CN114773256B - Synthesis method of 4-cyano piperidine - Google Patents

Synthesis method of 4-cyano piperidine Download PDF

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CN114773256B
CN114773256B CN202210294378.1A CN202210294378A CN114773256B CN 114773256 B CN114773256 B CN 114773256B CN 202210294378 A CN202210294378 A CN 202210294378A CN 114773256 B CN114773256 B CN 114773256B
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cyano
chloride
piperidine
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张�成
唐文韬
熊材明
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China Agricultural University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The invention discloses a method for synthesizing 4-cyano piperidine, which takes 4-cyano-4-piperidine carboxylate or nitrogen-protected 4-cyano-4-piperidine carboxylate as a reaction raw material, and high-efficiency synthesis of high-purity 4-cyano piperidine is realized through decarboxylation or decarboxylation deprotection, alkaline hydrolysis and other steps, and the yield is up to 88%. The method has the characteristics of low-cost and easily-obtained reaction raw materials, more environment-friendly reaction conditions, high product yield and the like.

Description

Synthesis method of 4-cyano piperidine
Technical Field
The invention relates to the field of chemical synthesis, in particular to a novel method for synthesizing 4-cyano piperidine by decarboxylation and deprotection of 4-cyano-4-piperidine carboxylate.
Background
4-Cyanopiperidine is an important intermediate for the synthesis of medicines and pesticides, such as new pesticide Oxathiapiprolin (biorg. Med. Chem.,2016,24,354-361.) and many bioactive molecules also use it as an essential intermediate for synthesis, which is widely demanded by industry and laboratory research and thus has great significance for its synthesis research.
Currently, the synthesis of 4-cyanopiperidine is essentially limited to synthesis by dehydration of 4-piperidinamide. The patent US5869663, US4284636, US2006084808A and the like take 4-piperidine amide as raw materials, and are dehydrated in the presence of dehydrating agents such as phosphorus oxychloride, trifluoroacetic anhydride, thionyl chloride and the like, respectively, so that the synthesis of 4-cyano piperidine is realized. Patent CN104557356a uses 4-piperidinecarboxylic acid and ammonia gas as raw materials to produce 4-piperidinamide, which is then dehydrated in the presence of phosphorus pentoxide to produce 4-cyanopiperidine.
In the method, the synthesis condition of the 4-piperidinamide is harsh, the price is high, the used dehydrating agent has strong corrosiveness, and the requirements on equipment and subsequent environmental protection are high. Therefore, the method for synthesizing the 4-cyano piperidine has high development yield, low cost and less three-waste emission, and has important economic and social values.
Disclosure of Invention
The invention aims to provide a more environment-friendly synthesis method of 4-cyano piperidine, so as to improve the reaction yield and reduce the production cost.
The invention adopts the following technical scheme to achieve the aim:
A first solution, comprising the steps of:
(1) The 4-cyano-4-piperidine carboxylate is used as raw material, and reacts in the presence of alkali metal salt in aqueous strong polar aprotic solvent to remove ester group and directly produce the final product 4-cyano piperidine.
The second scheme is as follows: the method comprises the following steps:
(1) The method is characterized in that nitrogen atom protected 4-cyano-4-piperidine carboxylate is used as a raw material, and the raw material reacts in an aqueous strong polar aprotic solvent in the presence of alkali metal salt to generate the nitrogen atom protected 4-cyano piperidine.
(2) The 4-cyano piperidine protected by nitrogen atom is hydrogenated under the condition of adding a chlorinating reagent, a polar solvent and a Pd/C catalyst to obtain 4-cyano piperidine hydrochloride.
(3) The 4-cyano piperidine hydrochloride is hydrolyzed under alkaline condition to obtain the final product 4-cyano piperidine.
The specific synthetic route is as follows:
Wherein R is C1-C40 alkyl, C3-C12 cycloalkyl with substituent, phenyl or substituted phenyl, benzyl or substituted benzyl; x is H, benzyl or substituted benzyl, acyl; when X is H, the compound 2 is the final product 4-cyano piperidine; when X is other group, compound 4 is the final product 4-cyanopiperidine.
The alkali metal salt is one or more of sodium chloride, potassium chloride, lithium chloride, calcium chloride, barium chloride, cesium carbonate, sodium bromide, potassium bromide, lithium bromide, sodium iodide, potassium iodide, and lithium iodide, and more preferably sodium chloride, potassium chloride, and lithium chloride.
The molar ratio of the alkali metal salt to the compound 1 is 1:1-100:1, more preferably 2:1.
The strong polar solvent is N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, hexamethylphosphoramide, 1, 4-dioxane and the like, and more preferably is N, N-dimethylformamide.
The water content of the aqueous strong polar solvent used for synthesizing the compound 2 from the compound 1 is 1 to 10% by volume, more preferably 2.5%.
