Preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate

Abstract

The present invention discloses a preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate, which comprises the following steps: (1) firstly, carrying out a nitrogen alkylation reaction on compound 4 and 3-chloropropionate, then carrying out an asymmetric reduction reaction under the action of a chiral catalyst, trichlorosilane and an auxiliary agent, and finally forming a salt with oxalic acid to obtain compound 5; (2) alkalizing compound 5 and then carrying out a quaternization reaction with methyl benzenesulfonate, and purifying the reaction product in a purification solvent to obtain the target compound 1. The method of the present invention has easily available raw materials, mild reaction conditions, low production cost, high purity of the obtained quaternary ammonium salt with a cis configuration, and can be used to prepare qualified cis-atracurium besylate.

Description

Technical Field

[0001] The present invention relates to a preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate, and particularly relates to a preparation method of 3-[(1R,2R)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline]-propionate benzenesulfonate which can be used for preparing atracurium besilate. Background Art

[0002] Atracurium besilate (Formula A), chemically named (1R,1′R,2R,2′R-cis)-2,2′-(3,11-dioxo-4,10-dioxatetradecamethylene)-bis(1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinoline) dibenzenesulfonate, is a neuromuscular blocker developed by GlaxoSmihtKline (UK). It is a single isomer among the ten isomers of atracurium. Although it has the same metabolic pathway as atracurium, it does not undergo enzymatic decomposition. Its muscle relaxation effect is three times that of atracurium. The clinical application dose is significantly lower than that of atracurium, and the risk of convulsions is small. In addition, it hardly causes histamine release, has no cumulative effect, and its metabolites have no toxicity and muscle relaxation effect, and it has good cardiovascular stability, so it is an ideal muscle relaxant in clinical applications. The structural formula of atracurium besilate is:

[0003]

[0004] Regarding the preparation of atracurium besilate, there have been many literature reports. The representative one is to react 3-[(1R,2R)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline]-propionate benzenesulfonate (Compound 1) with 1,5-pentanediol for a binary esterification reaction and then saltify it with benzenesulfonic acid. Therefore, Compound 1 is the most critical intermediate for synthesizing atracurium besilate and is of great significance for the preparation of atracurium besilate.

[0005] For compound 1, its synthesis methods have been reported in the literature, mainly including two methods. The first is the synthesis method reported in Patent US20100168431A1: This method uses R-tetrahydroberberine hydrochloride as the raw material. After alkalizing this salt with ammonia water, R-tetrahydroberberine is obtained. R-tetrahydroberberine undergoes a Michael addition reaction with acrylate and then forms a salt with oxalic acid to obtain the intermediate R-3-[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline]-propionate oxalate. This intermediate then undergoes a quaternization reaction with methyl benzenesulfonate to obtain a quaternary ammonium salt intermediate with two cis-trans configurations. This intermediate is then purified in a mixed solvent of ethyl acetate and dichloromethane to obtain the cis-configured quaternary ammonium salt, that is, compound 1, and the purity of compound 1 is above 97%. The synthesis route is as follows:

[0006]

[0007] The starting material R-tetrahydroberberine hydrochloride of this synthesis method needs to first prepare racemic tetrahydroberberine through the hydrogenation and hydrogen addition reaction of dihydroberberine under high temperature and high pressure. The racemic tetrahydroberberine is then resolved by using a stoichiometric amount of chiral carboxylic acids such as L-amino acids as resolving agents. This method requires high temperature and high pressure hydrogenation first, and secondly, the chiral resolution process is complex, requiring multiple low-temperature crystallization purifications, which takes a long time, is difficult to control the purity, and chiral resolution will cause waste of another configurational compound, and the conversion rate of the raw material is at most no more than 50%. In addition, the ratio of the quaternary ammonium salts with two cis-trans configurations obtained through quaternization is about 4:1. Then this cis-trans mixture is purified in a solvent of dichloromethane and ether to prepare the cis-configured quaternary ammonium salt, that is, compound 1. However, it is very difficult to achieve a purity of 98.5% for compound 1 using the above purification solvents, while the preparation of the final product cis-atracurium besylate requires a purity of compound 1 above 98.5%. Therefore, the starting materials of this process are not easily available, the preparation process is not safe, the cost is high, the total yield is low, and it is very difficult to meet the purity requirements of the target product.

