Synthetic carbamate compound based on 3-substituted dioxazolone as well as preparation method and application of synthetic carbamate compound

Abstract

The invention discloses a synthetic carbamate compound based on 3-substituted dioxazolone as well as a preparation method and application of the synthetic carbamate compound, and belongs to the technical field of organic synthesis. The synthesis method comprises the following steps: (1) preparing 3-substituted dioxazolone from hydroximic acid with different substituent groups and phosgene under an ice bath condition; and (2) reacting the 3-substituted dioxazolone obtained in the step (1) with different phenols (alcohols) under an alkaline condition to obtain corresponding carbamate compounds. According to the method, the yield of carbamate is further improved by adjusting the conditions of alkali, equivalent weight, temperature and the like; the preparation method provided by the invention is novel and has the advantages of mild reaction conditions, few generated impurities, high yield, high safety, convenience in operation and the like; and the compound shows good cholinesterase activity in activity screening, and can be used in insecticides or pesticides.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing carbamate compounds based on 3-substituted dioxazolone, its preparation method, and its application. Background Technology

[0002] There are several methods for producing carbamates, including the phosgene method, the nitrate urea method, and the urea alcoholysis method. The most commonly used method is the phosgene method, which involves reacting phosgene with amines to generate isocyanates, which then react with hydroxyl groups under alkaline conditions to obtain carbamates. However, this method has low synthesis efficiency and is prone to generating symmetrical urea byproducts.

[0003] As an organic synthesis intermediate, urethane can be used to synthesize isocyanates, non-toxic polyurethanes, melamine derivatives, dialkyl carbonates, and polyethyleneamine. It can react with unsaturated hydrocarbons, aldehydes, ketones, polyols, and aromatic rings to generate derivatives for various applications. It can also be used to synthesize heterocyclic compounds such as pyrroles, triazolones, quinazolinones, and triazines, showing great application prospects.

[0004] In their research on the synthesis of asymmetric urea compounds, Sauer and Mayer introduced a series of 1,2,4-dioxazol-5-ones as precursors for N-acylnitroso intermediates. Upon heating in dimethyl sulfoxide (DMSO) at 150 °C, the 3-(2-methylphenyl)dioxazolone underwent decarboxylation and rearrangement to generate the corresponding isocyanate. Then, aqueous hydrolysis yielded in-situ generated o-toluidine, which gradually reacted with the remaining phenyl isocyanate to generate the symmetrical 1,3-di-o-toluene byproduct. Dube et al. investigated the application of dioxazolones as isocyanate precursors in the three-step one-pot synthesis of monoaryl-substituted urea derivatives, including the in-situ generation of dioxazolone from hydroxamic acid and carbonyl diimidazole (CDI) in acetonitrile, followed by mild thermal decomposition at 60 °C to generate the in-situ isocyanate, and then the addition of an amine to generate an asymmetric urea. Summary of the Invention

[0005] One of the objectives of this invention is to provide a method for synthesizing carbamate compounds based on 3-substituted dioxazolone, in order to solve the problems of low synthesis efficiency, easy generation of symmetrical urea byproducts, and difficulty in achieving good biological activity in carbamate compounds synthesized by traditional phosgene processes.

[0006] The second objective of this invention is to provide a method for preparing carbamate compounds based on 3-substituted dioxazolone. This method is used to prepare the aforementioned carbamate compounds by designing a synthetic route for 3-substituted dioxazolone intermediates and combining a two-step process (intermediate synthesis-phenol / alcohol coupling) with a one-pot integrated process. At the same time, key conditions such as reaction solvent, catalyst, material equivalence, and reaction temperature are optimized to achieve a mild, efficient, low-impurity, and high-yield synthesis of carbamate compounds.

[0007] The third objective of this invention is to provide an application of carbamate compounds synthesized from 3-substituted dioxazolone in pesticides.

[0008] The objective of this invention can be achieved through the following technical solutions: A method for synthesizing carbamate compounds based on 3-substituted dioxazolones has the following general structural formula:

[0009] R is selected from aryl or substituted aryl groups, including Any one of them; R1 is selected from straight-chain alkyl, branched-chain alkyl, cycloalkyl, substituted cycloalkyl, aryl (hetero)yl, or substituted aryl (hetero)yl, including Any one of them.

[0010] The above-mentioned aryl or substituted aryl means aryl, aryl heterol, substituted aryl and substituted aryl heterol.

[0011] A method for preparing carbamate compounds based on 3-substituted dioxazolones includes the following steps: (1) Hydroxyxamic acids with different substituents were reacted with phosgene under ice bath conditions to prepare 3-substituted dioxazolone; (2) The 3-substituted dioxazolone obtained in (1) was reacted with different phenols (alcohols) under alkaline conditions to obtain the corresponding carbamate compounds.

[0012] The reaction processes in steps (1) and (2) are as follows: .

[0013] Furthermore, the method for preparing the 3-substituted dioxazolone carbamate compound includes, but is not limited to, the following steps: (1) Triethylamine was added dropwise to the reaction solvent of hydroxamic acid and triphosgene in an ice bath at 0 °C and stirred. The reaction solution was extracted and washed with dilute hydrochloric acid and saturated sodium chloride aqueous solution. The organic phase was dried with anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain pure 3-substituted dioxazolone (3-phenyl dioxazolone can be further recrystallized from petroleum ether / ethyl acetate to obtain pure 3-phenyl dioxazolone solid). (2) Mix different phenols (alcohols) with 3-substituted dioxazolones, react with catalyst base and solvent under certain temperature conditions for 1-12 h. After the reaction is completed, extract the reaction solution with ethyl acetate, wash with dilute hydrochloric acid and saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate the solvent under reduced pressure, purify the sample by column chromatography with mobile phase petroleum ether: ethyl acetate, recrystallize the obtained product with petroleum ether: ethyl acetate, and filter to obtain pure solid carbamate compound.

[0014] Furthermore, the hydroxamic acid in (1) includes any one of acetoxyxamic acid, cyclopropylhydroxamic acid, cyclobutylhydroxamic acid, cyclopentylhydroxamic acid, cyclohexylhydroxamic acid, and benzohydroxamic acid.

[0015]

[0016] Furthermore, the 3-substituted dioxazolone in (2) includes any one of 3-methyl dioxazolone, 3-cyclopropyl dioxazolone, 3-cyclobutyl dioxazolone, 3-cyclopentyl dioxazolone, 3-cyclohexyl dioxazolone and 3-phenyl dioxazolone.

[0017]

[0018] Furthermore, the phenol (alcohol) in (2) includes any one of m-methylphenol, 2-sec-butylphenol, 2-isopropoxyphenol, α-naphthol and 2,2-dihydro-2,2-dimethyl-7-hydroxybenzofuran.

[0019]

[0020] Furthermore, (1) and (2) can be combined into one step, the specific implementation steps of which include: dissolving and mixing hydroxamic acid, triphosgene and acetonitrile, stirring and adding triethylamine at 0°C, transferring the reaction system to a pot at 60-70°C after 30-40 min, adding phenol and potassium carbonate and reacting for 20-30 min, and obtaining the corresponding carbamate compound after purification.

[0021] Furthermore, to improve the reaction efficiency of the above preparation method, reduce the formation of byproducts, and increase the product yield, this invention selects the reaction system of 2,2-dihydro-2,2-dimethyl-7-hydroxybenzofuran and 3-cyclopentyldioxazolone as a model reaction, and optimizes the key reaction conditions. The specific optimization results are as follows:

[0022] (1) According to the above model reaction, the selected reaction solvent is any one of dichloromethane, ethyl acetate, methanol, acetonitrile, acetone, tetrahydrofuran, acetone, toluene, N,N-dimethylformamide and dimethyl sulfoxide; considering that acetone has a low boiling point, acetonitrile is preferred as the solvent.

[0023] (2) According to the above model reaction, the selected catalyst base is any one of potassium acetate, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), sodium carbonate, potassium carbonate, cesium carbonate and sodium hydroxide; the preferred base is cesium carbonate.

[0024] (3) According to the above model reaction, the equivalent of the selected 3-cyclopentyldioxazolone (4a) is any one of 1, 1.2, 1.5, 2, 3 and 4; the preferred equivalent is 4.

[0025] (4) According to the above model reaction, the equivalent of the selected catalyst base is any one of 0.1, 0.2, 0.5, 1 and 2; the preferred equivalent is 0.5.

[0026] (5) The reaction is carried out according to the above model, and the selected reaction temperature is any one of 30℃, 40℃, 50℃, 60℃, 70℃ and 80℃; the preferred temperature is 70℃.

