WO2014005546A1

WO2014005546A1 - Preparation method of tapentadol hydrochloride and compounds for preparation of tapentadol hydrochloride

Info

Publication number: WO2014005546A1
Application number: PCT/CN2013/078870
Authority: WO
Inventors: 杨相平; 李超; 张桂森; 彭卫娟
Original assignee: 江苏恩华药业股份有限公司
Priority date: 2012-07-06
Filing date: 2013-07-05
Publication date: 2014-01-09
Also published as: CN103159633A; CN103159633B

Abstract

The present invention relates to a preparation method of tapentadol hydrochloride and compounds for preparation of the tapentadol hydrochloride. The preparation method comprises steps using a compound in a formula V or a hydrochloride thereof as a raw material for preparation of the tapentadol hydrochloride, and is characterized in that the preparation method of the hydrochloride of the compound in the formula V comprises the following step that in solvent, a hydrochloride of a compound in a formula IV reacts with a hydrogenolysis reagent under existence of a catalytic agent. According to the process, chiral column separation is not needed, a removal condition of protecting group allyl is mild, yield is high, and industrialization production is benefited.

Description

Preparation of tapentadol and compounds for the preparation of tapentadol CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to Chinese Patent Application No. 201210234055.X, filed on Jul. 6, 2012, which is incorporated herein by reference. Join this application. Technical field

The invention belongs to the technical field of drug synthesis. In particular, the present invention provides a method of preparing Tafolo 1 and a compound for the preparation of tapentadol. Background technique

The chemical name of Tapentadol is 3-[(lR,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride, which is produced by Gruenenthal, Germany. The central nervous analgesic drug developed by the company has dual effects of opioid μ receptor agonism and norepinephrine reuptake inhibition. It was approved by the US FDA as an immediate release tablet in November 2008, and is clinically used to relieve the adult center. Moderate to severe acute pain in the nervous system. This compound has the following structure:

According to the literature, the current synthetic routes mainly include the following:

ΕΡ 0693475 first reported the synthesis of his tapenta. As shown in the following synthetic route, it comprises: 1-(dimethylamino)-2-methyl-3-pentanone and m-bromoanisole as starting materials, 4 by Grignard Reaction Isomers, after separation of the chiral column, the hydroxyl group is replaced by thionyl chloride, the hydroboration is reduced, and the concentrated hydrobromic acid is demethylated to obtain a single configuration of tapentadol.

The method has a long reaction step and is cumbersome to operate, and requires separation of the intermediate by a chiral column, so that it is difficult to industrialize. Moreover, this method uses a methyl group as a protecting group, and decarbonylation requires the use of volatile concentrated hydrobromic acid, which is susceptible to corrosion and is harmful to the environment.

CN 101948397 An improved method for the above route is provided: First, 1-(dimethylamino) _-2 -methyl-3-pentanone is resolved to give (dimethylamino) _-2 -methyl-3-pentene C The ketone is then subjected to a Grignard reaction with m-bromoanisole without chiral separation, by replacing the hydroxyl group with thionyl chloride, by hydroboration, and by dehydromethylation of concentrated hydrobromic acid to give a single configuration of tapentadol.

Although this method does not require a chiral column, the Grignard reaction yield is less than 50%, and a large amount of chlorinating reagent is used in chlorination, which is highly polluting to the environment, and thus is not environmentally friendly and industrialized. This method uses sodium borohydride for reduction, which is expensive and expensive, and the yield is still unsatisfactory. In addition, the method still uses a methyl group as a protecting group, and a volatile concentrated hydrobromic acid is used for demethylation, which is easily corroded and harmful to the environment.

WO 2008/012047 (CN 101495445) discloses a process for the preparation of tapentadol comprising: (S 3- (dimethylamino)-1-(3-methoxyphenyl)-2-methyl-1 - Acetone is obtained by Grignard reaction to obtain (2S,3R)-1-(dimethylamino 3-(3-methoxyphenyl 2-methyl-3-pentanol, which is in acid, anhydride or immobilized acid Dehydration under the catalysis of an ion exchange resin to form unsaturated (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine, and then Phase or heterogeneously catalyzed hydrogenation to give (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine in a single configuration, further salt formation Methyl gets him sprayed.

The advantage of this method over the method of EP 0693475 is that the route is significantly shortened and therefore more suitable for industrial production. However, there are still some shortcomings: there are by-products in the catalytic dehydration to form (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine. 3-(3-methoxyphenyl)-N,N,2-trimethylpent-2-en-1-amine is formed, which will introduce by-products of opposite configuration after reduction, which cannot be removed by simple methods. , is not conducive to getting high optical purity of his spray. Moreover, the Grignard reaction conditions are harsh, the steps are numerous, and the operation is cumbersome, which is not conducive to industrial production. In addition, the method still uses a methyl group as a protecting group, and a volatile concentrated hydrochloric acid is used in demethylation, which is liable to corrode equipment and is harmful to the environment. Summary of the invention

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for the preparation of tapentadol and a compound for the preparation of tapentadol to overcome the deficiencies of the prior art.

In a first aspect, the invention relates to a process for the preparation of tapentadol comprising the step of preparing tapentadol starting from the hydrochloride salt of a compound of formula V, characterized in that the hydrochloride salt of the compound of formula V The preparation method comprises the following steps:

The hydrochloride salt of the compound of formula IV is reacted with a hydrogenolysis reagent in the presence of a catalyst in a solvent to provide the hydrochloride salt of the compound of formula V.

Hydrochloride of a compound of formula IV Hydrochloride salt of a compound of formula V In one embodiment, the hydrochloride salt of the compound of formula IV is reacted with a hydrogenolysis reagent at a temperature of from 50 to 100. C, preferably 70-80 ° C; the reaction time is 5-20 hours, preferably 12-15 hours.

In another embodiment, the catalyst is selected from the group consisting of palladium, palladium on carbon (Pd/C), platinum, platinum on carbon, ruthenium and rhodium on carbon, preferably palladium on carbon (Pd/C).

In another embodiment, the hydrogenolysis reagent is ammonium formate.

In a preferred embodiment, the solvent is selected from the group consisting of ethanol, methanol, water, acetonitrile, tetrahydrofuran, isopropanol, acetone, and any mixture thereof, preferably methanol.

In another embodiment, the hydrochloride salt of the compound of formula IV: hydrogenolysis reagent has a molar ratio of 1:4:8, preferably 1:6.

In another preferred embodiment, the hydrochloride salt of the compound of the formula IV: catalyst has a mass ratio of 1:0.05-1:0.15, preferably 1:0.1.

The compound of the formula V or its hydrochloride can be used, for example, for the preparation of tapentadol. The method for preparing tapentadol from a compound of the formula V or its hydrochloride is a conventional method, for example, the method reported in CN 101495447. For example, a method for preparing tapentadol starting from a hydrochloride salt of a compound of formula V may include the following steps (step F in the reaction scheme):

i) adding the hydrochloride salt of the compound of the formula V to water, adding a basic substance thereto to a pH of 8-9 of the system, and then extracting and collecting the oil from the reaction product,

Wherein the alkaline substance is selected from 10-30% by weight of ammonia water or 5-30% by weight of sodium hydroxide; ii) an acylating agent is added to the above oil at -15 ° C to 5 ° C, and the reaction is 0.5. -5 hours, wherein the acylating agent is selected from the group consisting of acetic anhydride, acetyl chloride, trifluoroacetic anhydride, chloroacetic anhydride, chloroacetyl chloride, dichloroacetic anhydride, trichloroacetic anhydride, benzoic anhydride, benzoyl chloride, adjacent One or more of phthalic anhydride, phthaloyl dichloride, succinic anhydride, succinyl chloride, ethyl oxalyl chloride, methyl oxalyl chloride, methyl acid, methyl chloroformate and acetyl salicyl chloride;

Iii) adding a catalyst, introducing hydrogen into the reaction mixture and pressurizing it to 5 atmospheres, The reaction is carried out at 0-45 ° C for 1-5 h, and then the target product, heptastat, is recovered.

