Preparation method for 8-[2,4-dioxo-2h-benzo[e][1,3]oxazin-3(4H)-yl]octanoate

Abstract

The object of the present invention is to provide a new preparation method for 8-[2,4-dioxo-2H-benzo[E][1,3]oxazin-3(4H)-yl]octanoate (formula I). In the present invention, the high-purity key intermediate compound of formula VII, i.e., a (2,4-dioxo-4H-benzo[E][1,3]oxazin-3-salt) solid is creatively separated out, and is reacted with the compound of formula IV (halooctanoate) to prepare the compound of formula I.

Description

Process for the preparation of 8-[2,4-dioxo-2H-benzo[e][1,3]oxazin-3(4H)-yl]octanoic acid ester TECHNICAL FIELD

[0001] The present invention belongs to the technical field of chemical medicine synthesis, and relates to a preparation method of 8-[2,4-dioxo-2H-benzo[e][1,3]oxazin-3(4H)-yl]octanoic acid ester. TECHNICAL BACKGROUND

[0002] SNAC, the chemical name of which is sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate, is a fatty acid derivative absorption promoter, which can promote the oral absorption of a variety of protein drugs such as heparin and human growth hormone, and can be used for treating gastrointestinal diseases. SNAC is a high-efficiency molecule screened out by Emisphere Company from a plurality of penetration promoters.

[0003] 8-[2,4-dioxo-2H-benzo[e][1,3]oxazin-3(4H)-yl]octanoic acid ester (Formula I):

[0004] ,

[0005] The R is a C 1-6 alkyl group.

[0006] is a key intermediate for synthesizing SNAC. The patent WO 00 / 46182A discloses the compound and a preparation method thereof, which comprises the following steps:

[0007] Step 1: 2-hydroxybenzamide is used as a starting material, acetonitrile is used as a solvent, and ethyl chloroformate is reacted with 2-hydroxybenzamide under the action of pyridine to obtain 2H-1,3-benzoxazin-2,4(3H)-dione (cassiol), and the yield is 85%;

[0008]

[0009] Step 2: cassiol is mixed with 8-octanoic acid ethyl ester, N,N-dimethylacetamide is used as a solvent, and sodium carbonate is used to react to obtain the compound of Formula I (8-[2,4-dioxo-2H-benzo[e][1,3]oxazin-3(4H)-yl]octanoic acid ethyl ester), and the total yield of the process is about 76%.

[0010]

[0011] In the preparation process, the cyclization reagent ethyl chloroformate in step 1 is a highly toxic chemical with high environmental hazard, and its use is strictly regulated; the mixed solvent of pyridine and acetonitrile cannot be recycled and reused, and the neutralization of the post-treatment acid and alkali produces high-salt wastewater. In step 2, the condensation reaction, the solvent and casal, bromoester (organic phase), and sodium carbonate (inorganic phase) form a three-phase reaction system, the solubility of the reaction material is not good, which leads to low reaction rate and yield, a large amount of gas is generated during the reaction, which has safety risks, and the solvent N,N-dimethylacetamide is toxic, the reaction product is high-salt wastewater, and the generated mixture of sodium carbonate, sodium bromide, and sodium bicarbonate cannot be separated and recycled; all of which greatly increase the process cost and the cost of waste treatment, which is not conducive to environmental protection.

[0012] In other prior art, casal is also used as the raw material for preparing the compound of formula I, and the improvement of the process is mostly focused on the preparation step of casal, so there are defects in the condensation reaction in step 2 as described above. SUMMARY

[0013] The present application aims to provide a new preparation method of 8-[2,4-dioxo-2H-benzo[E][1,3]oxazin-3(4H)-yl]octanoate (formula I), and the present application creatively separates the key intermediate compound of formula VII (2,4-dioxo-4H-benzo[E][1,3]oxazin-3-salt) solid with high purity, and reacts it with the compound of formula IV (Y(CH2)7CO2R) to prepare the compound of formula I.

[0014] , ,

[0015] The X is Li, Na or K; the Y is Cl, Br or I; and the R is C 1-6 alkyl.

