Process for the preparation of R-3-benzyl-3-piperidinecarboxylic trimethylhydrazine

Abstract

The present application solves the problems in the prior art and provides a preparation method of R-3-benzyl-3-piperidine formyltrimethylhydrazine or a pharmaceutically acceptable salt thereof. The method is simple and safe in operation, free of harsh reaction conditions, high in reaction purity and yield, low in process cost, suitable for large-scale production, convenient in material recovery, in line with the principle of green chemistry and capable of meeting the needs of industrial production.

Description

1. Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology and discloses a method for preparing R-3-benzyl-3-piperidinecarboxyltrimethylhydrazine or a pharmaceutically acceptable salt thereof. 2. Background Technology

[0002] Cancer cachexia is a common cause of death from malignant tumors. Most cancer patients do not die from the cancer itself, but from severe tissue wasting and organ failure. Furthermore, cachexia severely impairs patients' physical activity, directly affecting the effectiveness of cancer treatment, increasing the incidence of complications, reducing quality of life, and impacting prognosis.

[0003] Ghrelin is an endogenous peptide primarily secreted by the stomach. It binds to growth hormone secretagogue receptors, promoting the release of growth hormone and increasing appetite, thus stimulating multiple pathways to positively regulate body weight, muscle mass, appetite, and metabolism. Alamorin is a novel, orally administered, selective ghrelin receptor agonist that mimics ghrelin secreted from the gastrointestinal tract, improving weight loss and loss of appetite in patients with cancer cachexia. Alamorin hydrochloride tablets were the first approved drug in Japan for the treatment of cancer cachexia, used for cachexia in four types of cancer (non-small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer). Alamorin hydrochloride was recognized by the European Society for Medical Oncology (ASCO) as one of the most important innovations in oncology in 2014. Clinical trials have demonstrated that alamorin tablets improve lean body mass (LBM), appetite, and QoL in patients, exhibiting good efficacy and safety.

[0004]

[0005] Alamorin Hydrochloride

[0006] R-3-benzyl-3-piperidinoyltrimethylhydrazine is a key intermediate in the preparation of aramoline, and its quality and cost determine the quality and cost of the final aramoline product. However, the yields of this intermediate reported in current publications are all low.

[0007]

[0008] R-3-Benzyl-3-piperidinyltrimethylhydrazine

[0009] Patent CN115960080A reports a yield of only 11% for the preparation of acylhydrazides using an EDCI / HOBt condensation system. Patent CN1420878A reports a method that uses the more expensive tripyrrolidinyl phosphonium hexafluorophosphate bromide as a condensing agent to improve the conversion rate of the acylhydrazide step, followed by silica gel chromatography to purify the complex reaction system. Literature (Organic Process Research & Development 2004, 8, 360) reports that using conventional condensing agents such as CDI and EDCI in the acylhydrazide condensation step makes it difficult for the reaction to proceed normally. However, special condensing agents not only have low atom utilization and high cost, but are also unsuitable for large-scale commercial production.

[0010] Patent CN108129357A and literature (Organic Process Research & Development 2004, 8, 360) report a method of first preparing N-Boc-3-benzyl-3-piperidinecarboxylic acid into an acyl chloride before carrying out an acyl hydrazine reaction. The reaction temperature cannot exceed -20°C, the reaction time needs to be at least 20 hours, and the amount of reaction solvent used exceeds 40 times the normal amount. Patent CN115960080A reports a resolution yield of only 11%, while patent CN108129357A reports a yield of approximately 35%.

[0011] Therefore, there is an urgent need to establish a simple but high-yield and quality-controllable preparation process for the intermediate compound R-3-benzyl-3-piperidinecarboxyltrimethylhydrazine. 3. Summary of the Invention

[0012] This invention solves the problems existing in the prior art and establishes a method for preparing compound R-3-benzyl-3-piperidinecarboxyltrimethylhydrazine, which is simple and safe to operate, has no harsh reaction conditions, high reaction purity and yield, low process cost, is suitable for large-scale production, facilitates material recovery, and conforms to the principles of green chemistry, so as to meet the needs of industrial production.

