CN117736093A - Preparation method of 3-fluorocyclobutane carboxylic acid ethyl ester - Google Patents
Preparation method of 3-fluorocyclobutane carboxylic acid ethyl ester Download PDFInfo
- Publication number
- CN117736093A CN117736093A CN202311209010.1A CN202311209010A CN117736093A CN 117736093 A CN117736093 A CN 117736093A CN 202311209010 A CN202311209010 A CN 202311209010A CN 117736093 A CN117736093 A CN 117736093A
- Authority
- CN
- China
- Prior art keywords
- reaction
- ethyl
- temperature
- fluorocyclobutane
- ethyl ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- CWIRVCXYJTUNBI-UHFFFAOYSA-N ethyl 3-fluorocyclobutane-1-carboxylate Chemical compound CCOC(=O)C1CC(F)C1 CWIRVCXYJTUNBI-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 112
- KTVUZBJHOAPDGC-UHFFFAOYSA-N ethyl 3-hydroxycyclobutane-1-carboxylate Chemical compound CCOC(=O)C1CC(O)C1 KTVUZBJHOAPDGC-UHFFFAOYSA-N 0.000 claims abstract description 55
- BXBRFSMPBOTZHJ-UHFFFAOYSA-N ethyl 3-oxocyclobutane-1-carboxylate Chemical compound CCOC(=O)C1CC(=O)C1 BXBRFSMPBOTZHJ-UHFFFAOYSA-N 0.000 claims abstract description 37
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims abstract description 34
- IENOFRJPUPTEMI-UHFFFAOYSA-N 3-oxocyclobutane-1-carboxylic acid Chemical compound OC(=O)C1CC(=O)C1 IENOFRJPUPTEMI-UHFFFAOYSA-N 0.000 claims abstract description 25
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims abstract description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 15
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 15
- 238000004821 distillation Methods 0.000 claims abstract description 12
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 claims abstract description 11
- PVZMXULSHARAJG-UHFFFAOYSA-N N,N-diethylethanamine molecular hydrogen Chemical compound [H][H].CCN(CC)CC PVZMXULSHARAJG-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 150000007530 organic bases Chemical class 0.000 claims abstract description 7
- 238000004321 preservation Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 239000000706 filtrate Substances 0.000 claims description 32
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 27
- 238000005406 washing Methods 0.000 claims description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 22
- 239000012044 organic layer Substances 0.000 claims description 22
- 239000000047 product Substances 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 20
- 238000000967 suction filtration Methods 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- -1 paratoluenesulfonic acid monohydrate Chemical class 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 238000006386 neutralization reaction Methods 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000005580 one pot reaction Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229940127554 medical product Drugs 0.000 abstract description 4
- LQXHCYIDZUPZNK-UHFFFAOYSA-N 3-fluorocyclobutane-1-carboxylic acid Chemical compound OC(=O)C1CC(F)C1 LQXHCYIDZUPZNK-UHFFFAOYSA-N 0.000 abstract 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 239000010410 layer Substances 0.000 description 24
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 18
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 16
- 238000001816 cooling Methods 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 230000001276 controlling effect Effects 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000003682 fluorination reaction Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 230000000630 rising effect Effects 0.000 description 6
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004334 fluoridation Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- IHLHSAIBOSSHQV-UHFFFAOYSA-N methyl 3-oxocyclobutane-1-carboxylate Chemical compound COC(=O)C1CC(=O)C1 IHLHSAIBOSSHQV-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of ethyl 1, 3-fluorocyclobutane carboxylate, which comprises the following steps: 1. anhydrous ethanol and 3-oxo-cyclobutanecarboxylic acid are adopted, concentrated sulfuric acid is used as a catalyst, and the reaction is carried out at a constant temperature; 2. adding sodium borohydride into ethyl 3-oxo-cyclobutanecarboxylate, absolute ethyl alcohol and p-toluenesulfonic acid monohydrate in batches at 0-10 ℃, reacting for 1-2 hours at the temperature of 0-10 ℃ in a heat preservation way, and performing post-treatment to obtain ethyl 3-hydroxy-cyclobutanecarboxylate; 3. under the condition of an organic solvent, adding 3-hydroxy cyclobutanecarboxylic acid ethyl ester, triethylamine hydrogen trifluoride and organic base, dropwise adding trifluoromethanesulfonic anhydride at the temperature of-10-0 ℃, carrying out heat preservation reaction at the temperature of-10-0 ℃ after dropwise adding, and then carrying out heat preservation reaction at the temperature of 25-55 ℃; after-treatment, reduced pressure distillation is carried out to obtain the product of 3-fluorocyclobutane carboxylic acid ethyl ester. The invention has the advantages that: the whole preparation process can obtain various products, the purity of the products is high, the yield is good, the quality is good, the cis-trans isomer ratio of the third step of products is 1 to 1, and the requirements of medical products are met.
Description
Technical Field
The invention relates to the technical field of compound synthesis, in particular to preparation of 3-fluorocyclobutane carboxylic acid ethyl ester.
Background
Organic fluorine-containing compounds are being studied in the fields of pharmaceutical chemistry, agrochemical chemistry, and materials science. Fluorine atoms have special chemical properties and the incorporation into organic compounds can significantly alter the acidity, dipole moment, polarity, absorbability and metabolic stability of the compounds.
The 3-fluorocyclobutane carboxylic acid ethyl ester is an important fluorine-containing molecular building block, and the carboxylic acid ethyl ester group at the 1-position of the building block has higher activity, is easily converted into active groups such as hydroxyl, halogenated groups, amino groups, cyano groups, aldehyde groups and the like under certain conditions, and is an important intermediate of a plurality of bioactive organic compounds. Therefore, it is of great importance to study the preparation method of ethyl 3-fluorocyclobutane carboxylate. At present, a method for synthesizing 3-fluorocyclobutane carboxylic acid ethyl ester is not reported in the literature.
Patent CN106478651 discloses a method for preparing methyl 3-oxo-cyclobutanecarboxylate by using 3-oxo-cyclobutanecarboxylic acid as raw material, catalytic esterification by sulfuric acid aqueous solution, reduction by sodium borohydride, and DAST fluorination at-78 ℃. The method has low reduction yield, the fluorination needs ultralow temperature, the reaction condition is harsh, the final product is not purified, the purity and the cis-trans isomer ratio are unknown, and the intermediate is purified in a column chromatography mode, so that the method is not suitable for industrialization.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: the preparation method of the 3-fluorocyclobutane carboxylic acid ethyl ester is provided, and the product prepared by the method has the advantages of high purity, good yield, good quality, simple production process, easy control and production cost.
