Method for preparing tapentadol or a pharmaceutically acceptable salt thereof by continuous flow reaction

Abstract

The present disclosure relates to a method for preparing tapentadol or a pharmaceutically acceptable salt thereof by continuous flow reaction. Specifically, the method includes the step of injecting a substrate and a catalyst suspension and hydrogen into a microreactor for a hydrogenation reaction, thereby efficiently obtaining tapentadol or a pharmaceutically acceptable salt thereof in a single configuration.

Description

Technical Field

[0001] The present invention relates to a method for preparing tapentadol or a pharmaceutically acceptable salt thereof by continuous flow reaction. Background Art

[0002] Tapentadol, with the chemical name (lR,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol hydrochloride, is a novel orally administered analgesic drug acting on the central nervous system developed by Grunenthal. It has a dual mechanism of action of opioid μ-receptor agonism and norepinephrine reuptake inhibition, and is used to relieve moderate and severe acute pain.

[0003] 。

[0004] Currently, the main synthetic route of tapentadol is to construct 1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol through a Grignard reaction, and then obtain a single configuration intermediate by resolution using a chiral column or a chiral reagent (2R, 3R)-dibenzoyl tartaric acid. Subsequently, tapentadol hydrochloride is obtained through steps such as chlorination, elimination, reduction, and salification. 。

[0005] For example, Route 1 (EP0693475): Using 1-(dimethylamino)-2-methyl-3-pentanone and m-bromoanisole as starting materials, through a Grignard reaction, chiral column separation, then chlorination with thionyl chloride, reduction with zinc borohydride, demethylation, and salification to obtain a single configuration of tapentadol hydrochloride. 。

[0006] Route 2 (WO2008016047): Using m-methoxypropiophenone as the starting material, through the Mannich reaction of dimethylamine hydrochloride and formaldehyde, and then using a chiral resolving agent to resolve to obtain the intermediate S-3-dimethylamino-1-(3-methoxyphenyl)-2-methylpropanone, and then through steps such as Grignard reaction, elimination, catalytic hydrogenation, and methionine demethylation to obtain tapentadol. 。

[0007] Route 3 (WO2008016047 / WO2008012283): Under the condition of a heterogeneous catalyst, 1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol is eliminated and then reduced through a stepwise or "one-pot synthesis" method to obtain a tapentadol intermediate. A similar synthetic process can be seen in 2944MUM2011.

[0008] 。

[0009] During the chlorination, elimination, or reduction process of a single-configuration intermediate, it has been verified that two diastereoisomers are formed. Removing the unwanted isomers by crystallization will lead to a decrease in product yield.

[0010] WO2012001571 reported a new method for reducing the formation of unwanted stereoisomers by activating the hydroxyl group with an acylating reagent and then removing the acyl ester group under the conditions of a palladium-carbon / hydrogen catalyst. .

[0011] However, in actual production, as the batch size gradually increases, the problem of the formation of unwanted diastereoisomers cannot be well controlled, accounting for about 6 - 8%. At the same time, as the batch size increases, the raw materials cannot react completely, and other impurities during the hydrogenation process cannot be effectively controlled. The overall process still needs to be further improved.

[0012] Flow reaction has become a new reaction technology and has been successfully used in the synthesis of various organic compounds. Its reaction device consists of an injection pump, connecting microtubes, a microreactor, a detector, etc. Its advantage lies in significantly increasing the area-volume ratio of the fluid environment, resulting in a series of special effects related to the object surface in the microfluidic system, such as laminar flow effect, surface tension, capillary effect, rapid heat conduction effect, etc. Therefore, the continuous reactor technology can strengthen the factors affecting organic synthesis reactions such as mass transfer and heat transfer effects, and can change the flow pattern and mixing procedure of the substrate by designing channels, regulate the direction and degree of the reaction, improve the selectivity, speed, and operation safety of the reaction, and meet the needs of industrial production.