[0027] This paper describes the application of carbamate compounds synthesized from 3-substituted dioxazolone in pesticides, specifically in the field of agricultural insecticides. Given the excellent acetylcholinesterase activity of these compounds, they can provide a new source of compounds and application strategies for developing novel, highly effective, and low-toxicity agricultural insecticides.

[0028] The beneficial effects of this invention are: (1) This invention provides a novel and high-performance carbamate molecule, effectively overcoming the core defects of low synthesis efficiency and easy generation of symmetrical urea byproducts in the traditional phosgene synthesis of this type of compound. Furthermore, acetylcholinesterase activity evaluation confirms its good inhibitory effect on key targets of the insect nervous system. Simultaneously, by controlling the types of R (aromatic / heteroaryl and their substituents) and R1 (straight-chain / branched alkyl, cycloalkyl, aromatic / heteroaryl and their substituents), a series of compounds can be flexibly synthesized, with controllable structural diversity, adaptable to the performance requirements of different scenarios. The carbamate molecules provided by this invention exhibit good cholinesterase activity in activity screening and can be used in insecticides or pesticides, showing broad prospects for industrialization.

[0029] (2) The present invention adopts a synthetic route with 3-substituted dioxazolone as the key intermediate. The intermediate is prepared by hydroxamic acid and triphosgene under mild conditions. The reaction has high selectivity and reduces side reactions from the source. At the same time, it provides two processes: two-step method and one-pot method. The two-step method can obtain high-purity products through step-by-step purification and is suitable for purity-sensitive scenarios. The one-pot method integrates intermediate preparation with phenol / alcohol coupling reaction, eliminating the need to separate intermediates, greatly simplifying the operation process and shortening the reaction cycle. Detailed Implementation

[0030] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below.

[0031] In some embodiments, a method for synthesizing carbamate compounds based on 3-substituted dioxazolones has the following general structural formula:

[0032] R is selected from aryl or substituted aryl; R1 is selected from straight-chain alkyl, branched alkyl, cycloalkyl, substituted cycloalkyl, aryl (hetero)yl or substituted aryl (hetero)yl.

[0033] R is selected from aryl (hetero) groups or their substituents (such as α-naphthyl, 2,2-dimethylbenzofuranyl). Their aromatic ring structure can bind to the hydrophobic active cavity of acetylcholinesterase through hydrophobic interactions, enhancing the affinity between the molecule and the target enzyme. Substituents (such as methyl, isopropoxy) can regulate molecular polarity and optimize permeability across the insect epidermis. R1 is selected from straight-chain / branched alkyl groups, cycloalkyl groups, etc., whose steric hindrance can regulate the relationship between the molecule and the enzyme's active site (e.g., the rigid structures of cyclopentyl and cyclohexyl groups can complement the spatial conformation of the enzyme). Simultaneously, the alkyl group can stabilize the carbamate bond, preventing premature hydrolysis and inactivation.

[0034] In some embodiments, a method for preparing carbamate compounds based on 3-substituted dioxazolone includes the following steps: (1) Hydroxyxamic acids with different substituents were reacted with phosgene under ice bath conditions to prepare 3-substituted dioxazolone; (2) The 3-substituted dioxazolone obtained in (1) was reacted with different phenols (alcohols) under alkaline conditions to obtain the corresponding carbamate compounds.

[0035] Step (1) uses ice bath conditions: the cyclization reaction of phosgene and hydroxamic acid is an exothermic reaction, and low temperature can suppress the side reactions caused by excess phosgene; Step (2) uses alkaline conditions: The hydroxyl group (-OH) of phenol (alcohol) is weakly acidic. An alkaline environment can cause it to dissociate into a phenol oxide anion, which enhances nucleophilicity and thus allows it to undergo a ring-opening reaction with the carbonyl group of dioxazolone, avoiding the decomposition of dioxazolone under acidic conditions.

[0036] In some embodiments, the preparation method includes, but is not limited to, the following steps: (1) Triethylamine was added dropwise to the reaction solvent of hydroxamic acid and triphosgene in an ice bath at 0°C and stirred. The reaction solution was extracted and washed with dilute hydrochloric acid and saturated sodium chloride aqueous solution. The organic phase was dried with anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain pure 3-substituted dioxazolone (3-phenyldioxazolone can be further recrystallized from petroleum ether / ethyl acetate to obtain pure 3-phenyldioxazolone solid).

[0037] Triethylamine acts as an acid-binding agent, neutralizing the HCl generated in the reaction and preventing HCl from catalyzing the ring-opening of dioxazolone; washing with dilute hydrochloric acid can remove excess triethylamine, saturated sodium chloride solution can reduce the moisture in the organic phase, and drying with anhydrous sodium sulfate can further remove water (to prevent hydrolysis of dioxazolone); 3-phenyldioxazolone has good crystallinity of aromatic ring, and recrystallization can improve its purity.

[0038] (2) Mix different phenols (alcohols) with 3-substituted dioxazolones and react them with catalyst base and solvent at a certain temperature for 1-12 h. After the reaction is completed, extract the reaction solution with ethyl acetate and wash it with dilute hydrochloric acid and saturated sodium chloride aqueous solution. After drying and filtering with anhydrous sodium sulfate, concentrate the solvent under reduced pressure and purify the sample by column chromatography (mobile phase petroleum ether: ethyl acetate). The product is obtained by recrystallization of petroleum ether: ethyl acetate and filtration.

[0039] Reaction time 1-12 h: Adjusted according to the reactivity of phenol (alcohol) (2,2-dimethylbenzofuran phenol can be completed in 2-3 h due to the activation of the benzofuran ring; α-naphthol requires 8-12 h due to greater steric hindrance) to ensure full conversion of the raw materials. Column chromatography mobile phase (petroleum ether: ethyl acetate) separates the product from the unreacted raw materials through a polar gradient, and recrystallization further removes trace impurities.

[0040] In some embodiments, the hydroxamic acid in (1) includes any one of acetoxyxamic acid, cyclopropylhydroxamic acid, cyclobutylhydroxamic acid, cyclopentylhydroxamic acid, cyclohexylhydroxamic acid, and benzohydroxamic acid.

[0041] When R1 is alkyl or aryl, it has high reactivity with phosgene in cyclization (the distance between the carboxyl and hydroxylamine groups is suitable for forming a five-membered ring); the ring structure of cycloalkyl hydroxamic acid (cyclopentyl) can enhance the stability of the generated dioxazolone (steric hindrance inhibits ring opening), and the aromatic ring of benzohydroxamic acid stabilizes the intermediate through conjugation.

[0042] In some embodiments, the 3-substituted dioxazolone in (2) includes any one of 3-methyl dioxazolone, 3-cyclopropyl dioxazolone, 3-cyclobutyl dioxazolone, 3-cyclopentyl dioxazolone, 3-cyclohexyl dioxazolone, and 3-phenyl dioxazolone.

[0043] The methyl group of 3-methyldioxazolone is small in size and has high reactivity with phenols (due to low steric hindrance); cycloalkyl-substituted dioxazolones (3-cyclopentyl) have a more selective reaction with phenols due to their rigid ring structure; the aromatic ring of 3-phenyldioxazolone can form π-π stacking with the aryl group of phenol, which accelerates the reaction process.

[0044] In some embodiments, the phenol (alcohol) in (2) includes any one of m-methylphenol, 2-sec-butylphenol, 2-isopropoxyphenol, α-naphthol, and 2,2-dihydro-2,2-dimethyl-7-hydroxybenzofuran. The methyl group of m-methylphenol is an electron-donating group, which enhances the activity of the phenolic hydroxyl group.

[0045] In some embodiments, (1) and (2) can be combined into one step, specifically including: dissolving and mixing hydroxamic acid, triphosgene and acetonitrile, stirring and adding triethylamine at 0°C, transferring the reaction system to a pot at 60-70°C after 30-40 min, adding phenol and potassium carbonate and reacting for 20-30 min, and obtaining the corresponding carbamate compound after purification.

[0046] Acetonitrile has good solubility for hydroxamic acid, triphosgene, and phenol, enabling homogeneous preparation of intermediates and coupling reactions; the addition of triethylamine at 0°C ensures stable formation of dioxazolone and avoids intermediate decomposition caused by high temperature.

[0047] In some embodiments, using 2,2-dihydro-2,2-dimethyl-7-hydroxybenzofuran and 3-cyclopentyldioxazolone as a model reaction, the key conditions were optimized as follows: (1) The preferred solvent is acetonitrile (alternatives: dichloromethane, ethyl acetate, etc.).

[0048] Acetone has a low boiling point (56℃), and the reaction will boil violently at 70℃, leading to system instability. Acetonitrile has a boiling point of 78℃, which matches the optimized temperature of 70℃, and its polarity is moderate, which can simultaneously dissolve ionic intermediates and neutral raw materials, thus accelerating the reaction rate.

