CN115974747A - Preparation method and application of 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester - Google Patents
Preparation method and application of 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester Download PDFInfo
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Abstract
The application relates to the technical field of compound synthesis, in particular to a preparation method and application of 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester. The method comprises the following steps: 1) Reacting glycine ester or an acceptable salt thereof with chloroformate to prepare a compound II; 2) Reacting the compound II prepared in the step 1) with acrylic ester to obtain a compound III; 3) Reacting the compound III prepared in the step 2) with orthoformate or alcohol to prepare a compound IV; 4) Reacting the compound IV prepared in the step 3) with 1,3-halogenated chloropropane to prepare a compound V; 5) Hydrolyzing and decarboxylating the compound V prepared in the step 4) to obtain a compound VI. The method protects the compound III, avoids the generation of byproducts and the recovery treatment of the byproducts, uses glycine ester or acceptable salt thereof to replace benzylamine as a raw material, avoids the generation of carcinogens, reduces the harm to the environment and health, and has high production efficiency.
Description
Technical Field
The application relates to the field of compound synthesis, in particular to a preparation method and application of 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester. .
Background
The cisasamide is an artificially synthesized fourth-generation quinolone antibacterial agent, has the advantages of strong antibacterial property, wide antibacterial spectrum, difficulty in generating drug resistance, effectiveness to common drug-resistant bacteria, long half-life period, few adverse reactions and the like, and is widely applied to treatment of adults suffering from upper respiratory tract and lower respiratory tract infection, such as acute sinusitis, acute attack of chronic bronchitis, community-acquired pneumonia and skin and soft tissue infection. Ethyl 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylate is one of the starting materials for the preparation of its key intermediate (S, S) -2,8-diazabicyclo [4.3.0] nonane.
The preparation method reported in the prior art at present is shown as the following figure: the synthesis of the 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester takes benzylamine and ethyl acrylate as raw materials, and the target product is prepared by addition, two-step substitution, condensation, hydrolysis and debenzylation reactions, a large amount of benzyl chloride is generated in the process, the compound belongs to carcinogens, has liver and kidney toxicity and great harm to ecology and health, the route has multiple processes, the operation steps are complicated, the production period is greatly prolonged, the yield is 37 to 40 percent, and the production efficiency is low.
In another reported preparation method II, as shown in the figure, compound D is prepared by synthesizing 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester and performing substitution reaction with dihalopropane under alkaline conditions through compound C, and meanwhile, a byproduct D1 is generated in about 30% of the ratio, the compound D1 needs to be recovered and converted into C, the process is complicated, and the production efficiency is not high.
Disclosure of Invention
In view of the above disadvantages of the prior art, the present invention aims to provide a method for preparing ethyl 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylate and its use, which are used to solve the problems of the prior art, in order to solve the technical problems of the prior art, such as more by-products, complicated processes, large environmental and health hazards, and low production efficiency.
To achieve the above and other related objects, according to one aspect of the present invention, there is provided a method for preparing ethyl 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylate, comprising:
1) Reacting glycine ester or acceptable salt thereof with chloroformate under alkaline condition to prepare a compound II;
wherein R is 1 And R 2 Each independently selected from linear or branched C 1 ~C 3 Alkyl groups of (a);
reacting the compound II prepared in the step 1) with acrylic ester under an alkaline condition to prepare a compound III;
wherein R is 3 Selected from straight-chain or branched C 1 ~C 3 Alkyl groups of (a);
3) Reacting the compound III obtained in the step 2) with orthoformate or alcohol under an acidic condition to obtain a compound IV;
4) Reacting the compound IV prepared in the step 3) with 1,3-halogenated chloropropane under an alkaline condition to prepare a compound V;
wherein R is 4 Selected from straight-chain or branched C 1 ~C 3 Alkyl groups of (a); x is selected from halogen;
5) Hydrolyzing and decarboxylating the compound V prepared in the step 4) under an acidic condition to prepare a compound VI;
in another aspect, the invention provides 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester, which is prepared by the method described above.
In another aspect, the invention provides the use of ethyl 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylate according to the invention in an antibacterial medicament.
Compared with the prior art, the invention has the beneficial effects that:
1. protecting the compound III, wherein the step is simple to operate, and can be directly carried out in the next step through neutralization, suction filtration and concentration;
2. the compound IV reacts with 3-halogenated chloropropane to prepare a compound V, so that the generation of byproducts and the recycling treatment and the reuse of the byproducts are avoided;
3. the post-treatment process of the step four is simplified, the operation is simple, the production period is shortened, and the method is suitable for industrial production;
4. glycine ester or acceptable salt thereof, especially glycine ethyl ester hydrochloride is used as a starting material, benzylamine is replaced as a raw material, the step of subsequent debenzylation by using a noble metal catalyst is avoided, and the harm to the environment and health is reduced;
5. the total yield of the process is about 75 percent, the recovery efficiency is high, and the process is suitable for mass production.
Drawings
FIG. 1 shows the chromatogram and mass spectrum of Compound VI of example 1. Wherein, FIG. 1a is a chromatogram of the compound VI of example 1, and FIG. 1b is a mass spectrum of the compound VI of example 1.
FIG. 2 shows a hydrogen nuclear magnetic resonance image of Compound VI of example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention is further described below with reference to the following embodiments. It should be understood that the examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. The experimental procedures used in the following examples are conventional and, unless otherwise indicated, other advantages and effects of the present invention will be readily apparent to those skilled in the art from the disclosure herein.
