CN113956157A - Method for synthesizing 2-formyl-1-cyclopropane ethyl formate - Google Patents
Method for synthesizing 2-formyl-1-cyclopropane ethyl formate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 24
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 title claims abstract description 18
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 15
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000007864 aqueous solution Substances 0.000 claims abstract description 19
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 claims abstract description 16
- OGFKTAMJLKHRAZ-UHFFFAOYSA-N 2,2-dimethoxyacetaldehyde Chemical compound COC(OC)C=O OGFKTAMJLKHRAZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 239000012074 organic phase Substances 0.000 claims description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 57
- 239000000243 solution Substances 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 26
- 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 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 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 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000000203 mixture Substances 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
- MDWXTLNIZCHBJE-UHFFFAOYSA-N ethyl 2-formylcyclopropane-1-carboxylate Chemical compound CCOC(=O)C1CC1C=O MDWXTLNIZCHBJE-UHFFFAOYSA-N 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- 229910052757 nitrogen 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
- 150000003839 salts Chemical class 0.000 claims description 5
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 239000000706 filtrate Substances 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
- SIRJFJKWVNTUKV-UHFFFAOYSA-N ethyl 4,4-dimethoxybut-2-enoate Chemical compound CCOC(=O)C=CC(OC)OC SIRJFJKWVNTUKV-UHFFFAOYSA-N 0.000 description 7
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 238000001914 filtration Methods 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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229910004039 HBF4 Inorganic materials 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000004508 fractional distillation Methods 0.000 description 3
- 238000005194 fractionation Methods 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
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 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
- 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
- 241001575999 Hakka Species 0.000 description 1
- 235000016278 Mentha canadensis Nutrition 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 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
- 238000002360 preparation method Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
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- 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
Abstract
The application relates to the field of chemical pharmacy, and particularly discloses a method for synthesizing 2-formyl-1-cyclopropane ethyl formate. The method comprises the following steps: step S1: adding 2, 2-dimethoxyacetaldehyde, triethyl phosphonoacetate and a catalyst 1 into an organic solvent 1 and water to prepare an intermediate 1; step S2: adding a catalyst 2 into an organic solvent 2, adding trimethyl sulfonium oxide iodide, cooling to 0 ℃, adding an intermediate 1, and reacting at room temperature to obtain an intermediate 2; step S3: and adding the intermediate 2 into an organic solvent 3, cooling to 0 ℃, dropwise adding a dilute acid aqueous solution, and reacting at room temperature to obtain the 2-formyl-1-cyclopropane ethyl formate. The application has the advantages of easily available raw materials, proper price and higher safety; the experimental temperature condition is suitable, and the industrial production can be more easily met.
Description
Technical Field
The application relates to the field of chemical pharmacy, in particular to a method for synthesizing 2-formyl-1-cyclopropane ethyl formate.
Background
2-formyl-1-cyclopropanecarboxylic acid ethyl ester is medicine compoundOne commonly used intermediate segment in the synthesis, but the existing synthetic method of 2-formyl-1-cyclopropane ethyl formate is not mature; the structural formula of the 2-formyl-1-cyclopropane ethyl formate is as follows:
。
in the related art, when preparing ethyl 2-formyl-1-cyclopropanecarboxylate, using dichloromethane, diethyl ether or pentane as solvent, adding acrolein, ethyl diazoacetate and 10% HBF4·OEt2，HBF4·OEt2As a catalyst, stirring at-78 ℃ for 24 hours to obtain a product of ethyl 2-formyl-1-cyclopropanecarboxylate containing both cis-trans isomers (ratio 40: 60); the reaction formula is as follows:
aiming at the related technologies, the inventor considers that ethyl diazoacetate as a reaction raw material is easy to explode, the reaction temperature is-78 ℃, the conditions are harsh, and the difficulty of actual industrial production is increased.
Disclosure of Invention
In order to provide a synthesis method of 2-formyl-1-cyclopropane ethyl formate, which has mild reaction conditions and is more suitable for industrial production, the application provides a method for synthesizing 2-formyl-1-cyclopropane ethyl formate.