[0013] This invention provides a method for preparing R-3-benzyl-3-piperidincarboxylic acid trimethylhydrazine, comprising the following steps:

[0014]

[0015] (1) N-protection step: 3-Benzyl-3-piperidinic acid is reacted with a protecting group introducing reagent in a solvent to prepare compound (I);

[0016] (2) Resolution step: Compound (I) is crystallized by salting with resolving reagents such as R-phenylethylamine in a suitable solvent, and then post-processed to obtain compound (II);

[0017] (3) Acylhydrazide reaction: Compound (II) is first reacted with an acyl halide reagent, and then reacted with trimethylhydrazine to prepare compound (III);

[0018] (4) R-3-benzyl-3-piperidincarbamoyltrimethylhydrazine was prepared by deprotection of compound (III);

[0019] Wherein, R is Preferred

[0020] In the N-protection step, the protecting group introducing reagent includes benzyl chloroformate, allyl chloroformate, or dibenzyl pyrocarbonate. In the resolution step, the resolving agent includes R-phenylethylamine or R-1-phenylpropylamine, preferably R-phenylethylamine. The resolution solvent includes water, ethyl acetate, acetonitrile, ethanol, methanol, isopropanol, or a mixture of two or more of these. In the acylhydrazide reaction, the acylhalogenating reagent includes oxalyl chloride, sulfonyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, or phosphorus oxybromide, preferably sulfonyl chloride.

[0021] This invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0022]

[0023] Where R is Preferably, R is

[0024] The present invention provides a method for preparing a compound of formula (I), comprising the following steps: 3-benzyl-3-piperidinecarboxylic acid is reacted with a protecting group introducing reagent in a solvent to prepare the compound of formula (I);

[0025]

[0026] Where R is Preferably, R is

[0027] The protecting group introducing reagents include benzyl chloroformate, allyl chloroformate, or dibenzyl pyrocarbonate.

[0028] This invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0029]

[0030] Where R is Preferably, R is

[0031] This invention provides a method for preparing a compound of formula (II), comprising the following steps:

[0032]

[0033] (1) N-protection step: 3-Benzyl-3-piperidinic acid is reacted with a protecting group introducing reagent in a solvent to prepare compound (I);

[0034] (2) Resolution step: Compound (I) is crystallized by salting with resolving reagents such as R-phenylethylamine in a suitable solvent, and then post-processed to obtain compound (II);

[0035] Where R is Preferably, R is

[0036] In the N-protection step, the protecting group introducing reagent includes benzyl chloroformate, allyl chloroformate, or dibenzyl pyrocarbonate. In the resolution step, the resolving agent includes R-phenylethylamine, R-1-phenylpropylamine, preferably R-phenylethylamine. The resolution solvent includes water, ethyl acetate, acetonitrile, ethanol, methanol, isopropanol, or a mixture of two or more of these.

[0037] This invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0038]

[0039] Where R is Preferably, R is

[0040] This invention provides a method for preparing a compound of formula (III), comprising the following steps:

[0041]

[0042] (1) N-protection step: 3-Benzyl-3-piperidinic acid is reacted with a protecting group introducing reagent in a solvent to prepare compound (I);

[0043] (2) Resolution step: Compound (I) is crystallized by salting with resolving reagents such as R-phenylethylamine in a suitable solvent, and then post-processed to obtain compound (II);

[0044] (3) Acylhydrazide reaction: Compound (II) is first reacted with an acyl halide reagent, and then reacted with trimethylhydrazine to prepare compound (III);

[0045] Where R is Preferably, R is

[0046] In the N-protection step, the protecting group introducing reagent includes benzyl chloroformate, allyl chloroformate, or dibenzyl pyrocarbonate. In the resolution step, the resolving agent includes R-phenylethylamine or R-1-phenylpropylamine. R-phenylethylamine is preferred. The resolution solvent includes water, ethyl acetate, acetonitrile, ethanol, methanol, isopropanol, or a mixture of two or more of these. In the hydrazideation reaction, the acylhalogenating reagent includes oxalyl chloride, sulfonyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, or phosphorus oxybromide. Sulfonyl chloride is preferred.

[0047] This invention provides the use of a compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof in the preparation of R-3-benzyl-3-piperidinyltrimethylhydrazine.

[0048]

[0049] Where R is Preferably, R is

[0050] The pharmaceutically acceptable salts described in this invention include hydrochloride, hydrobromide, sulfate, phosphate, acetate, trifluoroacetate, methanesulfonate, benzylsulfonate, or citrate. Hydrochloride and hydrobromide are preferred.

[0051] The beneficial technical effects of this invention are as follows:

[0052] (1) The present invention uses benzyloxycarbonyl (Cbz) and allyloxycarbonyl (Allco) as protecting groups, which have high stability to both acids and bases. The reaction selectivity and molecular utilization rate are higher than those of existing processes, and have significant advantages in quality control and scalability of intermediates and APIs.

[0053] (2) Compared with the N-Boc-3-benzyl-3-piperidinecarboxylic acid reported in the existing literature, the compound of formula (II) of the present invention has a higher resolution efficiency. The resolution yield of N-Cbz-3-benzyl-piperidine-3 carboxylic acid is not less than 45%, and the resolution yield of N-Allco-3-benzyl-piperidine-3 carboxylic acid is not less than 38%. Under the premise that the optical purity of the R-type formula (II) compound isomer is >99%, the yield is increased by more than 10%.

[0054] (3) This invention uses CBz and Allco-protected intermediates to prepare acyl hydrazides via the acyl chloride method, which can increase the reaction yield to over 90% and the solid yield after purification to over 85%. The reaction conditions are mild, the post-processing is simple, no column separation purification is required, and the process is easy to scale up for industrial production. Compared with the processes reported in existing literature, the overall yield of R-3-benzyl-3-piperidincarboxyltrimethylhydrazine is doubled. Moreover, the cost is significantly reduced, and the solvent and high-value materials such as trimethylhydrazine can be easily recovered and reused by simple acid-base treatment of the reaction mother liquor. The process difficulty and waste emissions are significantly reduced, making it more environmentally friendly. 4. Description of the attached drawings

[0055] Figure 1 The H of N-Cbz-3-benzyl-3-piperidinecarboxylic acid prepared in Example 1 1 -NMR.

[0056] Figure 2 MS of N-Cbz-3-benzyl-3-piperidinecarboxylic acid was prepared as in Example 1.

[0057] Figure 3 The H of N-fluorenoxycarbonyl-3-benzyl-3-piperidinecarboxylic acid prepared in Example 2 1 -NMR.

[0058] Figure 4 MS of N-fluorenoxycarbonyl-3-benzyl-3-piperidinecarboxylic acid prepared in Example 2.

[0059] Figure 5 MS of N-benzyl-3-benzyl-3-piperidinecarboxylic acid prepared in Example 3.

[0060] Figure 6 The H of N-allyloxycarbonyl-3-benzyl-3-piperidinecarboxylic acid prepared in Example 4 1 -NMR.

[0061] Figure 7 MS of N-allyloxycarbonyl-3-benzyl-3-piperidinecarboxylic acid prepared in Example 4.

[0062] Figure 8 The image shows the liquid phase detection spectrum of the reaction solution in Example 11.

[0063] Figure 9 The H of (3R)-1-N-Cbz-3-benzyl-3-piperidincarboxyl-(N,N',N'-trimethyl)hydrazine hydrochloride prepared in Example 11 1 -NMR.

[0064] Figure 10MS of (3R)-1-N-Cbz-3-benzyl-3-piperidinoyl-(N,N',N'-trimethyl)hydrazine hydrochloride prepared in Example 11.

[0065] Figure 11 The H of RN-allyl-3-benzyl-3-piperidincarboxyltrimethylhydrazine prepared in Example 12 1 -NMR.

[0066] Figure 12 MS of RN-allyl-3-benzyl-3-piperidincarboxyltrimethylhydrazine prepared in Example 12.

[0067] Figure 13 The liquid phase detection spectrum of RN-Boc-3-benzyl-3-piperidinyltrimethylhydrazine prepared in Example 13 is shown.

[0068] Figure 14 H of R-3-benzyl-3-piperidincarboxylic acid trimethylhydrazine prepared in Example 14 1 -NMR. 5. Detailed Implementation Methods

[0069] The specific embodiments of the present invention are described in detail below. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0070] Example 1: Preparation of N-Cbz-3-benzyl-3-piperidinecarboxylic acid

[0071] 438 g of 3-benzyl-3-piperidinecarboxylic acid was dissolved in 750 mL of acetonitrile. 2000 g of 10% sodium hydroxide solution was added, and the mixture was cooled to 0 °C. 350 g of benzyl chloroformate was added dropwise. The mixture was extracted and separated into layers. The upper reaction layer was taken and the pH was adjusted to 3–4 with 1 M hydrochloric acid. Crystals were precipitated by stirring, filtered, and dried to obtain 675 g of solid, with a yield of 95.6%. The structural confirmation data of N-Cbz-3-benzyl-3-piperidinecarboxylic acid are shown in Table 1 and Appendix. Figure 1 Appendix Figure 2 .

[0072] Example 2: Preparation of N-Fomc-3-benzyl-3-piperidinecarboxylic acid

[0073] 10.0 g of 3-benzyl-3-piperidinecarboxylic acid and 14.1 g of chloroformate-9-fluorenylmethyl ester were used to prepare 19.1 g of N-Fomc-3-benzyl-3-piperidinecarboxylic acid, with a yield of 94%, following the procedure in Example 1. The structural confirmation data for N-Fomc-3-benzyl-3-piperidinecarboxylic acid are shown in Table 2 and Appendix. Figure 3 Appendix Figure 4 .

[0074] Example 3: Preparation of N-benzyl-3-benzyl-3-piperidinecarboxylic acid

[0075] 10.0 g of 3-benzyl-3-piperidinecarboxylic acid and 7.0 g of benzyl chloride were used to prepare 13.4 g of N-benzyl-3-benzyl-3-piperidinecarboxylic acid, with a yield of 96%, following the procedure in Example 1. The structural confirmation data for N-benzyl-3-benzyl-3-piperidinecarboxylic acid are shown in Table 1 and Appendix. Figure 5 .

[0076] Example 4: Preparation of N-allyloxycarbonyl-3-benzyl-3-piperidinecarboxylic acid

[0077] 10.0 g of 3-benzyl-3-piperidinecarboxylic acid and 6.6 g of allyl chloroformate were used to prepare 12.8 g of N-allyloxycarbonyl-3-benzyl-3-piperidinecarboxylic acid, with a yield of 93%, following the procedure in Example 1. The structural confirmation data of N-allyloxycarbonyl-3-benzyl-3-piperidinecarboxylic acid are shown in Table 1 and Appendix. Figure 6 Appendix Figure 7 .

[0078] Example 5: Preparation of N-Boc-3-benzyl-3-piperidinecarboxylic acid

[0079] 10.0 g of 3-benzyl-3-piperidinic acid and 12.0 g of di-tert-butyl pyrocarbonate were added to 80 mL of dichloromethane and stirred at room temperature for 2 hours. After the reaction was completed, 80 mL of 5% sodium carbonate aqueous solution was added and stirred for 30 minutes, followed by separation. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 12.8 g of N-Boc-3-benzyl-3-piperidinic acid, with a yield of 93%.