[0049] (2) The preferred catalyst base is cesium carbonate (alternatives: potassium acetate, triethylamine, etc.).

[0050] Cesium carbonate is more basic than potassium carbonate and can efficiently activate phenolic hydroxyl groups; and C The ionic radius is large and the solvation effect is weak, so it will not over-stabilize the phenol oxide anion, while strong bases such as NaOH can easily lead to phenol oxidation side reactions.

[0051] (3) 3-Cyclopentyldioxazolone is preferably equivalent to 4 (alternatives: 1-3).

[0052] The reaction is a reversible equilibrium, and increasing the dioxazolone equivalent can shift the equilibrium to the right. When the equivalent is 4, the conversion rate of the raw material reaches more than 95%. When the equivalent is further increased to 5, the conversion rate does not improve significantly, but the cost increases significantly.

[0053] (4) The catalyst base is preferably 0.5 equivalent (alternative: 0.1-2).

[0054] When the base equivalent is <0.5, the phenol is not sufficiently activated; when the equivalent is >0.5, excess base will catalyze the decomposition of dioxazolone into isocyanate; a base equivalent of 0.5 can ensure that more than 90% of the phenol is activated, while avoiding side reactions.

[0055] (5) The preferred reaction temperature is 70℃ (alternative: 30-80℃).

[0056] At temperatures below 70°C, the reaction rate is slow; at temperatures above 70°C, the thermal stability of dioxazolone decreases, leading to an increase in byproducts.

[0057] In some embodiments, the application of a carbamate compound synthesized based on 3-substituted dioxazolone in pesticides, specifically in the field of agricultural insecticides.

[0058] Acetylcholinesterase is a key enzyme in insect nerve conduction. The compound of this invention can covalently bind to the Ser residue of the enzyme through a carbamate bond, irreversibly inhibiting the enzyme activity, leading to the accumulation of neurotransmitters, paralysis and death in insects.

[0059] The specific embodiments of the present invention will be described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments.

[0060] Example 1

[0061] Preparation of 3-methyl-1,4,2-dioxazol-5-one (1a):

[0062] The procedure is as follows: A solution of acetyloxyoxime acid (I, 750 mg, 10.0 mmol) and triphosgene (1.2 g, 4.0 mmol) in dichloromethane (30 ml) was added to a reaction flask. The mixture was cooled to 0 °C, and triethylamine (1.5 ml) was added dropwise. The reaction was continued with stirring for 30 min. The mixture was washed with dilute hydrochloric acid (50 ml, 1N) and saturated sodium chloride aqueous solution (2 × 40 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product 3-methyl-1,4,2-dioxazol-5-one (1a).

[0063] Preparation of methyl m-methylbenzocarbamate (A1):

[0064] In a reaction flask, m-methylphenol (A, 216 mg, 2.0 mmol), 3-methyl-1,4,2-dioxazol-5-one (1a, 404 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added, and the mixture was heated and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, extracted with ethyl acetate (30 ml), and the organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1), recrystallized from petroleum ether: ethyl acetate (20:1), and filtered to obtain the product methyl m-methylbenzocarbamate (A1).

[0065] Structural data representation: m-tolyl methylcarbamate (A1). White solid. 238 mg, 72 %yield. 1 H NMR (500 MHz, CDCl3) δ 7.23 (dd, J = 15.2, 7.4 Hz, 1H), 7.00 (d, J =7.6 Hz, 1H), 6.97 – 6.86 (m, 2H), 5.02 (s, 1H), 2.86 (d, J = 4.9 Hz, 3H), 2.34 (s, 3H).

[0066] Example 2

[0067] Preparation of 3-cyclopropyl-1,4,2-dioxazol-5-one (2a):

[0068] The steps are as follows: Add to the reaction flask N A solution of 3-hydroxycyclopropaneformamide (II, 1.01 g, 10.0 mmol) and triphosgene (1.2 g, 4.0 mmol) in dichloromethane (30 ml) was cooled to 0 °C, and triethylamine (1.5 ml) was added dropwise. The reaction was continued with stirring for 30 min. The mixture was washed with dilute hydrochloric acid (50 ml, 1N) and saturated sodium chloride aqueous solution (2 × 40 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product 3-cyclopropyl-1,4,2-dioxazol-5-one (2a).

[0069] Preparation of m-methylphenylcarbamate cyclopropylcarbamate (A2):

[0070] In a reaction flask, m-methylphenol (A, 216 mg, 2.0 mmol), 3-cyclopropyl-1,4,2-dioxazol-5-one (2a, 508 mg, 4.0 mmol), cesium acid (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added, and the mixture was stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, washed with ethyl acetate (30 ml) and saturated sodium chloride aqueous solution (2 × 40 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1). The residue was then recrystallized from petroleum ether: ethyl acetate (20:1) to give the product m-methylphenylcarbamate cyclopropylcarbamate (A2).

[0071] Structural data representation: m-tolyl cyclopropylcarbamate (A2). White solid. 288 mg,75 % yield. 1 H NMR (500 MHz, CDCl3) δ 7.23 (dd, J = 15.9, 8.4 Hz, 1H), 7.05 –6.86 (m, 3H), 5.26 (s, 1H), 2.67 (s, 1H), 2.34 (s, 3H), 0.76 (q, J = 6.8 Hz, 2H), 0.67 – 0.55 (m, 2H).

[0072] Example 3

[0073] Preparation of 3-cyclobutyl-1,4,2-dioxazol-5-one (3a):

[0074] The steps are as follows: Add to the reaction flask N A solution of 3-hydroxycyclobutaneformamide (III, 1.15 g, 10.0 mmol) and triphosgene (1.2 g, 4.0 mmol) in dichloromethane (30 ml) was cooled to 0 °C, and triethylamine (1.5 ml) was added dropwise. The reaction was continued with stirring for 30 min. The mixture was washed with dilute hydrochloric acid (50 ml, 1N) and saturated sodium chloride aqueous solution (2 × 40 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product 3-cyclobutyl-1,4,2-dioxazol-5-one (3a).

[0075] Preparation of m-methylphenylcarbamate cyclobutylcarbamate (A3):

[0076] In a reaction flask, m-methylphenol (A, 216 mg, 2.0 mmol), 3-cyclobutyl-1,4,2-dioxazol-5-one (3a, 564 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added, and the mixture was stirred in an oil bath at 70 °C for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 40 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1). The residue was then recrystallized from petroleum ether: ethyl acetate (20:1) to give the product m-methylphenylcarbamate cyclobutylcarbamate (A3).

[0077] Structural data representation: m-tolyl cyclobutylcarbamate (A3). White solid. 284 mg, 69% yield. 1 H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 7.8 Hz, 1H), 7.00 (d, J =7.7 Hz, 1H), 6.94 (s, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.26 (d, J = 8.3 Hz, 1H), 4.22 (h, J = 8.3 Hz, 1H), 2.42 – 2.35 (m, 2H), 2.35 – 2.32 (m, 3H), 1.98– 1.87 (m, 2H), 1.70 (dd, J = 11.0, 6.6 Hz, 2H).

[0078] Example 4

[0079] Preparation of 3-cyclopentyl-1,4,2-dioxazol-5-one (4a):

[0080] The steps are as follows: Add to the reaction flask NA solution of 3-hydroxycyclopentaneformamide (IV, 1.29 g, 10.0 mmol) and triphosgene (1.2 g, 4.0 mmol) in dichloromethane (30 ml) was cooled to 0 °C, and triethylamine (1.5 ml) was added dropwise. The reaction was continued with stirring for 30 min. The mixture was washed with dilute hydrochloric acid (50 ml, 1N) and saturated sodium chloride aqueous solution (2 × 40 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product 3-cyclopentyl-1,4,2-dioxazol-5-one (4a).

[0081] Preparation of cyclopentyl carbamate m-methylphenylcarbamate (A4):

[0082] In a reaction flask, m-methylphenol (A, 216 mg, 2.0 mmol), 3-cyclopentyl-1,4,2-dioxazol-5-one (4a, 620 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added, and the mixture was stirred in an oil bath at 70 °C for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 40 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1). The residue was then recrystallized from petroleum ether: ethyl acetate (20:1) to give the product m-methylphenylcarbamate cyclopentylcarbamate (A4).

[0083] Structural data representation: m-tolyl cyclopentylcarbamate (A4). White solid, 340 mg, 78% yield. 1 H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 7.8 Hz, 1H), 7.00 (d, J =7.8 Hz, 1H), 6.95 (s, 1H), 6.92 (d, J = 8.3 Hz, 1H), 5.01 (d, J = 7.5 Hz, 1H), 4.05 (h, J = 7.2 Hz, 1H), 2.35 (s, 3H), 2.01 (dq, J = 12.5, 6.4 Hz, 2H),1.81 – 1.68 (m, 2H), 1.67 (d, J = 7.7 Hz, 1H), 1.61 (td,J = 7.5, 3.9 Hz, 2H), 1.48 (dq, J = 13.3, 6.6 Hz, 2H).

