阅读说明：本技术 蒈酸基1,2,3-***化合物及其制备方法和应用 (Carane acidyl 1,2, 3-triazole compound and preparation method and application thereof ) 是由 段文贵 康国强 林桂汕 岑波 刘陆智 于 2019-08-09 设计创作，主要内容包括：本发明公开了一种蒈酸基1,2,3-三唑化合物及其制备方法和应用,属于有机合成技术领域,是采用氯化钌为催化剂,以去离子水和叔丁醇作溶剂、高碘酸钠为氧化剂,将3-蒈烯分子中的碳碳双键氧化开环得到蒈酮酸,再利用Wolf-Kishner-黄鸣龙还原反应将蒈酮酸的羰基还原为亚甲基得到蒈酸,进而与溴丙炔反应生成含有末端炔的蒈酸炔酯,最后与系列取代的叠氮发生铜催化的叠氮-炔基环加成反应,合成得到蒈酸基1,2,3-三唑化合物。本发明首次实现了蒈酸基1,2,3-三唑化合物的合成。抑菌活性测试表明,蒈酸基1,2,3-三唑化合物具有一定的抑菌活性,扩大了3-蒈烯的应用范围。(The invention discloses a carane acid group 1,2, 3-triazole compound and a preparation method and application thereof, and belongs to the technical field of organic synthesis, ruthenium chloride is used as a catalyst, deionized water and tert-butyl alcohol are used as solvents, sodium periodate is used as an oxidant, a carbon-carbon double bond in a 3-carene molecule is subjected to oxidative ring opening to obtain carane acid, carbonyl of the carane acid is reduced to methylene by using Wolf-Kishner-Huang Minlon reduction reaction to obtain carane acid, the carane acid is further reacted with bromopropyne to generate carane acid alkyne ester containing terminal alkyne, and finally, the carane acid group 1,2, 3-triazole compound is synthesized by carrying out copper-catalyzed azide-alkyne cycloaddition reaction with series substituted azides. The invention realizes the synthesis of the carane acyloxy 1,2, 3-triazole compound for the first time. The bacteriostatic activity test shows that the carane acyloxy 1,2, 3-triazole compound has certain bacteriostatic activity, and the application range of the 3-carene is expanded.)

1. a carane acid radical 1,2, 3-triazole compound is characterized in that the structural general formula of the compound is as follows:

wherein R is any one of phenyl, o-tolyl, m-tolyl, p-tolyl, 2, 6-dimethylphenyl, m-fluorophenyl, 2, 6-difluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, 2, 6-dichlorophenyl, o-methoxyphenyl, m-methoxyphenyl, o-nitrophenyl, m-nitrophenyl, p-bromophenyl, p-cyanophenyl, p-methylthiophenyl, p-vinylphenyl, alpha-Cl-beta-pyridylmethyl and alpha-Cl-beta-thiazolylmethyl.

2. The carane acid group 1,2, 3-triazole compound of claim 1, having the specific structure:

Any one of the above.

3. A method for preparing carane acid group 1,2, 3-triazole compound as described in claim 1 or 2, wherein ruthenium chloride is used as a catalyst, deionized water and tert-butanol are used as solvents, sodium periodate is used as an oxidizing agent, a carbon-carbon double bond in a 3-carene molecule is subjected to oxidative ring opening to obtain carane acid, carbonyl of the carane acid is reduced to a methylene group by using Wolf-Kishner-Huang dragon reduction reaction to obtain carane acid, the carane acid is further reacted with bromopropyne to generate carane acid alkynyl containing terminal alkyne, and then the obtained carane acid alkynyl is subjected to copper-catalyzed azide-alkyne cycloaddition reaction with the series of substituted azide compounds to synthesize the carane acid group 1,2, 3-triazole compound.

4. The method of preparing carane acid group 1,2, 3-triazole compound of claim 3, wherein the carane acid is prepared by adding 3-carene, t-butanol, deionized water, NaIO4, and ruthenium chloride hydrate to a vessel; under mechanical stirring, firstly reacting for 1-1.5h at 40-45 ℃, and then heating to 50-55 ℃ for reacting for 1.5-2 h; after the reaction is finished, cooling to room temperature, performing vacuum filtration by using a Buchner funnel, washing a filter cake by using EA, then combining organic layers, alkalizing the organic layers by using NaOH solution until the pH value is 9-10, and extracting the organic layers by using equivalent deionized water for 3 times; taking a water layer, acidifying the water layer by hydrochloric acid until the pH value is 3-4, extracting a water phase by EA for 3 times, then combining obtained organic layers, washing the organic layer by a saturated NaCl solution for 3 times to obtain a dehydrated organic layer, removing the EA from the dehydrated organic layer by rotary evaporation, carrying out reduced pressure distillation by an oil pump, and collecting a fraction with the concentration of 160-; wherein the dosage ratio of the 3-carene, the tertiary butanol, the deionized water, the NaIO4 and the ruthenium chloride hydrate is 45-55: 270-280: 540-560: 240-260: 0.45-0.55.

5. The method for preparing carane acid radical 1,2, 3-triazole compounds according to claim 3, wherein the carane acid preparation process is as follows: adding KOH and ethylene glycol into a three-necked bottle provided with an oil-water separator, stirring and dissolving, and then adding hydrazine hydrate and carane acid with the mass fraction of 80%; then placing the three-necked bottle in an oil bath for heating, heating and refluxing for 3-4h, discharging water after water distribution, continuously heating to 170-180 ℃, and maintaining the reaction for 6-8 h; cooling to room temperature after the reaction is finished, adjusting the pH value in the three-necked flask to 3 by hydrochloric acid, adding deionized water with the same amount as the substances in the container, extracting for 3 times by cyclohexane, combining the obtained organic layers, washing the organic layer for 3 times by using a saturated NaCl solution, removing cyclohexane by rotary evaporation, performing reduced pressure distillation by using an oil pump, and collecting 110-fold 115 ℃/5mmHg fractions to obtain the carane acid; wherein the dosage ratio of KOH, glycol, hydrazine hydrate with the mass fraction of 80 percent and carane acid is 13-15:45-55:35-45: 12-13.

6. The method for preparing carane acid radical 1,2, 3-triazole compounds according to claim 3, wherein the preparation process of the carane acid propargyl ester is as follows: adding carane acid, anhydrous potassium carbonate, DMF (dimethyl formamide) and bromopropyne into a container, and reacting for 3-4h at normal temperature; after the reaction is finished, pouring the obtained solution into 150-200mL ice water, extracting with EA for 3 times, combining organic layers, washing the organic layers with a saturated NaCl solution for 3 times, removing EA by rotary evaporation, then carrying out reduced pressure distillation with an oil pump, and collecting a fraction at 90-95 ℃/5mmHg to obtain the propargyl carbonate containing the terminal alkyne; wherein the dosage ratio of the carane acid to the anhydrous potassium carbonate to the DMF to the bromopropyne is 5.0-5.2: 9-9.6:35-45:2-3.

7. The method for preparing carane acid group 1,2, 3-triazole compound according to claim 3, wherein the azide compound is prepared by: adding a substituent compound, NaN3 and absolute ethyl alcohol into a container, heating and refluxing under stirring, and tracking the reaction by TLC; after the reaction is finished, removing ethanol by rotary evaporation, extracting the reaction solution by EA for 2-3 times, combining organic layers, washing the organic layers by saturated NaCl solution for 3 times, and after EA is removed by rotary evaporation, performing silica gel column chromatography separation and purification on the residual substances by using petroleum ether as an eluent to obtain an azide compound; wherein the dosage ratio of the substituent compound, NaN3 and absolute ethyl alcohol is 5-6:0.6-0.8: 4-5.

8. The method of claim 7, wherein the substituent compound is any one of benzyl chloride, o-methylbenzyl chloride, m-methylbenzyl chloride, p-methylbenzyl chloride, 2, 6-dimethylbenzyl chloride, m-fluorobenzyl chloride, 2, 6-difluorobenzyl chloride, o-chlorobenzyl chloride, m-chlorobenzyl chloride, p-chlorobenzyl chloride, 2, 6-dichlorobenzyl chloride, o-methoxybenzyl chloride, m-methoxybenzyl chloride, o-nitrobenzyl chloride, m-nitrobenzyl chloride, p-bromobenzyl chloride, p-cyanobenzyl chloride, p-methylthiobenzyl chloride, p-vinylbenzyl chloride, α -Cl- β -pyridylmethyl chloride, and α -Cl- β -chlorothianyl.

9. The method for preparing carane acid group 1,2, 3-triazole compound according to claim 3, wherein the azide-alkynyl cycloaddition reaction process is as follows: adding an azide compound, carane acid propargyl ester, sodium ascorbate and anhydrous copper sulfate into a container, adding a mixed solvent of tetrahydrofuran and deionized water, and reacting for 4-5h at normal temperature; extracting with CH2Cl2 for 3 times after the reaction is finished, combining organic layers, washing the organic layer with saturated NaCl solution for 3 times, drying with anhydrous magnesium sulfate, removing CH2Cl2 by rotary evaporation, and separating and purifying the obtained residue with silica gel column chromatography to obtain the carane acidic group 1,2, 3-triazole compound; wherein, the eluent used in the purification process is a mixture of ethyl acetate and petroleum ether according to the volume ratio of 1: 25-30; the using amount ratio of the azide compound, the carane acid alkyne ester, the sodium ascorbate, the anhydrous copper sulfate, the tetrahydrofuran and the deionized water is 1.8-2.1:0.4-0.45:0.03-0.04:0.04-0.05:4-5: 4-5.

10. The use of a carane acid group 1,2, 3-triazole compound as defined in claim 1 or 2, wherein the carane acid group 1,2, 3-triazole compound is used in the preparation of a bacteriostatic agent.

Technical Field

the invention relates to the technical field of organic synthesis, in particular to a carane acid radical 1,2, 3-triazole compound, and a preparation method and application thereof.

background

3-carene, chemical name is 3,7, 7-trimethyl bicyclo [4.1.0] hept-3-ene, molecular formula is C10H16, and the compound is oily volatile monoterpene compound with irritant pine fragrance. The 3-carene has wide biological activities of bacteriostasis, anticancer, anti-inflammation, antioxidation, chemical pheromone and the like, contains a plurality of chiral stereocenters and geminal dimethylcyclopropane structures, is a rare natural 'chiral source' and 'ternary cyclic source', and the geminal dimethylcyclopropane structural unit is one of pharmacodynamic groups and can be used for synthesizing various bioactive compounds or complex natural products. For example, the synthesized pyrethroid compounds contain gem-dimethyl cyclopropane and ester active groups, and the commercialized insecticides have the characteristics of high efficiency, broad spectrum, low toxicity, biodegradability and the like. Therefore, oxidative ring opening of the double bond of 3-carene to obtain caronic acid containing cyclopropane and carboxyl is one of the ways for developing and utilizing the carane acid.

On the other hand, 1,2, 3-triazole compounds are favored by chemists because of their abundant biological activity and their ability to be synthesized by green chemistry. A large number of documents report that the 1,2, 3-triazole compounds have wide biological activities of antibiosis, anticancer, antivirus, disinsection, weeding and the like, and are widely applied to the fields of pharmaceutical chemistry and agriculture and pharmacy. Currently, azole drugs such as 1,2, 4-triazole and imidazole are used in many antifungal compounds. 1,2, 3-triazole, an analogue of 1,2, 4-triazole, has become a new member of antifungal drugs. Especially, the substituent 1,2, 3-triazole ring is introduced into the existing antifungal drugs, so that the physicochemical property of the compound can be improved, and active molecules with lower toxicity and better activity can be obtained. Therefore, the carane acid radical 1,2, 3-triazole compound is a novel functional compound, and the substance and the synthetic method thereof are not reported at home and abroad up to now.

disclosure of Invention

the invention aims to provide a carane acyloxy 1,2, 3-triazole compound, and a preparation method and application thereof, wherein the obtained product is low in cost, simple in preparation method and further has a certain antibacterial activity, and the application range of 3-carene is expanded.

a carane acid radical 1,2, 3-triazole compound has the following structural formula:

Wherein R is any one of phenyl, o-tolyl, m-tolyl, p-tolyl, 2, 6-dimethylphenyl, m-fluorophenyl, 2, 6-difluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, 2, 6-dichlorophenyl, o-methoxyphenyl, m-methoxyphenyl, o-nitrophenyl, m-nitrophenyl, p-bromophenyl, p-cyanophenyl, p-methylthiophenyl, p-vinylphenyl, alpha-Cl-beta-pyridylmethyl and alpha-Cl-beta-thiazolylmethyl.

Further, the specific structure of the compound is as follows:

any one of the above.

the invention provides a preparation method of the carane acid group 1,2, 3-triazole compound,

Ruthenium chloride is used as a catalyst, deionized water and tert-butyl alcohol are used as solvents, sodium periodate is used as an oxidant, a carbon-carbon double bond in a 3-carene molecule is subjected to oxidative ring opening to obtain carenic acid, Wolf-Kishner-Huang Minlon reduction reaction is used for reducing the carbonyl of the carenic acid into methylene to obtain carenic acid, the carenic acid is further reacted with bromopropyne to generate a propargyl carane acid ester containing terminal alkyne, and the obtained propargyl carane acid ester and a series of substituted azide compounds are subjected to copper-catalyzed azide-alkyne cycloaddition reaction to synthesize the carane acid group 1,2, 3-triazole compound.

Further, the preparation process of the caronic acid is that 3-carene, tertiary butanol, deionized water, NaIO4 and ruthenium chloride hydrate are added into a container; under mechanical stirring, firstly reacting for 1-1.5h at 40-45 ℃, and then heating to 50-55 ℃ for reacting for 1.5-2 h; after the reaction is finished, cooling to room temperature, performing vacuum filtration by using a Buchner funnel, washing a filter cake by using EA, then combining organic layers, alkalizing the organic layers by using NaOH solution until the pH value is 9-10, and extracting the organic layers by using equivalent deionized water for 3 times; taking a water layer, acidifying the water layer by hydrochloric acid until the pH value is 3-4, extracting a water phase by EA for 3 times, then combining obtained organic layers, washing the organic layer by a saturated NaCl solution for 3 times to obtain a dehydrated organic layer, removing the EA from the dehydrated organic layer by rotary evaporation, carrying out reduced pressure distillation by an oil pump, and collecting fractions with the concentration of 160-; wherein the dosage ratio of the 3-carene, the tertiary butanol, the deionized water, the NaIO4 and the ruthenium chloride hydrate is 45-55: 270-280: 540-560: 240-260: 0.45-0.55.

Further, the preparation process of the carane acid is as follows: adding KOH and ethylene glycol into a three-necked bottle provided with an oil-water separator, stirring and dissolving, and then adding hydrazine hydrate and caronic acid with the mass fraction of 80%; then placing the three-necked bottle in an oil bath for heating, heating and refluxing for 3-4h, discharging water after water distribution, continuously heating to 170-180 ℃, and maintaining the reaction for 6-8 h; cooling to room temperature after the reaction is finished, adjusting the pH value in the three-necked flask to 3 by hydrochloric acid, adding deionized water with the same amount as the substances in the container, extracting for 3 times by cyclohexane, combining the obtained organic layers, washing the organic layer for 3 times by using a saturated NaCl solution, removing the cyclohexane by rotary evaporation, performing reduced pressure distillation by using an oil pump, and collecting 110-dose 115 ℃/5mmHg fractions to obtain the carane acid; wherein the dosage ratio of KOH, glycol, hydrazine hydrate with the mass fraction of 80 percent and carane acid is 13-15:45-55:35-45: 12-13.

further, the preparation process of the carane acid alkyne ester comprises the following steps: adding carane acid, anhydrous potassium carbonate, DMF (dimethyl formamide) and bromopropyne into a container, and reacting for 3-4h at normal temperature; after the reaction is finished, pouring the obtained solution into 150-200mL ice water, extracting with EA for 3 times, combining organic layers, washing the organic layers with a saturated NaCl solution for 3 times, removing EA by rotary evaporation, then carrying out reduced pressure distillation with an oil pump, and collecting a fraction at 90-95 ℃/5mmHg to obtain the propargyl carbonate containing the terminal alkyne; wherein the dosage ratio of the carane acid to the anhydrous potassium carbonate to the DMF to the bromopropyne is 5.0-5.2: 9-9.6:35-45:2-3.

Further, the preparation process of the azide compound is as follows: adding a substituent compound, NaN3 and absolute ethyl alcohol into a container, heating and refluxing under stirring, and tracking the reaction by TLC; after the reaction is finished, removing ethanol by rotary evaporation, extracting the reaction solution by EA for 2-3 times, combining organic layers, washing the organic layers by saturated NaCl solution for 3 times, and after EA is removed by rotary evaporation, performing silica gel column chromatography separation and purification on the residual substances by using petroleum ether as an eluent to obtain an azide compound; wherein the dosage ratio of the substituent compound, NaN3 and absolute ethyl alcohol is 5-6:0.6-0.8: 4-5.

the substituent compound is any one of benzyl chloride, o-methylbenzyl chloride, m-methylbenzyl chloride, p-methylbenzyl chloride, 2, 6-dimethylbenzyl chloride, m-fluorobenzyl chloride, 2, 6-difluorobenzyl chloride, o-chlorobenzyl chloride, m-chlorobenzyl chloride, p-chlorobenzyl chloride, 2, 6-dichlorobenzyl chloride, o-methoxybenzyl chloride, m-methoxybenzyl chloride, o-nitrobenzyl chloride, m-nitrobenzyl chloride, p-bromobenzyl chloride, p-cyanobenzyl chloride, p-methylthiobenzyl chloride, p-vinylbenzyl chloride, α -Cl- β -pyridylmethyl chloride, and α -Cl- β -thiazolyl chloride.

Further, the azide-alkynyl cycloaddition reaction process is as follows: adding an azide compound, carane acid propargyl ester, sodium ascorbate and anhydrous copper sulfate into a container, adding a mixed solvent of tetrahydrofuran and deionized water, and reacting for 4-5h at normal temperature; extracting with CH2Cl2 for 3 times after the reaction is finished, combining organic layers, washing the organic layer with saturated NaCl solution for 3 times, drying with anhydrous magnesium sulfate, removing CH2Cl2 by rotary evaporation, and separating and purifying the obtained residue with silica gel column chromatography to obtain the carane acidic group 1,2, 3-triazole compound; wherein, the eluent used in the purification process is a mixture of ethyl acetate and petroleum ether according to the volume ratio of 1: 25-30; the dosage ratio of the azido compound, the carane acid alkyne ester, the sodium ascorbate, the anhydrous copper sulfate, the tetrahydrofuran and the deionized water is 1.8-2.1:0.4-0.45:0.03-0.04:0.04-0.05:4-5: 4-5.

the invention provides application of a carane acid group 1,2, 3-triazole compound, wherein the carane acid group 1,2, 3-triazole compound is applied to preparation of a bacteriostatic agent.

The raw materials used in the invention are as follows: 3-carene, tert-butyl alcohol, NaIO4, ruthenium chloride hydrate, EA, KOH, ethylene glycol, hydrazine hydrate, NaN3, sodium ascorbate, anhydrous copper sulfate and substituent compounds are all purchased from chemical raw material companies at home and abroad and are directly used without purification.

the principle of the invention is as follows: according to the active substructure splicing principle, introducing a 1,2, 3-triazole ring into a geminal dimethylcyclopropane structure through multi-step reaction to prepare a carane acid group 1,2, 3-triazole compound; specifically, ruthenium chloride is used as a catalyst, deionized water and tert-butyl alcohol are used as solvents, sodium periodate is used as an oxidant, a carbon-carbon double bond in a 3-carene molecule is subjected to oxidative ring opening to obtain carenic acid, carbonyl of the carenic acid is reduced to methylene through Wolf-Kishner-Huang Minlon reduction reaction to obtain the carenic acid, the carenic acid is further reacted with bromopropyne to generate a carane acid alkyne ester containing terminal alkyne, and finally, the substituted azide compound and the series of azide compounds are subjected to copper-catalyzed azide-alkyne cycloaddition reaction to synthesize the carane acid group 1,2, 3-triazole compound.

The invention has the following beneficial effects:

1. the synthesis of the carane acyloxy 1,2, 3-triazole compound is realized for the first time; the obtained carane acid alkyne ester is light yellow liquid, and the yield of the carane acid alkyne ester is over 85.10%; the yield of the carane acid group 1,2, 3-triazole compound is 80-85%, the purity is 95-97%, and all target compounds are light yellow oily liquid.

2. the carane acid group 1,2, 3-triazole compound has a certain inhibiting effect on various pathogenic bacteria, has a wide application prospect, is applied to the field of bacteriostats, can screen out efficient pesticide lead compounds, and provides an experimental basis for high-value utilization of forest biomass resources 3-carene.

Drawings

FIG. 1 shows the chemical formula of carane acid radical 1,2, 3-triazole compound of the present invention.

FIG. 2 is a flow diagram of the organic synthesis of the present invention.

in the figure, R is any one of phenyl, o-tolyl, m-tolyl, p-tolyl, 2, 6-dimethylphenyl, m-fluorophenyl, 2, 6-difluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, 2, 6-dichlorophenyl, o-methoxyphenyl, m-methoxyphenyl, o-nitrophenyl, m-nitrophenyl, p-bromophenyl, p-cyanophenyl, p-methylthiophenyl, p-vinylphenyl, alpha-Cl-beta-pyridylmethyl chloride and alpha-Cl-beta-thiazolyl chloride.

Detailed Description

The technical solution of the present invention is further illustrated by the following specific examples.

Pretreatment examples for preparing caronic acid, preparing caronic acid and preparing caronic acid alkyne ester

pretreatment example 1

the method comprises the following steps:

(1) preparing carane acid: to a 2000mL three-necked flask were added 50mL of 3-carene, 275mL of t-butanol, 550mL of deionized water, 250.00g of NaIO4, and 0.50g of ruthenium chloride hydrate; under mechanical stirring, firstly reacting for 1.5h at 45 ℃, and then heating to 55 ℃ for reacting for 2 h; after the reaction is finished, cooling to room temperature, performing vacuum filtration by using a Buchner funnel, washing a filter cake by using EA, then combining organic layers, alkalizing the organic layers by using NaOH solution until the pH value is 9-10, and extracting the organic layers by using equivalent deionized water for 3 times; taking a water layer, acidifying the water layer by hydrochloric acid until the pH value is 3-4, extracting a water phase by EA for 3 times, then combining obtained organic layers, washing the organic layer by a saturated NaCl solution for 3 times to obtain a dehydrated organic layer, removing the EA from the dehydrated organic layer by rotary evaporation, carrying out reduced pressure distillation by an oil pump, and collecting a fraction with the concentration of 160-;

(2) Preparing carane acid: adding 14.00g of KOH and 50mL of ethylene glycol into a three-necked bottle provided with an oil-water separator, stirring and dissolving, and then adding 40mL of hydrazine hydrate with the mass fraction of 80% and 12.88g of the carane acid in the step (1); placing the three-necked bottle in an oil bath for heating, heating up and refluxing for 4h, dividing water, continuously heating up to 180 ℃, and then maintaining the reaction for 8 h; cooling to room temperature after the reaction is finished, adjusting the pH value in the three-necked flask to 3 by hydrochloric acid, adding deionized water with the same amount as the substances in the container, extracting for 3 times by cyclohexane, combining the obtained organic layers, washing the organic layer for 3 times by using a saturated NaCl solution, removing cyclohexane by rotary evaporation, performing reduced pressure distillation by using an oil pump, and collecting 110-fold 115 ℃/5mmHg fractions to obtain the carane acid;

(3) Preparing carane acid alkynyl ester: adding 5.10g of carane acid, 9.40g of anhydrous potassium carbonate, 40mL of DMF (dimethyl formamide) and 2.8mL of bromopropyne into a 100mL round-bottom flask, and reacting for 4 hours at normal temperature; after the reaction is finished, pouring the obtained reaction solution into 200mL of ice water, extracting with EA for 3 times, combining organic layers, washing the organic layers with a saturated NaCl solution for 3 times, performing rotary evaporation to remove the EA, performing reduced pressure distillation with an oil pump, and collecting a fraction at 90-95 ℃/5mmHg to obtain the carane acid alkynyl ester containing the terminal alkyne. The yield of obtained carane acid propargyl ester is 86.20%.

pretreatment example 2

the method comprises the following steps:

(1) preparing carane acid: to a 2000mL three-necked flask were added 45mL of 3-carene, 270mL of t-butanol, 540mL of deionized water, 240.00g of NaIO4, and 0.45g of ruthenium chloride hydrate; under mechanical stirring, firstly reacting for 1h at 40 ℃, and then heating to 50 ℃ for reacting for 1.5 h; after the reaction is finished, cooling to room temperature, performing vacuum filtration by using a Buchner funnel, washing a filter cake by using EA, then combining organic layers, alkalizing the organic layers by using NaOH solution until the pH value is 9-10, and extracting the organic layers by using equivalent deionized water for 3 times; taking a water layer, acidifying the water layer by hydrochloric acid until the pH value is 3-4, extracting a water phase by EA for 3 times, then combining obtained organic layers, washing the organic layer by a saturated NaCl solution for 3 times to obtain a dehydrated organic layer, removing the EA from the dehydrated organic layer by rotary evaporation, carrying out reduced pressure distillation by an oil pump, and collecting a fraction with the concentration of 160-;

(2) preparing carane acid: adding 13.00g of KOH and 45mL of ethylene glycol into a three-necked bottle provided with an oil-water separator, stirring and dissolving, and then adding 35mL of hydrazine hydrate with the mass fraction of 80% and 12g of carane acid in the step (1); placing the three-necked bottle in an oil bath for heating, heating up and refluxing for 3h, dividing water, continuously heating up to 170 ℃, and then maintaining the reaction for 6 h; cooling to room temperature after the reaction is finished, adjusting the pH value in the three-necked flask to 3 by hydrochloric acid, adding deionized water with the same amount as the substances in the container, extracting for 3 times by cyclohexane, combining the obtained organic layers, washing the organic layer for 3 times by using a saturated NaCl solution, removing cyclohexane by rotary evaporation, performing reduced pressure distillation by using an oil pump, and collecting 110-fold 115 ℃/5mmHg fractions to obtain the carane acid;

(3) preparing carane acid alkynyl ester: adding 5.0g of carane acid, 9.0g of anhydrous potassium carbonate, 35mL of DMF (dimethyl formamide) and 2mL of bromopropyne into a 100mL round-bottom flask, and reacting for 3h at normal temperature; after the reaction is finished, pouring the obtained reaction solution into 150mL of ice water, extracting with EA for 3 times, combining organic layers, washing the organic layers with a saturated NaCl solution for 3 times, performing rotary evaporation to remove the EA, performing reduced pressure distillation with an oil pump, and collecting a fraction at 90-95 ℃/5mmHg to obtain the carane acid alkynyl ester containing the terminal alkyne. The yield of obtained carane acid propargyl ester is 85.80%.

pretreatment example 3

the method comprises the following steps:

(1) Preparing carane acid: to a 2000mL three-necked flask were added 55mL of 3-carene, 280mL of t-butanol, 560mL of deionized water, 260.00g of NaIO4, and 0.55g of ruthenium chloride hydrate; under mechanical stirring, firstly reacting for 1.2h at 42 ℃, and then heating to 53 ℃ for reacting for 1.6 h; after the reaction is finished, cooling to room temperature, performing vacuum filtration by using a Buchner funnel, washing a filter cake by using EA, then combining organic layers, alkalizing the organic layers by using NaOH solution until the pH value is 9-10, and extracting the organic layers by using equivalent deionized water for 3 times; taking a water layer, acidifying the water layer by hydrochloric acid until the pH value is 3-4, extracting a water phase by EA for 3 times, then combining obtained organic layers, washing the organic layer by a saturated NaCl solution for 3 times to obtain a dehydrated organic layer, removing the EA from the dehydrated organic layer by rotary evaporation, carrying out reduced pressure distillation by an oil pump, and collecting a fraction with the concentration of 160-;

(2) preparing carane acid: adding 15.00g of KOH and 55mL of ethylene glycol into a three-necked bottle provided with an oil-water separator, stirring and dissolving, and then adding 45mL of hydrazine hydrate with the mass fraction of 80% and 13g of carane acid in the step (1); placing the three-necked bottle in an oil bath for heating, heating up and refluxing for 3.5h, dividing water, continuously heating up to 175 ℃, and then maintaining the reaction for 7 h; cooling to room temperature after the reaction is finished, adjusting the pH value in the three-necked flask to 3 by hydrochloric acid, adding deionized water with the same amount as the substances in the container, extracting for 3 times by cyclohexane, combining the obtained organic layers, washing the organic layer for 3 times by using a saturated NaCl solution, removing the cyclohexane by rotary evaporation, performing reduced pressure distillation by using an oil pump, and collecting 110-dose 115 ℃/5mmHg fractions to obtain the carane acid;

(3) Preparing carane acid alkynyl ester: adding 5.20g of carane acid, 9.60g of anhydrous potassium carbonate, 45mL of DMF (dimethyl formamide) and 3mL of bromopropyne into a 100mL round-bottom flask, and reacting for 3.5h at normal temperature; after the reaction is finished, pouring the obtained reaction solution into 180mL of ice water, extracting with EA for 3 times, combining organic layers, washing the organic layers with a saturated NaCl solution for 3 times, performing rotary evaporation to remove the EA, performing reduced pressure distillation with an oil pump, and collecting a fraction at 90-95 ℃/5mmHg to obtain the propargyl ester containing the terminal alkyne. The yield of obtained carane acid propargyl ester is 85.10%.

secondly, the propargyl carane acid ester obtained in the pretreatment example 1 in the step (I) is used for preparing the compounds of the following examples