The temperature used for synthesizing compound 2 from compound 1 is from 0℃to 200℃and more preferably from 150℃to 200 ℃.
The mass content of Pd in the Pd/C catalyst is 0.1% -20%, more preferably 10%.
The mass ratio of the Pd/C catalyst to the compound 3 is 1:100-50:100, and more preferably 10:100.
The pressure of the hydrogen is 1atm to 10atm, more preferably 1atm.
The chlorinating agent is selected from alkyl acyl chloride, aryl acyl chloride (such as acetyl chloride, propionyl chloride, benzoyl chloride and the like), oxalyl chloride, thionyl chloride, polychloroalkane (such as 1, 2-trichloroethane, 2-dichloropropane and the like), and more preferably 1, 2-trichloroethane.
The polar solvent used for producing the compound 3 from the compound 2 is an alcoholic solvent such as ethanol, methanol, isopropanol, etc., or acetonitrile, more preferably methanol.
The alkali in the alkali hydrolysis is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and the like.
The invention takes 4-cyano-4-piperidine carboxylate or nitrogen-protected 4-cyano-4-piperidine carboxylate as a reaction raw material, and realizes the synthesis of 4-cyano piperidine through the steps of decarboxylation or decarboxylation deprotection, alkaline hydrolysis and the like, and has the following advantages:
1. The reaction raw materials are cheap and easy to prepare. The 4-cyano piperidine carboxylate or the nitrogen atom protected 4-cyano piperidine carboxylate can be prepared from cyano acetate and diethanolamine or nitrogen atom protected diethanolamine through nucleophilic substitution reaction, and is cheap and easy to obtain.
2. The reaction conditions are more environment-friendly. The alkali metal salt used in the reaction is low in toxicity, while the Pd/C catalyst can be reused, so that the environmental pollution is small.
3. The reaction yield is high. The deprotection reaction yield can reach 99%, and the total reaction yield can reach 88%.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the final product prepared in example 1;
Detailed Description
The invention will now be described in detail with reference to the drawings and examples, which are not intended to limit the same. Nuclear magnetic resonance is determined by a 500M NMR apparatus. Compound 1 is prepared from α -cyanoacetate and diethanolamine or N-protected diethanolamine (ref. J. Med. Chem.2003,46,2376-2396 and patent WO2015150337 A1).
EXAMPLE 1 preparation of 4-cyanopiperidine from N-benzyl-4-cyano-4-piperidinecarboxylic acid ethyl ester
To a 250mL single flask containing a stirrer were added 16.1g (58.8 mmol) of compound 1a, 3.44g (118 mmol) of sodium chloride solid, 80mL of N, N-dimethylformamide and 2mL of water, the flask was capped, and the single flask was placed in an oil bath at 160℃with stirring and heating, and reacted for 12 hours. The reaction was quenched with 150mL of saturated sodium bicarbonate, then extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered over silica gel, the filter cake was rinsed with 50mL of ethyl acetate, and the filtrate was concentrated to give compound 2a. Compound 2a was used directly in the next reaction without further purification.
Into a 500mL single-necked flask equipped with a stirrer, 2a,250mL of methanol as the above-mentioned compound was added, followed by 1.1g of 10% Pd/C and 8.1g of 1, 2-trichloroethane. The three-necked flask was connected with a hydrogen balloon, and after the reaction flask was replaced with hydrogen three times, the reaction was stirred at room temperature until the hydrogen was no longer absorbed. After the reaction, the system was filtered through celite, the filtrate was concentrated to 20mL of liquid in a bottle, 100mL of diethyl ether was added, and a large amount of white solid was precipitated. The solid was collected by suction filtration, washed with 20mL of diethyl ether and dried to give Compound 3.
NaOH solution with mass fraction of 30% is added into the above compound 3 to pH greater than 13, extracted with toluene (100 mL. Times.3), toluene layers are combined, dried with 20g of sodium sulfate, filtered, concentrated, and the obtained oily substance is distilled under reduced pressure to obtain the final product 5.67g of 4-cyanopiperidine (compound 4) with a yield of 88%. The nuclear magnetic resonance hydrogen spectrum of the product is shown in figure 1.
EXAMPLE 2 Synthesis of 4-cyanopiperidine from ethyl 4-cyanopiperidine carboxylate
To a 100mL single flask equipped with a stirrer were added 3.64g (20 mmol) of compound 1b, 2.34g (40 mmol) of sodium chloride solid, 25mL of N, N-dimethylformamide and 0.7mL of water, the flask was covered with a stopper, and the single flask was placed in an oil bath at 160℃and heated with stirring, and reacted for 12 hours. The reaction was quenched with 50mL of saturated sodium bicarbonate, then extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered over silica gel, the filter cake was rinsed with 20mL of ethyl acetate, and the filtrate was concentrated to give the crude compound 4. The crude product, compound 4, was distilled under reduced pressure to give 1.12g of pure 4-cyanopiperidine in a yield of 51%.
