A key intermediate of Ivancasser and its preparation method

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a key intermediate of Ivankasel and a preparation method thereof. D-malic acid undergoes a first dehydration condensation reaction under the action of acetyl chloride, and then undergoes an amidation reaction with a p-aminophenylacetic acid ester compound, and then undergoes a second dehydration condensation reaction under the action of acetyl chloride to obtain intermediate I; intermediate I undergoes a carbonyl reduction reaction on a five-membered ring under the action of a reducing agent, and then removes the acetyl protecting group under acidic conditions, and then undergoes an esterification reaction with a sulfonyl chloride compound under alkaline conditions to obtain intermediate II; intermediate II undergoes a substitution reaction with (R)-1-(1-naphthyl)ethylamine under the action of a base, and then undergoes a salt-forming reaction with hydrogen chloride to obtain Ivankasel intermediate III. The synthetic method of the present invention has low production cost, no metal catalyst, is green and environmentally friendly, has a high yield of the target product, has no metal residue, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and relates to a key intermediate of ivancaser and a preparation method thereof. Background Art

[0002] Evocalcet, chemical name 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid, has the following chemical structure:

[0003]

[0004] Evocalcet is a second-generation calcium-sensitive receptor (CaSR) agonist small molecule oral drug discovered by Mitsubishi Tanabe Pharma and developed by Kyowa Hakko Kirin Pharmaceutical. On March 23, 2018, it was approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) and sold by Kyowa Hakko Kirin Co., Ltd. for the treatment of secondary hyperparathyroidism (SHPT) in maintenance dialysis patients. A large number of clinical studies have shown that the first-generation calcium-sensitive receptor agonist Cinacalcet can not only maintain serum calcium and phosphorus levels within the normal range and control parathyroid hormone (PTH) and vitamin D3 levels in hemodialysis patients, but also has significant benefits in reducing the risk of death and non-fatal cardiovascular events. However, the problem of frequent gastrointestinal adverse events associated with Cinacalcet in clinical practice has not been solved. Compared with Cinacalcet, Evocalcet has similar efficacy in the treatment of SHPT in patients undergoing dialysis, but has significantly fewer gastrointestinal-related adverse events and drug interactions. In particular, a reduction in gastrointestinal-related adverse events may improve medication adherence and facilitate adequate dose escalation, leading to better management of SHPT.

[0005] CN108484469A reports the following synthetic route of ivankasel: the route uses N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol to be protected by an o-nitrobenzenesulfonyl group and then subjected to a substitution reaction with (R)-1-(1-naphthyl)ethylamine, then the Boc protecting group is removed, and the salt is formed in hydrogen chloride / isopropanol, and then the freed under alkaline conditions is coupled with ethyl 4-bromophenylacetate in the presence of palladium and a ligand, and finally the ethyl ester protecting group is removed under alkaline conditions to obtain ivankasel. This route uses heavy metal catalysts such as palladium in the coupling, which brings risks to the subsequent purification operation. At the same time, the palladium catalyst and materials such as N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol, ethyl 4-bromophenylacetate, and palladium acetate are expensive, which increases a lot of production costs.

[0006]

[0007] CN113620855A reports a synthetic route for an ivankasert intermediate II: the route uses L-malic acid and p-aminophenylacetic acid ester compounds as starting materials, and condenses at high temperature to obtain an ivankasert intermediate II. Detailed studies have found that the route using L-malic acid not only fails to obtain a raw material drug (API) of the correct configuration, but we have also tried the conditions of the route and found that the system has a lot of impurities and the conversion rate is less than 10% (see Comparative Example 1), and it is impossible to achieve scale-up production.

[0008] Summary of the invention

[0009] The technical problem to be solved by the present invention is to provide a key intermediate of ivancasser and a preparation method thereof in view of the deficiencies in the prior art. The method has low reaction cost, good safety, high yield and high reaction efficiency and is suitable for large-scale industrial production.

[0010] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0011] The present invention provides an ivankasser intermediate I, wherein the intermediate I has the structural formula:

[0012]

[0013] Among them, R 1 C 1-6 The alkyl group is further selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.

[0014] The present invention also provides a method for preparing the above-mentioned ivankasser intermediate I, comprising the following steps (I): D-malic acid undergoes a first dehydration condensation reaction under the action of acetyl chloride, followed by an amidation reaction with a p-aminophenylacetic acid ester compound, and then undergoes a second dehydration condensation reaction under the action of acetyl chloride to obtain the intermediate I;

[0015]

[0016] Wherein, R 1 C 1-6 The alkyl group is further selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.

[0017] The starting materials D-malic acid and p-aminophenylacetic acid ester compounds for preparing intermediate I are easily available and inexpensive. The discovery of intermediate I is crucial for the preparation of ivancaser, which significantly reduces the cost of preparing ivancaser.

[0018] In some embodiments, in step (I), the feeding ratio of the D-malic acid to the acetyl chloride used in the first dehydration condensation reaction is 1g:2.5-7.5mL, preferably 1g:3.0-6.0mL, and more preferably 1g:3.5-4.5mL; the reaction temperature of the first dehydration condensation reaction is 25-100°C, preferably 30-80°C, and more preferably 35-60°C.

[0019] In some embodiments, in step (I), the p-aminophenylacetic acid ester compound is any one of methyl p-aminophenylacetate, ethyl p-aminophenylacetate, propyl p-aminophenylacetate, butyl p-aminophenylacetate, and isopropyl p-aminophenylacetate, and is more preferably ethyl p-aminophenylacetate; the molar ratio of D-malic acid to p-aminophenylacetic acid ester compound is 1:0.6-4.5, preferably 1:0.8-3.0, and more preferably 1:1-1.5; the reaction temperature of the amidation reaction is 25-100°C, preferably 30-80°C, and more preferably 35-60°C.

[0020] In some embodiments, in step (I), the molar ratio of the D-malic acid to the acetyl chloride used in the second dehydration condensation reaction is 1:2.5-7.5, preferably 1:3.0-6.0, and more preferably 1:3.5-4.5; the reaction temperature of the second dehydration condensation reaction is 25-100°C, preferably 30-80°C, and more preferably 35-60°C.

[0021] Furthermore, the present invention provides an ivankasser intermediate II, the structural formula of the intermediate II is:

[0022]

[0023] Among them, R 1 C 1-6 Alkyl is further selected from methyl, ethyl, n-propyl, isopropyl or n-butyl; R 2 is a substituted sulfonyl group further selected from methanesulfonyl, p-toluenesulfonyl or o-nitrobenzenesulfonyl.

