CN109721551B - Preparation method of 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate - Google Patents
Preparation method of 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate Download PDFInfo
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Abstract
The invention relates to the technical field of organic chemistry and medicine, in particular to a preparation method of 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate. The invention provides a preparation method of gefitinib 3, 4-dihydro-7-methoxy-4-oxoquinazoline-6-alcohol acetate, which comprises the following steps: nitration reaction, oxidation reaction, selective demethylation reaction, reduction reaction, cyclization reaction and phenolic hydroxyl acetylation reaction. The preparation method provided by the invention can simultaneously reduce the cost, is easy to refine and purify, and is easy to prepare and control various related impurities, the whole preparation process route is greatly optimized, and the preparation method is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of organic chemistry and medicine, in particular to a preparation method of 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate.
Background
3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate (CAS number: 179688-53-0) is a key intermediate for synthesizing anti-tumor small molecules such as EGFR inhibitor Gefitinib, pan HER inhibitor Poziotinib and the like, and the structure is shown as formula I:
the preparation methods of the intermediates in the prior art mainly comprise the following steps:
gibson (Zeneca limited) reports a gefitinib intermediate synthesis method (US5770599), and the synthesis route is as follows:
the method comprises the steps of taking 6, 7-dimethoxy quinazoline-4 (3H) ketone as a raw material, selectively demethylating by methanesulfonic acid and L-methionine to obtain 6-hydroxy-7-methoxy-3, 4-dihydro quinazoline-4-ketone, then acetylating on phenolic hydroxy to obtain a key intermediate 3, 4-dihydro-7-methoxy-4-oxo quinazoline-6-alcohol acetate, and then chlorinating, phenylating, deacetylating and etherifying a morpholine ring side chain to obtain a target product gefitinib. In the method, the selective demethylation of methanesulfonic acid and L-methionine is adopted, so that the yield is low, a large amount of methanesulfonic acid and L-methionine which are difficult to recover are used, the environmental pollution is large, the total yield of the route is low, and the industrial production is limited. 6, 7-dimethoxy quinazoline-4 (3H) ketone is not a general chemical raw material, and CN1150948 reports that 4, 5-dimethoxy-2-nitrobenzoic acid is required to be prepared through three steps of esterification, reduction and cyclization.
Another synthetic route for preparing gefitinib is reported by gilday (astrazeneca pharmaceuticals) in patent WO2004024703 as follows:
according to the method, 3-hydroxy-4-methoxybenzaldehyde is used as a starting material, aldehyde groups are converted into cyano groups, and then etherification, nitration, reduction, hydrolysis, cyclization and chloro-and aromatic amine substitution are carried out to obtain gefitinib through eight steps of reaction, although the defect that a large amount of methanesulfonic acid and L-methionine are used for demethylation is overcome, the starting material 3-hydroxy-4-methoxybenzaldehyde is expensive, is more than 20 times of 3, 4-dimethoxybenzaldehyde, and the yield of certain steps is low, so that the production cost is relatively high.
Chinese patent CN1733738 reports that gefitinib is synthesized by using 3, 4-dimethoxybenzoic acid as a raw material, and the route is as follows:
according to the method, 3, 4-dimethoxybenzoic acid is used as a raw material, and the gefitinib is obtained by nitration, demethylation, reduction, cyclization, chlorination and aromatic amine substitution and morpholine N-alkyl side chain introduction. In the fourth step of cyclization reaction, 2-amino-4-methoxy-5-hydroxybenzoic acid is directly cyclized with formamide to construct 4-carbonyl quinazoline parent ring, the reaction temperature is preferably 170-180 ℃, the reaction temperature is high, the byproducts are more, and the yield is low. In addition, due to the existence of active group hydroxyl, side reaction is easy to occur because the hydroxyl is not protected during the next step of aromatic amine substitution reaction.
In addition, chinese patent publication nos. CN103130729A and CN105693630A report preparation methods of chlorination reaction steps of intermediate 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate, and do not relate to the preparation method of the intermediate.
