CN112851571A

CN112851571A - Preparation method and application of 2- (2, 2,6, 6-tetramethylpiperidine nitroxide radical-4-subunit) acetic acid derivative

Info

Publication number: CN112851571A
Application number: CN202110102924.2A
Authority: CN
Inventors: 王灿辉; 黄治炎; 杨爽; 王伟; 李文亮; 李敬强; 胡西儒
Original assignee: Shaanxi Haichen Fengyang Pharmaceutical Technology Co ltd
Current assignee: Shaanxi Haichen Fengyang Pharmaceutical Technology Co ltd
Priority date: 2021-01-26
Filing date: 2021-01-26
Publication date: 2021-05-28

Abstract

The invention discloses a preparation method and application of a 2- (2, 2,6, 6-tetramethyl piperidine nitroxide free radical-4-subunit) acetic acid derivative. The 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid derivative is prepared by obtaining 4-carbonyl-2, 2,6, 6-tetramethyl piperidine nitroxide radical through simple oxidation of commercial 2,2,6, 6-tetramethyl-4-piperidone, then reacting with a corresponding phosphonylation reagent and hydrolyzing, raw materials used by the method are cheap and easy to obtain, the production process is easier and more convenient than that of the 2,2,6, 6-tetramethyl piperidine nitroxide radical, the cost is low, the compound has stable property, does not have any odor basically, is convenient to store, can be stored at room temperature, and the preparation method is simple and easy to obtain, and when the compound is used as a catalyst, the activity is high, and the solubility is high in an aqueous phase, the catalyst consumption is very small.

Description

Preparation method and application of 2- (2, 2,6, 6-tetramethylpiperidine nitroxide radical-4-subunit) acetic acid derivative

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method and application of a 2- (2, 2,6, 6-tetramethyl piperidine nitroxide free radical-4-subunit) acetic acid derivative.

Background

The oxidation of alcohols to the corresponding aldehydes or ketones is one of the most widely used functional group transformations in organic synthesis and plays a very important role in the basic research field and fine chemical production. The method of catalytic oxidation using 2,2,6, 6-tetramethylpiperidine nitroxide radical (abbreviated as "TEMPO") is one of the best oxidation methods currently considered. In the method, TEMPO is converted into an oxyammonium salt type active intermediate with oxidation activity under the action of an oxidizing agent, and the intermediate can oxidize alcohol into aldehyde or ketone under the condition of 0 ℃ to room temperature; meanwhile, sodium hypochlorite, air or oxygen used in the oxidation process is an oxidant, and byproducts are salt and water, so that the method has little harm to the environment and avoids the use of high-toxicity transition metal oxides. Thus, such green-friendly oxidation processes are a recent focus of research and have made numerous advances.

Meanwhile, because the steric hindrance of an active site in a TEMPO molecule is large, the solubility of the compound in a water phase is limited, so that in the oxidation process of a secondary alcohol with large para-position resistance, the amount of a catalyst is generally 1% -10% of that of a substrate, the using amount is large, and the reaction is poor or non-reaction occurs. After the TEMPO catalytic oxidation reaction is finished, TEMPO can be separated from the reaction product by washing for many times, so that a large amount of nitrogen-containing wastewater is generated.

Secondly, TEMPO is expensive in industrial production, the compound itself is not very stable and has an unpleasant taste, and needs to be preserved in a refrigerated state, which limits its application and development in the fields of fine chemicals and pharmaceuticals.

Disclosure of Invention

The invention aims to make up the defects of the prior art and provides a preparation method and application of a 2- (2, 2,6, 6-tetramethylpiperidine nitroxide radical-4-subunit) acetic acid derivative.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a preparation method of a 2- (2, 2,6, 6-tetramethyl piperidine nitroxide free radical-4-subunit) acetic acid derivative, which comprises the following steps:

(1) dissolving 1 equivalent of 2,2,6, 6-tetramethyl-4-piperidone in a mixed solvent of methanol and water, slowly dropwise adding a mixture of 0.1-0.2 equivalent of sodium tungstate hydrate and 1.5-6 equivalent of hydrogen peroxide, stirring and reacting for 2-24h at the reaction temperature of 0-65 ℃, extracting with an organic solvent after complete reaction, drying, and concentrating to obtain an orange-red solid 4-carbonyl-2, 2,6, 6-tetramethyl piperidine nitroxide radical;

