CN113698365A - Preparation method of cefditoren side chain - Google Patents

Preparation method of cefditoren side chain Download PDF

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CN113698365A
CN113698365A CN202111007933.XA CN202111007933A CN113698365A CN 113698365 A CN113698365 A CN 113698365A CN 202111007933 A CN202111007933 A CN 202111007933A CN 113698365 A CN113698365 A CN 113698365A
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chloride
acid
side chain
cefditoren
compound
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石克金
李江红
陈林
张斌
唐美玲
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Chengdu University
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Chengdu University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Abstract

The invention provides a preparation method of a cefditoren side chain. The method comprises the following steps: 2-chloro-3, 4-dimethoxybenzaldehyde is taken as a raw material, and methyl is removed under the catalysis of Lewis acid or alkali to obtain 2-chloro-3, 4-dihydroxybenzaldehyde; then protecting the hydroxyl group; oxidizing aldehyde group, carrying out sulfonic anhydride reaction, and finally carrying out amidation reaction with 1- (2-aminoethyl) pyrrolidine to obtain the 3-position side chain of the cefditoren. The invention uses a new starting material, and is prepared by four steps of demethylation, hydroxyl protection, aldehyde group oxidation and amidation. The method is green and environment-friendly, has easily obtained raw materials, is simple and convenient to operate, has high product yield and purity, is low in cost, and is easy for industrial production.

Description

Preparation method of cefditoren side chain
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a cefditoren side chain.
Background
Cefditorel (see formula 1) is a novel cephalosporin antibacterial developed by japan halobios (Shionogi) under the trade name Fetroja, code No. S-649266 and GSK-696266, and approved by the U.S. FDA on 11/14 days 2019 for the treatment of complicated urinary tract infection (cluti) caused by gram-negative bacteria. Is suitable for patients of 18 years old and above with limited or no alternative treatment options to treat cUTI and pyelonephritis caused by susceptible gram-negative bacteria. The successful marketing of cefditoren provides an effective solution to the problem of antibiotic resistance.
Figure 1
Cefditoren is a novel siderophore cephalosporin antibacterial, has a unique action mechanism of penetrating the cell membrane of gram-negative bacteria, is complexed with ferric ions, penetrates the outer membrane of the cell membrane through a bacterial iron transporter, is transported to the inner wall of the bacterial cell to reach higher concentration in the bacterial cytoplasm, is combined with a receptor to inhibit the synthesis of the bacterial cell wall, has strong killing activity on all gram-negative bacteria, comprises carbapenem-resistant gram-negative non-fermented acinetobacter baumannii, pseudomonas aeruginosa and refractory carbapenem-resistant enterobacteriaceae, and creates a serious disease field which has high death rate and fails to meet medical requirements, 12 and 14 days in 2018, Japan salt wild pharmaceutical company provides new marketing approval to the United states Food and Drug Administration (FDA) and the European drug administration (EMA), is accepted, and the FDA grants qualified anti-infective drug (QIDP) qualification and rapid channel qualification on the cefditoren, EMA also qualifies cefditorel for accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP), and salt wild pharmaceutical Co., Ltd. 4/2.2019 promulgated a positive result of a clinical study on cefditorel treatment of complicated urinary tract infections (cUTI) stage III, which reached the primary endpoint of clinical cure and pathogen eradication. 16/10/2019, FDA council vote to recommend cefditor intravenous injection from salt novelties pharmaceutical company for the treatment of highly resistant gram-negative bacteria including cluti in pyelonephritis, 14/11/2019, FDA approved cefditor intravenous injection on the market under the trade name of cefditor
Figure BSA0000250710800000012
Figure BSA0000250710800000021
This is the 3 rd cephalosporin new antibacterial drug approved by the FDA since 2010 following approval of Ceftaroline fosamil (Ceftaroline fosamil) and Ceftolozane (Ceftolozane) on the market.
Meanwhile, the structure of the side chain at the 3-position of the cefditoren is shown as formula 2, and the chemical structure of the side chain is shown as a compound in the following formula:
Figure 2
r is an ether, an acyl, an acetal, a silyl ether or the like, for example, p-methoxybenzyl, benzyl, allyl, trityl ether, p-nitrobenzoyl, acetyl, methoxymethyl, 2-tetrahydropyranyl, trimethylsilyl, t-butyldimethylsilyl or the like.
