A method for preparing a piperidine compound

Abstract

The application discloses a preparation method of a piperidine compound. The application specifically provides a preparation method of a piperidine compound, which comprises the following steps: compound 1-8 and compound 1-9 are subjected to a condensation reaction in an organic solvent in the presence of a base and 18-crown-6 to obtain compound 1-11; the base is LiHMDS and / or NaHMDS; and the solvent is selected from one or more of benzene solvents, halogenated hydrocarbon solvents and furan solvents. The preparation method of the application can increase the proportion of Z configuration in the product from about 30% to about 45%, and the proportion of Z configuration in the product is even increased to more than 89% in some methods, so that the yield of the target product is greatly improved.

Description

Technical Field

[0001] This invention relates to a method for preparing piperidine compounds. Background Technology

[0002] WO2022022559A1 discloses an antiplatelet drug. It can serve as an important intermediate in the synthesis of the aforementioned antiplatelet drugs (hereinafter referred to as the Z configuration). However, in the preparation of the Z configuration compound, the ratio of E configuration to Z configuration is approximately 7:3, and the proportion of the Z configuration compound is only about 30%, resulting in a low yield. Therefore, the existing preparation methods suffer from the drawback of low yield of the Z configuration product. Summary of the Invention

[0003] This invention aims to address the low yield of Z-configuration products in existing preparation methods, and provides a method for preparing piperidine compounds. The preparation method of this invention can increase the proportion of Z-configuration in the product from approximately 30% to approximately 45%, and in some methods even to over 89%, significantly improving the yield of the target product.

[0004] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0005] This invention provides a method for preparing piperidine compounds, comprising the following steps: in an organic solvent, in the presence of a base and 18-crown-6, compounds 1-8 undergo a condensation reaction with compounds 1-9 to obtain compounds 1-11; wherein the base is LiHMDS and / or NaHMDS; and the solvent is selected from one or more of benzene solvents, halogenated hydrocarbon solvents, and furan solvents.

[0006]

[0007] The reaction system of the condensation reaction may also include LiBr.

[0008] In the condensation reaction, when the organic solvent is a benzene-based solvent, the organic solvent may be toluene.

[0009] In the condensation reaction, when the organic solvent is a halohydrocarbon solvent, the halohydrocarbon solvent may be dichloromethane.

[0010] In the condensation reaction, when the organic solvent is a furan solvent, the furan solvent is tetrahydrofuran.

[0011] In the condensation reaction, the organic solvent may be toluene, dichloromethane, or tetrahydrofuran, for example, toluene.

[0012] In the condensation reaction, the base can be LiHMDS or NaHMDS, for example, LiHMDS.

[0013] In the condensation reaction, the base may be a base existing in solution form, such as a tetrahydrofuran solution of a base, a tetrahydrofuran solution of LiHMDS, or a 1M tetrahydrofuran solution of LiHMDS.

[0014] In the condensation reaction, the molar ratio of compounds 1-8 to compounds 1-9 is conventional in the art, for example, 1:(0.8-2), or even 1:1 or 1:1.5.

[0015] In the condensation reaction, the volume-to-mass ratio of the organic solvent to compounds 1-8 is conventional in the art, for example, 5-15 g / mL, or for example, 7.8 g / mL.

[0016] In the condensation reaction, the molar ratio of compounds 1-8 to the base is conventional in the art, for example 1:(5-10), or even 1:6.3 or 1:9.4.

[0017] In the condensation reaction, the molar ratio of compounds 1-8 to 18-crown-6 is conventional in the art, for example 1:(0.8-2), or even 1:1 or 1:1.2.

[0018] In the condensation reaction, when the reaction system contains LiBr, the molar ratio of compounds 1-8 to LiBr is conventional in the art, for example, 1:(0.8-2), or even 1:1 or 1:1.3.

[0019] The temperature of the condensation reaction can be conventional in the art, and can be carried out at (-75℃ to 30℃), for example at -70℃ to -60℃ and 0℃ to 10℃.

[0020] The reaction system of the condensation reaction may contain or be composed of the following reactants: compounds 1-9, toluene, 18-crown-6, LiBr, LiHMDS and compounds 1-8.

[0021] The condensation reaction may include the following steps: after mixing the compounds 1-9, the organic solvent and 18-crown-6, cooling, and mixing with the base to obtain mixture A; and reacting the compounds 1-8 with mixture A.

