CN113956157B - Method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate - Google Patents
Method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate Download PDFInfo
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- formyl
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- cyclopropanecarboxylate
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- MDWXTLNIZCHBJE-WDSKDSINSA-N ethyl (1S,2R)-2-formylcyclopropane-1-carboxylate Chemical compound CCOC(=O)[C@H]1C[C@H]1C=O MDWXTLNIZCHBJE-WDSKDSINSA-N 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003960 organic solvent Substances 0.000 claims abstract description 23
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 claims abstract description 22
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 claims abstract description 21
- OGFKTAMJLKHRAZ-UHFFFAOYSA-N 2,2-dimethoxyacetaldehyde Chemical compound COC(OC)C=O OGFKTAMJLKHRAZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 14
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 238000001816 cooling Methods 0.000 claims abstract description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims abstract description 5
- 239000012074 organic phase Substances 0.000 claims description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 58
- 238000006243 chemical reaction Methods 0.000 claims description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 239000000243 solution Substances 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 238000000605 extraction Methods 0.000 claims description 13
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000012071 phase Substances 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 238000009776 industrial production Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 239000007788 liquid Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- SIRJFJKWVNTUKV-AATRIKPKSA-N ethyl (e)-4,4-dimethoxybut-2-enoate Chemical compound CCOC(=O)\C=C\C(OC)OC SIRJFJKWVNTUKV-AATRIKPKSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 5
- MDWXTLNIZCHBJE-UHFFFAOYSA-N ethyl 2-formylcyclopropane-1-carboxylate Chemical compound CCOC(=O)C1CC1C=O MDWXTLNIZCHBJE-UHFFFAOYSA-N 0.000 description 5
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 3
- 238000004508 fractional distillation Methods 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 229910004039 HBF4 Inorganic materials 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to the field of chemical pharmacy, and particularly discloses a method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate. The method comprises the following steps: step S1: adding 2, 2-dimethoxy acetaldehyde, triethyl phosphonoacetate and a catalyst 1 into an organic solvent 1 and water to prepare an intermediate 1; step S2: adding the catalyst 2 into the organic solvent 2, adding trimethyl sulfoxonium iodide, cooling to 0 ℃, adding the intermediate 1, and reacting at room temperature to obtain an intermediate 2; step S3: and adding the intermediate 2 into the organic solvent 3, cooling to 0 ℃, dropwise adding a dilute acid aqueous solution, and reacting at room temperature to obtain the 2-formyl-1-cyclopropaneethyl formate. The application has the advantages of easily available raw materials, proper price and higher safety; the experimental temperature condition is proper, and the industrial production advantage is more easily satisfied.
Description
Technical Field
The application relates to the field of chemical pharmacy, in particular to a method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate.
Background
Ethyl 2-formyl-1-cyclopropanecarboxylate is a common intermediate fragment in pharmaceutical synthesis, but the existing synthesis method of ethyl 2-formyl-1-cyclopropanecarboxylate is not mature; the structural formula of the 2-formyl-1-cyclopropanecarboxylic acid ethyl ester is as follows:
。
In the related art, when preparing the ethyl 2-formyl-1-cyclopropanecarboxylate, methylene dichloride, diethyl ether or pentane are used as solvents, acrolein, ethyl diazoacetate and 10% HBF 4·OEt2,HBF4·OEt2 are added as catalysts, and the mixture is stirred for 24 hours at the temperature of minus 78 ℃, so that the obtained product is the ethyl 2-formyl-1-cyclopropanecarboxylate and contains cis-trans isomers (the ratio is 40:60); the reaction formula is:
。
Aiming at the related technology, the inventor considers that the reaction raw material ethyl diazoacetate is easy to explode, the reaction temperature is minus 78 ℃, the condition is more severe, and the actual industrial production difficulty is increased.
Disclosure of Invention
In order to provide a synthesis method of 2-formyl-1-cyclopropaneethyl formate, which has mild reaction conditions and is more suitable for industrial production, the application provides a method for synthesizing 2-formyl-1-cyclopropaneethyl formate.
