Preparation method of (S)-3-methyl-(2-piperidyl phenyl)-1-butylamine acetyl glutamate

Abstract

The invention discloses a preparation method of (S)-3-methyl-(2-piperidyl phenyl)-1-butylamine acetyl glutamate, and belongs to the field of medicinal chemistry. According to the method, a solvent DMF commonly used in the condensation step is changed into acetonitrile or DMSO, generation of a large number of o-dimethylamino cyanophenyl impurities is avoided, the solvent for Grignard addition reaction is changed into a high-boiling-point ether solvent from methylbenzene, generation of benzyl impurities is avoided, and the yield of the product is improved. According to the present invention, with the application of the preparation method, the purity and the yield of the (S)-3-methyl-(2-piperidyl phenyl)-1-butylamine acetyl glutamate are improved, and the other process parameters are improved, such that the total yield and the product quality are substantially improved, and the yield of the repagramide racemate is far higher than the yield of the currently reported process.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical chemistry, and in particular to a method for preparing (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate. Background Art

[0002] Repaglinide, chemical name is (S)-2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoic acid, the structure is as follows:

[0003] ;

[0004] It is a CBMA-type oral hypoglycemic drug jointly developed by Novo Nordisk and Boehringer Ingelheim. It was first launched in the United States in 1998 and is mainly used in the treatment of type 2 diabetes. Repaglinide can promote insulin secretion. Its binding site with β cells is different from that of sulfonylurea drugs such as glimepiride. It has the characteristics of rapid absorption, rapid onset and short duration of action. It has a high protein binding rate and will not accumulate in tissues. It has good safety and has a synergistic effect with biguanides such as metformin. It can be used alone as a first-line antidiabetic drug, or in combination with other hypoglycemic drugs such as rosiglitazone to increase the efficacy, providing a new means for the treatment of type 2 diabetes.

[0005] (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine glutamate (commonly known as reglinide glutamate) is a key intermediate of repaglinide. It is obtained by the reaction of (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine and glutamate. It has a large market demand. Therefore, it is of great significance to develop a simple, safe and inexpensive synthesis process. The main representative synthesis routes of reglinide or reglinide glutamate are as follows:

[0006] There is a method that uses o-chlorobenzaldehyde as a raw material, undergoes asymmetric allylation reaction, halogenation reaction, and configuration inversion reaction with azide compounds, and then undergoes hydrogenation reduction and piperidine substitution to obtain the final product, regamine. The chiral auxiliary group used in this route is expensive, the optical purity of the obtained product is low, and it involves the use of azide, which is highly dangerous and not suitable for industrial production. The reaction route is as follows:

[0007] .

[0008] There is a method that uses o-fluorobenzaldehyde as a raw material, which is successively substituted with piperidine, subjected to Grignard addition, and oxidized under the action of sodium dichromate and dilute sulfuric acid, and then subjected to a reductive amination reaction with formate and formamide to obtain the racemic form of regamine with a yield of 28%. The yield of the reductive amination reaction in this method is low, and a large amount of 3-methyl-1-(2-(1-piperidinyl)phenyl)butene by-product is generated in the process of converting ketone to amine, which reduces the quality and yield of the product and increases the cost of separation and purification. The reaction route is as follows:

[0009] .

[0010] There is a method that uses o-chlorobenzonitrile as a raw material, condenses with piperidine, and undergoes Grignard addition to obtain an imine, and then undergoes sodium borohydride reduction to obtain the racemic form of regamine, and chiral separation to obtain the target product, regamine glutamate, and the Grignard addition uses toluene as a solvent. This route uses low reagent costs, readily available raw materials, and simple operations, but o-chlorobenzonitrile has low activity, high reaction temperature, long reaction time, and high impurities, and the total yield of regamine glutamate is only 30.48%. The reaction route is shown below:

[0011] .

[0012] In addition, a journal article ("Synthesis of the Key Intermediate of Repaglinide (S)-(+)-3-Methyl-1-[2-(1-piperidinyl)phenyl]butylamine", Chen Huilai et al., Journal of Shenyang Pharmaceutical University, Issue 6, 2012) reported that the racemic form of Repaglinide was prepared by 5 steps of reaction using o-fluorobenzaldehyde as the raw material, and then the target product Repaglinide glutamate was obtained by chiral separation. DMF was used as the solvent for piperidine condensation, and toluene was used as the solvent for Grignard addition. This method also has many impurities that are difficult to remove, and the product yield and purity are low. The reaction route is as follows:

[0013] .

