Synthesis method of 4-(2-H-pyranoloxy) phenylmalonic acid-4-methoxy benzyl monoester

Abstract

The invention relates to a synthesis method of a latamoxef 7-position side-chain compound 4-(2-H-pyranoloxy) phenylmalonic acid-4-methoxy benzyl monoester, which comprises the following steps: by taking p-hydroxyphenylacetic acid and p-methoxybenzyl chloride as initial raw materials, carrying out esterification reaction in the presence of an acid-binding agent sodium bicarbonate or potassium bicarbonate to prepare an intermediate I, and then reacting the intermediate I with 2, 4-dimethoxybenzyl monoester to obtain the latamoxef 7-position side-chain compound 4-(2-H-pyranoloxy) phenylmalonic acid-4-methoxy benzyl monoester. The preparation method comprises the following steps: carrying out etherification reaction on 2, 3-dihydropyran to prepare an intermediate II, and finally carrying out carboxylation reaction on the intermediate II and carbon dioxide to prepare 4-(2-H-pyranoloxy) phenylmalonic acid-4-methoxy benzyl monoester. Selective protection of hydroxyl and carboxyl in p-hydroxyphenylacetic acid is achieved by selecting the mild acid-binding agent, the purity and yield of the target product are improved, and the method is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis and relates to a method for synthesizing the 7-side chain of latamoxef, in particular to a method for synthesizing 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester. Background Art

[0002] Latamoxef disodium, chemical name 7-[[2-carboxy-(4-hydroxyphenyl)acetyl]amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)sulfur]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt, is a new third-generation oxygen cephalosporin antibiotic with a broad antibacterial spectrum. It has good antibacterial effects on a variety of Gram-negative bacteria, Escherichia coli, Klebsiella pneumoniae, Proteus, etc. It is 4 to 16 times stronger than general cephalosporins and is significantly superior to other similar varieties. It is widely used in the treatment of infections in pneumonia, tracheitis, pleurisy, peritonitis, meningitis, sepsis and other parts.

[0003] 4-(4-methoxybenzyloxy)phenylmalonic acid-4-methoxybenzyl monoester, commonly known as the 7-position side chain of latamoxef, is a key intermediate in the synthesis of latamoxef disodium.

[0004] The structure of the 7-position side chain of latamoxepin is shown below, and its hydroxyl group and carboxyl group are protected by p-methoxybenzyl. In the process of synthesizing the downstream product latamoxepin disodium with the side chain, an excessive amount of strong acid is required to remove the p-methoxybenzyl protecting group introduced by the side chain. However, the strong acid will damage the parent nucleus of latamoxepin, resulting in a decrease in the yield and purity of the downstream product and an increase in impurities.

[0005]

[0006] US 4336196A relates to another 7-position side chain of latamoxef, which has the structural formula shown below and the chemical name 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester:

[0007]

[0008] The hydroxyl group of the 7-position side chain of latamoxepin in this structure is protected by a tetrahydropyranyl ether protecting group, which can be removed under weak acid conditions during the subsequent synthesis of latamoxepin disodium. Since weak acid has little damage to the parent nucleus, the purity and yield of downstream products will be relatively improved, so it is widely welcomed.

[0009] The synthesis of the 7-position side chain of the latamoxepin is to prepare strong organic bases such as phenyl sodium or ethynyl sodium by reacting chlorinated benzene or acetylene with metallic sodium, and then reacting these strong organic bases with the raw material (2-H-pyran-4-p-methoxy)benzyloxyphenylacetic acid (p-methoxy)benzyl ester to synthesize sodium arylacetate enol, and adding dry ice at -20 to -40°C to prepare 4-(2-H-pyranyloxy)benzylmalonate-4-methoxybenzyl monoester. However, the patent does not explain the source and synthesis method of the raw material (2-H-pyran-4-p-methoxy)benzyloxyphenylacetic acid (p-methoxy)benzyl ester, and metallic sodium reacts violently with organic compounds, and the synthesized strong organic base has poor stability and is difficult to produce industrially.