In a first aspect, the application provides a method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate, comprising the following steps:
Step S1: synthetic intermediate 1
S1a: adding 2, 2-dimethoxy acetaldehyde, triethyl phosphonoacetate and a catalyst 1 into an organic solvent 1 and water, stirring, and reacting at room temperature to obtain a reaction solution 1;
S1b: firstly removing the organic solvent 1 in the reaction liquid 1, then extracting to obtain an organic phase 1, and washing, drying, concentrating and fractionating to obtain an intermediate 1;
the mol ratio of the 2, 2-dimethoxy acetaldehyde to the triethyl phosphonoacetate is (3-1) 1, and the dosage ratio of the organic solvent 1 to the triethyl phosphonoacetate is (5-15) L1 kg;
Step S2: synthesis of intermediate 2
S2a: adding the catalyst 2 into the organic solvent 2, stirring, adding the trimethylsulfoxonium iodide in batches, cooling to 0 ℃, adding the intermediate 1, and reacting at room temperature to obtain a reaction solution 2;
S2b: adding the reaction solution 2 into an ice-water mixture, extracting to obtain an organic phase 2, washing, drying, concentrating and fractionating to obtain an intermediate 2;
The molar ratio of the trimethyl sulfoxonium iodide to the triethyl phosphonoacetate is (1.05-2) 1;
step S3: synthesis of ethyl 2-formyl-1-cyclopropanecarboxylate
S3a: adding the intermediate 2 into the organic solvent 3, stirring, cooling to 0 ℃, dropwise adding a dilute acid aqueous solution, heating, and reacting at room temperature to obtain a reaction solution 3;
S3b: removing the organic solvent 3 in the reaction liquid 3, extracting to obtain an organic phase 3, washing, drying and concentrating to obtain the ethyl 2-formyl-1-cyclopropanecarboxylate.
By adopting the technical scheme, the raw materials 2, 2-dimethoxy acetaldehyde, triethyl phosphonoacetate and trimethyl sulfoxonium iodide are all easy to obtain, the price is proper, the safety is higher, and the method is suitable for common industrial production; the existing synthesis method needs to react at the temperature of minus 78 ℃, and the synthesis method of the application reacts at the room temperature, has milder reaction conditions, is easier to reach and can meet industrial production more easily.
Optionally, the reaction time in the step S1a is 8-15h; the reaction time in the step S2a is 2-8h; the reaction time in S3a is 8-20h.
By adopting the technical scheme, the reaction time is controlled, and the high yield and purity of the intermediate 1, the intermediate 2 and the ethyl 2-formyl-1-cyclopropanecarboxylate can be ensured.
Alternatively, the step S2a of adding trimethylsulfoxonium iodide in batches means that the dripping time is controlled within 1 h.
By adopting the technical scheme, the time for adding the trimethylsulfoxonium iodide into the organic solvent 2 is limited, so that the trimethylsulfoxonium iodide can form a cyclopropyl reagent in the gradual dripping process, and the trimethylsulfoxonium iodide can be further reacted with the intermediate 1 to generate the intermediate 2 with higher yield and purity.
Alternatively, methyl tert-butyl ether is used as extractant in the extraction in step S2 b.
By adopting the technical scheme, the methyl tertiary butyl ether is used as the extractant for extracting the organic phase and the water phase, and the impurities which are difficult to remove in the subsequent steps can be completely left in the water phase after extraction, unlike other common extractants, so that the purity of the intermediate 2 obtained by extraction is higher.
Optionally, the extraction mode in the step S1b is adding water and dichloromethane, stirring and extracting, and separating out an organic phase; adding dichloromethane into the water phase, stirring and extracting, separating out an organic phase, and repeating twice; combining the organic phases to obtain an organic phase 1; the extraction in step S3b is the same as in step S1 b.
By adopting the technical scheme, the extraction is carried out by using dichloromethane twice repeatedly, the impurities insoluble in the dichloromethane in the organic phase 1 are separated into water, the required target object is dissolved in the dichloromethane, and the purity of the extracted organic phase 1 is higher; the purity of the organic phase 3 obtained by extraction by the same method is also higher.
Optionally, the organic solvent 1 is one of acetone, tetrahydrofuran, dimethyl tetrahydrofuran or N, N-dimethylformamide; the organic solvent 2 is one of anhydrous dimethyl sulfoxide or anhydrous tetrahydrofuran; the organic solvent 3 is one of acetone or tetrahydrofuran.