In a first aspect, the present application provides a method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate, comprising the following steps:
step S1: synthesis of intermediate 1
S1 a: adding 2, 2-dimethoxyacetaldehyde, 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;
s1 b: removing the organic solvent 1 in the reaction solution 1, extracting to obtain an organic phase 1, washing, drying, concentrating and fractionating to obtain an intermediate 1;
the molar ratio of the 2, 2-dimethoxyacetaldehyde to the triethyl phosphonoacetate is (3-1): 1, and the dosage ratio of the organic solvent 1 to the triethyl phosphonoacetate is (5-15) L:1 kg;
step S2: synthesis of intermediate 2
S2 a: adding a catalyst 2 into an organic solvent 2, stirring, adding trimethyl sulfonium iodide in batches, cooling to 0 ℃, adding an intermediate 1, and reacting at room temperature to obtain a reaction solution 2;
s2 b: 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 trimethyl sulfoxonium iodide to triethyl phosphonoacetate is (1.05-2) to 1;
step S3: synthesis of 2-formyl-1-cyclopropanecarboxylic acid ethyl ester
S3 a: 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;
s3 b: removing the organic solvent 3 in the reaction solution 3, extracting to obtain an organic phase 3, washing, drying and concentrating to obtain the 2-formyl-1-cyclopropane ethyl formate.
By adopting the technical scheme, the raw materials of 2, 2-dimethoxyacetaldehyde, triethyl phosphonoacetate and trimethyl sulfonium iodide are easy to obtain, the price is proper, the safety is high, and the method is suitable for common industrial production; the existing synthesis method needs to react at-78 ℃, but the synthesis method of the application has the advantages of mild reaction conditions, easy achievement and easy industrial production satisfaction due to the reaction at room temperature.
Optionally, the reaction time in the step S1a is 8-15 h; the reaction time in the step S2a is 2-8 h; the reaction time in S3a is 8-20 h.
By adopting the technical scheme and controlling the reaction time, the yield and the purity of the intermediate 1, the intermediate 2 and the 2-formyl-1-cyclopropane ethyl formate can be ensured to be higher.
Optionally, the step of adding trimethylsulfoxonium iodide in the step S2a in batches means that the dropping time is controlled within 1 hour.
By adopting the technical scheme, the time for adding the trimethyl sulfonium oxide iodide into the organic solvent 2 is limited, and a cyclopropyl reagent can be formed in the process of gradually dropwise adding the trimethyl sulfonium oxide iodide, so that the trimethyl sulfonium oxide iodide can further react with the intermediate 1 conveniently, and the intermediate 2 with high yield and purity is generated.
Optionally, methyl tert-butyl ether is used as an extracting agent in the extraction in the step S2 b.
By adopting the technical scheme, the methyl tert-butyl ether is used as an extractant for extracting the organic phase and the aqueous phase, and is different from other common extractants, so that after extraction, impurities which are difficult to remove in subsequent steps can be completely left in the aqueous phase, and the high purity of the intermediate 2 obtained by extraction is ensured.
Optionally, the extraction manner of step S1b is to add water and dichloromethane, stir and extract, and separate 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 performed in the same manner as in step S1 b.
By adopting the technical scheme, the extraction is carried out by using the dichloromethane twice, impurities which are insoluble in the dichloromethane in the organic phase 1 are separated into water, the required target substance is dissolved in the dichloromethane, and the purity of the organic phase 1 obtained by extraction is higher; the organic phase 3 obtained by the same extraction method has higher purity.
Optionally, the organic solvent 1 is one of acetone, tetrahydrofuran, dimethyltetrahydrofuran 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 solvent is a conventional solvent, has wide sources and low price, and is safer during reaction, thereby being more suitable for industrial production.
Optionally, in the step S3a, the dosage ratio of the dilute acid aqueous solution to the intermediate 2 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 diluted acid aqueous solution promotes the reverse reaction of the acetal reaction, if the mass percentage of the diluted acid aqueous solution is too high, the reaction property is changed, and the final product of 2-formyl-1-cyclopropane ethyl formate cannot be obtained; selecting a proper dosage ratio of the dilute acid aqueous solution to the intermediate 2, which is very 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 2-formyl-1-cyclopropane ethyl formate is difficult to generate; therefore, the mass percentage and the dosage of the dilute acid aqueous solution are reasonably selected, so that the generation of excessive byproducts can be avoided, and the finally prepared 2-formyl-1-cyclopropane ethyl formate has high purity.