EXAMPLE 3 preparation of 4-cyanopiperidine from N-benzyl-4-cyano-4-piperidinecarboxylic acid methyl ester
To a 100mL single flask equipped with a stirrer were added 5.17g (20 mmol) of compound 1c, 2.34g (40 mmol) of sodium chloride solid, 25mL of N, N-dimethylformamide and 0.7mL of water, the flask was covered with a stopper, and the single flask was placed in an oil bath at 160℃and heated with stirring, and reacted for 12 hours. The reaction was quenched with 50mL of saturated sodium bicarbonate, then extracted with ethyl acetate (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered over silica gel, the filter cake was rinsed with 20mL of ethyl acetate, and the filtrate was concentrated to give compound 2a, which was used directly in the next reaction without purification.
In a 250mL single port flask with a stirrer was added 2a,100mL of methanol as above, followed by 0.4g of 10% Pd/C and 3.0g of 1, 2-trichloroethane. The three-necked flask was connected with a hydrogen balloon, and after the reaction flask was replaced with hydrogen three times, the reaction was stirred at room temperature until the hydrogen was no longer absorbed. After the reaction, the system was filtered through celite, the filtrate was concentrated to 10mL of liquid in a bottle, 40mL of diethyl ether was added, and a large amount of white solid was precipitated. The solid was collected by suction filtration, washed with 10mL of diethyl ether and dried to give Compound 3.
NaOH solution with mass fraction of 30% was added to the above-mentioned compound 3 to pH above 13, extracted with toluene (50 mL. Times.3), toluene layers were combined, dried over 10g of sodium sulfate, filtered, concentrated, and the resulting oil was distilled under reduced pressure to give the final product 1.83g of 4-cyanopiperidine (compound 4) in a yield of 83%.
EXAMPLE 4 preparation of 4-cyanopiperidine from N-p-methoxybenzyl-4-cyano-4-piperidinecarboxylic acid ethyl ester
To a 100mL single flask equipped with a stirrer were added 6.0g (20 mmol) of the compound 1d, 2.34g (40 mmol) of sodium chloride solid, 25mL of N, N-dimethylformamide and 0.7mL of water, the flask was covered with a stopper, and the single flask was placed in an oil bath at 160℃and heated with stirring, and reacted for 12 hours. The reaction was quenched with 50mL of saturated sodium bicarbonate, then extracted with ethyl acetate (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered over silica gel, the filter cake was rinsed with 20mL of ethyl acetate, and the filtrate was concentrated to give compound 2b, which was used directly in the next reaction without purification.
In a 250mL single-necked flask containing a stirrer, 2b of the above-mentioned compound, 100mL of methanol was added, followed by 0.4g of 10% Pd/C and 3.0g of 1, 2-trichloroethane. The three-necked flask was connected with a hydrogen balloon, and after the reaction flask was replaced with hydrogen three times, the reaction was stirred at room temperature until the hydrogen was no longer absorbed. After the reaction, the system was filtered through celite, the filtrate was concentrated to 10mL of liquid in a bottle, 40mL of diethyl ether was added, and a large amount of white solid was precipitated. The solid was collected by suction filtration, washed with 10mL of diethyl ether and dried to give Compound 3.
NaOH solution with mass fraction of 30% is added into the above compound 3 to pH greater than 13, extracted with toluene (50 mL. Times.3), toluene layers are combined, dried with 10g of sodium sulfate, filtered, concentrated, and the obtained oily substance is distilled under reduced pressure to obtain the final product 1.87g of 4-cyanopiperidine (compound 4) in 85% yield.
EXAMPLE 5 preparation of 4-cyanopiperidine from N-benzyloxycarbonyl-4-cyano-4-piperidinecarboxylic acid ethyl ester
To a 100mL single flask equipped with a stirrer were added 6.3g (20 mmol) of compound 1e, 2.34g (40 mmol) of sodium chloride solid, 25mL of N, N-dimethylformamide and 0.7mL of water, the flask was covered with a stopper, and the single flask was placed in an oil bath at 160℃and heated with stirring, and reacted for 12 hours. The reaction was quenched with 50mL of saturated sodium bicarbonate, then extracted with ethyl acetate (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered over silica gel, the filter cake was rinsed with 20mL of ethyl acetate, and the filtrate was concentrated to give compound 2c, which was used directly in the next reaction without purification.