[0010] CN 113372316A discloses a new preparation method of the 7-position side chain of latamoxef. The method comprises the following steps: using p-hydroxyphenylacetic acid as a starting material, firstly reacting the raw material with 2,3-dihydropyran in the presence of p-toluenesulfonic acid or a cation exchange resin to synthesize an intermediate p-(2-H-pyranyl)phenylacetic acid; then dissolving the raw material in an inert solvent, adding p-methoxybenzyl alcohol and concentrated sulfuric acid as a catalyst, and subjecting the mixture to a reflux esterification reaction to obtain 4-(2-H-pyranyloxy)phenylacetic acid-4-methoxybenzyl ester; and finally introducing carbon dioxide under the action of an organic strong base to react to obtain 4-(2-H-pyranyloxy)phenylmalonic acid-4-methoxybenzyl monoester.

[0011] During the esterification reaction of the intermediate in the above preparation method, the added concentrated sulfuric acid catalyst easily leads to the removal of the pyran ring protecting the hydroxyl group on the intermediate, resulting in the generation of by-products, and the purity and yield of 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester are reduced. Summary of the invention

[0012] The purpose of the present invention is to provide a new method for synthesizing 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester, so as to solve the problems of purity and yield of 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester in the existing synthesis method.

[0013] The synthesis method of 4-(2-H-pyranyloxy)phenylmalonic acid-4-methoxybenzyl monoester of the present invention comprises the following steps: firstly, p-hydroxyphenylacetic acid and p-methoxybenzyl chloride are used as starting materials, and an esterification reaction is carried out in the presence of an acid-binding agent, sodium bicarbonate or potassium bicarbonate, to prepare 4-hydroxyphenylacetic acid-4-methoxybenzyl ester as an intermediate I; then, the intermediate I is subjected to an etherification reaction with 2,3-dihydropyran to prepare 4-(2-H-pyranyloxy)phenylacetic acid-4-methoxybenzyl ester as an intermediate II; and finally, the intermediate II is subjected to a carboxylation reaction with carbon dioxide to prepare a 7-position side chain compound, 4-(2-H-pyranyloxy)phenylmalonic acid-4-methoxybenzyl monoester.

[0014] Furthermore, the synthesis method of 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester of the present invention specifically comprises the following steps:

[0015] 1) In an organic solvent system in which an acid-binding agent, sodium bicarbonate or potassium bicarbonate, is present, esterification reaction is carried out with p-hydroxyphenylacetic acid and p-methoxybenzyl chloride to prepare an intermediate I solution;

[0016] 2), dissolving 2,3-dihydropyran in the intermediate I solution, carrying out etherification reaction in the presence of a Lewis acid catalyst, and separating the reaction product to obtain intermediate II;

[0017] 3) Introducing carbon dioxide gas into the organic solvent of intermediate II in the presence of an organic strong base to carry out a carboxylation reaction to prepare 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester.

[0018] The specific synthetic route of the synthetic method of the present invention is as follows:

[0019]

[0020] The present invention selects sodium bicarbonate or potassium bicarbonate as an acid-binding agent. When p-methoxybenzyl chloride is used as a protecting group to react with p-hydroxyphenylacetic acid, only the carboxyl group is selectively protected while avoiding reaction with the hydroxyl group. Thus, the hydroxyl group can be further etherified and protected with dihydropyran under Lewis acid catalyst conditions.

[0021] The synthetic route of the present invention overcomes the disadvantage that the intermediate p-(2-H-pyrano)phenylacetic acid is easily hydrolyzed by acid when the hydroxyl group of p-hydroxyphenylacetic acid is first protected with dihydropyran and then with p-methoxybenzyl alcohol under strong acid conditions in CN 113372316A, and the purity and yield of the final product are significantly improved.

[0022] The raw materials of the invention are cheap and readily available, the process is simple, the whole process is easy to control, the reaction conditions are mild, and industrial production can be realized. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the HPLC spectra of the raw material p-hydroxyphenylacetic acid, the intermediate I (4-hydroxyphenylacetic acid-4-methoxybenzyl ester) prepared in Example 1, and the intermediate I (4-(4-methoxybenzyloxy)phenylacetic acid-4-methoxybenzyl monoester) prepared in Comparative Example 2.

[0024] Figure 2 This is the infrared spectrum of 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester prepared in Example 1.

[0025] Figure 3This is the infrared spectrum of 4-(4-methoxybenzyloxy)benzenemalonic acid-4-methoxybenzyl monoester prepared in Comparative Example 2. Implementation

[0026] The specific implementation of the present invention is further described in detail below in conjunction with the accompanying drawings and examples. The following examples are only used to more clearly illustrate the technical solution of the present invention so that those skilled in the art can well understand and utilize the present invention, rather than limiting the scope of protection of the present invention.

[0027] The production processes, experimental methods or detection methods involved in the embodiments and comparative examples of the present invention are all conventional methods in the prior art unless otherwise specified, and their names and / or abbreviations are all conventional names in the field and are very clear and unambiguous in the relevant application fields. Those skilled in the art can understand the conventional process steps based on the names and apply the corresponding equipment to implement them according to conventional conditions or the conditions recommended by the manufacturer.

[0028] The various instruments, equipment, raw materials or reagents used in the embodiments of the present invention are not particularly limited in terms of their sources, and are all conventional products that can be purchased through regular commercial channels, or can be prepared according to conventional methods well known to those skilled in the art.

[0029] The present invention provides a novel method for synthesizing 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester, which specifically comprises:

[0030] 1) Dissolve p-hydroxyphenylacetic acid and p-methoxybenzyl chloride in an organic solvent, add an acid-binding agent, sodium bicarbonate or potassium bicarbonate, and carry out an esterification reaction in the presence of a phase transfer catalyst. After the reaction is completed, wash with water and dry to obtain an intermediate I solution;

[0031] 2) Dissolve 2,3-dihydropyran in the intermediate I solution, add Lewis acid catalyst to carry out etherification reaction, wash with alkali, dry and remove the solvent after the reaction is completed to obtain intermediate II;

[0032] 3) At low temperature, carbon dioxide gas is introduced into the organic solvent of intermediate II in the presence of an organic strong base to carry out a carboxylation reaction to prepare 4-(2-H-pyranyloxy)benzenemalonic acid 4-methoxybenzyl monoester salt, and the product 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester is obtained by acidification.

[0033] The organic solvent in step 1) can be any organic solvent that has good solubility in p-hydroxyphenylacetic acid and does not react with p-hydroxyphenylacetic acid and p-methoxybenzyl chloride.

[0034] Preferably, the organic solvent may include, but is not limited to, any one or more of toluene, tetrahydrofuran, ethyl acetate, and dichloroethane.

[0035] The phase transfer catalyst in step 1) can be any conventional quaternary ammonium salt phase transfer catalyst, including but not limited to any one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride.

[0036] Wherein, the step 1) is preferably carried out at a reaction temperature of 40 to 70° C., and more preferably, the reaction time is 4 to 10 hours.

[0037] More preferably, in step 1), the molar ratio of p-hydroxyphenylacetic acid to p-methoxybenzyl chloride is 1:(1.0-1.1).

[0038] More preferably, in step 1), the molar ratio of p-hydroxyphenylacetic acid to the acid-binding agent is 1:(1.1-1.3).

[0039] More preferably, the amount of the phase transfer catalyst used in step 1) is 5-10% of the mass of p-hydroxyphenylacetic acid.

[0040] The Lewis acid catalyst in step 2) may be any conventional Lewis acid catalyst, including but not limited to any one or two of pyridinium p-toluenesulfonate, p-toluenesulfonic acid, and methanesulfonic acid.

[0041] Wherein, the step 2) is preferably carried out at a reaction temperature of 15 to 35° C., and more preferably, the reaction time is 7 to 13 h.

[0042] More preferably, the molar amount of dihydropyran in step 2) is 1.0 to 1.2 times the molar amount of p-hydroxyphenylacetic acid.

[0043] More preferably, the amount of Lewis acid catalyst used in step 2) is 3-5% of the mass of p-hydroxyphenylacetic acid.