[0014] When repeating this method, the inventor unexpectedly found that when DMF is used as a solvent for piperidine condensation, the product contains a large amount of o-dimethylaminobenzonitrile impurities, and when toluene is used as a solvent for Grignard addition, a large amount of benzyl impurities will also be produced. Based on this, it is necessary to further optimize the preparation process to avoid the generation of the above impurities, thereby improving the purity and yield of (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate. Summary of the invention

[0015] Based on this, it is necessary to provide a method for preparing (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate, by changing the solvent DMF commonly used in the condensation step to acetonitrile or DMSO, avoiding the generation of a large amount of o-dimethylaminobenzonitrile impurities, and by changing the solvent of the Grignard addition reaction from toluene to a high-boiling point ether solvent, avoiding the generation of benzyl impurities, thereby improving the purity and yield of (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate.

[0016] In one aspect of the present application, a method for preparing (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate is provided, comprising the following steps:

[0017] (1) 2-Fluorobenzonitrile and piperidine undergo condensation reaction in a first solvent to generate o-piperidinylbenzonitrile;

[0018] (2) the o-piperidinylbenzonitrile and isobutylmagnesium halide undergo a Grignard addition reaction in a second solvent to generate regrignimide;

[0019] (3) reacting the regremine in the presence of a reducing agent to generate a regremine racemate;

[0020] (4) reacting the racemic form of regrinamide with N-acetyl-L-glutamic acid to generate (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate;

[0021] The first solvent includes acetonitrile and / or DMSO; the second solvent includes a high-boiling-point ether solvent; the high-boiling-point ether solvent includes an ether solvent with a boiling point of 135-200°C.

[0022] In some embodiments, the high boiling point ether solvent includes at least one of anisole, phenethyl ether, n-butyl ether, isoamyl ether and n-amyl ether.

[0023] In some embodiments, the reaction scheme of the (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate is as follows:

[0024] .

[0025] In some embodiments, the preparation of the isobutyl magnesium halide comprises the following steps: mixing magnesium, iodine particles, a third solvent and halogenated isobutane to prepare the isobutyl magnesium halide.

[0026] In some embodiments, the halogenated isobutane includes at least one of brominated isobutane and chloroisobutane.

[0027] In some embodiments, the third solvent includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether.

[0028] In some embodiments, in step (1), the temperature of the condensation reaction is 40-90° C., and the time of the condensation reaction is 15-45 hours.

[0029] In some embodiments, the molar ratio of the 2-fluorobenzonitrile to the piperidine is 1:(1.5-2.5).

[0030] In some embodiments, the halogen element in the isobutylmagnesium halide includes at least one of chlorine and bromine.

[0031] In some embodiments, the molar ratio of the o-piperidinylbenzonitrile to the isobutylmagnesium halide is 1:(2-5).

[0032] In some embodiments, the conditions of the Grignard addition reaction include: a reaction temperature of 80-120° C. and a reaction time of 4-8 h.

[0033] In some embodiments, the reducing agent includes at least one of potassium borohydride, sodium borohydride, and lithium borohydride.

[0034] In some embodiments, the molar ratio of the grisin to the reducing agent is 1:(2-5).

[0035] In some embodiments, the reaction conditions in step (3) include: reaction temperature of 20-40° C., and reaction time of 1-5 h.

[0036] In some embodiments, the reaction solvent in step (3) comprises at least one of methanol and ethanol.

[0037] In some embodiments, the molar ratio of the regrinamide racemate to the N-acetyl-L-glutamic acid is 1:(0.8-1.2).

[0038] In some embodiments, after the reaction in step (4) is completed, a crystallization step is further included; the crystallization temperature is 0~30°C.

[0039] The beneficial effects of this application are:

[0040] 1. The present application changes the solvent DMF commonly used in the condensation step to acetonitrile or DMSO, thereby avoiding the generation of a large amount of o-dimethylaminobenzonitrile impurities and greatly improving the quality and yield of this step.