[0024] The present invention also provides a method for preparing the above-mentioned ivankasser intermediate II, comprising the following step (II): intermediate I undergoes a carbonyl reduction reaction on the five-membered ring under the action of a reducing agent, then removes the acetyl protecting group under acidic conditions, and then undergoes an esterification reaction with a sulfonyl chloride compound substituted with a sulfonyl group under alkaline conditions to obtain intermediate II;

[0025]

[0026] Among them, R 1is selected from methyl, ethyl, n-propyl, isopropyl or n-butyl; R 2 is a substituted sulfonyl group, the sulfonyl group is substituted, or the R 2 Further selected from methanesulfonyl, p-toluenesulfonyl or o-nitrobenzenesulfonyl.

[0027] The starting material for preparing the intermediate II, the sulfonyl chloride compound with substituted sulfonyl group, is easily available and inexpensive. The discovery of the intermediate II is crucial for the preparation of ivancaser, which significantly reduces the cost of preparing ivancaser.

[0028] In some embodiments, in step (II), the reducing agent is any one of sodium borohydride and potassium borohydride or a combination of both, preferably sodium borohydride; the molar ratio of the intermediate I to the reducing agent is 1:2 to 6.8, preferably 1:2.5 to 5.1, and more preferably 1:3 to 3.4; the reduction reaction has a reaction temperature of -25 to 15°C, preferably -20 to 10°C, and more preferably -15 to 5°C.

[0029] In some embodiments, in step (II), a first catalyst is added to the reduction reaction; preferably, the first catalyst is any one of a Lewis acid and a Bronst acid or a combination of two, more preferably a Lewis acid; wherein the Lewis acid is boron trifluoride or titanium tetrachloride; the Bronst acid is sulfuric acid; more preferably, the first catalyst is boron trifluoride; the molar ratio of the intermediate I to the first catalyst is 1:0.45-3.75, preferably 1:0.6-2.5, and further preferably 1:0.75-1.25.

[0030] In some embodiments, in step (II), the acidic condition is controlled by adding a second catalyst; preferably, the second catalyst is any one or a combination of trifluoroacetic acid, hydrogen chloride and methanesulfonic acid, more preferably hydrogen chloride; the molar ratio of the intermediate I to the second catalyst is 1:2.4-18, preferably 1:3.2-12, and more preferably 1:4-6; the removal of the acetyl protecting group is carried out at a temperature of 15-85°C, preferably 25-75°C, and more preferably 35-65°C.

[0031] In some embodiments, in step (II), the sulfonyl chloride compound is any one of methanesulfonyl chloride, p-toluenesulfonyl chloride and o-nitrobenzenesulfonyl chloride, more preferably o-nitrobenzenesulfonyl chloride; the molar ratio of the intermediate I to the sulfonyl chloride compound is 1:0.6-3.6, preferably 1:0.8-2.4, and more preferably 1:1.0-1.2; the alkaline condition is controlled by adding triethylamine and trimethylammonium hydrochloride; preferably, the molar ratio of the intermediate I to triethylamine is 1:0.6-6, more preferably 1:0.8-4, and more preferably 1:1-2; preferably, the molar ratio of trimethylammonium hydrochloride to the intermediate I is 1:2.4-18, more preferably 1:3.2-12, and more preferably 1:4-6; the reaction temperature of the esterification reaction is -15-35°C, preferably -10-25°C, and more preferably -5-15°C.

[0032] The use of the above-mentioned Ivancasser intermediate I or the above-mentioned Ivancasser intermediate II in the preparation of Ivancasser intermediate III or in the preparation of Ivancasser is also within the protection scope of the present invention.

[0033] Furthermore, the present invention provides a method for preparing an ivankasser intermediate III, comprising the following steps:

[0034] (I) D-malic acid undergoes a first dehydration condensation reaction under the action of acetyl chloride, then undergoes an amidation reaction with a p-aminophenylacetic acid ester compound, and then undergoes a second dehydration condensation reaction under the action of acetyl chloride to obtain intermediate I;

[0035]

[0036] (II) Intermediate I undergoes a carbonyl reduction reaction on the five-membered ring under the action of a reducing agent, and then removes the acetyl protecting group under acidic conditions, and then undergoes an esterification reaction with a sulfonyl chloride compound substituted with a sulfonyl group under alkaline conditions to obtain intermediate II;

[0037]

[0038] (III) intermediate II undergoes a substitution reaction with (R)-1-(1-naphthyl)ethylamine in the presence of a base, and then undergoes a salt-forming reaction with hydrogen chloride to obtain ivankaser intermediate III;

[0039]

[0040] Among them, R 1 is selected from methyl, ethyl, n-propyl, isopropyl or n-butyl; R 2 is a substituted sulfonyl group, the sulfonyl group is substituted, or the R 2Further selected from methanesulfonyl, p-toluenesulfonyl or o-nitrobenzenesulfonyl.

[0041] In some embodiments, in step (I), the feeding ratio of the D-malic acid to the acetyl chloride used in the first dehydration condensation reaction is 1g:2.5-7.5mL, preferably 1g:3.0-6.0mL, and more preferably 1g:3.5-4.5mL; the reaction temperature of the first dehydration condensation reaction is 25-100°C, preferably 30-80°C, and more preferably 35-60°C, and the reaction time is 10-44h, preferably 14-33h, and more preferably 18-22h.

[0042] In some embodiments, in step (I), the p-aminophenylacetic acid ester compound is any one of methyl p-aminophenylacetate, ethyl p-aminophenylacetate, propyl p-aminophenylacetate, butyl p-aminophenylacetate, and isopropyl p-aminophenylacetate, and is more preferably ethyl p-aminophenylacetate; the molar ratio of D-malic acid to p-aminophenylacetic acid ester compound is 1:0.6-4.5, preferably 1:0.8-3.0, and more preferably 1:1-1.5; the amidation reaction has a reaction temperature of 25-100°C, preferably 30-80°C, and more preferably 35-60°C, and a reaction time of 0.5-7.5h, preferably 1-5h, and more preferably 1.5-2.5h.

[0043] In some embodiments, in step (I), the molar ratio of the D-malic acid to the acetyl chloride used in the second dehydration condensation reaction is 1:2.5-7.5, preferably 1:3.0-6.0, and more preferably 1:3.5-4.5; the reaction temperature of the second dehydration condensation reaction is 25-100°C, preferably 30-80°C, and more preferably 35-60°C, and the reaction time is 2.5-7.5h, preferably 3.0-6.0h, and more preferably 3.5-4.5h.

