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

Abstract

The present disclosure relates to a process for the preparation of tapentadol or a pharmaceutically acceptable salt thereof by a continuous flow reaction. Specifically, the method comprises the step of injecting a suspension containing a substrate and a catalyst and hydrogen into a microreactor to carry out hydrogenation reaction, so as to efficiently obtain the single-configuration tapentadol or the medicinal salt thereof.

Description

Technical Field

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

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

[0003] .

[0004] At present, the synthetic route of tapentadol is mainly to construct 1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentane-3-ol through Grignard reaction, and then split it with the help of chiral column or chiral reagent (2R, 3R)-dibenzoyltartaric acid to obtain a single configuration intermediate, and then obtain tapentadol hydrochloride through chlorination or elimination, reduction and salt formation. .

[0005] For example, Route 1 (EP0693475): 1-(dimethylamino)-2-methyl-3-pentanone and m-bromoanisole are used as starting materials, and a single-configuration tapentadol hydrochloride is obtained by Grignard reaction, chiral column separation, thionyl chloride chlorination, zinc borohydride reduction, demethylation and salt formation. .

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

[0007] Route 3 (WO2008016047 / WO2008012283): Under heterogeneous catalyst conditions, 1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentane-3-ol is eliminated and reduced to obtain the tapentadol intermediate by stepwise or one-pot synthesis. Similar synthesis process can be found in 2944MUM2011.

[0008] .

[0009] It has been verified that two diastereoisomers are formed during the chlorination, elimination or reduction of a single-configuration intermediate. Removing the unwanted isomer by crystallization will result in a decrease in product yield.

[0010] WO2012001571 reports that after activating the hydroxyl group with an acylating agent, the acyl ester group is removed under catalyst palladium carbon / hydrogen conditions, providing a new method for reducing the formation of unwanted stereoisomers. .

[0011] However, in actual production, as the batch size gradually increases, the problem of unwanted diastereoisomer formation 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 in the hydrogenation process cannot be effectively controlled. The overall process needs to be further improved.

[0012] Continuous flow reaction has become a new reaction technology and has been successfully used to synthesize a variety of organic compounds. Its reaction device consists of a syringe pump, connecting microtubes, microreactors, detectors, etc. Its advantage is that it significantly increases the area-volume ratio of the fluid environment, resulting in a series of unique effects related to the surface of the object in the microfluidic system, such as laminar flow effect, surface tension, capillary effect, rapid heat conduction effect, etc. Therefore, the use of continuous reactor technology can enhance factors that affect organic synthesis reactions such as mass transfer and heat transfer effects, and can change the flow pattern and mixing program of the substrate by designing channels, regulate the direction and degree of the reaction, and improve the selectivity, speed and control safety of the reaction, which is suitable for industrial production needs.

[0013] To this end, the present invention provides a new synthesis idea and route, the entire synthesis route is short, and the synthesis cost is reduced; at the same time, harsh reaction conditions are avoided, the reaction conditions are simple, the process operability is strong, it is beneficial to its industrial production needs, and the environmental pressure is reduced. Summary of the invention

[0014] The disclosure provides a method for preparing tapentadol or a pharmaceutically acceptable salt thereof, comprising the steps of: injecting a suspension containing 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; , where R 1 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, methoxyacyl, acetyl, ethoxyacyl, trifluoroacetyl, chloroacetyl, trichloroacetyl, propionyl, cyclopropylformyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, n-hexanoyl, isohexanoyl, 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, the alkyl, alkoxy or phenyl is optionally substituted with halogen or methyl, further said R 2 Preferably methyl, ethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl, methoxy, ethoxy, phenyl or p-methylphenyl; R 3 Each independently selected from C 1-6 Alkyl, wherein the alkyl 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.

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

[0016] In some embodiments, the 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, methoxyacyl, acetyl, ethoxyacyl, trifluoroacetyl, chloroacetyl, trichloroacetyl, propionyl, cyclopropylformyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, n-hexanoyl, isohexanoyl, n-heptanoyl, isoheptanoyl, benzoyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl. In some embodiments, the R 1 is selected from hydrogen, methyl or benzyl.