[0008] The second is the preparation method of compound 1 (R = methyl) reported in the literature by Fu Haiyan, "Synthesis Research of Cis-Atracurium Monobenzene Sulfonate" [D]. Shanghai: East China University of Science and Technology, 2011. This method uses R-tetrahydroberberine-N-acetyl-L-leucine salt as the raw material. After alkalizing this salt with ammonia water, R-tetrahydroberberine is obtained. R-tetrahydroberberine undergoes a Michael addition reaction with methyl acrylate and then forms a salt with oxalic acid to obtain the intermediate R-3-[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline]-propionate methyl oxalate. This intermediate then undergoes a quaternization reaction with methyl benzenesulfonate to obtain a quaternary ammonium salt intermediate with two cis-trans configurations. This intermediate is then purified in an acetone solvent to obtain the cis-configured quaternary ammonium salt, that is, compound 1 (R = methyl). The synthesis route is as follows:

[0009]

[0010] This synthesis method requires the use of expensive R-tetrahydropapaverine-N-acetyl-L-leucinate as a raw material. This salt also needs to be obtained by reacting the racemic tetrahydropapaverine with the resolving agent N-acetyl-L-leucine to form a salt, and then through three recrystallizations. It still has some defects of the first method. In addition, the ratio of the cis- and trans-configured quaternary ammonium salts obtained from the quaternization reaction is 1:3, and the literature only mentions that the cis-configured quaternary ammonium salt, namely compound 1 (R = methyl), is obtained through purification in an acetone solvent, without reporting the purity of compound 1 (R = methyl). Summary of the Invention

[0011] Object of the Invention: The object of the present invention is to provide a preparation method of 3-[(1R,2R)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline]-propionate benzenesulfonate. This method has easily available raw materials, mild reaction conditions, low production costs, and a high purity of the cis-configured quaternary ammonium salt obtained, and can be used for the preparation of atracurium besylate.

[0012] Technical Solution: The preparation method of the chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate of the present invention includes the following steps:

[0013] (1) First, carry out a nitrogen alkylation reaction between compound 4 and 3-chloropropionate, then carry out an asymmetric reduction reaction under the action of a chiral catalyst, trichlorosilane, and an auxiliary agent, and finally form a salt with oxalic acid to obtain compound 5; wherein, the chiral catalyst is a chiral N-formylpipecolic acid amide derivative;

[0014] (2) After alkalizing compound 5, carry out a quaternization reaction with methyl benzenesulfonate, and purify the reaction product in a purification solvent to obtain the target compound 1; the synthesis route is:

[0015]

[0016] Wherein, R1 is an alkyl group with 1 to 4 carbon atoms.

[0017] Wherein, in step (1), compound 4 is prepared by the following method: First, carry out an amidation reaction between compound 2 and compound 3, and then heat and close the ring under the action of phosphorus oxychloride to obtain compound 4; wherein, the temperature of the ring-closing reaction is 80 - 140 °C;

[0018] The reaction route is:

[0019]

[0020] Among them, in step (1), during the N-alkylation reaction of compound 4 with 3-chloropropionate, the molar ratio of 3-chloropropionate to compound 4 is 1 to 1.3:1.

[0021] Among them, in step (1), the temperature of the N-alkylation reaction is 50 to 80 °C.

[0022] Among them, in step (1), the structural formula of the chiral catalyst is:

[0023]

[0024] Among them, R2 is an alkyl group with 1 to 4 carbon atoms, acetyl (-Ac) or methoxymethyl (-MOM), preferably -MOM.

[0025] Among them, in step (1), the asymmetric reduction reaction can only be completed under the combined action of a chiral catalyst, trichlorosilane and an auxiliary agent. The auxiliary agent is water, a saturated alcohol with 1 to 4 carbon atoms or benzoic acid, preferably water.

[0026] Among them, in step (1), the molar ratio of the chiral catalyst to compound 4 is 0.05 to 0.1:1; the molar ratio of the auxiliary agent to compound 4 is 1 to 1.3:1; the molar ratio of trichlorosilane to compound 4 is 1 to 1.3:1.

[0027] Among them, in step (1), the temperature of the asymmetric reduction reaction is 0 to 30 °C.

[0028] Among them, in step (1), the reaction solvent for the asymmetric reduction reaction is chloroform, dichloroethane, toluene or benzene, preferably chloroform.

[0029] Among them, in step (2), the temperature of the quaternization reaction is -10 to 20 °C.