[0044] In some embodiments, in step (II), the reducing agent is any one of sodium borohydride and potassium borohydride or a combination of both, preferably sodium borohydride; the molar ratio of the intermediate I to the reducing agent is 1:2-6.8, preferably 1:2.5-5.1, and more preferably 1:3-3.4; the reduction reaction has a reaction temperature of -25-15°C, preferably -20-10°C, and more preferably -15-5°C; the reaction time is 4-40h, preferably 8-30h, and more preferably 12-20h.

[0045] In some embodiments, in step (II), a first catalyst is added to the reduction reaction; preferably, the first catalyst is any one of a Lewis acid and a Bronst acid or a combination of two, more preferably a Lewis acid; wherein the Lewis acid is boron trifluoride or titanium tetrachloride; the Bronst acid is sulfuric acid; more preferably, the first catalyst is boron trifluoride; the molar ratio of the intermediate I to the first catalyst is 1:0.45-3.75, preferably 1:0.6-2.5, and further preferably 1:0.75-1.25.

[0046] Wherein, in step (II), a first catalyst is added to the reduction reaction; the complexing solvent of the first catalyst is any one or a combination of tetrahydrofuran, ether and acetonitrile, more preferably tetrahydrofuran.

[0047] In some embodiments, in step (II), the acidic condition is controlled by adding a second catalyst; preferably, the second catalyst is any one or a combination of trifluoroacetic acid, hydrogen chloride and methanesulfonic acid, more preferably hydrogen chloride; the molar ratio of the intermediate I to the second catalyst is 1:2.4-18, preferably 1:3.2-12, and more preferably 1:4-6; the removal of the acetyl protecting group, the removal temperature is 15-85°C, preferably 25-75°C, and more preferably 35-65°C, and the removal time is 2-18h, preferably 3-12h, and more preferably 4-6h.

[0048] Wherein, in step (II), when the second catalyst is hydrogen chloride, the hydrogen chloride is prepared by reacting anhydrous ethanol and acetyl chloride.

[0049] In some embodiments, in step (II), the sulfonyl chloride compound is any one of methanesulfonyl chloride, p-toluenesulfonyl chloride and o-nitrobenzenesulfonyl chloride, more preferably o-nitrobenzenesulfonyl chloride; the molar ratio of the intermediate I to the sulfonyl chloride compound is 1:0.6-3.6, preferably 1:0.8-2.4, and more preferably 1:1.0-1.2; the alkaline condition is controlled by adding triethylamine and trimethylammonium hydrochloride; preferably, the molar ratio of the intermediate I to triethylamine is 1 : 0.6~6, more preferably 1:0.8~4, further preferably 1:1~2; preferably, the molar ratio of trimethylamine hydrochloride to intermediate I is 1:2.4~18, more preferably 1:3.2~12, further preferably 1:4~6; the esterification reaction, the reaction temperature is -15~35°C, preferably -10~25°C, further preferably -5~15°C, the reaction time is 0.5~4.5h, preferably 0.5~3h, further preferably 0.5~1.5h.

[0050] In some embodiments, in step (III), the base is an inorganic base or an organic base, preferably an inorganic base; wherein the inorganic base is cesium carbonate, potassium carbonate, sodium carbonate or potassium phosphate; the organic base is triethylamine or N,N-diisopropylethylamine; more preferably, the base is sodium carbonate or potassium phosphate; further preferably, the base is sodium carbonate; the molar ratio of the intermediate II to the base is 1:0.6-3.6, preferably 1:0.8-2.4, further preferably 1:1-1.2; the molar ratio of the intermediate II to (R)-1-(1-naphthyl)ethylamine is 1:0.6-4.2, preferably 1:0.8-2.8, further preferably 1:1-1.4; the substitution reaction, the reaction temperature is 40-100°C, preferably 50-90°C, further preferably 60-80°C, the reaction time is 12-96h, preferably 16-64h, further preferably 20-32h.

[0051] In some embodiments, in step (III), the molar ratio of the intermediate II to hydrogen chloride is 1:0.6-4.2, preferably 1:0.8-2.8, and more preferably 1:1-1.4; the reaction temperature of the salt-forming reaction is 0-50°C, preferably 5-40°C, and more preferably 10-30°C.

[0052] Wherein, in step (III), the hydrogen chloride is present in a hydrogen chloride ethyl acetate solution, and the concentration of hydrogen chloride in the hydrogen chloride ethyl acetate solution is 2 mol / L to 4 mol / L, preferably 4 mol / L.

[0053] Finally, the present invention also provides a method for preparing ivankasser, comprising the steps shown in the following route:

[0054] The preparation method of Ivankasser, wherein the intermediate III can be prepared according to the existing technical method to obtain Ivankasser, wherein the intermediate III is prepared according to the above method of the present invention.

[0055] Beneficial effects:

[0056] Compared with the prior art, the present invention has the following advantages:

[0057] (1) The starting raw materials D-malic acid and p-aminophenylacetic acid ester compounds used in the preparation of intermediates I, II and III of the present invention are low in price, which reduces the production cost compared with the raw materials such as N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol, ethyl 4-bromophenylacetate and palladium acetate used in the synthesis of ivankasser in the prior art.

[0058] (2) The preparation of the intermediate III of the present invention does not require the participation of a palladium catalyst, so that there is no heavy metal residue in the target product intermediate III, which is green and environmentally friendly, and further improves the safety of the process.

[0059] (3) The inventor tried to use the experimental reaction route in the comparative document 2 and found that the conversion rate of the raw materials L-malic acid and p-aminophenylacetic acid ester compounds was less than 10%, and the API with the correct configuration could not be obtained. However, the synthetic route of the present invention has a high raw material conversion rate and can obtain the API with the correct configuration, which is conducive to scale-up production.