A250 mL single vial containing a stirrer was charged with 2C,100mL of methanol, followed by 0.4g of 10% Pd/C and 3.0g of 1, 2-trichloroethane. The three-necked flask was connected with a hydrogen balloon, and after the reaction flask was replaced with hydrogen three times, the reaction was stirred at room temperature until the hydrogen was no longer absorbed. After the reaction, the system was filtered through celite, the filtrate was concentrated to 10mL of liquid in a bottle, 40mL of diethyl ether was added, and a large amount of white solid was precipitated. The solid was collected by suction filtration, washed with 10mL of diethyl ether and dried to give Compound 3.
NaOH solution with mass fraction of 30% was added to the above-mentioned compound 3 to pH above 13, extracted with toluene (50 mL. Times.3), toluene layers were combined, dried over 10g of sodium sulfate, filtered, concentrated, and the resulting oil was distilled under reduced pressure to obtain 1.51g of 4-cyanopiperidine (compound 4) as a final product in 69% yield.
Example 6
The sodium chloride of example 1 was replaced with lithium chloride, with the remainder being the same as example 1. The yield of the final product 4-cyanopiperidine was 80%.
Example 7
The sodium chloride of example 1 was replaced with sodium iodide, and the remainder was the same as in example 1. The yield of the final product 4-cyanopiperidine was 73%.
Example 8
The sodium chloride of example 1 was replaced with potassium iodide, with the remainder being the same as in example 1. The yield of the final product 4-cyanopiperidine was 79%.
Example 9
The N, N-dimethylformamide in example was replaced with dimethyl sulfoxide, and the remainder was the same as in example 1. The yield of the final product 4-cyanopiperidine was 83%.
Example 10
The 1, 2-trichloroethane of example 1 was replaced with acetyl chloride, and the remainder was the same as in example 1. The yield of the final product 4-cyanopiperidine was 68%.
Example 11
The methanol of example 1 was replaced with acetonitrile, and the rest was the same as in example 1. The yield of the final product 4-cyanopiperidine was 84%.

Claims (6)

1. A method for synthesizing 4-cyano piperidine is characterized in that: the method comprises the following steps:
(1) Taking 4-cyano-4-piperidine carboxylate as a raw material, reacting in an aqueous strong polar aprotic solvent in the presence of alkali metal salt, and removing ester groups to directly produce a final product 4-cyano piperidine;
The specific synthetic route is as follows:
wherein R is selected from C1-C40 alkyl, C3-C12 cycloalkyl with substituent, phenyl or substituted phenyl, benzyl or substituted benzyl; x is H;
The molar ratio of the alkali metal salt to the compound 1 is 2:1, the strong polar aprotic solvent is N, N-dimethylformamide, the water content in the aqueous strong polar aprotic solvent is 1-10% by volume, and the step (1) is carried out at the temperature of 150-200 ℃.
2. A method for synthesizing 4-cyano piperidine is characterized in that: the method comprises the following steps:
(1) Taking 4-cyano-4-piperidine carboxylic acid ester protected by nitrogen atoms as a raw material, and reacting in an aqueous strong-polarity aprotic solvent in the presence of alkali metal salts to generate 4-cyano piperidine protected by nitrogen atoms;
(2) Adding a chlorinating agent, a polar solvent and a Pd/C catalyst into the 4-cyano piperidine protected by nitrogen atoms to obtain 4-cyano piperidine hydrochloride;
(3) Hydrolyzing the 4-cyano piperidine hydrochloride under alkaline conditions to obtain a final product 4-cyano piperidine;
The specific synthetic route is as follows:
Wherein R is selected from C1-C40 alkyl, C3-C12 cycloalkyl with substituent, phenyl or substituted phenyl, benzyl or substituted benzyl; x is selected from benzyl or substituted benzyl and acyl;
the molar ratio of the alkali metal salt to the compound 1 is 2:1, the strong polar aprotic solvent is N, N-dimethylformamide, the water content in the aqueous strong polar aprotic solvent is 1-10% by volume, and the step (1) is carried out at the temperature of 150-200 ℃; the Pd content in the Pd/C catalyst is 0.1% -20%.
3. The synthesis method according to claim 1 or 2, characterized in that: the alkali metal salt is one or more selected from sodium chloride, potassium chloride, lithium chloride, calcium chloride, barium chloride, cesium carbonate, sodium bromide, potassium bromide, lithium bromide, sodium iodide, potassium iodide and lithium iodide.
4. The synthesis method according to claim 2, characterized in that: the chlorinating agent is selected from the group consisting of alkyl acyl chloride, aryl acyl chloride, oxalyl chloride, thionyl chloride and polychloroalkanes.
5. The synthesis method according to claim 2, characterized in that: the polar solvent in the step (2) is an alcohol solvent or acetonitrile.
6. The synthesis method according to claim 2, characterized in that: the alkali in the hydrolysis under the alkaline condition in the step (3) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate.
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