[0022] When the reaction system contains LiBr, the condensation reaction may include the following steps: after mixing the compounds 1-9, the organic solvent, 18-crown-6 and LiBr, cooling, and mixing with the base to obtain mixture A; and reacting the compounds 1-8 with mixture A.

[0023] In the condensation reaction step, compounds 1-8 may be in solution form, such as a toluene solution of compounds 1-8.

[0024] In the condensation reaction step, the cooling temperature can be -60 to -70°C.

[0025] In the condensation reaction step, the reaction temperature of compounds 1-8 with the mixture A can be -60 to -0℃; for example, after reacting at -65±5℃, the temperature can be raised to -10 to 0℃ for further reaction.

[0026] The condensation reaction may include a post-processing step, which is: mixing the reaction solution with ammonium chloride, extracting, concentrating to obtain a concentrated solution, mixing the concentrated solution with n-heptane, filtering, and obtaining a filtrate.

[0027] In the condensation reaction, the reaction can be monitored using conventional methods in the art, such as HPLC or TLC. Generally, the reaction endpoint is taken as when the compounds 1-8 disappear or no longer react, and the reaction is stopped. For example, the reaction time of the condensation reaction is 0.5 to 10 hours, such as 0.5 hours, 1 hour, or 2 hours.

[0028] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0029] In this invention, the structure of 18-crown-6 is as follows:

[0030] The reagents and raw materials used in this invention are all commercially available.

[0031] The positive and progressive effects of this invention are as follows: the preparation method of this invention can increase the proportion of Z configuration in the product from about 30% to about 45%, and some methods even increase it to more than 89%, which greatly improves the yield of the target product. Detailed Implementation

[0032] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0033] Preparation Example 1 Synthesis 1-8

[0034] Step 1. Synthesize 1-2

[0035]

[0036] 1-1 (4.00 kg) and mCPBA (6.65 g, 1.5 eq., 85%) were added in portions to DCM (22 L) at 5 ± 5 °C. The mixture was stirred and maintained at 5 ± 5 °C during the addition. After the addition was complete, stirring continued at 5 ± 5 °C for 1 hour. The temperature was then raised to 10 ± 5 °C and stirred for 1 hour, followed by a further increase to 20 ± 5 °C and stirring for over 1 hour. The reaction mixture was filtered, the filter cake was washed with DCM, and the filtrate was collected. The filtrate was then washed with saturated NaHSO3, and the organic phase was collected and washed twice with NaOH solution. The organic phase was then washed with water, concentrated, and toluene was added. The mixture was concentrated to give an oily 1-2 (3.19 kg, 73% yield).

[0037] Step 2. Synthesize 1-3

[0038]

[0039] Thiobenzoic acid (4.13 kg) was added dropwise to a mixture of 1-2 (5.65 kg), tetrabutylammonium chloride (0.394 kg), and toluene (28.3 L) at 15 ± 5 °C. After the addition was complete, the mixture was stirred at 30 ± 5 °C for 4 hours. The mixture was cooled to 20 ± 5 °C, washed twice with water, and then the organic phase was concentrated under vacuum. Ethyl acetate was added to the concentrated mixture, and the mixture was then concentrated. n-Heptane was added to the mixture, and the mixture was stirred at 15 ± 5 °C for 2 hours. The mixture was filtered, and the filter cake was purified with ethyl acetate / n-heptane (v:v = 1:2). After filtration and drying, a grayish-white solid 1-3 (4.85 kg, 50.0% yield) was obtained.

[0040] LC-MS[M+1-100] + =238.1

[0041] 1 H NMR (400MHz, chloroform-d) δ7.97(d,J=7.2Hz,2H),7.59(s,1H),7.46(t,J=7.7Hz,2H),4.24(d,J=16.3Hz,1H),4.17-3.81(m,1H),3 .73(s,1H),3.60(s,1H),2.92(t,J=24.3Hz,2H),2.72(s,1H),2.12(d,J=16.8Hz,1H),1.71(d,J=11.6Hz,1H),1.46(s,9H).