[0017] In some embodiments, the R 3The group selected from methyl 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, the 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 steps of: injecting a compound of formula g-1, a catalyst suspension and hydrogen into a microreactor for a hydrogenation reaction, In some embodiments, R 2 Selected from methyl or trifluoromethyl.

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

[0021] In some embodiments, the O-methyl group can be removed by methanesulfonic acid / methionine conditions. The specific reaction conditions can be referred to in CN102958868, and the relevant content is explained herein.

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

[0023] In some embodiments, the method for preparing tapentadol or a pharmaceutically acceptable salt thereof comprises the steps of injecting a compound of formula g-4, a catalyst suspension and hydrogen into a microreactor for hydrogenation reaction, In some embodiments, R 2 is selected from methyl or trifluoromethyl. Further, the compound of formula h-2 is generated by methylation of the amino group, and then the compound of formula h-2 is converted into the compound of formula h-1 (tapentadol) by demethylation. .

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

[0025] In some embodiments, the O-methyl group can be removed by methanesulfonic acid / methionine conditions. The specific reaction conditions can be referred to in CN102958868A, and the relevant content is explained herein.

[0026] On the other hand, in the continuous flow reactor, the ratio of the flow rate of the suspension containing the compound of formula g and the catalyst to the flow rate of hydrogen is selected from 1:6 to 1:30, which 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 any two values. In some embodiments, the ratio of the flow rate of the suspension containing the compound of formula g and the catalyst to the flow rate of hydrogen is 1:6 to 1:20. In some embodiments, the ratio of the flow rate of the suspension containing the compound of formula g and the catalyst to the flow rate of hydrogen 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 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, which 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. 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 flow rate is selected from 40 to 1500 ml / min, preferably 100 to 400 In some embodiments, the hydrogen 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, the suspension containing the compound of formula g and the catalyst is injected into the microreactor at a flow rate of 15-30 ml / min, the hydrogen flow rate is selected from 40-1500 ml / min, and the reaction temperature is 60-80°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 0-10 MPa, i.e., 0-100 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 3-15%, preferably 5-10% by weight of the compound of formula g. 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 comprises the step of reacting a compound of formula f with an acylating agent to form a compound of formula g, wherein the acylating agent is preferably acetic anhydride or trifluoroacetic anhydride. .

[0034] In some embodiments, a condensing agent may be appropriately added during the acylation reaction to accelerate the esterification process. The condensing agent is selected from dicyclohexyl diimide (DCC), hydroxybenzotriazole (HOBT), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) (EDC) or 2-propanephosphoric 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 in a "one-pot synthesis" without any separation of intermediates, and the reagents used in each step of the reaction are added in stages to complete the corresponding reaction process. For example, taking trifluoroacetic anhydride as an example of an acylating agent, after obtaining an acylate using trifluoroacetic anhydride, hydrogenation is subsequently performed without any intermediate treatment operation, 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, comprising the following steps: .

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

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

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

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

[0042] Furthermore, the method disclosed herein also includes post-processing operations, such as one or more steps of filtration, extraction, concentration, column chromatography or hand-type separation to obtain a pure target product.

[0043] The pharmaceutically acceptable salts disclosed herein are products of salt formation between a compound and an acid, wherein the acid is selected from, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, malic acid or oxalic acid.

[0044] Unless otherwise stated, the terms used in this disclosure have the following meanings: The term "to form" and "to convert" in the present disclosure does not specifically mean that the conversion reaction between two substrates is a single step, 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 a step of deamination of the protecting agent, and then reacts with the corresponding substrate to obtain the corresponding target product.

[0045] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 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. Alkyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, 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.

[0046] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen or methyl.

[0047] The term "hydroxy" refers to an -OH group.

[0048] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0049] The term "amino" refers to -NH2.