[0080] Table 1. Confirmation data of the structure of the N-protected product of 3-benzyl-3-piperidinecarboxylic acid

[0081]

[0082] Example 6: Preparation of (R)-N-Cbz-3-benzyl-3-piperidinecarboxylic acid

[0083] Add 6700g of ethyl acetate and 300g of purified water to a reaction flask, then add 670g of N-Cbz-3-benzyl-3-piperidinecarboxylic acid and 230g of R-(+)-1-phenylethylamine. Heat to reflux for 30 minutes. During cooling, add 0.67g of seed crystals to induce crystallization. Continue cooling to 25°C, filter, and obtain a filter cake.

[0084] The filter cake was added to 2000g of ethyl acetate, and the pH was adjusted to 2-3 with hydrochloric acid. After stirring until dissolved, the mixture was separated. The organic phase was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to dryness. 2000g of n-heptane was added to the residue, and the mixture was stirred to crystallize, filtered, and dried to obtain 302g of solid, with a yield of 45% and isomer purity >99%.

[0085] Example 7: Preparation of R-N-Fomc-3-benzyl-3-piperidinecarboxylic acid

[0086] Referring to the procedure in Example 6, R-(+)-1-phenylethylamine was used for resolution in ethyl acetate. N-benzyl-3-benzyl-3-piperidinecarboxylic acid could not be crystallized by salt formation, and the target product with a single optical configuration was not obtained.

[0087] Example 8: Preparation of R-N-benzyl-3-benzyl-3-piperidinecarboxylic acid

[0088] Referring to the procedure in Example 6, R-(+)-1-phenylethylamine was used for resolution in ethyl acetate. N-benzyl-3-benzyl-3-piperidinecarboxylic acid could not be crystallized by salt formation, and the target product with a single optical configuration was not obtained.

[0089] Example 9: Preparation of R-N-allyloxycarbonyl-3-benzyl-3-piperidinecarboxylic acid

[0090] 12.0 g of N-allyloxycarbonyl-3-benzyl-3-piperidinecarboxylic acid and 4.8 g of R-(+)-1-phenylethylamine were separated according to the procedure of Example 6 to obtain 4.6 g, with a yield of 38% and isomer purity > 97%.

[0091] Example 10: Preparation of R-N-Boc-3-benzyl-3-piperidinecarboxylic acid

[0092] 300 g of N-Boc-3-benzyl-3-piperidinic acid and 4.5 kg of ethyl acetate were added to a 5 L three-necked flask. After stirring until dissolved, 120 g of purified water and 62.5 g of R-(+)-1-phenylethylamine were added, and the mixture was heated to reflux and stirred for 30 min. The mixture was slowly cooled to room temperature, and a solid began to precipitate. The temperature was further lowered to 0 °C and maintained for crystal growth for 1 h. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filter cake was added to a mixed solvent of 810 g of ethyl acetate and 600 g of purified water, and 72.0 g of sodium bisulfate was added and stirred to dissolve. The upper organic phase was separated, washed with pure water, and concentrated to dryness under reduced pressure. 1100 mL of n-heptane was added to the residue, and the mixture was heated and stirred to produce a large amount of white solid. The filter cake was filtered and dried by blast drying to obtain 107.7 g of product, with a yield of 36% and isomer purity >99%.

[0093] Example 11: Preparation of (3R)-1-N-Cbz-3-benzyl-3-piperidincarboxyl-(N,N',N'-trimethyl)hydrazine