[0042] Step 3. Synthesize 1-4

[0043]

[0044] TBSCl (23.2 kg) was added to a solution of 1-3 (40 kg) and imidazole (16 kg) in DCM (200 L). After addition, the mixture was stirred at 30 ± 5 °C for 8 hours. The mixture was cooled to 20 ± 5 °C, filtered, and the filter cake was washed twice with DCM (40 L). The mixture was washed twice with water, and the organic phase was concentrated. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 10 / 1) with methanol to give 1-4 as a white solid (273.0 g, 94% yield). LC-MS [M+1-100] + =352.1.

[0045] Step 4. Synthesize 1-5

[0046]

[0047] Hydrazine hydrate (80%) (16.40 kg) was added to a 1-4 (40 kg) MeCN (120 L) solution at room temperature. After addition, the mixture was stirred at 30 ± 5 °C for 2 hours. The mixture was cooled to 20 ± 5 °C, and the pH of the reaction system was adjusted to 6 with 2N HCl aqueous solution. The mixture separated into two layers, and the upper organic phase was collected. Heptane and water were added to the organic phase. After stirring and standing, the mixture separated into two layers, and the upper organic phase was collected. The organic phase was washed with water and 25% NaCl aqueous solution, and then concentrated under vacuum. Acetone was added to the mixture, and the mixture was then concentrated. Another portion of acetone was added to the mixture, followed by K2CO3 (24.4 kg), NaI (16 kg), and chloromethyl isopropyl carbonate (15.6 kg) added sequentially with stirring. After addition, the mixture was stirred at 50 ± 5 °C for 16 hours. The mixture was cooled to 20 ± 5 °C, filtered, and the filter cake was washed with acetone. The filtrate was concentrated to 60 L under vacuum. Ethyl acetate and water were added to the mixture at 20 ± 5 °C. After stirring and standing, the mixture separated into two layers, and the upper organic phase was collected. The organic phase was washed with water and then concentrated. i-PrOH (120 L) was added to the mixture, and the mixture was concentrated. Water and seed crystals were added to the mixture at 20 ± 5 °C, and the mixture was then stirred at 5 ± 5 °C. After filtration and drying, a grayish-white solid 1-6 (35.24 kg) was obtained, with a yield of 85%.

[0048] 1¹H NMR (400MHz, chloroform-d) δ 5.25 (q, J = 12.0 Hz, 2H), 4.92–4.79 (m, 1H), 3.85 (d, J = 58.8 Hz, 2H), 3.45 (s, 1H), 2.97–2.74 (m, 3H), 2.13–2.02 (m, 1H), 1.59–1.47 (m, 1H), 1.41 (s, 9H), 1.25 (dd, J = 15.5, 4.6 Hz, 6H), 0.89 (s, 9H), 0.19–0.01 (m, 6H).

[0049] Step 5. Synthesize 1-7

[0050]

[0051] At room temperature, 16.40 kg of 80% triethylamine trihydrofluoric acid was added to a 22.8 L THF solution of 1-6 (5.17 kg). After addition, the mixture was stirred at 50 ± 5 °C for 21 hours. The mixture was concentrated under vacuum. DCM and water were added to the mixture at 20 ± 5 °C. After stirring and settling, the mixture separated into two layers, and the upper organic phase was collected. The organic phase was washed with a saturated sodium chloride aqueous solution and then concentrated to 10 L. The concentration of 1-7 in the concentrated mixture was 37.32%, with a yield of 98.8%.

[0052] Step 6. Synthesize 1-8

[0053]

[0054] At 20±5℃, 6.22 kg of Des Martin periodane (DCM) was added in portions at 20-30 minute intervals to a 3.94 kg DCM solution of 1-7. After addition, the mixture was stirred at 20±5℃ for 1 hour. A saturated sodium thiosulfate solution and a saturated sodium bicarbonate solution (20 L, v:v = 1:1) were added to the mixture at 20±5℃. The mixture was filtered, and the filter cake was washed with DCM. The filtrate separated into two layers after standing. The lower organic phase was collected, and the upper phase was extracted with DCM. All organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated. The mixture was purified with silica gel, and the eluent was then concentrated. Toluene was added to the mixture, and the mixture was concentrated. The solution weight was 7.17 kg, the content of 1-8 in the solution was 34.54%, and the yield was 63.27%.