Wherein the catalyst is one or more of palladium, palladium on carbon, platinum, platinum on carbon, ruthenium on carbon and rhodium.

The hydrochloride salt of the compound of the formula V or the method for preparing tapentadol starting from the compound of the formula V or its hydrochloride salt may, for example, comprise the following steps:

i) Steps in the reaction plan G

Dehydrating a compound of formula V in the presence of an acidic material to provide the hydrochloride salt of a compound of formula VI, wherein the acidic material is selected from one or more of the group consisting of hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid and formic acid, The reaction temperature is 30-100 ° C, and the reaction time is 5-12 hours;

ϋ) Step H in the reaction scheme:

The compound of the formula VI is hydrogenated by hydrogen in the presence of a catalyst in the presence of a catalyst. After completion of the reaction, the desired product 3-[(lR,2R 3-(dimethylamino)-1-ethyl-2-methylpropyl) is obtained. Phenol monohydrochloride, the reaction process was followed by TLC until the reaction was complete.

Wherein the reaction temperature is 10-50 ° C, the solvent is selected from one or more of the group consisting of ethanol, methanol, water, tetrahydrofuran, isopropanol and dichloromethane, and the catalyst used is palladium on carbon (Pd/C).

In a second aspect, the method of preparing a compound of formula IV comprises the steps of:

The compound of formula III is reacted with an organic solution of ethylmagnesium halide in an inert reaction medium under an inert atmosphere to provide a compound of formula IV which is optionally further converted to the hydrochloride salt.

III IV Hydrochloride of the compound of formula IV In one embodiment, the temperature of the reaction of the compound of formula III with an organic solution of ethylmagnesium halide is 5-50 ° C _{; the} reaction time is 5-15 hours.

In another embodiment, the inert reaction medium is selected from one or more of the group consisting of diethyl ether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, and tert-butyl methyl ether.

In another embodiment, the inert atmosphere is preferably a nitrogen atmosphere.

In one embodiment, the organic solution of the ethylmagnesium halide is a solution of ethylmagnesium halide in diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or toluene.

In another embodiment, the organic solution of the ethylmagnesium halide has a concentration of from 0.5 M to 3 M, preferably from 1 M to 2 M.

In a preferred embodiment, the ethyl magnesium halide is ethyl magnesium bromide.

In another preferred embodiment, the molar ratio of the compound of formula III to ethylmagnesium halide is from 1:1 to 1:3.

In a further preferred embodiment, the obtained compound of the formula IV is reacted with a solution of hydrogen chloride in ethyl acetate to obtain the hydrochloride salt of the compound of the formula IV. Preferably, the obtained compound of the formula IV is dissolved in a solvent (preferably acetone), and a solution of hydrogen chloride in ethyl acetate (concentration preferably 18-22% w/w) is added to the resulting mixture until the pH is acidic (for example 3- 5), optionally stir for 1-10 h, then back The hydrochloride salt of the compound of formula IV is obtained.

In a third aspect, the method of preparing a compound of formula III comprises the steps of:

The compound of formula II is reacted with a resolving reagent in an organic solvent to provide a compound of formula III.

In one embodiment, the temperature at which the compound of formula II is reacted with the resolving agent is from 10 to 50 ° C, preferably from 35 to 40. C; The reaction time is from 10 to 60 hours, preferably from 30 to 50 hours.

In another embodiment, the organic solvent is one or more of acetone, ethanol, acetonitrile, ethyl acetate, methanol, isopropanol, and diethyl ether, preferably acetone.

In another embodiment, the resolving agent is selected from the group consisting of L-(-dibenzoyltartaric acid, L-(-dibenzoyltartaric acid monohydrate, and D-(+ dibenzoyltartaric acid, preferably LO-) Dibenzoyl tartaric acid monohydrate.

In a preferred embodiment, the molar ratio of the compound of formula II to the resolving agent is from 1:0.90-1:1.1.

In a preferred embodiment, a resolved salt is obtained after reaction of the compound of formula II with a resolving agent, the resolved salt is added to water, the pH of the resulting mixture is adjusted to be basic (eg, 8-11), and then recovered. III compound. The pH is preferably adjusted by an aqueous sodium hydroxide solution (concentration preferably 5-20% by weight).

In a fourth aspect, the method of preparing a compound of formula II comprises the steps of:

The compound of the formula I is reacted with dimethylamine hydrochloride and paraformaldehyde in the presence of an acidic substance in a solvent to give a compound of the formula II.

In one embodiment, the temperature of the reaction of the compound of formula I with dimethylamine hydrochloride and paraformaldehyde is from 50 to 100 ° C; the reaction time is from 10 to 25 hours, preferably from 15 to 18 hours. In another embodiment, the solvent is selected from one or more of the group consisting of methanol, ethanol, isopropanol, acetonitrile, and tetrahydrofuran, or the solvent is water and methanol, ethanol, isopropanol, acetonitrile or tetrahydrofuran. One or more mixtures mixed in any ratio.

In one embodiment, the acidic material is selected from one or more of the group consisting of hydrochloric acid, sulfuric acid, acetic acid, formic acid, methanesulfonic acid, and p-toluenesulfonic acid.

In a preferred embodiment, the molar ratio of the components is:

a compound of formula I: dimethylamine hydrochloride = 1 : 2 - 1 : 4, preferably 1: 3;

Compound of formula I: paraformaldehyde = 1:2:4, preferably 1:3;

Compound of formula I: Acidic substance = 1: 0.01-1: 0.3, preferably 1:0.1.

In another preferred embodiment, after reacting the compound of formula I with dimethylamine hydrochloride and paraformaldehyde, water is added to the reaction system and the pH of the reaction system is adjusted to be basic (eg, 9-11). The compound of formula II is then recovered, for example by extraction from the aqueous phase followed by concentration. The pH is preferably adjusted by an aqueous sodium hydroxide solution (concentration of 5 to 30% by weight, preferably 5 to 15% by weight).

In a fifth aspect, the method of preparing a compound of formula I comprises the steps of:

The 3-hydroxypropiophenone is reacted with 3-chloropropene in the presence of a catalyst and a basic substance in a solvent to obtain a compound of the formula I.

In one embodiment, the temperature at which 3-hydroxypropiophenone is reacted with 3-chloropropene is 30-110 ° C, preferably 50-60 ° C; the reaction time is 20-60 hours, preferably 30-50 hours.

In another embodiment, the solvent is selected from one or more of the group consisting of ethanol, methanol, acetonitrile, toluene, tetrahydrofuran, acetone, and methylene chloride, preferably acetone.

In one embodiment, the basic substance is selected from one or more of the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydrogencarbonate.

In another embodiment, the catalyst is selected from one or more of the group consisting of sodium iodide, potassium iodide, sodium bromide and potassium bromide, preferably sodium iodide.

In a further preferred embodiment, the molar ratio of the components is:

3-hydroxypropiophenone: 3-chloropropene=1:1-1:1.5, preferably 1:1.2; 3-hydroxypropiophenone: catalyst = 1: 0.05-1: 0.15, preferably 1:0.1;

3-hydroxypropiophenone: basic substance = 1 : 1-2, preferably 1: 1.5.