By adopting the technical scheme, the organic solvents are conventional solvents, have wide sources and lower prices, are safer during reaction, and are more suitable for industrial production.
Optionally, the dosage ratio of the dilute acid aqueous solution to the intermediate 2 in the step S3a is (3.25-5) L:1kg, and the mass percentage of the dilute acid aqueous solution is 5% -10%.
By adopting the technical scheme, in the reaction, the reverse reaction of the acetal reaction is promoted by the dilute acid aqueous solution, and if the mass percentage of the dilute acid aqueous solution is too high, the reaction property is changed, so that the final product of the ethyl 2-formyl-1-cyclopropanecarboxylate cannot be obtained; the proper dosage ratio of the dilute acid aqueous solution to the intermediate 2 is selected, which is extremely important for the reaction of the dilute acid aqueous solution and the intermediate 2, and if the dosage of the dilute acid aqueous solution is too small, the ethyl 2-formyl-1-cyclopropanecarboxylate is difficult to generate; therefore, the mass percent and the dosage of the dilute acid aqueous solution are reasonably selected, the generation of excessive byproducts can be avoided, and the finally prepared ethyl 2-formyl-1-cyclopropanecarboxylate has high purity.
Optionally, the reactions in steps S1a, S2a, S3a are all performed under nitrogen protection.
By adopting the technical scheme, the reaction of S1a, S2a and S3a is difficult to contact with air due to the protection of nitrogen, so that the purity of a reaction product is higher.
Optionally, the catalyst 1 refers to carbonate, and the carbonate is one of potassium carbonate or sodium carbonate; the catalyst 2 is a hydrogenated salt, and the hydrogenated salt is one of sodium hydride, potassium hydride or calcium hydride.
By adopting the technical scheme, the carbonate is the catalyst for the reaction of 2, 2-dimethoxy acetaldehyde and triethyl phosphonoacetate, and the catalytic reaction efficiency is high, so that the purity of the synthesized intermediate 1 is higher; the hydrogenation salt is a catalyst of trimethyl sulfoxonium iodide and the intermediate 1, so that the catalytic reaction efficiency is high, and the purity of the synthesized intermediate 2 is higher; and the price of carbonate and hydrogenate is proper, so the catalytic reaction safety is higher, and the method is suitable for industrial production.
In a second aspect, the application provides ethyl 2-formyl-1-cyclopropanecarboxylate prepared by the method.
By adopting the technical scheme, the ethyl 2-formyl-1-cyclopropane formate prepared by adopting the method has higher purity.
In summary, the application has the following beneficial effects:
1. The raw materials 2, 2-dimethoxy acetaldehyde, triethyl phosphonoacetate and trimethyl sulfoxonium iodide are easy to obtain, the price is proper, the safety is high, and the method is suitable for common industrial production; the existing synthetic method needs to react at the temperature of minus 78 ℃, while the synthetic method of the application reacts at the room temperature, has milder reaction conditions, is easier to reach and can meet industrial production more easily;
2. In the application, the trimethyl sulfoxonium iodide gradually drops into the solvent 2 to form a cyclopropyl reagent, so that the cyclopropyl reagent can be further reacted with the intermediate 1 to generate the intermediate 2 with higher yield;
3. In the application, the methyl tertiary butyl ether is used as an extractant for extracting an organic phase and a water phase, and compared with other commonly used extractants, the purity of the extracted intermediate 2 is higher.
Drawings
FIG. 1 is a gas chromatogram of ethyl 2-formyl-1-cyclopropanecarboxylate prepared in example 3;
FIG. 2 is a hydrogen spectrum of ethyl 2-formyl-1-cyclopropanecarboxylate prepared in example 3.
Detailed Description
The present application will be described in further detail with reference to examples and comparative examples.
The raw material sources are as follows: 2, 2-dimethoxy acetaldehyde (60% (m/m), available from saen chemical technologies, inc; triethyl phosphonoacetate, available from Shanghai Aldamus reagent Co., ltd; acetone, tetrahydrofuran, dimethyl tetrahydrofuran, N-dimethylformamide, anhydrous dimethyl sulfoxide, anhydrous tetrahydrofuran, commercially available from Shanghai Aldamus reagent Co., ltd; trimethylsulfoxonium iodide, available from Shanghai Bi De medical science and technology Co., ltd; sodium hydride, available from Shanghai Meilin Biochemical technologies Co.