[0060] (4) The present invention optimizes the currently known synthesis process of ivankasert. By using the intermediate II of the present invention as a substrate, reacting it with (R)-1-(1-naphthyl)ethylamine under the action of a base, and then reacting it with hydrogen chloride to form a salt, the hydrogen chloride can be removed and the ester group can be hydrolyzed according to the existing technical method to obtain ivankasert. The operation is simple, the steps are short, the by-products caused by multi-step reactions are reduced, and the yield of the product is improved. At the same time, no metal catalyst is required in the synthesis process, which is green and environmentally friendly, so that ivankasert has no metal residue, thereby improving the biosafety of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0062] Figure 1 : H NMR spectrum of intermediate I obtained in Example 1;

[0063] Figure 2 : NMR carbon spectrum of intermediate I obtained in Example 1;

[0064] Figure 3 : High resolution mass spectrum of intermediate I obtained in Example 1;

[0065] Figure 4 : H NMR spectrum of intermediate II obtained in Example 1;

[0066] Figure 5 : NMR carbon spectrum of intermediate II obtained in Example 1;

[0067] Figure 6 : High resolution mass spectrum of intermediate II obtained in Example 1;

[0068] Figure 7 : H NMR spectrum of intermediate III obtained in Example 1;

[0069] Figure 8 : NMR carbon spectrum of intermediate III obtained in Example 1;

[0070] Fig. 9 : High resolution mass spectrum of intermediate III obtained in Example 1;

[0071] Fig.10 : LC-MS graph of the reaction solution of Comparative Example 1. DETAILED DESCRIPTION

[0072] The present invention will be described in more detail below through examples. These examples are used for further explanation and can better understand the content of the present invention, but should not be regarded as limiting the present invention.

[0073] The term "controlling the internal temperature" in the embodiments of the present invention refers to the internal temperature of the reaction.

[0074] In the embodiments of the present invention, the concentrations expressed in % are by mass unless otherwise specified.

[0075] Embodiment 1:

[0076] Synthesis of Intermediate I:

[0077]

[0078] Acetyl chloride (400 mL) and D-malic acid (100 g) were added to a 1000 mL three-necked flask, and the atmosphere was replaced with nitrogen. The first dehydration condensation reaction was carried out at 40-50 ° C with stirring for 20 h. After the reaction, ethyl p-aminophenylacetate (160.39 g) and ethyl acetate (600 mL) were added to the reaction solution, and the atmosphere was replaced with nitrogen. The amidation reaction was carried out at 40-50 ° C with stirring for 2 h. After the reaction, acetyl chloride (234.17 g) was added to the reaction solution, and the second dehydration condensation reaction was continued at 40-50 ° C for 4 h. After the reaction, ethyl acetate (700 mL) was added to the reaction solution, and the temperature was lowered to 0-10 ° C. Anhydrous ethanol (1000 mL) was added dropwise to control the internal temperature at 0-10 ° C. After the addition, the mixture was stirred at 0-10 ° C for 10-20 min, filtered, the filter cake was washed with anhydrous ethanol, and dried under reduced pressure to obtain 211.48 g of a white crystalline intermediate I solid with a yield of about 88.81%.

[0079] 1 H NMR (400MHz, d 6 -DMSO): δ7.4 (d, 2H), δ7.2 (d, 2H), δ5.6 (q, 1H), δ4.1 (q, 2H), δ3.7 (s, 2H), δ3.2 (dd, 1H), δ2.9 (dd, 1H), δ2.1 (s, 3H), δ1.2 (t, 3H), the H NMR spectrum of intermediate I is shown in Figure 1 .

[0080] 13C-NMR (100MHz, d 6 -DMSO): δ173.8, δ173.7, δ171.4, δ170.3, δ135.4, δ131.1, δ130.5, δ127.3, δ68.6, δ60.9, δ40.3, δ35.8, δ20.9, δ14.5. See the NMR carbon spectrum of intermediate I. Figure 2 .

[0081] MS·ACQ(m / z):374.2587[M+CH 3 OH+Na] + The high-resolution mass spectrum of intermediate I is shown in Figure 3 .

[0082] Synthesis of Intermediate II:

[0083]

[0084] Among them, R 2 Selected from o-nitrobenzenesulfonyl.

[0085] (1) Tetrahydrofuran (800 mL) and intermediate I (100.00 g) were added to a 2000 mL three-necked flask, replaced with nitrogen, cooled to -5±5°C, sodium borohydride (39.22 g) was added, stirred for 15 min, and then 50% boron trifluoride tetrahydrofuran solution (87.90 g) was added dropwise to the reaction solution at -5±5°C. After the addition was complete, reduction reaction was carried out at -5±5°C for 16 h. After the reaction was completed, the internal temperature was controlled at 0±5°C, anhydrous ethanol (400 mL) was added dropwise to quench the reaction, and the reaction was continued at 0±5°C. ℃ and stirred for 1.0-2.0h, then slowly heated to 20-30℃ and stirred for 1.0-2.0h, after stirring, distilled under reduced pressure at 40-50℃ until about 200-300mL of material remained in the kettle, added purified water (1000mL) and toluene (500mL) into the kettle, stirred for 10min, after stirring, adjusted the pH of the aqueous phase to 7.0-8.0 with 5% sodium carbonate aqueous solution, separated, and retained the organic phase; the organic phase was washed with purified water (500mL) and saturated brine (500mL) in turn, and retained the organic phase;

[0086] (2) Controlling the internal temperature at 0-10° C., dropwise adding acetyl chloride (123.3 g) into 500 mL of anhydrous ethanol, preparing a hydrogen chloride ethanol solution, adding the solution to the organic phase finally obtained in the above step (1), slowly heating to 40-55° C., stirring the reaction for 5 h to remove the acetyl protecting group, distilling under reduced pressure at 40-50° C. after the reaction is completed until about 400-600 mL of material remains in the kettle, then cooling to 20-30° C., adding purified water (500 mL) to the reaction solution, adjusting the pH of the aqueous phase to 7.0-8.0 with a 5% sodium carbonate aqueous solution, separating the liquids, and retaining the organic phase; washing the organic phase with purified water (500 mL) and saturated brine (500 mL) in sequence, and retaining the organic phase; distilling the organic phase under reduced pressure at 40-50° C. until about 200-300 mL of material remains in the kettle, and obtaining a concentrate;

[0087] (3) Toluene (100 mL), acetonitrile (200 mL), triethylamine (47.56 g), and trimethylamine hydrochloride (5.99 g) were added to the concentrate obtained in step (2), and a toluene (200 mL) solution containing o-nitrobenzenesulfonyl chloride (76.39 g) was added to the reaction solution at a temperature of 0 to 10° C. After the addition was complete, the reaction solution was stirred at 0 to 10° C. for esterification reaction for 1 h. After the reaction was complete, purified water (500 mL) was added to the reaction solution, and the aqueous phase was adjusted with a 5% citric acid aqueous solution. H to 6.0-7.0, separate the liquids and retain the organic phase; add purified water (500 mL) to the organic phase, adjust the pH of the aqueous phase to 7.0-8.0 with 5% sodium carbonate aqueous solution, separate the liquids and retain the organic phase; add saturated brine (500 mL) to the organic phase for washing, separate the liquids and retain the organic phase; add anhydrous ethanol (2100 mL) dropwise to the organic phase, after the dropwise addition, cool to 0-10°C and stir for 2h to crystallize, filter after the crystallization is completed, rinse the filter cake with anhydrous ethanol, and dry under reduced pressure to obtain 69.3 g of yellow powdery solid intermediate II with a yield of about 51%.