Disclosure of Invention
In view of the disadvantages of the prior art mentioned above, the present invention aims to provide a preparation method of 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate (compound of formula I), and further to obtain gefitinib by the preparation of the compound of formula I, so as to solve the problems in the prior art.
In order to achieve the above objects and other related objects, the first aspect of the present invention provides a method for preparing 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate (compound of formula I), which comprises the following steps:
1) nitration reaction: nitrating 3, 4-dimethoxy benzaldehyde to prepare a compound shown in a formula II;
2) and (3) oxidation reaction: oxidizing the compound of the formula II to prepare a compound of a formula III;
3) selective demethylation reaction: reacting a compound in a formula III in the presence of alkali to prepare a compound in a formula IV;
4) reduction reaction: reacting a compound shown in a formula IV in the presence of a catalyst in a hydrogen atmosphere to prepare a compound shown in a formula V;
5) and (3) cyclization reaction: reacting the compound shown in the formula V with formamidine acetate to prepare a compound shown in a formula VI;
6) and (3) acetylation reaction of phenolic hydroxyl: reacting the compound of formula VI with acetic anhydride in the presence of a base catalyst to obtain the compound of formula I.
The reaction route of the preparation method of the compound of the formula I is as follows:
in some embodiments of the present invention, in step 1), the nitration reagent used in the nitration reaction is one or more of nitric acid, mixed acid of nitric acid and sulfuric acid, mixed acid of nitric acid and acetic acid, and the like.
In some embodiments of the invention, in step 1), the nitrating agent is nitric acid, more specifically an aqueous solution of nitric acid, the concentration of which is 63 to 67 wt%.
In some embodiments of the invention, in the step 1), the molar ratio of the 3, 4-dimethoxybenzaldehyde to the nitrating agent in the nitration reaction is 1: 1.5-3.
In some embodiments of the present invention, in the step 1), the nitration reaction is performed in the presence of a solvent, and the solvent used in the nitration reaction is selected from one or more of dichloroethane, chloroform, acetic acid, n-hexane, and the like.
In some embodiments of the invention, in step 1), the reaction temperature is from 25 to 45 ℃.
In some embodiments of the present invention, the post-treatment method of step 1) comprises: after the reaction is finished, adding water for extraction and separation to obtain an organic phase, washing off acid in the organic phase, and then desolventizing to obtain the compound shown in the formula II.
In some embodiments of the present invention, in the step 2), the oxidant used in the oxidation reaction is selected from one or more of sodium chlorite, hydrogen peroxide, sodium hypochlorite, and the like.
In some embodiments of the invention, in step 2), the oxidizing agent is sodium chlorite, more specifically an aqueous sodium chlorite solution, and the concentration of the aqueous sodium chlorite solution is 8 to 12 weight percent.
In some embodiments of the invention, in step 2), the molar ratio of the compound of formula II to the oxidizing agent in the oxidation reaction is 1: 1.2-2.
In some embodiments of the present invention, in the step 2), the oxidation reaction is performed in the presence of a solvent, and the solvent used in the oxidation reaction is selected from one or more of acetonitrile, water, dimethyl sulfoxide, dimethylformamide and the like.
In some embodiments of the invention, in step 2), the oxidation reaction is performed in the presence of a pH buffer selected from one or more of potassium dihydrogen phosphate, sodium dihydrogen phosphate, and the like, and the concentration of the pH buffer is 0.15 to 0.25 mol/L.
In some embodiments of the invention, in step 2), the reaction temperature is 25 to 45 ℃.
In some embodiments of the present invention, the post-treatment method of step 2) comprises: after the reaction is finished, adjusting the pH value of the reaction system to be acidic, carrying out solid-liquid separation, and drying a solid phase substance to obtain the compound shown in the formula III. More specifically, after completion of the reaction, the pH of the reaction system was adjusted to pH 2 to 3.
In some embodiments of the invention, in step 3), the reaction is carried out at a pH of 13 to 14.
In some embodiments of the present invention, in the step 3), the base is selected from one or more of NaOH, KOH, and the like.
In some embodiments of the invention, the reaction temperature in step 3) is 95-100 ℃.