Optionally, the reactions of steps S1a, S2a, and S3a are all performed under the protection of nitrogen.
By adopting the technical scheme, the nitrogen protection can make the reactions of S1a, S2a and S3a difficult to contact air, so that the purity of the reaction product is high.
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 a catalyst for the reaction of 2, 2-dimethoxyacetaldehyde and triethyl phosphonoacetate, the catalytic reaction efficiency is high, and the purity of the synthesized intermediate 1 is high; the hydrogenated salt is a catalyst of trimethyl sulfonium iodide and the intermediate 1, and the catalytic reaction efficiency is high, so that the purity of the synthesized intermediate 2 is high; and because the price of the carbonate and the hydrogenated salt is proper, the safety of the catalytic reaction is higher, so the method is suitable for industrial production.
In a second aspect, the present application provides ethyl 2-formyl-1-cyclopropanecarboxylate, which is prepared by the above method.
By adopting the technical scheme, the 2-formyl-1-cyclopropane ethyl formate prepared by the method has higher purity.
In summary, the present application has the following beneficial effects:
1. the raw materials of the preparation method are 2, 2-dimethoxyacetaldehyde, triethyl phosphonoacetate and trimethyl sulfonium iodide, are easy to obtain, have proper price and higher safety, and are suitable for common industrial production; the existing synthesis method needs to react at-78 ℃, but the synthesis method of the application has the advantages of mild reaction conditions, easy achievement and easy industrial production satisfaction due to the reaction at room temperature;
2. in the application, a cyclopropyl reagent is formed in the process of gradually dropwise adding trimethyl sulfonium oxide iodide into a solvent 2, so that the subsequent further reaction with an intermediate 1 is facilitated, and the intermediate 2 with high yield is generated;
3. methyl tert-butyl ether is used as an extractant for extracting an organic phase and a water phase in the application, and compared with other commonly used extractants, the purity of the intermediate 2 obtained by extraction 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-Dimethoxyacetaldehyde (60% (m/m)), available from Sahn chemical technology, Inc.; triethyl phosphonoacetate, available from Hakka Hainans reagent, Inc.; acetone, tetrahydrofuran, dimethyltetrahydrofuran, N-dimethylformamide, anhydrous dimethyl sulfoxide, anhydrous tetrahydrofuran, available from shanghai hadamard reagent ltd; trimethylsulfoxonium iodide, available from Shanghai Bigdi pharmaceutical science and technology Limited; sodium hydride, available from Shanghai Michelin Biochemical technology, Inc.
Example 1
Step S1: synthesis of 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 added to a 50L reactor, (triethyl phosphonoacetate: 2, 2-dimethoxyacetaldehyde: 1 (n/n) and triethyl phosphonoacetate: tetrahydrofuran: 5: 1 (v/m));
stirring under the protection of nitrogen, and reacting at room temperature for 12 hours to obtain a reaction solution 1;
(S2 a) heating the reaction solution 1 to 40 ℃, and evaporating tetrahydrofuran under reduced pressure; adding 5.0L of deionized water and 6.0L of dichloromethane, stirring, 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 solution once to obtain an organic phase 1;
transferring the organic phase 1 into a reaction kettle; adding 1.5kg of anhydrous sodium sulfate into the organic phase 1, starting stirring, and drying the organic phase 1; filtering to remove sodium sulfate, and concentrating the filtrate under reduced pressure; the concentrated solution was subjected to fractional distillation under reduced pressure, and fractions at 80 ℃ were collected to obtain 3.3kg of intermediate 1.