In order to solve the problems, the invention adopts the following technical scheme: the preparation method of the 3-fluorocyclobutane carboxylic acid ethyl ester comprises the following steps: 1. the reaction raw materials adopt absolute ethyl alcohol and 3-oxo-cyclobutanecarboxylic acid, concentrated sulfuric acid is used as a catalyst, the reaction is carried out at a constant temperature, and alkali is added into the reaction liquid for neutralization after the reaction is completed, so that 3-oxo-cyclobutanecarboxylic acid ethyl ester is prepared;
2. the reactant adopts 3-oxo-cyclobutanecarboxylic acid ethyl ester, absolute ethyl alcohol and p-toluenesulfonic acid monohydrate, sodium borohydride is added in batches at the temperature of 0-10 ℃, the reaction is carried out for 1-2 hours at the temperature of 0-10 ℃, and the 3-hydroxy-cyclobutanecarboxylic acid ethyl ester is obtained after the reaction is finished; the feeding mole ratio of the paratoluenesulfonic acid monohydrate to the 3-oxo-naphthenic carboxylic acid ethyl ester is 0.03-0.05; the feeding molar ratio of sodium borohydride to ethyl 3-oxo-cyclobutanecarboxylate is 0.3-0.35;
3. under the condition of an organic solvent, adding 3-hydroxy cyclobutanecarboxylic acid ethyl ester, triethylamine hydrogen trifluoride and organic base, dropwise adding trifluoromethanesulfonic anhydride at the temperature of-10-0 ℃, carrying out heat preservation reaction at the temperature of-10-0 ℃ after dropwise adding, and then carrying out heat preservation reaction at the temperature of 25-55 ℃; the organic base is selected from one or more of triethylamine, DBU and N, N-diisopropylethylamine; after-treatment, reduced pressure distillation is carried out to obtain the product of 3-fluorocyclobutane carboxylic acid ethyl ester. The feeding molar ratio of the triethylamine to the ethyl 3-hydroxycyclobutane carboxylate is 1.2-2, preferably 1.5; the feeding molar ratio of the organic base to the ethyl 3-hydroxycyclobutane carboxylate is 2-3, preferably 2; the molar ratio of the trifluoro methanesulfonic anhydride to the 3-hydroxy cyclobutanecarboxylic acid ethyl ester is 1.1-2, preferably 1.5.
Further, in the preparation method of the ethyl 3-fluorocyclobutane carboxylate, in the first step, the feeding molar ratio of sulfuric acid to 3-oxo-cyclobutanecarboxylic acid is 0.01-0.05.
Further, in the aforementioned method for producing ethyl 3-fluorocyclobutane carboxylate, the molar ratio of sulfuric acid to 3-oxocyclobutanecarboxylic acid in the first step is 0.03.
Further, in the preparation method of the 3-fluorocyclobutane carboxylic acid ethyl ester, in the first step, the reaction is carried out at the temperature of 70-80 ℃ for 16-26 hours.
Further, in the aforementioned preparation method of ethyl 3-fluorocyclobutane carboxylate, after the neutralization by adding alkali in the first step, the reaction solution is post-treated and purified to prepare ethyl 3-oxo-cyclobutane carboxylate, and then the ethyl 3-oxo-cyclobutane carboxylate is reacted in the second step, and the post-treatment step of the reaction solution comprises the following steps: standing, layering, washing an organic layer with water, drying with anhydrous sodium sulfate, carrying out suction filtration, concentrating filtrate under reduced pressure, recovering dichloromethane, and carrying out reduced pressure distillation on residual liquid by using an oil pump to collect a fraction at 55-58 ℃ to obtain the compound 3-oxo-cyclobutanecarboxylic acid ethyl ester; or after the alkali is added for neutralization in the first step, the reaction liquid is directly reacted in the second step by adopting a one-pot method without post-treatment.
Further, in the preparation method of the 3-fluorocyclobutane carboxylic acid ethyl ester, in the second step, the sodium borohydride is added, and the reaction is carried out at the temperature of 10 ℃ for 1 hour after the addition.
Further, in the aforementioned preparation method of ethyl 3-fluorocyclobutane carboxylate, in the second step, the post-treatment step after the reaction is completed includes: and (3) dropwise adding dilute hydrochloric acid to adjust the pH value to 7, controlling the temperature to be-5 ℃, carrying out suction filtration after dropwise adding, concentrating the filtrate under reduced pressure, adding water and an extraction solvent, layering, extracting, washing, drying, carrying out suction filtration, concentrating the filtrate under reduced pressure, and carrying out reduced pressure distillation on the concentrated solution.
Further, the preparation method of the 3-fluorocyclobutane carboxylic acid ethyl ester, wherein the organic solvent in the third step is one or more selected from dichloromethane, methyl tertiary butyl ether and toluene. The amount of the organic solvent used is preferably such that the concentration of ethyl 3-hydroxycyclobutane carboxylate in the organic solvent is 0.5mol/L.
Further, in the aforementioned preparation method of ethyl 3-fluorocyclobutane carboxylate, in the third step, the post-treatment step after the reaction is completed includes: adding water to quench reaction, standing, layering, extracting with organic solvent, washing with alkali, washing with water, drying, filtering, concentrating, and distilling under reduced pressure to collect fraction 3-fluorocyclobutane carboxylic acid ethyl ester.
Further, in the third step, the temperature is kept at-10-0 ℃ for reaction, and then the temperature is raised to 35 ℃ for reaction for 10 hours.
The invention has the advantages that: 1. two or three products can be prepared in one production line, and the preparation cost is effectively reduced. 2. The added paratoluenesulfonic acid monohydrate is reduced by adopting sodium borohydride, so that the generation of polymeric impurities is reduced, and the reaction yield is improved; the method adopts a trifluoro methanesulfonic anhydride/triethylamine hydrogen trifluoride salt system for fluorination, and overcomes the defects of low reaction temperature, high equipment requirement, multiple side reactions such as alkene formation, hydrolysis, condensation and the like, unbalanced cis-trans isomer ratio of products and the like when DAST or BAST is adopted for fluorination in the traditional preparation process. 3. The whole preparation process has mild reaction conditions and convenient operation, can effectively reduce side reactions and reduce the generation of byproducts, thereby effectively improving the yield and purity, the purity of the intermediate product obtained in each step can be more than 99%, and the cis-trans isomer ratio of the target product in the third step is 1:1 to meet the requirement of the pharmaceutical industry on the high quality of the product, so that the preparation process is suitable for industrial production.
Drawings
FIG. 1 is a GC purity profile for ethyl 3-fluorocyclobutane carboxylate of example 12, with cis at 3.681min and trans at 4.027 min.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of ethyl 3-fluorocyclobutane carboxylate in example 12, 1 H NMR (400MHz, CDCl3) δ5.33-4.83 (dt, 1H), 4.17 (q,2H), 3.12-2.49 (m,5H), 1.28 ( t,3H)。
FIG. 3 is a GC purity profile of ethyl 3-oxocyclobutanecarboxylate of example 1.
FIG. 4 is a GC purity profile of ethyl 3-hydroxycyclobutane carboxylate of example 6.
Detailed Description
The present invention will be described in further detail with reference to the following examples.
Example 1: the first step: preparing 3-oxo-cyclobutane carboxylic acid ethyl ester.