The side chain at the 3-position of the cefditoren is an important intermediate for synthesizing novel antibiotic cefditoren, and the synthesis of the intermediate has great significance and great social and economic benefits. At present, two methods are used for synthesizing a 3-position side chain of cefditoren, 2-chloro-3, 4-dimethoxybenzoic acid is taken as a raw material in a patent US9238657 and is synthesized through four-step reaction, demethylation, p-methoxybenzyl protection reaction, p-methoxybenzyl chloride protection reaction on carboxyl removal and amidation reaction; in patent WO2016035847, isovanillin is used as a raw material, and is synthesized by five-step reactions, namely, a chlorination reaction, a demethylation reaction, a p-methoxybenzyl protected dihydroxy reaction, a reaction in which aldehyde groups are oxidized into benzoic acid by hydrogen peroxide, and a continuous reaction of methanesulfonic acid chloride and a primary amine compound amide compound after sulfonic anhydride formation. The initial raw materials of the method I are expensive, and the synthesis cost is high. The second method adds synthesis steps, is not environment-friendly and is difficult to operate, and both the two synthesis methods adopt methanesulfonyl chloride which has high toxicity and great environmental pollution as a sulfonic anhydride reagent, so that the method is not suitable for industrial production. The process adopts 2-chloro-3, 4-dimethoxybenzaldehyde as a starting material, and synthesizes a target product through four steps of demethylation, hydroxyl protection, aldehyde group oxidation and amidation reaction. The invention has the advantages of easily obtained starting materials, short synthetic route, convenient operation, low cost and environmental protection. Provides a new method for synthesizing the side chain at the 3-position of the cefditoren.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of a cefditoren 3-site side chain, and solves the problem of how to provide a new synthetic route, so that the preparation method has the advantages of simple operation, environmental protection, easy synthesis of products and higher yield and purity requirements.
The purpose of the invention is realized by the following technical scheme:
a process for the preparation of a cefditoren side chain, comprising the steps of:
2-chloro-3, 4-dimethoxybenzaldehyde (II) is demethylated under the catalysis of Lewis acid or alkali to obtain 2-chloro-3, 4-dihydroxybenzaldehyde (III); protecting the hydroxyl of the compound III to obtain a compound (IV); oxidizing the aldehyde group of the compound IV to obtain a compound (V); carrying out amidation reaction on the 1- (2-aminoethyl) pyrrolidine (VI) and the sulfonic acid anhydrified compound V to obtain a cefaclor 3-site side chain (I).
Figure BSA0000250710800000031
Wherein R is an ether, an acyl, an acetal, a silyl ether, etc., for example, p-methoxybenzyl, benzyl, allyl, trityl ether, p-nitrobenzoyl, acetyl, methoxymethyl, 2-tetrahydropyranyl, trimethylsilyl, t-butyldimethylsilyl, etc.
The specific preparation method of the cedarl side chain comprises the following steps:
in the step 1, 2-chloro-3, 4-dimethoxybenzaldehyde, under the catalysis of Lewis acid or alkali, reacting at-20-100 ℃ for 0.5-72.0h, and adding acid to separate out solids to obtain 2-chloro-3, 4-dihydroxybenzaldehyde;
reacting 2, 2-chloro-3, 4-dihydroxybenzaldehyde with a protective reagent at the temperature of-30-100 ℃ under the action of alkali for 0.5-12.0h, and crystallizing with a solvent to obtain a compound (IV) after post-treatment;
step 3, under the action of an oxidizing reagent, adding water or acid into the compound IV to obtain a compound (V), wherein the reaction temperature is-20-60 ℃, and the reaction time is 0.5-12.0 h;
and 4, adding a sulfonic acid anhydrization reagent into the compound V to perform sulfonic acid anhydrization for 0 to 10.0 hours at the reaction temperature of between 80 and 60 ℃ under the action of alkali, adding 1- (2-aminoethyl) pyrrolidine into the compound V to perform amidation reaction for 0.5 to 24.0 hours at the reaction temperature, adjusting the pH value to between 7.0 and 12.0 by using alkali, and adding a solvent to perform crystallization to obtain the compound I after post-treatment.
The Lewis acid is respectively and independently selected from one or more of aluminum chloride, aluminum bromide, aluminum iodide, zinc chloride, titanium tetrachloride, ferric chloride, copper chloride, molybdenum chloride, bismuth chloride, manganese dichloride, niobium pentachloride, boron trifluoride, boron trichloride, boron tribromide, boron triiodide, zinc p-toluenesulfonate, zinc trifluoroacetate, zinc acetate, zinc acetylacetonate, zinc bromide, zinc trifluoromethanesulfonate, hydrogen iodide, hydrogen bromide, hydrogen chloride, sodium alkoxide, sodium amide and the like; the base is an organic base, such as triethylamine, pyridine, dimethylaminopyridine, trimethylamine, N-methylmorpholine, N-methylpyridine and the like; the mol ratio of the compound II, the Lewis acid and the alkali is 1.0: 1.0-5.0: 1.0-10.0.
The reaction of step 1 in the present invention is preferably carried out in a single solvent or a mixed solvent of dichloromethane, chloroform, toluene, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, tetrahydrofuran, acetonitrile, and acetone; the acid is inorganic acid or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, and the like.
The protecting agent in step 2 of the present invention is preferably p-methoxybenzyl chloride, benzyl bromide, benzyl iodide, 2-methylpropene, benzyl chloromethyl ether, triphenylmethyl chloride, p-nitrobenzoyl chloride, acetyl chloride, methoxymethyl chloride, 2-methyl-4-acetoxy-2-naphthol, trimethylchlorosilane, hexamethyldisilazane, tert-butyldimethylsilyl chloride, or the like.