Step S2: synthesis intermediate 2 (2' - (dimethoxymethyl) -1-cyclopropylcarboxylic acid ethyl ester)
[ S2a ], 138.0g of sodium hydride and 4.0L of anhydrous dimethyl sulfoxide were put into a 10L reaction flask; gradually adding 0.08kg of trimethyl sulfonium oxide iodide for 1 h; cooling to 0 deg.C, adding 1.0kg of ethyl 4, 4-dimethoxy-2-butenoate (trimethyl sulfoxonium iodide: ethyl 4, 4-dimethoxy-2-butenoate is 1.05: 1 (n/n));
reacting at room temperature for 2 hours to obtain a reaction solution 2;
[ S2b ], pouring the reaction solution 2 into 5.0L of an ice-water mixture; extracting the above mixture with 3L methyl tert-butyl ether, repeating for three times, and washing the separated organic phase with 4.0L saturated saline solution to obtain organic phase 2;
adding 0.5kg of anhydrous sodium sulfate into the organic phase 2 and drying; filtering to remove sodium sulfate, and concentrating the filtrate under reduced pressure; and carrying out reduced pressure fractionation on the concentrated solution, and collecting fractions at 85 ℃ to obtain 417.0g of colorless liquid, namely the intermediate 2.
Step S3: synthesis of 2-formyl-1-cyclopropanecarboxylic acid ethyl ester
[ S3a ], adding 255.0g of ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate and 1970mL of acetone into a 5L reaction kettle, and cooling; 730mL of a 10% aqueous solution of sulfuric acid (the aqueous solution of sulfuric acid: ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate: 3.25: 1 (v/m));
after the dropwise addition, reacting at room temperature for 12 hours to obtain a reaction solution 3;
(S3 b) 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 once with 500.0mL of saturated saline solution to obtain an organic phase 3;
adding 100.0g of anhydrous sodium sulfate into the organic phase 3 and drying; the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 155.3g of a pale yellow liquid, i.e., ethyl 2-formyl-1-cyclopropanecarboxylate.
Example 2
Step S1: synthesis of 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 added to a 50L reactor, (triethyl phosphonoacetate: 2, 2-dimethoxyacetaldehyde: 3: 1 (n/n) and triethyl phosphonoacetate: 15: 1 (v/m));
stirring under the protection of nitrogen, and reacting at room temperature for 12 hours to obtain a reaction solution 1;
(S2 a) heating the reaction solution 1 to 40 ℃, and evaporating tetrahydrofuran under reduced pressure; adding 5.0L of deionized water and 6.0L of dichloromethane, stirring, 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 solution once to obtain an organic phase 1;
transferring the organic phase 1 into a reaction kettle; adding 1.5kg of anhydrous sodium sulfate into the organic phase 1, starting stirring, and drying the organic phase 1; filtering to remove sodium sulfate, and concentrating the filtrate under reduced pressure; the concentrated solution was subjected to fractional distillation under reduced pressure, and fractions at 80 ℃ were collected to obtain 3.21kg of intermediate 1.
Step S2: synthesis intermediate 2 (2' - (dimethoxymethyl) -1-cyclopropylcarboxylic acid ethyl ester)
[ S2a ], 138.0g of sodium hydride and 4.0L of anhydrous dimethyl sulfoxide were put into a 10L reaction flask; gradually adding 0.08kg of trimethyl sulfonium oxide iodide for 1 h; cooling to 0 deg.C, adding 1.0kg of ethyl 4, 4-dimethoxy-2-butenoate (trimethyl sulfoxonium iodide: ethyl 4, 4-dimethoxy-2-butenoate is 1.05: 1 (n/n));
reacting at room temperature for 2 hours to obtain a reaction solution 2;
[ S2b ], pouring the reaction solution 2 into 5.0L of an ice-water mixture; extracting the above mixture with 3L methyl tert-butyl ether, repeating for three times, and washing the separated organic phase with 4.0L saturated saline solution to obtain organic phase 2;
adding 0.5kg of anhydrous sodium sulfate into the organic phase 2 and drying; filtering to remove sodium sulfate, and concentrating the filtrate under reduced pressure; and carrying out reduced pressure fractionation on the concentrated solution, and collecting fractions at 85 ℃ to obtain 416.4g of colorless liquid, namely the intermediate 2.
Step S3: synthesis of 2-formyl-1-cyclopropanecarboxylic acid ethyl ester
[ S3a ], adding 255.0g of ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate and 1970mL of acetone into a 5L reaction kettle, and cooling; 1125mL of a 10% by mass aqueous solution of sulfuric acid was added dropwise at 0 deg.C (aqueous solution of sulfuric acid: ethyl 2' - (dimethoxymethyl) -1-cyclopropylformate: 5: 1 (v/m)).