[0030] Among them, in step (2), the proportion of the cis-configured quaternary ammonium salt obtained in the quaternization reaction in reaction solvents such as tetrahydrofuran, dioxane, tert-butanol or isobutanol is high. The reaction solvent is preferably tetrahydrofuran; when the quaternization reaction is carried out in tetrahydrofuran, the mass ratio of the cis- and trans-configured quaternary ammonium salts obtained is 9:1.

[0031] Among them, in step (2), the purification solvent is isopropyl ether, chloroform, dichloroethane or ether, preferably isopropyl ether. When a mixture of cis- and trans-configured quaternary ammonium salts with a mass ratio of 9:1 is purified in isopropyl ether, the purity of the target compound 1 (cis-configured quaternary ammonium salt) can reach more than 99.99%.

[0032] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages: In the prior art, it is necessary to first prepare racemic tetrahydropapaverine through a hydrogenation and hydrogenation reaction under high temperature and high pressure for dihydropapaverine, and then the racemic tetrahydropapaverine is resolved by a chiral resolving agent to obtain the reaction raw material (R-tetrahydropapaverine hydrochloride). There are problems such as complex preparation processes, high costs, low conversion rates of the initial raw materials, low content of the cis-configured quaternary ammonium salt in the mixture of cis- and trans-configured quaternary ammonium salts obtained by subsequent quaternization, and low purity of the final product, compound 1 (cis-configured quaternary ammonium salt). The method of the present invention undergoes an asymmetric reduction reaction of compound 4 under the combined action of a chiral catalyst, trichlorosilane, and an auxiliary agent to obtain a chiral structural molecular compound 5 with high optical purity. It has the advantages of easily available raw materials, mild reaction conditions, low production costs, and high conversion rates of the initial raw materials. Moreover, the content of the cis-configured quaternary ammonium salt in the mixture of cis- and trans-configured quaternary ammonium salts obtained by subsequent quaternization is high, and the purity of the finally purified cis-configured quaternary ammonium salt is high, up to more than 99.99%, so that it can be used as an intermediate for preparing qualified cis-atracurium besylate. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 1H NMR spectrum of compound 5 (R1 = tert-butyl); 1

[0034] Figure 2 1H NMR spectrum of compound 1 (R1 = tert-butyl); 1

[0035] Figure 3 HPLC chromatogram of compound 5 (R1 = tert-butyl);

[0036] Figure 4 HPLC chromatogram of compound 1 (R1 = tert-butyl). DETAILED DESCRIPTION OF THE INVENTION

[0037] Example 1

[0038] Preparation of Compound 4 (Dihydropapaverine): Install a water-separating device on the reaction flask. Add 50 mmol of Compound 2 (3,4-Dimethoxyphenylacetic Acid), 50 mmol of Compound 3 (3,4-Dimethoxyphenethylamine), and 150 mL of xylene to the reaction flask (in the amidation reaction, install a water-separating device and reflux in xylene solvent. Timely separating the water generated during the reaction is beneficial to the progress of the reaction). After stirring and mixing evenly, raise the temperature of the system to the reflux temperature, and keep stirring and reacting while continuously separating the water generated during the reaction. When no more water is separated, stop heating, distill off about 30 mL of xylene solvent under reduced pressure. Add 30 mL of phosphorus oxychloride to the concentrated solution, raise the temperature of the system to 80 °C, and keep reacting under nitrogen protection. Monitor the reaction process by TLC, and the developing agent is a mixed solvent of petroleum ether and ethyl acetate mixed in a volume ratio of 3:1. After the reaction is completed in about 5 h, distill off the solvent under reduced pressure to obtain the crude product, and the yield is 80%.

[0039] Example 2

[0040] Preparation of Compound 4: Install a water-separating device on the reaction flask. Add 50 mmol of Compound 2, 50 mmol of Compound 3, and 150 mL of xylene to the reaction flask. After stirring and mixing evenly, raise the temperature of the system to the reflux temperature, and keep stirring and reacting while continuously separating the water generated during the reaction. When no more water is separated, stop heating, distill off about 30 mL of xylene solvent under reduced pressure. Add 30 mL of phosphorus oxychloride to the concentrated solution, raise the temperature of the system to 110 °C, and keep reacting under nitrogen protection. Monitor the reaction process by TLC, and the developing agent is a mixed solvent of petroleum ether and ethyl acetate mixed in a volume ratio of 3:1. After the reaction is completed in about 5 h, distill off the solvent under reduced pressure to obtain the crude product, and the yield is 85%.