[0084] Example 5

[0085] Preparation of 3-cyclohexyl-1,4,2-dioxazol-5-one (5a):

[0086] The steps are as follows: Add to the reaction flask N A solution of 3-hydroxycyclohexaneformamide (V, 1.43 g, 10.0 mmol) and triphosgene (1.2 g, 4.0 mmol) in dichloromethane (30 ml) was cooled to 0 °C, and triethylamine (1.5 ml) was added dropwise. The reaction was continued with stirring for 30 min. The mixture was washed with dilute hydrochloric acid (50 ml, 1N) and saturated sodium chloride aqueous solution (2 × 40 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product 3-cyclohexyl-1,4,2-dioxazol-5-one (5a).

[0087] Preparation of m-methylphenylcarbamate cyclohexylcarbamate (A5):

[0088] In a reaction flask, m-methylphenol (A, 216 mg, 2.0 mmol), 3-cyclohexyl-1,4,2-dioxazol-5-one (5a, 1.02 g, 6.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added, and the mixture was stirred in an oil bath at 70 °C for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 40 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The residue was then recrystallized from petroleum ether: ethyl acetate (30:1) to give the product m-methylphenylcarbamate cyclohexylcarbamate (A5).

[0089] Structural data representation: m-tolyl cyclohexylcarbamate (A5). White solid. 372 mg,80% yield. 1 H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 7.8 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 6.95 (s, 1H), 6.92 (d, J = 7.8 Hz, 1H), 5.21 – 4.81 (m, 1H), 3.62 – 3.50 (m, 1H), 2.35 (s, 3H), 2.00 (dd, J = 12.4, 4.3 Hz, 2H), 1.80 –1.71 (m, 2H), 1.71 – 1.45 (m, 2H), 1.42 – 1.31 (m, 2H), 1.25 – 1.17 (m, 3H).

[0090] Example 6

[0091] Preparation of 3-phenyl-1,4,2-dioxazol-5-one (6a):

[0092] The steps are as follows: Add to the reaction flask N A solution of 3-hydroxybenzamide (VI, 1.37 g, 10.0 mmol) and triphosgene (1.2 g, 4.0 mmol) in dichloromethane (30 ml) was cooled to 0 °C, and triethylamine (1.5 ml) was added dropwise. The reaction was continued with stirring for 30 min. The mixture was washed with dilute hydrochloric acid (50 ml, 1N) and saturated sodium chloride aqueous solution (2 × 40 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product 3-phenyl-1,4,2-dioxazol-5-one (6a).

[0093] Preparation of m-methylphenylcarbamate (A6):

[0094] In a reaction flask, m-methylphenol (A, 216 mg, 2.0 mmol), 3-phenyl-1,4,2-dioxazol-5-one (6a, 0.98 g, 6.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added, and the mixture was stirred in an oil bath at 70 °C for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give m-methylphenylcarbamate (A6).

[0095] Structural data representation: m-tolyl phenylcarbamate (A6). White solid. 295 mg, 65%yield. 1 H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 7.8 Hz, 2H), 7.35 – 7.28 (m,2H), 7.28 – 7.22 (m, 1H), 7.09 (t, J = 7.4 Hz, 1H), 7.06 – 6.94 (m, 4H), 2.35(s, 3H).

[0096] Example 7

[0097] Preparation of 2-(sec-butyl)phenyl methyl carbamate (B1):

[0098] 2-sec-butylphenol (B, 300 mg, 2.0 mmol), 3-methyl-1,4,2-dioxazol-5-one (1a, 404 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give the product 2-(sec-butyl)phenylmethylcarbamate (B1).

[0099] Structural data representation: 2-(sec-butyl)phenyl methylcarbamate (B1). Colorless oil.364 mg, 88% yield. 1 H NMR (400 MHz, CDCl3) δ 7.24 (dd, J = 5.8, 3.6 Hz, 1H),7.19 (t, J = 3.7 Hz, 1H), 7.17 (t, J = 3.7 Hz, 1H), 7.06 (d, J = 9.4 Hz, 1H), 5.00 (m, 1H), 2.90 (d, J = 4.9 Hz, 3H), 2.89 – 2.82 (m, 1H), 1.62 – 1.53 (m,2H), 1.20 (d, J = 6.9 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).

[0100] Example 8

[0101] Preparation of 2-(sec-butyl)phenylcyclopropylcarbamate (B2):

[0102] 2-sec-butylphenol (B, 300 mg, 2.0 mmol), 3-cyclopropyl-1,4,2-dioxazol-5-one (2a, 508 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product 2-(sec-butyl)phenylcyclopropylcarbamate (B2) was then recrystallized from petroleum ether: ethyl acetate (30:1).

[0103] Structural data representation: 2-(sec-butyl)phenyl cyclopropylcarbamate (B2). Whitesolid. 414mg, 89% yield. 1 H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 6.7 Hz, 1H),7.19 (s, 1H), 7.17 (s, 1H), 7.07 (s, 1H), 5.18 (d, J = 77.0 Hz, 1H), 2.94 –2.79 (m, 1H), 2.70 (s, 1H), 1.66 – 1.47 (m, 2H), 1.20 (d, J = 7.0 Hz, 3H), 0.83 (t, J = 7.6 Hz, 3H), 0.78 (dt, J = 6.9, 3.3 Hz, 2H), 0.63 (d, J = 7.6Hz, 2H).

[0104] Example 9

[0105] Preparation of 2-(sec-butyl)phenylcyclobutylcarbamate (B3):

[0106] 2-sec-butylphenol (B, 300 mg, 2.0 mmol), 3-cyclobutyl-1,4,2-dioxazol-5-one (3a, 564 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 2-(sec-butyl)phenylcyclobutylcarbamate (B3).

[0107] Structural data representation: 2-(sec-butyl)phenyl cyclobutylcarbamate (B3). Whitesolid. 386mg, 83% yield. 1 H NMR (400 MHz, CDCl3) δ 7.24 (t, J = 4.7 Hz, 1H),7.18 (s, 1H), 7.18 – 7.13 (m, 1H), 7.11 – 6.96 (m, 1H), 5.22 (d, J = 8.4 Hz, 1H), 4.23 (h, J = 8.2 Hz, 1H), 2.86 (h, J = 7.0 Hz, 1H), 2.44 – 2.33 (m, 2H), 1.94 (dt, J = 20.5, 9.8 Hz, 2H), 1.70 (q, J = 9.4 Hz, 2H), 1.58 (dq, J =16.4, 6.9 Hz, 2H), 1.20 (d, J = 6.9 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H).

[0108] Example 10

[0109] Preparation of 2-(sec-butyl)phenylcyclopentylcarbamate (B4):

[0110] 2-sec-butylphenol (B, 300 mg, 2.0 mmol), 3-cyclopentyl-1,4,2-dioxazol-5-one (4a, 620 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 2-(sec-butyl)phenylcyclopentylcarbamate (B4).

[0111] Structural data representation: 2-(sec-butyl)phenyl cyclopentylcarbamate (B4). Whitesolid. 480mg, 92% yield. 1 H NMR (400 MHz, CDCl3) δ 7.27 – 7.22 (m, 1H), 7.19(d, J = 4.3 Hz, 1H), 7.17 (d, J = 5.1 Hz, 1H), 7.09 – 7.04 (m, 1H), 5.02 (d, J = 7.7 Hz, 1H), 4.06 (h, J = 6.9 Hz, 1H), 2.86 (h, J = 7.1 Hz, 1H), 2.02(dq, J = 12.8, 6.5 Hz, 2H), 1.75 – 1.68 (m, 2H), 1.62 (dd, J = 10.3, 4.9 Hz, 2H), 1.56 (q, J = 6.3 Hz, 2H), 1.49 (dt, J = 12.6, 6.2 Hz, 2H), 1.20 (d, J =7.0 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).

[0112] Example 11

[0113] Preparation of 2-(sec-butyl)phenylcyclohexylcarbamate (B5):

[0114] 2-sec-butylphenol (B, 300 mg, 2.0 mmol), 3-cyclohexyl-1,4,2-dioxazol-5-one (5a, 1.02 g, 6.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1). The product 2-(sec-butyl)phenylcyclohexylcarbamate (B5) was then recrystallized from petroleum ether: ethyl acetate (20:1).