After the dropwise addition, reacting at room temperature for 12 hours to obtain a reaction solution 3;
(S3 b) 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 once with 500.0mL of saturated saline solution to obtain an organic phase 3;
adding 100.0g of anhydrous sodium sulfate into the organic phase 3 and drying; the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 155.0g of a pale yellow liquid, i.e., ethyl 2-formyl-1-cyclopropanecarboxylate.
Example 3
Step S1: synthesis of intermediate 1 (4, 4-dimethoxy-2-butenoic acid ethyl ester)
[ S1a ], 3.00kg of 2, 2-dimethoxyacetaldehyde, 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 reactor, (triethyl phosphonoacetate: 2-dimethoxyacetaldehyde: 1 (n/n), and triethyl phosphonoacetate: 10: 1 (v/m));
stirring under the protection of nitrogen, and reacting at room temperature for 12 hours to obtain a reaction solution 1;
(S2 a) heating the reaction solution 1 to 40 ℃, and evaporating tetrahydrofuran under reduced pressure; adding 5.0L of deionized water and 6.0L of dichloromethane, stirring, 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 solution once to obtain an organic phase 1;
transferring the organic phase 1 into a reaction kettle; adding 1.5kg of anhydrous sodium sulfate into the organic phase 1, starting stirring, and drying the organic phase 1; filtering to remove sodium sulfate, and concentrating the filtrate under reduced pressure; the concentrated solution was subjected to fractional distillation under reduced pressure, and fractions at 80 ℃ were collected to obtain 3.48kg of intermediate 1.
Step S2: synthesis intermediate 2 (2' - (dimethoxymethyl) -1-cyclopropylcarboxylic acid ethyl ester)
[ S2a ], 138.0g of sodium hydride and 4.0L of anhydrous dimethyl sulfoxide were put into a 10L reaction flask; 1.33kg of trimethyl sulfonium oxide iodide is added in batches, and the feeding time is 1 h; cooling to 0 deg.C, adding 1.0kg of 4, 4-dimethoxy-2-butenoic acid ethyl ester (trimethyl sulfoxonium iodide: 4, 4-dimethoxy-2-butenoic acid ethyl ester is 2: 1 (n/n));
reacting at room temperature for 2 hours to obtain a reaction solution 2;
[ S2b ], pouring the reaction solution 2 into 5.0L of an ice-water mixture; extracting the above mixture with 3L methyl tert-butyl ether, repeating for three times, and washing the separated organic phase with 4.0L saturated saline solution to obtain organic phase 2;
adding 0.5kg of anhydrous sodium sulfate into the organic phase 2 and drying; filtering to remove sodium sulfate, and concentrating the filtrate under reduced pressure; and carrying out reduced pressure fractionation on the concentrated solution, and collecting fractions at 85 ℃ to obtain 420.0g of colorless liquid, namely the intermediate 2.
Step S3: synthesis of 2-formyl-1-cyclopropanecarboxylic acid ethyl ester
[ S3a ], 255.0g of ethyl 2'- (dimethoxymethyl) -1-cyclopropylcarboxylate and 1970mL of acetone were charged into a 5L reactor, and 827.8mL of a 10% aqueous solution of sulfuric acid (aqueous solution of sulfuric acid: ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate: 3.67: 1 (v/m)) was added dropwise at 0 ℃;
after the dropwise addition, reacting at room temperature for 12 hours to obtain a reaction solution 3;
(S3 b) 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 once with 500.0mL of saturated saline solution to obtain an organic phase 3;
adding 100.0g of anhydrous sodium sulfate into the organic phase 3 and drying; the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain 157.0g of a pale yellow liquid, i.e., ethyl 2-formyl-1-cyclopropanecarboxylate.
Comparative example 1
1.0 equivalent acrolein and 10% mole percent HBF4·OEt2Adding CH at-78 deg.C2Cl2In, and add CH dropwise2Cl2Diluted 1.2 equivalents of ethyl diazoacetate are added dropwise over 30 minutes, and the reaction mixture is stirred at-78 ℃ for 24 hours to give the product ethyl 2-formyl-1-cyclopropanecarboxylate.