In some embodiments of the present invention, the post-treatment method of step 3) comprises: after the reaction is finished, adjusting the pH value of the reaction system to be acidic, carrying out solid-liquid separation, and drying a solid phase substance to obtain the compound shown in the formula IV. More specifically, after completion of the reaction, the pH of the reaction system was adjusted to pH 2 to 3.
In some embodiments of the present invention, in the step 4), the catalyst is selected from one or more of a palladium catalyst (e.g., palladium carbon), a nickel catalyst (e.g., raney nickel), sodium hydrosulfite, and the like.
In some embodiments of the present invention, in the step 4), the catalyst is palladium on carbon, and more specifically, the palladium content in the palladium on carbon is 8 to 12 wt%.
In some embodiments of the present invention, in step 4), the catalyst is used in a catalytic amount, more specifically 5 to 10 wt% of the compound of formula IV.
In some embodiments of the present invention, in the step 4), the reduction reaction is performed in the presence of a solvent, and the solvent used in the reduction reaction is selected from one or more of methanol, ethanol, ethyl acetate and the like.
In some embodiments of the present invention, in the step 4), the reaction temperature is 30 to 40 ℃ and the reaction pressure is 1.5 to 2 atmospheres.
In some embodiments of the present invention, the post-treatment method of step 4) comprises: and after the reaction is finished, washing the product by using a solvent to obtain the compound shown in the formula V, wherein the solvent used for washing is selected from one or more of methanol, ethanol, ethyl acetate and the like.
In some embodiments of the invention, the molar ratio of the compound of formula V to formamidine acetate in step 5) is 1:2 to 2.5.
In some embodiments of the present invention, in the step 5), the cyclization reaction is performed in the presence of a solvent, and the solvent used in the cyclization reaction is selected from one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, xylene, and the like.
In some embodiments of the invention, in step 5), the reaction temperature is in the range of 110 ℃ to 120 ℃.
In some embodiments of the present invention, the post-treatment method of step 5) comprises: and after the reaction is finished, removing the solvent, washing with water, and drying to obtain the compound shown in the formula VI.
In some embodiments of the invention, the weight ratio of the compound of formula VI to acetic anhydride in step 6) is from 1:4 to 6.
In some embodiments of the present invention, in the step 6), the base catalyst is selected from one or more of pyridine, triethylamine, diisopropylethylamine and the like.
In some embodiments of the invention, the molar ratio of the compound of formula VI to the base catalyst in step 6) is 1:4 to 6.
In some embodiments of the present invention, in the step 6), the acetylation of the phenolic hydroxyl group is performed in the presence of a solvent, and the solvent used in the acetylation of the phenolic hydroxyl group is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide and the like.
In some embodiments of the invention, in step 6), the reaction temperature is from 40 ℃ to 50 ℃.
In some embodiments of the present invention, the post-treatment method of step 6) comprises: adding water for crystallization after the reaction is finished, and carrying out solid-liquid separation to obtain the compound shown in the formula VI.
The invention provides a preparation method of gefitinib, a compound of formula I prepared by the preparation method is used as a key intermediate to prepare the gefitinib, and then the gefitinib is prepared by the prior art, wherein the prior art can refer to documents in the background such as US5770599, CN1733738, CN96193526 and the like, and the specific reaction equation is as follows:
the method takes 3, 4-dimethoxybenzaldehyde with low price as a raw material, has mild reaction conditions, generates a single product in the preparation process, is stable and controllable, is environment-friendly, and has the characteristics of good yield, simple and convenient process, safety and the like; the veratraldehyde nitration is milder and has higher yield than the veratric acid nitration, the problem of selective demethylation is well solved through the positioning effect, the phenomenon that methanesulfonic acid and L-methionine are used for demethylation in the old process to generate a large amount of waste acid water is avoided, the reduction reaction is cleaner than the reduction of iron powder in the document CN1733738, the purity is higher, and the acetyl protection of the intermediate is also beneficial to the subsequent preparation of gefitinib. The compound of the formula I prepared by the preparation method has the advantages of excellent yield and quality, good stability, high purity, convenient storage and the like.
Generally, the preparation method provided by the invention can simultaneously reduce the cost, is easy to refine and purify, and is easy to prepare and control various related impurities, the whole preparation process route is greatly optimized, and the preparation method is suitable for industrial large-scale production.
Drawings
FIG. 1 shows the 1H-NMR spectrum of the compound of formula I prepared in example 6 of the present invention.
FIG. 2 shows the mass spectrum of the compound of formula I prepared in example 6 of the present invention.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
It is to be understood that the processing equipment or apparatus not specifically identified in the following examples is conventional in the art.
Furthermore, it is to be understood that one or more method steps mentioned in the present invention does not exclude that other method steps may also be present before or after the combined steps or that other method steps may also be inserted between these explicitly mentioned steps, unless otherwise indicated; it is also to be understood that a combined connection between one or more devices/apparatus as referred to in the present application does not exclude that further devices/apparatus may be present before or after the combined device/apparatus or that further devices/apparatus may be interposed between two devices/apparatus explicitly referred to, unless otherwise indicated. Moreover, unless otherwise indicated, the numbering of the method steps is only a convenient tool for identifying each method step, and is not intended to limit the order of the method steps or the scope of the invention, and changes or modifications in the relative relationship thereof may be regarded as the scope of the invention without substantial change in the technical content.
Example 1
Preparation of the compound of formula II:
200g (1.2mol) of 3, 4-dimethoxybenzaldehyde is added into a 2L three-necked bottle, 1L of dichloroethane is added, stirring is carried out at 25 ℃ until complete dissolution, 200mL (2.93mol) of 65% nitric acid is added into the reaction bottle dropwise, the dropwise adding temperature is controlled between 25 ℃ and 40 ℃, and the dropwise adding is finished for about 1 hour. Stirring was continued for 6 hours at 35 ℃ and the reaction was monitored by HPLC for completion. Water (1.5L) was added for extraction, the organic phase was collected, washed with saturated sodium bicarbonate solution 1 time, saturated brine 1 time, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude compound of formula ii, slurried with n-hexane, filtered to give 226.2g of yellow compound of formula ii, 89% molar yield and 98% purity. 1 H-NMR(CDCl 3 ，400MHz)δ4.04(3H，s)，4.05(3H，s)，7.42(1H，s)，7.65(1H，s)，10.45(1H，s)；MS(ESI，m/z)：212[M+H] + 。
Example 2
Preparation of the compound of formula III:
370g (1.75mol) of the compound of formula II was put into a 5L three-necked flask, 1.75L of acetonitrile, 0.7L of water and 64.4g (0.47mol) of potassium dihydrogen phosphate were added thereto, and the mixture was stirred to obtain a turbid solution. 2.38kg (2.63mol) of 10% sodium chlorite solution is dripped, the dripping temperature is controlled to be 25-35 ℃, stirring is continued for 1 hour after dripping, and the reaction is monitored by HPLC to be finished. 36% hydrochloric acid was added dropwise to a pH of about 2 to precipitate a large amount of solid, which was then filtered, collected and dried by blowing at 50 ℃ to obtain 350.5g of the yellow compound of formula III in a molar yield of 88% and a purity of 97%. 1 H-NMR(DMSO-d 6 ，400MHz)δ3.83(6H，s)，7.72(1H，s)，7.90(1H，s)，11.00(1H，s)；MS(ESI，m/z)：228[M+H] + 。
Example 3
Preparation of the compound of formula IV:
227g (1mol) of the compound of formula III is added to a 2L three-necked flask, a solution prepared from 224g (4mol) of 85% potassium hydroxide and 900mL of water is added, the mixture is heated to 98-100 ℃, stirred for 3-4 hours under constant temperature, and the reaction is monitored by HPLC to be complete. Cooling to 10 deg.C, adding 36% hydrochloric acid dropwise until pH is about 2, precipitating a large amount of solid, filtering, collecting solid, blowing at 50 deg.CDrying to obtain 181g of yellow compound IV with 85% molar yield and 96% purity. 1 H-NMR(CDCl 3 ，400MHz)δ3.80(3H，s)，6.89(1H，s)，7.34(1H，s)；MS(ESI，m/z)：214[M+H] + 。