The inventor of the invention discovers, through a great deal of research and research, a preparation method of 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester, which takes glycine ethyl ester hydrochloride as a raw material, obtains a compound II through ethoxycarbonyl protection, obtains a compound III through addition cyclization with ethyl acrylate, obtains a compound IV through protection, obtains a compound V after alkylation, and removes ethoxycarbonyl to obtain a target product. The present invention has been completed based on this finding.
The invention provides a preparation method of 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester, which comprises the following steps:
1) Reacting glycine ester or acceptable salt thereof with chloroformate under alkaline condition to obtain a compound II;
wherein R is 1 And R 2 Each independently selected from linear or branched C 1 ~C 3 Alkyl groups of (a);
reacting the compound II prepared in the step 1) with acrylic ester under an alkaline condition to prepare a compound III;
wherein R is 3 Selected from straight-chain or branched C 1 ~C 3 Alkyl groups of (a);
3) Reacting the compound III obtained in the step 2) with orthoformate or alcohol under an acidic condition to obtain a compound IV;
4) Reacting the compound IV prepared in the step 3) with 1,3-halogenated chloropropane under an alkaline condition to prepare a compound V;
wherein R is 4 Selected from straight-chain or branched C 1 ~C 3 Alkyl groups of (a); x is selected from halogen;
5) Hydrolyzing and decarboxylating the compound V prepared in the step 4) under an acidic condition to prepare a compound VI;
in the preparation method provided by the invention, the step 1) is to react glycine ester or acceptable salt thereof with chloroformate under alkaline condition to prepare the compound II.
In step 1) of the present application, the glycine ester is selected from glycine methyl ester and/or glycine ethyl ester. The glycine ester acceptable salt is selected from glycine methyl ester acceptable salt and/or glycine ethyl ester acceptable salt. Preferably, the glycine methyl ester acceptable salt is selected from glycine methyl ester hydrochloride, and the glycine ethyl ester acceptable salt is selected from glycine ethyl ester hydrochloride; more preferably, the glycine ester acceptable salt is selected from glycine ethyl ester hydrochloride. The structural formula of the glycine ester is as follows:
in the step 1), the chloroformate is selected from methyl chloroformate and/or ethyl chloroformate, and the structural formula of the chloroformate is as follows:
in the step 1), the base in the alkaline condition is selected from an organic base and/or an inorganic base, preferably, the organic base is selected from triethylamine and/or diisopropylethylamine; the inorganic base is selected from one or more of potassium carbonate, sodium carbonate and sodium bicarbonate.
In step 1), the reaction of the glycine ester or the acceptable salt thereof with the chloroformate is usually carried out in the presence of a reaction solvent, the reaction solvent is usually a good solvent of the reaction system, and the reaction solvent used may be an organic solvent, and specifically may be an alkane and/or toluene.
In step 1), one skilled in the art can select suitable temperature conditions to allow the reaction of the glycine ester or acceptable salt thereof with the chloroformate to proceed sufficiently forward. For example, in the preparation process of the compound II, the reaction temperature can be 0 to 35 ℃; preferably 0 to 10 ℃, 10 to 20 ℃, or 20 to 35 ℃ and the like. The reaction time can be adjusted by one skilled in the art according to the reaction progress, for example, the reaction time can be 1 to 3.5h in the preparation process of the compound II; preferably 1 to 2h, 2 to 2.5h, 2.5 to 3h, or the like.
In step 1), the molar ratio of said glycine ester, said chloroformate, and said base under basic conditions is 1:1.0 to 1.2:1.0 to 1.5; preferably 1:1.0 to 1.1:1.0 to 1.2, 1:1.0 to 1.1:1.2 to 1.3, 1:1.0 to 1.1:1.3 to 1.4 or 1:1.1 to 1.2:1.4 to 1.5, and the like. The molar ratio of said glycine ester acceptable salt, said chloroformate, and said base under basic conditions is 1:1.0 to 1.2:1.0 to 1.5; preferably 1:1.0 to 1.1:1.0 to 1.2, 1:1.0 to 1.1:1.2 to 1.3, 1:1.0 to 1.1:1.3 to 1.4 or 1:1.1 to 1.2:1.4 to 1.5, and the like.
In step 1), the R is 1 、R 2 Each independently is specifically selected from methyl and/or ethyl.
In the preparation method provided by the invention, the step 2) is to react the compound II prepared in the step 1) with acrylate under an alkaline condition to prepare a compound III.
In step 2) of the present application, the acrylate is selected from methyl acrylate and/or ethyl acrylate; preferably, the acrylate is selected from ethyl acrylate. The structural formula of the acrylate is as follows:
in the step 2), the alkali under the alkaline condition is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and sodium hydrogen, preferably, the alkali under the alkaline condition is selected from sodium methoxide and/or sodium ethoxide.
In step 2), the skilled person can select suitable temperature conditions so that the reaction of the compound II with the acrylate proceeds sufficiently forward. For example, in the preparation process of the compound III, the reaction temperature can be 40 to 65 ℃; preferably 40 to 48 ℃, 48 to 58 ℃ or 58 to 65 ℃. The reaction time can be adjusted by a person skilled in the art according to the reaction progress, for example, in the preparation process of the compound III, the reaction time can be 1 to 3 hours; preferably 1 to 2h, 2 to 2.5h, 2.5 to 3h, or the like.
In step 2), the R 3 In particular selected from methyl and/or ethyl.
In the step 2), the molar ratio of the compound II, the acrylate and the alkali in the alkaline condition is 1:1.0 to 1.2:1.0 to 1.5; preferably 1:1.0 to 1.1:1.0 to 1.2, 1:1.0 to 1.1:1.2 to 1.3, 1:1.0 to 1.1:1.3 to 1.4, or 1:1.1 to 1.2:1.4 to 1.5, and the like.