Performance test
Yield, purity and hydrogen spectrum tests were carried out using the intermediate 1, the intermediate 2 and ethyl 2-formyl-1-cyclopropanecarboxylate prepared in examples 1 to 3 and comparative example 1, and the test results are shown below;
example 1
Intermediate 1: 2.4kg of a colorless liquid, i.e., ethyl 4, 4-dimethoxy-2-butenoate, in a yield of 88.0% and 95.0% (GC);
1 HNMR（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, i.e. ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate; the yield was 38.8%, 95.0% (GC);
1 HNMR（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)。
ethyl 2-formyl-1-cyclopropanecarboxylate: 157.0g of light yellow liquid is obtained; the yield is 80.5%, 96.0% (GC), the trans isomer accounts for more than 90%;
1 HNMR（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 a colorless liquid, i.e., ethyl 4, 4-dimethoxy-2-butenoate, in a yield of 87.8% and 95.0% (GC);
1 HNMR（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, i.e. ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate; the yield was 38.6%, 95.0% (GC);
1 HNMR（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)。
ethyl 2-formyl-1-cyclopropanecarboxylate: 157.0g of light yellow liquid is obtained; the yield is 81.2 percent, 96.0 percent (GC) is trans-isomer, and the trans-isomer accounts for more than 90 percent;
1 HNMR（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 a colorless liquid, i.e., ethyl 4, 4-dimethoxy-2-butenoate, in a yield of 88.2% and 95.0% (GC);
1 HNMR（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, i.e. ethyl 2' - (dimethoxymethyl) -1-cyclopropylcarboxylate; the yield was 38.8%, 95.0% (GC);
1 HNMR（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)。
ethyl 2-formyl-1-cyclopropanecarboxylate: 157.0g of light yellow liquid is obtained; the yield was 81.5%, 96.0% (GC), the trans isomer accounted for more than 90%;
1 HNMR（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
Ethyl 2-formyl-1-cyclopropanecarboxylate: while containing the cis-trans isomer (ratio 40: 60).
By combining the examples 1 and 2 with the example 3, the purity of the synthesized intermediate 1, the intermediate 2 and the ethyl 2-formyl-1-cyclopropanecarboxylate is higher although the raw material dosage ratios of the three examples are different; wherein, the raw material dosage ratio in the example 3 is the optimal ratio, and the synthesized intermediate 1, intermediate 2 and 2-formyl-1-cyclopropane ethyl formate not only has high purity, but also has slightly higher yield than the yield in the examples 1 and 2.
By combining example 3 with comparative example 1, it can be seen that the ethyl 2-formyl-1-cyclopropanecarboxylate prepared by the method of comparative example 1 simultaneously contains cis-trans isomers, and the ratio is 40:60, the trans isomer accounts for more than 90% of the product, and the product has higher purity compared with the comparative document.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. A method for synthesizing 2-formyl-1-cyclopropane ethyl formate is characterized by comprising the following steps:
step S1: synthesis of intermediate 1
S1 a: adding 2, 2-dimethoxyacetaldehyde, 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;
s1 b: removing the organic solvent 1 in the reaction solution 1, extracting to obtain an organic phase 1, washing, drying, concentrating and fractionating to obtain an intermediate 1;
the molar ratio of the 2, 2-dimethoxyacetaldehyde to the triethyl phosphonoacetate is (3-1): 1, and the dosage ratio of the organic solvent 1 to the triethyl phosphonoacetate is (5-15) L:1 kg;
step S2: synthesis of intermediate 2
S2 a: adding a catalyst 2 into an organic solvent 2, stirring, adding trimethyl sulfonium iodide in batches, cooling to 0 ℃, adding an intermediate 1, and reacting at room temperature to obtain a reaction solution 2;
s2 b: 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 trimethyl sulfoxonium iodide to triethyl phosphonoacetate is (1.05-2) to 1;
step S3: synthesis of 2-formyl-1-cyclopropanecarboxylic acid ethyl ester
S3 a: 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;
s3 b: removing the organic solvent 3 in the reaction solution 3, extracting to obtain an organic phase 3, washing, drying and concentrating to obtain the 2-formyl-1-cyclopropane ethyl formate.