In a dry reaction kettle equipped with a thermometer, stirring and reflux condenser, absolute ethanol (1000 mL) and 3-oxo-cyclobutanecarboxylic acid (114.1 g,1 mol) were added, stirring was started, concentrated sulfuric acid (4.9 g,0.05 mol) was further added, heating was performed, the internal temperature was controlled at 80 ℃, the reaction was kept at a temperature for 16 hours, and the peak area ratio of the 3-oxo-cyclobutanecarboxylic acid and the ethyl 3-oxo-cyclobutanecarboxylate, which were compounds, was controlled in GC, was less than 0.5%. Concentrating the reaction solution under reduced pressure, and recovering absolute ethyl alcohol; cooling the concentrated solution to 25 ℃, adding dichloromethane (1000 mL), stirring, dropwise adding sodium bicarbonate aqueous solution, and adjusting the pH to 7-8; standing, layering, washing an organic layer with water, drying by anhydrous sodium sulfate, carrying out suction filtration, concentrating filtrate under reduced pressure, and recycling dichloromethane. The residue was distilled under reduced pressure using an oil pump to collect a 55 to 58 ℃ fraction, namely ethyl 3-oxocyclobutanecarboxylate (volatile colorless transparent liquid), 117.5g, see the GC purity chart shown in FIG. 3, with a GC purity of 99.6% and a yield of 82.7% (calculated as 3-oxocyclobutanecarboxylic acid).
And a second step of: preparing 3-hydroxy cyclobutane carboxylic acid ethyl ester.
To a dry reaction vessel equipped with a thermometer, stirrer, and constant pressure dropping funnel, absolute ethanol (500 mL) and ethyl 3-oxocyclobutanecarboxylate (71.1 g,0.5 mol) were added, stirring was turned on, cooling was performed, and sodium borohydride (5.7 g,0.15 mol) was added in 5 portions at 10℃to give an exotherm; after the addition, the reaction is carried out for 1 hour at the temperature of 10 ℃, and the peak area ratio of the 3-oxo-cyclobutanecarboxylic acid ethyl ester and the 3-hydroxy-cyclobutanecarboxylic acid ethyl ester of the GC central control compound is less than 0.5 percent. Slowly adding 1mol/L dilute hydrochloric acid (150 mL), regulating pH to 7, controlling the internal temperature to-5 ℃, naturally rising to normal temperature (25 ℃) after the dripping, stirring for 15 minutes, carrying out suction filtration, concentrating the filtrate under reduced pressure, adding water (250 mL) and ethyl acetate (250 mL), stirring, standing, layering, extracting the water layer with ethyl acetate twice (250 mL x 2), merging the organic layers, washing with saturated saline (250 mL), drying with anhydrous sodium sulfate, carrying out suction filtration, and concentrating the filtrate under reduced pressure. The obtained concentrated solution is distilled under reduced pressure by an oil pump to collect 64-66 ℃ fractions, namely the compound ethyl 3-hydroxycyclobutane carboxylate, 25.4g, the GC purity is 99.1%, and the yield is 35.2% (calculated by ethyl 3-oxo-cyclobutane carboxylate).
And a third step of: preparing 3-fluorocyclobutane carboxylic acid ethyl ester.
To a dry reaction vessel equipped with a thermometer, stirrer, and constant pressure dropping funnel were added dichloromethane (100 mL) and ethyl 3-hydroxycyclobutane carboxylate (14.4 g,0.1 mol), stirring was turned on, and DAST (24.2 g,0.15 mol) was added dropwise at-65℃under nitrogen protection, followed by heat release; after the dripping, the reaction is carried out for 1 hour at the temperature of minus 65 ℃, and then the reaction is carried out for 16 hours at the temperature of normal temperature (25 ℃). The reaction was quenched by slowly dropping water (75 mL) at 0 ℃, allowed to stand, separated, the aqueous layer extracted twice with dichloromethane (100 mL x 2), the combined organic layers were washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate concentrated under reduced pressure to give a brown liquid, 14.2g, 34% gc purity (the main impurity is a by-product of elimination reaction), cis-trans isomer ratio was 13 to 1, yield 97.1% (calculated as ethyl 3-hydroxycyclobutane carboxylate). The chinese name DAST is diethylaminosulfur trifluoride.
Example 2: the first step: preparing 3-oxo-cyclobutane carboxylic acid ethyl ester.
In a dry reaction kettle equipped with a thermometer, stirring and reflux condenser, absolute ethanol (500 mL) and 3-oxo-cyclobutanecarboxylic acid (114.1 g,1 mol) were added, stirring was started, concentrated sulfuric acid (1.0 g,0.01 mol) was further added, heating was performed, the internal temperature was controlled at 70 ℃, the reaction was kept at a temperature for 26 hours, and the peak area ratio of the 3-oxo-cyclobutanecarboxylic acid and the ethyl 3-oxo-cyclobutanecarboxylate, which were compounds, was controlled in GC, was less than 0.5%. Concentrating the reaction solution under reduced pressure, and recovering absolute ethyl alcohol; cooling the concentrated solution to 25 ℃, adding dichloromethane (1000 mL), stirring, dropwise adding sodium bicarbonate aqueous solution, and adjusting the pH to 7-8; standing, layering, washing an organic layer with water, drying with anhydrous sodium sulfate, carrying out suction filtration, and concentrating the filtrate under reduced pressure to obtain a pale yellow transparent liquid, namely 3-oxo-cyclobutanecarboxylic acid ethyl ester, 140.8g, and 99.0% GC purity and 99.0% yield (calculated by 3-oxo-cyclobutanecarboxylic acid).
And a second step of: preparing 3-hydroxy cyclobutane carboxylic acid ethyl ester.
To a dry reaction vessel equipped with a thermometer, stirrer, and constant pressure dropping funnel, absolute ethanol (500 mL) and ethyl 3-oxocyclobutanecarboxylate (71.1 g,0.5 mol) were added, stirring was turned on, p-toluenesulfonic acid monohydrate (4.7 g,0.025 mol) was added, cooling was performed, and sodium borohydride (5.7 g,0.15 mol) was added in 5 portions at 0℃to give an exotherm; after the addition, the reaction is carried out at the temperature of 0 ℃ for 1 hour, and the peak area ratio of the compound B to the compound C in the GC is controlled to be less than 0.5 percent. Slowly adding 1mol/L dilute hydrochloric acid (150 mL), regulating pH to 7, controlling the internal temperature to-5 ℃, naturally rising to normal temperature (25 ℃) after the dripping, stirring for 15 minutes, carrying out suction filtration, concentrating the filtrate under reduced pressure, adding water (250 mL) and ethyl acetate (250 mL), stirring, standing, layering, extracting the water layer with ethyl acetate twice (250 mL x 2), merging the organic layers, washing with saturated saline (250 mL), drying with anhydrous sodium sulfate, carrying out suction filtration, and concentrating the filtrate under reduced pressure. The obtained concentrated solution was distilled under reduced pressure by an oil pump to collect a fraction at 64 to 66℃of ethyl 3-hydroxycyclobutane carboxylate, 60.4g, a GC purity of 99.2% and a yield of 83.8% (based on ethyl 3-oxocyclobutane carboxylate).
And a third step of: preparing 3-fluorocyclobutane carboxylic acid ethyl ester.