[0055] Example 2: Synthesis of 1-10 and 1-11

[0056]

[0057] At 20±5℃, 18-crown-6 (4.87 kg) and LiBr (1.6 kg) were added to a solution of 1-9 (6.96 kg) in toluene (25 L). The mixture was cooled to -65±5℃, and LiHMDS (19.34 L, in 1 M THF) was added at -65±5℃. After addition, the mixture was stirred at -65±5℃ for 0.5 h. 1-8 (6.4 kg, dissolved in 25 L toluene) was added at -65±5℃. After addition, the mixture was stirred at -65±5℃ for 0.5 h. The mixture was heated to -5±5℃ and stirred for 1 h. Then, a saturated ammonium chloride solution was added at 0±5℃. After stirring and standing, the mixture was separated into two layers at 20±5℃, and the upper organic phase was collected. The organic phase was washed with water, dried with anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified with silica gel, and the eluent was then concentrated. Add n-heptane to the mixture, stir for 2 hours, then filter, and wash the filter cake with n-heptane. Concentrate the filtrate. The solution weighs 8.18 kg, with a total content of 1-10 and 1-11 of 64.61% and a total yield of 64%. The mass percentages of 1-10 and 1-11 are 10.3% and 89.7%, respectively (the yield of the target product 1-11 is 64% * 89.7% = 57.2%).

[0058] 1-11 1 H NMR data:

[0059] 1 H NMR (400MHz, CD3Cl-d4) δ5.75(s,1H),5.49(s,1H),5.34-5.26(m,1H),5.16(d,J=12.0Hz,1H),4.93-4.84(m,1H),4.2 4(br,1H),3.96(s,2H),3.20-3.10(m,1H),2.10-2.01(m,1H),1.91-1.86(m,1H),1.45(s,18H),1.30(d,J=6.3Hz,6H).

[0060] Example 3: Synthesis of 1-10 and 1-11

[0061]

[0062] At 20±5℃, 18-crown-6 (6.0 kg) and LiBr (2.0 kg) were added to a solution of 1-9 (10.44 kg) in toluene (25 L). The mixture was cooled to -65±5℃, and LiHMDS (29.01 L, in 1 M THF) was added at -65±5℃. After addition, the mixture was stirred at -65±5℃ for 0.5 h. 1-8 (6.4 kg, dissolved in 25 L toluene) was added at -65±5℃. After addition, the mixture was stirred at -65±5℃ for 0.5 h. The mixture was heated to -5±5℃ and stirred for 1 h. Then, a saturated ammonium chloride solution was added at 0±5℃. After stirring and standing, the mixture was separated into two layers at 20±5℃, and the upper organic phase was collected. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified with silica gel, and the eluent was then concentrated. Add n-heptane to the mixture, stir for 2 hours, then filter, and wash the filter cake with n-heptane. Concentrate the filtrate. The solution weighs 8.18 kg, and the total content of products 1-10 and 1-11 is 66.62%, with an overall yield of 66%. The mass percentages of 1-10 and 1-11 are 10.1% and 89.9%, respectively (the yield of the target product 1-11 is 66% * 89.9% = 59.3%).

[0063] Example 4

[0064] In Example 2, toluene was replaced with the solvents listed in the table below. Whether or not LiBr was added depended on the information in the table. Everything else remained the same. The results are as follows:

[0065]

[0066] Example 5

[0067] In Example 2, LiHMDS was replaced with the bases listed in the table below, while the rest remained unchanged. The results are as follows:

[0068] Serial Number alkali 1-10 and 1-11 mass ratio 1 NaHMDS 54.1:45.9 2 t-BuOK 56.5:43.5 3 EtONa 57.4:42.6

[0069] Comparative Example 1: Synthesis of 1-10 and 1-11

[0070]

[0071] At 20±5℃, 18-crown-6 (4.1 kg) and LiBr (1.5 kg) were added to a solution of 1-9' (5.35 kg) in toluene (25 L). The mixture was cooled to -65±5℃, and LiHMDS (15.48 L, in 1 M THF) was added at -65±5℃. After addition, the mixture was stirred at -65±5℃ for 0.5 h. 1-8 (6.4 kg, dissolved in 25 L toluene) was added at -65±5℃. After addition, the mixture was stirred at -65±5℃ for 0.5 h. The mixture was heated to -5±5℃ and stirred for 1 h. Then, a saturated ammonium chloride solution was added at 0±5℃. After stirring and standing, the mixture was separated into two layers at 20±5℃, and the upper organic phase was collected. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified with silica gel, and the eluent was then concentrated. Add n-heptane to the mixture, stir for 2 hours, then filter, and wash the filter cake with n-heptane. Concentrate the filtrate. The solution weighs 8.28 kg, with a total content of 55.32% for 1-10 and 1-11, and an overall yield of 55%. The mass percentages of 1-10 and 1-11 are 78.0% and 22.0%, respectively (the yield of the target product 1-11 is 64% * 22.0% = 14%).

[0072] Comparative Example 2

[0073] In Example 2, toluene was replaced with the solvents listed in the table below. Whether or not LiBr was added depended on the information in the table. Everything else remained the same. The results are as follows:

[0074]

[0075] Comparative Example 3

[0076] In Example 2, LiHMDS was replaced with the bases listed in the table below, while the rest remained unchanged. The results are as follows:

[0077] Serial Number Base 1-10 and 1-11 mass ratio 2 KHMDS 90.4：9.6 5 <![CDATA[Cs2CO3]]> 89.4：10.6 8 TMG 81.3：18.7 9 DBU 66.4：33.6

Claims

1. A method for preparing a piperidine compound, characterized in that, It includes the following steps: In an organic solvent, in the presence of a base and 18-crown-6, compounds 1-8 and 1-9 undergo a condensation reaction to yield compounds 1-11; the base is LiHMDS; the solvent is toluene; the reaction system of the condensation reaction also includes LiBr; in the condensation reaction, the molar ratio of compounds 1-8 to LiBr is 1:(0.8-2). 。 2. The method for preparing the piperidine compound according to claim 1, characterized in that, The alkali is an alkali existing in solution form.

3. The method for preparing the piperidine compound according to claim 2, characterized in that, It meets one or more of the following conditions: (1) In the condensation reaction, the base is a tetrahydrofuran solution; (2) In the condensation reaction, the molar ratio of compounds 1-8 to compounds 1-9 is 1:(0.8-2). (3) In the condensation reaction, the volume-to-mass ratio of the organic solvent to compounds 1-8 is 5-15 g / mL; (4) In the condensation reaction, the molar ratio of compounds 1-8 to the base is 1:(5-10); and (5) In the condensation reaction, the molar ratio of compound 1-8 to 18-crown-6 is 1:(0.8-2).

4. The method for preparing the piperidine compound according to claim 2, characterized in that, It meets one or more of the following conditions: (1) In the condensation reaction, the base is a tetrahydrofuran solution of LiHMDS; (2) In the condensation reaction, the molar ratio of compounds 1-8 to compounds 1-9 is 1:1 or 1:1.5; (3) In the condensation reaction, the volume-to-mass ratio of the organic solvent to compounds 1-8 is 7.8 g / mL; (4) In the condensation reaction, the molar ratio of compounds 1-8 to the base is 1:6.3 or 1:9.4; (5) In the condensation reaction, the molar ratio of compound 1-8 to 18-crown-6 is 1:1 or 1:1.2; and (6) In the condensation reaction, the molar ratio of compound 1-8 to LiBr is 1:1 or 1:1.

3.

5. The method for preparing the piperidine compound according to claim 2, characterized in that, It consists of the following reactants: compounds 1-9, toluene, 18-crown-6, LiBr, LiHMDS and compounds 1-8.

6. The method for preparing the piperidine compound according to claim 2, characterized in that, The condensation reaction includes the following steps: the compounds 1-9, the organic solvent, 18-crown-6 and LiBr are mixed and cooled, and then mixed with the base to obtain mixture A; the compounds 1-8 react with mixture A.

7. The method for preparing the piperidine compound according to claim 6, characterized in that, It meets one or more of the following conditions: (1) The compounds 1-8 are in solution form; (2) The cooling temperature is -60~-70℃; and (3) The reaction temperature of compounds 1-8 with the mixture A is -60~0℃.

8. The method for preparing the piperidine compound according to claim 6, characterized in that, It meets one or two of the following conditions: (1) Compounds 1-8 are toluene solutions of compounds 1-8; and (2) The reaction temperature of compounds 1-8 with the mixture A is -65±5℃, and then the temperature is raised to -10~0℃.

9. The method for preparing the piperidine compound according to claim 7, characterized in that, The reaction time for the condensation reaction is 0.5 to 10 hours.

10. The method for preparing the piperidine compound according to claim 7, characterized in that, The reaction time for the condensation reaction is 0.5 h, 1 h, or 2 h.

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