A method for synthesizing 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid

Abstract

The present invention provides a process route for synthesizing 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid using ethyl cyanoacetate and benzoyl chloride as starting materials. The process of the present invention selects ethyl cyanoacetate and benzoyl chloride, which are abundantly supplied and inexpensive in the market, as starting materials. Although the process route is relatively long, each step of the reaction is easy to control, the yields and qualities of the intermediates are relatively stable, and the quality of the product prepared by this route can meet the requirements for the synthesis of alamoline, and the production cost is relatively low.

Description

Technical Field

[0001] The present invention belongs to small molecule chemical drug intermediates, and particularly relates to the synthesis of 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid. Background Art

[0002] Almorelin is a ghrelin receptor agonist drug used for the treatment of cancer cachexia in patients with malignant tumors such as non-small cell lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, etc., and has been marketed in Japan by Ono Pharmaceutical Co., Ltd.

[0003] 3-Benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid is one of the important starting materials for the preparation of almorelin. The preparation methods reported in the literature are as follows:.

[0004]

[0005] Ethyl 3-piperidinecarboxylate reacts with Boc 2 O to obtain an N-protected product; the N-protected product reacts with benzyl bromide in the presence of LDA at -70 °C to obtain a benzyl bromide-substituted product; the substituted product is hydrolyzed to obtain 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (raw material for almorelin synthesis); due to the high cost of the starting material (ethyl 3-piperidinecarboxylate), and the use of LDA and low temperature (-70 °C) conditions in the key reaction process, the potential safety risks and operation difficulties in the industrialization process of this route are increased, and the production cost is increased. Summary of the Invention

[0006] In order to avoid the potential safety risks and operation limitations of the literature process, reduce the production cost, and promote the domestic industrialization process of almorelin, our company has developed a new synthetic route for 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid.

[0007] The present invention uses ethyl cyanoacetate and benzoyl chloride as starting materials. First, an acylation reaction is carried out to obtain ethyl 2-benzoylcyanoacetate (H, yield 88%); H then reacts with N-(3-bromopropyl)phthalimide in the presence of an alkali metal base to obtain a condensation product G (yield 94%); G is reduced with zinc powder in an ethanol medium while removing the phthalyl group to obtain product F (yield 91%); F is refluxed in a toluene medium to form a cyclization product E (yield 92%); E is reduced with BH 3 -THF complex in an anhydrous tetrahydrofuran solution, and then the cyano group is hydrolyzed to form compound D (yield 79.9%); D is esterified in a methanol medium to obtain compound C; C reacts with Boc 2 O to obtain an N-protected product B; B is hydrolyzed in an ethanol medium to obtain 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (D-A, yield 83.9%), and the total reaction yield is 46.4%.

[0008] The method and process of the present invention selects ethyl cyanoacetate and benzoyl chloride, which are abundantly supplied and inexpensive in the market, as starting materials. Although the process route is relatively long, each step of the reaction is easy to control, the yields and qualities of each intermediate are relatively stable. The products prepared by this route can meet the synthesis requirements of alamoline, and the production cost is relatively low.

[0009] One of the reaction processes of the method of the present invention is as follows:

[0010] Specific embodiments

[0011] The following examples are intended to further illustrate some preferred embodiments of the present invention, not all embodiments. Other embodiments made by those skilled in the art based on the present invention without creative efforts fall within the scope of the rights protection of the present invention.

[0012] In the present invention, unless otherwise specified, each abbreviation has its conventional meaning understood by those skilled in the art.

[0013] Example 1) Preparation of ethyl 2-cyano-3-oxo-3-phenylpropionate

[0014]

[0015] Under nitrogen filling and stirring, add ethyl cyanoacetate (68 g, 0.6 mol), ethanol (92 g, 2.0 mol), magnesium powder (24.5 g, 0.61 mol), carbon tetrachloride (15 ml), and toluene (700 ml) into a 2000 ml three-necked flask, and stir at room temperature for 30 minutes; carefully raise the temperature (the reaction is exothermic), and reflux for 1 hour; lower the temperature of the reaction solution to 0-5 °C, and dropwise add benzoyl chloride (85 g, 0.61 mol). During the dropping process, keep the internal temperature at 0-5 °C, and finish adding in about 30 minutes; then raise the temperature of the reaction solution to room temperature and continue stirring for 1 hour; then lower the temperature of the reaction solution to 0-5 °C, and wash with 5% hydrochloric acid aqueous solution (300 ml), saturated sodium bicarbonate solution (300 ml), and semi-saturated brine (300 ml) respectively. The organic layer is dried with anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 114.7 g of a light yellow liquid, with a yield of 88%.