To a dry reaction kettle equipped with a thermometer, stirrer, and constant pressure dropping funnel were added dichloromethane (100 mL) and ethyl 3-hydroxycyclobutane carboxylate (14.4 g,0.1 mol), stirring was turned on, and BAST (33.2 g,0.15 mol) was added dropwise at-65℃under nitrogen protection, followed by heat release; after the dripping, the mixture is reacted for 1 hour at the temperature of minus 65 ℃ and then is heated to the normal temperature of 25 ℃ for 16 hours. The reaction was quenched by slowly dropping water (75 mL) at 0 ℃, allowed to stand, separated, the aqueous layer extracted twice with dichloromethane (100 mL x 2), the combined organic layers were washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate concentrated under reduced pressure to give a brown liquid, 14.5g, gc purity 37% (the main impurity is by-product of elimination reaction), cis-trans isomer ratio was 9 to 1, yield 99.2% (calculated as ethyl 3-hydroxycyclobutane carboxylate). The chinese name of BAST is bis (2-methoxyethyl) amino sulfur trifluoride.
Example 3: the first and second steps are the same as in example 2.
And a third step of: preparing 3-fluorocyclobutane carboxylic acid ethyl ester.
To a dry reaction vessel equipped with a thermometer, stirrer, and constant pressure dropping funnel, methylene chloride (100 mL) and ethyl 3-hydroxycyclobutane carboxylate (14.4 g,0.1 mol) were added, stirring was turned on, and a solution of DAST fluoroborate (34.4 g,0.15 mol) and methylene chloride (50 mL) was added dropwise at-65℃under nitrogen protection, followed by heat release; after the dripping, the mixture is reacted for 1 hour at the temperature of minus 65 ℃ and then is heated to the normal temperature of 25 ℃ for 16 hours. The reaction was quenched by slowly dropping water (75 mL) at 0 ℃, allowed to stand, separated, the aqueous layer extracted twice with dichloromethane (100 mL x 2), the combined organic layers were washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate concentrated under reduced pressure to give a brown liquid, 14.5g, 45% gc purity (the main impurity is a by-product of elimination reaction), cis-trans isomer ratio was 10 to 1, yield 99.2% (calculated as ethyl 3-hydroxycyclobutane carboxylate).
Example 4: the first and second steps are the same as in example 2.
And thirdly, preparing the ethyl 3-fluorocyclobutane carboxylate.
To a dry reaction vessel equipped with a thermometer, stirrer, and constant pressure dropping funnel, methylene chloride (600 mL), ethyl 3-hydroxycyclobutane carboxylate (43.2 g,0.3 mol), triethylamine hydrogen trifluoride (96.6 g,0.6 mol), and triethylamine (91.2 g, 0.9 mol) were successively added, stirring was turned on, and the mixture was cooled under nitrogen protection, and trifluoromethanesulfonic anhydride (169.2 g,0.6 mol) was added dropwise at-10℃to give an exothermic reaction; after the dripping, the temperature is kept at minus 10 ℃ for reaction for 1 hour, and then the temperature is raised to normal temperature for reaction for 16 hours. The reaction was quenched by slowly dropping water (300 mL) at 0 ℃, standing, separating layers, extracting the aqueous layer with dichloromethane twice (300 mL. Times.2), combining the organic layers, washing with saturated aqueous sodium bicarbonate (300 mL), washing with water (300 mL), drying with anhydrous sodium sulfate, suction filtering, concentrating the filtrate under reduced pressure, and collecting the 85-86 ℃ fractions by water pump distillation under reduced pressure to obtain the product ethyl 3-fluorocyclobutane carboxylate, a colorless transparent liquid, 35.5g, a gc purity of 99.0%, a cis-trans isomer ratio of 1 to 1, and a yield of 81.0% (calculated as ethyl 3-hydroxycyclobutane carboxylate).
Example 5: the first and second steps are the same as in example 2.
And thirdly, preparing the ethyl 3-fluorocyclobutane carboxylate.
Tetrahydrofuran (800 mL), ethyl 3-hydroxycyclobutane carboxylate (43.2 g,0.3 mol), tetrabutylammonium fluoride (156.9 g,0.6 mol), and triethylamine (91.2 g, 0.9 mol) were added in this order to a dry reaction vessel equipped with a thermometer, a stirrer, and a constant pressure dropping funnel, and the mixture was cooled under nitrogen with stirring and then trifluoromethanesulfonic anhydride (169.2 g,0.6 mol) was added dropwise at-10℃to give an exothermic reaction; after the dripping, the reaction is carried out for 1 hour at the temperature of minus 10 ℃, and then the reaction is carried out for 16 hours at the temperature of normal temperature (25 ℃). The reaction was quenched by slowly dropping water (300 mL) at 0 ℃, allowed to stand, separated, the aqueous layer was extracted twice with dichloromethane (300 mL. Times.2), the organic layers were combined, washed with saturated aqueous sodium bicarbonate (300 mL), washed with water (300 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, the residue was distilled under reduced pressure with a water pump to collect a 85 to 90 ℃ fraction, compound D, a colorless transparent liquid, 15.7g, a gc purity of 91.6% (the main impurity was unreacted ethyl 3-hydroxycyclobutane carboxylate), a cis-trans isomer ratio of 1.2 to 1, and a yield of 35.8% (calculated as ethyl 3-hydroxycyclobutane carboxylate).
The following conclusions are drawn from examples 1 to 5.
And in the first step, the reaction liquid is subjected to post-treatment, and a colorless and transparent intermediate product of 3-oxo-cyclobutane carboxylic acid ethyl ester can be obtained through reduced pressure distillation, so that the purity is high, the yield is good, and the quality is good.
In the second step, p-toluenesulfonic acid monohydrate and p-toluenesulfonic acid monohydrate are used, the two are greatly different, the p-toluenesulfonic acid monohydrate is not used, and the yield of the intermediate 3-hydroxycyclobutane carboxylic acid ethyl ester is very low and is only 35.2%. And by adding the p-toluenesulfonic acid monohydrate, the generation of polymeric impurities is effectively reduced, and the yield of the intermediate product of the second step, namely the ethyl 3-hydroxycyclobutane carboxylate is greatly improved.
Thirdly, DAST, BAST or DAST fluoroborate is adopted as a fluorination reagent, and the proportion of the obtained 3-fluorocyclobutane carboxylic acid ethyl ester and the cis-trans isomer is seriously unbalanced, so that the requirement of the pharmaceutical industry on the cis-trans isomer 1:1 in the product can not be met; when tetrabutylammonium fluoride is used, the cis-trans isomer ratio in the product is improved but still in an unbalanced state, the yield is greatly reduced, and the medical requirement cannot be met. When the fluoridation reagent adopts a system of trifluoromethanesulfonic anhydride/triethylamine hydrogen trifluoride salt (example 4), the cis-trans isomer ratio of the product 3-fluorocyclobutane carboxylic acid ethyl ester is 1:1, and meets the requirements of medical products.
The following is a further detailed description of the preparation method of ethyl 3-fluorocyclobutane carboxylate according to the present invention by examples 6 to 12, wherein the reaction solution obtained in the first step is directly subjected to the second reaction without post-treatment, and the preparation process is further described in one pot method.
Example 6: the first step prepares ethyl 3-oxo-cyclobutanecarboxylate.
In a dry reaction vessel equipped with a thermometer, stirrer and reflux condenser, absolute ethanol (500 mL) and 3-oxocyclobutanecarboxylic acid (114.1 g,1 mol) were added, stirring was started, sulfuric acid (2.9 g,0.03 mol) was further added, heating was performed, the internal temperature was controlled at 75℃and the reaction was kept at a temperature for 26 hours, the peak area ratio of 3-oxocyclobutanecarboxylic acid, a GC-center control compound, to ethyl 3-oxocyclobutanecarboxylate was less than 0.5%, cooling was performed, sodium bicarbonate solid (5.0 g,0.06 mol) was added, and stirring was performed directly next step.