[0041] 2. The Grignard reactions reported in the literature all use toluene as the material solvent, which reacts with cyano to produce a large amount of benzyl impurities, which are difficult to remove, seriously affecting the quality and yield. The present application changes the material solvent of this step to a high-boiling ether solvent, and the impurity is no longer produced, which greatly improves the quality and yield of this step. Furthermore, combined with the improvement of other process parameters, the total yield and product quality of the present application are greatly improved, the yield of the racemic form of regamine is much higher than that of the currently reported process, and the starting materials selected are easy to obtain and low in price, which is conducive to reducing process costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The liquid chromatogram of the o-piperidinylbenzonitrile prepared in Basic Example 1;

[0043] Figure 2 Liquid chromatogram of the pure product of (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate prepared in Basic Example 1;

[0044] Figure 3 for Figure 1 The mass spectrum of the component with a retention time of 8.029 min;

[0045] Figure 4 for Figure 2 The mass spectrum of the component with a retention time of 17.454min;

[0046] Figure 5 This is a liquid chromatogram of the pure product of (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate prepared in Example 14. DETAILED DESCRIPTION

[0047] In order to facilitate the understanding of the present application, the present application will be described more comprehensively below in conjunction with specific embodiments. Preferred embodiments of the present application are provided hereinafter. However, the present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0049] In this article, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0050] In this article, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the quantity of the indicated technical features.

[0051] In the description herein, "at least one" means more than one, including one or more than two, for example, one, two, three, etc., unless otherwise clearly defined.

[0052] Herein, when it comes to numerical ranges, unless otherwise specified, the numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0053] In this article, when referring to the unit of a data range, if there is a unit only after the right endpoint, it means that the units of the left and right endpoints are the same. For example, 500-600rpm means that the units of the left endpoint "500" and the right endpoint "600" are both rpm (revolutions per minute).

[0054] The temperature parameters herein, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows for temperature fluctuations within the precision range of instrument control.

[0055] In one aspect of the present application, a method for preparing (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate is provided, comprising the following steps:

[0056] (1) 2-Fluorobenzonitrile and piperidine undergo condensation reaction in a first solvent to generate o-piperidinylbenzonitrile;

[0057] (2) the o-piperidinylbenzonitrile and isobutylmagnesium halide undergo a Grignard addition reaction in a second solvent to generate regrignimide;

[0058] (3) reacting the regremine in the presence of a reducing agent to generate a regremine racemate;

[0059] (4) reacting the racemic form of regrinamide with N-acetyl-L-glutamic acid to generate (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate;

[0060] The first solvent includes acetonitrile and / or DMSO; the second solvent includes a high-boiling-point ether solvent; the high-boiling-point ether solvent includes an ether solvent with a boiling point of 135-200°C.

[0061] In some embodiments, the high boiling point ether solvent includes at least one of anisole, phenethyl ether, n-butyl ether, isoamyl ether and n-amyl ether.

[0062] It can be understood that the first solvent can be a single solvent or a combination of different solvents, such as acetonitrile, DMSO, or a combination of acetonitrile and DMSO; similarly, the second solvent can be a single solvent or a combination of different solvents, such as anisole, n-pentyl ether, or a combination of anisole and n-pentyl ether.

[0063] It can be understood that the amounts of the first solvent and the second solvent can be adjusted in combination with the reaction effect. For example, the volume mass ratio of the first solvent to 2-fluorobenzonitrile can be (2-5) mL:1g, specifically 2 mL:1g, 2.5 mL:1g, 3 mL:1g, 3.4 mL:1g, 4 mL:1g, 4.5 mL:1g, 5 mL:1g, etc.; the volume mass ratio of the second solvent to o-piperidinylbenzonitrile can be (5-20) mL:1g, specifically 5 mL:1g, 10 mL:1g, 12 mL:1g, 13 mL:1g, 14 mL:1g, 15 mL:1g, 20 mL:1g, etc.

[0064] The cleavable compound may also be subjected to a catalyst in step (1) to improve the reaction efficiency; the catalyst comprises potassium carbonate, and the mass ratio of the catalyst to 2-fluorobenzonitrile is (1.5-3):1, specifically 1.5:1, 2:1, 2.5:1, 3:1, etc.