Example 1
Step S1: synthetic intermediate 1 (4, 4-dimethoxy-2-butenoic acid ethyl ester)
[ S1a ], 1.56kg of 2, 2-dimethoxyacetaldehyde, 17.5L of tetrahydrofuran, 4.9L of deionized water, 3.5kg of triethyl phosphonoacetate and 2.5kg of potassium carbonate were charged into a 50L reaction vessel, (2, 2-dimethoxyacetaldehyde: triethyl phosphonoacetate: 1:1 (n/n), tetrahydrofuran: triethyl phosphonoacetate: 5:1 (v/m));
Nitrogen protection, stirring and room temperature reaction for 12 hours to obtain a reaction liquid 1;
[ S2a ], heating the reaction solution 1 to 40 ℃, and decompressing and distilling off tetrahydrofuran; adding 5.0L of deionized water and 6.0L of dichloromethane, stirring and extracting, and layering to obtain a first organic phase; adding 6.0L of dichloromethane into the water phase, stirring and extracting, and layering to obtain a second organic phase; adding 6.0L of dichloromethane into the water phase, stirring and extracting, layering to obtain a third organic phase, combining the first organic phase, the second organic phase and the third organic phase, and washing with 8.0L of saturated saline water once to obtain an organic phase 1;
Transferring the organic phase 1 into a reaction kettle; 1.5kg of anhydrous sodium sulfate is added into the organic phase 1, stirring is started, and the organic phase 1 is dried; filtering out sodium sulfate, and concentrating the filtrate under reduced pressure; the concentrate was subjected to vacuum fractionation, and the fraction at 80℃was collected to obtain 3.3kg of intermediate 1.
Step S2: synthesis of intermediate 2 (2' - (dimethoxymethyl) -1-cyclopropanecarboxylic acid ethyl ester
[ S2a ], 138.0g of sodium hydride and 4.0L of anhydrous dimethyl sulfoxide are added into a 10L reaction flask; gradually adding 0.08kg of trimethylsulfoxonium iodide, wherein the feeding time is 1h; cooling to 0 ℃, adding 1.0kg of 4, 4-dimethoxy-2-ethyl butenoate, (trimethyl sulfoxonium iodide: 4, 4-dimethoxy-2-ethyl butenoate is 1.05:1 (n/n));
After reacting for 2 hours at room temperature, obtaining a reaction liquid 2;
[ S2b ], pouring the reaction solution 2 into 5.0L of ice-water mixture; the mixture was extracted with 3L of methyl tert-butyl ether and repeated three times, and the separated organic phase was washed once with 4.0L of saturated saline to obtain an organic phase 2;
to the organic phase 2 was added 0.5kg of anhydrous sodium sulfate and dried; filtering out sodium sulfate, and concentrating the filtrate under reduced pressure; the concentrated solution was subjected to fractional distillation under reduced pressure, and the fraction at 85℃was collected to give 417.0g of a colorless liquid, intermediate 2.
Step S3: synthesis of ethyl 2-formyl-1-cyclopropanecarboxylate
[ S3a ], 255.0g of ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate and 1970mL of acetone are added into a 5L reaction kettle, and the temperature is reduced; at 0deg.C, 730mL of 10% strength by mass aqueous sulfuric acid solution (aqueous sulfuric acid solution: 3.25:1 (v/m) of ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate);
after the dripping is finished, reacting for 12 hours at room temperature to obtain a reaction solution 3;
[ S3b ], heating the reaction solution 3 to 30 ℃, distilling under reduced pressure to remove acetone, extracting the residual solution with 500.0mL of dichloromethane, repeating the extraction for three times, and washing the separated organic solution with 500.0mL of saturated saline once to obtain an organic phase 3;
To the organic phase 3 was added 100.0g of anhydrous sodium sulfate and dried; filtering out sodium sulfate, concentrating the filtrate under reduced pressure to obtain 155.3g of light yellow liquid, namely the ethyl 2-formyl-1-cyclopropanecarboxylate.
Example 2
Step S1: synthetic intermediate 1 (4, 4-dimethoxy-2-butenoic acid ethyl ester)
[ S1a ], 4.68kg of 2, 2-dimethoxyacetaldehyde, 52.5L of tetrahydrofuran, 5.0L of deionized water, 3.5kg of triethyl phosphonoacetate and 2.5kg of potassium carbonate were charged into a 50L reaction vessel, (2, 2-dimethoxyacetaldehyde: triethyl phosphonoacetate: 3:1 (n/n), tetrahydrofuran: triethyl phosphonoacetate: 15:1 (v/m));
Nitrogen protection, stirring and room temperature reaction for 12 hours to obtain a reaction liquid 1;
[ S2a ], heating the reaction solution 1 to 40 ℃, and decompressing and distilling off tetrahydrofuran; adding 5.0L of deionized water and 6.0L of dichloromethane, stirring and extracting, and layering to obtain a first organic phase; adding 6.0L of dichloromethane into the water phase, stirring and extracting, and layering to obtain a second organic phase; adding 6.0L of dichloromethane into the water phase, stirring and extracting, layering to obtain a third organic phase, combining the first organic phase, the second organic phase and the third organic phase, and washing with 8.0L of saturated saline water once to obtain an organic phase 1;
Transferring the organic phase 1 into a reaction kettle; 1.5kg of anhydrous sodium sulfate is added into the organic phase 1, stirring is started, and the organic phase 1 is dried; filtering out sodium sulfate, and concentrating the filtrate under reduced pressure; the concentrate was subjected to vacuum fractionation, and a fraction at 80℃was collected to obtain 3.21kg of intermediate 1.
Step S2: synthesis of intermediate 2 (2' - (dimethoxymethyl) -1-cyclopropanecarboxylic acid ethyl ester
[ S2a ], 138.0g of sodium hydride and 4.0L of anhydrous dimethyl sulfoxide are added into a 10L reaction flask; gradually adding 0.08kg of trimethylsulfoxonium iodide, wherein the feeding time is 1h; cooling to 0 ℃, adding 1.0kg of 4, 4-dimethoxy-2-ethyl butenoate, (trimethyl sulfoxonium iodide: 4, 4-dimethoxy-2-ethyl butenoate is 1.05:1 (n/n));
After reacting for 2 hours at room temperature, obtaining a reaction liquid 2;
[ S2b ], pouring the reaction solution 2 into 5.0L of ice-water mixture; the mixture was extracted with 3L of methyl tert-butyl ether and repeated three times, and the separated organic phase was washed once with 4.0L of saturated saline to obtain an organic phase 2;
To the organic phase 2 was added 0.5kg of anhydrous sodium sulfate and dried; filtering out sodium sulfate, and concentrating the filtrate under reduced pressure; the concentrated solution was subjected to fractional distillation under reduced pressure, and the fraction at 85℃was collected to obtain 416.4g of a colorless liquid, intermediate 2.
Step S3: synthesis of ethyl 2-formyl-1-cyclopropanecarboxylate
[ S3a ], 255.0g of ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate and 1970mL of acetone are added into a 5L reaction kettle, and the temperature is reduced; at 0℃1125mL of 10% strength by mass aqueous sulfuric acid solution (5:1 (v/m) of 2' - (dimethoxymethyl) -1-cyclopropanecarboxylic acid ethyl ester) was added dropwise.
After the dripping is finished, reacting for 12 hours at room temperature to obtain a reaction solution 3;
[ S3b ], heating the reaction solution 3 to 30 ℃, distilling under reduced pressure to remove acetone, extracting the residual solution with 500.0mL of dichloromethane, repeating the extraction for three times, and washing the separated organic solution with 500.0mL of saturated saline once to obtain an organic phase 3;
to the organic phase 3 was added 100.0g of anhydrous sodium sulfate and dried; filtering out sodium sulfate, concentrating the filtrate under reduced pressure to obtain 155.0g of light yellow liquid, namely the ethyl 2-formyl-1-cyclopropanecarboxylate.