In a sixth aspect, the invention also relates to a method of preparing tapentadol, the method comprising the steps wherein the parameters and conditions of each step are as detailed above:

A) reacting 3-hydroxypropiophenone with 3-chloropropene in the presence of a catalyst and a basic substance in a solvent to obtain a compound of formula I;

B) reacting a compound of formula I with dimethylamine hydrochloride and paraformaldehyde in the presence of an acidic species in a solvent to provide a compound of formula II;

C) reacting a compound of formula II with a resolving reagent in an organic solvent to obtain a compound of formula III; D) reacting a compound of formula III with an organic solution of ethylmagnesium halide in an inert reaction medium under an inert atmosphere to give a compound of IV, which is optionally further converted to the hydrochloride salt;

E) reacting the hydrochloride salt of the compound of formula IV with a hydrogenolysis reagent in the presence of a catalyst to provide the hydrochloride salt of the compound of formula V;

F) or G)-H) Preparation of tapentadol from the hydrochloride salt of the compound of formula V.

The method disclosed in the invention uses 3-hydroxypropiophenone as a starting material, prepares a compound of formula I by allyl protection, prepares a compound of formula II by Mannich reaction, and dismantles The compound of formula III is prepared by fractional reagent, the compound of formula IV is prepared by addition with ethylmagnesium bromide, and the compound of formula V is prepared by deprotecting the allyl group; finally, it can be obtained by dehydration or catalytic hydrogenation, or by acyl group. Chemical, hydrodeesterification to obtain heptadol. The method of the present invention does not require the use of a chiral column for resolution, the removal conditions of the protecting allylic group are mild, the yield is high, and industrial production is easy.

In a seventh aspect, the invention also relates to the following compounds or their respective salts:

The above compounds and their respective salts can be used as intermediates for the synthesis of tapentadol. Thus, compounds I-IV and/or their salts may also be referred to herein as intermediates I-IV, respectively.

In a preferred embodiment, the salts of the above compounds are each independently a methanesulfonate, an oxalate, a maleate, a hydrochloride, etc., preferably a hydrochloride.

The compounds of the invention can be converted to their salt forms as desired, for example the hydrochloride salt. For example, the hydrochloride salt of the compound of the present invention can be obtained by reacting the compound with an ethyl acetate solution of hydrogen chloride

It is obtained by a reaction (concentration is preferably 18-22% w/w). Thus, as used herein, reference to "a compound" also encompasses salts of the compound, including but not limited to mesylate, oxalate, maleate, hydrochloride, and the like, preferably the hydrochloride, and the present invention Salts of the compounds are also included within the scope of the invention. detailed description

Preferred embodiments of the method of the invention are described in more detail below. Those skilled in the art will appreciate that these preferred embodiments are merely illustrative of the invention and are not to be construed as limiting thereof. The patents, patent publications, and scientific literature and other publications cited herein are hereby incorporated by reference in their entirety.

The raw materials and reagents used in this article are all commercially available. The main raw materials and reagent sources are as follows:

3-hydroxypropiophenone was purchased from Hangzhou Meike Pharmaceutical Technology Co., Ltd., 3-chloropropene was purchased from Shanghai Jiachen Chemical Co., Ltd., and L-(-dibenzoyltartaric acid monohydrate (L-(-)-DBTA) was purchased from Zhejiang Dongyang Lingxing Biochemical Co., Ltd. Other reagents and compounds are purchased from Lingfeng Chemical Reagent Co., Ltd. unless otherwise specified. The proportions and percentages used herein are based on the weight ratio unless otherwise indicated. Example 1: 3-Allyl

3-Hydroxypropiophenone (300.1 g), potassium carbonate (450.0 g) and sodium iodide (40.0 g) were added to acetone (2 L), and stirred at room temperature and 3-chloropropene (208.0 g) was added dropwise. After the addition was completed, the reaction mixture was heated to reflux temperature and stirred for 36 h. After completion of the reaction, the reaction mixture was cooled to 25 ° C, and potassium carbonate was removed by suction filtration, and acetone was evaporated under reduced pressure. After washing, the organic phase was dried over magnesium sulfate, and the organic layer was evaporated.

ifiNMR (400 MHz, DMSO-i/ ₆ ) δ: 7.52 (d, /= 8.0 Hz, 1H, ArH), 7.49 (s, 1H)

ArH), 7.33(t, / = 8.0 Hz, 1H, ArH), 7.09(d, / = 8.0 Hz, 1H, ArH), 6.09-5.99(m, 1H, CH), 5.42(d, / = 13.2 Hz , 1H, CH ₂ ), 5.28 (d, / = 10.4 Hz, 1H, CH ₂ ), 4.56 (d, J = 5.2 Hz, 2H, CH ₂ ), 2.96 (dd J _} = 7.6 Hz, / ₂ =14 · 4 Hz, 2H, CH ₂ ) 1.20 (t, J = 7.2 Hz, 3H, CH ₃ ). Example 2: Synthesis of 3-allyloxypropiophenone (compound of formula I)

3-Hydroxypropiophenone (30.1 g), sodium carbonate (51.0 g) and sodium bromide (3.5 g) were added to ethanol (150 mL), and stirred at room temperature, and 3-chloropropene (18.0 g) was added dropwise. After the completion of the dropwise addition, stirring was further carried out for 1 h, and then the reaction mixture was heated to 40 ° C and stirred under reflux for 30 h. After completion of the reaction, the reaction mixture was cooled to 25 ° C, and sodium carbonate was removed by suction filtration, and ethanol was evaporated under reduced pressure, and then the oil was dissolved by adding ethyl acetate (120 mL) and washed with 50 mL of water. After washing, the organic phase was dried (MgSO4), and evaporated.

ifiNMR (400 MHz, DMSO-i/ ₆ ) δ: 7.52 (d, /= 8.0 Hz, 1H, ArH), 7.49 (s, 1H)

ArH), 7.33(t, / = 8.0 Hz, 1H, ArH), 7.09(d, / = 8.0 Hz, 1H, ArH), 6.09-5.99(m, 1H, CH), 5.42(d, / = 13.2 Hz , 1H, CH ₂ ), 5.28(d, / = 10.4 Hz, 1H, CH ₂ ), 4.56(d,

J = 5.2 Hz, 2H, CH ₂ ), 2.96 (dd J _} = 7.6 Hz, / ₂ =14·4 Hz, 2H, CH ₂ )1.20(t, J =

7.2Hz, 3H, CH ₃ ). Example 3: Synthesis of 3-allyloxypropiophenone (compound of formula I)

3-Hydroxypropiophenone (25.3 g), sodium hydrogencarbonate (38.0 g) and potassium bromide (2.5 g) were added to toluene (100 mL), and 3-chloropropene (18.0 g) was stirred at room temperature. Stir for 1 h after the addition. Then, the reaction mixture was heated to 110 ° C and stirred under reflux for 28 ho. After the reaction was completed, the reaction mixture was cooled to 25 ° C, sodium bicarbonate was removed by suction filtration, and toluene was removed under reduced pressure. Wash with 50 mL of water. After the completion of the washing, the organic phase was dried over magnesium sulfate, and the organic layer was evaporated to dryness to afford to afford ethyl 3- propyloxypropiophenone (24.8 g).

IfiNMR (400 MHz, DMSO-i/ ₆ ) δ: 7.52 (d, / = 8.0 Hz, 1H, ArH), 7.49 (s, 1H ArH), 7.33 (t, J = 8.0 Hz, 1H, ArH), 7.09 (d, J = 8.0 Hz, 1H, ArH), 6.09-5.99 (m, 1H, CH), 5.42 (d, / = 13.2 Hz, 1H, CH ₂ ), 5.28 (d, / = 10.4 Hz, 1H, CH ₂ ), 4.56 (d, J = 5.2 Hz, 2H, CH ₂ ), 2.96 (dd J _} = 7.6 Hz, / ₂ =14·4 Hz, 2H, CH ₂ )1.20 (t, J = 7.2 Hz, 3H, CH ₃ ).

Synthesis

I II

To a mixture of isopropanol (2 L) and 3-allyloxypropiophenone (370.8 g) was added dimethylamine hydrochloride (489.2 g) at room temperature and stirred, then paraformaldehyde (180.5 g) was added. And aqueous hydrochloric acid (50 mL, 36% w/w). The mixture was heated to reflux temperature and stirred at reflux for 18 h.

The reaction product was cooled to 20 ° C, and after removing the isopropanol under reduced pressure, water (1.5 L) and ethyl acetate (0.3 L) were added, and the upper organic phase was discarded. An aqueous sodium hydroxide solution (30% w/w) was added dropwise to the aqueous layer with stirring until pH = 10 while maintaining the temperature below 25 °C. Extracted with EtOAc (EtOAc) (EtOAc) , the yield was 94.3%.

IfiNMR (400 MHz, DMSO- ₆ ) δ: , 7.66 (d, J = 7.6 Hz, 1H, ArH), 7.56 (s, 1H, ArH), 7.41 (t, / = 8.0 Hz, 1H, ArH), 7.18 (d , / = 8.0 Hz, 1H, ArH), 6.11-6.02 (m, 1H, CH), 5.45 (d, /= 13.2 Hz, 1H, CH ₂ ), 5.31 (d, /= 10.4 Hz, 1H, CH ₂ ), 4.45 (t, /= 7.6 Hz, 1H, CH), 3.13 (d, /= 12.4 Hz, 1H, CH ₂ ), 2.85 (d, J = 4.8 Hz, 3H, CH ₃ ), 2.57 (d, / = 4.4 Hz, 3H, CH ₃ ) 1.31 (d, /= 7.2 Hz, 3H, CH ₃ ). Example 5: l-(3-allyloxyphenyl 2-methyl-3-(dimethylamino I-acetone (compound of formula II) )Synthesis

To a mixture of acetonitrile (200 mL) and 3-allyloxypropiophenone (35.8 g) was added dimethylamine hydrochloride (24.5 g) and stirred at room temperature, then paraformaldehyde (10.3 g) and Aqueous sulfuric acid (1 mL, 98% w/w). The mixture was heated to 55 ° C and stirred for 18 h. The reaction mixture was cooled to 20 ° C. After acetonitrile was removed under reduced pressure, water (150mL) and ethyl acetate (30mL) were added and the upper organic phase was discarded. An aqueous sodium hydroxide solution (30% w/w) was added dropwise to the aqueous layer with stirring to pH = 9, while maintaining the temperature below 25 °C. Extracted with 100 mL of ethyl acetate, dried over magnesium sulfate and evaporated to give crystals of 1-(3-propenyloxyphenyl)-2-methyl-3-(dimethylamino)-1-propanone (41.2 g) , the yield was 88.4%.

IfiNMR (400 MHz, DMSO- ₆ ) δ: , 7.66 (d, J = 7.6 Hz, 1H, ArH), 7.56 (s, 1H, ArH), 7.41 (t, / = 8.0 Hz, 1H, ArH), 7.18 (d , / = 8.0 Hz, 1H, ArH), 6.11-6.02 (m, 1H, CH), 5.45 (d, /= 13.2 Hz, 1H, CH ₂ ), 5.31 (d, /= 10.4 Hz, 1H, CH ₂ ), 4.45 (t, /= 7.6 Hz, 1H, CH), 3.13 (d, /= 12.4 Hz, 1H, CH ₂ ), 2.85 (d, J = 4.8 Hz, 3H, CH ₃ ), 2.57 ( d, / = 4.4 Hz, 3H, CH ₃ ) 1.31 (d, / = 7.2 Hz, 3H, CH ₃ ). Example 6: 1-(3-allyloxyphenyl 2-methyl-3- ( Dimethylamino I-acetone hydrochloride (formula II)

I hydrochloride of the compound of formula II

To a mixture of isopropanol (2 L) and 3-allyloxypropiophenone (370.8 g) was added dimethylamine hydrochloride (489.2 g) at room temperature and stirred, then paraformaldehyde (180.5 g) was added. And aqueous hydrochloric acid (50 mL, 36% w/w). The mixture was heated to reflux temperature and stirred at reflux for 18 h. The reaction mixture was cooled to 20 ° C, isopropanol was removed under reduced pressure, water was added (1.5 L) ₀ was added dropwise with stirring aqueous sodium hydroxide solution (30% w / w) to the aqueous layer to pH = 10, while Keep the temperature below 25 °C. With 0.8 L Extracted with ethyl acetate, dried over magnesium sulfate and concentrated to give 1-(3-ethylpropoxyphenyl-2-methyl-3-(dimethylamino)-1-propane as an oil.

All the above oils were added to acetone (1.8 L), completely dissolved, and then a solution of hydrogen chloride in ethyl acetate (19.6% w/w) was added dropwise to pH=4. After stirring for 1 h, solids appeared, stirring was continued for 5 h and then filtered. . The product was dried at 65 ° C to give the hydrochloride salt of the compound of formula II (496.0 g) in a yield of 89.5%.

IfiNMR (400 MHz, DMSO-i/ ₆ ) δ: 12.69 (s, 1 Η, HC1), 7.69 (d, J = 7.6 Hz, 1H, ArH), 7.58 (s, 1H, ArH), 7.43 (t, / = 8.0 Hz, 1H, ArH), 7.20 (d , / = 8.0 Hz, 1H, ArH), 6.11-6.02 (m, 1H, CH), 5.47 (d, /= 13.2 Hz, 1H, CH ₂ ), 5.32 (d, /= 10.4 Hz, 1H, CH ₂ ), 4.46 (t, J = 7.6 Hz, 1H, CH), 3.15 (d, J = 12.4 Hz, 1H, CH ₂ ), 2.87 (d, J = 4.8 Hz, 3H, CH ₃ ), 2.59 (d, / = 4.4 Hz, 3H, CH ₃ ) 1.32 (d, / = 7.2 Hz, 3H, CH ₃ ). mp = 132-133 ° C. Example 7: 1 Synthesis of 3-(3-allyloxyphenyl 2-methyl-3-(dimethylamino I-acetone hydrochloride (hydrochloride of compound of formula II)

To a mixture of acetonitrile (200 mL) and 3-allyloxypropiophenone (35.8 g) was added dimethylamine hydrochloride (24.5 g) and stirred at room temperature, then paraformaldehyde (10.3 g) and Aqueous sulfuric acid (1 mL, 98% w/w). The mixture was heated to 55 ° C and stirred for 18 h. The reaction mixture was cooled to 20 ° C, acetonitrile was removed under reduced pressure and water (150 mL). An aqueous solution of sodium hydroxide (30% w/w) was added dropwise to the aqueous layer with stirring to pH = l l while maintaining the temperature below 25 °C. It was extracted with 100 mL of ethyl acetate, dried over magnesium sulfate and evaporated to ethylamine.

Add all the above oils to acetone (150 mL), completely dissolve, then add hydrogen chloride in ethyl acetate solution (20.4% w/w) to pH=4, continue to stir at room temperature for 1 h, solids continue, stirring for 5 h After suction filtration. The product was dried at 65 ° C to give the hydrochloride salt of Intermediate II (47.3 g).