(2) adding 1.0-2.0 equivalent of alkali into an organic solvent with the weight 3-30 times of that of the alkali, reacting at 0-25 ℃, adding 1.0-2.0 equivalent of a phosphoryl reagent into the reaction solution, then adding 1 equivalent of 4-carbonyl-2, 2,6, 6-tetramethylpiperidine nitroxide radical, reacting at 0-50 ℃ for 2-10h, quenching with a saturated ammonium chloride solution, extracting with an organic solvent, and concentrating to obtain a red oily liquid;

(3) dissolving the red oily liquid obtained in the step (2) into a mixed solvent of an organic solvent and water, wherein the weight of the mixed solvent is 3-10 times that of the red oily liquid, and adding 1.0-3.0 equivalent of inorganic base; the reaction temperature is 0-50 ℃, the reaction time is 2-16h, after the reaction is completed, the reaction liquid is extracted by an organic solvent, the pH value of a water phase is adjusted to be 1.5-3.5 by inorganic acid, the solution is concentrated under reduced pressure to obtain a solid, the solid is dissolved by alcohol, the solution is filtered, the solution is concentrated under reduced pressure and then added into a mixed solvent of petroleum ether and ethyl acetate, and the solid is separated out, so that the 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid derivative is obtained.

Further, the structural formula of the 2- (2, 2,6, 6-tetramethylpiperidinyloxy, oxy-4-ylidene) acetic acid derivative is characterized as follows:

wherein G is H, alkyl and substituted alkyl with 1-6 carbon atoms, 3-6 membered cycloalkyl, benzene ring and substituted benzene ring, carboxyl and cyano;

m is H, Li, Na and K.

Further, the organic solvent in the organic solvent extraction is selected from at least one of ethyl acetate, propyl acetate, butyl acetate, toluene, methyl tert-butyl ether, dichloromethane and 1, 2-dichloroethane.

Further, the base in the step (2) is selected from one of sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.

Further, the organic solvent in the mixture of the organic solvent and water in the step (3) is selected from one or more of methanol, ethanol, tetrahydrofuran and 1, 4-dioxane.

Further, the inorganic base in the step (3) is selected from one of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

The invention also provides application of the 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid derivative, and the 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid derivative is used as a catalyst for catalyzing and oxidizing benzyl alcohol to prepare benzaldehyde.

Further, the process for preparing benzaldehyde by catalyzing and oxidizing benzyl alcohol by using the 2- (2, 2,6, 6-tetramethyl piperidine nitroxide free radical-4-subunit) acetic acid derivative as a catalyst comprises the following steps:

adding 1 equivalent of benzyl alcohol into a mixed solvent of an organic solvent and water which is 3-10 times of the weight of the benzyl alcohol, adding a 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid derivative which is 0.01-1% of the weight of the benzyl alcohol and serves as a catalyst, dropwise adding 1.0-3.0 equivalent of sodium hypochlorite solution at the temperature of 0-40 ℃, reacting for 1-10h, standing for layering, concentrating an organic phase, and distilling under reduced pressure to obtain benzaldehyde.

Further, the organic solvent is selected from one or more of ethyl acetate, propyl acetate, butyl acetate, toluene, dichloromethane and 1, 2-dichloroethane.

The invention has the advantages that:

the 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid derivative is prepared by obtaining 4-carbonyl-2, 2,6, 6-tetramethyl piperidine nitroxide radical through simple oxidation of commercial 2,2,6, 6-tetramethyl-4-piperidone, then reacting with a corresponding phosphonylation reagent and hydrolyzing, raw materials used by the method are cheap and easy to obtain, the production process is easier and more convenient than that of the 2,2,6, 6-tetramethyl piperidine nitroxide radical, the cost is low, the compound has stable property, does not have any odor basically, is convenient to store, can be stored at room temperature, and the preparation method is simple and easy to obtain, and when the compound is used as a catalyst, the activity is high, and the solubility is high in an aqueous phase, the catalyst has little dosage, and after the reaction, the catalyst is washed by a small amount of weak alkaline water, so the catalyst is conveniently removed from the reaction system and is easily separated from the reaction system, the corresponding product quality is improved, and the generation of waste water is reduced.