[0013] Therefore, the present invention provides a new synthetic idea and route. The entire synthetic route is short, reducing its synthesis cost; at the same time, harsh reaction conditions are avoided, the reaction conditions are simple, the process is highly operable, which is conducive to industrial production needs, and reduces the environmental protection pressure. Summary of the Invention

[0014] The disclosure provides a method for preparing tapentadol or a pharmaceutically acceptable salt thereof, comprising: the step of injecting a suspension of a compound of formula g and a catalyst and hydrogen into a microreactor for a hydrogenation reaction, wherein the catalyst is selected from palladium, palladium hydroxide, or platinum oxide. , wherein R 1 is selected from hydrogen, C 1-6alkyl, benzyl, benzyloxymethyl, 2,6-dimethylbenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, o-nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2,6-dichlorobenzyl, formyl, methoxycarbonyl, acetyl, ethoxycarbonyl, trifluoroacetyl, chloroacetyl, trichloroacetyl, propionyl, cyclopropylcarbonyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, n-caproyl, isocaproyl, n-heptanoyl, isoheptanoyl, benzoyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl; R 2 selected from C 1-6 alkyl, C 1-6 alkoxy or phenyl, said alkyl, alkoxy or phenyl being optionally substituted by halogen or methyl, and further said R 2 is preferably methyl, ethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, methoxy, ethoxy, phenyl or p-methylphenyl; R 3 each independently selected from C 1-6 alkyl, said alkyl being optionally substituted by phenyl, 2,6-dimethylphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, o-nitrophenyl, 4-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl or 2,6-dichlorophenyl.

[0015] In some embodiments, the catalyst is palladium on carbon.

[0016] In some embodiments, said R 1 is selected from hydrogen, methyl, ethyl, benzyl, benzyloxymethyl, 2,6-dimethylbenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, o-nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2,6-dichlorobenzyl, formyl, methoxycarbonyl, acetyl, ethoxycarbonyl, trifluoroacetyl, chloroacetyl, trichloroacetyl, propionyl, cyclopropylcarbonyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, n-caproyl, isocaproyl, n-heptanoyl, isoheptanoyl, benzoyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl. In some embodiments, said R 1 is selected from hydrogen, methyl or benzyl.

[0017] In some embodiments, said R 3Selected from methyl, which is optionally substituted by phenyl, 2,6-dimethylphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, o-nitrophenyl, 4-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl or 2,6-dichlorophenyl, preferably methyl or benzyl.

[0018] In some embodiments, said R 2 is selected from methyl, trifluoromethyl, trichloromethyl, methoxy or ethoxy.

[0019] In some embodiments, the method for preparing tapentadol or a pharmaceutically acceptable salt thereof comprises: the step of subjecting a compound of formula g-1, a catalyst suspension and hydrogen to a hydrogenation reaction by injecting them into a microreactor, . In some embodiments, R in the compound of formula g-1 2 is selected from methyl or trifluoromethyl.

[0020] In some embodiments, the method for preparing tapentadol or a pharmaceutically acceptable salt thereof comprises: the step of subjecting a compound of formula g-2, a catalyst suspension and hydrogen to a hydrogenation reaction by injecting them into a microreactor, . In some embodiments, R in the compound of formula g-2 2 is selected from methyl or trifluoromethyl. Further, the method further comprises the step of converting a compound of formula h-2 into a compound of formula h-1, .

[0021] In some embodiments, the removal of O-methyl can be carried out under the conditions of methanesulfonic acid / methionine. The specific reaction conditions can be referred to those described in CN102958868, and the relevant content is hereby incorporated by reference.

[0022] In some embodiments, the method for preparing tapentadol or a pharmaceutically acceptable salt thereof comprises: the step of subjecting a compound of formula g-3, a catalyst suspension and hydrogen to a hydrogenation reaction by injecting them into a microreactor, . In some embodiments, R in the compound of formula g-3 2 is selected from methyl or trifluoromethyl.

[0023] In some embodiments, the method for preparing tapentadol or a pharmaceutically acceptable salt thereof comprises: the step of subjecting a compound of formula g-4, a catalyst suspension and hydrogen to a hydrogenation reaction by injecting them into a microreactor, . In some embodiments, R in the compound of formula g-4 2 is selected from methyl or trifluoromethyl. Further, methylation of the amino group is carried out to generate a compound of formula h-2, and then O-demethylation is carried out to convert the compound of formula h-2 into a compound of formula h-1 (tapentadol), .