[0065] The present application changes the solvent DMF commonly used in the condensation step to acetonitrile or DMSO, avoiding the generation of a large amount of o-dimethylaminobenzonitrile impurities (according to the preparation literature, the impurity content is as high as 27%), greatly improving the quality and yield of this step.

[0066] The Grignard reactions reported in the literature all use toluene as the raw material solvent, which reacts with cyano to produce a large amount of benzyl impurities (according to the preparation in the literature, the impurity content is as high as 10%), and it is difficult to remove, which seriously affects the quality and yield. The present application changes the raw material solvent of this step to a high-boiling point ether solvent, and the impurity is no longer produced, which greatly improves the quality and yield of this step.

[0067] It is understandable that the replacement of the solvent in the above reaction steps not only avoids the generation of o-dimethylaminobenzonitrile impurities and benzyl impurities, but also promotes the synthesis of the target product from the reaction raw materials, thereby not only improving the purity but also improving the yield.

[0068] In some embodiments, the total yield of the (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate can reach 61.22% and the purity can reach 99.77%.

[0069] In some embodiments, the reaction route of the (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate is as follows:

[0070] .

[0071] It is understandable that the isobutyl magnesium halide can be a commercial product or synthesized by itself, which is not limited here.

[0072] In some embodiments, the preparation of the isobutyl magnesium halide comprises the following steps: mixing magnesium, iodine particles, a third solvent and halogenated isobutane to prepare the isobutyl magnesium halide.

[0073] It is understandable that the dosage ratio of magnesium, iodine particles, the third solvent and halogenated isobutane can be adjusted conventionally and is not specifically limited in the present application. For example, the dosage ratio of magnesium to halogenated isobutane can be (8-15):1, the volume mass ratio of the third solvent to magnesium can be (3-5) mL:1 g, and the dosage ratio of iodine to magnesium can be (0.1-1):100.

[0074] In some embodiments, the halogenated isobutane includes at least one of brominated isobutane and chloroisobutane.

[0075] In some embodiments, the third solvent includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether.

[0076] It is understandable that, in the preparation process of isobutyl magnesium halide, toluene is not used as a solvent, so that the introduced toluene can be prevented from reacting with cyano groups in the Grignard addition reaction step to produce benzyl impurities.

[0077] In some embodiments, in step (1), the temperature of the condensation reaction is 40-90°C, and the time of the condensation reaction is 15-45h. It is understandable that the temperature and time of the condensation reaction can be adjusted according to the reaction efficiency. Generally, the higher the reaction temperature, the shorter the reaction time. The temperature of the condensation reaction can be 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc.; the time of the condensation reaction can be 15h, 20h, 25h, 30h, 35h, 40h, 45h, etc.

[0078] In some embodiments, the molar ratio of the 2-fluorobenzonitrile to the piperidine is 1:(1.5-2.5), for example, it can be 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, etc.

[0079] In some embodiments, the halogen element in the isobutylmagnesium halide includes at least one of chlorine and bromine.

[0080] In some embodiments, the molar ratio of the o-piperidinylbenzonitrile to the isobutylmagnesium halide is 1:(2-5), for example, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, etc.

[0081] In some embodiments, the conditions of the Grignard addition reaction include: a reaction temperature of 80-120°C and a reaction time of 4-8 hours. Specifically, the reaction temperature can be 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, etc.; the reaction time can be 4h, 5h, 6h, 7h, 8h, etc.

[0082] In some embodiments, the reducing agent includes at least one of potassium borohydride, sodium borohydride, and lithium borohydride.

[0083] In some embodiments, the molar ratio of the grilimide to the reducing agent is 1:(2-5), specifically 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, etc.

[0084] In some embodiments, the reaction conditions in step (3) include: a reaction temperature of 20-40°C and a reaction time of 1-5 hours. Specifically, the reaction temperature can be 20°C, 25°C, 30°C, 45°C, 40°C, etc.; the reaction time can be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, etc.

[0085] In some embodiments, the reaction solvent in step (3) comprises at least one of methanol and ethanol.

[0086] In some embodiments, the molar ratio of the regromide racemate to the N-acetyl-L-glutamic acid is 1:(0.8-1.2), for example, it can be 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, etc.