[0094] 200g of compound B, 10g of DMAP, and 80g of thionyl chloride were added to 800g of dichloromethane, and the mixture was reacted at room temperature for 3 hours. The system was concentrated to dryness under reduced pressure, and then 2000g of dichloromethane was added and stirred until dissolved. The mixture was then cooled to below 0°C, and 800g of a dichloromethane solution of trimethylhydrazine (containing 126g of trimethylhydrazine) was added dropwise. The reaction was maintained at this temperature for 1 hour. The reaction was monitored by HPLC until completion, and the HPLC chromatogram is attached. Figure 8The reaction solution had a liquid phase purity of 92%. After the reaction was complete, the system was heated to room temperature, and 2700 g of purified water and 300 g of hydrochloric acid were added. The mixture was stirred for 10 minutes and allowed to stand before separation. The lower organic phase, anhydrous magnesium sulfate, was dried and concentrated to dryness under reduced pressure. Heptane was added and stirred to solidify the mixture. The solid was filtered and dried under vacuum to constant weight to obtain 217 g of white solid, with a yield of 86%. The structural confirmation data of (3R)-1-N-Cbz-3-benzyl-3-piperidincarboxyl-(N,N',N'-trimethyl)hydrazine are shown in Table 2 and Appendix. Figure 9 Appendix Figure 10 .

[0095] Example 12: Preparation of R-N-allyl-3-benzyl-3-piperidinyltrimethylhydrazine

[0096] 4.0 g of RN-allyl-3-benzyl-3-piperidinic acid was used to prepare 4.3 g of RN-allyl-3-benzyl-3-piperidinic trimethylhydrazine hydrochloride, with a yield of 82.4%, following the procedure in Example 11. The structural confirmation data for RN-allyl-3-benzyl-3-piperidinic trimethylhydrazine are shown in Table 2 and Appendix. Figure 11 Appendix Figure 12 .

[0097] Example 13: Preparation of R-N-Boc-3-benzyl-3-piperidinyltrimethylhydrazine

[0098] Verification and optimization were performed according to CN108129357 and the literature (Organic Process Research & Development 2004, 8, 360).

[0099] Add 1500 g of dichloromethane, 100.0 g of RN-Boc-3-benzyl-3-piperidinic acid, and 10 g of DMF to a 5 L reaction flask and stir until dissolved. Cool to -20 °C. Add 104 g of thionyl chloride in a 50% dichloromethane solution dropwise. Incubate at -15 ± 5 °C with stirring for 2 h. Concentrate the system to dryness under reduced pressure. Add 1500 g of dichloromethane to the residue, cool to -20 °C, add a trimethylhydrazine solution in dioxane, and incubate at -15 ± 5 °C for 10 h. Monitor the reaction for completion by TLC. Add 600 g of 30% potassium carbonate solution, stir, and separate the layers. Concentrate the upper organic phase to dryness under reduced pressure. Add 200.0 g of n-heptane to the concentrate, stir for 0.5 h, and filter. Wash the filter cake with 50 g of n-heptane. Dry the filter cake under vacuum to constant weight to obtain 83 g of solid. The external standard content in the liquid chromatography is 59.5%, and the actual yield is 42%. See attached Figure 13 .

[0100] Analysis revealed that various impurities generated during the removal of the Boc protecting group were the main factors affecting the yield. The structures of the impurities with the largest detection amounts under different conditions are shown below:

[0101]

[0102] Table 2. Structural analysis data of the N-protected product of 3-benzyl-3-piperidinyltrimethylhydrazine

[0103]

[0104] Example 14: Preparation of R-3-benzyl-3-piperidinyltrimethylhydrazine

[0105] 100.0 g of (3R)-1-N-Cbz-3-benzyl-3-piperidincarboxyl-(N,N',N'-trimethyl)hydrazine hydrochloride was dissolved in 1000 mL of methanol, and 0.8 g of palladium on carbon was added. The reaction was carried out at 4 atm and 45 °C for 1 hour. After the reaction was completed, the palladium on carbon was recovered by filtration. The filtrate was evaporated to dryness, and then crystallized by stirring in n-hexane. The crystals were filtered, and the filter cake was dried under vacuum at 45 °C to obtain 61 g of R-3-benzyl-3-piperidincarboxyltrimethylhydrazine, with a yield of 91%.