2. The method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate according to claim 1, wherein the reaction time in step S1a is 8-15 h; the reaction time in the step S2a is 2-8 h; the reaction time in the step S3a is 8-20 h.
3. The method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate according to claim 1, wherein the step of adding trimethylsulfoxonium iodide in batches in step S2a means that the addition time is controlled within 1 h.
4. The method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate according to any one of claims 1 to 3, wherein methyl tert-butyl ether is used as an extractant in the extraction in the step S2 b.
5. The method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate according to claim 1, wherein the extraction manner of step S1b is to add water and dichloromethane, stir and extract, and separate 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 performed in the same manner as in step S1 b.
6. The method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate according to claim 1, wherein the organic solvent 1 is one of acetone, tetrahydrofuran, dimethyltetrahydrofuran 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.
7. The method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate according to claim 1, wherein the amount ratio of the diluted acid aqueous solution to the intermediate 2 in the step S3a is (3.25-5) L:1kg, and the mass percentage of the diluted acid aqueous solution is 5% -10%.
8. The method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate according to claim 1, wherein the reactions of the steps S1a, S2a and S3a are all carried out under the protection of nitrogen.
9. The method for synthesizing ethyl 2-formyl-1-cyclopropanecarboxylate according to claim 1, wherein catalyst 1 is carbonate; catalyst 2 refers to a hydrogenation salt.
10. 2-formyl-1-cyclopropanecarboxylic acid ethyl ester, which is prepared by the method of any one of claims 1-9.
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|---|---|---|---|---|
| CN114989013A (en) * | 2022-06-24 | 2022-09-02 | 安徽华业香料合肥有限公司 | Synthesis method of trans-2-cis-4-decadienoic acid ethyl ester |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090221593A1 (en) * | 2005-08-22 | 2009-09-03 | Giorgio Bonanomi | Triazole derivatives as modulators of dopamine d3 receptors |
| CN101743005A (en) * | 2007-07-02 | 2010-06-16 | 伊莱利利公司 | Chemotherapy for cancer enhancement with 7-(2, 5-dihydro-4-imidazolo [1,2-a] pyridin-3-yl-2, 5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1, 2,3, 4-tetrahydro-2-(1-piperidinylcarbonyl)-pyrrolo [3,2,1-jk] [1,4] benzodiaz [1,4] benzodiaz |
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090221593A1 (en) * | 2005-08-22 | 2009-09-03 | Giorgio Bonanomi | Triazole derivatives as modulators of dopamine d3 receptors |
| CN101743005A (en) * | 2007-07-02 | 2010-06-16 | 伊莱利利公司 | Chemotherapy for cancer enhancement with 7-(2, 5-dihydro-4-imidazolo [1,2-a] pyridin-3-yl-2, 5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1, 2,3, 4-tetrahydro-2-(1-piperidinylcarbonyl)-pyrrolo [3,2,1-jk] [1,4] benzodiaz [1,4] benzodiaz |
Non-Patent Citations (2)
| Title |
|---|
| GEORGE B. PAYN ET AL.: "Cyclopropanes from Reactions of Ethyl (Dimethylsulfurany1idene)acetate with a, β-Unsaturated Compounds", 《J. ORG. CHEM.》, vol. 32, pages 3351 - 3355, XP002235537, DOI: 10.1021/jo01286a017 * |
| SU YONG SHIM ET AL.: "Enantioselective Cyclopropanation with α‑ Alkyl- α -diazoesters Catalyzed by Chiral Oxazaborolidinium Ion: Total Synthesis of (+)-Hamavellone B", 《ORGANIC LETTERS》, vol. 18, pages 160 - 163 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114989013A (en) * | 2022-06-24 | 2022-09-02 | 安徽华业香料合肥有限公司 | Synthesis method of trans-2-cis-4-decadienoic acid ethyl ester |
| CN114989013B (en) * | 2022-06-24 | 2023-12-22 | 安徽华业香料合肥有限公司 | Synthesis method of trans-2-cis-4-ethyl decadienoate |
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