[0016] The advantages are:

[0017] The one-pot method for preparing the compound of formula I reduces the operation steps and equipment occupation, greatly reduces the energy consumption, and significantly reduces the production cost;

[0018] The cyclization reagent dialkyl carbonate is non-toxic, low in price, and has low environmental pressure, and its use is not regulated;

[0019] In the process for preparing the compound of formula I by reacting the compound of formula VII with the compound of formula IV, the reaction temperature is significantly reduced, the reaction time is significantly shortened, and the side reactions are reduced; no acid-binding agent is used, the material consumption is reduced, the gas generation is avoided, the process safety is improved; the selected solvent has low environmental hazard, the reaction solvent can be recycled and reused, the main by-product is a solid salt which can be separated and recycled for reuse, the amount of three wastes and the treatment cost of three wastes are reduced; in addition, the reaction does not exist in inorganic phase, it is a two-phase system, the solvent selection range is wider, and the solubility of the reactants is better, so that the reaction rate, yield and product purity are improved.

[0020] Based on the above purposes, the application provides a preparation method of 8-[2,4-dioxo-2H-benzo[E][1,3]oxazin-3(4H)-yl]octanoate shown in formula I, which comprises the following reaction steps:

[0021] The compound of formula VII in a separated state is dissolved in an organic solvent, and a compound of formula I is obtained by reacting in the presence of a phase transfer catalyst, and the reaction formula is as follows:

[0022]

[0023] The X is Li, Na or K; the Y is Cl, Br or I; the R is C 1-6 alkyl.

[0024] Preferably, the organic solvent is selected from one of acetone, butanone, acetonitrile, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, or a two-solvent mixed system of the former and one of DMF, DMAc, DMSO and dioxane.

[0025] Preferably, the phase transfer catalyst is selected from 18-crown-6, TBAB, TBAC, TBAI or polyethylene glycol dimethyl ether.

[0026] Preferably, the amount of the compound of formula IV is 0.9-1.0 times, most preferably 0.95-0.97 times (molar ratio) based on the compound of formula VII; the amount of the organic solvent is 5-15 times, most preferably 5-10 times (v / w, volume weight ratio); and the amount of the phase transfer catalyst is 0.01-0.10 times, most preferably 0.01-0.05 times (molar ratio).

[0027] Preferably, the reaction temperature is 20-60°C, most preferably 25-50°C; and the reaction time is 0.5-6 hours, most preferably 1-5 hours.

[0028] Preferably, the compound of formula VII is obtained by the following route:

[0029] Route 1: Step A: reacting the compound of formula V with a basic substance in an organic solvent to obtain a compound of formula VI; Step B: mixing the compound of formula VI with a dialkyl carbonate, the alkyl of which is selected from C 1-6 alkyl; and reacting in an organic solvent in the presence of an alkali metal salt to obtain a compound of formula VII:

[0030] ; or

[0031] Route 2: Step C: reacting the compound of formula V with a basic substance and a dialkyl carbonate to obtain a compound of formula VIII; Step D: dissolving the compound of formula VIII in an organic solvent and reacting in the presence of a basic substance to obtain a compound of formula VII:

[0032] , wherein R1 is C 1-6 alkyl.

[0033] Preferably, the dialkyl carbonate is dimethyl carbonate or diethyl carbonate.

[0034] Preferably, in Route 1, the organic solvent in Step A is selected from toluene, methanol, ethanol or tert-butanol; and the basic substance is an alkali metal Li, Na, K hydroxide, carbonate or other basic salt.

[0035] Preferably, in Route 1, the organic solvent in Step B is selected from ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol or a mixture of one or two solvents of dimethyl carbonate; and the alkali metal salt is an alkoxide of Li, Na, K.

[0036] Preferably, in Route 1, the amount of the organic solvent in Step A is 5-15 times (v / w, volume to weight ratio) based on the compound of formula V; the amount of the base is 1.0-1.1 times (molar ratio); the reaction temperature is 10-30°C; and the reaction time is 1-3 hours.