[0050] As used herein, an "effective therapeutic amount" includes an amount sufficient to improve or prevent the symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0051] The values ​​in this disclosure are instrumental measurements, which have a certain degree of error. Generally speaking, plus or minus 10% is within the reasonable error range. Of course, the context in which the value is used needs to be considered. For example, the particle size of the active ingredient, the value is the error change after measurement does not exceed plus or minus 10%, 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%.

[0052] 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.

[0053] HPLC determination can be performed using an Agilent 1260 high performance liquid chromatograph coupled with a Waters Sunfire C18 4.6*250mm 5μ chromatographic column). BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 : Schematic diagram of the continuous flow reactor, including preheating module + reaction module (microreactor) + quenching module, the slurry is injected into them at A and B by diaphragm pumps respectively. DETAILED DESCRIPTION

[0055] The present disclosure will be described in detail below in conjunction with specific embodiments so that those skilled in the art can have a more comprehensive understanding 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 disclosure in any way.

[0056] Embodiment 1:

[0057] Step 1: In a 1000L reactor, a tetrahydrofuran solution of compound 1a (52.4kg) was added, and 80kg of tetrahydrofuran was added, stirred to dissolve, and nitrogen was protected. The temperature was lowered to 0-5°C, and 131L of 2M ethylmagnesium chloride tetrahydrofuran solution was added dropwise. After the addition was completed, the temperature was raised to 25-30°C and stirred to react until the reaction was complete. A 20% aqueous ammonium chloride solution was slowly added, and the reaction solution was transferred to a 2000L reactor. About 1100kg of water and 360kg of ethyl acetate were added and stirred. The mixture was allowed to stand, and the organic phase was separated. The mixture was extracted with 360kg of ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain 55.2kg of an oil with a yield of 97.2%.

[0058] Step 2: In a 500L reactor, a methanol solution of compound 1b (53.8kg) was added, 180kg of methanol was added, 112kg of 25% aqueous sodium hydroxide solution was added, and the mixture was heated to 70-85°C. TLC detected that the raw materials were basically reacted completely, and the mixture was concentrated under reduced pressure to dryness. 110kg of water was added to dissolve the mixture, and the mixture was extracted with 70kg×4 of isopropyl ether. The pH of the aqueous phase was adjusted to 9-10 with 18% aqueous hydrochloric acid solution, and ethyl acetate was added for extraction. The organic phase was washed with water and saturated saline solution in turn, dried over anhydrous sodium sulfate, and filtered to obtain 18.0kg of solid with a yield of 61.2%.

[0059] Embodiment 2:

[0060] Step 1: Compound 1c (100 g) and methyl tert-butyl ether (500 mL) were added to a 1 L reaction bottle. Trifluoroacetic anhydride (221 g, 2.5 eq) was added dropwise under a nitrogen flow while controlling the temperature to no higher than 20 °C. The mixture was stirred until the reaction was complete. The mixture was concentrated under reduced pressure to obtain compound 1d. The crude product weighed 290 g. The oil was directly used for the next continuous reaction.

[0061] Step 2: Compound 1d (290 g) was dissolved in methanol (2.0 L) solvent, and 10 wt% palladium carbon catalyst (25 g) was added to prepare a slurry for continuous reaction; The slurry containing compound 1d and the catalyst was injected into the microreactor from port A through the preheated reaction plate at a flow rate of 27 ml / min, and a hydrogen flow was injected into the microreactor from port B at a flow rate of 220 ml / min. The pressure of the microreactor was maintained at 0.8-1.4 MPa, the reaction temperature was 60°C, the reaction residence time was 90-120 seconds, and the entire slurry was completely discharged in about 85 minutes (HPLC control, wherein 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 diastereomers was 1.1%, and the content of O-methyl impurities was 3.1%. Filter, concentrate to dryness under reduced pressure to obtain an oily substance, dilute with dichloromethane, adjust the pH to 9-10 with aqueous ammonia, separate layers, wash with brine, concentrate to obtain an oily substance, and recrystallize from ethyl acetate / n-heptane to obtain 65 g of a solid.