[0088] 1 H NMR (400MHz, d 6 -DMSO): δ7.9 (d, 1H), δ7.5 (m, 3H), δ7.1 (d, 2H), δ6.6 (d, 2H), δ5.4 (d, 1H), δ4.1 (q, 2H), δ3.6~3.5 (m, 2H), δ3.5 (s, 2H), δ3.4~3.3 (m, 2H), δ2.4 (m, 2H), δ1.2 (t, 3H), the H NMR spectrum of intermediate II is shown in Figure 4 .

[0089] 13 C-NMR (100MHz, d 6-DMSO): δ172.01, δ146.61, δ140.33, δ130.94, δ130.29, δ130.14, δ129.61, δ12 2.70, δ112.65, δ87.77, δ60.42, δ54.53, δ45.85, δ32.11, δ14.54. See the NMR carbon spectrum of intermediate II. Figure 5 .

[0090] MS·ACQ(m / z):435.2726[M+H] + The high-resolution mass spectrum of intermediate II is shown in Figure 6 .

[0091] Synthesis of intermediate III:

[0092]

[0093] Among them, R 2 Selected from o-nitrobenzenesulfonyl.

[0094] Ethyl acetate (160 mL), intermediate II (40.00 g), (R)-1-(1-naphthyl)ethylamine (18.92 g), and sodium carbonate (10.74 g) were added to a 500 mL three-necked flask, replaced with nitrogen, heated to 65-75° C., stirred for substitution reaction for 26 h, cooled to 20-40° C. after the reaction, purified water (200 mL) was added to the reaction solution, stirred, allowed to stand for separation, and the organic phase was retained; 10% sodium chloride aqueous solution (200 mL) was added to the organic phase for washing, separation, and the organic phase was retained; Add 10% sodium chloride aqueous solution (200 mL) to the organic phase for washing, separate the liquids, and retain the organic phase; add anhydrous ethanol (40 mL) and toluene (320 mL) to the organic phase, add 4.0 M hydrogen chloride ethyl acetate solution (26.86 g) under stirring, control the internal temperature at 15-25° C. and stir for 1 h to form a salt, then slowly add methyl tert-butyl ether (480 mL) dropwise, control the internal temperature at 15-25° C. and stir for 6 h, filter after stirring, rinse the filter cake with methyl tert-butyl ether, and dry under reduced pressure to obtain 29.89 g of off-white solid powder intermediate III with a yield of 74.08%.

[0095] 1 H NMR (400MHz, d 6-DMSO): δ10.4(s,1H),δ10.0(s,1H),δ8.4(d,1H),δ8.2(d,1H),δ8.0(m,2H),δ7.6(m,3H),δ7.0(d,2H),δ6.5(d,2H),δ5.4(q,1H),δ4.0(t,2H),δ3.8(m,1H),δ3.5(m,2H),δ3.5(s,2H),δ3.4(m,1H),δ3.1(m,1H),δ2.4(m,1H),δ2.2(m,1H),δ1.8(d,3H),δ1.2(t,3H), see the H NMR spectrum of intermediate III Figure 7 .

[0096] 13 C-NMR (100MHz, d 6 -DMSO): δ172.14, δ146.53, δ134.48, δ133.90, δ130.70, δ130.32, δ129.51, δ129.48, δ127.56, δ126.70, δ126.08, δ12 5.45, δ123.06, δ122.28, δ112.39, δ60.49, δ54.73, δ51.58, δ50.46, δ46.04, δ28.24, δ20.69, δ14.58, see the NMR carbon spectrum of intermediate III. Figure 8 .

[0097] MS·ACQ(m / z):403.8311[M+H] + The high-resolution mass spectrum of intermediate III is shown in Fig. 9 .

[0098] Embodiment 2:

[0099] Synthesis of Intermediate I:

[0100] Acetyl chloride (350 mL) and D-malic acid (100 g) were added to a 1000 mL three-necked flask, and the atmosphere was replaced with nitrogen. The first dehydration condensation reaction was carried out at 35-45 ° C with stirring for 24 h. After the reaction, ethyl p-aminophenylacetate (133.64 g) and ethyl acetate (550 mL) were added to the reaction solution, and the atmosphere was replaced with nitrogen. The amidation reaction was carried out at 50-60 ° C with stirring for 1 h. After the reaction, acetyl chloride (204.90 g) was added to the reaction solution, and the second dehydration condensation reaction was continued at 40-50 ° C for 3 h. After the reaction, ethyl acetate (800 mL) was added to the reaction solution, and the temperature was lowered to 0-10 ° C. Anhydrous ethanol (800 mL) was added dropwise while controlling the internal temperature at 0-10 ° C. After the addition, the mixture was kept warm and stirred at 0-10 ° C for 5-15 min, filtered, the filter cake was washed with anhydrous ethanol, and dried under reduced pressure to obtain 190.52 g of a white crystalline intermediate I solid with a yield of about 80.2%. Synthesis of Intermediate II:

[0101] (1) Tetrahydrofuran (600 mL) and intermediate I (100.00 g) were added to a 2000 mL three-necked flask, replaced with nitrogen, cooled to -10-0°C, sodium borohydride (35.65 g) was added, stirred for 5 min, and then 50% boron trifluoride tetrahydrofuran solution (65.92 g) was added dropwise to the reaction solution at -5±5°C. After the addition was complete, reduction reaction was carried out at -5±5°C for 20 h. After the reaction was completed, anhydrous ethanol (450 mL) was added dropwise to control the internal temperature at 0±5°C to quench the reaction. After the quenching was completed, the reaction was continued at 0±5°C. ℃, stirred for 1.0-2.0h, then slowly heated to 15-25℃, stirred for 1.0-2.0h, after stirring, distilled under reduced pressure at 40-60℃, distilled until about 150-250mL of material remained in the kettle, added purified water (1200mL) and toluene (600mL) into the kettle, stirred for 15min, after stirring, adjusted the pH of the aqueous phase to 7.0-8.0 with 5% sodium carbonate aqueous solution, separated, and retained the organic phase; the organic phase was washed with purified water (600mL) and saturated brine (400mL) in turn, and retained the organic phase;