IfiNMR (400 MHz, DMSO- ₆ ) δ: 12.69 (s, 1 Η, HC1), 7.69 (d, J = 7.6 Hz, 1H, ArH), 7.58 (s, 1H, ArH), 7.43 (t, / = 8.0 Hz, 1H, ArH), 7.20(d , / = 8.0 Hz, 1H, ArH), 6.11-6.02(m, 1H, CH), 5.47(d, /= 13.2 Hz, 1H, CH ₂ ), 5.32(d , /= 10.4 Hz, 1H, CH ₂ ), 4.46(t, J = 7.6 Hz, 1H, CH), 3.15(d, J = 12.4Hz, 1H, CH ₂ ), 2.87 (d, J = 4.8 Hz, 3H, CH ₃ ), 2.59 (d, / = 4.4 Hz, 3H, CH ₃ ) 1.32 (d, / = 7.2 Hz, 3H, CH ₃ ). mp=132-133° C. Example 8: Synthesis of 1-(3-allyloxyphenyl 2-methyl-3-(dimethylamino I-acetone hydrochloride (hydrochloride of the compound of formula II)

To a mixture of aqueous ethanol (150 mL, 70% by volume) and 3-allyloxypropiophenone (30.0 g) was added dimethylamine hydrochloride (22.0 g) at room temperature and stirred, then paraformaldehyde was added. (9.9 g) and aqueous formic acid (5 mL, 88% w/w). The mixture was heated to 90 ° C and stirred for 17 h. The reaction mixture was cooled to 20 ° C, and ethanol was evaporated under reduced pressure and water (100 mL). An aqueous sodium hydroxide solution (30% w/w) was added dropwise to the aqueous layer with stirring to pH = 10 while maintaining the temperature below 25 °C. Extracted with 100 mL of ethyl acetate, dried (MgSO4)

All the above oils were added to acetone (130 mL), completely dissolved, and then a solution of hydrogen chloride in ethyl acetate (20.4% w/w) was added dropwise to pH=4. After stirring at room temperature for 1 h, solids appeared and stirring was continued for 5 h. After suction filtration. The product was dried at 65 ° C to give the hydrochloride salt (34.5 g) of Intermediate II with a yield of 76.9%.

IfiNMR (400 MHz, DMSO-i/ ₆ ) δ: 12.69 (s, 1H, HCl), 7.69 (d, J = 7.6 Hz, 1H, ArH), 7.58 (s, 1H, ArH), 7.43 (t, / = 8.0 Hz, 1H, ArH), 7.20 (d , / = 8.0 Hz, 1H, ArH), 6.11-6.02 (m, 1H, CH), 5.47 (d, /= 13.2 Hz, 1H, CH ₂ ), 5.32 (d, /= 10.4 Hz, 1H, CH ₂ ), 4.46 (t, J = 7.6 Hz, 1H, CH), 3.15 (d, J = 12.4 Hz, 1H, CH ₂ ), 2.87 (d, J = 4.8 Hz, 3H, CH ₃ ), 2.59 (d, / = 4.4 Hz, 3H, CH ₃ ) 1.32 (d, / = 7.2 Hz, 3H, CH ₃ ). mp = 132-133 ° C. Example 9: Alkene Synthesis of propoxyphenyl 2-methyl-3-(dimethylamino I-acetone (compound of formula III)

Add L-(-)-dibenzoyltartaric acid monohydrate (694.8 g) to acetone (2 L) and stir The solution was completely dissolved, and then a solution of 1-(3-allyloxyphenyl 2-methyl-3-(dimethylamino 1-propanone (454.0 g) in acetone (0.5 L) was added dropwise. Heat to 38 ° C and stir at this temperature for 48 h, then slowly cool the reaction mixture to 23 ° C. The precipitate was filtered off and dried under vacuum at 45 ° C to give (2 -1-(3- ally Oxyphenyl)-2-methyl-3-(dimethylamino)-1-propanone L-(-)-dibenzoyl tartrate (i.e., resolved salt) (862.9 g).

The resolved salt (862.9 g) was added to water (2 L) and stirred, and sodium hydroxide (10% w/w) was added to the mixture to pH = 9. The organic phase was extracted with ethyl acetate (1.5 L). After separation of the phases, the organic phase was dried and concentrated to give (2 -1-(3-propenyloxyphenyl 2-methyl-3-(dimethylamino) 1- Acetone (354.3 g), yield 78.0%.

ifiNMR (400 MHz, DMSO- ₆ ) δ: , 7.66 (d, J = 7.6 Hz, 1H, ArH), 7.56 (s,

1H, ArH), 7.41 (t , / = 8.0 Hz, 1H, ArH), 7.18 (d , / = 8.0 Hz, 1H, ArH), 6.11-6.02 (m, 1H, CH), 5.45 (d, / = 13.2 Hz, 1H, CH ₂ ), 5.31(d, /= 10.4 Hz, 1H, CH ₂ ), 4.45(t, / = 7.6 Hz, 1H, CH), 3.13(d, / = 12.4Hz, 1H, CH ₂ ), 2.85 (d, J = 4.8 Hz, 3H, CH ₃ ), 2.57 (d, / = 4.4 Hz, 3H, CH ₃ ) 1.31 (d, /= 7.2 Hz, 3H, CH ₃ ). Example 10 : i2 Vl-i3-allyloxyphenyl 2-methyl-3-(dimethylamino I-acetone hydrochloride (salt of compound of formula III)

The hydrochloride salt of the compound of formula III

Add L-(-)-dibenzoyltartaric acid monohydrate (694.8 g) to acetone (2 L) and stir to dissolve completely, then add 1-(3-allyloxyphenyl)- A solution of 2-methyl-3-(dimethylamino)-1-propanone (454.0 g) in acetone (0.5 L). After completion of the dropwise addition, the reaction mixture was heated to 38 ° C and stirred at this temperature for 48 h, then the reaction mixture was slowly cooled to 23 ° C. The precipitate was filtered off and dried under vacuum at 45 ° C to give (2-1-(3-allyloxyphenyl)-2-methyl-3-(dimethylamino)-1-propanone L- ( -) - Dibenzoyl tartrate (ie, split salt) (862.9 g).

The resolved salt (862.9 g) was added to water (2 L) and stirred, and sodium hydroxide (10% w/w) was added dropwise to the obtained mixture to pH=9. The organic phase was extracted with ethyl acetate (1.5 L). After separation of the phases, the organic phase was dried and concentrated to give (2 -1-(3-propenyloxyphenyl 2-methyl-3-(dimethylamino) 1- Acetone (intermediate oxime).

The obtained intermediate III was all added to acetone (1.8 L), completely dissolved, and then a solution of hydrogen chloride in ethyl acetate (20.4% w/w) was added dropwise to pH=4, and stirring was continued at room temperature for 1 hour, solids continued and stirring was continued. 5 h, then suction filtration. The obtained product was dried at 65 ° C to give the hydrochloride salt (354.3 g) of Intermediate III. The yield was 78.0%.

IfiNMR (400 MHz, DMSO-i/ ₆ ) δ: 12.69 (s, 1 Η, HC1), 7.69 (d, J = 7.6 Hz, 1H, ArH), 7.58 (s, 1H, ArH), 7.43 (t, / = 8.0 Hz, 1H, ArH), 7.20 (d , / = 8.0 Hz, 1H, ArH), 6.11-6.02 (m, 1H, CH), 5.47 (d, / = 13.2 Hz, 1H, CH ₂ ), 5.32 (d, / = 10.4 Hz, 1H, CH ₂ ), 4.46 (t, J = 7.6 Hz, 1H, CH), 3.15 (d, J = 12.4 Hz, 1H, CH ₂ ), 2.87 (d, J = 4.8 Hz, 3H, CH ₃ ), 2.59 (d, J = 4.4 Hz, 3H, CH ₃ ) 1.32 (d, J = 7.2 Hz, 3H, CH ₃ ).

