution is orange-red, cooled to below 20°C in an ice bath, slowly Slowly add the compound of formula III: (S)-3-dimethylamino-2-methyl-1-[3-(4-methoxybenzyloxy)phenyl]-1-propanone (163.7g, 0.5mol ) toluene solution (300mL), after the dropwise addition was completed, the temperature was raised to 60°C for 3 hours, and then slowly lowered to room temperature; Filtration; HCl ethyl acetate solution was added to the solution obtained by filtration, a white solid was precipitated, stirred and crystallized for 30min, filtered, the solid was washed with 50mL ethyl acetate, and dried in vacuo to obtain: (R)-3-[3 -(4-methoxybenzyloxy)phenyl]-N,N,2-trimethylpent-3-en-1-amine hydrochloride (170.7g, molar yield is 91%, HPLC purity is 99%); directly used in the next reaction. MS-ESI (m/z): 340.2 (M+H)+.

Embodiment 10: Synthesis of tapentadol hydrochloride (compound of formula I)

Dissolve 6.9g of the compound of formula II: (R)-3-(3-benzyloxyphenyl)-N,N,2-trimethylpent-3-en-1-amine in 20mL of methanol, add 350mg of palladium Pd/C with a content of 10% was replaced by hydrogen for 3 times, and then stirred overnight at room temperature; filtered with diatomaceous earth to remove the Pd/C solid, washed with 5 mL of methanol, and the filtrate was evaporated to dryness under reduced pressure to obtain off-white solid 5.1 g; this solid was recrystallized with ethyl acetate to obtain the white solid product tapentadol hydrochloride (4.2g, molar yield was 82%, ee=100%); MS-ESI (m/z): 222.1 (M +H)+.

Example 11: Synthesis of tapentadol hydrochloride (compound of formula I)

7.5g of formula II compound: (R)-3-[3-(4-methoxybenzyloxy)phenyl]-N,N,2-trimethylpent-3-en-1-amine was dissolved in Add 350 mg of Pd/C with a palladium content of 10% to 20 mL of methanol, replace with hydrogen three times, and stir overnight at room temperature; filter with diatomaceous earth to remove the Pd/C solid, wash with 5 mL of methanol, and evaporate the filtrate under reduced pressure dry to obtain off-white solid 5.0g; this solid was recrystallized with ethyl acetate to obtain the white solid product tapentadol hydrochloride (4.1g, molar yield was 80%, ee=100%); MS-ESI (m /z): 222.1 (M+H)+.

Example 12: Synthesis of (R)-3-m-hydroxyphenyl-N,N,2-trimethylpent-3-en-1-amine (formula Ⅰ' compound)

The compound of formula Ⅱ: (R)-3-m-bromophenyl-N,N,2-trimethylpent-3-en-1-amine (5.6g, 20mmol), biboronic acid pinacol ester (5.6g , 22mmol), Pd(PPh ₃ ) ₄ (1.16g, 1mmol), anhydrous potassium acetate (0.39g, 40mmol) were dissolved in 1,4-dioxane (20mL), heated to 80°C under the protection of nitrogen to react Overnight, cool to room temperature; add water (5mL), NaBO ₃ 3H ₂ O (6.8g, 50mmol), stir at room temperature for 8 hours; filter to remove insoluble matter, add water (100mL) to the filtrate, add NaOH aqueous solution to adjust the pH value to 9 -10, extracted with ethyl acetate (30mL*3), combined the organic layers, dried, and filtered; the organic layer was dropped into HCl ethyl acetate solution, a white solid precipitated, filtered to obtain: (R)-3-m-hydroxyphenyl -N,N,2-trimethylpent-3-en-1-amine hydrochloride (3.33g, molar yield 65%, HPLC purity 92%); MS-ESI (m/z): 220.1 (M+H)+.

Example 13: Synthesis of tapentadol hydrochloride (compound of formula I)

Dissolve 3.33g of the compound of formula Ⅰ': (R)-3-m-hydroxyphenyl-N,N,2-trimethylpent-3-en-1-amine hydrochloride in 15mL of methanol, add 150mg of palladium It was 10% Pd/C, replaced by hydrogen 3 times, and stirred at room temperature overnight; filtered through diatomaceous earth to remove the Pd/C solid, washed with 5 mL of methanol, and the filtrate was evaporated to dryness under reduced pressure to obtain 3.20 g of off-white solid; This solid was recrystallized with ethyl acetate to obtain the white solid product tapentadol hydrochloride (2.70g, molar yield was 81%, ee=100%); MS-ESI (m/z): 222.1 (M+H )+.

Example 14: Synthesis of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)aniline hydrochloride (compound of formula Ⅰ)

Dissolve 5.70g of the compound of formula II: (R)-3-m-nitrophenyl-N,N,2-trimethylpent-3-en-1-amine in 20mL of methanol, add 350mg of palladium to make it 10% Pd/C, hydrogen replacement 3 times, placed at room temperature and stirred overnight; filtered with diatomaceous earth, removed Pd/C solid, washed with 5mL of methanol, and the filtrate was evaporated to dryness under reduced pressure to obtain 4.72g of off-white solid; Recrystallization with ethyl acetate gave a white solid product: (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)aniline hydrochloride (3.78g, molar yield The rate was 73.6%, ee=100%); MS-ESI (m/z): 221.2 (M+H)+.

Example 15: Synthesis of tapentadol hydrochloride (compound of formula I)

Add 20mL of sulfuric acid aqueous solution with a mass fraction of 30-35% into a 100mL flask, cool in an ice-water bath to 0-5°C, and then add 3.78g of the compound of formula I": (1R,2R)-3-(3-Dimethylamino -1-ethyl- ₂ -methylpropyl) aniline hydrochloride, then 5mL of 0.304g/mL NaNO2 aqueous solution is slowly dripped in; After dripping and stirring for 1 hour, the diazonium salt reaction solution is obtained; Add 20mL of sulfuric acid aqueous solution with a mass fraction of 10-15% to another round-bottomed flask, heat it to 110°C, add the aforementioned diazonium salt reaction solution slowly, and control the foam not to overflow. Then cool to room temperature; add NaOH solution to adjust the pH value to 10-11, extract with ethyl acetate three times, each time with 30 mL; collect the organic layer to dry, filter, add HCl in ethyl acetate solution, a large amount of white solid is produced; After filtration, the white solid product tapentadol hydrochloride (2.85 g, molar yield 75%, ee=100%) was obtained; MS-ESI (m/z): 222.1 (M+H)+.

Finally, it is necessary to explain here that: the above examples are only used to further describe the technical solutions of the present invention in detail, and cannot be interpreted as limiting the protection scope of the present invention. Non-essential improvements and adjustments all belong to the 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.