Example 3
Step S1: synthetic intermediate 1 (4, 4-dimethoxy-2-butenoic acid ethyl ester)
[ S1a ], 3.00kg of 2, 2-dimethoxy acetaldehyde, 34.0L of tetrahydrofuran, 4.9L of deionized water, 3.5kg of triethyl phosphonoacetate and 2.5kg of potassium carbonate were added to a 50L reaction vessel, (2, 2-dimethoxy acetaldehyde: triethyl phosphonoacetate 1.93:1 (n/n), tetrahydrofuran: triethyl phosphonoacetate 10:1 (v/m));
Nitrogen protection, stirring and room temperature reaction for 12 hours to obtain a reaction liquid 1;
[ S2a ], heating the reaction solution 1 to 40 ℃, and decompressing and distilling off tetrahydrofuran; adding 5.0L of deionized water and 6.0L of dichloromethane, stirring and extracting, and layering to obtain a first organic phase; adding 6.0L of dichloromethane into the water phase, stirring and extracting, and layering to obtain a second organic phase; adding 6.0L of dichloromethane into the water phase, stirring and extracting, layering to obtain a third organic phase, combining the first organic phase, the second organic phase and the third organic phase, and washing with 8.0L of saturated saline water once to obtain an organic phase 1;
transferring the organic phase 1 into a reaction kettle; 1.5kg of anhydrous sodium sulfate is added into the organic phase 1, stirring is started, and the organic phase 1 is dried; filtering out sodium sulfate, and concentrating the filtrate under reduced pressure; the concentrate was subjected to vacuum fractionation, and a fraction at 80℃was collected to obtain 3.48kg of intermediate 1.
Step S2: synthesis of intermediate 2 (2' - (dimethoxymethyl) -1-cyclopropanecarboxylic acid ethyl ester
[ S2a ], 138.0g of sodium hydride and 4.0L of anhydrous dimethyl sulfoxide are added into a 10L reaction flask; 1.33kg of trimethylsulfoxonium iodide is added in batches, and the feeding time is 1h; cooling to 0 ℃, adding 1.0kg of 4, 4-dimethoxy-2-ethyl butenoate, (trimethyl sulfoxonium iodide: 4, 4-dimethoxy-2-ethyl butenoate is 2:1 (n/n));
After reacting for 2 hours at room temperature, obtaining a reaction liquid 2;
[ S2b ], pouring the reaction solution 2 into 5.0L of ice-water mixture; the mixture was extracted with 3L of methyl tert-butyl ether and repeated three times, and the separated organic phase was washed once with 4.0L of saturated saline to obtain an organic phase 2;
To the organic phase 2 was added 0.5kg of anhydrous sodium sulfate and dried; filtering out sodium sulfate, and concentrating the filtrate under reduced pressure; the concentrated solution was subjected to fractional distillation under reduced pressure, and the fraction at 85℃was collected to obtain 420.0g of a colorless liquid, intermediate 2.
Step S3: synthesis of ethyl 2-formyl-1-cyclopropanecarboxylate
[ S3a ], 255.0g of ethyl 2'- (dimethoxymethyl) -1-cyclopropylcarboxylate, 1970mL of acetone, and 827.8mL of 10% aqueous sulfuric acid (3.67:1 (v/m) of ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate) were added dropwise at 0deg.C;
after the dripping is finished, reacting for 12 hours at room temperature to obtain a reaction solution 3;
[ S3b ], heating the reaction solution 3 to 30 ℃, distilling under reduced pressure to remove acetone, extracting the residual solution with 500.0mL of dichloromethane, repeating the extraction for three times, and washing the separated organic solution with 500.0mL of saturated saline once to obtain an organic phase 3;
to the organic phase 3 was added 100.0g of anhydrous sodium sulfate and dried; filtering out sodium sulfate, concentrating the filtrate under reduced pressure to obtain 157.0g of light yellow liquid, namely the ethyl 2-formyl-1-cyclopropanecarboxylate.
Comparative example 1
1.0 Equivalent of acrolein and 10 mole percent of HBF 4·OEt2 were added to CH 2Cl2 at-78℃and 1.2 equivalents of ethyl diazoacetate diluted with CH 2Cl2 were added dropwise over a period of more than 30 minutes, and the reaction mixture was stirred at a temperature of-78℃for 24 hours to give ethyl 2-formyl-1-cyclopropanecarboxylate.