[0115] Structural data representation: 2-(sec-butyl)phenyl cyclohexylcarbamate (B5). Whitesolid. 471mg, 86% yield. 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.26 (m, 1H), 7.22 (s, 1H), 7.21 – 7.17 (m, 1H), 7.12 – 7.07 (m, 1H), 5.02 (d, J = 8.2 Hz, 1H), 3.60 (td, J = 13.5, 8.1 Hz, 1H), 2.90 (h, J = 7.0 Hz, 1H), 2.04 (dd, J =12.4, 4.3 Hz, 2H), 1.81 – 1.73 (m, 2H), 1.72 – 1.63 (m, 2H), 1.58 (dt, J =13.7, 6.9 Hz, 2H), 1.38 (t, J = 12.5 Hz, 2H), 1.33 – 1.25 (m, 2H), 1.25 –1.22 (m, 3H), 0.87 (t, J = 7.5 Hz, 3H).

[0116] Example 12

[0117] Preparation of 2-(sec-butyl)phenylphenylcarbamate (B6):

[0118] 2-sec-butylphenol (B, 300 mg, 2.0 mmol), 3-phenyl-1,4,2-dioxazol-5-one (6a, 0.98 g, 6.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product, 2-(sec-butyl)phenylcarbamate (B6), was then recrystallized from petroleum ether: ethyl acetate (30:1) to give the product 2-(sec-butyl)phenylcarbamate (B6).

[0119] Structural data representation: 2-(sec-butyl)phenyl phenylcarbamate (B6). White solid.436mg, 82% yield. 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.0 Hz, 2H), 7.38 –7.31 (m, 2H), 7.32 – 7.27 (m, 1H), 7.26 – 7.19 (m, 2H), 7.18 – 7.11 (m, 2H), 2.93 (h, J = 7.1 Hz, 1H), 1.61 (ddt, J = 16.8, 9.4, 4.2 Hz, 2H), 1.23 (d, J =6.9 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H).

[0120] Example 13

[0121] Preparation of 2-isopropoxyphenyl methyl carbamate (C1):

[0122] 2-Isopropoxyphenol (C, 304 mg, 2.0 mmol), 3-methyl-1,4,2-dioxazol-5-one (1a, 404 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give the product 2-isopropoxyphenyl methyl carbamate (C1).

[0123] Structural data representation: 2-isopropoxyphenyl methylcarbamate (C1). White solid.322 mg, 77% yield. 1 H NMR (400 MHz, CDCl3) δ 7.16 – 7.11 (m, 1H), 7.08 (dd, J = 8.0, 1.7 Hz, 1H), 6.96 (dd, J = 8.2, 1.5 Hz, 1H), 6.91 (td, J = 7.7, 1.5Hz, 1H), 5.05 (s, 1H), 4.51 (hept, J = 6.1 Hz, 1H), 2.88 (d, J = 4.9 Hz, 3H), 1.33 (d, J = 6.0 Hz, 6H).

[0124] Example 14

[0125] Preparation of 2-isopropoxyphenylcyclopropylcarbamate (C2):

[0126] 2-Isopropoxyphenol (C, 304 mg, 2.0 mmol), 3-cyclopropyl-1,4,2-dioxazol-5-one (2a, 508 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product, 2-isopropoxyphenylcyclopropylcarbamate (C2), was then recrystallized from petroleum ether: ethyl acetate (30:1) to give the product 2-isopropoxyphenylcyclopropylcarbamate (C2).

[0127] Structural data representation: 2-isopropoxyphenyl cyclopropylcarbamate (C2). Whitesolid. 383mg, 81% yield. 1 H NMR (500 MHz, CDCl3) δ 7.17 – 7.11 (m, 1H), 7.08(d, J = 8.3 Hz, 1H), 6.95 (dd, J = 8.2, 1.4 Hz, 1H), 6.90 (t, J = 7.7 Hz, 1H), 5.31 (d, J = 19.9 Hz, 1H), 4.51 (p, J = 4.9 Hz, 1H), 2.68 (s, 1H), 1.33(d, J = 6.1 Hz, 6H), 0.80 – 0.73 (m, 2H), 0.66 (dd, J = 54.1, 5.2 Hz, 2H).

[0128] Example 15

[0129] Preparation of 2-isopropoxyphenylcyclobutylcarbamate (C3):

[0130] 2-Isopropoxyphenol (C, 304 mg, 2.0 mmol), 3-cyclobutyl-1,4,2-dioxazol-5-one (3a, 564 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 2-isopropoxyphenylcyclobutylcarbamate (C3).

[0131] Structural data representation: 2-isopropoxyphenyl cyclobutylcarbamate (C3). Whitesolid. 368mg, 74% yield. 1 H NMR (500 MHz, CDCl3) δ 7.15 – 7.10 (m, 1H), 7.08(d, J = 7.9 Hz, 1H), 6.95 (dd, J = 8.2, 1.5 Hz, 1H), 6.94 – 6.87 (m, 1H), 5.26 (d, J = 8.0 Hz, 1H), 4.50 (hept, J = 6.1 Hz, 1H), 4.21 (h, J = 8.3 Hz, 1H), 2.36 (q, J = 7.7 Hz, 2H), 1.99 – 1.88 (m, 2H), 1.75 – 1.65 (m, 2H), 1.32(d, J = 6.1 Hz, 6H).

[0132] Example 16

[0133] Preparation of 2-isopropoxyphenylcyclopentylcarbamate (C4):

[0134] 2-Isopropoxyphenol (C, 304 mg, 2.0 mmol), 3-cyclopentyl-1,4,2-dioxazol-5-one (4a, 620 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 2-isopropoxyphenylcyclopentylcarbamate (C4).

[0135] Structural data representation: 2-isopropoxyphenyl cyclopentylcarbamate (C4). Whitesolid. 447mg, 85% yield. 1 H NMR (600 MHz, CDCl3) δ 7.17 – 7.04 (m, 1H), 6.99– 6.93 (m, 1H), 6.90 (t, J = 7.7 Hz, 1H), 4.51 (p, J = 6.0 Hz, 1H), 2.00 (dt, J = 12.5, 6.2 Hz, 1H), 1.76 – 1.44 (m, 3H), 1.33 (d, J = 6.1 Hz, 3H).

[0136] Example 17

[0137] Preparation of 2-isopropoxyphenylcyclohexylcarbamate (C5):

[0138] 2-Isopropoxyphenol (C, 304 mg, 2.0 mmol), 3-cyclohexyl-1,4,2-dioxazol-5-one (5a, 1.02 g, 6.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1). The product, 2-isopropoxyphenylcyclohexylcarbamate (C5), was then recrystallized from petroleum ether: ethyl acetate (20:1) to give the product 2-isopropoxyphenylcyclohexylcarbamate (C5).

[0139] Structural data representation: 2-isopropoxyphenyl cyclohexylcarbamate (C5). Whitesolid. 428mg, 77% yield. 1 H NMR (600 MHz, CDCl3) δ 7.18 – 7.04 (m, 1H), 6.98 – 6.86 (m, 1H), 4.51 (p, J = 6.0 Hz, 1H), 2.00 (d, J = 9.9 Hz, 1H), 1.77 –1.67 (m, 1H), 1.61 (dt, J = 12.5, 3.6 Hz, 1H), 1.47 – 1.29 (m, 4H), 1.26 –1.10 (m, 2H).

[0140] Example 18

[0141] Preparation of 2-isopropoxyphenylcarbamate (C6):

[0142] 2-Isopropoxyphenol (C, 304 mg, 2.0 mmol), 3-phenyl-1,4,2-dioxazol-5-one (6a, 0.98 g, 6.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product, 2-isopropoxyphenylcarbamate (C6), was then recrystallized from petroleum ether: ethyl acetate (30:1) to give the product 2-isopropoxyphenylcarbamate (C6).

[0143] Structural data representation: 2-isopropoxyphenyl phenylcarbamate (C6). White solid.384mg, 71% yield. 1 H NMR (500 MHz, CDCl3) δ 7.52 – 7.46 (m, 1H), 7.45 (s, 1H),7.34 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H),7.18 – 7.15 (m, 1H), 7.12 – 7.08 (m, 1H), 7.00 (d, J = 6.8 Hz, 1H), 6.95 (t, J = 7.7 Hz, 1H), 4.56 (hept, J = 6.1 Hz, 1H), 1.33 (d, J = 6.0 Hz, 6H).

[0144] Example 19

[0145] 1-Naphthyl- N Preparation of 2-methylcarbamate (D1):

[0146] 1-Naphthol (D, 288 mg, 2.0 mmol), 3-methyl-1,4,2-dioxazol-5-one (1a, 404 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction mixture was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give the product 1-naphthyl- N -Methylcarbamate (D1).