Example 4
Preparation of a Compound of formula V:
181g (0.85mol) of the compound of formula IV was charged into a 5L three-necked flask, 3L of anhydrous methanol was added, 18g of 10% palladium on carbon was added, hydrogen gas was replaced, the mixture was stirred at room temperature for 4 hours, and the reaction was monitored by HPLC to be completed. Filtering, eluting with methanol, and directly spin-drying the filtrate to obtain 143.2g of the off-white compound of formula V, with a molar yield of 92% and a purity of 94%. 1 H-NMR(DMSO-d 6 ，400MHz)δ3.73(3H，s)，6.29(1H，s)，7.09(1H，s),8.1-8.4(2H，brs)，9.27(1H，s)，13.11(1H，brs)；MS(ESI，m/z)：184[M+H] + 。
Example 5
Preparation of a Compound of formula VI:
120g (0.66mol) of the compound of the formula V is added into a 5L three-necked bottle, 2L of ethylene glycol monomethyl ether and 137.4g (1.32mol) of formamidine acetate are added, the reaction is heated and refluxed for 3 to 4 hours, and the reaction is monitored by HPLC to be finished. Ethylene glycol monomethyl ether is evaporated out under reduced pressure, 1L of water is added, stirring and pulping are carried out, filtering is carried out, solids are collected, and light brown compounds of the formula VI are obtained by blowing air and drying at 50 ℃, wherein the molar yield is 93 percent, and the purity is 98 percent. 1 H-NMR(DMSO-d 6 ，400MHz)δ3.88(3H，s)，7.08(1H，s)，7.36(1H，s)，7.89(1H，s)9.48(1H，s)，11.4(1H，brs)；MS(ESI，m/z)：193[M+H] + 。
Example 6
Preparation of a Compound of formula I:
100g (0.52mol) of the compound of formula VI, 500mL of N, N-dimethylformamide and 200mL of pyridine are added into a 2L three-necked flask, 500mL of acetic anhydride is added dropwise, and after the addition is finished, the temperature is raised to 40-45 ℃ for reaction for 1 hour. The reaction was monitored by HPLC for completion. The reaction solution was poured into 1.2L of ice water, crystallized, filtered, the solid was collected and dried by blowing air at 50 ℃ to obtain 117g of light brown compound I, the molar yield was 96% and the purity was 99%. 1 H-NMR(DMSO-d 6 ，400MHz)δ2.31(3H，s)，3.91(3H，s)，7.28(1H，s)，7.76(1H，s)，8.09(1H，s)12.22(1H，brs)；MS(ESI，m/z)：235[M+H] + 。
In conclusion, the present invention effectively overcomes various disadvantages of the prior art and has high industrial utilization value.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which may be made by those skilled in the art without departing from the spirit and scope of the present invention as defined in the appended claims.
Claims (6)
1. A method for preparing 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate, comprising the steps of:
1) nitration reaction: nitrating 3, 4-dimethoxy benzaldehyde to prepare a compound shown in a formula II;
2) and (3) oxidation reaction: oxidizing the compound of the formula II to prepare a compound of a formula III;
3) selective demethylation reaction: reacting a compound in a formula III in the presence of alkali to prepare a compound in a formula IV;
4) reduction reaction: reacting a compound shown in a formula IV in the presence of a catalyst in a hydrogen atmosphere to prepare a compound shown in a formula V;
5) and (3) cyclization reaction: reacting the compound shown in the formula V with formamidine acetate to prepare a compound shown in a formula VI;
6) and (3) acetylation reaction of phenolic hydroxyl: reacting a compound shown in formula VI with acetic anhydride in the presence of a base catalyst to prepare a compound shown in formula I;
preparation of the compound of formula II: adding 1.2mol of 3, 4-dimethoxybenzaldehyde 200g into a 2L three-necked flask, adding 1L of dichloroethane, stirring at 25 ℃ until the dichloroethane is completely dissolved, dropwise adding 2.93mol of 200mL of 65% nitric acid into the reaction flask,
controlling the dripping temperature to be between 25 and 40 ℃ and finishing dripping within about 1 hour; stirring is continued for 6 hours at 35 ℃, and the reaction is monitored by HPLC to be finished; adding 1.5L of water for extraction, collecting an organic phase, washing with a saturated sodium bicarbonate solution for 1 time, washing with a saturated salt solution for 1 time, drying the organic phase with anhydrous sodium sulfate, filtering the organic phase, concentrating under reduced pressure to obtain a crude product of a compound of a formula II, pulping with n-hexane, and filtering to obtain a yellow compound of the formula II;