[0102] (2) Controlling the internal temperature at 5-15° C., dropwise adding acetyl chloride (147.96 g) into 600 mL of anhydrous ethanol, preparing a hydrogen chloride ethanol solution, adding the solution to the organic phase finally obtained in the above step (1), slowly heating to 50-65° C., stirring the reaction for 6 h to remove the acetyl protecting group, and distilling under reduced pressure at 45-55° C. after the reaction is completed until about 550-650 mL of material remains in the kettle, then cooling to 25-35° C., adding purified water (600 mL) to the reaction solution, adjusting the pH of the aqueous phase to 7.0-8.0 with a 5% sodium carbonate aqueous solution, separating the liquids, and retaining the organic phase; washing the organic phase with purified water (600 mL) and saturated brine (600 mL) in sequence, and retaining the organic phase; distilling the organic phase under reduced pressure at 45-55° C. until about 250-350 mL of material remains in the kettle, and obtaining a concentrate;

[0103] (3) To the concentrate obtained in step (2), toluene (50 mL), acetonitrile (250 mL), triethylamine (63.58 g), and trimethylamine hydrochloride (7.51 g) were added, and a toluene (250 mL) solution containing o-nitrobenzenesulfonyl chloride (83.54 g) was added to the reaction solution at a temperature of 5 to 15° C. After the addition was complete, the esterification reaction was carried out by stirring at 5 to 15° C. for 2 h. After the reaction was completed, purified water (600 mL) was added to the reaction solution, and the aqueous phase was adjusted with a 5% citric acid aqueous solution. H to 6.0-7.0, separate the liquids, and retain the organic phase; add purified water (600 mL) to the organic phase, adjust the pH of the aqueous phase to 7.0-8.0 with 5% sodium carbonate aqueous solution, separate the liquids, and retain the organic phase; add saturated brine (600 mL) to the organic phase for washing, separate the liquids, and retain the organic phase; add anhydrous ethanol (2400 mL) dropwise to the organic phase, after the dropwise addition, cool to 5-15°C and stir for 3h to crystallize, filter after the crystallization is completed, rinse the filter cake with anhydrous ethanol, and dry under reduced pressure to obtain 64.15 g of yellow powdery solid intermediate II with a yield of about 47%.

[0104] Synthesis of intermediate III:

[0105] Ethyl acetate (120 mL), intermediate II (40.00 g), (R)-1-(1-naphthyl)ethylamine (15.77 g), and sodium carbonate (9.76 g) were added to a 500 mL three-necked flask, replaced with nitrogen, heated to 60-70° C., stirred for substitution reaction for 20 h, cooled to 15-35° C. after the reaction, purified water (160 mL) was added to the reaction solution, stirred, allowed to stand for separation, and the organic phase was retained; 10% sodium chloride aqueous solution (160 mL) was added to the organic phase for washing, separation, and the organic phase was retained; Add 10% sodium chloride aqueous solution (160 mL) to the organic phase for washing, separate the liquids, and retain the organic phase; add anhydrous ethanol (20 mL) and toluene (280 mL) to the organic phase, add 4.0 M hydrogen chloride ethyl acetate solution (22.38 g) under stirring, control the internal temperature at 10-20° C. and stir for 0.5 h to form a salt, then slowly add methyl tert-butyl ether (400 mL) dropwise, control the internal temperature at 10-20° C. and stir for 8 h, filter after stirring, rinse the filter cake with methyl tert-butyl ether, and dry under reduced pressure to obtain 28.24 g of off-white solid powder intermediate III with a yield of 70%.

[0106] Embodiment 3:

[0107] Synthesis of Intermediate I:

[0108] Acetyl chloride (450 mL) and D-malic acid (100 g) were added to a 1000 mL three-necked flask, and the atmosphere was replaced with nitrogen. The first dehydration condensation reaction was carried out at 50-60 ° C with stirring for 15 h. After the reaction, ethyl p-aminophenylacetate (200.46 g) and ethyl acetate (650 mL) were added to the reaction solution, and the atmosphere was replaced with nitrogen. The amidation reaction was carried out at 35-45 ° C with stirring for 2.5 h. Acetyl chloride (263.44 g) was added to the reaction solution, and the second dehydration condensation reaction was continued at 45-55 ° C for 5 h. After the reaction, ethyl acetate (600 mL) was added to the reaction solution, and the temperature was lowered to 0-10 ° C. Anhydrous ethanol (1200 mL) was added dropwise while controlling the internal temperature at 0-10 ° C. After the addition, the mixture was kept warm and stirred at 0-10 ° C for 15-25 min, filtered, the filter cake was washed with anhydrous ethanol, and dried under reduced pressure to obtain 196.01 g of a white crystalline intermediate I solid with a yield of about 82.51%. Synthesis of Intermediate II:

[0109] (1) Tetrahydrofuran (1000 mL) and intermediate I (100.00 g) were added to a 2000 mL three-necked flask, replaced with nitrogen, cooled to 5±5°C, sodium borohydride (40.40 g) was added, stirred for 30 min, and 50% boron trifluoride tetrahydrofuran solution (109.88 g) was added dropwise to the reaction solution at 5±5°C. After the addition was complete, reduction reaction was carried out at 5±5°C for 12 h. After the reaction was completed, the internal temperature was controlled at 0±5°C, anhydrous ethanol (350 mL) was added dropwise to quench the reaction, and the reaction was continued at 0±5°C after the quenching. ℃, stirred for 1.0-2.0h, then slowly heated to 25-35℃, stirred for 1.0-2.0h, after stirring, distilled under reduced pressure at 30-50℃, distilled until about 250-350mL of material remained in the kettle, added purified water (800mL) and toluene (400mL) into the kettle, stirred for 5min, after stirring, adjusted the pH of the aqueous phase to 7.0-8.0 with 5% sodium carbonate aqueous solution, separated, and retained the organic phase; the organic phase was washed with purified water (400mL) and saturated brine (400mL) in turn, and retained the organic phase;