[0041] Example 3

[0042] Preparation of Compound 4: Install a water-separating device on the reaction flask. Add 50 mmol of Compound 2, 50 mmol of Compound 3, and 150 mL of xylene to the reaction flask. After stirring and mixing evenly, raise the temperature of the system to the reflux temperature, and keep stirring and reacting while continuously separating the water generated during the reaction. When no more water is separated, stop heating, distill off about 30 mL of xylene solvent under reduced pressure. Add 30 mL of phosphorus oxychloride to the concentrated solution, raise the temperature of the system to 140 °C, and keep reacting under nitrogen protection. Monitor the reaction process by TLC, and the developing agent is a mixed solvent of petroleum ether and ethyl acetate mixed in a volume ratio of 3:1. After the reaction is completed in about 4 h, distill off the solvent under reduced pressure to obtain the crude product, and the yield is 92%. This crude product can be directly used for the next reaction without purification.

[0043] Example 4

[0044] Preparation of Compound 5: Add 20 mmol of Compound 4 prepared in Example 3, 20 mmol of tert-butyl 3-chloropropionate (R1 = tert-butyl), and 40 mL of chloroform into a reaction flask, and stir to mix evenly; raise the temperature of the system to 60 °C, and stir the reaction at this temperature. Monitor the reaction progress by TLC, with the developing solvent being a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After the reaction is completed, stop heating. When the temperature of the system drops to room temperature, add 20 mmol of HSiCl3, 20 mmol of water, and 20 mL of chloroform into the reaction flask, then add 1 mmol of chiral formamide catalyst (R2 = -MOM) into the reaction flask. Maintain the temperature of the system at 20 - 30 °C, and stir the reaction overnight at this temperature. Stop the reaction, add 60 mL of water, stir for 0.5 h, then let it stand. Separate the organic layer, and extract the aqueous layer twice with 30 mL of chloroform each time. Combine the organic layers, dry over anhydrous sodium sulfate, and then evaporate the solvent under reduced pressure to obtain a crude solid; dissolve 23 mmol of oxalic acid dihydrate in 20 mL of acetone and add it to the crude solid. Stir at room temperature to obtain a suspension, then add 50 mL of ethyl acetate, stir at room temperature for 20 min, filter, wash the filter cake twice with ethyl acetate, and dry to obtain Compound 5 (R1 = tert-butyl) with a yield of 63% (calculated based on Compound 2) and an ee value of 81.9%. The structure of Compound 5 was confirmed by 1 HNMR. 1 HNMR (500 MHz, CDCl3) δ: 6.76 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 3.5 Hz, 2H), 6.52 (d, J = 7.9 Hz, 1H), 5.67 (s, 1H), 4.40 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.78 - 3.67 (m, 1H), 3.62 (d, J = 12.1 Hz, 1H), 3.56 (dd, J = 13.8, 6.8 Hz, 1H), 3.46 (s, 3H), 3.45 - 3.37 (m, 2H), 3.22 (s, 1H), 3.00 (dd, J = 17.9, 6.1 Hz, 1H), 2.87 - 2.71 (m, 3H), 1.44 (s, 9H).

[0045] Example 5

[0046] Preparation of Compound 5: 20 mmol of Compound 4 obtained in Example 3, 22 mmol of tert-butyl 3-chloropropionate (R1 = tert-butyl), and 40 mL of chloroform were added to a reaction flask and stirred until evenly mixed. The temperature of the system was raised to 60 °C, and the reaction was stirred at this temperature. The reaction progress was monitored by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate mixed in a volume ratio of 4:1. After the reaction was completed, heating was stopped. When the temperature of the system dropped to room temperature, 22 mmol of HSiCl3, 22 mmol of water, and 20 mL of chloroform were added to the reaction flask. The temperature of the system was lowered to 10 °C, and then 1 mmol of a chiral formamide catalyst (R2 = -MOM) was added to the reaction flask. The temperature of the system was maintained at 10 °C, and the reaction was stirred overnight at this temperature. The reaction was stopped, 60 mL of water was added, and after stirring for 0.5 h, it was allowed to stand. The organic layer was separated, and the aqueous layer was extracted twice with 30 mL of chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude solid. 23 mmol of oxalic acid dihydrate was dissolved in 20 mL of acetone, and this crude solid was added. After stirring at room temperature, a suspension was obtained. Then 50 mL of ethyl acetate was added, and it was stirred at room temperature for 20 min. It was filtered, and the filter cake was washed twice with ethyl acetate and dried to obtain Compound 5 (R1 = tert-butyl) with a yield of 60% (calculated based on Compound 2) and an ee value of 85.6%.