[0044] The organic solvent in step 3) can be one or more of toluene, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, and dichloromethane.

[0045] The organic strong base in step 3) can be any one of lithium isopropylamide, potassium tert-butoxide, and sodium hexamethyldisilazide.

[0046] Wherein, the low temperature of the carbon dioxide gas introduced in step 3) is preferably -60 to -35°C.

[0047] More preferably, the molar amount of the organic strong base in step 3) is 2.0 to 2.2 times the molar amount of p-hydroxyphenylacetic acid.

[0048] Specifically, the synthesis process of step 3) of the present invention substantially comprises: intermediate II is first dehydrogenated under alkaline conditions to obtain transition state molecule 1 (carbonyl α-carbon anion form of 4-(2-H-pyranyloxy)phenylacetic acid-4-methoxybenzyl ester), and then conjugated isomerized to generate transition state molecule 2 (enol form of 4-(2-H-pyranyloxy)phenylacetic acid-4-methoxybenzyl ester), the transition state molecule 2 is unstable under low temperature conditions, and further reacts with carbon dioxide to generate 4-(2-H-pyranyloxy)phenylmalonic acid-4-methoxybenzyl monoester salt shown in molecule 3, and finally acidified to obtain the product 4-(2-H-pyranyloxy)phenylmalonic acid-4-methoxybenzyl monoester.

[0049]

[0050] More preferably, the acidification in step 3) is to adjust the pH of the reaction solution to 2.0-4.0 with dilute hydrochloric acid at room temperature after the carboxylation reaction is completed, stand the reaction mixture to separate into layers, recover the solvent from the organic layer, and recrystallize the organic layer to obtain the product. Example

[0051] Example 1

[0052] 50.0 g of p-hydroxyphenylacetic acid, 51.5 g of p-methoxybenzyl chloride, 30.4 g of sodium bicarbonate and 2.5 g of tetrabutylammonium bromide were weighed and added into a reaction bottle, and then 400 mL of toluene was added, and the temperature was raised to 45° C. and reacted for 10 h to prepare intermediate I (4-hydroxyphenylacetic acid-4-methoxybenzyl ester).

[0053] Figure 1 In the reaction, the HPLC retention time of the raw material p-hydroxyphenylacetic acid is approximately 3.1 min. In the HPLC spectrum after the reaction is completed, the chromatographic peak of the raw material at 3.1 min almost disappears, while the chromatographic peak of the intermediate I appears near the retention time of 9.6 min, indicating that the above reaction has been carried out thoroughly.

[0054] After the reaction was completed by HPLC detection, the mixture was cooled to room temperature, washed twice with 100 mL of deionized water, allowed to stand for stratification, and the organic layer was dehydrated with anhydrous sodium sulfate to obtain a toluene solution of intermediate I.

[0055] 27.6 g of 2,3-dihydropyran was dissolved in the toluene solution of the intermediate I obtained above, and 1.5 g of pyridinium p-toluenesulfonate was added, and the mixture was reacted at 35° C. for 7 h.

[0056] After the reaction was completed as determined by HPLC, the reaction solution was adjusted to neutral with 2% aqueous sodium hydroxide solution, allowed to stand for stratification, the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent toluene was evaporated under reduced pressure to obtain 103.1 g of intermediate II as a light yellow viscous liquid.

[0057] The intermediate II was dissolved in 200 mL of anhydrous toluene, 330 g of 40% sodium hexamethyldisilazide toluene solution was added, stirred for 2 h, cooled to -45°C, and carbon dioxide gas was introduced to react.

[0058] After the reaction was completed by HPLC detection, the pH value of the reaction solution was adjusted to 2.0-4.0 with 12% dilute hydrochloric acid at room temperature, stirred for 10 minutes, and allowed to stand for stratification. The aqueous layer was extracted with 200 mL of toluene and allowed to stand for stratification. The two organic layers were combined, dehydrated with anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, and 100 mL of methyl tert-butyl ether was added. The temperature was cooled to -5-0°C for crystallization, filtered, and vacuum dried to obtain 86.1 g of the final product, with a molar yield (based on p-hydroxyphenylacetic acid) of 65.4% and a product purity of 98.2%.