[0037] Preferably, in Route 1, the amount of the organic solvent in Step B is 10-20 times (v / w, volume to weight ratio) based on the compound of formula V; the amount of the alkali metal salt is 0.05-0.5 times (molar ratio); the reaction temperature is 80-100°C; and the reaction time is 0.5-3 hours.

[0038] Preferably, in Route 2, the basic substance in Step C and Step D is selected from an alkali metal Li, Na, K methoxide, ethanol or tert-butanol salt;

[0039] Preferably, in Route 2, the organic solvent in Step D is selected from ethanol, isopropanol, n-butanol, tert-butanol or tert-amyl alcohol.

[0040] Preferably, in Route 2, the amount of the carbonic acid dialkyl ester is 5-20 times (molar ratio) based on the compound of Formula V; the amount of the base is 1.0-1.5 times (molar ratio); the reaction temperature is 30-60°C; and the reaction time is 15-20 hours.

[0041] Preferably, in Route 2, the amount of the organic solvent is 3-6 times (v / w, volume to weight ratio) based on the compound of Formula V; the amount of the base is 0.1-1.0 times (molar ratio); the reaction temperature is 80-100°C; and the reaction time is 0.5-2 hours. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1: HPLC profile of compound VI potassium salt

[0043] Figure 2: HPLC profile of compound VI sodium salt

[0044] Figure 3: HPLC profile of compound VII potassium salt

[0045] Figure 4: HPLC profile of compound VII sodium salt

[0046] Figure 5: HPLC profile of compound VIII

[0047] Figure 6: HPLC profile of compound I

[0048] Figure 7: NMR of casanthranol

[0049] Figure 8: NMR of compound VII potassium salt

[0050] Figure 9: NMR of compound VII sodium salt

[0051] Figure 10: NMR of compound I DETAILED DESCRIPTION

[0052] The following examples will enable those skilled in the art to more fully understand the present application, but should not be construed as limiting the present application in any way.

[0053] The reagents used in the present application can be purchased from the market or prepared by the methods described in the present application.

[0054] Comparative Example 1 (WO 00 / 46182, Example 1)

[0055] Preparation of 2H-l,3-benzoxazin-2,4(3H)-dione (Casanthranol)

[0056]

[0057] Salicylamide (59.0 g, 0.43 mol, 1.0 eq), pyridine (500 ml) and acetonitrile (125 ml) were charged into a 500 ml three necked flask equipped with magnetic stirring, thermometer and dropping funnel. The reaction mixture was cooled to about 5 °C using an ice-salt bath and ethyl chloroformate (45.2 ml, 0.47 mol, 1.1 eq) was added dropwise over 25 min, maintaining the temperature below 10 °C. The dropping funnel was replaced by a water cooled condenser and the reaction mixture was heated to a distillation temperature of about 90 °C. The distillation was continued until the internal temperature reached about 124 °C (200 ml of distillate were removed). The temperature was then lowered to reflux for 1 h and the reaction mixture was cooled to 25 °C and poured into 400 ml of water. Concentrated hydrochloric acid (24 ml) was added and a white solid was formed. The solid was filtered, washed with 200 ml of water and dried under reduced pressure. The product, 2H-l,3-benzoxazin-2,4(3H)-dione, was obtained as a white solid (59.3 g, 84.5% yield).

[0058] Comparative Example 2 (WO 00 / 46182, Example 8)

[0059] 8-[2,4-dioxo-2H-benzo[E][l,3]oxazin-3(4H)-yl]octanoic acid ethyl ester

[0060]