[0016] Example 2) Preparation of ethyl 2-cyano-3-oxo-3-phenylpropionate

[0017] The feeding and operation are the same as in Example 1) without adding carbon tetrachloride, and 100.4 g of ethyl 2-cyano-3-oxo-3-phenylpropionate (light yellow liquid) is obtained, with a yield of 77%

[0018] Example 3) Preparation of Ethyl 2-benzoyl-2-cyano-5-(1,3-dioxoisoindolin-2-yl)valerate

[0019]

[0020] Under nitrogen protection, into a 2000 ml three-necked flask, add ethyl 2-cyano-3-oxo-3-phenylpropionate (108.6 g, 0.5 mol) and 300 ml of tetrahydrofuran. Slowly lower the temperature of the reaction system to -5 - -10 °C, and add sodium hydride (60%, 26.0 g, 0.65 mol) in portions, controlling the reaction system not to exceed -5 °C. Slowly dropwise add a solution of N-(3-bromopropyl)phthalimide (134.0 g, 0.5 mol) in tetrahydrofuran (200 ml). After adding, slowly raise the temperature of the reaction solution to room temperature and stir at room temperature for 4 hours; cool down to 0 - 5 °C, add saturated ammonium chloride solution (500 ml) and stir for 30 minutes, extract with dichloromethane (500 ml × 2), combine the extraction solutions, wash with sodium bicarbonate solution (500 ml), dry over anhydrous sodium sulfate, and then concentrate under reduced pressure to obtain 190 g of ethyl 2-benzoyl-2-cyano-5-(1,3-dioxoisoindolin-2-yl)valerate (yellow oil), with a yield of 94%.

[0021] Example 4) Preparation of Ethyl 2-benzoyl-2-cyano-5-(1,3-dioxoisoindolin-2-yl)valerate

[0022] The feeding and operation are the same as in Example 3), using NaOH (26 g, 0.65 mol) instead of sodium hydride, to obtain 150 g of ethyl 2-benzoyl-2-cyano-5-(1,3-dioxoisoindolin-2-yl)valerate (yellow oil), with a yield of 74%.

[0023] Example 5) Preparation of Ethyl 5-amino-2-benzyl-2-cyanovalerate

[0024]

[0025] With stirring, add ethyl 2-benzoyl-2-cyano-5-(1,3-dioxoisoindolin-2-yl)valerate (150 g, 0.371 mol), ethanol (600 ml), and zinc powder (65 g, 1.0 mol) into a 2000 ml three-necked flask. At room temperature, quickly add concentrated hydrochloric acid (37%, 300 ml), maintain the internal temperature at 35 - 45 °C, and stir the reaction for 30 minutes; quickly cool the reaction solution to 0 - 5 °C, add ice water (1000 ml), and stir for 1 hour; extract with dichloromethane (500 ml × 3), combine the extraction solutions, wash with sodium bicarbonate solution (500 ml), dry over anhydrous sodium sulfate, and then concentrate under reduced pressure to obtain 87.9 g of oily ethyl 5-amino-2-benzyl-2-cyanovalerate, with a yield of 91%.

[0026] Example 6) Preparation of Ethyl 5-Amino-2-benzyl-2-cyanopentanoate

[0027] The feeding and operation were the same as in Example 5), and the reaction time was extended to 5 hours to obtain 47.9 g of oily ethyl 5-amino-2-benzyl-2-cyanopentanoate with a yield of 49.6%.

[0028] Example 7) Preparation of 3-Benzyl-3-cyano-2-oxopiperidine

[0029]

[0030] Into a 1000 ml three-necked flask, add ethyl 5-amino-2-benzyl-2-cyanopentanoate (78.0 g, 0.3 mol), toluene (300 ml), and p-toluenesulfonic acid monohydrate (0.6 g), and reflux at elevated temperature for 12 hours; distill off the solvent under reduced pressure, add dichloromethane (300 ml) and semi-saturated brine (300 ml), stir at room temperature for 30 minutes, and separate the layers; extract the aqueous layer with dichloromethane (200 ml) again, combine the organic layers, and wash with semi-saturated aqueous sodium bicarbonate solution (200 ml); separate the aqueous layer, dry the organic layer over anhydrous sodium sulfate, and then remove the solvent to obtain 59.1 g of pale yellow oily 3-benzyl-3-cyano-2-oxopiperidine with a yield of 92.0%.