[0147] Structural data representation: naphthalen-1-yl methylcarbamate (D1). White solid.307mg, 76% yield. 1 H NMR (400 MHz, CDCl3) δ 7.98 – 7.93 (m, 1H), 7.89 – 7.84 (m, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 5.5 Hz, 1H), 7.50 (d, J = 4.9Hz, 1H), 7.48 – 7.44 (m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 5.21 (s, 1H), 2.95(d, J = 4.9 Hz, 3H).

[0148] Example 20

[0149] 1-Naphthyl- N Preparation of cyclopropyl carbamate (D2):

[0150] 1-Naphthol (D, 288 mg, 2.0 mmol), 3-cyclopropyl-1,4,2-dioxazol-5-one (2a, 508 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction mixture was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The purified product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 1-naphthyl- N -Cyclopropylcarbamate (D2).

[0151] Structural data representation: naphthalen-1-yl cyclopropylcarbamate (D2). White solid.381mg, 84% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 8.26 (d, J = 3.3 Hz, 1H), 8.02 –7.95 (m, 1H), 7.92 – 7.86 (m, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 2.5Hz, 1H), 7.57 – 7.53 (m, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 2.63 (tq, J = 7.2, 3.6 Hz, 1H), 0.67 (dt, J = 6.8, 3.3 Hz, 2H), 0.57(dd, J = 5.1, 2.4 Hz, 2H).

[0152] Example 21

[0153] 1-Naphthyl- N Preparation of cyclobutylcarbamate (D3):

[0154] 1-Naphthol (D, 288 mg, 2.0 mmol), 3-cyclobutyl-1,4,2-dioxazol-5-one (3a, 564 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction mixture was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The purified product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 1-naphthyl- N - Cyclobutylcarbamate (D3).

[0155] Structural data representation: naphthalen-1-yl cyclobutylcarbamate (D3). White solid.379mg, 79% yield. 1 H NMR (500 MHz, DMSO- d 6) δ 8.36 (d, J = 8.0 Hz, 1H), 7.99 –7.96 (m, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.60 – 7.57(m, 1H), 7.57 – 7.54 (m, 1H), 7.52 – 7.47 (m, 1H), 7.29 (d, J = 7.5 Hz, 1H), 4.06 (h, J = 8.0 Hz, 1H), 2.28 – 2.19 (m, 2H), 2.09 – 1.99 (m, 2H), 1.64 (dd, J = 24.9, 10.0 Hz, 2H).

[0156] Example 22

[0157] 1-Naphthyl- N Preparation of cyclopentyl carbamate (D4):

[0158] 1-Naphthol (D, 288 mg, 2.0 mmol), 3-cyclopentyl-1,4,2-dioxazol-5-one (4a, 620 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction mixture was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The purified product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 1-naphthyl- N - Cyclobutylcarbamate (D4).

[0159] Structural data representation: naphthalen-1-yl cyclopentylcarbamate (D4). White solid.448mg, 88% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 8.07 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.61– 7.53 (m, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 3.89 (h, J = 7.2 Hz, 1H), 1.87 (dd, J = 9.2, 5.4 Hz, 2H), 1.70 (d, J = 7.7 Hz, 2H),1.61 – 1.48 (m, 4H).

[0160] Example 23

[0161] 1-Naphthyl- N Preparation of cyclohexyl carbamate (D5):

[0162] 1-Naphthol (D, 288 mg, 2.0 mmol), 3-cyclohexyl-1,4,2-dioxazol-5-one (5a, 1.02 g, 6.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction mixture was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1). The purified product was then recrystallized from petroleum ether: ethyl acetate (20:1) to give 1-naphthyl- N -Cyclopentylcarbamate (D5).

[0163] Structural data representation: naphthalen-1-yl cyclohexylcarbamate (D5). White solid.441mg, 82% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.97 (dd, J = 6.3, 3.1 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.59 – 7.53 (m, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 7.5, 0.8 Hz, 1H), 3.35 (d, J = 7.7 Hz, 1H), 1.89 (d, J = 8.1 Hz,1H), 1.80 – 1.67 (m, 1H), 1.39 – 1.07 (m, 3H).

[0164] Example 24

[0165] 1-Naphthyl- N Preparation of phenylcarbamate (D6):

[0166] 1-Naphthol (D, 288 mg, 2.0 mmol), 3-phenyl-1,4,2-dioxazol-5-one (6a, 0.98 g, 6.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction mixture was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The purified product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 1-naphthyl- N -Phenylacetyl carbamate (D6).

[0167] Structural data representation: naphthalen-1-yl phenylcarbamate (D6). White solid.396mg, 75% yield. 1 H NMR (400 MHz, CDCl3) δ 10.13 (d, J = 1.6 Hz, 1H), 8.67(s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.8Hz, 1H), 7.49 – 7.46 (m, 1H), 7.46 – 7.44 (m, 1H), 7.43 (d, J = 1.6 Hz, 1H),7.33 – 7.31 (m, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 6.97(t, J = 7.4 Hz, 1H), 6.88 (d, J = 7.0 Hz, 1H).

[0168] Example 25

[0169] Preparation of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylmethylcarbamate (E1):

[0170] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 328 mg, 2.0 mmol), 3-methyl-1,4,2-dioxazol-5-one (1a, 404 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) to give the product 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylmethylcarbamate (E1).

[0171] Structural data representation: 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl methylcarbamate (E1). White solid. 358 mg, 81% yield. 1 H NMR (400 MHz, CDCl3) δ 6.97 (dd, J =7.3, 1.2 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.82 – 6.74 (m, 1H), 5.03 (s,1H), 3.03 (d, J = 1.0 Hz, 2H), 2.88 (d, J = 4.9 Hz, 3H), 1.49 (s, 6H).

[0172] Example 26

[0173] Preparation of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclopropylcarbamate (E2):

[0174] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 328 mg, 2.0 mmol), 3-cyclopropyl-1,4,2-dioxazol-5-one (2a, 508 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclopropylcarbamate (E2).

[0175] Structural data representation: 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl cyclopropylcarbamate (E2). White solid. 420 mg, 85% yield. 1 H NMR (600 MHz, CDCl3) δ 6.93 (t, J = 7.3 Hz, 1H), 3.01 (s, 1H), 1.46 (s, 3H), 0.79 – 0.69(m, 1H), 0.60 (s, 1H).

[0176] Example 27

[0177] Preparation of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclobutylcarbamate (E3):

[0178] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 328 mg, 2.0 mmol), 3-cyclobutyl-1,4,2-dioxazol-5-one (3a, 564 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclobutylcarbamate (E3).

[0179] Structural data representation: 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl cyclobutylcarbamate (E3). White solid. 397mg, 76% yield. 1 H NMR (600 MHz, CDCl3) δ 7.00 – 6.91 (m, 1H), 6.77 (t, J = 7.7 Hz, 1H), 3.02 (s, 1H), 2.36(q, J = 7.8 Hz, 1H), 1.99 – 1.85 (m, 1H), 1.77 – 1.60 (m, 1H), 1.48 (s, 3H).

[0180] Example 28

[0181] Preparation of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclopentylcarbamate (E4):

[0182] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 328 mg, 2.0 mmol), 3-cyclopentyl-1,4,2-dioxazol-5-one (4a, 620 mg, 4.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product was then recrystallized from petroleum ether: ethyl acetate (30:1) to give 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclopentylcarbamate (E4).

[0183] Structural data characterization: 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclopentylcarbamate (E4). White solid. 473 mg, 86% yield. 1 H NMR (500 MHz, CDCl3) δ 6.97 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 1.1 Hz, 1H), 6.77 (t,J = 7.7Hz, 1H), 5.24 – 4.81 (m, 1H), 4.04 (h, J = 6.8 Hz, 1H), 3.03 (s, 2H), 2.00(dq, J = 12.7, 6.8 Hz, 2H), 1.69 (dd, J = 7.5, 4.3 Hz, 2H), 1.64 – 1.57 (m,2H), 1.51 (d, J = 5.5 Hz, 2H), 1.49 (s, 6H).

[0184] Example 29

[0185] Preparation of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclohexylcarbamate (E5):

[0186] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 328 mg, 2.0 mmol), 3-cyclohexyl-1,4,2-dioxazol-5-one (5a, 1.02 g, 6.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction mixture was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1). The product, 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclohexylcarbamate (E5), was then recrystallized from petroleum ether: ethyl acetate (20:1).

[0187] Structural data characterization: 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclohexylcarbamate (E5). White solid. 462 mg, 73% yield. 1 H NMR (500 MHz, CDCl3) δ 6.97 (d, J = 5.2 Hz, 1H), 6.95 (d, J = 5.0 Hz, 1H), 6.77 (t, J= 7.7Hz, 1H), 5.00 (d, J = 8.0 Hz, 1H), 3.64 – 3.49 (m, 1H), 3.03 (s, 2H), 2.01(dd, J = 12.9, 3.9 Hz, 2H), 1.72 (dd, J = 9.6, 4.1 Hz, 2H), 1.68 – 1.55 (m,1H), 1.49 (s, 6H), 1.40 – 1.31 (m, 2H), 1.22 – 1.17 (m, 2H).

[0188] Example 30

[0189] Preparation of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylphenylcarbamate (E6):

[0190] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 328 mg, 2.0 mmol), 3-phenyl-1,4,2-dioxazol-5-one (6a, 0.98 g, 6.0 mmol), cesium carbonate (325 mg, 1.0 mmol), and acetonitrile (20 ml) were added to a reaction flask and stirred in a 70 °C oil bath for 20 min. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1). The product, 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylphenylcarbamate (E6), was then recrystallized from petroleum ether: ethyl acetate (30:1) to give the product 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylphenylcarbamate (E6).

[0191] Structural data characterization: 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl phenylcarbamate (E6). White solid. 413 mg, 73 % yield. 1 H NMR (600 MHz, CDCl3) δ 7.42 (d, J =7.9 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.07 (t, J= 7.4 Hz, 1H), 7.02 – 6.97(m, 1H), 3.04 (s, 1H), 1.48 (s, 3H).

[0192] An example of a one-pot method for preparing carbamate compounds is shown below (compound B1 was prepared using this method):

[0193] Acetoxyxamic acid (I, 7.51 g, 0.10 mol), triphosgene (11.9 g, 40 mmol), and acetonitrile (200 ml) were added to a reaction flask. The mixture was stirred and cooled to 0 °C in an ice bath. Triethylamine (18.0 ml) was added dropwise, and the reaction was stirred for another 60 min. The reaction mixture was then placed in a 70 °C oil bath, and 2-sec-butylphenol (B, 6.0 g, 40 mmol) and cesium carbonate (6.5 g, 20 mmol) were added. The mixture was stirred for another 15 min. The reaction mixture was cooled to room temperature, and ethyl acetate (200 ml) was added. The organic phase was washed with saturated sodium chloride aqueous solution (2 × 150 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) to give 6.6 g of 2-(sec-butyl)phenylmethylcarbamate (B1), with a yield of 80%.

[0194] The specific steps for optimizing reaction conditions are as follows: Preferably, the reaction of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol (E) with 3-cyclopentyl-1,4,2-dioxazol-5-one (4a) to generate 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylcyclopentylcarbamate (E4) is optimized. To detect and verify the optimized yield, high-performance liquid chromatography (HPLC) is preferably used to detect the reactants and products. The HPLC experiments are performed on a Shimadzu instrument (e.g., J&K, RP-C18, 5 μM, 4.6 × 150 mm). The HPLC content of E4 in the reaction system is determined using a pure compound as an external standard. Unless otherwise specified, acetonitrile (A)-water (B) gradient elution is generally used: 0–2 min to maintain 60% A, 2–3 min to linearly increase to 80% A, 3–7 min to maintain 80% A, 7–8 min to increase to 90% A, 8–10 min to maintain 90% A, 10–11 min to decrease to 60% A, and 11–14 min to equilibrate the system. The total run time is 20 min, with a flow rate of 1 mL / min. (TR, E4 = 6.520 min, λmax, E4 = 254.0 nm; E = 3.526 min). All reagents used in the reaction were purchased from commercial companies.

[0195] Solvent optimization:

[0196] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 32.8 mg, 0.2 mmol), 3-cyclopentyl-1,4,2-dioxazol-5-one (4a, 31.1 mg, 0.2 mmol, 1.0 equiv.), anhydrous potassium carbonate (27.6 mg, 1.0 equiv.), and different solvents (2 ml) were added to a reaction tube and stirred. The mixture was then reacted at 30 °C for 8 h. Samples were taken at 8 h, and the yield was determined by HPLC using pure E4 as an external standard. The calculated yields are shown in Table 1. Table 1: Yields of different solvents

[0197] As shown in Table 1, acetone and acetonitrile are preferred. Since acetonitrile has a slightly higher boiling point, it will be used as a solvent in subsequent condition optimization.

[0198] Optimization of catalyst base:

[0199] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 32.8 mg, 0.2 mmol), 3-cyclopentyl-1,4,2-dioxazol-5-one (4a, 31.1 mg, 0.2 mmol, 1.0 equiv.), different bases (1.0 equiv.), and acetonitrile (2.0 ml) were added to a reaction tube and stirred. The mixture was reacted at 30 °C for 8 hours. Samples were taken at 8 h, and the yield was determined by HPLC using pure E4 as an external standard. The calculated yields are shown in Table 2. Table 2: Yields of bases with different catalysts

[0200] As shown in Table 2, cesium carbonate is preferred as the catalyst base.

[0201] Equivalent optimization of 3-substituted dioxazolone:

[0202] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 32.8 mg, 0.2 mmol), different equivalents of 3-cyclopentyl-1,4,2-dioxazol-5-one (4a), cesium carbonate (1.0 equiv.), and acetonitrile (2.0 ml) were added to a reaction tube and stirred. The mixture was then reacted at 30 °C for 8 hours. Samples were taken at 8 h, and the yield was determined by HPLC using pure E4 as an external standard. The calculated yields are shown in Table 3. Table 3: Equivalent yields of different 3-substituted dioxazolones

[0203] Based on the information in Table 3, the higher the equivalent of 3-substituted dioxazolone, the higher the yield. When the equivalent is greater than 2, the yield increase is limited. Therefore, 2 equivalents are preferred for 3-substituted dioxazolone.

[0204] Optimization of catalyst base equivalent:

[0205] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 32.8 mg, 0.2 mmol), 3-cyclopentyl-1,4,2-dioxazol-5-one (4a, 62.2 mg, 0.4 mmol, 2.0 equiv.), different equivalents of cesium carbonate and acetonitrile (2.0 ml) were added to a reaction tube and stirred. The mixture was reacted at 30 °C. The yield was determined by high-performance liquid chromatography (HPLC) at 2 h, 4 h, 6 h, 8 h, and 12 h, using pure E4 as an external standard. The calculated yields are shown in Table 4. Table 4: Yields of different cesium carbonate equivalents

[0206] According to the information in Table 4, the equivalent amount of cesium carbonate does not affect the yield but has a significant impact on the reaction time. In order to facilitate the control of the reaction time, a cesium carbonate equivalent of 0.5 is selected.

[0207] Optimization of temperature and reaction time:

[0208] 2,2-Dimethyl-2,3-dihydrobenzofuran-7-ol (E, 32.8 mg, 0.2 mmol), 3-cyclopentyl-1,4,2-dioxazol-5-one (4a, 62.2 mg, 0.4 mmol, 2.0 equiv.), cesium carbonate (32.6 mg, 0.1 mmol, 0.5 equiv.), and acetonitrile (2.0 ml) were added to a reaction tube and stirred. The mixture was then reacted at 40, 50, 60, 70, and 80 °C.

[0209] The yield of the reaction system at 40 °C was determined by high-performance liquid chromatography (HPLC) by sampling the reaction solution every 30 min over 3–5 h, with the highest yield reaching 4 h; the yield of the reaction system at 50 °C was determined by sampling the reaction solution every 15 min over 1–3 h, with the highest yield reaching 2 h; the yield of the reaction system at 60 °C was determined by sampling the reaction solution every 10 min over 0.5–1.5 h, with the highest yield reaching 1 h; the yield of the reaction system at 70 °C was determined by sampling the reaction solution every 2 min over 15–30 min, with the highest yield reaching 21 min; and the yield of the reaction system at 80 °C was determined by sampling the reaction solution every 1 min over 5–15 min, with the highest yield reaching 8 min. Pure E4 was used as an external standard. The calculated yields are shown in Table 5. Table 5: Maximum Yield at Different Reaction Temperatures

[0210] Based on the information in Table 5, the preferred reaction temperature is 70℃.

[0211] Validation experiment on cholinesterase activity inhibition: To verify that the carbamate compounds disclosed in this invention have anticholinesterase activity, the carbamate compounds (A1-E6) prepared in the above examples were selected for eeAChE inhibition experiments.

[0212] 1. Experimental Principle: The experiment uses the Ellman method, employing eel acetylcholinesterase (AChE) and its substrate iodoacetylcholine iodide to simulate the in vivo reaction environment. 5,5'-ditiobis-2-nitrobenzoico (DTNB) binds to the enzyme-substrate complex to generate a yellow anion 5-thio-2-nitrobenzoic acid. The inhibitory activity of the compound against the enzyme is calculated by measuring the absorbance.

[0213] 2. The experimental steps are as follows: (1) Prepare the compound using a phosphate buffer solution with a pH of 8.0; (2) The 48-well plates were divided into four groups: positive control group (donepezil + AChE + solvent + iodoacetylcholine iodide + DTNB), experimental group (compound + AChE + solvent + iodoacetylcholine iodide + DTNB), blank control group (AChE + solvent + iodoacetylcholine iodide + DTNB), and background group (solvent + DTNB). (3) Add 100 μL of solutions of the compounds (0.05, 0.5, 5, 50, 100 μM) to the 48-well plate, and replace the blank control wells and background wells with solvent; (4) Add 100 μL of AChE (0.18 U / mL) solution to the 48-well plate, replace the background wells with solvent, and incubate at 37℃ and 100 r / min for 20 min in a constant temperature shaker. (5) Add 100 μL of solvent to the 48-well plate; (6) Add 100 μL of a solution of iodoacetylcholine iodide / thiobutyrylcholine iodide (0.35 mM / 0.5 mM) to the 48-well plate, except for the background wells which are replaced with solvent; (7) Add 100 μL of DTNB (0.35 mM) solution to a 48-well plate and incubate at 37 ℃ and 100 r / min in a constant temperature shaker in the dark for 40 min. (8) Use an enzyme-linked immunosorbent assay (ELISA) reader to measure the absorbance at 410 nm and calculate the inhibition rate.

[0214] (9) All reactions were performed in three independent runs, and the results were analyzed using SPSS 17.0 statistical analysis software to determine the inhibition rate and IC50. 50 .

[0215] 3. The experimental results are shown in Table 6: Table 6: Statistical table of antiacetylcholinesterase data for corresponding numbered compounds in each example

[0216] Note a "na" indicates inactivity.

[0217] The structure of a carbamate is shown in the following formula:

[0218] Table 6 shows that compounds B1, B3, C1, C3, E1, E2, E3, E4, E5, and E6 all exhibit good acetylcholinesterase inhibitory activity. The E series compounds all demonstrate excellent acetylcholinesterase activity, with E1 exhibiting nanomolar-level inhibitory activity. Based on compounds 1-6 of each series (A-E), it can be determined that the carbamate exhibits the best activity when the amino-terminal substituent (R1) is methyl, and the acetylcholinesterase inhibitory activity generally decreases with increasing R1 carbon number (except when R1 is a cyclobutyl group, which increases activity). The carbamate exhibits better activity when the phenol (alcohol) end (R) is a heteroatom substituent with 3-5 carbon atoms in the ortho position. In conclusion, this series of carbamate compounds has potential and broad application prospects in pesticides or Alzheimer's disease treatment.

[0219] This invention relates to the fields of organic chemistry and medicinal chemistry, specifically a process for synthesizing carbamate compounds via 3-position substituted dioxazolones. It also includes optimization of reaction conditions and evaluation of the cholinesterase activity of the synthesized carbamate compounds. The preparation method provided by this invention is novel and has advantages such as mild reaction conditions, low impurity formation, high yield, high safety, and convenient operation. Furthermore, the compounds exhibit good cholinesterase activity in activity screening and can be used in insecticides or pesticides.

[0220] The above-disclosed embodiments are merely a few specific examples of the present invention. However, the embodiments of the present invention are not limited thereto, and any variations that can be conceived by those skilled in the art should fall within the protection scope of the present invention.

Claims

1. A method for synthesizing carbamate compounds based on 3-substituted dioxazolone, characterized in that, Its general structural formula is as follows: R is selected from any one of aryl, aryl-heteroyl, substituted aryl, and substituted aryl-heteroyl, including Any one of them; R1 is selected from straight-chain alkyl, branched-chain alkyl, cycloalkyl, substituted cycloalkyl, aryl, aromatic heteroyl, substituted aryl, and substituted aromatic heteroyl, including... Any one of them.

2. The method for synthesizing carbamate compounds based on 3-substituted dioxazolone according to claim 1, characterized in that, The carbamate compounds include the following compounds numbered: 。 3. A method for preparing carbamate compounds based on 3-substituted dioxazolone, characterized in that, The preparation of the 3-substituted dioxazolone carbamate compound according to any one of claims 1-2 comprises the following steps: (1) Hydroxyxamic acids with different substituents were reacted with phosgene under ice bath conditions to prepare 3-substituted dioxazolone; (2) The 3-substituted dioxazolone obtained in (1) was reacted with different phenols (alcohols) under alkaline conditions to obtain the corresponding carbamate compounds; The reaction processes of (1) and (2) are as follows: 。 4. The method for preparing carbamate compounds based on 3-substituted dioxazolone according to claim 3, characterized in that, The preparation method specifically includes, but is not limited to, the following steps: (1) Triethylamine was added dropwise to the reaction solvent of hydroxamic acid and triphosgene in an ice bath at 0 °C and stirred. The reaction solution was extracted and washed with dilute hydrochloric acid and saturated sodium chloride aqueous solution. The organic phase was dried with anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain pure 3-substituted dioxazolone (3-phenyl dioxazolone can be further recrystallized from petroleum ether / ethyl acetate to obtain pure 3-phenyl dioxazolone solid). (2) Mix different phenols (alcohols) with 3-substituted dioxazolones, react with catalyst base and solvent under certain temperature conditions for 1-12 h. After the reaction is completed, extract the reaction solution with ethyl acetate, wash with dilute hydrochloric acid and saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate the solvent under reduced pressure, purify the sample by column chromatography with mobile phase petroleum ether: ethyl acetate, recrystallize the obtained product with petroleum ether: ethyl acetate, and filter to obtain pure solid carbamate compound.

5. The method for preparing carbamate compounds based on 3-substituted dioxazolone according to claim 4, characterized in that, The preparation method uses the reaction system of 2,2-dihydro-2,2-dimethyl-7-hydroxybenzofuran and 3-cyclopentyldioxazolone as a model reaction, and optimizes the key reaction conditions. The specific optimization results are as follows: (1) The reaction solvent selected according to the above model is any one of dichloromethane, ethyl acetate, methanol, acetonitrile, acetone, tetrahydrofuran, acetone, toluene, N,N-dimethylformamide and dimethyl sulfoxide; (2) According to the above model reaction, the selected catalyst base is any one of potassium acetate, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), sodium carbonate, potassium carbonate, cesium carbonate and sodium hydroxide; (3) According to the above model reaction, the equivalent of the selected 3-cyclopentyldioxazolone (4a) is any one of 1, 1.2, 1.5, 2, 3 and 4; (4) According to the above model reaction, the equivalent of the base catalyst is any one of 0.1, 0.2, 0.5, 1 and 2; (5) The reaction is carried out according to the above model, and the selected reaction temperature is any one of 30℃, 40℃, 50℃, 60℃, 70℃ and 80℃.

6. The method for preparing carbamate compounds based on 3-substituted dioxazolone according to claim 3, characterized in that, The hydroxamic acid in (1) includes any one of acetoxyxamic acid, cyclopropylhydroxamic acid, cyclobutylhydroxamic acid, cyclopentylhydroxamic acid, cyclohexylhydroxamic acid, and benzohydroxamic acid.

7. The method for preparing carbamate compounds based on 3-substituted dioxazolone according to claim 3, characterized in that, The 3-substituted dioxazolone in (2) includes any one of 3-methyl dioxazolone, 3-cyclopropyl dioxazolone, 3-cyclobutyl dioxazolone, 3-cyclopentyl dioxazolone, 3-cyclohexyl dioxazolone, and 3-phenyl dioxazolone.

8. The method for preparing carbamate compounds based on 3-substituted dioxazolone according to claim 3, characterized in that, The phenol (alcohol) in (2) includes any one of m-methylphenol, 2-sec-butylphenol, 2-isopropoxyphenol, α-naphthol and 2,2-dihydro-2,2-dimethyl-7-hydroxybenzofuran.

9. The method for preparing carbamate compounds based on 3-substituted dioxazolone according to claim 3, characterized in that, The steps (1) and (2) can also be combined into one step. The specific implementation steps include: dissolving and mixing hydroxamic acid, triphosgene and acetonitrile, stirring and adding triethylamine at 0°C, transferring the reaction system to a pot at 60-70°C after 30-40 min, adding phenol and potassium carbonate and reacting for 20-30 min, and obtaining the corresponding carbamate compound after purification.

10. An application of carbamate compounds synthesized from 3-substituted dioxazolone in pesticides, specifically in the field of agricultural insecticides, characterized in that... The carbamate compounds synthesized using 3-substituted dioxazolone are those described in any one of claims 1-2.

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