[0110] (2) Controlling the internal temperature at -5 to 5°C, dropwise add acetyl chloride (98.64 g) to 400 mL of anhydrous ethanol to prepare a hydrogen chloride ethanol solution, add the solution to the organic phase finally obtained in the above step (1), slowly raise the temperature to 35 to 50°C, stir the reaction for 4 h to remove the acetyl protecting group, and after the reaction is completed, perform vacuum distillation at 35 to 45°C until about 350 to 450 mL of material remains in the kettle, then cool the temperature to 15 to 25°C, add purified water (400 mL) to the reaction solution, adjust the pH of the aqueous phase to 7.0 to 8.0 with a 5% sodium carbonate aqueous solution, separate the liquids, and retain the organic phase; wash the organic phase with purified water (400 mL) and saturated brine (400 mL), respectively, and retain the organic phase; perform vacuum distillation at 35 to 45°C until about 150 to 250 mL of material remains in the kettle to obtain a concentrate;

[0111] (3) Toluene (150 mL), acetonitrile (150 mL), triethylamine (31.79 g), and trimethylamine hydrochloride (5.01 g) were added to the concentrate obtained in step (2), and a toluene (150 mL) solution containing o-nitrobenzenesulfonyl chloride (69.62 g) was added to the reaction solution at a temperature of -5 to 5°C. After the addition was complete, the esterification reaction was carried out by stirring at -5 to 5°C for 0.5 h. After the reaction was completed, purified water (400 mL) was added to the reaction solution, and the pH of the aqueous phase was adjusted to 6.0 to 7 with a 5% citric acid aqueous solution. .0, separate the liquids and retain the organic phase; add purified water (400 mL) to the organic phase, adjust the pH of the aqueous phase to 7.0-8.0 with 5% sodium carbonate aqueous solution, separate the liquids and retain the organic phase; add saturated brine (400 mL) to the organic phase for washing, separate the liquids and retain the organic phase; add anhydrous ethanol (1800 mL) dropwise to the organic phase, after the dropwise addition, cool to -5-5°C and stir for 1h to crystallize, filter after the crystallization is completed, rinse the filter cake with anhydrous ethanol, and dry under reduced pressure to obtain 65.51 g of yellow powdery solid intermediate II with a yield of about 48.00%.

[0112] Synthesis of intermediate III:

[0113] Ethyl acetate (200 mL), intermediate II (40.00 g), (R)-1-(1-naphthyl)ethylamine (22.07 g), and sodium carbonate (11.71 g) were added to a 500 mL three-necked flask, replaced with nitrogen, heated to 70-80° C., stirred for substitution reaction for 32 h, cooled to 25-45° C. after the reaction, purified water (240 mL) was added to the reaction solution, stirred, allowed to stand for separation, and the organic phase was retained; 10% sodium chloride aqueous solution (240 mL) was added to the organic phase for washing, separation, and the organic phase was retained; Add 10% sodium chloride aqueous solution (240 mL) to the organic phase for washing, separate the liquids, and retain the organic phase; add anhydrous ethanol (60 mL) and toluene (360 mL) to the organic phase, add 4.0 M hydrogen chloride ethyl acetate solution (31.33 g) under stirring, control the internal temperature at 20-30° C. and stir for 1.5 h to form a salt, then slowly add methyl tert-butyl ether (560 mL) dropwise, control the internal temperature at 15-25° C. and stir for 4 h, filter after stirring, rinse the filter cake with methyl tert-butyl ether, and dry under reduced pressure to obtain 29.15 g of off-white solid intermediate III in a yield of 72.25%.

[0114] Comparative Example 1: Synthesis of key intermediate II in patent CN113620855A

[0115] The preparation method of the key intermediate II in Example 113620855A was followed. After stirring for 12 to 13 hours, the obtained reaction solution was sent for LC-MS (LC-MS spectrum is shown in Fig.10), the reaction system is extremely complex, no solid product is obtained, and the yield cannot be calculated. Among them, the structural formula of the key intermediate II in Example CN113620855A is as follows:

[0116] wherein R is selected from methyl.

[0117] LC-MS results show that when the method in CN113620855A is used, the reaction system is extremely complex and the product conversion rate is only less than 10%, making it difficult to obtain relevant products.

[0118] The present invention provides a key intermediate of ivancaser and a method for preparing the same. There are many methods and approaches to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A method for preparing an ivankasser intermediate I, characterized in that: The method comprises the following steps (I): D-malic acid undergoes a first dehydration condensation reaction under the action of acetyl chloride, and then undergoes an amidation reaction with a p-aminophenylacetic acid ester compound, and then undergoes a second dehydration condensation reaction under the action of acetyl chloride to obtain an intermediate I; Wherein, R1 of the p-aminophenylacetic acid ester compound is C 1-6 alkyl.

2. The preparation method according to claim 1, characterized in that: R1 is selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.

3. A method for preparing an ivankasser intermediate III, characterized in that: The steps include: (I) D-malic acid undergoes a first dehydration condensation reaction under the action of acetyl chloride, then undergoes an amidation reaction with a p-aminophenylacetic acid ester compound, and then undergoes a second dehydration condensation reaction under the action of acetyl chloride to obtain intermediate I; (II) Intermediate I undergoes a carbonyl reduction reaction on the five-membered ring under the action of a reducing agent, and then removes the acetyl protecting group under acidic conditions, and then undergoes an esterification reaction with a sulfonyl chloride compound substituted with a sulfonyl group under alkaline conditions to obtain intermediate II; (III) intermediate II undergoes a substitution reaction with (R)-1-(1-naphthyl)ethylamine in the presence of a base, and then undergoes a salt-forming reaction with hydrogen chloride to obtain ivankaser intermediate III; Wherein, R1 is selected from methyl, ethyl, n-propyl, isopropyl or n-butyl; R2 is substituted sulfonyl.

4. The preparation method according to claim 3, characterized in that: R2 is selected from methanesulfonyl, p-toluenesulfonyl or o-nitrobenzenesulfonyl.

5. The preparation method according to claim 1 or the preparation method according to claim 3, characterized in that: In step (I), the feeding amount ratio of the D-malic acid to the acetyl chloride used in the first dehydration condensation reaction is 1 g: 2.5-7.5 mL; the reaction temperature of the first dehydration condensation reaction is 25-100° C.; the molar ratio of the D-malic acid to the p-aminophenylacetic acid ester compound is 1: 0.6-4.5; the reaction temperature of the amidation reaction is 25-100° C.; the molar ratio of the D-malic acid to the acetyl chloride used in the second dehydration condensation reaction is 1: 2.5-7.5; the reaction temperature of the second dehydration condensation reaction is 25-100° C.