[0031] Example 8) Preparation of 3-Benzyl-3-cyano-2-oxopiperidine

[0032] The feeding and operation were the same as in Example 7), and the reaction time was shortened to 6 hours to obtain 49.1 g of pale yellow oily 3-benzyl-3-cyano-2-oxopiperidine with a yield of 76.4%

[0033] Example 9) Preparation of 3-Benzylpiperidine-3-carboxylic Acid

[0034]

[0035] Under nitrogen filling, add borane tetrahydrofuran solution (1.0 M, 550 ml) to a 2000 ml three-necked flask, stir and cool down to below -10 °C, and slowly add a solution of 3-benzyl-3-cyano-2-oxopiperidine (53.6 g, 0.25 mol) in tetrahydrofuran (500 ml); after adding, warm the reaction solution to room temperature and stir for 1 hour; then heat it to reflux and continue the reaction for 6 hours; after the reaction is completed, cool the reaction solution to below 0 °C, slowly dropwise add 6N hydrochloric acid (700 ml), and stir for 30 minutes; heat up, concentrate under reduced pressure to remove tetrahydrofuran, and keep the reaction at 80 - 90 °C for 5 hours; cool down to below 25 °C, extract with dichloromethane (500 ml × 2); combine the extraction solutions, wash with semi-saturated brine, and dry with anhydrous sodium sulfate; evaporate dichloromethane under reduced pressure to obtain 43.8 g of oily 3-benzylpiperidine-3-carboxylic acid, with a yield of 79.9%.

[0036] Example 10) Preparation of 3-benzylpiperidine-3-carboxylic acid

[0037] The feeding and operation are the same as in Example 9), reduce the amount of borane tetrahydrofuran solution (1.0 M, 350 ml), 33.8 g of 3-benzylpiperidine-3-carboxylic acid, with a yield of 61.7%

[0038] Example 11) Preparation of 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid

[0039]

[0040] ① Add 3-benzylpiperidine-3-carboxylic acid (41 g, 0.187 mol), methanol (300 ml), and 2 ml of concentrated sulfuric acid to a 500 ml reaction flask, stir and heat up, reflux for 12 hours; concentrate under reduced pressure to recover methanol, then cool the residue to below 10 °C, add 100 ml of water, extract with dichloromethane (250 ml × 2), combine the extraction solutions, wash with saturated sodium bicarbonate aqueous solution (150 ml), separate the organic layer, and dry with anhydrous magnesium sulfate;

[0041] ② Filter to remove the desiccant, place the filtrate in a 1000 ml reaction flask, cool down to 0 °C, and dropwise add a solution of di-tert-butyl dicarbonate (41 g, 0.187 mol) in dichloromethane (100 ml) using a constant pressure funnel; after adding, slowly warm the temperature of the reaction solution to room temperature and continue the reaction for 3 hours; add saturated sodium bicarbonate aqueous solution (150 ml) to wash, separate the organic layer, and dry with anhydrous magnesium sulfate;

[0042] ③ Filter out the desiccant, place the filtrate in a 1000 ml reaction flask, remove the solvent (dichloromethane) under reduced pressure, add ethanol (200 ml), water (200 ml), and sodium hydroxide (15 g, 0.375 mol), heat to reflux, and react for 6 hours; after the reaction is completed, cool the reaction solution to below 20 °C, extract with ethyl acetate (30 ml × 2) (to remove impurities); control the temperature of the aqueous solution below 15 °C, adjust the pH to 3 with concentrated hydrochloric acid, and precipitate a white solid; continue to stir for 1 hour below 15 °C, filter and dry to obtain 50.1 g of a milky white solid of 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, with a yield (based on 3-benzylpiperidine-3-carboxylic acid) of 83.9%; the total yield (based on ethyl cyanoacetate) is 46.4%.

[0043] It should be noted that the above preferred embodiments are only used to illustrate the technical concept and features of the present invention. The purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and it cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. A method for synthesizing 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, characterized in that, the method uses ethyl cyanoacetate and benzoyl chloride as starting materials. First, through an acylation reaction, ethyl 2-benzoylcyanoacetate, namely H, is obtained; then H reacts with N-(3-bromopropyl)phthalimide in the presence of an alkali metal base to obtain a condensation product G; the condensation product G is reduced with zinc powder in an ethanol medium while removing the phthalyl group to obtain a product F; the product F is refluxed in a toluene medium to form a cyclization product E; E is reduced with a BH3-THF complex in an anhydrous tetrahydrofuran solution, and then the cyano group is hydrolyzed to form a compound D; D is esterified in a methanol medium to obtain a compound C; C reacts with Boc2O to obtain an N-protected product B; B is hydrolyzed in an ethanol medium to obtain 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid; Structure of compound H: Structure of compound G: Structure of compound F: Structure of compound E: Structure of compound D: Structure of compound C: Structure of compound B:

2. The method for synthesizing 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid according to claim 1, characterized in that, the method further includes the following preparation steps for compound H: Add ethyl cyanoacetate, ethanol, magnesium powder, toluene, with or without carbon tetrachloride, stir at room temperature for 30 minutes; carefully raise the temperature and reflux for 1 hour; lower the temperature of the reaction solution to 0-5°C, and dropwise add benzoyl chloride. During the dropping process, keep the internal temperature at 0-5°C and finish adding in 30 minutes; then raise the temperature of the reaction solution to room temperature and continue to stir for 1 hour; then lower the temperature of the reaction solution to 0-5°C, and wash with 5% hydrochloric acid aqueous solution, saturated sodium bicarbonate solution, and semi-saturated brine respectively; after drying the organic layer, concentrate under reduced pressure to obtain compound H.