[0047] Example 6

[0048] Preparation of Compound 5: 20 mmol of Compound 4 obtained in Example 3, 24 mmol of tert-butyl 3-chloropropionate (R1 = tert-butyl), and 40 mL of chloroform were added to a reaction flask and stirred until evenly mixed. The temperature of the system was raised to 60 °C, and the reaction was stirred at this temperature. The reaction progress was monitored by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate mixed in a volume ratio of 4:1. After the reaction was completed, heating was stopped. When the temperature of the system dropped to room temperature, 24 mmol of HSiCl3, 24 mmol of water, and 20 mL of chloroform were added to the reaction flask. The temperature of the system was lowered to 0 °C, and then 1 mmol of a chiral formamide catalyst (R2 = -MOM) was added to the reaction flask. The temperature of the system was maintained at 0 °C, and the reaction was stirred overnight at this temperature. The reaction was stopped, and when the temperature rose to room temperature, 60 mL of water was added. After stirring for 0.5 h, it was allowed to stand. The organic layer was separated, and the aqueous layer was extracted twice with 30 mL of chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude solid. 23 mmol of oxalic acid dihydrate was dissolved in 20 mL of acetone and added to this crude solid. After stirring at room temperature, a suspension was obtained. Then 50 mL of ethyl acetate was added, and it was stirred at room temperature for 20 min. It was filtered, and the filter cake was washed twice with ethyl acetate and dried to obtain Compound 5 (R1 = tert-butyl) with a yield of 59% (calculated based on Compound 2) and an ee value of 88.4%.

[0049] Example 7

[0050] Preparation of Compound 5: 20 mmol of Compound 4 prepared in Example 3, 26 mmol of tert-butyl 3-chloropropionate (R1 = tert-butyl), and 40 mL of chloroform were added to a reaction flask and stirred until evenly mixed. The temperature of the system was raised to 60 °C and the reaction was stirred at this temperature. The reaction progress was monitored by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After the reaction was completed, heating was stopped. When the temperature of the system dropped to room temperature, 26 mmol of HSiCl3, 26 mmol of water, and 20 mL of chloroform were added to the reaction flask. The temperature of the system was lowered to 0 °C, and then 1 mmol of a chiral formamide catalyst (R2 = -MOM) was added to the reaction flask. The temperature of the system was maintained at 0 °C and the reaction was stirred overnight at this temperature. The reaction was stopped. When the temperature rose to room temperature, 60 mL of water was added, stirred for 0.5 h, and then allowed to stand. The organic layer was separated, and the aqueous layer was extracted twice with 30 mL of chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude solid. 23 mmol of oxalic acid dihydrate was dissolved in 20 mL of acetone and added to the crude solid. After stirring at room temperature, a suspension was obtained. Then 50 mL of ethyl acetate was added, and the mixture was stirred at room temperature for 20 min, filtered, and the filter cake was washed twice with ethyl acetate and dried to obtain Compound 5 (R1 = tert-butyl) with a yield of 63% (calculated based on Compound 2) and an ee value of 89.1%.

[0051] Example 8

[0052] Preparation of Compound 5: 20 mmol of Compound 4 prepared in Example 3, 26 mmol of tert-butyl 3-chloropropionate (R1 = tert-butyl), and 40 mL of chloroform were added to a reaction flask and stirred until evenly mixed. The temperature of the system was raised to 60 °C and the reaction was stirred at this temperature. The reaction progress was monitored by TLC, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. After the reaction was completed, heating was stopped. When the temperature of the system dropped to room temperature, 26 mmol of HSiCl3, 24 mmol of water, and 20 mL of chloroform were added to the reaction flask. The temperature of the system was lowered to 0 °C, and then 1.4 mmol of a chiral formamide catalyst (R2 = -MOM) was added to the reaction flask. The temperature of the system was maintained at 0 °C and the reaction was stirred overnight at this temperature. The reaction was stopped. When the temperature rose to room temperature, 60 mL of water was added, stirred for 0.5 h, and then allowed to stand. The organic layer was separated, and the aqueous layer was extracted twice with 30 mL of chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude solid. 23 mmol of oxalic acid dihydrate was dissolved in 20 mL of acetone and added to the crude solid. After stirring at room temperature, a suspension was obtained. Then 50 mL of ethyl acetate was added, and the mixture was stirred at room temperature for 20 min, filtered, and the filter cake was washed twice with ethyl acetate and dried to obtain Compound 5 (R1 = tert-butyl) with a yield of 65% (calculated based on Compound 2), an ee value of 94.6%, and a purity of 97.8%.