And a second step of: preparing 3-hydroxy cyclobutane carboxylic acid ethyl ester.
Absolute ethanol (500 mL), p-toluenesulfonic acid monohydrate (9.5 g,0.05 mol) were added, stirred, cooled, sodium borohydride (11.4 g,0.3 mol) was added in 5 portions at 0 ℃ and exothermic; after the addition, the reaction is carried out for 2 hours at the temperature of 0 ℃, and the peak area ratio of the 3-oxo-cyclobutanecarboxylic acid ethyl ester and the 3-hydroxy-cyclobutanecarboxylic acid ethyl ester of the GC central control compound is less than 0.5 percent. Slowly adding 1mol/L dilute hydrochloric acid (300 mL), regulating pH to 7, controlling the internal temperature to-5 ℃, naturally rising to normal temperature, stirring for 15 minutes after the completion of the dripping, carrying out suction filtration, concentrating the filtrate under reduced pressure, adding water (500 mL) and ethyl acetate (500 mL), stirring, standing, layering, extracting the water layer with ethyl acetate twice (500 mL x 2), merging the organic layers, washing with saturated saline (500 mL), drying with anhydrous sodium sulfate, carrying out suction filtration, and concentrating the filtrate under reduced pressure. The obtained concentrated solution was distilled under reduced pressure by an oil pump to collect ethyl 3-hydroxycyclobutane carboxylate, which is a fraction at 64 to 66℃and 120.3g of colorless transparent liquid, see GC diagram shown in FIG. 4, with GC purity of 99.0% and yield of 83.4% (based on 3-oxocyclobutanecarboxylic acid).
And a third step of: preparing 3-fluorocyclobutane carboxylic acid ethyl ester.
To a dry reaction vessel equipped with a thermometer, stirrer, and constant pressure dropping funnel, methyl tert-butyl ether (600 mL), ethyl 3-hydroxycyclobutane carboxylate (43.2 g,0.3 mol), triethylamine hydrogen trifluoride (96.6 g,0.6 mol), DBU (137.0 g, 0.9 mol) were successively added, stirring was turned on, cooling was performed under nitrogen protection, and trifluoromethanesulfonic anhydride (169.2 g,0.6 mol) was added dropwise at-10℃to give an exothermic reaction; after the dripping, the temperature is kept at minus 10 ℃ for reaction for 1 hour, and then the temperature is raised to normal temperature for reaction for 16 hours. The reaction was quenched by slowly dropping water (300 mL) at 0 ℃, standing, separating layers, extracting the aqueous layer with methyl tert-butyl ether twice (300 mL x 2), combining the organic layers, washing with saturated aqueous sodium bicarbonate (300 mL), washing with water (300 mL), drying with anhydrous sodium sulfate, suction filtering, concentrating the filtrate under reduced pressure, collecting the 85-86 ℃ fractions by water pump distillation under reduced pressure, namely the product ethyl 3-fluorocyclobutane carboxylate, a colorless transparent liquid, 38.7g, GC purity 99.5%, cis-trans isomer ratio 1 to 1, yield 88.3% (calculated as ethyl 3-hydroxycyclobutane carboxylate).
Example 7: the first and second steps were the same as in example 6.
And thirdly, preparing the ethyl 3-fluorocyclobutane carboxylate.
Toluene (600 mL), ethyl 3-hydroxycyclobutane carboxylate (43.2 g,0.3 mol), triethylamine hydrogen trifluoride (96.6 g,0.6 mol), N-diisopropylethylamine (116.3 g, 0.9 mol), stirring, cooling under nitrogen protection, dropwise adding trifluoromethanesulfonic anhydride (169.2 g,0.6 mol) at-10 ℃ and releasing heat are sequentially added to a dry reaction kettle equipped with a thermometer, stirring and constant pressure dropping funnel; after the dripping, the temperature is kept at minus 10 ℃ for reaction for 1 hour, and then the temperature is raised to normal temperature for reaction for 16 hours. The reaction was quenched by slowly dropping water (300 mL) at 0 ℃, standing, separating layers, extracting the aqueous layer with methyl tert-butyl ether twice (300 mL x 2), combining the organic layers, washing with saturated aqueous sodium bicarbonate (300 mL), washing with water (300 mL), drying with anhydrous sodium sulfate, suction filtering, concentrating the filtrate under reduced pressure, distilling the residue with a water pump under reduced pressure to collect 85-86 ℃ fractions, namely the product ethyl 3-fluorocyclobutane carboxylate, a colorless transparent liquid, 37.5g, gc purity 98.6%, cis-trans isomer ratio 1 to 1, yield 85.5% (calculated as ethyl 3-hydroxycyclobutane carboxylate).
Example 8: in the first step, ethyl 3-oxocyclobutanecarboxylate is prepared.
In a dry reaction vessel equipped with a thermometer, stirrer and reflux condenser, absolute ethanol (800 mL) and 3-oxocyclobutanecarboxylic acid (114.1 g,1 mol) were added, stirring was started, sulfuric acid (2.9 g,0.03 mol) was further added, heating was performed, the internal temperature was controlled at 80℃and the reaction was kept at a temperature for 26 hours, the peak area ratio of 3-oxocyclobutanecarboxylic acid, a GC-center control compound, to ethyl 3-oxocyclobutanecarboxylate was less than 0.5%, cooling was performed, sodium bicarbonate solid (5.0 g,0.06 mol) was added, and stirring was performed directly next step.
In the second step, ethyl 3-hydroxycyclobutane carboxylate is prepared.
Absolute ethanol (200 mL), p-toluenesulfonic acid monohydrate (5.7 g,0.03 mol) were added, stirred, cooled, sodium borohydride (13.2 g,0.35 mol) was added in 5 portions at 0 ℃ and exothermic; after the addition, the reaction is carried out for 2 hours at the temperature of 10 ℃, and the peak area ratio of the compound B to the compound C in the GC is controlled to be less than 0.5 percent. Slowly adding 1mol/L dilute hydrochloric acid (300 mL) dropwise, regulating the pH to 7, controlling the internal temperature to be-5 ℃, naturally rising to normal temperature, stirring for 15 minutes after the completion of the dropwise, carrying out suction filtration, concentrating the filtrate under reduced pressure, adding water (500 mL) and ethyl acetate (500 mL), stirring, standing, layering, extracting the water layer with ethyl acetate twice (500 mL x 2), merging the organic layers, washing with saturated saline (500 mL), drying with anhydrous sodium sulfate, carrying out suction filtration, concentrating the filtrate under reduced pressure to obtain a yellow liquid, namely compound C,137.4g, wherein the GC purity is 98.5%, and the yield is 95.3% (calculated by 3-oxo cyclobutanecarboxylic acid).
And thirdly, preparing the ethyl 3-fluorocyclobutane carboxylate.