The base in the step 2 can be organic base or inorganic base, the inorganic base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, and the organic base is triethylamine, pyridine, N-butylamine, diethylamine, ammonia water, dimethylaminopyridine, tetramethylguanidine, N-methylmorpholine, N-methylpyridine, diisopropylethylamine and the like; the mol ratio of the compound III, the protective reagent and the alkali is 1.0: 2.0-4.0: 1.0-5.0.
Step 2 reaction solvent in the present inventionIs carried out in single or mixed solvent of N, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, dichloromethane, chloroform, toluene, tetrahydrofuran, acetonitrile and acetone; the crystallization solvent is C1-5Low carbon alcohols such as methanol, ethanol, isopropanol, etc., ethers, isopropyl ether, petroleum ether, methyl tert-butyl ether, etc. or their mixture.
The oxidizing reagent is NaH2PO4Hydrogen peroxide, Jones reagent (dissolving chromium trioxide in concentrated sulfuric acid), Pinnick oxidation reagent (NaH)2PO4/NaClO2Mixed of (2), Cu (OAc)2·H2O and Co (OAc)2·4H2O bimetal is used as catalyst.
The solvent of step 3 of the invention is tetrahydrofuran, acetonitrile, toluene, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, dichloromethane, chloroform and acetone or the mixture of the solvents.
The sulfonic anhydrization reagent is paratoluensulfonyl chloride, benzenesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, methanesulfonyl chloride and the like; the molar ratio of the compound V, the sulfonic acid anhydrization reagent and the 1- (2-aminoethyl) pyrrolidine is 1.0: 1.0-3.0: 0.8-3.0.
The solvent in step 4 of the present invention is not particularly limited as long as the above reaction can be efficiently carried out. Preferably in N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, propyl acetate, dichloromethane, chloroform, toluene, benzene, hexane, tetrahydrofuran, acetonitrile, propionitrile, acetone, and dimethylsulfoxide or a mixed solvent thereof; the alkali can be organic alkali and inorganic alkali, and the inorganic alkali can be sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.; the organic base is triethylamine, pyridine ethylenediamine, propylamine, methylamine, ethylamine and the like; the crystallization solvent is a single solvent or a mixed solvent composed of isopropyl acetate, ethyl acetate, petroleum ether, propyl acetate, butyl acetate, isopropyl ether, ethyl formate, butyl formate, isopropyl benzoate and the like.
Compared with the prior art, the invention has the following characteristics:
1. the process takes 2-chloro-3, 4-dimethoxybenzaldehyde as a raw material, and through demethylation, hydroxyl protection, oxidation and amidation reactions, the reaction operation in each step is simple and convenient, the process is green and environment-friendly, the yield and purity in each step are high, the quality is good, the cost is saved, the industrial production is easy, and the problem of high cost caused by the direct use of the existing side chain is solved.
2. The process adopts p-toluenesulfonyl chloride as a sulfonating reagent and can replace methanesulfonyl chloride, and the process is green and environment-friendly and has safe industrialized conditions.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Example 1
Step 1, 2-chloro-3, 4-dihydroxybenzaldehyde preparation
Under nitrogen, 10.0g (49.85mmol) of 2-chloro-3, 4-dimethoxybenzaldehyde and 50mL of CH were placed in a 250mL three-necked flask2Cl214.0g (104.99mmol) of anhydrous AlCl are added with stirring at room temperature3Then, 33.8mL (419.98 mmol) of pyridine was added dropwise thereto, and the mixture was refluxed for 8.0 hours. 200mL of dilute HCl solution was added and stirred to precipitate a solid. Cooling for 1.0h, filtering, washing with water for 3 times, pumping, drying at 50 deg.C under reduced pressure to obtain 7.8g of off-white solid III with yield of 90.6%.
1H NMR(600MHz，DMSO-d6)δ10.92(s，1H,OH)，10.07(s，1H,CHO)，9.66(s，1H,OH)，7.33(d， J＝51.0Hz，1H,ArH)，6.83(d，J＝15.1Hz，1H,ArH).
13C-NMR(150MHz，DMSO-d6)δ189.21，153.25，142.68，125.19，124.36，122.28，114.04.
Step 2, 2-chloro-3, 4-bis ((4-methoxybenzyl) oxy) benzaldehyde preparation
Under nitrogen protection, 10.0g (57.95mmol) of 2-chloro-3, 4-dihydroxybenzaldehyde and 18.4g (133.13mmol) of K were placed in a 250mL three-necked flask2CO3、1.9g(11.45mmol) KI and 80mL of N, N-dimethylformamide are stirred at room temperature, 19.1g (121.96mmol) of p-methoxybenzyl chloride is added dropwise, and after the dropwise addition is finished, the temperature is raised to 40 ℃ for reaction for 3.0 h. The organic solvent was distilled off under reduced pressure, and 50mL of water and 50mL of CH were added2Cl2Stirred, the phases were separated, the organic phase was washed with 30mL of saturated NaCl and then with anhydrous MgSO4Dehydrating, filtering, concentrating the organic phase, adding 60mL of isopropanol into the concentrated solution, precipitating a large amount of white solid, cooling for 1.0h, filtering, washing with isopropanol for 3 times, and drying under reduced pressure at 40 ℃ to obtain 20.7g of off-white solid IV with the yield of 86.6%.
1H NMR(600MHz，CDCl3)δ10.32(s，1H,CHO)，7.69(d，J＝9.0Hz,1H)，7.31-7.36(m,4H)， 6.98(d，J＝8.3Hz,1H)，6.93(dt，J＝11.9，2.6Hz,2H)，6.81-6.83(m,2H)，5.12(t，J＝14.8Hz,2H)， 4.97(t，J＝15.1Hz,2H)，3.82(s,3H)，3.79(s,3H).
13C NMR(150MHz，CDCl3)：δ189.06，159.85，158.13，144.58，133.15，130.52，129.46，128.84， 127.62，126.60，125.71，114.21，113.81，111.82，77.12，74.83，71.08，55.38，55.26.
Step 3, 2-chloro-3, 4-bis ((4-methoxybenzyl) oxy) benzoic acid preparation
10.00g (24.22mmol) of 2-chloro-3, 4-bis ((4-methoxybenzyl) oxy) benzaldehyde and 50mL of tetrahydrofuran are introduced into a 250mL three-necked flask under nitrogen, dissolved with stirring, and 10.0mL of 2, 3-dimethyl-1-butene are added. 21.9g (140.48mmol) of sodium dihydrogen phosphate dihydrate and 1.90g (21.06mmol) of NaClO were taken2Then, 50mL of water was added to dissolve the reaction mixture, and the mixture was added dropwise to the reaction mixture to react for 1.0 hour. Concentrating under reduced pressure until no liquid flows out, and adding 50mLH2O, a large amount of solid is separated out, cooled and stirred for 2.0h, filtered, washed by a small amount of water and dried under reduced pressure at 50 ℃ to obtain 10.3g of white solid V with the yield of 99.10 percent.
1H NMR(600MHz，DMSO-d6)：δ7.56(t，J＝9.3Hz,1H),7.40(d，J＝8.3Hz,2H)，7.25(d， J＝8.3Hz,2H)，7.20(t，J＝9.3Hz,1H)，6.95(d，J＝8.3Hz,2H)，6.81(d，J＝8.3Hz，2H)，5.13(s,2H)，4.86 (d，J＝28.9Hz，2H)，3.74(s，3H)，3.70(s,3H).
13C NMR(150MHz，DMSO-d6)：δ166.67，159.80，159.71，155.73，144.79，130.78，130.37， 129.24，128.58,127.99,127.52,124.14,114.44,114.05,112.49,74.33,70.73,55.66,55.58.
Step 4, preparation of the side chain at the 3-position of cefditoren
2.00g (4.67mmol) 2-chloro-3, 4-bis ((4-methoxybenzyl) oxy) benzoic acid and 18mL CH were added to a 100mL three-necked flask under nitrogen2Cl2Then, 0.84mL of triethylamine was added dropwise while stirring. The reaction solution was cooled to-15 ℃ and 0.4mL (5.13mmol) of methanesulfonyl chloride was added dropwise thereto, followed by reaction at this temperature for 1.0 h. Then 0.72mL (5.68mmol) of 1- (2-aminoethyl) pyrrolidine was slowly added dropwise and the reaction was stirred for 1.0 h. Adjusting pH to 8-9 with 5% NaOH solution, adding 10mL of 2CH2Cl2And (4) extracting. The organic phase was over anhydrous MgSO4Drying, filtering, concentrating the filtrate under reduced pressure to dryness, and adding 12mL of isopropyl acetate into the concentrate to precipitate a large amount of solid. Cooled and stirred for 2.0h, filtered, washed 3 times with isopropyl acetate and dried under reduced pressure at 40 ℃ to obtain 1.28g of the target compound as a white solid with a yield of 52.3%.
1H NMR(600MHz，CDCl3)：δ8.47(s，1H)，7.23-7.32(m，5H,ArH)，6.84(t，J＝8.3Hz，2H,ArH)， 6.76-6.78(m，3H,ArH)，4.94(s，2H)，4.85(s，2H)，3.78(s，3H)，3.75(s，3H)，3.30(t，J＝6.5Hz,2H)， 3.07(t，J＝7.3Hz,4H)，2.07(t，J＝6.1Hz,2H)，1.35(t，J＝7.6Hz,4H).
13C NMR(150MHz，CDCl3)：δ167.75,159.64,159.60,154.57,144.93，130.43，129.55，129.43， 128.58，128.23，126.81，125.69，114.03，113.69，112.04，74.67，71.07，55.62，54.18,53.18，46.30， 36.69，23.33.
Example 2
Step 1, 2-chloro-3, 4-dihydroxybenzaldehyde preparation
10.0g (49.85mmol) of 2-chloro-3, 4-dimethoxybenzaldehyde and 50mL of N, N-dimethylacetamide are added dropwise to a 250mL three-necked flask under nitrogen atmosphere, and 18.6g (139.57 m) of the resulting mixture are added dropwise with stirringmol)AlCl3Anisole (56 mL). Then 11.2mL (139.57mmol) of pyridine was added dropwise, heated to 55 ℃ and reacted for 5.0 h. Adding 100mL of dilute HCl solution and 100mL of tetrahydrofuran, concentrating under reduced pressure to separate out a large amount of solid, cooling and stirring for 2.0h, filtering, and washing with water for 3 times. Drying at 50 ℃ under reduced pressure gave 8.1g of off-white solid III in 94.2% yield.
1H NMR(600MHz，DMSO-d6)δ10.89(s，1H,OH)，10.03(s，1H,CHO)，9.62(s，1H,OH)，7.30(d， J＝51.1Hz，1H,ArH)，6.83(d，J＝15.3Hz,1H,ArH).
13C NMR(150MHz，DMSO-d6)δ190.12，153.65，141.36，125.40，123.23，122.19，113.93.
Step 2, 2-chloro-3, 4-dibenzyloxybenzaldehyde preparation
Under nitrogen protection, 10.0g (57.95mmol) of 2-chloro-3, 4-dihydroxybenzaldehyde and 14.1g (133.13mmol) of Na were added into a 250mL three-necked flask2CO30.43g (2.90mmol) of NaI and 50mL of N, N-dimethylformamide are stirred, 15.4g (121.65mmol) of p-benzyl chloride is added dropwise, and after the addition is finished, the temperature is raised to 40 ℃ for reaction for 2.0 h. Distilling under reduced pressure to remove solvent, adding 50mLH2O and CH2Cl2Stirred, the phases were separated, the organic phase was washed with 30mL of saturated NaCl and then with anhydrous MgSO4Dehydrating, filtering, concentrating the organic phase, adding 60mL of isopropanol into the concentrated solution, precipitating a large amount of solid, cooling and stirring for 1.0h, filtering, and washing with isopropanol for 3 times. Drying at 40 deg.C under reduced pressure to obtain 19.5g yellow white solid IV with yield 83.2%.
1H NMR(600MHz，CDCl3)δ10.30(s，1H,CHO)，7.68(d，J＝9.1Hz,1H)，7.31-7.35(m,4H)， 7.06-7.13(m,2H)，6.96(d，J＝8.3Hz,1H)，6.90(dt，J＝11.9,2.6Hz,2H)，6.81-6.84(m,2H)，5.09(t， J＝14.8Hz,2H)，4.95(t，J＝15.1Hz,2H).
13C NMR(150MHz，CDCl3)：δ189.78，160.06，158.56，143.97，133.12，130.63，129.83， 129.01，128.12，126.98，125.81，113.99，113.61，111.72，77.62，75.03，71.36.
Step 3, 2-chloro-3, 4-dibenzyloxybenzoic acid preparation
10.00g (24.22mmol) of 2-chloro-3, 4-dibenzyloxybenzaldehyde and 80mL of N, N-dimethylformamide were added to a 250mL three-necked flask under nitrogen, the mixture was dissolved with stirring, heated to 30 ℃, and 0.94g (6.03mmol) of sodium dihydrogen phosphate dihydrate and 3.3g of 30% hydrogen peroxide (29.06mmol) were added. The temperature was reduced to 5 ℃ and 3.28g (36.38mmol) of aqueous NaClO solution was slowly added dropwise and the reaction was carried out for 3.0 h. Then 100mL of dilute hydrochloric acid is added, a large amount of solid is precipitated, cooled and stirred for 2.0h, filtered, and washed with water for 3 times. Drying at 50 deg.C under reduced pressure to obtain 10.0g of off-white solid V with yield of 96.3%.
1H NMR(600MHz，DMSO-d6)：δ7.58(t，J＝9.3Hz,1H)，7.41(d，J＝8.3Hz，2H)，7.23(d， J＝8.3Hz,2H)，7.21(t，J＝9.3Hz,1H)，7.08-7.15(m,2H)，6.97(d，J＝8.3Hz,2H)，6.83(d，J＝8.3Hz，2H)， 5.15(s,2H)，4.88(d，J＝28.9Hz,2H).
13C NMR(150MHz，DMSO-d6)：δ167.05，159.67，159.53，156.03，145.10，130.83，130.27， 129.35,128.43，128.02,127.16，123.96,114.75,113.97,112.61,73.99,70.81.
Step 4, preparation of the side chain at the 3-position of cefditoren
2.00g (4.67mmol) of 2-chloro-3, 4-dibenzyloxybenzoic acid and 12mL of tetrahydrofuran were added to a 100mL three-necked flask under nitrogen, stirred, and 0.97mL (7.00mmol) of triethylamine was added. The reaction solution was cooled to-15 ℃ and 1.07g (5.60mmol) of p-toluenesulfonyl chloride was added to slowly precipitate a large amount of solid, and the reaction was carried out at this temperature for 1.0 h. Then 0.64g (5.6mmol) of 1- (2-aminoethyl) pyrrolidine was slowly added dropwise and the reaction was stirred for 2.0 h. With saturated Na2CO3The pH of the solution is adjusted to between 8 and 10, 10mL of 2CH is added2Cl2Extracting, and collecting the organic phase with anhydrous MgSO4Dehydrating, filtering, concentrating the filtrate under reduced pressure, adding 15mL petroleum ether into the concentrate, precipitating a large amount of solid, cooling and stirring for 2.0h, filtering, washing with petroleum ether for 3 times, and drying under reduced pressure at 40 ℃ to obtain 1.7g of a white solid target compound with a yield of 69.4%.
1H NMR(600MHz，CDCl3)：δ8.36(s，1H)，7.24-7.35(m,5H,ArH)，7.03-7.11(m,2H),6.80(t，J ＝8.5Hz，2H,ArH)，6.73-6.76(m,3H,ArH)，4.86(s,2H)，4.77(s,2H)，3.38(t，J＝6.3Hz,2H)，3.12(t，J ＝7.0Hz,4H)，2.07(t，J＝6.1Hz,2H)，1.39(t，J＝7.6Hz,4H).
13C NMR(150MHz，CDCl3)：δ168.13，159.81，159.65，154.61，145.03，130.56，129.78，129.76， 128.62，128.35，127.01，125.83，113.94，113.73，112.23，74.86，71.35，55.73，46.43，36.85，23.51.
Example 3
Step 1, 2-chloro-3, 4-dihydroxybenzaldehyde preparation
Under nitrogen, 10.0g (49.85mmol) of 2-chloro-3, 4-dimethoxybenzaldehyde and 60mLCH were placed in a 250mL three-necked flask2Cl2Cooled to 0 ℃ and 50.0g (199.38mmol) of BBr are slowly added dropwise3And raising the temperature to 25 ℃ for reaction for 3.0 h. The mixture was concentrated under reduced pressure until no liquid flowed out, and then 100mL of dilute HCl solution was added, and an off-white solid was precipitated. Cooling and stirring for 1.0h, filtering, washing with water for 3 times, and pumping to dry. Drying at 50 ℃ under reduced pressure gave 7.3g of white solid III in 84.9% yield.
1H NMR(600MHz，DMSO-d6)δ10.90(s，1H,OH)，10.05(s，1H,CHO)，9.68(s，1H,OH)，7.32(d， J＝51.0Hz,1H,ArH)，6.83(d，J＝15.3Hz，1H,ArH).
13C-NMR(150MHz，DMSO-d6)δ189.65，153.33，142.41，126.38，123.39，122.11，113.89.
Step 2, 2-chloro-3, 4-bis ((4-methoxybenzyl) oxy) benzaldehyde preparation
Under nitrogen protection, 10.0g (57.95mmol) of 2-chloro-3, 4-dihydroxybenzaldehyde and 16.8g (121.70mmol) of K are placed in a 250mL three-necked flask2CO38.7g (57.95mmol) of NaI and 70mL of N, N-dimethylformamide are stirred, 18.7g (133.29mmol) of p-methoxybenzyl chloride is added dropwise, and after the addition is finished, the temperature is raised to 60 ℃ for reaction for 3.0 h. Distilling under reduced pressure to remove solvent, adding 50mLH2O and CH2Cl2Stirred, the phases were separated, the organic phase was washed with 30mL of saturated NaCl and then with anhydrous MgSO4Drying, filtering and concentratingThe organic phase is condensed, 50mL of isopropyl ether is added into the concentrated solution, a large amount of white solid is separated out, the mixture is cooled and stirred for 1.5h, filtered, and washed by isopropyl ether for 3 times. Drying at 40 deg.C under reduced pressure to obtain 20.3g of off-white solid IV with yield of 84.8%.
1H NMR(600MHz,CDCl3)δ10.33(s，1H,CHO)，7.67(d，J＝9.0Hz,1H)，7.30-7.37(m,4H)，6.99 (d，J＝8.3Hz,1H)，6.96(dt，J＝11.9,2.6Hz,2H)，6.81-6.83(m,2H)，5.15(t，J＝14.8Hz,2H)，4.96(t，J＝ 15.1Hz,2H)，3.81(s,3H)，3.78(s,3H).
13C NMR(150MHz，CDCl3)：δ190.26，160.35，158.87，144.10，133.53，130.91，129.67，129.13， 128.73，128.08，125.96，114.05，113.76，111.95，77.87，75.14，71.43，55.78，55.38.
Step 3, 2-chloro-3, 4-bis ((4-methoxybenzyl) oxy) benzoic acid preparation
10.00g (24.22mmol) of 2-chloro-3, 4-bis ((4-methoxybenzyl) oxy) benzaldehyde and 60mL of N, N-dimethylformamide are added to a 250mL three-necked flask under nitrogen protection, the mixture is dissolved with stirring, heated to 40 ℃, and 0.94g (6.03mmol) of sodium dihydrogen phosphate dihydrate and 3.3g of 30% hydrogen peroxide (29.06mmol) are added. The temperature was reduced to 5 ℃ and 3.28g (36.38mmol) of aqueous NaClO solution was slowly added dropwise and the reaction was carried out for 2.0 h. Then 100mL of dilute hydrochloric acid is added, cooled and stirred for 2.0h, filtered, washed with water for 3 times and drained. Drying at 50 ℃ under reduced pressure gave 9.8g of off-white solid V, yield 94.3%.
1H NMR(600MHz，DMSO-d6)：δ7.58(t，J＝9.3Hz,1H)，7.42(d，J＝8.3Hz,2H)，7.26(d， J＝8.3Hz,2H)，7.22(t，J＝9.2Hz,1H)，6.97(d，J＝8.3Hz,2H)，6.83(d，J＝8.3Hz,2H)，5.15(s,2H)，4.87(d， J＝28.9Hz,2H)，3.73(s,3H)，3.71(s,3H).
13C NMR(150MHz，DMSO-d6)：δ166.90，159.52，159.45，155.83，145.06，130.66，130.00， 129.21，128.30,127.94,127.11，123.73,114.55,113.76，112.41，74.17,70.61,55.50,55.56.
Step 4, preparation of the side chain at the 3-position of cefditoren
In nitrogen2.00g (4.67mmol) of 2-chloro-3, 4-bis ((4-methoxybenzyl) oxy) benzoic acid and 20mL of N, N-dimethylformamide were added to a 100mL three-necked flask under the protection of gas, stirred, 0.84mL (6.06mmol) of triethylamine was added, the reaction solution was cooled to-15 ℃, 0.98g (5.14mmol) of p-toluenesulfonyl chloride was added, and the reaction was carried out at this temperature for 1.5 hours. Then, 1.0g (9.33mmol) of 1- (2-aminoethyl) pyrrolidine was slowly added dropwise and the reaction was stirred for 1.0 h. With 5% NaHCO3Adjusting pH of the solution to 8-10, adding 10mL × 2 ethyl acetate for extraction, washing organic phase with saturated sodium chloride 10mL × 2, and adding anhydrous MgSO4Drying, filtering, concentrating the filtrate under reduced pressure, adding 20mL isopropyl ether into the concentrated solution, precipitating a large amount of solid, stirring at low temperature for 2.0h, filtering, washing with isopropyl ether for 3 times, and drying under reduced pressure at 40 deg.C to obtain white solid 1.63g, with yield of 66.5%.
1H NMR(600MHz,CDCl3)：δ8.47(s，1H)，7.23-7.32(m,5H,ArH)，6.84(t，J＝8.3Hz,2H,ArH)， 6.76-6.78(m,3H,ArH)，4.94(s,2H)，4.85(s,2H)，3.78(s，3H)，3.75(s，3H)，3.30(t，J＝6.5Hz,2H)，3.07(t，J ＝7.3Hz,4H)，2.07(t，J＝6.1Hz,2H)，1.35(t，J＝7.6Hz,4H).
13C NMR(150MHz,CDCl3)：δ167.96,159.74,159.55,154.53,144.89，130.71，129.62，129.73， 128.53，128.26，126.85，125.66，113.87，113.53，112.43，74.67，71.33，55.62，54.10,53.36，46.37， 36.68，23.56.

Claims (10)

1. A process for the preparation of a cefditoren side chain, comprising the steps of:
2-chloro-3, 4-dimethoxybenzaldehyde (II) is demethylated under the catalysis of Lewis acid or alkali to obtain 2-chloro-3, 4-dihydroxybenzaldehyde (III); protecting the hydroxyl of the compound III to obtain a compound (IV); oxidizing the aldehyde group of the compound IV to obtain a compound (V); carrying out amidation reaction on 1- (2-aminoethyl) pyrrolidine (VI) and a compound V subjected to sulfonic anhydride esterification to obtain a cefaclor 3-site side chain (I);
Figure FSA0000250710790000011
wherein R is an ether, an acyl, an acetal, a silyl ether, etc., for example, p-methoxybenzyl, benzyl, allyl, trityl ether, p-nitrobenzoyl, acetyl, methoxymethyl, 2-tetrahydropyranyl, trimethylsilyl, t-butyldimethylsilyl, etc.
The specific preparation method of the cefditoren side chain comprises the following steps:
in the step 1, 2-chloro-3, 4-dimethoxybenzaldehyde, under the catalysis of Lewis acid or alkali, reacting at-20-100 ℃ for 0.5-72.0h, and adding acid to separate out solids to obtain 2-chloro-3, 4-dihydroxybenzaldehyde;
reacting 2, 2-chloro-3, 4-dihydroxybenzaldehyde with a protective reagent at the temperature of-30-100 ℃ under the action of alkali for 0.5-12.0h, and crystallizing with a solvent to obtain a compound (IV) after post-treatment;
step 3, under the action of an oxidizing reagent, adding water or acid into the compound IV to obtain a compound (V), wherein the reaction temperature is-20-60 ℃, and the reaction time is 0.5-12.0 h;
and 4, adding a sulfonic acid anhydrization reagent into the compound V to perform sulfonic acid anhydrization for 0 to 10.0 hours at the reaction temperature of between 80 and 60 ℃ under the action of alkali, adding 1- (2-aminoethyl) pyrrolidine into the compound V to perform amidation reaction for 0.5 to 24.0 hours at the reaction temperature, adjusting the pH value to between 7.0 and 12.0 by using alkali, and adding a solvent to perform crystallization to obtain the compound I after post-treatment.
2. The method for preparing a cefditoren side chain as claimed in claim 1, wherein the lewis acids of step 1 are independently selected from one or more of aluminum chloride, aluminum bromide, aluminum iodide, zinc chloride, titanium tetrachloride, ferric chloride, cupric chloride, molybdenum chloride, bismuth chloride, manganese dichloride, niobium pentachloride, boron trifluoride, boron trichloride, boron tribromide, boron triiodide, zinc p-toluenesulfonate, zinc trifluoroacetate, zinc acetate, zinc acetylacetonate, zinc bromide, zinc trifluoromethanesulfonate, hydrogen iodide, hydrogen bromide, hydrogen chloride, sodium alkoxide, sodium amide, etc.; the base is an organic base, such as triethylamine, pyridine, dimethylaminopyridine, trimethylamine, N-methylmorpholine, N-methylpyridine and the like; the mol ratio of the compound II, the Lewis acid and the alkali is 1.0: 1.0-5.0: 1.0-10.0.
3. The method for preparing a cefditoren side chain as claimed in claim 1, wherein the reaction in step 1 is preferably carried out in a solvent selected from dichloromethane, chloroform, toluene, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, tetrahydrofuran, acetonitrile, acetone, or a mixture thereof; the acid is inorganic acid or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, and the like.
4. The method for preparing a cefditoren side chain as claimed in claim 1, wherein the protecting reagent in step 2 is p-methoxybenzyl chloride, benzyl bromide, benzyl iodide, 2-methylpropene, benzyl chloromethyl ether, triphenylchloromethane, p-nitrobenzoyl chloride, acetyl chloride, methoxymethyl chloride, 2-methyl-4-acetoxy-2-naphthol, trimethylchlorosilane, hexamethyldisilazane, tert-butyldimethylchlorosilane, etc.
5. The method for preparing a cefditoren side chain as claimed in claim 1, wherein the base in step 2 is an organic base or an inorganic base, the inorganic base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc., the organic base is triethylamine, pyridine, N-butylamine, diethylamine, ammonia, dimethylaminopyridine, tetramethylguanidine, N-methylmorpholine, N-methylpyridine, diisopropylethylamine, etc.; the mol ratio of the compound III, the protective reagent and the alkali is 1.0: 2.0-4.0: 1.0-5.0.
6. The method for preparing a cefditoren side chain as claimed in claim 1, wherein the reaction is carried out in the reaction solvent of N, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, dichloromethane, chloroform, toluene, tetrahydrofuran, acetonitrile, acetone or a mixture thereof in step 2; the crystallization solvent is C1-5Lower alcohols, e.g. methanol, ethanol, isopropanol, etc., ethers, e.g. isopropyl etherPetroleum ether, methyl tert-butyl ether and the like or a mixed solvent composed of the petroleum ether, the methyl tert-butyl ether and the like.
7. Process for the preparation of a cefditoren side chain as claimed in claim 1, wherein the oxidising agent of step 3, such as NaH2PO4Hydrogen peroxide, Jones reagent, Pinnick oxidizing reagent, Cu (OAc)2·H2O and Co (OAc)2·4H2O bimetal is used as catalyst.
8. The method for preparing a cefditoren side chain as claimed in claim 1, wherein the reaction solvent of step 3 is tetrahydrofuran, acetonitrile, toluene, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, dichloromethane, chloroform, acetone or a mixture thereof.
9. The method for preparing a cefditoren side chain according to claim 1, wherein the sulfonic anhydrization reagent in step 4 is p-toluenesulfonyl chloride, benzenesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, methanesulfonyl chloride, or the like; the molar ratio of the compound V, the sulfonic acid anhydrization reagent and the 1- (2-aminoethyl) pyrrolidine is 1.0: 1.0-3.0: 0.8-3.0.
10. The process for producing a cefditoren side chain as claimed in claim 1, wherein the solvent used in step 4 is not particularly limited as long as the reaction can be efficiently carried out. Preferably in N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, propyl acetate, dichloromethane, chloroform, toluene, benzene, hexane, tetrahydrofuran, acetonitrile, propionitrile, acetone, and dimethylsulfoxide or a mixed solvent thereof; the alkali can be organic alkali and inorganic alkali, and the inorganic alkali can be sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.; the organic base is triethylamine, pyridine ethylenediamine, propylamine, methylamine, ethylamine and the like; the crystallization solvent is a single solvent or a mixed solvent composed of isopropyl acetate, ethyl acetate, petroleum ether, propyl acetate, butyl acetate, isopropyl ether, ethyl formate, butyl formate, isopropyl benzoate and the like.
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