[a ⁰ = 11.5° (c 1.0, CH ₃ OH), mp = 134-135 ° C. Example 11: (2 -1-(3-allyloxyphenyl 2-methyl-3-) Synthesis of methylamino I-acetone hydrochloride (hydrochloride salt of compound of formula III)

L-(-dibenzoyltartaric acid (67.5 g) was added to isopropanol (80 mL) and stirred to complete dissolution, and 1-(3-allyloxyphenyl)- was added dropwise to the resulting mixture. 2-methyl-3-(dimethylamino)-1-propanone (45.4 g), after the addition was completed, the reaction mixture was heated to 50 ° C and stirred at this temperature 18 and then the reaction mixture was slowly cooled to 18 ° C. The precipitate was filtered off and dried under vacuum at 45 ° C to give (2-1-(3-allyloxyphenyl)-2-methyl-3-(dimethylamino)-1-propanone L - (-)-Dibenzoyl tartrate (ie, split salt) (78.9 g).

78.9 g of the resolved salt was added to 200 mL of water, stirred, and sodium hydroxide (10% w/w) was added dropwise to pH=10. The organic phase was extracted with ethyl acetate (100 mL). After separation of two phases, the organic phase was dried and concentrated to give (2-1-(3-propenyloxyphenyl)-2-methyl-3- (2) Methylamino)-1-propanone (Intermediate III)

The obtained intermediate III was all added to acetone (180 mL), completely dissolved, and then a solution of hydrogen chloride in ethyl acetate (20.4% w/w) was added dropwise to pH=4, and stirring was continued for 1 hour at room temperature. Stir for 5 h, then suction filtration. The obtained product was dried at 65 ° C to obtain the hydrochloride (28.3 g) of Intermediate III in a yield of 62.3%.

ifiNMR (400 MHz, DMSO-i/ ₆ ) δ: 12.69 (s, 1 Η, HC1), 7.69 (d, J = 7.6 Hz, 1H, ArH), 7.58(s, 1H, ArH), 7.43(t , / = 8.0 Hz, 1H, ArH), 7.20(d , / = 8.0 Hz, 1H, ArH), 6.11-6.02 (m, 1H, CH), 5.47(d, /= 13.2 Hz, 1H, CH ₂ ), 5.32(d, /= 10.4 Hz, 1H, CH ₂ ), 4.46(t, J = 7.6 Hz, 1H, CH), 3.15(d , J = 12.4Hz, 1H, CH ₂ ), 2.87(d, J = 4.8Hz, 3H, CH ₃ ), 2.59(d, / = 4.4Hz, 3H, CH ₃ )1.32(d, / = 7.2Hz, 3H, CH ₃ ).

[a ⁰ = 11.5° (c 1.0, CH ₃ OH), mp = 134-135 ° C. Example 12: (2 & 3RV1-(dimethylamino 2-methyl-3-(3-allyloxy) Synthesis of Phenyl 3-pentanol (Compound of Formula IV)

III IV

Magnesium dust (86.1 g) was added to tetrahydrofuran (100 mL) under a nitrogen atmosphere, and then a solution of bromoacetone (356.2 g) in tetrahydrofuran (600 mL) (10 mL) was added dropwise. The resulting mixture was heated to 35 ° C to 40 ° C to initiate a Grignard reaction, maintaining the temperature at 45 ° C to 50 ° C and continuing to dropwise add the remaining ethidium bromide in tetrahydrofuran. After the addition was completed, the reaction mixture was kept at 60 ° C for 1 h, and then the mouth of the reaction (2 -1-(3-allyloxyphenyl)-2-methyl-3-(dimethylamino) - 1-Acetone (354.3 g) in tetrahydrofuran (700 mL), maintaining the temperature at 10 ° C. After the addition was completed, the reaction mixture was stirred at room temperature for 18 ho then a saturated aqueous solution of ammonium chloride (340 mL) was added dropwise. The reaction mixture was stirred at room temperature for 10 min. EtOAc (EtOAc) (EtOAc) Methyl-3-(3-allyloxyphenyl)-3-pentanol (Intermediate IV) (362.3 g).

IfiNMR (400 MHz, DMSO-i/ ₆ ) δ: 7.26-7.20 (m, 1H, ArH), 6.97-6.93 (m, 2H ArH), 6.79 (d, / = 8.0 Hz, 1H, ArH), 6.08- 6.00 (m, 1H, CH), 5.40 (d, / = 13.2 Hz _: 1H, CH ₂ ), 5.29 (d, / = 10.4 Hz, 1H, CH ₂ ), 4.53 (d, / = 5.2 Hz, 2H, CH ₂ ), 2.85(s, 6H, CH ₃ ), 2.55-2.53 (m, 1H, CH ₂ ), 2.36-2.33 (m, 1H, CH ₂ ), 2.16-2.12 (m, 1H, CH ₂ ), 1.97-1.91 (m, 1H, CH ₂ ), 1.07 (d, J = 6.8 Hz, 3H, CH ₃ ), 0.79 (t, J = 7.2 Hz, 3H, CH ₃ ). Example 13: Synthesis of OS, 3R dimethylamino 2-methyl-3-(3-allyloxyphenyl 3-pentanol (compound of formula IV) and its hydrochloride

III IV Hydrochloride salt of the compound of formula IV Magnesium (86.1 g) was added to tetrahydrofuran (100 mL) under a nitrogen atmosphere, and a solution of bromoacetone (356.2 g) in tetrahydrofuran (600 mL) (10 mL) was added dropwise. The resulting mixture was heated to 35 ° C to 40 ° C to initiate a Grignard reaction, maintaining the temperature at 45 ° C to 50 ° C and continuing to dropwise add the remaining ethidium bromide in tetrahydrofuran. After the addition was completed, the reaction mixture was kept at 60 ° C for 1 h. Then, a solution of (2-1-(3-allyloxyphenyl)-2-methyl-3-(dimethylamino)-1-propanone (354.3 g) in tetrahydrofuran (700 mL) was added dropwise to maintain the temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 18 ho. A saturated aqueous solution of ammonium chloride (340 mL) was added dropwise to the reaction mixture and stirred at room temperature for 10 min. After the extraction, the organic phase was dried, and the organic layer was evaporated to dryness to give (2 & 3R)-1-(dimethylamino)-2-methyl-3-(3-allyloxyphenyl 3-pentanol (Intermediate IV) (362.3 g).

The oil obtained above was all added to acetone (1.8 L) at room temperature. After the dissolution was completed, a solution of hydrogen chloride in ethyl acetate (20.4% w/w) was added dropwise to pH=4. After the addition was completed, the mixture was stirred at room temperature. . After 30 min, the solid precipitated, stirring was continued for 5 h at room temperature, and suction filtration gave (2 3R)-1-(dimethylamino) _-2 -methyl- _3- ( ₃ -propenyloxyphenyl) _-3 -pentane Alcohol hydrochloride, which is dried at ₆₅ ° _C to obtain

349.1 g of a white product (hydrochloride of intermediate IV), yield 77.5%.

IfiNMR (400 MHz, DMSO-i/ ₆ ) δ: 11.02 (s, 1 Η, HC1), 7.29-7.23 (m, 1H, ArH), 6.99-6.95 (m, 2H, ArH), 6.81 (d, / = 8.0 Hz, 1H, ArH), 6.10-6.02 (m, 1H, CH), 5.42 (d, / = 13.2 Hz, 1H, CH ₂ ), 5.31 (d, / = 10.4 Hz, 1H, CH ₂ ), 4.55 (d, / = 5.2 Hz, 2H, CH ₂ ), 2.87 (s, 6H, CH ₃ ), 2.56-2.54 (m, 1H, CH ₂ ), 2.38-2.35 (m, 1H, CH ₂ ), 2.18- 2.14(m, 1H, CH ₂ ), 1.98-1.93(m, 1H, CH ₂ ), 1.09 (d, / = 6.8 Hz, 3H, CH ₃ ), 0.80 (t, / = 7.2 Hz, 3H, CH ₃ ).

[a ⁰ = 10.4° (c 1.0, CH ₃ OH), mp=157-158°C Example 14: Synthesis of OS, 3RVl-(dimethylamino 2-methyl-3-(3-hydroxyphenyl 3-pentanol (Compound of Formula V) and its hydrochloride

:. HCI

The hydrochloride salt of the compound of formula IV is the hydrochloride salt of the compound of formula V at room temperature, (2 & 3R)-1-(dimethylamino)-2-methyl-3-(3-allyloxyphenyl) 3-pentanol hydrochloride (349.1 g) and ammonium formate (300.2 g) were added to methanol (2.1 L) and stirred. After complete dissolution, Pd/C (35.0 g, 10% wet) was added to the reaction mixture, heated to reflux temperature, and reacted at reflux temperature for 12 h, and the reaction was followed by TLC. After completion of the reaction, the reaction mixture was cooled to 25 ° C, methanol was removed under reduced pressure, water (1000 mL) was added, and 30% by weight aqueous ammonia was added dropwise to pH = 8. The organic phase was washed with water (200 mL). EtOAc (EtOAc m. Hydroxyphenyl)-3-pentanol (Intermediate V).

The oil obtained above was all added to acetone (1.7 L) at room temperature, and after completely dissolved, a solution of hydrogen chloride in ethyl acetate (20.4% w/w) was added dropwise to pH = 3. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature, and the solid was precipitated after 1.5 h. Stirring was continued for 6 h at room temperature, and suction filtration gave (2 & 3R)-1-(dimethylamino 2-methyl-3-(3-hydroxyphenyl 3-pentanol hydrochloride) at 65 ° C Drying was carried out to obtain 245.4 g of a white product (yield of Intermediate V), yield: 80.6%.

[a ⁰ = 12.4° (c 1.0, CH ₃ OH), mp = 182-183. C.

Example 15 : (RVN, N, 2-trimethyl-3-(3-hydroxyphenyl 3-pentene-1-amine hydrochloride (formula VI)

Combination of

The hydrochloride salt of the compound of formula V is the hydrochloride salt of the compound of formula VI (2 3R)-1-(dimethylamino)-2-methyl-3-(3-hydroxyphenyl)-3-pentanol hydrochloride (24.5 g) Into formic acid (160 mL), the resulting mixture was heated to reflux temperature and reacted at reflux temperature for 9 h, and the entire reaction was followed by TLC. After completion of the reaction, formic acid was removed under reduced pressure, then water (1.2 L) was added and concentrated aqueous ammonia was added dropwise to pH = 9. Extracted with ethyl acetate (100 mL), EtOAc (EtOAc m.) .

The obtained oily substance was all added to acetone (150 mL), stirred at room temperature until completely dissolved, and then a solution of hydrogen chloride in ethyl acetate (20.4% w/w) was added dropwise to pH = 3. After the completion of the dropwise addition, the mixture was stirred at room temperature, and the solid precipitated after 1 h. Stirring was continued for 6 h at room temperature, and suction filtration gave (RN,N,2-trimethyl-3-(3-hydroxyphenyl)-3-penten-1-amine hydrochloride (15.8 g). It is 68.5%.

[α]ο = -11.0° (c 1.0, CH ₃ OH), mp=141-142 ° C Example 16: (RVN.N.2-trimethyl-3-(3-hydroxyphenyl 3-pentane) Synthesis of ene-1-amine hydrochloride (hydrochloride salt of compound of formula VI)

Add (2 3R)-1-(dimethylamino)-2-methyl-3-(3-hydroxyphenyl)-3-pentanol hydrochloride (32.0 g) to formic acid (300 mL). The mixture was heated to 50 ° C and reacted at this temperature for 15 h, and the reaction was followed by TLC. After completion of the reaction, the reaction mixture was cooled to 25 ° C or lower, and 30% by weight of aqueous ammonia was added dropwise to pH = 9. Extracted with ethyl acetate (80 mL), EtOAc (EtOAc)EtOAc. -penten-1-amine.

The oil obtained above was all added to acetone (100 mL) at room temperature, and after completely dissolved, a solution of hydrogen chloride in ethyl acetate (20.4% w/w) was added dropwise to pH = 4. After the completion of the dropwise addition, the mixture was stirred at room temperature, and after 0.5 h, a solid precipitated. Stirring was continued for 5 h at room temperature, and suction filtration gave (R)-N,N,2-trimethyl

-3-(3-Hydroxyphenyl)-3-pentene-1-amine hydrochloride, which was dried at 65 ° C to give 18.6 g of white

[a ⁰ = -11.0° (c 1.0, CH ₃ OH), mp=141-142 ° C Example 17: (RVN.N.2-trimethyl-3-(3-hydroxyphenyl 3-pentene) Synthesis of 1-amine hydrochloride

(2 3R)-1-(Dimethylamino)-2-methyl-3-(3-hydroxyphenyl)-3-pentanol hydrochloride (10.0 g) was added to hydrochloric acid (70 mL, 36% w/ In w), the resulting mixture was heated to 40 ° C, reacted at this temperature for 9 h, and the entire reaction was followed by TLC. Water (120 mL) was added to the reaction mixture and concentrated aqueous ammonia was added dropwise to pH = 8.5. Extracted with ethyl acetate (100 mL), dried EtOAc m.jjjjjjjjjjjjj . The above oily substance was all added to acetone (100 mL), stirred at room temperature, and completely dissolved, and then a solution of hydrogen chloride in ethyl acetate (20.4% w/w) was added dropwise to pH=3.5. After the completion of the dropwise addition, the mixture was stirred at room temperature, and after 1 hour, a solid precipitated. Stirring was continued for 3 h at room temperature, and suction-purified (RN,N,2-trimethyl-3-(3-hydroxyphenyl)-3-penten-1-amine hydrochloride (6.9 g), yield It is 73.9%.

[a ⁰ = -11.0° (c 1.0, CH ₃ OH), mp=141-142 ° C Example 18: 3-"gR,2RV3-(dimethylamino I-ethyl-2-methylpropyl 1 Phenol monohydrochloride (target product heptadol)

The hydrochloride salt of the compound of formula VI is soluble in (R)-N,N,2-trimethyl-3-(3-hydroxyphenyl)-3-penten-1-amine hydrochloride (15.8 g). To the obtained mixture, Pd/C (1.5 g, 10% w/w) was added to water ethanol (80 mL). Hydrogen was introduced into the reaction mixture at room temperature, and hydrogenation was carried out under normal pressure until the reaction was completed.

After removing the Pd/C by filtration, the solvent was removed under reduced pressure, water (80 mL) was added, then concentrated aqueous ammonia was added dropwise to pH=9 o. The organic phase was extracted with ethyl acetate (100 mL). The organic phase is reduced to give an oil which solidifies upon cooling. Acetone (90 mL) was added to the obtained product, and the mixture was completely dissolved, and then ethyl acetate (20.4% w/w) of hydrogen chloride was added dropwise to pH = 4. After the completion of the dropwise addition, the mixture was stirred at room temperature, and solids were precipitated after 1 h. Stirring was continued for 6 h at room temperature, and heptadol was obtained by suction filtration, which was dried to give 13.0 g of product in a yield of 81.3%.

[α]ο = -28.1° (c 1.0, CH ₃ OH), mp=191-193. C. Example 19: Synthesis of 3-"R,2RV3-(dimethylamino I-ethyl-2-methylpropyl 1 phenol and its hydrochloride)

(R)-N,N,2-trimethyl-3-(3-hydroxyphenyl 3-penten-1-amine hydrochloride (10.1 g) was dissolved in tetrahydrofuran (80 mL). Pd/C (1.lg, 10% w/w) was added to the mixture, hydrogen was introduced into the reaction mixture at room temperature, and hydrogenation was carried out to 3 atm. to complete the reaction. Pd/C was removed by filtration, and the solvent was removed under reduced pressure. Thereafter, 60 mL of water was added, and then concentrated aqueous ammonia was added dropwise until pH = 8. The organic phase was extracted with ethyl acetate (100 mL), the organic phase was separated and the organic phase was concentrated. To the oil, it solidifies after cooling. Acetone (55 mL) was added to the obtained product, and after completely dissolved, a solution of hydrogen chloride in ethyl acetate (20.4% w/w) was added dropwise to pH=3. After the completion of the dropwise addition, the mixture was stirred at room temperature, and after 1 hour, a solid precipitated. Stirring was continued for 5 h at room temperature, and heptadol was obtained by suction filtration, which was dried to give 8.7 g of product, yield 86.3%.

[a ⁰ = -28.1° (c 1.0, CH ₃ OH), mp = 191-193 ° C Example 20: Synthesis of tapentadol

The hydrochloride salt of the compound of formula V dissolves (2 3R)-1-(dimethylamino)-2-methyl-3-(3-hydroxyphenyl)-3-pentanol hydrochloride (100.0 g) in water In (300 mL), concentrated aqueous ammonia was added dropwise to the obtained mixture until pH = 9. After extraction with ethyl acetate (400 mL), EtOAc was evaporated. Trifluoroacetic anhydride (62 mL) was added dropwise to the above oil, and the temperature was controlled to 10 °C. After the dropwise addition was completed, the mixture was stirred at room temperature for 30 min. Pd/C (6.2 g, 10% w/w) was added to the reaction mixture, and hydrogen gas was introduced and pressurized to 5 atm. The reaction mixture was heated to 45 ° C and reacted at this temperature for 5 ho. After completion of the reaction, Pd/C was removed by filtration, water (400 mL) was added to the reaction mixture, and then aqueous sodium hydroxide (10%) was added dropwise to pH. =9.6. After extraction with ethyl acetate (500 mL), EtOAc m. The obtained oily substance was dissolved in acetone (500 mL), and a solution of hydrogen chloride in ethyl acetate (20.4% w/w) was added dropwise to pH=4. After the addition was completed, the mixture was stirred at room temperature, and the solid was precipitated after lh. Stirring was continued for 6 h at room temperature, and suction-dried to give 3-[(lR,2R3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride, which was taken at 65 ° C Drying down gave 83.5 g of product in a yield of 88.7%.

[a ⁰ = -28.1° (c 1.0, CH ₃ OH), mp=191-193°C

Claims

The hydrochloride salt of the compound of formula IV is the hydrochloride salt of the compound of formula V.

2. The method according to claim 1, wherein the catalyst is selected from the group consisting of palladium, palladium on carbon, platinum, platinum on carbon, ruthenium and rhodium on carbon; the hydrogenolysis reagent is ammonium formate; the solvent is selected from Ethanol, methanol, water, acetonitrile, tetrahydrofuran, isopropanol, acetone and any mixture thereof; and the reaction temperature is 50-100 ° C, and the reaction time is 5-20 hours.

The method according to any one of claims 1 to 2, wherein the hydrochloride of the compound of the formula IV: the molar ratio of the hydrogenolysis reagent is 1:4-1:8; and the hydrochloride of the compound of the formula IV : The mass ratio of the catalyst is 1:0.05-1:0.15.

The method according to any one of claims 1 to 3, wherein the compound of the formula IV can be produced by a method comprising the following steps:

The compound of formula III is reacted with an organic solution of ethylmagnesium halide in an inert reaction medium under an inert atmosphere to provide a compound of formula IV, which is optionally further converted to the hydrochloride salt.

III IV The hydrochloride salt of the compound of formula IV

The method according to claim 4, wherein the organic solution of the ethyl magnesium halide is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or a toluene solution of the ethylmagnesium halide; the compound of the formula III and the ethyl magnesium halide. The molar ratio is 1:1-1:3; and the temperature of the reaction of the compound of the formula III with an organic solution of ethylmagnesium halide is 5-50 ° C, and the reaction time is 5-15 hours.

The method according to any one of claims 4 to 5, wherein the compound of the formula III can be obtained by a method comprising the following steps:

Reacting a compound of formula II with a resolving reagent in an organic solvent

7. The method according to claim 6, wherein the resolving agent is selected from the group consisting of LO-dibenzoyltartaric acid, L-(-)-dibenzoyltartaric acid monohydrate and D-(+)-di Benzoyl tartaric acid; the molar ratio of the hydrazine compound to the resolving agent is 1:0.90-1:1 mountain and the reaction temperature is 10-50 ° C, and the reaction time is 10-60 hours.

The method according to any one of claims 6 to 7, wherein the compound of the formula II can be obtained by a method comprising the following steps:

Reaction of a compound of formula I with dimethylamine hydrochloride and paraformaldehyde in the presence of an acidic substance in a solvent

I II

9. The method according to claim 8, wherein the compound of the formula I is reacted with dimethylamine hydrochloride and paraformaldehyde at a temperature of 50 to 100 ° C for a period of 10 to 25 hours; and the acidity The substance is selected from one or more of the group consisting of hydrochloric acid, sulfuric acid, acetic acid, formic acid, methanesulfonic acid and p-toluenesulfonic acid.

The method according to any one of claims 8 to 9, wherein the molar ratio of each component is:

Compound of formula I: dimethylamine hydrochloride =1:2-1:4;

Compound of formula I: paraformaldehyde = 1:2-1:4;

Compound of formula I: Acidic substance =1: 0.01-1: 0.3.

The method according to any one of claims 8 to 10, wherein the compound of the formula I can be obtained by a process comprising the steps of:

Reaction of 3-hydroxypropiophenone with 3-chloropropene in the presence of a catalyst and a basic substance in a solvent

12. The method according to claim 11, wherein the temperature at which 3-hydroxypropiophenone is reacted with 3-chloropropene is 30-110 ° C, and the reaction time is 20-60 hours; the basic substance is selected from sodium carbonate And one or more of potassium carbonate, cesium carbonate and sodium hydrogencarbonate; and the catalyst is selected from one or more of sodium iodide, potassium iodide, sodium bromide and potassium bromide.

The method according to any one of claims 11 to 12, wherein the molar ratio of each component is:

3-hydroxypropiophenone: 3-chloropropene = 1:1-1:1.5;

3-hydroxypropiophenone: catalyst = 1:0.05-1:0.15;

3-hydroxypropiophenone: basic substance = 1:1-1:2.

A compound of the formula I or a salt thereof, a compound of the formula II or a salt thereof, a compound of the formula or a salt thereof and a formula

IV compound or a salt thereof

The compound of the formula I or a salt thereof, the compound of the II or a salt thereof, the compound of the III or a salt thereof, and the compound of the IV or a salt thereof, according to claim 14, wherein the salts are each independently a mesylate salt, Oxalate, maleate or hydrochloride.