[0024] In some embodiments, methylation of the amino group can be carried out by a methylation reagent or by means of a reductive methylation method. The methylation reagent can be selected from methyl iodide, methyl bromide, methyl chloride, dimethyl sulfate, and methyl esters of substituted or unsubstituted sulfuric acid or benzenesulfonic acid. In other embodiments, the reductive methylation reaction is carried out by the Eschweiler-Clarke reaction. The specific reaction conditions can be referred to as described in A of CN102958868, and the relevant content is hereby incorporated by reference.

[0025] In some embodiments, removal of the O-methyl group can be carried out under the conditions of methanesulfonic acid / methionine. The specific reaction conditions can be referred to as described in CN102958868A, and the relevant content is hereby incorporated by reference.

[0026] On the other hand, in a continuous flow reactor, the ratio of the flow rate of the compound of formula g and the catalyst suspension to the flow rate of the hydrogen gas is selected from 1:6 to 1:30, and can be 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30 or a value between any two of these values. In some embodiments, the ratio of the flow rate of the compound of formula g and the catalyst suspension to the flow rate of the hydrogen gas is from 1:6 to 1:20. In some embodiments, the ratio of the flow rate of the compound of formula g and the catalyst suspension to the flow rate of the hydrogen gas is 1:6 or 1:8.

[0027] Further, in a continuous flow reactor, the molar ratio of the compound of formula g to hydrogen is 1:1.5 to 1:4, and can be 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.0 or a value between any two of these values. In some embodiments, the suspension containing the compound of formula g and the catalyst is injected into the microreactor at a flow rate of 10 to 50 ml / min, and can be 10 ml / min, 11 ml / min, 12 ml / min, 13 ml / min, 14 ml / min, 15 ml / min, 16 ml / min, 17 ml / min, 18 ml / min, 19 ml / min, 20 ml / min, 21 ml / min, 22 ml / min, 23 ml / min, 24 ml / min, 25 ml / min, 26 ml / min, 27 ml / min, 28 ml / min, 29 ml / min, 30 ml / min, 31 ml / min, 32 ml / min, 33 ml / min, 34 ml / min, 35 ml / min, 36 ml / min, 37 ml / min, 38 ml / min, 39 ml / min, 40 ml / min, 41 ml / min, 42 ml / min, 43 ml / min, 44 ml / min, 45 ml / min, 46 ml / min, 47 ml / min, 48 ml / min, 49 ml / min, 50 ml / min or a value between any two of these values. In some embodiments, the suspension containing the compound of formula g and the catalyst is injected into the microreactor at a flow rate of 15 to 30 ml / min.

[0028] In some embodiments, the hydrogen gas flow rate is selected from 40 to 1500 ml / min, preferably 100 to 400 ml / min, and can be 100 ml / min, 110 ml / min, 120 ml / min, 130 ml / min, 140 ml / min, 150 ml / min, 160 ml / min, 170 ml / min, 180 ml / min, 190 ml / min, 200 ml / min, 210 ml / min, 220 ml / min, 230 ml / min, 240 ml / min, 250 ml / min, 260 ml / min, 270 ml / min, 280 ml / min, 290 ml / min, 300 ml / min, 310 ml / min, 320 ml / min, 330 ml / min, 340 ml / min, 350 ml / min, 360 ml / min, 370 ml / min, 380 ml / min, 390 ml / min, 400 ml / min or a value between any two values. In some embodiments, the hydrogen gas flow rate is selected from 220 ml / min.

[0029] In some embodiments, the hydrogenation reaction temperature is selected from 60 to 80 °C and can be 60 °C, 65 °C, 70 °C, 75 °C, 80 °C or a value between any two values. In some embodiments, the hydrogenation reaction time is 60 seconds to 200 seconds and can be 60, 70, 80, 90, 100, 110, 120, 130, 150, 160, 170, 180, 190, 200 seconds or a value between any two values.

[0030] In some embodiments, a suspension of the compound of formula g and the catalyst is injected into the microreactor at a flow rate of 15 to 30 ml / min, the hydrogen gas flow rate is selected from 40 to 1500 ml / min, and the reaction temperature is 60 to 80 °C.