preparation of the compound of formula III: 370g of compound shown in the formula II in an amount of 1.75mol, 1.75L of acetonitrile, 0.7L of water and 64.4g of monopotassium phosphate in an amount of 0.47mol are added into a three-necked flask with 5L, and stirred to obtain a turbid solution; 2.38kg of 2.63mol 10% sodium chlorite solution is dripped, the dripping temperature is controlled to be 25-35 ℃, stirring is continued for 1 hour after dripping, and HPLC monitoring reaction is finished; dropwise adding 36% hydrochloric acid until the pH value is about 2, precipitating a large amount of solid, filtering, collecting the solid, and drying by blowing air at 50 ℃ to obtain a yellow compound shown in the formula III;
2. the method of claim 1, further comprising one or more of the following features:
C1) in the step 3), the reaction is carried out under the condition that the pH value is 13-14;
C2) in the step 3), the alkali is selected from one or more of NaOH and KOH;
C3) in the step 3), the reaction temperature is 95-100 ℃;
C4) the post-processing method of the step 3) comprises the following steps: after the reaction is finished, adjusting the pH value of the reaction system to be acidic, carrying out solid-liquid separation, and drying a solid phase substance to obtain the compound shown in the formula IV.
3. The production method according to claim 2, wherein after completion of the reaction, the pH of the reaction system is adjusted to 2 to 3.
4. The method of claim 1, further comprising one or more of the following technical features:
D1) in the step 4), the catalyst is selected from one or more of palladium catalyst, nickel catalyst and sodium hydrosulfite;
D2) in the step 4), the catalyst is used in an amount of 5-wt 10% of the compound of the formula IV;
D3) in the step 4), the reduction reaction is carried out in the presence of a solvent, wherein the solvent used in the reduction reaction is selected from one or more of methanol, ethanol and ethyl acetate;
D4) in the step 4), the reaction temperature is 30-40 ℃, and the reaction pressure is 1.5-2 atmospheric pressures;
D5) the post-processing method of the step 4) comprises the following steps: and after the reaction is finished, washing the product by using a solvent to obtain the compound shown in the formula V, wherein the solvent used for washing is one or a combination of more of methanol, ethanol and ethyl acetate.
5. The method of claim 1, further comprising one or more of the following technical features:
E1) in the step 5), the molar ratio of the compound shown in the formula V to formamidine acetate is 1: 2-2.5;
E2) in the step 5), the cyclization reaction is carried out in the presence of a solvent, and the solvent used in the cyclization reaction is selected from one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether and xylene;
E3) in the step 5), the reaction temperature is 110-120 ℃;
E4) the post-processing method of the step 5) comprises the following steps: and after the reaction is finished, removing the solvent, washing with water, and drying to obtain the compound shown in the formula VI.
6. The method of claim 1, further comprising one or more of the following features:
F1) in the step 6), the weight ratio of the compound in the formula VI to the acetic anhydride is 1: 4-6;
F2) in the step 6), the base catalyst is selected from one or more of pyridine, triethylamine and diisopropylethylamine;
F3) in the step 6), the molar ratio of the compound in the formula VI to the alkali catalyst is 1: 4-6;
F4) in the step 6), the acetylation of the phenolic hydroxyl group is carried out in the presence of a solvent, wherein the solvent used in the acetylation of the phenolic hydroxyl group is one or more selected from N, N-dimethylformamide and N, N-dimethylacetamide;
F5) in the step 6), the reaction temperature is 40-50 ℃;
F6) the post-processing method of the step 6) comprises the following steps: adding water for crystallization after the reaction is finished, and carrying out solid-liquid separation to obtain the compound shown in the formula VI.
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