[0062] At the current flow rate in the microreactor, the conversion rate is 83.8%. If the reaction is continued 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.

[0063] Note: O-methyl impurity is 3-(1-(dimethylamino)-3-methoxy-2-methylpentane-3-yl)phenol.

[0064] Embodiment 3:

[0065] After compound 1d was prepared according to the method of Example 2, compound 1d (290 g) was dissolved in methanol (2.0 L) solvent, and 10 wt% palladium carbon catalyst (25 g) was added to prepare a slurry for continuous reaction; The slurry containing compound 1d and the catalyst was injected into the microreactor from port A through the preheated reaction plate at a flow rate of 25 ml / min, and a hydrogen flow was injected into the microreactor from port B at a flow rate of 400 ml / min. The pressure of the microreactor was maintained at 0.8-1.4 MPa, the reaction temperature was 40°C, the reaction residence time was 60-80 seconds, and the entire flow was completed in about 90 minutes (HPLC control, wherein the content of tapentadol was 44.6%, the content of unreacted compound 1d was 18.0%, the content of compound 1c was 27%, the content of diastereomers was 0.9%, and the content of O-methyl impurities was 6.1%. Tapentadol solid can be obtained according to the above treatment steps.

[0066] Embodiment 4:

[0067] After compound 1d was prepared according to the method of Example 2, compound 1d (290 g) was dissolved in methanol (2.0 L) solvent, and 10 wt% palladium carbon catalyst (25 g) was added to prepare a slurry for continuous reaction; The slurry containing compound 1d and the catalyst was injected into the microreactor from port A through the preheated reaction plate at a flow rate of 27 ml / min, and a hydrogen flow was injected into the microreactor from port B at a flow rate of 220 ml / min. The pressure of the microreactor was maintained at 0.8-1.4 MPa, the reaction temperature was 40°C, the reaction residence time was 80-100 seconds, and all flowed out in about 85 minutes (HPLC central control, wherein the content of tapentadol was 57.6%, the content of unreacted compound 1d was 18.5%, the content of compound 1c was 19.1%, the content of diastereomers was 0.6%, and the content of O-methyl impurities was 2.2%. Tapentadol solid can be obtained according to the above treatment steps.

[0068] Embodiment 5:

[0069] After compound 1d was prepared according to the method of Example 2, compound 1d (290 g) was dissolved in methanol (2.0 L) solvent, and 10 wt% palladium carbon catalyst (25 g) was added to prepare a slurry for continuous reaction; The slurry containing compound 1d and the catalyst was injected into the microreactor from port A through the preheated reaction plate at a flow rate of 26 ml / min, and the hydrogen flow was injected into the microreactor from port B at a flow rate of 220 ml / min. The pressure of the microreactor was maintained at 0.8-1.4 MPa, the reaction temperature was 80°C, the reaction residence time was 80-100 seconds, and all flowed out in about 88 minutes (HPLC control, wherein 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 diastereomers was 2.1%, and the content of O-methyl impurities was 9.1%. Tapentadol solid can be obtained according to the above treatment steps.

[0070] Embodiment 6:

[0071] After compound 1d was prepared according to the method of Example 2, compound 1d (290 g) was dissolved in methanol (2.0 L) solvent, and 10 wt% palladium carbon catalyst (25 g) was added to prepare a slurry for continuous reaction; The slurry containing compound 1d and the catalyst was injected into the microreactor from port A through the preheated reaction plate at a flow rate of 26 ml / min, and a hydrogen flow was injected into the microreactor from port B at a flow rate of 220 ml / min. The pressure of the microreactor was maintained at 0.8-1.4 MPa, the reaction temperature was 100° C., the reaction residence time was 80-100 seconds, and all flowed out in about 88 minutes (HPLC control, wherein 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 diastereomers was 4.8%, and the content of O-methyl impurities was 23.2%. Tapentadol solid can be obtained according to the above treatment steps.