[0087] In some embodiments, after the reaction in step (4) is completed, a crystallization step is further included; the crystallization temperature is 0-30°C, for example, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, etc.

[0088] It is understandable that in steps (1) to (4), after the reaction is completed, solid-liquid separation, washing, drying and other steps may be further included. The conditions for the above solid-liquid separation, drying and washing are not particularly limited, and common solid-liquid separation methods (centrifugation, filtration, liquid separation, etc.), common drying methods (such as heating drying, vacuum drying, freeze drying, natural drying, etc.), and common washing methods may be used.

[0089] The following are specific embodiments:

[0090] Basic Example 1

[0091] According to the method described in the journal literature ("Synthesis of the Key Intermediate of Repaglinide (S)-(+)-3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine", Chen Huilai et al., Journal of Shenyang Pharmaceutical University, Issue 6, 2012), (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate was prepared using o-fluorobenzene and piperidine as starting materials. The specific process is as follows:

[0092] 1) Dissolve 20 g (0.165 mol) of o-fluorobenzene and 18.2 g (0.214 mol) of piperidine in 150 mL of DMF, stir evenly, add 46 g (0.34 mol) of potassium carbonate, and react at 90°C for 10 h. Cool the reaction solution to room temperature, pour it into 400 mL of water, extract with ethyl acetate (200 mL × 2), combine the organic layers, wash with water and saturated brine, dry over anhydrous sodium sulfate, and evaporate the ethyl acetate to obtain o-piperidinylbenzonitrile.

[0093] 2) Add 13.8g (0.575 mol) of magnesium chips, 54mL of THF and a small particle of iodine (about 0.126g) to the reaction flask. Under nitrogen protection, add 10 drops of isobutyl bromide at 35-40°C to initiate the reaction. After the reaction is initiated, add 160mL of toluene to the three-necked flask, and add a mixture of 85g (0.62mmol) of isobutyl bromide and 56mL of toluene from the dropping funnel. Add for 1.5h. After the addition is complete, stir for 2h to obtain the Grignard reagent.

[0094] Add 26g (0.214mol) of o-piperidinylbenzonitrile to a mixture of THF (84mL) and toluene (336mL), drip the above Grignard reagent from the dropping funnel, control the temperature at 35-40℃, and complete the addition in 0.5h. Reflux and stir for 4h, and leave at room temperature overnight. Add the reaction solution to a mixture of saturated ammonium chloride (600 mL) and concentrated ammonia (600mL) at -15℃, stir for 10min, and filter. Separate the organic layer, extract the aqueous layer with ethyl acetate twice (200mL×2), combine the organic phases, wash with water, wash with saturated brine, and dry. Evaporate the organic solvent to obtain Grignard amine.

[0095] 3) Add 32g of grilimine and 140mL of methanol to a three-necked flask equipped with a thermometer, cool to -2~0℃, slowly add 20g of sodium borohydride solid, add for about 1h, stir at the same temperature for 1h, and the reaction is complete by thin layer detection. Evaporate the methanol, slowly add 500mL of 10% hydrochloric acid in an ice-water bath, continue stirring for 1h, extract the reaction solution with dichloromethane (200mL×3), discard the organic layer, alkalize the aqueous layer with 5% NaOH, extract with dichloromethane (200mL×2), dry with anhydrous sodium sulfate, and spin dry to obtain 3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine (i.e., grilimine racemate).

[0096] 4) Dissolve the regamine racemate prepared in step 3) in 200 mL of acetone, add 24.7 g of N-acetyl-L-glutamic acid, and reflux for 1 hour. Cool and filter to obtain a crude product of N-acetyl-L-glutamate of 3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine (i.e., (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate).

[0097] Dissolve 40 g of crude (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate in 240 mL of a mixture of methanol and acetone (the volume ratio of methanol to acetone is 8:1) and heat until completely dissolved. Slowly cool and crystallize, and filter to obtain pure (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate.