[0053] Example 9

[0054] Preparation of Compound 5: Add 20 mmol of Compound 4 prepared in Example 3, 26 mmol of tert-butyl 3-chloropropionate (R1 = tert-butyl), and 40 mL of chloroform into a reaction flask, stir and mix evenly; raise the temperature of the system to 60 °C, and stir the reaction at this temperature. Monitor the reaction progress by TLC, and the developing agent is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 4:1. After the reaction is completed, stop heating. When the temperature of the system drops to room temperature, add 26 mmol of HSiCl3, 24 mmol of water, and 20 mL of chloroform into the reaction flask. Lower the temperature of the system to 0 °C, then add 2 mmol of chiral formamide catalyst (R2 = -MOM) into the reaction flask, maintain the temperature of the system at 0 °C, and stir the reaction overnight. Stop the reaction. When the temperature rises to room temperature, add 60 mL of water, stir for 0.5 h, then let it stand, separate the organic layer, and extract the aqueous layer twice with 30 mL of chloroform each time. Combine the organic layers, dry with anhydrous sodium sulfate, and then evaporate the solvent under reduced pressure to obtain a crude solid; dissolve 23 mmol of oxalic acid dihydrate in 20 mL of acetone and add it to the crude solid. Stir at room temperature to obtain a suspension, then add 50 mL of ethyl acetate, stir at room temperature for 20 min, filter, wash the filter cake twice with ethyl acetate, and dry to obtain Compound 5 (R1 = tert-butyl) with a yield of 66% (calculated based on Compound 2), an ee value of 97.5%, and a purity of 98.9%.

[0055] On the basis of Example 9, R1 in the 3-chloropropionate can be replaced by methyl, ethyl, isopropyl, or n-butyl instead of tert-butyl; R2 in the chiral N-formylpiperidinecarboxamide catalyst can be replaced by methyl, ethyl, isopropyl, tert-butyl, or -Ac instead of -MOM; the solvent for the asymmetric reduction reaction can be replaced by dichloroethane, toluene, or benzene instead of chloroform; the auxiliary agent can be replaced by saturated alcohols with C1 - C4 such as methanol or benzoic acid instead of water; the temperature of the N-alkylation reaction can be adjusted between 50 - 80 °C; with other conditions unchanged, some experimental results are shown in Table 1.

[0056] Table 1 shows the conditions and results for the preparation of Compound 5 in Examples 10 - 30

[0057]

[0058] Example 31

[0059] Preparation of Compound 1: 20 mmol of Compound 5 (R1 = tert-butyl) prepared in Example 9, 20 mL of toluene and 20 mL of water were added to a reaction flask, stirred until completely dissolved, then an ammonia aqueous solution was added dropwise to adjust the pH to 8 - 9, and then stirred for 10 min. The organic phase was separated, and the aqueous phase was extracted twice with 20 mL of toluene. The combined organic phases were washed twice with 20 mL of saturated brine, combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness under reduced pressure. 20 mL of tetrahydrofuran was added to the above residue, and after stirring evenly, the temperature of the reaction system was lowered to 5 °C, then 60 mmol of methyl benzenesulfonate was added, and the reaction was stirred while maintaining the temperature. The reaction progress was monitored by TLC. After the reaction was completed, the ratio (mass ratio) of the quaternary ammonium salts of the cis and trans configurations was detected by HPLC to be 9:1; it was concentrated under reduced pressure at 35 - 40 °C until almost no solvent flowed out, 50 mL of isopropyl ether was added dropwise to the residue and stirred for 20 min, and then allowed to stand for crystallization; the precipitated solid was filtered, and the filter cake was washed twice with isopropyl ether and dried to obtain white Compound 1 (R1 = tert-butyl) with a yield of 85% and a purity of 99.99%. The structure was confirmed by 1 1H NMR. 1 1H NMR (500 MHz, CDCl3) δ: 7.93 - 7.85 (m, 2H), 7.32 (dd, J = 6.5, 3.6 Hz, 3H), 6.69 (d, J = 8.2 Hz, 1H), 6.62 (s, 1H), 6.54 (d, J = 1.7 Hz, 1H), 6.46 (dd, J = 8.2, 1.7 Hz, 1H), 5.98 (s, 1H), 4.96 (d, J = 6.1 Hz, 1H), 4.22 (dt, J = 13.5, 6.9 Hz, 1H), 4.10 - 4.00 (m, 1H), 3.91 (dd, J = 12.7, 7.5 Hz, 1H), 3.83 (d, J = 6.3 Hz, 6H), 3.70 (s, 3H), 3.64 (m, 2H), 3.46 (d, J = 9.1 Hz, 3H), 3.30 - 3.20 (m, 4H), 3.13 (t, J = 7.1 Hz, 2H), 3.04 (dd, J = 18.2, 6.2 Hz, 1H), 2.92 (dd, J = 13.3, 9.4 Hz, 1H), 1.47 (s, 9H).