[0072] Embodiment 7:

[0073] After compound 1d was prepared according to the method of Example 2, compound 1d (290 g) was dissolved in methanol (2.0 L) solvent, and 10 wt% palladium carbon catalyst (25 g) was added to prepare a slurry for continuous reaction; The slurry containing compound 1d and the catalyst was injected into the microreactor from port A through the preheated reaction plate at a flow rate of 26 ml / min, and a hydrogen flow was injected into the microreactor from port B at a flow rate of 220 ml / min. The pressure of the microreactor was maintained at 0.8-1.4 MPa, the reaction temperature was 115°C, the reaction residence time was 80-100 seconds, and the entire flow was completed in about 88 minutes (HPLC central control, wherein 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 diastereomers was 8.1%, and the content of O-methyl impurities was 39.2%. Tapentadol solid can be obtained according to the above treatment steps.

[0074] Comparative Example 1:

[0075] In a reaction flask, 183 g of compound 1c was dissolved in 1000 ml of tetrahydrofuran, cooled to 0-5° C. in an ice bath under nitrogen protection, and 2.7 L of trifluoroacetic anhydride was added dropwise. After the addition was complete, the reaction was stirred until the reaction was complete. The reaction solution was transferred to a 3 L reaction flask, 0.366 g of 10% Pd / C was added, and 0.8-1.0 MPa of hydrogen was introduced and stirred at 45-50° C. until the raw material was basically reacted completely as detected by TLC (HPLC control, wherein 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%). The product was filtered and concentrated to dryness under reduced pressure to obtain an oily substance, which was diluted with dichloromethane, adjusted to pH 9-10 with aqueous ammonia, layered, washed with brine, and concentrated to obtain an oily substance. The solid was recrystallized from ethyl acetate / n-heptane to obtain 98.9 g of a solid with a yield of 58% for two steps.

Claims

1. A method for preparing tapentadol or a pharmaceutically acceptable salt thereof, comprising: The step of injecting a suspension containing a compound of formula g and a catalyst and hydrogen into a microreactor for hydrogenation reaction, wherein the catalyst is selected from palladium, palladium hydroxide or platinum oxide, , where R 1 Selected from hydrogen, C 1-6 alkyl, 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, methoxyacyl, acetyl, ethoxyacyl, trifluoroacetyl, chloroacetyl, trichloroacetyl, propionyl, cyclopropylformyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, n-hexanoyl, isohexanoyl, 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, the alkyl, alkoxy or phenyl is optionally substituted with halogen or methyl; R 3 Each independently selected from C 1-6 Alkyl, wherein the alkyl 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.

2. The method according to claim 1, wherein said R 1 is selected from hydrogen, methyl or benzyl.

3. The method according to claim 1 or 2, wherein R 3 Selected from methyl or benzyl.

4. The method according to claim 1, wherein R 2 is selected from methyl, trifluoromethyl, trichloromethyl, methoxy or ethoxy.

5. The method according to claim 1, wherein the flow rate of the suspension containing the compound of formula g and the catalyst is selected from the ratio of 1:6 to 1:30 to the flow rate of hydrogen.

6. The method according to claim 1, wherein the suspension containing the compound of formula g and the catalyst is injected into the microreactor at a flow rate of 10-50 ml / min.

7. The method according to claim 1, wherein the hydrogen flow rate is selected from 40 to 1500 ml / min.

8. The method according to claim 1, wherein the hydrogenation reaction temperature is selected from 60 to 80°C.

9. The method according to claim 1, wherein the solvent used in the hydrogenation reaction is selected from methanol or ethanol.

10. The method according to claim 1, comprising the step of injecting the compound of formula g-1, a catalyst suspension and hydrogen into a microreactor for hydrogenation reaction, , R 2 As defined in claim 1.

11. The method according to claim 1, further comprising the step of reacting the compound of formula f with an acylating agent to form a compound of formula g, wherein the acylating agent is selected from acetic anhydride or trifluoroacetic anhydride, , R 1 , R 2 As defined in claim 1.

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