In the preparation method provided by the invention, the step 3) is to react the compound III prepared in the step 2) with orthoformate or alcohol under an acidic condition to prepare a compound IV.
In step 3) of the present application, the orthoformate is selected from triethyl orthoformate and/or trimethyl orthoformate; preferably, the orthoformate is selected from trimethyl orthoformate. The orthoformate has the structural formula:
in the step 3), the alcohol is selected from one or more of methanol, ethanol and glycol; preferably, the alcohol is selected from ethylene glycol.
In the step 3), the acid under the acidic condition is selected from organic acid or inorganic acid, the organic acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid monohydrate and trifluoromethanesulfonic acid, and the inorganic acid is selected from hydrogen chloride; preferably, the acid of the acidic condition is selected from an organic acid selected from toluenesulfonic acid and/or p-toluenesulfonic acid monohydrate.
In the step 3), the reaction of the compound iii with orthoformate or alcohol is usually performed in the presence of a reaction solvent, where the reaction solvent is usually a good solvent of a reaction system, and the reaction solvent used may be an organic solvent, specifically may be one or a combination of more of methanol, ethanol, toluene, and cyclohexane; preferably, the reaction solvent is selected from cyclohexane.
In step 3), the molar ratio of the compound III, orthoformate and acid in the acidic condition is 1:2.0 to 5.0:0.005 to 0.05; preferably 1:2.0 to 3.0:0.005 to 0.01, 1:3.0 to 4.0:0.01 to 0.02, or 1:4.0 to 5.0:0.02 to 0.05 and the like. The molar ratio of the compound III, the alcohol, and the acid in the acidic condition is 1:2.0 to 5.0:0.005 to 0.05; preferably 1:2.0 to 3.0:0.005 to 0.01, 1:3.0 to 4.0:0.01 to 0.02, or 1:4.0 to 5.0:0.02 to 0.05 and the like.
In step 3), the skilled person can select suitable temperature conditions so that the reaction of said compound III with orthoformates or alcohols proceeds sufficiently forward. For example, in the preparation process of the compound IV, the reaction temperature can be 60-80 ℃; preferably 60 to 65 ℃, 65 to 70 ℃, 70 to 75 ℃, or 75 to 80 ℃ and the like. The reaction time can be adjusted by a person skilled in the art according to the reaction progress, for example, in the preparation process of the compound IV, the reaction time can be 3 to 6h; preferably 3 to 4h, 4 to 5h, or 5 to 6 h.
And 3) further comprising a post-treatment step, namely adding solid sodium carbonate to neutralize acid, performing suction filtration, concentrating the solvent under a vacuum condition, and then performing reduced pressure distillation to obtain a compound IV.
In the preparation method provided by the invention, the step 4) is to react the compound IV prepared in the step 3) with 1,3-halogenated chloropropane under an alkaline condition to prepare and obtain a compound V.
In step 4) of the present application, X specifically refers to one of Br, I, and CI. The 1,3-halochloropropane is selected from one or more of 1,3-dichloropropane, 1-bromo-3-chloropropane and 1-iodo-3-chloropropane; preferably, the 1,3-halochloropropane is selected from 1-bromo-3-chloropropane. The 1,3-halochloropropane has the structural formula:
in the step 4), the reaction of the compound IV and 1,3-halochloropropane is generally carried out in the presence of a reaction solvent, the reaction solvent is generally a good solvent of a reaction system, and the used reaction solvent is selected from one or more of toluene, alkane and tetrahydrofuran; preferably, the reaction solvent is selected from toluene or tetrahydrofuran.
In the step 4), the base in the alkaline condition is selected from inorganic bases, and the inorganic bases are selected from one or more of sodium hydrogen, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, butyl lithium, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide.
In step 4), one skilled in the art can select suitable temperature conditions so that the reaction of the compound II with the acrylate proceeds sufficiently forward. For example, in the preparation process of the compound IV, the reaction temperature can be-10 to 10 ℃; preferably-10 to-5 ℃, 5~0 ℃, 0~5 ℃ or 5 to 10 ℃. The reaction time can be adjusted by one skilled in the art according to the reaction progress, for example, the reaction time can be 3 to 6h in the preparation process of the compound V; preferably from 3 to 4.5 hours, from 4.5 to 5.5 hours, or from 5.5 to 6 hours.
In the step 4), the molar ratio of the compound IV, the 1,3-halochloropropane and the alkali in the alkaline condition is 1:1.2 to 4.0:1.0 to 1.5; preferably 1:1.2 to 2:1.0 to 1.2, 1:2~3:1.2 to 1.3, or 1:3~4:1.3 to 1.5, and the like.
In step 4), the R 4 In particular selected from methyl and/or ethyl.
In the step 4), after the reaction is finished, post-treatment is carried out: and dropwise adding 180ml of ammonium chloride solution into the system, continuing stirring for 15 minutes after the addition is finished, concentrating, adding 100ml of toluene, standing for liquid separation, extracting the water phase twice with 100ml of toluene each time, combining the organic phases, and concentrating the organic phase under reduced pressure to obtain the compound V.
In the preparation method provided by the invention, the step 5) is to hydrolyze and decarboxylate the compound V prepared in the step 4) under an acidic condition to prepare a compound VI.
In the step 5), the compound VI is 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester, and the structural formula of the compound VI is as follows:
in step 5), the acid under acidic conditions is selected from hydrochloric acid and/or sulfuric acid; preferably, the acid of the acidic condition is selected from sulfuric acid.