[0098] The o-piperidinylbenzonitrile prepared in step 1) and the pure (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate in step 4) were separated and analyzed by liquid chromatography-mass spectrometry (LC-MS, wherein the liquid chromatography model is Waters e2695 and the mass spectrometry is Waters Acquity). The chromatographic conditions (the chromatographic conditions of HPLC purity in this application are the same) are as follows:

[0099] Chromatographic column: octadecylsilane bonded silica gel as filler;

[0100] Mobile phase: Phosphate buffer (dissolve 6.8 g potassium dihydrogen phosphate in 900 ml water, adjust pH to 7.5 with sodium hydroxide solution, and add water to 1000 ml) is used as mobile phase A, acetonitrile is used as mobile phase B, and the gradient elution procedure is as follows:

[0101]

[0102] Flow rate: 1.0 mL / min; column temperature: 30°C; detection wavelength: 225 nm; injection volume: 20 μL.

[0103] Solution preparation:

[0104] Solvent: Mobile phase A: Mobile phase B (45:55)

[0105] Test sample solution: Take about 50 mg of the test sample, accurately weigh it, place it in a 25 mL volumetric flask, add solvent to dissolve and dilute to the scale, shake well, and use it as the test sample solution.

[0106] The liquid chromatogram of o-piperidinylbenzonitrile is as follows: Figure 1 The liquid chromatogram of pure (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate is as follows: Figure 2 .

[0107] right Figure 1 The component with retention time of 8.029min and Figure 2 The components with a retention time of 17.454 min were analyzed by mass spectrometry, and the results were as follows: Figure 3 and Figure 4 The mass spectrometry results showed that Figure 1 The molecular weight of the component at the retention time of 8.029 min is 147.00. Figure 2 The molecular weight of the component at a retention time of 17.454 min is 281.18.

[0108] The structural formula of o-dimethylaminobenzonitrile is as follows:

[0109] ;

[0110] Its [M+H] + The theoretical molecular formula is C 9 H 11 N 2 , [M+H] + The theoretical precise molecular weight is 147.09, so it can be seen that Figure 1 The component at the retention time of 8.029min is consistent with o-dimethylaminobenzonitrile, and the test value and the theoretical value meet the required error range. It can be seen that the o-piperidinylbenzonitrile prepared in step 1) contains the impurity o-dimethylaminobenzonitrile, and its content is 26.96%. It is speculated that the impurity o-dimethylaminobenzonitrile reaction formula is as follows:

[0111] .

[0112] The structure of the benzyl impurity is shown below:

[0113] ;

[0114] Its [M+H] + The theoretical molecular formula is C 19 H 25 N 2 , [M+H]+ The theoretical precise molecular weight is 281.20; the mass spectrometry results show that Figure 2 The [M+H] of the component with a retention time of 17.454min + The measured molecular weight is 281.18, and the test value and the theoretical value meet the required error range. The test value of 264.14 is the peak molecular weight of the fragments whose amino groups are bombarded. The above results can confirm that the pure (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate in step 4) of basic example 1 contains benzyl impurities, and its content is 9.98%. The benzyl impurity reaction formula is speculated to be as follows:

[0115] .

[0116] It can be seen from basic example 1 that when DMF is used as a solvent for piperidine condensation, the product contains a large amount of o-dimethylaminobenzonitrile impurities (26.96%), and when toluene is used as a solvent for Grignard addition, a large amount of benzyl impurities (9.98%) are also produced. Therefore, the inventors further optimized the preparation process to avoid the generation of the above impurities, thereby improving the purity and yield of (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate, as shown in Examples 1-14.

[0117] Example 1

[0118] Preparation of o-piperidinylbenzonitrile

[0119] Dissolve 88.00 g of 2-fluorobenzonitrile and 124.00 g of piperidine in 300.00 ml of acetonitrile, stir evenly, add 200.00 g of potassium carbonate, react at 80°C for 40 hours, and cool to room temperature after the reaction is complete. Pour into water, extract with ethyl acetate, combine the organic layers, wash with water and saturated brine, dry with anhydrous sodium sulfate, and evaporate the organic solvent to obtain 133 g of yellow oily liquid, with a yield of 98.27% and a HPLC purity of 98.78%.

[0120] Example 2

[0121] Preparation of o-piperidinylbenzonitrile

[0122] The same preparation method as in Example 1 was adopted, except that acetonitrile was replaced by DMSO, with a yield of 97.54% and a HPLC purity of 98.47%.