6. The preparation method according to claim 5, characterized in that: In step (I), the feeding ratio of the D-malic acid to the acetyl chloride used in the first dehydration condensation reaction is 1 g: 3.0-6.0 mL; the reaction temperature of the first dehydration condensation reaction is 30-80° C.; the molar ratio of the D-malic acid to the p-aminophenylacetic acid ester compound is 1: 0.8-3.0; the reaction temperature of the amidation reaction is 30-80° C.; the molar ratio of the D-malic acid to the acetyl chloride used in the second dehydration condensation reaction is 1: 3.0-6.0, and the reaction temperature of the second dehydration condensation reaction is 30-80° C.

7. The preparation method according to claim 6, characterized in that: In step (I), the feeding amount ratio of the D-malic acid to the acetyl chloride used in the first dehydration condensation reaction is 1 g: 3.5-4.5 mL; the reaction temperature of the first dehydration condensation reaction is 35-60° C.; the molar ratio of the D-malic acid to the p-aminophenylacetic acid ester compound is 1: 1-1.5; the reaction temperature of the amidation reaction is 35-60° C.; the molar ratio of the D-malic acid to the acetyl chloride used in the second dehydration condensation reaction is 1: 3.5-4.5; the reaction temperature of the second dehydration condensation reaction is 35-60° C.

8. The preparation method according to claim 3, characterized in that: In step (II), the reducing agent is any one of sodium borohydride and potassium borohydride or a combination of the two; the molar ratio of the intermediate I to the reducing agent is 1:2-6.8; the reduction reaction is carried out at a temperature of -25-15°C; during the reduction reaction, a first catalyst is added; the molar ratio of the intermediate I to the first catalyst is 1:0.45-3.75; the acidic condition is controlled by adding a second catalyst; the intermediate I and the second catalyst are reacted at a temperature of -25-15°C; the first catalyst is added to the reduction reaction; the molar ratio of the intermediate I to the first catalyst is 1:0.45-3.75; the acidic condition is controlled by adding a second catalyst; the intermediate I and the second catalyst are reacted at a temperature of -25-15°C; the first catalyst is added to the first catalyst; the first catalyst is reacted at a temperature of -25-15°C ... The molar ratio of the catalytic agent is 1:2.4-18; the removal temperature of the acetyl protecting group is 15-85°C; the molar ratio of the intermediate I to the sulfonyl chloride compound is 1:0.6-3.6; the alkaline condition is controlled by adding triethylamine and trimethylammonium hydrochloride; the molar ratio of the intermediate I to triethylamine is 1:0.6-6; the molar ratio of trimethylammonium hydrochloride to the intermediate I is 1:2.4-18; the reaction temperature of the esterification reaction is -15-35°C.

9. The preparation method according to claim 8, characterized in that: In step (II), the reducing agent is sodium borohydride; the molar ratio of the intermediate I to the reducing agent is 1:2.5-5.1; the reduction reaction is carried out at a temperature of -20-10°C; the first catalyst is any one or a combination of two of a Lewis acid and a Bronst acid, wherein the Lewis acid is boron trifluoride or titanium tetrachloride; the Bronst acid is sulfuric acid; the molar ratio of the intermediate I to the first catalyst is 1:0.6-2.5; the second catalyst is trifluoroethyl Acid, hydrogen chloride and methanesulfonic acid or a combination thereof; the molar ratio of the intermediate I to the second catalyst is 1:3.2-12; the removal temperature of the acetyl protecting group is 25-75°C; the molar ratio of the intermediate I to the sulfonyl chloride compound is 1:0.8-2.4; the molar ratio of the intermediate I to triethylamine is 1:0.8-4; the molar ratio of trimethylamine hydrochloride to the intermediate I is 1:3.2-12; the reaction temperature of the esterification reaction is -10-25°C.

10. The preparation method according to claim 9, characterized in that: In step (II), the molar ratio of the intermediate I to the reducing agent is 1:3-3.4; the reaction temperature of the reduction reaction is -15-5°C; the first catalyst is boron trifluoride; the molar ratio of the intermediate I to the first catalyst is 1:0.75-1.25; the second catalyst is hydrogen chloride; the molar ratio of the intermediate I to the second catalyst is 1:4-6; the removal temperature of the acetyl protecting group is 35-65°C; the molar ratio of the intermediate I to the sulfonyl chloride compound is 1:1.0-1.2; the molar ratio of the intermediate I to triethylamine is 1:1-2; the molar ratio of trimethylamine hydrochloride to the intermediate I is 1:4-6; the reaction temperature of the esterification reaction is -5-15°C.

11. The preparation method according to claim 3, characterized in that: In step (III), the base is an inorganic base or an organic base; wherein the inorganic base is cesium carbonate, potassium carbonate, sodium carbonate or potassium phosphate; the organic base is triethylamine or N,N-diisopropylethylamine; the molar ratio of the intermediate II to the base is 1:0.6-3.6; the molar ratio of the intermediate II to (R)-1-(1-naphthyl)ethylamine is 1:0.6-4.2; the reaction temperature of the substitution reaction is 40-100°C; the molar ratio of the intermediate II to hydrogen chloride is 1:0.6-4.2; the reaction temperature of the salt-forming reaction is 0-50°C.

12. The preparation method according to claim 11, characterized in that: In step (III), the base is an inorganic base; the molar ratio of the intermediate II to the base is 1:0.8-2.4; the molar ratio of the intermediate II to (R)-1-(1-naphthyl)ethylamine is 1:0.8-2.8; the reaction temperature of the substitution reaction is 50-90°C; the molar ratio of the intermediate II to hydrogen chloride is 1:0.8-2.8; the reaction temperature of the salt-forming reaction is 5-40°C.

13. The preparation method according to claim 12, characterized in that: In step (III), the base is sodium carbonate or potassium phosphate; the molar ratio of the intermediate II to the base is 1:1-1.2; the molar ratio of the intermediate II to (R)-1-(1-naphthyl)ethylamine is 1:1-1.4; the reaction temperature of the substitution reaction is 60-80°C; the molar ratio of the intermediate II to hydrogen chloride is 1:1-1.4; the reaction temperature of the salt-forming reaction is 10-30°C.

14. A method for preparing ivankasser, characterized in that: The steps include:

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