To a dry reaction vessel equipped with a thermometer, stirrer, and constant pressure dropping funnel, methyl tert-butyl ether (600 mL), ethyl 3-hydroxycyclobutane carboxylate (43.2 g,0.3 mol), triethylamine hydrogen trifluoride (72.5 g, 0.45 mol), DBU (91.3.0 g,0.6 mol) were successively added, stirring was turned on, cooling was performed under nitrogen protection, and trifluoromethanesulfonic anhydride (127.0 g, 0.45 mol) was added dropwise at-10℃to give an exothermic reaction; after the dripping, the reaction is carried out for 1 hour at the temperature of minus 10 ℃, and then the temperature is raised to 35 ℃ for 10 hours. The reaction was quenched by slowly dropping water (300 mL) at 0 ℃, standing, separating layers, extracting the aqueous layer with methyl tert-butyl ether twice (300 mL x 2), combining the organic layers, washing with saturated aqueous sodium bicarbonate (300 mL), washing with water (300 mL), drying with anhydrous sodium sulfate, suction filtering, concentrating the filtrate under reduced pressure, distilling the residue with a water pump under reduced pressure to collect 85-86 ℃ fractions, namely the product ethyl 3-fluorocyclobutane carboxylate, a colorless transparent liquid, 39.8g, a gc purity of 99.5%, a cis-trans isomer ratio of 1 to 1, and a yield of 90.8% (calculated as ethyl 3-hydroxycyclobutane carboxylate).
Example 9: the first and second steps are the same as in example 8.
And thirdly, preparing the ethyl 3-fluorocyclobutane carboxylate.
To a dry reaction vessel equipped with a thermometer, stirrer, and constant pressure dropping funnel, methyl tert-butyl ether (600 mL), ethyl 3-hydroxycyclobutane carboxylate (43.2 g,0.3 mol), triethylamine hydrogen trifluoride (58.0 g, 0.36 mol), DBU (91.3.0 g,0.6 mol) were successively added, stirring was turned on, cooling was performed under nitrogen protection, and trifluoromethanesulfonic anhydride (101.6 g, 0.36 mol) was added dropwise at 0℃to give an exothermic reaction; after the dripping, the reaction is carried out for 1 hour at the temperature of 0 ℃, and then the temperature is raised to 45 ℃ for 8 hours. The reaction was quenched by slowly dropping water (300 mL) at 0 ℃, standing, separating layers, extracting the aqueous layer with methyl tert-butyl ether twice (300 mL x 2), combining the organic layers, washing with saturated aqueous sodium bicarbonate (300 mL), washing with water (300 mL), drying with anhydrous sodium sulfate, suction filtering, concentrating the filtrate under reduced pressure, collecting the 85-86 ℃ fraction, i.e. ethyl 3-fluorocyclobutane carboxylate, as a colorless transparent liquid, 39.3g, gc purity 99.5%, isomer ratio 1 to 1, yield 89.6% (calculated as ethyl 3-hydroxycyclobutane carboxylate) by water pump reduced pressure distillation.
Example 10: the first and second steps are the same as in example 8.
And thirdly, preparing the ethyl 3-fluorocyclobutane carboxylate.
To a dry reaction vessel equipped with a thermometer, stirrer, and constant pressure dropping funnel, methyl tert-butyl ether (600 mL), ethyl 3-hydroxycyclobutane carboxylate (43.2 g,0.3 mol), triethylamine hydrogen trifluoride (58.0 g, 0.36 mol), DBU (91.3.0 g,0.6 mol) were successively added, stirring was turned on, cooling was performed under nitrogen protection, and trifluoromethanesulfonic anhydride (93.1 g, 0.33 mol) was added dropwise at 0℃to give an exothermic reaction; after the dripping, the reaction is carried out for 1 hour at the temperature of 0 ℃, and then the temperature is raised to 55 ℃ for 8 hours. The reaction was quenched by slowly dropping water (300 mL) at 0 ℃, allowed to stand, separated, the aqueous layer was extracted twice with methyl tert-butyl ether (300 mL. Times.2), the organic layers were combined, washed with saturated aqueous sodium bicarbonate (300 mL) and water (300 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, the residue was distilled under reduced pressure with a water pump to collect 85-86 ℃ fractions, namely ethyl 3-fluorocyclobutane carboxylate, a colorless transparent liquid, 40.1g, gc purity 99.6%, cis-trans isomer ratio 1 to 1.13, yield 91.4% (calculated as ethyl 3-hydroxycyclobutane carboxylate).
Example 11: in the first step, ethyl 3-oxocyclobutanecarboxylate is prepared.
In a dry reaction vessel equipped with a thermometer, stirrer and reflux condenser, absolute ethanol (800 mL) and 3-oxocyclobutanecarboxylic acid (114.1 g,1 mol) were added, stirring was started, sulfuric acid (2.9 g,0.03 mol) was further added, heating was performed, the internal temperature was controlled at 80℃and the reaction was kept at a temperature for 20 hours, the peak area ratio of 3-oxocyclobutanecarboxylic acid, a GC-center control compound, to ethyl 3-oxocyclobutanecarboxylate was less than 0.5%, cooling was performed, sodium bicarbonate solid (5.0 g,0.06 mol) was added, and stirring was performed directly to the next step.
In the second step, ethyl 3-hydroxycyclobutane carboxylate is prepared.
Absolute ethanol (200 mL), p-toluenesulfonic acid monohydrate (5.7 g,0.03 mol) were added, stirred, cooled, sodium borohydride (13.2 g,0.35 mol) was added in 5 portions at 0 ℃ and exothermic; after the addition, the reaction is carried out at 10 ℃ for 1 hour, and the peak area ratio of the compound B to the compound C in the GC is controlled to be less than 0.5 percent. Slowly adding 1mol/L dilute hydrochloric acid (300 mL) dropwise, regulating the pH to 7, controlling the internal temperature to be-5 ℃, naturally rising to normal temperature, stirring for 15 minutes after the completion of the dropwise addition, carrying out suction filtration, concentrating the filtrate under reduced pressure, adding water (500 mL) and ethyl acetate (500 mL), stirring, standing, layering, extracting the water layer twice (500 mL x 2) with ethyl acetate, merging the organic layers, washing with saturated saline (500 mL), drying with anhydrous sodium sulfate, carrying out suction filtration, concentrating the filtrate under reduced pressure to obtain yellow liquid, namely, the product of ethyl 3-hydroxycyclobutane carboxylate, 138.1g, GC purity of 98.4%, and yield of 95.8% (calculated by 3-oxo-cyclobutanecarboxylic acid).
And thirdly, ethyl 3-fluorocyclobutane carboxylate.
To a dry reaction vessel equipped with a thermometer, stirrer, and constant pressure dropping funnel, methyl tert-butyl ether (600 mL), ethyl 3-hydroxycyclobutane carboxylate (43.2 g,0.3 mol), triethylamine hydrogen trifluoride (72.5 g, 0.45 mol), DBU (91.3.0 g,0.6 mol) were successively added, stirring was turned on, cooling was performed under nitrogen protection, and trifluoromethanesulfonic anhydride (101.6 g, 0.36 mol) was added dropwise at-10℃to give an exothermic reaction; after the dripping, the reaction is carried out for 1 hour at the temperature of minus 10 ℃, and then the temperature is raised to 35 ℃ for 10 hours. The reaction was quenched by slowly dropping water (300 mL) at 0 ℃, allowed to stand, separated, the aqueous layer was extracted twice with methyl tert-butyl ether (300 mL x 2), the organic layers were combined, washed with saturated aqueous sodium bicarbonate (300 mL), washed with water (300 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, the residue was distilled under reduced pressure with a water pump to collect 85-86 ℃ fractions, compound D, a colorless clear liquid, 39.9g, gc purity 99.4%, cis-trans isomer ratio 1 to 1, yield 91.0% (calculated as ethyl 3-hydroxycyclobutane carboxylate).