[0031] On the other hand, maintaining the pressure in the microreactor increases the hydrogenation reaction rate, and the reactor pressure can be maintained at 0 to 10 Mpa, i.e., 0 to 100 atmospheres. In some embodiments, the reactor pressure is maintained at, for example, 0.8 - 1.2 Mpa, i.e., 8 - 12 atmospheres, including 0.9 Mpa, 1 Mpa or 1.1 Mpa.

[0032] On the other hand, in some embodiments, the amount of catalyst used in the hydrogenation reaction is 3 to 15% by weight of the compound of formula g, preferably 5 to 10%. In some embodiments, the solution used in the hydrogenation reaction is selected from methanol or ethanol.

[0033] Furthermore, the method for preparing tapentadol or a pharmaceutically acceptable salt thereof further includes the step of reacting the compound of formula f with an acylating agent to form the compound of formula g, and the acylating agent is preferably acetic anhydride or trifluoroacetic anhydride. .

[0034] In some embodiments, a condensing agent may be appropriately added in the acylation reaction to accelerate the esterification process. The condensing agent is selected from dicyclohexylcarbodiimide (DCC), hydroxybenzotriazole (HOBT), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or 2-propane phosphoric acid (T3P).

[0035] In some embodiments, the acylation reaction solvent is selected from tert-butyl methyl ether.

[0036] In some embodiments, the acylation reaction and the hydrogenation reaction are completed by "one-pot synthesis" without separation of any intermediates during this process, and the reagents used in each step of the reaction are added in segments to complete the corresponding reaction process. For example, taking trifluoroacetic anhydride as an example of the acylation reagent, after obtaining the acyl compound using trifluoroacetic anhydride, subsequent hydrogenation is carried out without any intermediate treatment operations, and the conversion of the compound of formula f to the compound of formula h can be completed.

[0037] On the other hand, the present disclosure provides a method for preparing tapentadol or a pharmaceutically acceptable salt thereof, which comprises the following steps shown below: .

[0038] In some embodiments, the method for preparing tapentadol or a pharmaceutically acceptable salt thereof comprises the following steps shown below: .

[0039] In some embodiments, the method for preparing tapentadol or a pharmaceutically acceptable salt thereof comprises the following steps shown below: .

[0040] In some embodiments, the method for preparing tapentadol or a pharmaceutically acceptable salt thereof comprises the following steps shown below: .

[0041] In some embodiments, the method for preparing tapentadol or a pharmaceutically acceptable salt thereof comprises the following steps shown below: .

[0042] Furthermore, the method of the present disclosure further comprises a post-treatment operation, such as one or more steps of filtration, extraction, concentration, column chromatography, or chiral separation to obtain a pure target product.

[0043] The pharmaceutically acceptable salt described in the present disclosure is the product of the compound forming a salt with an acid, and the acid is selected from, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, malic acid, or oxalic acid, etc.

[0044] The terms used in the present disclosure, unless otherwise stated, have the following meanings:

[0045] In the present disclosure, "to form" and "to be transformed into" do not specifically refer to the transformation reaction between two substrates as a single-step reaction, and can be a single-step or multi-step reaction between two substrates. If the intermediate contains an amino protecting group, the intermediate is subjected to one step of deaminating the protecting agent, and then reacted with the corresponding substrate to obtain the corresponding target product.

[0046] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups having 1 to 10 carbon atoms, preferably including 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available connection point, and is preferably one or more of the following groups, independently selected from halogen, methyl, phenyl, 2,6-dimethylphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, o-nitrophenyl, 4-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl or 2,6-dichlorophenyl.

[0047] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is defined as above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen or methyl.

[0048] The term "hydroxy" refers to the -OH group.

[0049] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0050] The term "amino" refers to -NH2.