[0060] On the basis of Example 31, R1 in Compound 5 can be replaced by methyl, ethyl, isopropyl, or n-butyl instead of tert-butyl; the quaternization reaction temperature can be adjusted between -10 - 20 °C, and the quaternization reaction solvent can be replaced by dioxane, tert-butanol, or isobutanol instead of tetrahydrofuran; the purification solvent can be replaced by chloroform, dichloroethane, or ether instead of isopropyl ether, and other conditions remain unchanged. Some experimental results are shown in Table 2.

[0061] Table 2 shows the conditions and results for the preparation of Compound 1 in Examples 32 - 44

[0062]

Claims

1. A preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate, characterized in that, It includes the following steps: (1) First, the compound 4 and 3-chloropropionate undergo a nitrogen alkylation reaction, then an asymmetric reduction reaction under the action of a chiral catalyst, trichlorosilane and an auxiliary agent, and finally form a salt with oxalic acid to obtain compound 5; The structural formula of the chiral catalyst is: Among them, R2 is MOM, methyl, ethyl, isopropyl, tert-butyl or Ac; The auxiliary agent is water, methanol, ethanol, isopropanol, n-butanol or benzoic acid; the solvent for the asymmetric reduction reaction is chloroform, dichloroethane, toluene or benzene; (2) After basifying compound 5, it undergoes a quaternization reaction with methyl benzenesulfonate, and the reaction product is purified in a purification solvent to obtain the target compound 1; the synthetic route is: Among them, R1 is an alkyl group with 1 to 4 carbon atoms.

2. The preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate according to claim 1, characterized in that: Compound 4 is prepared by the following method: First, compound 2 and compound 3 undergo an amidation reaction, and then ring closure is carried out by heating under the action of phosphorus oxychloride to obtain compound 4; the temperature of the ring closure reaction is 80 - 140 °C; The reaction route is:

3. The preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate according to claim 1, characterized in that: In step (1), during the nitrogen alkylation reaction of compound 4 and 3-chloropropionate, the molar ratio of 3-chloropropionate to compound 4 is 1 - 1.3:1; the temperature of the nitrogen alkylation reaction is 50 - 80 °C.

4. The preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate according to claim 1, characterized in that: In step (1), the molar ratio of the chiral catalyst to compound 4 is 0.05 - 0.1:1; the molar ratio of the auxiliary agent to compound 4 is 1 - 1.3:1; the molar ratio of trichlorosilane to compound 4 is 1 - 1.3:

1.

5. The preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate according to claim 1, characterized in that: In step (1), the temperature of the asymmetric reduction reaction is 0 - 30 °C.

6. The preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate according to claim 1, characterized in that: In step (2), the temperature of the quaternization reaction is -10 - 20 °C.

7. The preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzene sulfonate according to claim 1, characterized in that: In step (2), the solvent for the quaternization reaction is tetrahydrofuran, dioxane, tert-butanol or isobutanol.

8. The preparation method of chiral 3-(N-methyl-1,2,3,4-tetrahydroisoquinoline) propionate benzenesulfonate according to claim 1, characterized in that: In step (2), the purification solvent is isopropyl ether, chloroform, dichloroethane or ether.

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