[0106] 1 HNMR: (600MHz, MeOD-d4): δ1.56(1H,m), 1.66(1H,m), 1.93(1H,m), 2.59-2.62(4H,m), 2.67(3H,s), 2.82-2.87(1H,t d), 2.92-2.96 (2H, m), 3.01 (3H, s), 3.22 (2H, dd), 3.52 (1H, d, J = 14.4Hz), 7.16 (2H, d, J = 7.2Hz), 7.25-7.31 (3H, m). See attached Figure 14 .

[0107] Example 15: Preparation of R-3-benzyl-3-piperidinyltrimethylhydrazine

[0108] 100.0 g of (3R)-1-N-Cbz-3-benzyl-3-piperidincarboxyl-(N,N',N'-trimethyl)hydrazine hydrochloride was added to 270 g of 33% hydrobromic acid solution and stirred until dissolved at room temperature for 1 hour. 350 mL of purified water and 350 mL of n-hexane were added, and the mixture was stirred for 30 min. The mixture was then separated, retaining the lower aqueous phase. The pH of the aqueous phase was adjusted to 9-10 with saturated potassium carbonate solution, and extracted with 350 mL of dichloromethane twice. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness to obtain 63 g of R-3-benzyl-3-piperidincarboxyltrimethylhydrazine, with a yield of 94%.

[0109] Example 16: Preparation of R-3-benzyl-3-piperidincarboxyltrimethylhydrazine

[0110] 4.0 g of RN-allyl-3-benzyl-3-piperidinyltrimethylhydrazine hydrochloride and 1 mL of triethylamine were dissolved in 20 mL of tetrahydrofuran by stirring. 2 g of 1,3-dimethylbarbituric acid was added, and the mixture was purged with nitrogen three times. 50 mg of tetrakis(triphenylphosphine)palladium was then added, and the mixture was reacted at room temperature for 3 hours. 20 mL of 20% potassium carbonate solution was added to the system, and after stirring and separation, 0.2 g of activated carbon was added to the upper organic phase for adsorption for 30 minutes. The mixture was filtered, and the filtrate was dried under reduced pressure. 20 mL of n-heptane was added, and the mixture was stirred and solidified for 2 hours. After filtration and drying, 2.6 g of compound D was obtained, with a yield of 93%.

Claims

1. A method for preparing R-3-benzyl-3-piperidinecarboxylic acid trimethylhydrazine, characterized in that, Includes the following steps: ， (1) N-protection step: 3-Benzyl-3-piperidinecarboxylic acid is reacted with a protecting group introducing reagent in a solvent to prepare compound (I); (2) Resolution step: Compound (I) is crystallized by salting with a resolving agent in a suitable solvent, and then post-processed to obtain compound (II); (3) Acylhydrazine reaction: Compound (II) is first reacted with an acyl halide reagent and then with trimethylhydrazine to prepare compound (III); (4) R-3-benzyl-3-piperidincarbamoyltrimethylhydrazine was prepared by deprotection of compound (III); Wherein, R is or ; In the N-protection step, the protecting group introducing reagent is selected from benzyl chloroformate, allyl chloroformate, or dibenzyl pyrocarbonate; In the described splitting step, the splitting agent is selected from... R -Phenylacetamine, R -1-Phenylacetylpropane; the solvent for resolution is selected from water, ethyl acetate, acetonitrile, ethanol, methanol, isopropanol, or a mixture of two or more of them.

2. The method for preparing R-3-benzyl-3-piperidinecarboxylic acid trimethylhydrazine according to claim 1, characterized in that, The acylhydrazide reaction wherein the acyl halide reagent is selected from oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, and phosphorus tribromide.

3. A compound of formula (III) or a pharmaceutically acceptable salt thereof: ， in, R is or .

4. Use of the compound of formula (III) according to claim 3 or a pharmaceutically acceptable salt thereof in the preparation of R-3-benzyl-3-piperidinecarboxyltrimethylhydrazine.

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