Performance test
The intermediate 1, intermediate 2 and ethyl 2-formyl-1-cyclopropanecarboxylate prepared in examples 1 to 3 and comparative example 1 were used for the yield, purity and hydrogen spectrum test, and the test results are shown below;
example 1
Intermediate 1:2.4kg of colorless liquid, namely 4, 4-dimethoxy-2-butenoic acid ethyl ester, the yield is 88.0%,95.0% (GC);
1HNMR（400MHz,CDCl3）δ6.73 (dd, J = 15.9, 4.0 Hz, 1H), 6.10 (dd, J = 15.9, 1.4 Hz, 1H), 4.91 (dd, J = 4.0, 1.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.31 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H).
intermediate 2:420.0g of colorless liquid, namely, 2' - (dimethoxy methyl) -1-cyclopropanecarboxylic acid ethyl ester; yield 38.8%,95.0% (GC);
1HNMR（400MHz,CDCl3）δ4.27 (d, J = 4.0 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.31 (s, 6H), 1.68 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.14 (m, 1H), 1.01 (m, 1H).
2-formyl-1-cyclopropanecarboxylic acid ethyl ester: 157.0 g, obtaining a pale yellow liquid; the yield is 80.5 percent, 96.0 percent (GC), and the trans isomer accounts for more than 90 percent;
1HNMR（400MHz,CDCl3) δ9.29 (d, J = 4.2 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.41 (m, 1H), 2.24 (m, 1H), 1.58 (m, 1H), 1.49 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3H).
example 2
Intermediate 1:2.4kg of colorless liquid, namely 4, 4-dimethoxy-2-butenoic acid ethyl ester, the yield is 87.8 percent, 95.0 percent (GC);
1HNMR（400MHz,CDCl3）δ6.73 (dd, J = 15.9, 4.0 Hz, 1H), 6.10 (dd, J = 15.9, 1.4 Hz, 1H), 4.91 (dd, J = 4.0, 1.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.31 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H).
intermediate 2:420.0g of colorless liquid, namely, 2' - (dimethoxy methyl) -1-cyclopropanecarboxylic acid ethyl ester; yield 38.6%,95.0% (GC);
1HNMR（400MHz,CDCl3）δ4.27 (d, J = 4.0 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.31 (s, 6H), 1.68 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.14 (m, 1H), 1.01 (m, 1H).
2-formyl-1-cyclopropanecarboxylic acid ethyl ester: 157.0 g, obtaining a pale yellow liquid; the yield is 81.2 percent, 96.0 percent (GC) is trans isomer, and the trans isomer accounts for more than 90 percent;
1HNMR（400MHz,CDCl3) δ9.29 (d, J = 4.2 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.41 (m, 1H), 2.24 (m, 1H), 1.58 (m, 1H), 1.49 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3H).
example 3
Intermediate 1:2.4kg of colorless liquid, namely 4, 4-dimethoxy-2-butenoic acid ethyl ester, the yield is 88.2 percent, 95.0 percent (GC);
1HNMR（400MHz,CDCl3）δ6.73 (dd, J = 15.9, 4.0 Hz, 1H), 6.10 (dd, J = 15.9, 1.4 Hz, 1H), 4.91 (dd, J = 4.0, 1.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.31 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H).
intermediate 2:420.0g of colorless liquid, namely, 2' - (dimethoxy methyl) -1-cyclopropanecarboxylic acid ethyl ester; yield 38.8%,95.0% (GC);
1HNMR（400MHz,CDCl3）δ4.27 (d, J = 4.0 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.31 (s, 6H), 1.68 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.14 (m, 1H), 1.01 (m, 1H).
2-formyl-1-cyclopropanecarboxylic acid ethyl ester: 157.0 g, obtaining a pale yellow liquid; the yield is 81.5 percent, 96.0 percent (GC), and the trans isomer accounts for more than 90 percent;
1HNMR（400MHz,CDCl3) δ9.29 (d, J = 4.2 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.41 (m, 1H), 2.24 (m, 1H), 1.58 (m, 1H), 1.49 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3H).
comparative example 1
2-Formyl-1-cyclopropanecarboxylic acid ethyl ester: and also contains cis-trans isomers (40:60 ratio).
It can be seen from the combination of examples 1,2 and 3 that the purity of the synthesized intermediate 1, intermediate 2 and ethyl 2-formyl-1-cyclopropanecarboxylate is higher although the ratio of the raw materials used in the three examples is different; wherein the ratio of the raw materials in example 3 is the optimal ratio, the synthesized intermediate 1, intermediate 2 and ethyl 2-formyl-1-cyclopropanecarboxylate have high purity and slightly higher yield than those in example 1 and example 2.