[0051] The "effective therapeutic amount" as described in the present disclosure includes an amount sufficient to improve or prevent the symptoms or conditions of a medical condition. The effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health of the patient, the method of administration, the route and dose, and the severity of side effects. The effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0052] In this disclosure, the numerical values are instrument measurement values and there are certain degrees of errors. Generally speaking, both plus and minus 10% are within the reasonable error range. Of course, the context in which the numerical value is used needs to be considered. For example, for the particle size of the active ingredient, the change in the error after measurement of this numerical value does not exceed plus or minus 10%, and can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5%.

[0053] The continuous flow reactor (microchannel reactor) includes a preheating module, a reaction module (microreactor) and a quenching module, and a microchannel reactor produced by Corning can be used.

[0054] The determination by HPLC can use an Agilent 1260 high performance liquid chromatograph in combination with a Waters SunfireC18 4.6*250mm 5μ chromatographic column). Description of the Drawings

[0055] Figure 1 : Schematic diagram of the operation of the continuous flow reactor, including a preheating module + a reaction module (microreactor) + a quenching module, and the slurry is injected into it by a diaphragm pump at A and B respectively. Detailed Description of the Embodiments

[0056] The following will describe the present disclosure in detail with reference to specific embodiments, so that those skilled in the art can more comprehensively understand the content of the present disclosure. The specific embodiments are only used to illustrate the technical solutions of the present disclosure and do not limit the present invention in any way.

[0057] Example 1:

[0058]

[0059] Step 1:

[0060] In a 1000L reaction kettle, add a tetrahydrofuran solution of compound 1a (52.4 kg), add 80 kg of tetrahydrofuran, stir to dissolve, protect with nitrogen, cool down to 0 - 5°C, dropwise add 131 L of a 2M tetrahydrofuran solution of ethylmagnesium chloride. After the dropping is complete, warm up to 25 - 30°C and stir the reaction until it is complete. Slowly add a 20% aqueous ammonium chloride solution, transfer the reaction solution to a 2000L reaction kettle, add about 1100 kg of water and 360 kg of ethyl acetate, stir, let stand, separate the organic phase, extract with 360 kg of ethyl acetate again, combine the organic phases, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain 55.2 kg of an oily substance, with a yield of 97.2%.

[0061] Step 2:

[0062] In a 500 L reactor, a methanol solution of compound 1b (53.8 kg) was added, 180 kg of methanol was added, 112 kg of 25% aqueous sodium hydroxide solution was added, and the mixture was heated to 70 - 85 °C. TLC detection showed that the raw materials had basically reacted completely. The mixture was concentrated under reduced pressure until dry, 110 kg of water was added for dissolution, and extraction was carried out with 70 kg × 4 of isopropyl ether. The aqueous phase was adjusted to pH 9 - 10 with 18% aqueous hydrochloric acid solution, and extraction was carried out with ethyl acetate. After liquid separation, the organic phase was washed successively with water and saturated brine solution, dried over anhydrous sodium sulfate, filtered, and 18.0 kg of solid was obtained, with a yield of 61.2%.

[0063] Example 2:

[0064]

[0065] Step 1:

[0066] Compound 1c (100 g) and methyl tert - butyl ether (500 mL) were added to a 1 L reaction flask. Under the protection of a nitrogen stream, trifluoroacetic anhydride (221 g, 2.5 eq) was added dropwise while controlling the temperature not higher than 20 °C. Stirring reaction was carried out until the reaction was complete. After concentration under reduced pressure to dryness, compound 1d was obtained, with a crude product weight of 290 g. This oily substance was directly used for the next continuous reaction.

[0067] Step 2:

[0068] Compound 1d (290 g) was dissolved in methanol (2.0 L) solvent, and then 10 wt% palladium - carbon catalyst (25 g) was added to prepare a slurry for continuous reaction;

[0069] The slurry containing compound 1d and the catalyst was injected into the micro - reactor from port A through a pre - heated reaction plate at a flow rate of 27 ml / min, and a hydrogen stream was injected into the micro - reactor from port B at a flow rate of 220 ml / min. The pressure in the micro - reactor was maintained at 0.8 - 1.4 Mpa, the reaction temperature was 60 °C, and the reaction residence time was 90 - 120 seconds. It took about 85 minutes to flow through completely (monitored by HPLC, in which the content of tapentadol was 83.8%, the content of unreacted compound 1d was 4.8%, the content of compound 1c was 6.2%, the content of diastereoisomers was 1.1%, and the content of O - methyl impurity was 3.1%). After filtration and concentration under reduced pressure to dryness, an oily substance was obtained, diluted with dichloromethane, adjusted to pH 9 - 10 with ammonia water, layered, washed with brine, concentrated to obtain an oily substance, and recrystallized with ethyl acetate / n - heptane to obtain 65 g of solid.