[0123] Example 3

[0124] Preparation of regimide

[0125] Add 55.20g of magnesium chips, 216.00ml of tetrahydrofuran and a small grain of iodine (about 0.126g) to the reaction bottle. Under nitrogen protection, add 5g of isobutyl bromide at 35-45°C to initiate the reaction. After the reaction is initiated, add a mixture of 340.00g of isobutyl bromide and 336.00ml of tetrahydrofuran from the dropping funnel and control the temperature at 35-45°C. After the addition is complete, stir for 2h to obtain the Grignard reagent.

[0126] 105.72 g of o-piperidinylbenzonitrile (prepared in Example 1) was added to 1344.00 ml of anisole, and then dripped into the above-mentioned Grignard reagent from a dropping funnel, and the temperature was controlled at 35-45°C, and the addition was completed. The temperature was raised to 100°C and stirred for 6 hours. After the reaction was completed, the mixture was cooled to room temperature. The reaction solution was added to a mixture of saturated ammonium chloride and concentrated ammonia water at -10°C, ethyl acetate was added, the mixture was separated, washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was evaporated to obtain 137 g of a brown oil, with a yield of 98.77% and a HPLC purity of 86.27%.

[0127] Example 4

[0128] Preparation of regimide

[0129] The same preparation method as in Example 3 was adopted, except that isobutyl bromide was replaced by isobutyl chloride, yield: 94.72%, HPLC purity: 85.78%.

[0130] Example 5

[0131] Preparation of regimide

[0132] The same preparation method as in Example 3 was adopted, except that tetrahydrofuran was replaced with 2-methyltetrahydrofuran, yield: 97.60%, HPLC purity: 86.02%.

[0133] Example 6

[0134] Preparation of regimide

[0135] The same preparation method as in Example 3 was adopted, except that tetrahydrofuran was replaced by methyl tert-butyl ether, yield: 96.54%, HPLC purity: 84.75%.

[0136] Example 7

[0137] Preparation of regimide

[0138] The same preparation method as in Example 3 was adopted, except that anisole was replaced with phenethyl ether, with a yield of 98.63% and a HPLC purity of 86.14%.

[0139] Example 8

[0140] Preparation of regimide

[0141] The same preparation method as in Example 3 was adopted, except that anisole was replaced with n-butyl ether, yield: 95.32%, HPLC purity: 84.58%.

[0142] Example 9

[0143] Preparation of regimide

[0144] The same preparation method as in Example 3 was adopted, except that anisole was replaced with isoamyl ether, yield: 98.04%, HPLC purity: 85.33%.

[0145] Example 10

[0146] Preparation of regimide

[0147] The same preparation method as in Example 3 was adopted, except that anisole was replaced with n-pentyl ether, yield: 97.93%, HPLC purity: 85.97%.

[0148] Embodiment 11

[0149] Preparation of Reglucamide racemate

[0150] 137.00 g of regiamide (prepared in Example 3) and 600.00 ml of methanol were added to the reaction bottle, cooled to -5 to 5 ° C, and 121.00 g of potassium borohydride solid was slowly added in batches. After the addition was completed, the temperature was raised to 25 to 35 ° C for reaction for 3 hours. After the reaction was completed, methanol was evaporated, and water was slowly added at -5 to 5 ° C with stirring and dispersion, extracted with ethyl acetate, separated, washed with water, water was added to the organic phase, and concentrated hydrochloric acid was slowly added dropwise to acidify to PH = 2 to 3, separated, the organic layer was discarded, the aqueous layer was alkalized to PH = 8 to 10 with ammonia water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic solvent was evaporated to obtain 134 g of an orange oil with a yield of 97.01%.

[0151] Example 12

[0152] Preparation of Reglucamide racemate

[0153] The same preparation method as in Example 11 was adopted, except that potassium borohydride was replaced by sodium borohydride. Yield: 96.89%.

[0154] Embodiment 13

[0155] Preparation of Reglucamide racemate

[0156] The same preparation method as in Example 11 was adopted, except that potassium borohydride was replaced by lithium borohydride. Yield: 94.37%.