Drawings

FIG. 1 shows a representative compound of 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid derivatives according to the invention; wherein A is 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid; b is 2- (2, 2,6, 6-tetramethyl piperidine nitroxide free radical-4-subunit) propionic acid; c is 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) succinic acid; d is 2- (2, 2,6, 6-tetramethyl piperidine nitroxide free radical-4-subunit) phenylacetic acid; e is 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) malonic acid; f is 2-cyano-2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid.

FIG. 2 is a scheme showing the preparation of 2- (2, 2,6, 6-tetramethylpiperidinyloxy, oxy-4-ylidene) acetic acid derivatives according to the present invention; wherein G is H, hydrocarbyl and substituted hydrocarbyl of 1-6 carbon atoms, 3-6 membered cyclic hydrocarbyl; benzene rings and substituted benzene rings, carboxyl groups, cyano groups; alk is methyl, ethyl, n-propyl, isopropyl;

FIG. 3 is a process route of preparing benzaldehyde by catalytic oxidation of benzyl alcohol with 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-ylidene) acetic acid derivative as catalyst in the present invention;

FIG. 4 is a scheme showing the preparation of 4-carbonyl-2, 2,6, 6-tetramethylpiperidine nitroxide radical in example 1;

FIG. 5 is a process route for the preparation of 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid of example 2;

FIG. 6 is a process scheme for the preparation of 2- (2, 2,6, 6-tetramethylpiperidinyloxy, oxy-4-ylidene) propanoic acid, example 3;

FIG. 7 is a scheme showing the preparation process of 2- (2, 2,6, 6-tetramethylpiperidinyloxy, oxy-4-ylidene) succinic acid in example 4;

FIG. 8 is a scheme showing a preparation process of 2- (2, 2,6, 6-tetramethylpiperidinyloxy, oxy-4-ylidene) phenylacetic acid in example 5;

FIG. 9 is a scheme showing the preparation process of 2- (2, 2,6, 6-tetramethylpiperidinyloxy, oxy-4-ylidene) malonic acid of example 6;

FIG. 10 is a scheme showing a preparation process of 2-cyano-2- (2, 2,6, 6-tetramethylpiperidinyloxy, oxy-4-ylidene) acetic acid in example 7.

Detailed Description

The following examples are merely illustrative of the present invention in detail, but it should be understood that the scope of the present invention is not limited to these examples.

Example 1: preparation of 4-carbonyl-2, 2,6, 6-

tetramethylpiperidine nitroxide radical

2,2,6, 6-tetramethyl-4-piperidone (50g,0.322mol,1eq) was dissolved in a mixture of methanol (300mL) and water (200mL), sodium tungstate dihydrate (17.6g,0.055mol,0.17eq) and hydrogen peroxide (110mL, aq 30%, 3eq) were slowly added dropwise, the reaction was carried out at room temperature for 8h, TLC detection was complete, the aqueous layer was saturated with K2CO3, extracted with methyl tert-butyl ether, dried, and spun-dried to obtain orange-red solid 4-carbonyl-2, 2,6, 6-tetramethylpiperidine nitroxide radical 48.8g, yield 89%.

Example 2: preparation of 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid (Compound A)

Adding NaH (3.5g, 88.3mmol, 1.5eq) into a 500mL reaction bottle, adding 100mL dry THF under the protection of nitrogen, stirring at 0 ℃ for 15min, dropwise adding triethyl phosphonoacetate (19.8g, 88.3mmol, 1.5eq), adding after 15min, after the reaction liquid in the reaction bottle is clear and no gas is discharged, adding 4-carbonyl-2, 2,6, 6-tetramethylpiperidine nitroxide free radical (10g, 28.7mmol, 1eq), naturally heating to room temperature, reacting for 4h, after the HPLC shows that the raw material is completely reacted, quenching with 30mL saturated ammonium chloride solution, extracting with ethyl acetate, and concentrating to obtain red oily liquid.