[0059] Take a small amount of the final product for infrared spectrum detection, the result is as follows Figure 2 As shown, 2947cm -1 It is the -CH2- stretching vibration absorption peak, 2843cm -1 It is the CH3O stretching vibration absorption peak, 1735cm -1 and 1305cm -1 They are the C=O and CO stretching vibration absorption peaks in the ester carbonyl group, 1257 cm -1 and 1035cm -1 They are the Ar-O and CO stretching vibration absorption peaks in the ether structure, 1695 cm -1 It is the C=O stretching vibration absorption peak in the carboxyl group, 1614cm -1 、1517cm -1 、1465cm -1 It is the stretching vibration absorption peak of the benzene ring skeleton, 1116cm -1 It is the absorption peak of the stretching vibration of the pyran ring, which proves that the target product is indeed synthesized in this example.

[0060] Example 2

[0061] 50.0 g of p-hydroxyphenylacetic acid, 54.6 g of p-methoxybenzyl chloride, 28.6 g of sodium bicarbonate and 4.0 g of tetrabutylammonium chloride were weighed and added into a reaction bottle, and then 400 mL of ethyl acetate was added, and the temperature was raised to 50° C. and reacted for 8.5 h.

[0062] After the reaction was completed by HPLC detection, the mixture was cooled to room temperature, washed twice with 100 mL of deionized water, and allowed to stand for stratification. The organic layer was dehydrated with anhydrous sodium sulfate to obtain an ethyl acetate solution of intermediate I.

[0063] 33.2 g of 2,3-dihydropyran was dissolved in the ethyl acetate solution of the intermediate I obtained above, and 2.0 g of methanesulfonic acid was added, and the mixture was reacted at 30° C. for 9 h.

[0064] After the reaction was completed as determined by HPLC, the reaction solution was adjusted to neutral with 2% aqueous sodium carbonate solution, allowed to stand for stratification, the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent ethyl acetate was evaporated under reduced pressure to obtain 102.9 g of intermediate II as a light yellow viscous liquid.

[0065] The intermediate II was dissolved in 200 mL of anhydrous tetrahydrofuran, 73.8 g of potassium tert-butoxide was added, stirred for 2 h, cooled to -35°C, and carbon dioxide gas was introduced to react.

[0066] After the reaction was completed by HPLC detection, the pH value of the reaction solution was adjusted to 2.0-4.0 with 12% dilute hydrochloric acid at room temperature, stirred for 10 minutes, and allowed to stand for stratification. The aqueous layer was then extracted with 200 mL of ethyl acetate and allowed to stand for stratification. The two organic layers were combined, dehydrated with anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, and 100 mL of dichloromethane was added. The temperature was lowered to -5-0°C for crystallization, filtered, and vacuum dried to obtain 89.5 g of the final product, with a molar yield (based on p-hydroxyphenylacetic acid) of 68.0% and a product purity of 97.9%.

[0067] Example 3

[0068] 50.0 g of p-hydroxyphenylacetic acid, 56.6 g of p-methoxybenzyl chloride, 39.5 g of potassium bicarbonate and 4.0 g of tetrabutylammonium hydrogen sulfate were weighed and added into a reaction bottle, and then 400 mL of tetrahydrofuran was added, and the temperature was raised to 60° C. and reacted for 5.5 h.

[0069] After the reaction was completed by HPLC detection, the mixture was cooled to room temperature, washed twice with 100 mL of deionized water, allowed to stand for stratification, and the organic layer was dehydrated with anhydrous sodium sulfate to obtain a tetrahydrofuran solution of intermediate I.

[0070] 30.4 g of 2,3-dihydropyran was dissolved in the tetrahydrofuran solution of the intermediate I obtained above, and 2.5 g of p-toluenesulfonic acid was added, and the mixture was reacted at 20° C. for 11.5 h.

[0071] After the reaction was completed as determined by HPLC, the reaction solution was adjusted to neutral with 2% aqueous sodium carbonate solution, allowed to stand for stratification, the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent tetrahydrofuran was evaporated under reduced pressure to obtain 103.7 g of intermediate II as a light yellow viscous liquid.

[0072] The intermediate II was dissolved in 200 mL of anhydrous toluene, 330 g of 40% sodium hexamethyldisilazide toluene solution was added, stirred for 2 h, cooled to -50°C, and carbon dioxide gas was introduced to react.

[0073] After the reaction was completed by HPLC detection, the pH value of the reaction solution was adjusted to 2.0-4.0 with 12% dilute hydrochloric acid at room temperature, stirred for 10 minutes, and allowed to stand for stratification. The aqueous layer was then extracted with 200 mL of toluene and allowed to stand for stratification. The two organic layers were combined, dehydrated with anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, and 100 mL of ethyl acetate was added. The temperature was lowered to -5-0°C for crystallization, filtered, and vacuum dried to obtain 88.4 g of the final product, with a molar yield (based on p-hydroxyphenylacetic acid) of 67.2% and a product purity of 98.4%.

[0074] Example 4

[0075] Weigh 50.0 g of p-hydroxyphenylacetic acid, 55.5 g of p-methoxybenzyl chloride, 42.8 g of potassium bicarbonate and 5.0 g of dodecyltrimethylammonium chloride into a reaction bottle, then add 400 mL of dichloroethane, and heat to 70° C. to react for 4 h.

[0076] After the reaction was completed by HPLC detection, the mixture was cooled to room temperature, washed twice with 100 mL of deionized water, allowed to stand for stratification, and the organic layer was dehydrated with anhydrous sodium sulfate to obtain a dichloroethane solution of intermediate I.

[0077] 29 g of 2,3-dihydropyran was dissolved in the dichloroethane solution of the intermediate I obtained above, and 1.5 g of pyridinium p-toluenesulfonate was added, and the mixture was reacted at 15° C. for 13 h.

[0078] After the reaction was completed as determined by HPLC, the reaction solution was adjusted to neutral with 2% aqueous sodium hydroxide solution, allowed to stand for stratification, the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent dichloroethane was evaporated under reduced pressure to obtain 103.2 g of intermediate II as a light yellow viscous liquid.

[0079] The intermediate II was dissolved in 200 mL of anhydrous tetrahydrofuran, 380 g of 20% lithium isopropylamide tetrahydrofuran solution was added, stirred for 2.0 h, cooled to -60°C, and carbon dioxide gas was introduced to react.

[0080] After the reaction was completed by HPLC detection, the pH value of the reaction solution was adjusted to 2.0-4.0 with 12% dilute hydrochloric acid at room temperature, stirred for 10 minutes, and allowed to stand for stratification. The aqueous layer was then extracted with 200 mL of ethyl acetate and allowed to stand for stratification. The two organic layers were combined, dehydrated with anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, and 100 mL of toluene was added. The temperature was lowered to -5-0°C for crystallization, filtered, and vacuum dried to obtain 87.5 g of the final product, with a molar yield (based on p-hydroxyphenylacetic acid) of 66.5% and a product purity of 98.1%.

[0081] Comparative Example 1

[0082] CN 113372316A discloses a synthetic route for 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester which is different from the present invention, but does not provide the specific yield and purity of the final product. It only claims in the specification that the purity of the product can reach 97%, and that Example 12 thereof prepares 19.4 g of intermediate (II), which has the highest yield.

[0083] In this comparative example, the method of Example 12 of CN 113372316A was used, but the amount of raw materials was increased by 5 times, and 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester was prepared under the same conditions as in Example 1.

[0084] 50.0 g of p-hydroxyphenylacetic acid and 250 mL of dichloromethane were added to the reaction flask, and 5.0 g of cation exchange resin and 41.5 g of dihydropyran were added under stirring at room temperature, and the reaction was stirred at room temperature for 3 h. After the reaction was completed by HPLC detection, the reaction was filtered and the filtrate was concentrated under negative pressure to obtain 95 g of intermediate (I) as a yellow oil.

[0085] The intermediate (I) was dissolved in 500 mL of toluene, 90.0 g of p-methoxybenzyl alcohol was added, and 0.75 g of sulfuric acid was slowly added. The temperature was raised to reflux and water was separated for 15 h. After the reaction was completed by HPLC detection, the temperature was lowered to 30 ° C, 250 mL of 5% baking soda solution was added for washing for 10 min, and the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and isopropanol was added for crystallization. 97.0 g of intermediate (II) was obtained by filtration.

[0086] After testing, the purity of the prepared intermediate (II) was 95.3%, and the molar yield based on p-hydroxyphenylacetic acid was 82.8%; compared with the purity of the intermediate II prepared in Example 1 of the present invention, which was 99.2%, the molar yield based on p-hydroxyphenylacetic acid was 88.0%.

[0087] Dissolve intermediate II in 243 g of DMF, stir to dissolve, cool to -50°C, add 97.0 g of potassium tert-butoxide and stir for 30 min, introduce 73 g of carbon dioxide gas, and after HPLC detection, slowly add 485 g of deionized water for crystallization. After the addition is complete, keep warm at 5°C and stir for 1 h, filter, and rinse the filter cake with a mixture of deionized water and methanol to obtain 74.7 g of the final product.

[0088] After testing, the purity of the product was 97.0%, and the molar yield (based on p-hydroxyphenylacetic acid) was 56.8%. By comparison, the purity of the product prepared in Example 1 of the present invention was 98.2%, and the molar yield (based on p-hydroxyphenylacetic acid) was 65.4%.

[0089] It can be seen from the above comparison results that the synthesis method of the present invention is compared with CN 113372316A, and the purity and yield of both the intermediate II and the final 7-side chain of latamoxef are greatly improved.

[0090] Comparative Example 2

[0091] 50.0 g of p-hydroxyphenylacetic acid, 51.5 g of p-methoxybenzyl chloride, 38.3 g of sodium carbonate and 2.5 g of tetrabutylammonium bromide were weighed and added into a reaction bottle, and then 400 mL of toluene was added, and the temperature was raised to 45° C. and reacted for 10 h to prepare intermediate I.

[0092] HPLC detection of the reaction solution, Figure 1 In the above analysis, although the chromatographic peak of the p-hydroxyphenylacetic acid raw material at 3.1 min disappeared, the chromatographic peak of intermediate I did not appear near the retention time of 9.6 min, while another chromatographic peak appeared near the retention time of 19.5 min.

[0093] This is because after the acid-binding agent is replaced by sodium carbonate from sodium bicarbonate, the hydroxyl group and the carboxyl group on the p-hydroxyphenylacetic acid are protected by the p-methoxybenzyl group, generating an intermediate I with the chemical name 4-(4-methoxybenzyloxy)phenylacetic acid-4-methoxybenzyl monoester, which is an intermediate for preparing 4-(4-methoxybenzyloxy)phenylmalonic acid-4-methoxybenzyl monoester.

[0094] After the reaction was completed, the temperature was cooled to room temperature, washed twice with 100 mL of deionized water, and allowed to stand for stratification. The organic layer was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure to evaporate the solvent, and methanol was added for crystallization to obtain Intermediate I solid.

[0095] The intermediate I was dissolved in 200 mL of anhydrous toluene, 330 g of 40% sodium hexamethyldisilazide toluene solution was added, stirred for 2 h, cooled to -45°C, and carbon dioxide gas was introduced to react.

[0096] After the reaction was completed by HPLC detection, the pH value of the reaction solution was adjusted to 2.0-4.0 with 12% dilute hydrochloric acid at room temperature, stirred for 10 minutes, and allowed to stand for stratification. The aqueous layer was then extracted with 200 mL of toluene and allowed to stand for stratification. The two organic layers were combined, dehydrated with anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, and 100 mL of methyl tert-butyl ether was added, cooled to -5-0°C for crystallization, filtered, and vacuum dried to obtain the final product.

[0097] Take a small amount of the final product for infrared spectrum detection, the result is as follows Figure 3 As shown, 2935cm -1 It is the -CH2- stretching vibration absorption peak, 2833cm -1 It is the CH3O stretching vibration absorption peak, 1750cm -1 and 1303cm-1 They are the C=O and CO stretching vibration absorption peaks in the ester carbonyl group, 1250cm -1 and 1039cm -1 They are the Ar-O and CO stretching vibration absorption peaks in the ether structure, 3267 cm -1 and 1683cm -1 They are the stretching vibration absorption peaks of -OH and C=O in the carboxyl group, 1614 cm -1 、1517cm -1 、1465cm -1 It is the stretching vibration absorption peak of the benzene ring skeleton, 825cm -1 It is the =CH bending vibration absorption peak of the benzene ring, which proves that the final product is indeed 4-(4-methoxybenzyloxy)benzenemalonic acid-4-methoxybenzyl monoester.

[0098] The above embodiments of the present invention do not describe all the details in detail, nor limit the present invention to the above embodiments. Various changes, modifications, substitutions and variations made by ordinary technicians in this field without departing from the principles and purpose of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester, comprising: Using p-hydroxyphenylacetic acid and p-methoxybenzyl chloride as starting materials, an esterification reaction is carried out in the presence of an acid-binding agent, sodium bicarbonate or potassium bicarbonate, to prepare 4-hydroxyphenylacetic acid-4-methoxybenzyl ester as an intermediate I; The intermediate I is subjected to an etherification reaction with 2,3-dihydropyran to prepare 4-(2-H-pyranyloxy)phenylacetic acid-4-methoxybenzyl ester as intermediate II; The intermediate II is subjected to a carboxylation reaction with carbon dioxide to prepare the 7-side chain compound of latamoxepin 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester.

2. The method for synthesizing 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester according to claim 1, comprising: 1) In an organic solvent system in which an acid-binding agent, sodium bicarbonate or potassium bicarbonate, and a phase transfer catalyst are present, esterification reaction is carried out with p-hydroxyphenylacetic acid and p-methoxybenzyl chloride to prepare an intermediate I solution; 2), dissolving 2,3-dihydropyran in the intermediate I solution, carrying out etherification reaction in the presence of a Lewis acid catalyst, and separating the reaction product to obtain intermediate II; 3) At low temperature, carbon dioxide gas is introduced into the organic solvent of intermediate II in the presence of an organic strong base to carry out a carboxylation reaction to prepare 4-(2-H-pyranyloxy)benzenemalonic acid 4-methoxybenzyl monoester salt, and the product 4-(2-H-pyranyloxy)benzenemalonic acid-4-methoxybenzyl monoester is obtained by acidification.

3. The synthetic method according to claim 1 or 2, characterized in that The molar ratio of p-hydroxyphenylacetic acid to p-methoxybenzyl chloride and the acid-binding agent is 1:(1.0-1.1):(1.1-1.3).

4. The synthetic method according to claim 1 or 2, characterized in that The esterification reaction temperature is 40-70° C., and the reaction time is 4-10 hours.

5. The synthesis method according to claim 2, characterized in that the phase transfer catalyst is any one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride, and the amount used is 5-10% of the mass of p-hydroxyphenylacetic acid.

6. The synthetic method according to claim 1 or 2, characterized in that The molar amount of dihydropyran is 1.0 to 1.2 times the molar amount of p-hydroxyphenylacetic acid.

7. The synthetic method according to claim 1 or 2, characterized in that The etherification reaction temperature is 15-35° C., and the reaction time is 7-13 hours.

8. The synthesis method according to claim 2, characterized in that The Lewis acid catalyst is any one or two of pyridinium p-toluenesulfonate, p-toluenesulfonic acid, and methanesulfonic acid, and the amount used is 3-5% of the mass of p-hydroxyphenylacetic acid.

9. The synthetic method according to claim 1 or 2, characterized in that The carboxylation reaction temperature is -60 to -35°C.

10. The synthesis method according to claim 2, characterized in that The amount of any one of the organic strong base lithium isopropylamide, potassium tert-butoxide, and sodium hexamethyldisilazide is 2.0 to 2.2 times the molar amount of p-hydroxyphenylacetic acid.

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