As can be seen from the combination of example 3 and comparative example 1, the ethyl 2-formyl-1-cyclopropanecarboxylate prepared by the method of comparative example 1 contains both cis and trans isomers in a ratio of 40:60, and the trans isomer in the product of the application accounts for more than 90%, and compared with the comparative document, the purity of the product of the application is higher.
The present embodiment is only for explanation of the present application and is not to be construed as limiting the present application, and modifications to the present embodiment, which may not creatively contribute to the present application as required by those skilled in the art after reading the present specification, are all protected by patent laws within the scope of claims of the present application.
Claims (5)
1. A method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate, comprising the steps of:
Step S1: synthetic intermediate 1
S1a: adding 2, 2-dimethoxy acetaldehyde, triethyl phosphonoacetate and a catalyst 1 into an organic solvent 1 and water, stirring, and reacting at room temperature to obtain a reaction solution 1;
S1b: firstly removing the organic solvent 1 in the reaction liquid 1, then extracting to obtain an organic phase 1, and washing, drying, concentrating and fractionating to obtain an intermediate 1;
The mol ratio of the 2, 2-dimethoxy acetaldehyde to the triethyl phosphonoacetate is (3-1) 1, and the dosage ratio of the organic solvent 1 to the triethyl phosphonoacetate is (5-15) L1 kg;
Step S2: synthesis of intermediate 2
S2a: adding the catalyst 2 into the organic solvent 2, stirring, adding the trimethylsulfoxonium iodide in batches, cooling to 0 ℃, adding the intermediate 1, and reacting at room temperature to obtain a reaction solution 2;
S2b: adding the reaction solution 2 into an ice-water mixture, extracting to obtain an organic phase 2, washing, drying, concentrating and fractionating to obtain an intermediate 2;
The molar ratio of the trimethyl sulfoxonium iodide to the triethyl phosphonoacetate is (1.05-2) 1;
step S3: synthesis of ethyl 2-formyl-1-cyclopropanecarboxylate
S3a: adding the intermediate 2 into the organic solvent 3, stirring, cooling to 0 ℃, dropwise adding a dilute acid aqueous solution, heating, and reacting at room temperature to obtain a reaction solution 3;
The dosage ratio of the dilute acid aqueous solution to the intermediate 2 in the step S3a is (3.25-5) L:1kg, and the mass percentage of the dilute acid aqueous solution is 5% -10%; the dilute acid is dilute sulfuric acid;
s3b: firstly removing an organic solvent 3 in the reaction liquid 3, then extracting to obtain an organic phase 3, washing, drying and concentrating to obtain 2-formyl-1-cyclopropaneethyl formate;
The catalyst 1 refers to carbonate; catalyst 2 refers to sodium hydride;
The extraction mode of the step S1b is adding water and methylene dichloride, stirring and extracting, and separating out an organic phase; adding dichloromethane into the water phase, stirring and extracting, separating out an organic phase, and repeating twice; combining the organic phases to obtain an organic phase 1; the extraction mode of the step S3b is the same as that of the step S1 b;
the organic solvent 1 is one of acetone, tetrahydrofuran, dimethyl tetrahydrofuran or N, N-dimethylformamide; the organic solvent 2 is one of anhydrous dimethyl sulfoxide or anhydrous tetrahydrofuran; the organic solvent 3 is one of acetone or tetrahydrofuran.
2. The method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate according to claim 1, wherein the reaction time in the step S1a is 8-15h; the reaction time in the step S2a is 2-8h; the reaction time in the step S3a is 8-20h.
3. The method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate according to claim 1, wherein the step S2a is characterized in that the step of adding trimethylsulfoxonium iodide in batches means that the dripping time is controlled within 1 h.
4. A process for the synthesis of ethyl 2-formyl-1-cyclopropanecarboxylate according to any of claims 1-3, wherein methyl tert-butyl ether is used as extractant in the extraction in step S2 b.
5. A process for the synthesis of ethyl 2-formyl-1-cyclopropanecarboxylate according to claim 1, wherein the reactions of steps S1a, S2a, S3a are all carried out under nitrogen protection.
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