3. The method for synthesizing 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid according to claim 2, characterized in that, the method further includes the following preparation steps for compound G: Add compound H and tetrahydrofuran, slowly lower the temperature of the reaction system to -5 to -10°C, add sodium hydride in portions, control the reaction system not to exceed -5°C, slowly dropwise add a tetrahydrofuran solution of N-(3-bromopropyl)phthalimide. After adding, slowly raise the temperature of the reaction solution to room temperature and stir at room temperature for 4 hours; lower the temperature to 0-5°C, add saturated ammonium chloride solution and stir, extract with dichloromethane, combine the extraction solutions, wash with sodium bicarbonate solution, dry, and concentrate under reduced pressure to obtain compound G.

4. The method for synthesizing 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid according to claim 3, characterized in that, the method further includes the following preparation steps for compound F: Compound G, 600 ml of ethanol and zinc powder were added. At room temperature, concentrated hydrochloric acid was quickly added, and the internal temperature was maintained at 35 - 45 °C, followed by stirring for 30 minutes. The reaction solution was quickly cooled to 0 - 5 °C, ice water was added, and stirring was carried out for 1 hour. It was extracted with dichloromethane, the extraction solutions were combined, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound F.

5. A method for synthesizing 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid according to claim 4, characterized in that, the method further includes the following preparation steps of compound E: Compound F was added, and p-toluenesulfonic acid monohydrate was added and refluxed at an elevated temperature for 12 hours. The solvent was removed by distillation under reduced pressure, dichloromethane and semi-saturated brine were added, and stirring was carried out at room temperature for 30 minutes, followed by layering. The aqueous layer was extracted with dichloromethane again, the organic layers were combined, and washed with semi-saturated aqueous sodium bicarbonate solution. The aqueous layer was separated, the organic layer was dried over anhydrous sodium sulfate and then the solvent was removed to obtain compound E.

6. A method for synthesizing 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid according to claim 5, characterized in that, the method further includes the following preparation steps of compound D: Borane tetrahydrofuran solution was added, stirred and cooled to below -10 °C, and a tetrahydrofuran solution of compound E was slowly added. After addition, the reaction solution was warmed to room temperature and stirred for 1 hour. Then it was heated to reflux and the reaction continued for 6 hours. After the reaction was completed, the reaction solution was cooled to below 0 °C, 6N hydrochloric acid was slowly added dropwise, and stirring was carried out for 30 minutes. The temperature was raised, and tetrahydrofuran was removed by concentration under reduced pressure, and the reaction was carried out at 80 - 90 °C for 5 hours. The temperature was lowered to below 25 °C, and extraction was carried out with dichloromethane. The extraction solutions were combined, washed with semi-saturated brine, and dried over anhydrous sodium sulfate. Dichloromethane was removed by distillation under reduced pressure to obtain oily compound D.

7. A method for synthesizing 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid according to claim 6, characterized in that, the method further includes the following preparation steps of 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid: Step 1, Compound D, methanol, and concentrated sulfuric acid were added, stirred and heated, and refluxed for 12 hours. Methanol was recovered by concentration under reduced pressure, and then the residue was cooled to below 10 °C, water was added, and extraction was carried out with dichloromethane. The extraction solutions were combined, washed with saturated aqueous sodium bicarbonate solution, and the organic layer was separated and dried over anhydrous magnesium sulfate; Step 2, The desiccant was removed by filtration. The filtrate was cooled to 0 °C, and a dichloromethane solution of di-tert-butyl dicarbonate was added dropwise. After addition, the temperature of the reaction solution was slowly raised to room temperature, and the reaction continued for 3 hours. It was washed with saturated aqueous sodium bicarbonate solution, and the organic layer was separated and dried over anhydrous magnesium sulfate; Step 3, The desiccant was removed by filtration. The solvent of the filtrate was removed under reduced pressure, ethanol, water, and sodium hydroxide were added, and the temperature was raised to reflux and the reaction was carried out for 6 hours. After the reaction was completed, the reaction solution was cooled to below 20 °C, and extraction was carried out with ethyl acetate. The temperature of the aqueous solution was controlled below 15 °C, and the pH was adjusted to 3 with concentrated hydrochloric acid to precipitate a white solid. Stirring was continued for 1 hour below 15 °C, and filtration and drying were carried out to obtain 3-benzyl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid solid.

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