In the step 5), the hydrolysis and decarboxylation reaction of the compound V are generally carried out in the presence of a reaction solvent, the reaction solvent is generally a good solvent of a reaction system, and the reaction solvent is selected from one or more of alcohol, water and a mixed solution of alcohol and water; preferably, the reaction solvent is selected from a mixed solution of alcohol and water.
In step 5), one skilled in the art can select appropriate temperature conditions to allow the hydrolysis and decarboxylation of the compound V to proceed fully in the forward direction. For example, in the preparation process of the compound VI, the reaction temperature is 40 to 60 ℃; preferably 40 to 50 ℃ and 50 to 60 ℃. The reaction time can be adjusted by those skilled in the art according to the reaction progress, for example, in the preparation process of the compound VI, the reaction time can be from 20h to 24h; preferably from 20h to 22h, from 22h to 23h, or from 23h to 24h.
In step 5), the molar ratio of the compound V to the acid under acidic conditions is 1:1.0 to 3.0; preferably 1:1.0 to 2.0, 1:2.0 to 3.0, 1:3.0 to 4.0, or 1:4.0 to 5.0, and the like.
In another aspect, the invention provides 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester obtained by the preparation method of the 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester.
The invention also provides application of the 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester in antibacterial drugs.
The moxifloxacin antibacterial agent is synthesized by synthesizing (S, S) -2,8-diazabicyclo [4.3.0] nonane which is a key intermediate from 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester, and can be used for upper respiratory tract and lower respiratory tract infection diseases, such as: sinusitis, acute episodes of chronic bronchitis, community-acquired pneumonia, and skin and soft tissue infections, among others.
The preparation method of the 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester provided by the invention comprises the following steps:
1. in the prior art, a by-product is generated in the preparation process of the compound V, the proportion of the by-product is 30%, the route procedures are multiple, the operation steps are complicated, the production period is greatly prolonged, the yield is 37 to 40%, and the industrial efficiency is greatly reduced.
2. In the prior art, benzylamine is used as a raw material to generate a large amount of benzyl chloride, the compound belongs to carcinogens, has liver and kidney toxicity and has great harm to ecology and health, and glycine ethyl ester hydrochloride is used as a raw material to avoid the generation of carcinogens, avoid the step of using a noble metal catalyst to perform subsequent debenzylation and reduce the harm to environment and health.
3. The total yield of the process is about 75%, the process operation is simple, and the process is suitable for large-scale production.
In conclusion, the method has the advantages of protecting the compound III, avoiding the generation of byproducts and the recovery and treatment of the byproducts, using glycine ethyl ester hydrochloride to replace benzylamine as a raw material, avoiding the generation of carcinogens, reducing the harm to the environment and health, along with high production efficiency and simple process.
The invention of the present application is further illustrated by the following examples, which are not intended to limit the scope of the present application.
The examples are illustrated by reference to the following synthetic schemes:
in the following examples, materials, reagents and the like used were commercially available reagents and materials, unless otherwise specified.
Example 1
1. Adding glycine ethyl ester hydrochloride (1200 g, 8.597mol) and 3600ml of water into a 10L three-necked flask, stirring and dissolving, cooling to below 10 ℃, maintaining the temperature, adding sodium carbonate (1200 g, 11.322mol) in batches, continuing to stir for 15 minutes after the addition is finished, beginning to dropwise add ethyl chloroformate (979g, 9.021mol) for about 2 hours, controlling the temperature to 10 to 15 ℃, continuing to maintain the temperature to 10 to 15 ℃ for reaction for 2 hours after the dropwise addition is finished, controlling the reaction in TLC to be complete (ethyl acetate/methanol 5/1), adding 650ml of toluene, separating, extracting the aqueous phase once with 650ml of toluene, combining the organic phases, and concentrating under vacuum to obtain a compound 2:1426g, molar yield 95.7%.
2. Stirring is started in a 5L three-necked bottle, N-ethoxycarbonylglycine ethyl ester (380.0g, 2.19mol), ethyl acrylate (225.6g, 2.253mol) and methyl tertiary ether (1700 ml) are respectively added, after the addition is finished, the temperature is reduced to below 20 ℃, solid sodium ethoxide (182.8g, 2.686mol) is added in batches, the temperature is raised to 50 ℃ to 65 ℃ under the condition of mechanical stirring, the temperature is kept for reaction for 3 hours, TLC (ethyl acetate/N-hexane 1/3) is completely controlled to react, the temperature is reduced to about 25 ℃, the temperature is kept below 25 ℃, glacial acetic acid (176.8g, 2.944mol) is dropwise added, the stirring is continued for 10 minutes, then water is added for 500ml, the stirring is continued for 30 minutes, standing and liquid separation is carried out, the water phase is extracted twice with 300ml of methyl tertiary ether each time, the organic phases are combined, washed with 300ml of water, the organic phases are separated, and the organic phases are concentrated under the vacuum condition to obtain a compound 3:464.9g, molar yield 93.5%.
3. Compound 3 (73.3 g, 0.320mol), trimethyl orthoformate (84.9g, 0.80mol) and p-toluenesulfonic acid monohydrate (0.55g, 2.89mmol) were added to 300ml of anhydrous methanol, heating was started to reflux under nitrogen protection, the reaction was refluxed for 16 hours, cooled to room temperature, solid sodium carbonate (1g, 11.9mmol) was added to neutralize the acid, suction filtration was performed, the solvent was concentrated under vacuum, and then compound 4 as a colorless liquid was distilled off under reduced pressure: 84.6g, and the molar yield is 96%.
4. Adding a compound 4 dimethyl ketal (266.2g, 0.967 mol) and tetrahydrofuran (2.5L) into a 3L three-necked flask under mechanical stirring, controlling the temperature to be-10-0 ℃, dropwise adding lithium diisopropylamide tetrahydrofuran solution (2M, 0.58L), continuing to perform heat preservation reaction for 30 minutes after dropwise adding, beginning dropwise adding bromochloropropane (182.6 g, 1.160mol), continuing to perform reaction for 6 hours after dropwise adding, performing HPLC (high performance liquid chromatography) control, wherein the raw material content is lower than 2.5%, and performing post-treatment: and (2) dropwise adding 180ml of ammonium chloride solution into the system, continuing stirring for 15 minutes after the addition is finished, concentrating, adding 100ml of toluene, standing for liquid separation, extracting the water phase twice with 100ml of toluene each time, combining the organic phases, and concentrating the organic phases under reduced pressure to obtain a compound 5:323.2g, 95% molar yield.
5. Under mechanical stirring, respectively adding compound 5 (216.0 g, 0.614mol), 100g of water, 157.7g of sulfuric acid and 28.2g of 95% ethanol into a 2L three-necked bottle, stirring and heating to 50-60 ℃, maintaining the temperature for 24 hours, controlling raw materials in TLC to be reacted completely (1/3 of ethyl acetate/n-hexane), adding 300g of water into a reaction system, cooling to room temperature, extracting with 150ml of toluene for three times each time, combining organic phases, washing with 250ml of water twice each time, concentrating the organic phases under reduced pressure, adding 75ml of water, continuously concentrating under reduced pressure and carrying dry toluene to obtain an oily compound 6:131.0g, HPLC purity of 99.8%, molar yield of 91.3%, and five-step molar overall yield of 74.5%.
As shown in figure 1~2, the prepared compound 6 was tested: MS:234.2 (M + H) + )；1H NMR(400MHz CDCl 3 )δ4.15-4.22(m，3H)，3.92(m，1H)，3.70-3.75(m，1H)，3.53-3.57(m，2H)，3.30-3.35(m，1H)，2.60(bs，1H)，1.82-1.97(m，3H)，1.58-1.61(m，1H)，1.27-1.30(m，3H)。
Example 2
1. Adding glycine ethyl ester hydrochloride (600g, 4.3 mol) and 1800ml of water into a 5L three-necked bottle, stirring and dissolving, cooling to below 10 ℃, maintaining the temperature, adding sodium carbonate (546.8g, 5.1mol) in batches, continuing to stir for 15 minutes after the addition is finished, starting dropwise adding ethyl chloroformate (553.5g, 5.1mol) for about 2 hours, controlling the temperature to 10 to 15 ℃, continuing to react for 2 hours at 10 to 15 ℃ after the dropwise addition is finished, controlling the TLC to completely react (ethyl acetate/methanol 5/1), adding 320ml of toluene, separating, extracting the water phase once with 320ml of toluene, combining the organic phases, and concentrating under vacuum to obtain a compound 2:714.1g, molar yield 94.8%.
2. Stirring in a 5L three-necked flask, respectively adding N-ethoxycarbonylglycine ethyl ester (380.0 g,2.2 mol), ethyl acrylate (264.3 g,2.6 mol) and methyl tertiary ether (1760 ml), cooling to below 20 ℃ after the addition is finished, adding solid sodium ethoxide (176.9g, 2.6 mol) in batches, heating to 50-65 ℃ under the condition of mechanical stirring, carrying out heat preservation reaction for 3 hours, carrying out TLC (ethyl acetate/N-hexane 1/3) controlled reaction completely, cooling to about 25 ℃, keeping the temperature below 25 ℃, dropwise adding glacial acetic acid (156.1g, 2.6 mol), keeping stirring for 10 minutes after about 1 hour is finished, then adding water 500ml, continuing stirring for 30 minutes, standing for liquid separation, extracting the water phase twice with 300ml of methyl tertiary ether each time, combining the organic phases, washing with 300ml of water once, separating the organic phases, and concentrating under vacuum to obtain an oily compound 3:472.9g, 95.1% molar yield.
3. Compound 3 (68.8g, 0.3mol), trimethyl orthoformate (111.4g, 1.05mol) and p-toluenesulfonic acid monohydrate (0.57g, 3mmol) were added to 300ml of anhydrous methanol, heating was started to reflux under nitrogen protection, the reflux reaction was carried out for 16 hours, the temperature was reduced to room temperature, solid sodium carbonate (0.9g, 9.0 mmol) was added to neutralize the acid, suction filtration was carried out, the solvent was concentrated under vacuum, and then, colorless liquid compound 4 was distilled off under reduced pressure: 80.2g, and the molar yield is 97.1%.
4. Adding a compound 4 dimethyl ketone (247.8g, 0.9mol) and tetrahydrofuran (1.3L) into a 3L three-necked flask under mechanical stirring, controlling the temperature to be-10-0 ℃, dropwise adding lithium diisopropylamide tetrahydrofuran solution (2M, 1.1L), continuing carrying out heat preservation reaction for 30 minutes after dropwise adding, beginning dropwise adding bromochloropropane (354.2g, 2.25mol), continuing reacting for 6 hours after dropwise adding, controlling HPLC (high performance liquid chromatography) to be less than 2.5%, and carrying out aftertreatment: and (3) dropwise adding 300ml of ammonium chloride solution into the system, continuing stirring for 15 minutes after the addition is finished, concentrating, adding 100ml of toluene, standing for liquid separation, extracting the water phase twice with 100ml of toluene each time, combining the organic phases, and concentrating the organic phases under reduced pressure to obtain a compound 5:301.7g, 95.1% molar yield.
5. Respectively adding compound 5 (211.1g, 0.6 mol), 100g of water, 70.6g of sulfuric acid and 24g of 95% ethanol into a 2L three-necked bottle under mechanical stirring, stirring and heating to 50-60 ℃, maintaining the temperature for 24 hours, finishing the reaction of the control raw materials in TLC (ethyl acetate/n-hexane 1/3), adding 260g of water into the reaction system, cooling to room temperature, extracting with 110ml of toluene for three times each time, combining organic phases, washing with 150ml of water twice each time, concentrating the organic phases under reduced pressure, adding 63ml of water, continuously concentrating under reduced pressure and carrying dry toluene to obtain an oily compound 6:130.7g, HPLC purity 99.1%, molar yield 93.2%, five steps molar overall yield 77.5%.
Example 3
1. Adding glycine ethyl ester hydrochloride (1200 g,8.6 mol) and 3600ml of water into a 10L three-necked flask, stirring and dissolving, cooling to below 10 ℃, maintaining the temperature, adding sodium carbonate (1367g, 12.9 mol) in batches, continuing to stir for 15 minutes after the addition is finished, beginning to dropwise add ethyl chloroformate (1400 g,12.9 mol) for about 2 hours, controlling the temperature to 10 to 15 ℃, continuing to maintain the temperature to 10 to 15 ℃ for reaction for 2 hours after the dropwise addition is finished, controlling the reaction in TLC to be complete (ethyl acetate/methanol 5/1), adding 650ml of toluene, separating, extracting the aqueous phase once with 650ml of toluene, combining the organic phases, and concentrating under vacuum to obtain a compound 2:1448g, molar yield 96.1%.
2. Stirring in a 5L three-necked bottle, adding N-ethoxycarbonylglycine ethyl ester (368g, 2.1mol), ethyl acrylate (315g, 3.15mol) and methyl tertiary ether (1700 ml), cooling to below 20 ℃ after the addition is finished, adding solid sodium ethoxide (214g, 3.15mol) in batches, heating to 50-65 ℃ under the mechanical stirring condition, carrying out heat preservation reaction for 3 hours, carrying out TLC (ethyl acetate/N-hexane 1/3) for complete control reaction, cooling to about 25 ℃, keeping the temperature below 25 ℃, dropwise adding glacial acetic acid (189g, 3.15mol), carrying out about 1 hour dropwise addition, continuing stirring for 10 minutes, adding water 500ml, continuing stirring for 30 minutes, standing, extracting the water phase twice with 300ml methyl tertiary ether each time, combining organic phases, washing with 300ml water once, separating the organic phases, and concentrating under vacuum to obtain an oily compound 3:458.8g, 95.3% molar yield.
3. Compound 3 (68.7g, 0.3mol), trimethyl orthoformate (143g, 1.35mol) and p-toluenesulfonic acid monohydrate (2.8g, 15mmol) were added to 300ml of anhydrous methanol, heating was started to reflux under nitrogen protection, the reflux reaction was carried out for 16 hours, the temperature was reduced to room temperature, solid sodium carbonate (3.2g, 30mmol) was added to neutralize the acid, suction filtration was carried out, the solvent was concentrated under vacuum, and then colorless liquid compound 4 was distilled off under reduced pressure: 80g, and the molar yield is 97.2%.
4. Adding a compound 4-dimethyl acetal (275g, 1.mol) and tetrahydrofuran (2.5L) into a 3L three-necked bottle under mechanical stirring, controlling the temperature to be-10-0 ℃, dropwise adding a lithium diisopropylamide tetrahydrofuran solution (2M, 2.25L), continuously preserving the temperature for reacting for 30 minutes after dropwise adding, beginning dropwise adding bromochloropropane (551g, 3.5 mol), continuously reacting for 6 hours after dropwise adding, controlling the HPLC, wherein the content of raw materials is lower than 2.5%, and carrying out aftertreatment: and (3) dropwise adding 280ml of ammonium chloride solution into the system, continuing stirring for 15 minutes after the addition is finished, concentrating, adding 150ml of toluene, standing for liquid separation, extracting the water phase twice with 150ml of toluene each time, combining the organic phases, and concentrating the organic phases under reduced pressure to obtain a compound 5:336g, molar yield 95.6%.
5. Respectively adding compound 5 (137g, 0.5 mol), 100g of water, 98g of sulfuric acid and 28.2g of 95% ethanol into a 2L three-necked bottle under mechanical stirring, stirring and heating to 50-60 ℃, maintaining the temperature for 24 hours, controlling raw materials in TLC to react (ethyl acetate/n-hexane 1/3), adding 200g of water into a reaction system, cooling to room temperature, extracting with 100ml of toluene for three times each time, combining organic phases, washing with 250ml of water twice each time, concentrating the organic phases under reduced pressure, adding 75ml of water, continuously concentrating the water under reduced pressure to obtain an oily compound 6:108g, HPLC purity 99.5%, molar yield 92.3%, five steps molar yield 78.5%.
Example 4
3. Compound 3 (91.7g, 0.4mol), triethyl orthoformate (207.7g, 1.4mol) and p-toluenesulfonic acid monohydrate (0.7g, 4 mmol) were added to 320ml of absolute ethanol, heating was started to reflux under nitrogen protection, the reflux reaction was carried out for 16 hours, the temperature was reduced to room temperature, solid sodium carbonate (0.8g, 8.0mmol) was added to neutralize the acid, suction filtration was carried out, the solvent was concentrated under vacuum, and then colorless liquid compound 4 was distilled off under reduced pressure: 117.5g, molar yield 96.8%.
4. Adding a compound 4 diacetyl ketone (91g, 0.3 mol) and tetrahydrofuran (0.7L) into a 3L three-necked flask under mechanical stirring, controlling the temperature to be-10-0 ℃, dropwise adding lithium diisopropylamide tetrahydrofuran solution (2M, 375 mL), continuously carrying out heat preservation reaction for 30 minutes after dropwise adding, beginning dropwise adding bromochloropropane (118g, 0.75mol), continuously carrying out reaction for 6 hours after dropwise adding, carrying out HPLC (high performance liquid chromatography) control, wherein the raw material content is lower than 2.5%, and carrying out aftertreatment: and (2) dropwise adding 100ml of ammonium chloride solution into the system, continuing stirring for 15 minutes after the addition is finished, concentrating, adding 90ml of toluene, standing for liquid separation, extracting the water phase twice with 90ml of toluene each time, combining the organic phases, and concentrating the organic phases under reduced pressure to obtain a compound 5:109g, molar yield 96%.
5. Respectively adding compound 5 (190g, 0.5 mol), 80g of water, 65g of sulfuric acid and 20g of 95% ethanol into a 2L three-necked bottle under mechanical stirring, stirring and heating to 50-60 ℃, maintaining the temperature for 24 hours, completing the reaction of the raw materials in TLC (ethyl acetate/n-hexane 1/3), adding 200g of water into the reaction system, cooling to room temperature, extracting with 100ml of toluene for three times, combining organic phases, washing with 100ml of water twice each time, concentrating the organic phases under reduced pressure, adding 60ml of water, continuously concentrating under reduced pressure to carry dry toluene to obtain an oily compound 6:111g, 95% molar yield, 79% total molar yield.
Example 5
3. Compound 3 (45.8g, 0.2mol), ethylene glycol (43.4g, 0.7mol) and p-toluenesulfonic acid monohydrate (0.4g, 2mmol) were charged into a three-necked flask, heating was started to 90 ℃ under nitrogen protection, the reaction was incubated for 16 hours, the temperature was reduced to room temperature, solid sodium carbonate (0.4g, 4.0mmol) was added to neutralize the acid, suction filtration was performed, the solvent was concentrated under vacuum, and then colorless liquid compound 4 was distilled off under reduced pressure: 52.3g, 95.6% molar yield.
4. Adding a compound 4 ethylene glycol ketal (136.6 g,0.5 mol) and tetrahydrofuran (0.6L) into a 3L three-necked bottle under mechanical stirring, controlling the temperature to be-10-0 ℃, dropwise adding lithium diisopropylamide tetrahydrofuran solution (2M, 625 mL), keeping the temperature for reacting for 30 minutes after dropwise adding, beginning dropwise adding bromochloropropane (196.8g, 1.25mol), continuously reacting for 6 hours after dropwise adding, controlling the HPLC (high performance liquid chromatography) to be lower than 2.5%, and carrying out aftertreatment: and (3) dropwise adding 180ml of ammonium chloride solution into the system, continuing stirring for 15 minutes after the addition is finished, concentrating, adding 130ml of toluene, standing for liquid separation, extracting the aqueous phase twice with 130ml of toluene each time, combining the organic phases, and concentrating the organic phase under reduced pressure to obtain a compound 5:168g, and the molar yield is 96.3%.
5. Under mechanical stirring, respectively adding compound 5 (174.9g, 0.5 mol), 100g of water, 98g of sulfuric acid and 17g of 95% ethanol into a 2L three-necked bottle, stirring and heating to 50-60 ℃, maintaining the temperature for 24 hours, controlling raw materials in TLC to be completely reacted (ethyl acetate/n-hexane 1/3), adding 170g of water into a reaction system, cooling to room temperature, extracting with 90ml of toluene for three times, combining organic phases, washing with 100ml of water twice each time, concentrating the organic phases under reduced pressure, adding 50ml of water, and continuously concentrating under reduced pressure to obtain an oily compound 6:110g, 94.1 percent of molar yield and 77.5 percent of total molar yield.
Comparative example 1
3: compound 3 (221.6 g, 0.96mol), bromochloropropane (607.7g, 3.86mol) and triethylamine (122.3g, 1.21mol) were added to a 3L three necked flask with mechanical stirring, the temperature was controlled at 20-25 ℃, HPLC was controlled, the starting material was less than 2.5% and worked up: adding 180ml of 2N hydrochloric acid into the system, continuing stirring for 15 minutes after the addition is finished, standing, separating liquid, and concentrating the organic phase under reduced pressure to recover 385g of bromochloropropane to obtain 323.2g (the product is a mixture, the molar ratio of the ether group byproduct is about 35.3%, the molar ratio of the compound is about 64.7%), and the molar yield is 95%.
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 can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. A process for the preparation of the compound ethyl 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylate represented by the general formula vi, which comprises:
1) Reacting glycine ester or acceptable salt thereof with chloroformate under alkaline condition to prepare a compound II;
wherein R is 1 And R 2 Each independently selected from linear or branched C 1 ~C 3 Alkyl groups of (a);
2) Reacting the compound II prepared in the step 1) with acrylic ester under an alkaline condition to prepare a compound III;
wherein R is 3 Selected from straight-chain or branched C 1 ~C 3 Alkyl groups of (a);
3) Reacting the compound III obtained in the step 2) with orthoformate or alcohol under an acidic condition to obtain a compound IV;
4) Reacting the compound IV prepared in the step 3) with 1,3-halogenated chloropropane under an alkaline condition to prepare a compound V;
wherein R is 4 Selected from straight-chain or branched C 1 ~C 3 Alkyl groups of (a); x is selected from halogen;
5) Hydrolyzing and decarboxylating the compound V prepared in the step 4) under an acidic condition to prepare a compound VI;
2. the method of claim 1, wherein step 1) further comprises any one or more of the following features:
a1 In step 1), the glycine ester is selected from glycine methyl ester and/or glycine ethyl ester;
a2 In step 1), the glycine ester acceptable salt is selected from glycine methyl ester acceptable salt and/or glycine ethyl ester acceptable salt;
a3 In step 1), the base in the basic condition is selected from organic base and/or inorganic base, preferably, the organic base is selected from triethylamine and/or diisopropylethylamine; the inorganic base is one or more of potassium carbonate, sodium carbonate and sodium bicarbonate;
a4 Step 1), further comprising a reaction solvent selected from toluene and/or an alkane;
a5 ) in the step 1), the reaction temperature is 0 to 35 ℃.
3. The method of claim 2, wherein the glycine methyl ester acceptable salt is selected from glycine methyl ester hydrochloride; the acceptable salt of glycine ethyl ester is selected from glycine ethyl ester hydrochloride.
4. The method of claim 1, further comprising any one or more of the following features:
b1 In step 1), the chloroformate is selected from methyl chloroformate and/or ethyl chloroformate;
b2 Step 1), the molar ratio of said glycine ester or an acceptable salt thereof, said chloroformate, and said base under basic conditions is from 1:1.0 to 1.2:1.0 to 1.5;
b3 In step 1), the R 1 、R 2 Each independently is specifically selected from methyl and/or ethyl.
5. The method of claim 1, wherein step 2) further comprises any one or more of the following features:
c1 In step 2), the acrylate is selected from methyl acrylate and/or ethyl acrylate; preferably, the acrylate is selected from ethyl acrylate;
c2 In step 2), the alkali under the alkaline condition is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and sodium hydrogen, preferably, the alkali is selected from sodium methoxide and/or sodium ethoxide;
c3 In the step 2), the reaction temperature is 40 to 65 ℃;
c4 In step 2), the molar ratio of the compound II, the acrylate and the base in the alkaline condition is 1: 1.0-1.2: 1.0 to 1.5;
c5 In step 2), the R 3 In particular selected from methyl and/or ethyl.
6. The method of claim 1, wherein step 3) further comprises any one or more of the following features:
d1 In step 3), the orthoformate is selected from triethyl orthoformate and/or trimethyl orthoformate; preferably, the orthoformate is selected from trimethyl orthoformate;
d2 In step 3), the alcohol is selected from one or more of methanol, ethanol and glycol; preferably, the alcohol is selected from ethylene glycol;
d3 In step 3), the acid under acidic condition is selected from organic acid and/or inorganic acid, and the organic acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid monohydrate and trifluoromethanesulfonic acid; the inorganic acid is selected from hydrogen chloride; preferably, the acid of the acidic condition is selected from organic acids selected from toluenesulfonic acid and/or p-toluenesulfonic acid monohydrate;
d4 In step 3), a reaction solvent is further included, wherein the reaction solvent is one or more selected from methanol, ethanol, toluene and cyclohexane; preferably, the reaction solvent is selected from cyclohexane;
d5 In step 3), the molar ratio of said compound iii, said orthoformate or said alcohol, and said acid in acidic conditions is 1:2.0 to 5.0:0.005 to 0.05.
7. The method of claim 1, wherein step 4) further comprises any one or more of the following features:
e1 In the step 4), X is selected from one of Br, I and CI;
e2 1,3-halochloropropane selected from one or more of 1,3-dichloropropane, 1-bromo-3-chloropropane and 1-iodo-3-chloropropane in step 4); preferably, the 1,3-halochloropropanes are selected from 1-bromo-3-chloropropane;
e3 Step 4), further comprising a reaction solvent selected from one or more of toluene, alkane and tetrahydrofuran; preferably, the reaction solvent is selected from toluene or tetrahydrofuran;
e4 In step 4), the base in the basic conditions is selected from inorganic bases selected from one or more of sodium hydrogen, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) lithium, butyl lithium, sodium bis (trimethylsilyl) and potassium bis (trimethylsilyl) in combination;
e5 In the step 4), the reaction temperature is-10 to 10 ℃;
e6 In step 4), the molar ratio of the compound IV, the 1,3-halochloropropane and the base in the alkaline condition is 1: 1.2-4.0: 1.0 to 1.5;
e7 In step 4), the R 4 In particular selected from methyl and/or ethyl.
8. The method of claim 1, wherein step 5) further comprises any one or more of the following features:
f1 In step 5), the acid of the acidic condition is selected from hydrochloric acid and/or sulfuric acid; preferably, the acid of the acidic condition is selected from sulfuric acid;
f2 Step 5), further comprising a reaction solvent selected from one or more of alcohol, water and a mixed solution of alcohol and water; preferably, the reaction solvent is selected from a mixed solution of alcohol and water;
f3 In the step 5), the reaction temperature is 40 to 60 ℃;
f4 In step 5), the molar ratio of said compound v to said acid under acidic conditions is 1:1.0 to 3.0.
9. 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ethyl ester prepared by the process of any one of claims 1~8.
10. Use of ethyl 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylate according to claim 9 in antibacterial medicine.
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