[0070] At the current flow rate in the micro - reactor, the conversion rate is 83.8%. If the reaction continues for 20 hours, the daily production capacity is 1.4 Kg (tapentadol), which is equivalent to the production capacity of a traditional 20 L reactor.

[0071] Note: The O-methyl impurity is 3-(1-(dimethylamino)-3-methoxy-2-methylpentan-3-yl)phenol.

[0072] Example 3:

[0073]

[0074] After preparing compound 1d according to the method of Example 2, dissolve compound 1d (290 g) in methanol (2.0 L) solvent, and then add 10 wt% palladium on carbon catalyst (25 g) to prepare a slurry for continuous reaction;

[0075] Inject the slurry containing compound 1d and the catalyst into the microreactor from port A through the preheated reaction plate at a flow rate of 25 ml / min, and inject hydrogen gas into the microreactor from port B at a flow rate of 400 ml / min. Maintain the pressure in the microreactor at 0.8 - 1.4 Mpa, the reaction temperature at 40 °C, and the reaction residence time at 60 - 80 seconds. It takes about 90 minutes to flow through completely (monitored by HPLC, where the content of tapentadol is 44.6%, the content of unreacted compound 1d is 18.0%, the content of compound 1c is 27%, the content of diastereoisomers is 0.9%, and the content of O-methyl impurity is 6.1%. Tapentadol solid can be obtained according to the above treatment steps.

[0076] Example 4:

[0077]

[0078] After preparing compound 1d according to the method of Example 2, dissolve compound 1d (290 g) in methanol (2.0 L) solvent, and then add 10 wt% palladium on carbon catalyst (25 g) to prepare a slurry for continuous reaction;

[0079] Inject the slurry containing compound 1d and the catalyst into the microreactor from port A through the preheated reaction plate at a flow rate of 27 ml / min, and inject hydrogen gas into the microreactor from port B at a flow rate of 220 ml / min. Maintain the pressure in the microreactor at 0.8 - 1.4 Mpa, the reaction temperature at 40 °C, and the reaction residence time at 80 - 100 seconds. It takes about 85 minutes to flow through completely (monitored by HPLC, where the content of tapentadol is 57.6%, the content of unreacted compound 1d is 18.5%, the content of compound 1c is 19.1%, the content of diastereoisomers is 0.6%, and the content of O-methyl impurity is 2.2%. Tapentadol solid can be obtained according to the above treatment steps.

[0080] Example 5:

[0081]

[0082] After obtaining compound 1d by the method of Example 2, compound 1d (290 g) was dissolved in methanol (2.0 L) solvent, and then 10 wt% palladium on carbon catalyst (25 g) was added to prepare a slurry for continuous reaction;

[0083] The slurry containing compound 1d and the catalyst was injected into the microreactor from port A through a preheated reaction plate at a flow rate of 26 ml / min, and the hydrogen gas stream was injected into the microreactor from port B at a flow rate of 220 ml / min. The pressure in the microreactor was maintained at 0.8 - 1.4 Mpa, the reaction temperature was 80 °C, and the reaction residence time was 80 - 100 seconds. It all flowed out in about 88 minutes (monitored by HPLC, in which the content of tapentadol was 77.5%, the content of unreacted compound 1d was 0.3%, the content of compound 1c was 8.2%, the content of diastereoisomers was 2.1%, and the content of O-methyl impurity was 9.1%. Tapentadol solid could be obtained according to the above treatment steps.