The red oily liquid obtained in the above step was dissolved in 150mL (MeOH/H)₂O/═ 3/1), 4.7g of sodium hydroxide was added to the mixed solution, and the mixture was stirred at room temperature for 5 hours, after completion of the reaction, 50mL of water was added to the reaction flask, and the reaction mixture was washed with dichloromethane 20mL x3 to wash the aqueous phase, and then the pH of the aqueous phase was adjusted to 2.5 with hydrochloric acid, and the aqueous phase was concentrated under reduced pressure to obtain a solid; the product was dissolved in an appropriate amount of ethanol, filtered to remove NaCl solid, the solution was concentrated under reduced pressure to about 5mL, poured into a high-speed stirred petroleum ether/ethyl acetate solution (100mL) 5/1 to precipitate a solid, which was filtered to obtain an off-white solid 8g, purity 98.5%, total yield 63.7%.

Example 3: preparation of 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) propionic acid (Compound B)

The procedure is as in example 2, using triethyl 2-phosphonopropionate as phosphorylating reagent, giving 9.7g of off-white solid with a purity of 98.1% and an overall yield of 73%.

Example 4: preparation of 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) succinic acid (Compound C)

The procedure is as in example 2, the phosphorylating reagent used is O, O' -diethyl (2-diethyl succinate) phosphate, giving an off-white solid 10.1g, purity 98.6%, overall yield 63.7%.

Example 5: preparation of 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) phenylacetic acid (Compound D)

The procedure is as in example 2, using ethyl (diethoxyphosphonyl) phenylacetate as phosphorylating reagent and obtaining a white-like solid 13g with a purity of 98.5% and a total yield of 76.7%.

Example 6: preparation of 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) malonic acid (Compound E)

The procedure is as in example 2, the phosphorylating reagent used is diethyl diethoxyphosphonyl malonate, giving 7.5g of off-white solid with a purity of 98.2% and a total yield of 50%.

Example 7: preparation of 2-cyano-2- (2, 2,6, 6-tetramethylpiperidinyloxy-oxy-4-ylidene) acetic acid (Compound F)

The procedure is as in example 2, using ethyl 2-cyano-2-diethoxyphosphonoacetate as phosphorylating reagent, and obtaining off-white solid 5.5g with 98% purity and 39.9% total yield.

Example 8: process for synthesizing benzaldehyde

In a 100ml reaction bottle, 10.8g (0.1mol, 1eq) of benzyl alcohol is added, 0.1g of potassium bromide, 20g of water and 20g of dichloromethane are added as catalysts, which are 2- (2, 2,6, 6-tetramethylpiperidine nitroxide radical-4-ylidene) acetic acid derivatives corresponding to 0.1% of the weight of the benzyl alcohol, 1.5 equivalents of 10% sodium hypochlorite solution is added dropwise at 10 ℃, the reaction pH value is controlled to be 7.0-9.0 by using solid sodium bicarbonate, the reaction is carried out for 2 hours at 10-20 ℃, the mixture is kept stand and layered, an aqueous phase is extracted twice by 30gx2 of dichloromethane, an organic phase is combined and concentrated, and the colorless liquid benzaldehyde is obtained by reduced pressure distillation. Specific experimental data are shown in the following table:

experimental data for benzaldehyde preparation

Number of experiments	Kind of catalyst	Yield of
			1	Compound A	96.7％
2	Compound B	97.0％
			3	Compound C	93.5％
4	Compound D	83.5％
			5	Compound E	74.5％
6	Compound F	95.8％
			7	TEMPO	67.2％

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

A process for producing a 2- (2, 2,6, 6-tetramethylpiperidinyloxy, oxy-4-ylidene) acetic acid derivative, which comprises the steps of:

(1) dissolving 1 equivalent of 2,2,6, 6-tetramethyl-4-piperidone in a mixed solvent of methanol and water, slowly dropwise adding a mixture of 0.1-0.2 equivalent of sodium tungstate hydrate and 1.5-6 equivalent of hydrogen peroxide, stirring and reacting for 2-24h at the reaction temperature of 0-65 ℃, extracting with an organic solvent after complete reaction, drying, and concentrating to obtain an orange-red solid 4-carbonyl-2, 2,6, 6-tetramethyl piperidine nitroxide radical;

(2) adding 1.0-2.0 equivalent of alkali into an organic solvent with the weight 3-30 times of that of the alkali, reacting at 0-25 ℃, adding 1.0-2.0 equivalent of a phosphoryl reagent into the reaction solution, then adding 1 equivalent of 4-carbonyl-2, 2,6, 6-tetramethylpiperidine nitroxide radical, reacting at 0-50 ℃ for 2-10h, quenching with a saturated ammonium chloride solution, extracting with an organic solvent, and concentrating to obtain a red oily liquid;

(3) dissolving the red oily liquid obtained in the step (2) into a mixed solvent of an organic solvent and water, wherein the weight of the mixed solvent is 3-10 times that of the red oily liquid, and adding 1.0-3.0 equivalent of inorganic base; the reaction temperature is 0-50 ℃, the reaction time is 2-16h, after the reaction is completed, the reaction liquid is extracted by an organic solvent, the pH value of a water phase is adjusted to be 1.5-3.5 by inorganic acid, the solution is concentrated under reduced pressure to obtain a solid, the solid is dissolved by alcohol, the solution is filtered, the solution is concentrated under reduced pressure and then added into a mixed solvent of petroleum ether and ethyl acetate, and the solid is separated out, so that the 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid derivative is obtained.
2. The method of claim 1, wherein the structural formula of the 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid derivative is characterized as follows:

wherein G is H, alkyl and substituted alkyl with 1-6 carbon atoms, 3-6 membered cycloalkyl, benzene ring and substituted benzene ring, carboxyl and cyano;

m is H, Li, Na and K.
3. The method for preparing 2- (2, 2,6, 6-tetramethylpiperidinyloxy, 4-ylidene) acetic acid derivatives according to claim 1, wherein the organic solvent used in the organic solvent extraction is at least one selected from the group consisting of ethyl acetate, propyl acetate, butyl acetate, toluene, methyl t-butyl ether, methylene chloride, and 1, 2-dichloroethane.
4. The method for producing a 2- (2, 2,6, 6-tetramethylpiperidinyloxy, 4-ylidene) acetic acid derivative according to claim 1, wherein the base in the step (2) is one selected from the group consisting of sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
5. The method for preparing 2- (2, 2,6, 6-tetramethylpiperidinyloxy, oxy-4-ylidene) acetic acid derivatives according to claim 1, wherein the organic solvent in the mixture of organic solvent and water in step (3) is selected from one or more of methanol, ethanol, tetrahydrofuran, and 1, 4-dioxane.
6. The method for preparing 2- (2, 2,6, 6-tetramethylpiperidinyloxy, oxy-4-ylidene) acetic acid derivatives according to claim 1 wherein the inorganic base in step (3) is selected from one of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
7. Use of the 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid derivative according to any of claims 1-6 as a catalyst for the catalytic oxidation of benzyl alcohol to benzaldehyde.
8. The use of the 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid derivative according to claim 7, wherein the process for preparing benzaldehyde by catalytic oxidation of benzyl alcohol with the 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid derivative as a catalyst comprises:

adding 1 equivalent of benzyl alcohol into a mixed solvent of an organic solvent and water which is 3-10 times of the weight of the benzyl alcohol, adding a 2- (2, 2,6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid derivative which is 0.01-1% of the weight of the benzyl alcohol and serves as a catalyst, dropwise adding 1.0-3.0 equivalent of sodium hypochlorite solution at the temperature of 0-40 ℃, reacting for 1-10h, standing for layering, concentrating an organic phase, and distilling under reduced pressure to obtain benzaldehyde.
9. The use of the 2- (2, 2,6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid derivative according to claim 8 wherein the organic solvent is selected from one or more of ethyl acetate, propyl acetate, butyl acetate, toluene, methylene chloride, and 1, 2-dichloroethane.