[0157] Embodiment 14

[0158] Preparation of (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate

[0159] Dissolve 134.00 g of regamine racemate (prepared in Example 11) in 833.78 ml of acetone, add 102.88 g of N-acetyl-L-glutamic acid, heat to reflux, and stir for 1 hour. Cool to 20-30°C, stir and crystallize for 2 hours, filter, and rinse with acetone to obtain 98 g of crude (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate in the form of white powder, yield: 82.75%. HPLC purity = 96.60%. Optical purity = 80.96%, isomers = 17.42%.

[0160] Purification: Add 98.00g of the crude product to 98.00ml of methanol and 196.00ml of acetone, stir and heat to reflux to dissolve, add 588.00ml of acetone, reflux and stir for 1 hour. Cool to 20-30℃, stir and crystallize for 2 hours, filter, rinse with acetone, and obtain 77g of pure (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate in the form of white powder, with a yield of 78.57%. The liquid chromatogram of pure (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate is shown in Figure 5 , HPLC purity = 99.77%, ee value 99.80%. Total yield: 61.22%.

[0161] In summary, in Example 1-14, the generation of a large amount of o-dimethylaminobenzonitrile impurities is avoided by changing the solvent DMF commonly used in the condensation step to acetonitrile or DMSO, and the generation of benzyl impurities is avoided by changing the solvent of the Grignard addition reaction from toluene to a high-boiling point ether solvent, thereby improving the purity and yield of (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate. The total yield can reach 61.22%, and the HPLC purity can reach 99.77%.

[0162] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0163] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the attached claims.

Claims

1. A method for preparing (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate, characterized in that: The steps include: (1) 2-Fluorobenzonitrile and piperidine undergo condensation reaction in a first solvent to generate o-piperidinylbenzonitrile; (2) the o-piperidinylbenzonitrile and isobutylmagnesium halide undergo a Grignard addition reaction in a second solvent to generate regrignimide; (3) reacting the regremine in the presence of a reducing agent to generate a regremine racemate; (4) reacting the racemic form of regrinamide with N-acetyl-L-glutamic acid to generate (S)-3-methyl-(2-piperidinylphenyl)-1-butylamine acetylglutamate; The first solvent includes acetonitrile and / or DMSO; the second solvent includes a high-boiling-point ether solvent; the high-boiling-point ether solvent includes an ether solvent with a boiling point of 135-200°C.

2. The preparation method according to claim 1, characterized in that The high boiling point ether solvent includes at least one of anisole, phenethyl ether, n-butyl ether, isoamyl ether and n-amyl ether.

3. The preparation method according to any one of claims 1 to 2, characterized in that: The preparation of the isobutyl magnesium halide comprises the following steps: mixing magnesium, iodine particles, a third solvent and halogenated isobutane to prepare the isobutyl magnesium halide.

4. The preparation method according to claim 3, characterized in that: The halogenated isobutylene comprises at least one of brominated isobutylene and chloroisobutylene; And / or the third solvent includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether.

5. The preparation method according to any one of claims 1 to 2, characterized in that: In step (1), the temperature of the condensation reaction is 40-90°C, and the time of the condensation reaction is 15-45h; And / or the molar ratio of the 2-fluorobenzonitrile to the piperidine is 1:(1.5~2.5).

6. The preparation method according to any one of claims 1 to 2, characterized in that: The halogen element in the isobutylmagnesium halide includes at least one of chlorine and bromine.

7. The preparation method according to any one of claims 1 to 2, characterized in that: The molar ratio of the o-piperidinylbenzonitrile to the isobutylmagnesium halide is 1:(2-5); And / or the conditions of the Grignard addition reaction include: reaction temperature of 80-120° C., reaction time of 4-8 h.

8. The preparation method according to any one of claims 1 to 2, characterized in that: The reducing agent comprises at least one of potassium borohydride, sodium borohydride and lithium borohydride; And / or the molar ratio of the greimide to the reducing agent is 1:(2-5).

9. The preparation method according to any one of claims 1 to 2, characterized in that: The reaction conditions in step (3) include: reaction temperature of 20-40°C, reaction time of 1-5h; And / or the reaction solvent in step (3) includes at least one of methanol and ethanol.

10. The preparation method according to any one of claims 1 to 2, characterized in that: The molar ratio of the regamine racemate to the N-acetyl-L-glutamic acid is 1:(0.8-1.2).

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