Example 12: in the first step, ethyl 3-oxocyclobutanecarboxylate is prepared.
In a dry reaction kettle equipped with a thermometer, stirring and reflux condenser, absolute ethyl alcohol (16L) and 3-oxo-cyclobutanecarboxylic acid (2282 g,20 mol) were added, stirring was started, sulfuric acid (58.8 g,0.6 mol) was added dropwise, heating was performed, the internal temperature was controlled at 80 ℃, the reaction was kept at a temperature for 20 hours, the peak area ratio of the 3-oxo-cyclobutanecarboxylic acid compound to ethyl 3-oxo-cyclobutanecarboxylate, which was a GC-center control compound, was less than 0.5%, cooling was performed, sodium bicarbonate solid (100.8 g,1.2 mol) was added, and stirring was performed directly to the next step.
In the second step, ethyl 3-hydroxycyclobutane carboxylate is prepared.
Absolute ethanol (4L) and p-toluenesulfonic acid monohydrate (114.1 g,0.6 mol) were added, stirred, cooled, sodium borohydride (265 g,7 mol) was added in portions at 0deg.C, and the heat was released; after the addition, the reaction is carried out for 1 hour at the temperature of 10 ℃, and the peak area ratio of the ethyl 3-oxo-cyclobutanecarboxylate to the ethyl 3-hydroxy-cyclobutanecarboxylate in the GC is controlled to be less than 0.5 percent. Slowly adding 1mol/L of dilute hydrochloric acid (6L) dropwise, regulating the pH to 7, controlling the internal temperature to-5 ℃, naturally rising to normal temperature, stirring for 15 minutes after the completion of the dropwise addition, carrying out suction filtration, concentrating the filtrate under reduced pressure, adding water (10L) and ethyl acetate (10L), stirring, standing, layering, extracting the water layer twice (10L x 2) with ethyl acetate, merging the organic layers, washing with saturated saline (10L), drying with anhydrous sodium sulfate, carrying out suction filtration, concentrating the filtrate under reduced pressure to obtain yellow liquid, namely 3-hydroxycyclobutane carboxylic acid ethyl ester, 2753g, wherein the GC purity is 98.7%, and the yield is 95.5% (calculated by 3-oxo-cyclobutane carboxylic acid).
And thirdly, preparing the ethyl 3-fluorocyclobutane carboxylate.
Methyl tertiary butyl ether (15L), ethyl 3-hydroxycyclobutane carboxylate (1080 g, 7.5 mol), triethylamine hydrogen trifluoride (1815 g, 11.25 mol) and DBU (2285 g, 15 mol) were sequentially added to a dry reaction vessel equipped with a thermometer, a stirrer and a constant pressure dropping funnel, stirring was started, cooled under nitrogen protection, and trifluoromethanesulfonic anhydride (2540 g, 9 mol) was added dropwise at-10℃to give an exothermic reaction; after the dripping, the reaction is carried out for 1 hour at the temperature of minus 10 ℃, and then the temperature is raised to 35 ℃ for 10 hours. The reaction was quenched by slowly dropping water (7.5L) at 0deg.C, standing, separating the layers, extracting the aqueous layer with methyl tert-butyl ether twice (7.5 L.times.2), combining the organic layers, washing with saturated aqueous sodium bicarbonate (7.5L) and water (7.5L), drying over anhydrous sodium sulfate, suction filtering, concentrating the filtrate under reduced pressure, and collecting the 85-86℃ fraction, i.e., ethyl 3-fluorocyclobutane carboxylate, colorless transparent liquid, 1004.5g, GC purity 99.5%, cis-trans isomer ratio 1:1, yield 91.6% (calculated as ethyl 3-hydroxycyclobutane carboxylate) by water pump distillation.
In the above examples 6 to 12, the second step was directly carried out by one pot method after the first reaction was completed, thereby greatly simplifying the preparation process. The intermediate 3-hydroxy cyclobutanecarboxylic acid ethyl ester has high purity, good yield, no color, transparency and good quality; in the third step of preparation, under the condition that a trifluoromethanesulfonic anhydride/triethylamine hydrogen trifluoride salt system is adopted as a fluorination reagent, the 3-fluorocyclobutane carboxylic acid ethyl ester has high purity and good yield, and the cis-trans isomer ratio of 1 to 1 meets the requirements of medical products.
In the above examples, the normal temperature means a temperature of 25℃and a concentration of concentrated sulfuric acid of 18.4mol/L.
As can be seen from the above examples: according to the preparation method of the 3-fluorocyclobutane carboxylic acid ethyl ester, as the first step and the second step are respectively carried out the post-treatment purification, three products can be obtained in the preparation process, the purity of the three products is high, the yield is good, the quality is good, the cis-trans isomer ratio of the third step is 1 to 1, and the requirements of the pharmaceutical products are met, so that the three products can be prepared on one production line, and the preparation cost is effectively reduced. If the first step is not carried out after treatment and the second step is directly carried out by adopting a one-pot method, the production process is further simplified, the whole preparation process can obtain two products, the purity of the two products is high, the yield is good, the quality is good, and the cis-trans isomer ratio of the product in the third step is 1 to 1, which meets the requirements of medical products, so that the two products can be prepared by one production line, and the preparation cost is further effectively reduced. The whole preparation process has mild reaction condition, convenient operation and high yield, thereby being suitable for industrial production.
Claims (10)
- The preparation method of the ethyl 3-fluorocyclobutane carboxylate comprises the following steps: 1. the reaction raw materials adopt absolute ethyl alcohol and 3-oxo-cyclobutanecarboxylic acid, concentrated sulfuric acid is used as a catalyst, the reaction is carried out at a constant temperature, and alkali is added into the reaction liquid for neutralization after the reaction is completed, so that 3-oxo-cyclobutanecarboxylic acid ethyl ester is prepared;2. the reactant adopts 3-oxo-cyclobutanecarboxylic acid ethyl ester, absolute ethyl alcohol and p-toluenesulfonic acid monohydrate, sodium borohydride is added in batches at the temperature of 0-10 ℃, the reaction is carried out for 1-2 hours at the temperature of 0-10 ℃, and the 3-hydroxy-cyclobutanecarboxylic acid ethyl ester is obtained after the reaction is finished; the feeding mole ratio of the paratoluenesulfonic acid monohydrate to the 3-oxo-cyclobutanecarboxylic acid ethyl ester is 0.03-0.05; the feeding molar ratio of sodium borohydride to ethyl 3-oxo-cyclobutanecarboxylate is 0.3-0.35;3. under the condition of an organic solvent, adding 3-hydroxy cyclobutanecarboxylic acid ethyl ester, triethylamine hydrogen trifluoride and organic base, dropwise adding trifluoromethanesulfonic anhydride at the temperature of-10-0 ℃, carrying out heat preservation reaction at the temperature of-10-0 ℃ after dropwise adding, and then carrying out heat preservation reaction at the temperature of 25-55 ℃; the organic base is selected from one or more of triethylamine, DBU and N, N-diisopropylethylamine; post-treatment, and reduced pressure distillation to obtain a product of 3-fluorocyclobutane carboxylic acid ethyl ester; the feeding molar ratio of the triethylamine to the hydrogen trifluoride to the ethyl 3-hydroxycyclobutane carboxylate is 1.2-2; the feeding molar ratio of the organic base to the ethyl 3-hydroxycyclobutane carboxylate is 2-3; the feeding molar ratio of the trifluoro methanesulfonic anhydride to the 3-hydroxy cyclobutanecarboxylic acid ethyl ester is 1.1-2.