[0061] A 1 L reaction flask was charged with dry DMAc (233 ml) and stirring was started. Na2CO3(85.8 g, 0.81 mol, 2.24 eq), ethyl 8-bromooctanoate (90.7 g, 0.36 mol, 1.0 eq) and 2H-l,3-benzoxazin-2,4(3H)-dione (Cazarol) (66.0 g, 0.40 mol, 1.12 eq) were added sequentially at room temperature. The reaction mixture was heated to 70 °C and maintained at this temperature for 6-8 h. The reaction system became viscous and a large amount of gas was evolved. A vacuum pump was started to adjust the pressure to 180 mmHg. The reaction progress was monitored by HPLC until the complete consumption of ethyl 8-bromooctanoate. The results showed that a hydrolysis side reaction of the product occurred. The reaction mixture was cooled to about 40 °C and the mixture was filtered. The filter cake was washed with ethanol (125 ml) and the filtrates were combined. The filtrate was cooled to 25 °C and water was added dropwise with stirring. The suspension was cooled to 5-10 °C. The white solid was filtered. Ethanol (175 ml) and heptane (225 ml) were added to the reaction flask and cooled to 5-10 °C. The filter cake was washed with cooled ethanol and heptane, respectively. The filter cake was analyzed by GC. If ethyl 8-bromooctanoate was detected, more heptane was used for washing. The filter cake could be used in the subsequent reaction or stored after drying under reduced pressure at 40 °C. The yield of ethyl 8-[2,4-dioxo-2H-benzo[E][l,3]oxazin-3(4H)-yl]octanoate was about 90%.

[0062] In the process, the three phases of carboxazid, reaction solvent and bromoester (organic phase), and Na2CO3 (inorganic phase) are not mutually soluble, the solubility of the reactants is poor, the system is difficult to stir, resulting in long reaction time, high reaction temperature and low yield; the acid produced by the substitution reaction will undergo acid-base neutralization with Na2CO3 to produce CO2 gas and water, which can cause material flushing risk; water can also cause the product to hydrolyze into impurities, reducing product quality; a large amount of water is required for post-treatment to remove DMAc, and the generated wastewater cannot be recycled; the solid waste is a mixture of Na2CO3, NaHCO3 and NaBr, which cannot be separated.

[0063] Example 1:

[0064] Scheme 1:

[0065]

[0066] Step A: Synthesis of 2-amino carbonyl phenol potassium salt

[0067] Under nitrogen protection, 300 mL of methanol was added to a dry 1 L reaction bottle, 100 g of compound V (0.73 mol, 1.00 eq) was added under stirring, a solution of 41 g of KOH (0.73 mol, 1.00 eq) and 500 mL of methanol was added dropwise at a temperature of 20-30°C, and stirring was carried out at a temperature of 20-30°C for 2 hours. The reaction liquid was subjected to reduced pressure distillation (temperature: 40-50°C, vacuum degree: 0.09 Mpa) until basically no liquid flowed out; 400 mL of t-butyl alcohol was added three times (temperature: 50-60°C, vacuum degree: 0.09 Mpa), and white solid was obtained.

[0068] Compound VI is directly used in step B.

[0069] Step B: Synthesis of 2,4-dioxo-4H-benzo[E][1,3]oxazine-3-potassium salt

[0070] Under nitrogen protection, 400 mL of t-butyl alcohol was added to the reaction system of compound VI, and the temperature was raised to 50-60°C for stirring and dissolution. 1600 mL of dimethyl carbonate was added, the temperature was raised to 85-95°C, about 400 mL of solvent was distilled out, the temperature was lowered to 20-30°C, 8.2 g of t-BuOK (0.07 mol, 0.10 eq) was added, and the temperature was raised to 85-95°C for stirring reaction. The sample was taken for HPLC monitoring to ensure that the conversion of the raw material was complete. The reaction liquid was subjected to reduced pressure distillation (temperature: 45-55°C, vacuum degree: 0.09 Mpa) until no liquid flowed out; the reaction bottle was white solid.

[0071] Compound VII is directly used for the synthesis of compound of formula I.

[0072] Synthesis of compound of formula I: ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazin-3(4H)-yl]octanoate

[0073] Under nitrogen protection, 900 ml butanone, 174 g compound IV (0.69 mol, 0.95 eq) and 3.6 g 18-crown-6 (0.014 mol, 0.02 eq) were added into the reaction system of compound VII, and the stirring was started. The reaction was heated to 35-45 °C and stirred for 1-3 hours until the starting material was completely converted according to HPLC monitoring.

[0074] The reaction solution was cooled to 20-25 °C, and filtered. The filter cake was rinsed with 100 ml butanone (to recover solid KBr). The filtrate was combined and concentrated at 50-60 °C under reduced pressure until no liquid drops were observed (butanone was recovered). 900 ml purified water was added, and the mixture was heated to 50-60 °C, stirred and dispersed, and slowly cooled to 20-25 °C. The mixture was stirred for 6 hours to crystallize, filtered, and the filter cake was rinsed with purified water. The solid was dissolved in 450 ml ethanol by heating to 50-60 °C, and slowly cooled to 15-25 °C. The mixture was stirred for 2 hours to crystallize, filtered, and the filter cake was rinsed with ethanol and dried by suction. The white crystals of 210 g compound of formula I were obtained by air drying at 30-40 °C (total yield 90.9%).

[0075] Example 2:

[0076] Scheme 1:

[0077]

[0078] Step A: Synthesis of sodium salt of 2-aminocarbonyl phenol

[0079] Under nitrogen protection, 300 mL methanol was added into a 2 L dry reaction flask, and 100 g compound V (0.73 mol, 1.00 eq) was added with stirring. A solution of 29.2 g NaOH (0.73 mol, 1.00 eq) in 500 mL methanol was added dropwise at a temperature of 20-30 °C, and the mixture was stirred for 2 hours. The reaction solution was distilled under reduced pressure (temperature: 40-50 °C, vacuum degree: 0.09 MPa) until no liquid was observed. Tert-butyl alcohol was distilled three times, each time with 400 mL (temperature: 50-60 °C, vacuum degree: 0.09 MPa), to obtain white solid.

[0080] Compound VI was directly used in Step B

[0081] Step B: Synthesis of sodium salt of 2,4-dioxo-4H-benzo[E][1,3]oxazin-3

[0082] Under nitrogen protection, add 1500 mL of tert-butyl alcohol to the reaction system of compound VI, add 7.9 g of sodium methoxide (0.15 mol, 0.20 eq), and drop 328.8 g of dimethyl carbonate (3.65 mol, 5.00 eq) at 80-85°C. Continue to stir the reaction at 80-85°C, and take a sample for HPLC monitoring until the complete conversion of the raw material. Distill the reaction liquid under reduced pressure (temperature: 45-55°C, vacuum degree: 0.09 Mpa) until no liquid is discharged; the reaction bottle is filled with white solid.

[0083] Compound VII is directly used for the synthesis of compound of formula I.

[0084] Synthesis of compound of formula I: ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazin-3(4H)-yl]octanoate

[0085] Under nitrogen protection, add 900 mL of acetone to the reaction system of compound VII, add 174 g of compound IV (0.69 mol, 0.95 eq), and 11 g of TBAB (0.034 mol, 0.05 eq). Start stirring, heat to 40-50°C, and stir the reaction for 2-4 hours until the complete conversion of the raw material is monitored by HPLC.

[0086] Cool the reaction liquid to 20-25°C, filter, and rinse the filter cake with 100 mL of acetone (to recover solid NaBr from the filter cake). Combine the filtrate, concentrate under reduced pressure at 40-50°C until there is basically no liquid drop (to recover acetone), add 900 mL of purified water, heat to 50-60°C, stir and disperse, slowly cool to 20-25°C, stir for 6 hours for crystallization, filter, and rinse the filter cake with purified water. Add 450 mL of ethanol to the solid, heat to 50-60°C for dissolution, slowly cool to 15-25°C, stir for 2 hours for crystallization, filter, rinse the filter cake with ethanol, and dry by suction. Dry the white crystals at 30-40°C by air blowing to obtain 206 g of compound of formula I (total yield 89.2%).

[0087] Example 3

[0088] Route 2

[0089]

[0090] Step C: Synthesis of methyl 2-aminocarbonylphenyl carbonate

[0091] Under nitrogen protection, add 600 mL of dimethyl carbonate to a dry 1 L reaction bottle, start stirring, add 50 g of compound V (0.36 mol, 1.0 eq) and 23.6 g of NaOMe (0.44 mol, 1.2 eq), heat to 50-60°C after addition, and take a sample for HPLC monitoring until the complete conversion of the raw material.

[0092] The solution of compound VIII is used directly in step D.

[0093] Step D: Synthesis of 2,4-dioxo-4H-benzo[E][1,3]oxazin-3-sodium salt

[0094] Under nitrogen protection, 200 mL of t-butyl alcohol, 15.7 g of NaOMe (0.29 mol, 0.8 eq) are added to the reaction system of compound VIII, stirring is started, and the reaction is heated to 80-90°C, and sample HPLC is used to monitor the complete conversion of the raw material. The reaction liquid is distilled under reduced pressure (temperature: 45-55°C, vacuum degree: 0.09 Mpa) until no liquid is discharged; the reaction bottle is a white solid.

[0095] Compound VII is directly used for the synthesis of compound of formula I.

[0096] Synthesis of compound of formula I: ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazin-3(4H)-yl]octanoate

[0097] Under nitrogen protection, 500 ml of acetone, 87 g of compound IV (0.35 mol, 0.95 eq), and 5.5 g of TBAB (0.017 mol, 0.05 eq) are added to the reaction system of compound VII, stirring is started, and the reaction is heated to 40-50°C and stirred for 2-4 hours until HPLC monitors the complete conversion of the raw material.

[0098] The reaction liquid is cooled to 20-25°C, filtered, the filter cake is washed with 50 ml of acetone (to recover solid NaBr in the filter cake); the filtrate is combined, concentrated under reduced pressure at 40-50°C until there is basically no liquid drop (acetone is recovered); 500 ml of purified water is added, heated to 50-60°C, stirred and dispersed, slowly cooled to 20-25°C, stirred for 6 hours, filtered, and the filter cake is washed with purified water. The solid is added with 220 ml of ethanol, heated to 50-60°C, dissolved, slowly cooled to 15-25°C, stirred for 2 hours, filtered, the filter cake is washed with ethanol, and dried. The white crystal 101 g (total yield 87.5%) is obtained by air drying at 30-40°C.

[0099] Example 4

[0100] Scheme 2

[0101]

[0102] Synthesis of compound of formula I: ethyl 8-[2,4-dioxo-2H-benzo[E][1,3]oxazin-3(4H)-yl]octanoate

[0103] Under nitrogen protection, 100 g of 2,4-dioxo-4H-benzo[E][1,3]oxazin-3-potassium salt (0.5 mol) and 800 ml of butanone were sequentially added into a 2 L dry three-necked reaction flask, and then 100 g of 8-chlorooctanoic acid ethyl ester (compound IV, 0.48 mol, 0.97 eq) and 8.9 g of TBAI (0.024 mol, 0.05 eq) were added, and the reaction was stirred at 50°C for 4 hours, and HPLC was used to monitor the complete conversion of the raw material.

[0104] The reaction solution was cooled to 20-25°C, and then filtered, and the filter cake was rinsed with 80 ml of butanone (solid waste was potassium chloride); the filtrate was combined, and concentrated at 40-50°C under reduced pressure until there were basically no liquid drops (butanone was recovered); 800 ml of purified water was added, and the mixture was stirred and dispersed at 50-60°C, and then slowly cooled to 20-25°C, and then stirred for crystallization for 6 hours, and then filtered, and the filter cake was rinsed with purified water. The solid was added with 300 ml of ethanol, and then dissolved by heating to 50-60°C, and then slowly cooled to 15-25°C, and then stirred for crystallization for 2 hours, and then filtered, and the filter cake was rinsed with ethanol and dried by suction. The white crystals were obtained by air drying at 30-40°C, and the yield was 139 g (86.2%).

[0105] Compared with the prior art reaction using carboxazol as a reactant, the alkali metal salt of carboxazol is used as a reactant in the present application, the reaction temperature is reduced from 70°C to 35-50°C, and the reaction time is shortened to 1-4 hours.

[0106] The specific embodiments of the present application and the advantages of the present application are shown and described above. It should be understood by those skilled in the art that the present application is not limited by the above embodiments, and the above embodiments and descriptions in the specification are only to illustrate the principles of the present application, and the present application can be continuously changed and improved without departing from the spirit and scope of the present application, and these changes and improvements all fall within the scope of the claimed present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. A method for preparing 8-[2,4-dioxo-2H-benzo[E][1,3]oxazin-3(4H)-yl] octanoate of formula I, said method comprising the following reaction steps: dissolving the isolated compound of formula VII in an organic solvent and reacting in the presence of a phase transfer catalyst to obtain the compound of formula I, the reaction scheme being shown as follows: ###0001### Formula I Formula VII Formula IV The organic solvent is selected from one of acetone, butanone, acetonitrile, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or a mixture of two solvents of the former with DMF, DMAc, DMSO, dioxane. The phase transfer catalyst is selected from 18-crown-6, TBAB, TBAC, TBAI or polyethylene glycol dimethyl ether. The reaction temperature is 20-60°C, most preferably 25-50°C; the reaction time is 0.5-6 hours, most preferably 1-5 hours. The amount of the compound of formula IV is 0.9-1.0 times, most preferably 0.95-0.97 times (molar ratio) based on the compound of formula VII; the amount of the organic solvent is 5-15 times, most preferably 5-10 times (v / w, volume to weight ratio); the amount of the phase transfer catalyst is 0.01-0.10 times, most preferably 0.01-0.05 times (molar ratio). The compound of formula VII is obtained by the following routes: Route 1: Step A: reacting the compound of formula III with a base in an organic solvent to obtain the compound of formula V; Step B: reacting the compound of formula V with a base in an organic solvent to obtain the compound of formula VII: ###0002### Formula VII Formula III Formula V The base is selected from one of NaOH, KOH, LiOH, Na2CO3, K2CO3, Li2CO3, NaH, KH, LiH, NaOMe, KOtBu, LiOtBu, NaOtBu, KOtAmyl, LiOtAmyl, NaOtAmyl, NaOtPr, KOtPr, LiOtPr, NaOtSec-Bu, KOtSec-Bu, LiOtSec-Bu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtBu, LiOtBu, NaOtAmyl, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOtBu, KOtAmyl, LiOtAmyl, NaOt ​ X is Li, Na or K; Y is CI, Br or I; R is C 1-6 alkyl.

2. The production method according to claim 1, wherein ​ 3. The production method according to claim 1, wherein ​ 4. The production method according to claim 1, wherein ​ 5. The production method according to claim 1, wherein ​ 6. The production method according to claim 1, wherein ​ Route 1 : Step A: reacting a compound of formula V with a basic material in an organic solvent to give a compound of formula VI; Step B: mixing a compound of formula VI with a dialkyl carbonate, the alkyl group of which is selected from the group consisting of C 1-6 1-6 alkyl; Step C: reacting a compound of formula VII with a compound of formula VIII to give a compound of formula IX; Step D: reacting a compound of formula IX with a compound of formula X to give a compound of formula XI; Step E: reacting a compound of formula XI with a compound of formula XII to give a compound of formula XIII; Step F: reacting a compound of formula XIII with a compound of formula XIV to give a compound of formula XV; Step G: reacting a compound of formula XV with a compound of formula XVI to give a compound of formula XVII; Step H: reacting a compound of formula XVII with a compound of formula XVIII to give a compound of formula XIX; Step I: reacting a compound of formula XIX with ​ ​ , said R1is a C 1-6 alkyl group.

7. The production method according to claim 6, wherein ​ 8. The production method according to claim 6, wherein ​ 9. The production method according to claim 6, wherein ​ 10. The production method according to claim 6, wherein In the Route 1, the amount of the organic solvent in Step A is 5-15 times (v / w, volume / weight ratio) based on the compound of Formula V; the amount of the base is 1.0-1.1 times (molar ratio); and / or the amount of the organic solvent in Step B is 10-20 times (v / w, volume / weight ratio); the amount of the alkali metal salt is 0.05-0.5 times (molar ratio); In the Route 2, the amount of the dialkyl carbonate in Step C is 5-20 times (molar ratio) based on the compound of Formula V; the amount of the base is 1.0-1.5 times (molar ratio), and / or the amount of the organic solvent in Step D is 3-6 times (v / w, volume / weight ratio); the amount of the base is 0.1-1.0 times (molar ratio).

11. A compound having a structural formula as shown in Formula VII: ###0002### Formula VII, wherein X is Li, Na, or K. ​

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