[0084] Example 6:

[0085]

[0086] After obtaining compound 1d by the method of Example 2, compound 1d (290 g) was dissolved in methanol (2.0 L) solvent, and then 10 wt% palladium on carbon catalyst (25 g) was added to prepare a slurry for continuous reaction;

[0087] The slurry containing compound 1d and the catalyst was injected into the microreactor from port A through a preheated reaction plate at a flow rate of 26 ml / min, and the hydrogen gas stream was injected into the microreactor from port B at a flow rate of 220 ml / min. The pressure in the microreactor was maintained at 0.8 - 1.4 Mpa, the reaction temperature was 100 °C, and the reaction residence time was 80 - 100 seconds. It all flowed out in about 88 minutes (monitored by HPLC, in which the content of tapentadol was 54.9%, the content of unreacted compound 1d was 0%, the content of compound 1c was 10.2%, the content of diastereoisomers was 4.8%, and the content of O-methyl impurity was 23.2%. Tapentadol solid could be obtained according to the above treatment steps.

[0088] Example 7:

[0089]

[0090] After obtaining compound 1d by the method of Example 2, compound 1d (290 g) was dissolved in methanol (2.0 L) solvent, and then 10 wt% palladium on carbon catalyst (25 g) was added to prepare a slurry for continuous reaction;

[0091] The slurry containing Compound 1d and the catalyst was injected into the microreactor from port A through a preheated reaction plate at a flow rate of 26 ml / min, and hydrogen gas was injected into the microreactor from port B at a flow rate of 220 ml / min. The pressure in the microreactor was maintained at 0.8 - 1.4 Mpa, the reaction temperature was 115 °C, and the reaction residence time was 80 - 100 seconds. It took about 88 minutes to flow out completely (monitored by HPLC, where the content of tapentadol was 28.2%, the content of unreacted Compound 1d was 0%, the content of Compound 1c was 12.1%, the content of diastereoisomers was 8.1%, and the content of O-methyl impurity was 39.2%). The tapentadol solid can be obtained according to the above treatment steps.

[0092] Comparative Example 1:

[0093]

[0094] In a reaction flask, 183 g of Compound 1c was dissolved in 1000 ml of tetrahydrofuran. Under nitrogen protection, it was cooled to 0 - 5 °C in an ice bath, and 2.7 L of trifluoroacetic anhydride was added dropwise. After the addition was complete, the reaction was stirred until the reaction was completed. The reaction solution was transferred to a 3 L reaction flask, 0.366 g of 10% Pd / C was added, and hydrogen gas at 0.8 - 1.0 MPa was introduced. The reaction was stirred at 45 - 50 °C until the raw materials were basically completely reacted as detected by TLC (monitored by HPLC, where the content of tapentadol was 87.5%, the content of unreacted Compound 1d was 0.2%, the content of Compound 1c was 2.6%, and the content of diastereoisomers was 1.0%). It was filtered and concentrated under reduced pressure to dryness to obtain an oil. It was diluted with dichloromethane, the pH was adjusted to 9 - 10 with ammonia water, layered, washed with brine, and concentrated to obtain an oil. It was recrystallized from ethyl acetate / n-heptane to obtain 98.9 g of a solid, and the two-step yield was 58%.

Claims

1. A method for preparing tapentadol or a pharmaceutically acceptable salt thereof, comprising: The step of injecting a suspension of a compound of formula g-1, a catalyst, and hydrogen into a microreactor for a hydrogenation reaction, wherein the solvent used in the hydrogenation reaction is selected from methanol, the catalyst is selected from palladium on carbon, the suspension containing the compound of formula g-1 and the catalyst is injected into the microreactor at a flow rate of 27 ml / min, the ratio of the flow rate of the suspension containing the compound of formula g-1 and the catalyst to the hydrogen flow rate is selected from 1:6 to 1:9, the temperature of the hydrogenation reaction is selected from 60 °C, the pressure in the reactor is maintained at 0.8 - 1.2 Mpa, the hydrogen flow rate is selected from 220 ml / min, and the reaction time is 90 - 120 seconds. , wherein R 2 is selected from trifluoromethyl.

2. The method according to claim 1, further comprising the step of reacting a compound of formula f-1 with an acylation reagent to form a compound of formula g-1, wherein the acylation reagent is selected from trifluoroacetic anhydride. , where R 2 is selected from trifluoromethyl.

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