- 2. The method for producing ethyl 3-fluorocyclobutane carboxylate according to claim 1, wherein: in the first step, the feeding molar ratio of sulfuric acid to 3-oxo-cyclobutanecarboxylic acid is 0.01-0.05.
- 3. The method for producing ethyl 3-fluorocyclobutane carboxylate according to claim 2, characterized in that: in the first step, the molar ratio of sulfuric acid to 3-oxocyclobutanecarboxylic acid fed was 0.03.
- 4. The method for producing ethyl 3-fluorocyclobutane carboxylate according to claim 1, wherein: in the first step, the reaction is carried out for 16-26 hours at the temperature of 70-80 ℃.
- 5. The process for producing ethyl 3-fluorocyclobutane carboxylate as claimed in claim 1, 2, 3 or 4, characterized in that: after the first step of alkali addition and neutralization, the reaction solution is subjected to aftertreatment and purification to prepare the 3-oxo-cyclobutanecarboxylic acid ethyl ester, and then the 3-oxo-cyclobutanecarboxylic acid ethyl ester is used for the second step of reaction, wherein the reaction solution aftertreatment step comprises the following steps: standing, layering, washing an organic layer with water, drying with anhydrous sodium sulfate, carrying out suction filtration, concentrating filtrate under reduced pressure, recovering dichloromethane, and carrying out reduced pressure distillation on residual liquid by using an oil pump to collect a fraction at 55-58 ℃ to obtain the compound 3-oxo-cyclobutanecarboxylic acid ethyl ester; or after the alkali is added for neutralization in the first step, the reaction liquid is directly reacted in the second step by adopting a one-pot method without post-treatment.
- 6. The method for producing ethyl 3-fluorocyclobutane carboxylate according to claim 1, wherein: in the second step, the sodium borohydride is reacted for 1 hour at 10 ℃ after being added.
- 7. The method for producing ethyl 3-fluorocyclobutane carboxylate according to claim 1, wherein: in the second step, the post-treatment step after the reaction is finished comprises the following steps: and (3) dropwise adding dilute hydrochloric acid to adjust the pH value to 7, controlling the temperature to be-5 ℃, carrying out suction filtration after dropwise adding, concentrating the filtrate under reduced pressure, adding water and an extraction solvent, layering, extracting, washing, drying, carrying out suction filtration, concentrating the filtrate under reduced pressure, and carrying out reduced pressure distillation on the concentrated solution.
- 8. The method for producing ethyl 3-fluorocyclobutane carboxylate according to claim 1, wherein: the organic solvent in the third step is selected from one or more of dichloromethane, methyl tertiary butyl ether and toluene.
- 9. The method for producing ethyl 3-fluorocyclobutane carboxylate according to claim 1, wherein: in the third step, the post-treatment step after the reaction is finished comprises: adding water to quench reaction, standing, layering, extracting with organic solvent, washing with alkali, washing with water, drying, filtering, concentrating, and distilling under reduced pressure to collect fraction 3-fluorocyclobutane carboxylic acid ethyl ester.
- 10. The method for producing ethyl 3-fluorocyclobutane carboxylate according to claim 1, wherein: in the third step, after the dropping, the temperature is kept at-10 ℃ to 0 ℃ for reaction, and then the temperature is raised to 35 ℃ for reaction for 10 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311209010.1A CN117736093A (en) | 2023-09-19 | 2023-09-19 | Preparation method of 3-fluorocyclobutane carboxylic acid ethyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311209010.1A CN117736093A (en) | 2023-09-19 | 2023-09-19 | Preparation method of 3-fluorocyclobutane carboxylic acid ethyl ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117736093A true CN117736093A (en) | 2024-03-22 |
Family
ID=90278103
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311209010.1A Pending CN117736093A (en) | 2023-09-19 | 2023-09-19 | Preparation method of 3-fluorocyclobutane carboxylic acid ethyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117736093A (en) |
-
2023
- 2023-09-19 CN CN202311209010.1A patent/CN117736093A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108191604B (en) | Method for continuously preparing 2-methallyl alcohol | |
| WO2019091179A1 (en) | Method for preparing florfenicol intermediate v and method for preparing florfenicol using intermediate v | |
| EP2534130B1 (en) | Method for producing astaxanthin dimethyl disuccinate | |
| CN113072434A (en) | Method for preparing cyclopropyl methyl ketone by one-step method | |
| CN113527081B (en) | Preparation method of 3-oxocyclobutanecarboxylic acid | |
| CN113024489A (en) | Preparation method of oseltamivir synthesis process impurity | |
| CN113831242A (en) | Preparation method of 4-methoxy methyl acetoacetate | |
| JPS5826331B2 (en) | Method for producing stereo-regulated farnesyl acetate | |
| JP3315222B2 (en) | Method for producing α-fluoro-β-dicarbonyl compound | |
| CN117736093A (en) | Preparation method of 3-fluorocyclobutane carboxylic acid ethyl ester | |
| CN114736119B (en) | One-step preparation method of ethyl 4-bromobutyrate | |
| CN113773182B (en) | Method for synthesizing 6, 8-dichloro octanoate | |
| CN113416142B (en) | Preparation method of 5-ALA intermediate 5-bromolevulinate | |
| CN115448838A (en) | Preparation method of ethyl 2- (1, 5-trimethyl-2-cyclopentenyl) acetate | |
| CN109761868B (en) | Synthesis method of optically pure chlorprostenol | |
| CN111205184A (en) | Method for synthesizing (9Z,12E) -tetradeca-9, 12-diene-1-alcohol acetate | |
| JPS5826330B2 (en) | Method for producing stereo-regulated farnesyl acetate | |
| CN104910033A (en) | Method for preparing 5-aminolevulinic acid hydrochloride | |
| CN112266328B (en) | Synthetic route and preparation method of 3-fluoro-4-nitrobenzaldehyde | |
| CN115160134B (en) | Preparation method of 4-bromo-2-methyl benzoate | |
| CN115340455B (en) | Preparation method of fluoroalkyl ketoacid alkyl ester | |
| JPH0662489B2 (en) | Valproic acid manufacturing method | |
| CN113603581B (en) | Continuous device and method for industrial production of 4-chloroacetoacetic acid ethyl ester | |
| US20020022740A1 (en) | Octafluorotricyclodecane derivatives and processes for producing same | |
| CN113788754B (en) | Preparation method of bifenthrin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |