CN117567266A - Method for preparing 2-methylcyclopropyl carboxylic acid - Google Patents
Method for preparing 2-methylcyclopropyl carboxylic acid Download PDFInfo
- Publication number
- CN117567266A CN117567266A CN202311472803.2A CN202311472803A CN117567266A CN 117567266 A CN117567266 A CN 117567266A CN 202311472803 A CN202311472803 A CN 202311472803A CN 117567266 A CN117567266 A CN 117567266A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- propylene oxide
- carboxylic acid
- base
- 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
- 238000000034 method Methods 0.000 title claims abstract description 34
- AYEGPMGNMOIHDL-UHFFFAOYSA-N 2-methylcyclopropane-1-carboxylic acid Chemical compound CC1CC1C(O)=O AYEGPMGNMOIHDL-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- 229940125904 compound 1 Drugs 0.000 claims abstract description 22
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000007788 liquid Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 238000010992 reflux Methods 0.000 claims abstract description 7
- 229940125782 compound 2 Drugs 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000012071 phase Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- -1 alkyl lithium Chemical compound 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000003321 amplification Effects 0.000 abstract description 4
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 4
- AYEGPMGNMOIHDL-IMJSIDKUSA-N (1s,2s)-2-methylcyclopropane-1-carboxylic acid Chemical compound C[C@H]1C[C@@H]1C(O)=O AYEGPMGNMOIHDL-IMJSIDKUSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 239000003921 oil Substances 0.000 description 9
- XXDAXUSYDPWTPK-UHFFFAOYSA-N 2-(oxo-lambda5-phosphanylidyne)acetic acid Chemical compound P(=O)#CC(=O)O XXDAXUSYDPWTPK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- AYEGPMGNMOIHDL-QWWZWVQMSA-N (1r,2r)-2-methylcyclopropane-1-carboxylic acid Chemical compound C[C@@H]1C[C@H]1C(O)=O AYEGPMGNMOIHDL-QWWZWVQMSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 241001274216 Naso Species 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 3
- GOOHAUXETOMSMM-GSVOUGTGSA-N R-propylene oxide Chemical compound C[C@@H]1CO1 GOOHAUXETOMSMM-GSVOUGTGSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- KAKCLWUKLSECEM-UHFFFAOYSA-N 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound C1=NC(CC)=CC=C1B1OC(C)(C)C(C)(C)O1 KAKCLWUKLSECEM-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010963 scalable process Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a method for preparing 2-methylcyclopropyl carboxylic acid, and belongs to the technical field of chemical synthesis. The method comprises the following steps: (1) Uniformly mixing the compound 1, alkali and a solvent in a reaction container, heating to reflux, adding propylene oxide below the liquid level, and reacting to obtain a compound 2; compound 1 isCompound 2 isR 1 Is C 1‑3 Alkyl, R 2 Is C 1‑3 Alkyl, R 3 Is C 1‑3 An alkyl group; (2) And (3) carrying out hydrolysis reaction on the compound 2 and alkali to obtain the 2-methylcyclopropyl carboxylic acid. The method avoids the reaction of high Wen Fengguan at 150 ℃, the whole operation does not need airtight reaction, is convenient, safe and efficient,can achieve kilogram scale amplification, has high product yield and purity and wide application prospect.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing 2-methylcyclopropyl carboxylic acid.
Background
2-methyl cyclopropane carboxylic acid is a molecular building block compound and is an important intermediate for medical synthesis. Many drugs have fragments of 2-methylcyclopropane carboxylic acid, such as compound a reported in patent application WO2022/60836, which can be used to treat cancer.
At present, some methods for preparing 2-methylcyclopropane carboxylic acid have been reported, but these methods have problems such as more synthesis steps (Tetrahedron lett.1998,39,4311), limited enantioselectivity (Journal of Molecular Catalysis B: enzymic. 2002,18,267), use of expensive chiral auxiliary (Journal of the Chemical Society Perkin Transactions 1, 1994,461), lower overall yield, and the like.
To solve the above problems, document (Organic Process Research & Development,2007, 11 (4), 689-692) reports an improved synthesis method, which operates as follows: triethyl phosphorylacetate (4.5 g,19.7 mmol) was dissolved in anhydrous 2-methyltetrahydrofuran (40 mL) under nitrogen protection, the temperature was controlled at 19-25℃and n-hexyllithium (2.3M in n-hexane, 8mL,18.4 mmol) was added dropwise. After 30 minutes of reaction, (S) -propylene oxide (1.17 g,20.2 mmol) was added, and the reaction solution was transferred to a 160mL stainless steel autoclave. The temperature was raised to 150℃over 15 minutes and kept at 150℃for 16 hours. Water (50 mL) and 30% aqueous NaOH were added and the mixture refluxed for 5h. The aqueous phase was separated, concentrated hydrochloric acid (25 mL) was added, the mixture was extracted with isopropyl acetate (2X 50 mL), the organic phase was combined and washed with 10% aqueous sodium chloride (3X 25 mL), and the organic phase was concentrated to give 1.7g of a colorless oil. Crude (R, R) -2-methylcyclopropene carboxylic acid is purified using dicyclohexylamine as salt. However, on one hand, the synthesis method needs to be heated to 150 ℃ in a short time (15 minutes), and needs to be subjected to a long-time high-temperature airtight reaction in a stainless steel autoclave, so that the operation is inconvenient, and a great potential safety hazard exists; on the other hand, the synthesis method can only achieve gram scale and cannot realize large-scale production. Thus, there is a need for a new, safely scalable process for the synthesis of 2-methylcyclopropane carboxylic acids.
Disclosure of Invention
The invention aims to provide a method for preparing 2-methyl cyclopropanecarboxylic acid, which avoids the high Wen Fengguan reaction at 150 ℃ and can be amplified.
The invention provides a method for preparing 2-methyl cyclopropanecarboxylic acid, which comprises the following steps:
(1) Uniformly mixing the compound 1, alkali and a solvent in a reaction container, heating to reflux, adding propylene oxide below the liquid level, and reacting to obtain a compound 2; compound 1 isCompound 2 is->R 1 Is C 1-3 Alkyl, R 2 Is C 1-3 Alkyl, R 3 Is C 1-3 An alkyl group;
(2) And (3) carrying out hydrolysis reaction on the compound 2 and alkali to obtain the 2-methylcyclopropyl carboxylic acid.
Further, in step (1), the equivalent ratio of the compound 1 to propylene oxide is 1: (0.8-1.6);
the base is alkyl lithium, and the equivalent ratio of the compound 1 to the base is 1: (0.6-1.4);
the solvent is an organic solvent, and the mass volume ratio of the compound 1 to the solvent is 1g: (3-9) mL;
the reaction temperature is 65-80 ℃, and the reaction time is more than 8 hours.
Further, in step (1), the equivalent ratio of the compound 1 to propylene oxide is 1:1.17;
the base is n-butyllithium, and the equivalent ratio of the compound 1 to the base is 1:1.05;
the organic solvent is one or a mixture of two of 1,4 dioxane and n-hexane, and the mass volume ratio of the compound 1 to the solvent is 1g: (5-7) mL;
the reaction temperature is 70 ℃, and the reaction time is 12-16 hours.
Further, in the step (1), propylene oxide is added at a flow rate of 30-120mL/h.
Further, in the step (1), propylene oxide is added at a flow rate of 50-100mL/h.
Further, in step (2), the equivalent ratio of compound 1 to base is 1: (2-6), wherein the base is an inorganic base;
the solvent for the reaction is a mixed solution of an organic solvent and water;
the reaction temperature is 40-90 ℃, and the reaction time is 1-4 hours.
Further, in step (2), the equivalent ratio of compound 1 to base is 1: (3.36-4.48), wherein the alkali is sodium hydroxide;
the organic solvent is one or a mixture of two of 1,4 dioxane and n-hexane;
the reaction temperature is 70-80 ℃ and the reaction time is 2 hours.
Further, after the reaction in the step (2) is finished, the method further comprises the following purification steps: extracting with water and dichloromethane, separating, collecting water phase, adjusting pH to 1-2, extracting with methyl tert-butyl ether, separating, collecting organic phase, concentrating, and distilling under reduced pressure to obtain 2-methylcyclopropyl carboxylic acid.
Further, the R 1 Is ethyl, R 2 Is ethyl, R 3 Is ethyl.
Further, the propylene oxide isCompound 2 is->2-methylcyclopropionic acid as the main ingredient
Alternatively, the propylene oxide isCompound 2 is->2-methylcyclopropanecarboxylic acid is +.>
Alternatively, the propylene oxide isCompound 2 is->2-methylcyclopropanecarboxylic acid is +.>
The invention provides a method for preparing 2-methyl cyclopropanecarboxylic acid in an amplifying way, in the operation of the method, propylene oxide is slowly added below the liquid level in a reflux state, the high Wen Fengguan reaction at 150 ℃ is avoided, the whole operation does not need a closed reaction, and the method is convenient, safe and efficient, can achieve kilogram-level amplification, has high product yield and purity, and has wide application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 shows the results of a gas chromatograph-mass spectrometer (GCMS) test of trans-2-methylcyclopropionic acid obtained in example 1.
FIG. 2 shows the nuclear magnetic resonance hydrogen spectrum of trans-2-methylcyclopropionic acid obtained in example 1.
FIG. 3 shows the results of CHIRAL purity (CHIRAL-GC) testing of trans-2-methylcyclopropionic acid obtained in example 1.
FIG. 4 shows the GCMS test result of (S, S) -2-methylcyclopropane carboxylic acid obtained in example 2.
FIG. 5 shows nuclear magnetic resonance hydrogen spectrum of (S, S) -2-methylcyclopropane carboxylic acid obtained in example 2.
FIG. 6. CHIRAL-GC test results for (S, S) -2-methylcyclopropane carboxylic acid obtained in example 2.
FIG. 7 shows the GCMS test results of (R, R) -2-methylcyclopropane carboxylic acid obtained in example 3.
FIG. 8 shows nuclear magnetic resonance hydrogen spectra of (R, R) -2-methylcyclopropane carboxylic acid obtained in example 3.
FIG. 9 shows the results of CHIRAL-GC test of (R, R) -2-methylcyclopropane carboxylic acid obtained in example 3.
FIG. 10 shows the GCMS test result of (S, S) -2-methylcyclopropane carboxylic acid obtained in comparative example 1.
FIG. 11 shows nuclear magnetic resonance hydrogen spectra of (S, S) -2-methylcyclopropane carboxylic acid obtained in comparative example 1.
FIG. 12 shows the results of CHIRAL-GC test of (S, S) -2-methylcyclopropane carboxylic acid obtained in comparative example 1.
FIG. 13 shows the GCMS test result of (S, S) -2-methylcyclopropane carboxylic acid obtained in comparative example 2.
FIG. 14 shows nuclear magnetic resonance hydrogen spectra of (S, S) -2-methylcyclopropane carboxylic acid obtained in comparative example 2.
FIG. 15 shows the results of CHIRAL-GC test of (S, S) -2-methylcyclopropane carboxylic acid obtained in comparative example 2.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The operation of the examples of the present invention was carried out at room temperature of 25.+ -. 5 ℃ unless otherwise specified. Overnight refers to a reaction time of 12-16 hours.
Example 1: process for preparing trans-2-methylcyclopropionic acid
To a 10L reactor was added triethyl phosphorylacetate (800 g,3.57mol,1.0 eq) under nitrogen and ultra-dry 1,4 dioxane (4000 mL). N-hexane solution (2.5M, 1500mL,3.75mol,1.05 eq) of n-butyllithium (n-BuLi) was slowly added dropwise at 10℃for 1h, and after stabilizing the temperature, the temperature was raised to 20℃and the reaction was continued for 1h. Then, the temperature was raised to 70℃and the mixture was refluxed, propylene oxide (242.4 g,4.18mol,1.17 eq) was slowly added by a peristaltic pump, and the feeding tube was inserted below the liquid surface at a flow rate of 100mL/h, and the addition was completed in three hours. The reaction was continued at 70℃overnight and monitored by GCMS for completion. Then, the temperature was lowered to 20℃and a 30% aqueous NaOH solution (this solution was obtained by dissolving 480g of NaOH (12 mol,3.36 eq) in 1200ml of water) was slowly added dropwise; the temperature is raised to 70 ℃ for reaction for 2 hours. GCMS monitored the reaction was complete. Cooled to room temperature, 4000mL of water was added, extracted with dichloromethane (3X 1500 mL), the solution was separated, and the aqueous phase was collected. Lowering to 20 ℃, adjusting ph=1-2 with concentrated hydrochloric acid, extracting with methyl tert-butyl ether (3×1500 mL), collecting the organic phase; the organic phases were combined and concentrated to 310g (yield=86.7%) of a yellow oil. Vacuum distillation with oil pump (vacuum: -1700Pa, temperature: 85 ℃) gave 218g of colorless oil as trans-2-methylcyclopropionic acid, GCMS purity= 96.16%, yield=61%.
Example 2: process for preparing (S, S) -2-methylcyclopropane carboxylic acid
To a 5L jacketed kettle under nitrogen protection was added triethyl phosphorylacetate (400 g,1.79mol,1 eq), molecular sieve dried 1, 4-dioxane (2000 mL) was added, stirred to clarify, and the system was cooled to 10 ℃. N-butyllithium in n-hexane (2.5M, 750mL,1.88mol,1.05 eq) was slowly added dropwise, and after stabilizing the temperature, the reaction was carried out at 20℃for 1h. Then heating to reflux 70 ℃, slowly adding (R) -propylene oxide (121.2 g,2.09mol,1.17 eq) by a syringe pump, inserting a syringe pump needle into the bottom of the liquid level, setting the flow rate to be 50mL/h, continuing to control the temperature to 70 ℃ after the addition is finished, reacting overnight, and monitoring the reaction to be complete by GCMS. Then the temperature is reduced to 10 ℃. 800mL of 30% NaOH aqueous solution was slowly added dropwise, the temperature was raised to 70℃and the reaction was refluxed for 2 hours, and the completion of the reaction was monitored by GCMS. Cooling the system to room temperature, separating liquid, collecting water phase, and extracting with dichloromethane (2×1L); cooling the water phase to 10 ℃, and slowly dropwise adding concentrated hydrochloric acid to adjust the pH value to be 1-2; the aqueous phase was extracted with methyl tert-butyl ether (3X 1L) and the organic phase was collected; the organic phases were combined and concentrated by drying to give 191.7g of crude product as a pale yellow oil. The mixture was distilled under reduced pressure (vacuum: about-1500 Pa, temperature: 80 ℃ C.) by an oil pump to obtain 101.3g of colorless oil which was (S, S) -2-methylcyclopropane carboxylic acid. GCMS purity = 98.25%, e.e. = 99.28%, yield = 56.7%.
Example 3: process for preparing (R, R) -2-methylcyclopropanecarboxylic acid
To a 10L reactor was added triethyl phosphorylacetate (800 g,3.57mol,1.0 eq) under nitrogen, and ultra-dry 1,4 dioxane (4000 mL) was added and stirred for clarification. The system was cooled to 10 ℃. N-butyllithium in n-hexane (2.5M, 1500mL,3.75mol,1.05 eq) was slowly added dropwise. After the temperature is stable, the temperature is raised to 20 ℃ for reaction for 1h. Heating to 70 ℃ and refluxing. (S) -propylene oxide (242.4 g,4.18mol,1.17 eq) was slowly added by peristaltic pump, the flow rate was 100mL/h, the addition tube was inserted into the bottom of the liquid surface, the reaction was continued at 70℃overnight (solid formed) after the addition was completed, and GCMS monitored the reaction was complete. Then the temperature is reduced to 10 ℃, 1600mL of 30% NaOH aqueous solution is slowly added dropwise. The reaction was heated to 70℃and refluxed for 2 hours, and the GCMS was monitored to be complete. The system was cooled to room temperature, 4000mL of water was added and extracted with dichloromethane (3X 1500 mL); separating liquid and collecting water phase; cooling the water phase to 10 ℃, and slowly dropwise adding concentrated hydrochloric acid to adjust the pH value to be 1-2; the aqueous phase was extracted with methyl tert-butyl ether (3X 1.5L) and the organic phase was collected; the organic phases were combined and concentrated by drying to give 443.3g of crude product as a pale yellow oil. Distillation under reduced pressure with an oil pump (vacuum: -1500Pa or so, temperature: 80 ℃) gave 227.8g of colorless oil as (R, R) -2-methylcyclopropanecarboxylic acid, GCMS purity=97.5%, e.e. =96.82%, yield=63.8%.
The following is a comparative example for the preparation of (S, S) -2-methylcyclopropane carboxylic acid.
Comparative example 1: process for preparing (S, S) -2-methylcyclopropane carboxylic acid
The preparation of (S, S) -2-methylcyclopropanecarboxylic acid is described in reference (Organic Process Research & Development,2007, 11 (4), 689-692) by the following procedure:
triethyl phosphorylacetate (45 g,0.201mol,1.09 eq) was dissolved in dry 2-methyltetrahydrofuran (360 mL) at room temperature under nitrogen protection, a temperature was controlled at 25 ℃, and a n-hexane solution (2.3M, 80mL,0.184mol,1.0 eq) of n-hexyllithium (n-HexLi) was added dropwise to the reaction system, followed by stirring at room temperature for 30 minutes. (R) -propylene oxide (11.7 g,0.202mol,1.09 eq) was added at room temperature, the reaction solution was transferred to a dry 1000mL autoclave, and the autoclave was placed in an oil bath at 150℃and stirred overnight. GCMS monitored the reaction was complete. The reaction vessel was cooled to room temperature, water (70 mL) and 30% aqueous NaOH solution (200 mL) were added, the reaction was continued at 100℃for 5h, the temperature was cooled to room temperature, the solution was separated, the aqueous phase was collected and cooled to 10℃and concentrated hydrochloric acid (200 mL) was added dropwise, and the aqueous phase was extracted with ethyl acetate (3X 200 mL). The combined organic phases were washed with saturated aqueous NaCl (2X 200 mL), anhydrous NaSO 4 Dried and concentrated to give 18.5g (crude) of a pale yellow oily liquid. The crude product was dissolved in ethyl acetate (150 mL), dicyclohexylamine (30.1, 0.166mol,0.9 eq) was added dropwise at room temperature, the reaction was stirred overnight, filtered, the filter cake was washed with ethyl acetate (2X 30 mL) and diethyl ether (2X 30 mL), then the filter cake was dissolved in water (100 mL), and concentrated sulfuric acid was added dropwise to the reaction flask at room temperature until the pH was 1-2; extraction with methyl tert-butyl ether (3X 100 mL) and washing of the organic phase with saturated aqueous NaCl solution (100 mL)Anhydrous NaSO 4 Dried and concentrated to give 8.4g of a colorless oily liquid. GCMS purity = 96.6%, e.e.>99%, yield=45.7%.
It can be seen that, compared with the method for preparing (S, S) -2-methylcyclopropane carboxylic acid in comparative example 1, the method for preparing (S, S) -2-methylcyclopropane carboxylic acid in example 2 of the present invention not only avoids the high Wen Fengguan reaction at 150 ℃, improves the operation safety and convenience, but also can achieve kilogram-level amplification, and simultaneously improves the yield and purity of the product (S, S) -2-methylcyclopropane carboxylic acid.
Comparative example 2: process for preparing (S, S) -2-methylcyclopropane carboxylic acid
Triethyl phosphorylacetate (115 g, 0.313 mol,1 eq) and ultra-dry 1, 4-dioxane (1500 mL) were added to a 3L three-necked flask under the protection of nitrogen, stirred and clarified, and n-BuLi n-hexane solution (2.3M, 235mL,0.54mol,1.05 eq) was added dropwise to the reaction system at a temperature of 10-20℃with ice water, followed by stirring and reaction at room temperature for 30min. The reaction flask was transferred to an oil bath, the oil bath was heated to 90℃and refluxed, the condenser was cooled to 0℃and (R) -propylene oxide (35 g,0.613mol,1.17 eq) was added below the liquid surface with a syringe pump, the flow rate was set at 20mL/h, and after the completion of the dropwise addition, the reflux reaction was continued overnight. GCMS monitored the reaction was complete. Naturally cooling to room temperature, slowly dropwise adding 30% NaOH aqueous solution (600 mL), heating to 90 ℃ for continuous reaction for 5h, cooling to room temperature, separating liquid, collecting water phase, cooling to 10 ℃, dropwise adding concentrated hydrochloric acid (400 mL) to adjust pH=1, and extracting the water phase with ethyl acetate (3×500 mL). The combined organic phases were washed with saturated aqueous NaCl (2X 500 mL), anhydrous NaSO 4 Dried and concentrated to give 50g (crude) of a pale yellow oily liquid. The crude product was dissolved in ethyl acetate (400 mL), dicyclohexylamine (81.3, 0.45mol,0.9 eq) was added dropwise at room temperature, stirred overnight, filtered, the filter cake was washed with ethyl acetate (2X 100 mL) and diethyl ether (2X 100 mL), then the filter cake was dissolved in water (400 mL), and concentrated sulfuric acid was added dropwise to the reaction flask at room temperature until the pH was 1-2; extraction with methyl tert-butyl ether (3X 500 mL), washing of the organic phase with saturated aqueous NaCl solution (500 mL), anhydrous NaSO 4 Dried and concentrated to give 19.2g of a colourless oily liquid. GCMS purity = 95.2%, e.e.>99%, yield=37.4%.
It can be seen that, compared with the method of preparing (S, S) -2-methylcyclopropane carboxylic acid of comparative example 2, the method of preparing (S, S) -2-methylcyclopropane carboxylic acid of example 2 of the present invention allows the product (S,
the yield and purity of the S) -2-methyl cyclopropanecarboxylic acid are improved.
In summary, the invention provides a method for preparing 2-methylcyclopropyl carboxylic acid, which avoids the reaction at the temperature of 150 ℃ and is Wen Fengguan, the whole operation does not need airtight reaction, the method is convenient, safe and efficient, kilogram-level amplification can be realized, the product yield and purity are high, and the application prospect is wide.
Claims (10)
1. A process for preparing 2-methylcyclopropane carboxylic acid, the process comprising the steps of:
(1) Uniformly mixing the compound 1, alkali and a solvent in a reaction container, heating to reflux, adding propylene oxide below the liquid level, and reacting to obtain a compound 2; compound 1 isCompound 2 is->R 1 Is C 1-3 Alkyl, R 2 Is C 1-3 Alkyl, R 3 Is C 1-3 An alkyl group;
(2) And (3) carrying out hydrolysis reaction on the compound 2 and alkali to obtain the 2-methylcyclopropyl carboxylic acid.
2. The method of claim 1, wherein in step (1), the equivalent ratio of compound 1 to propylene oxide is 1: (0.8-1.6);
the base is alkyl lithium, and the equivalent ratio of the compound 1 to the base is 1: (0.6-1.4);
the solvent is an organic solvent, and the mass volume ratio of the compound 1 to the solvent is 1g: (3-9) mL;
the reaction temperature is 65-80 ℃, and the reaction time is more than 8 hours.
3. The method of claim 2, wherein in step (1), the equivalent ratio of compound 1 to propylene oxide is 1:1.17;
the base is n-butyllithium, and the equivalent ratio of the compound 1 to the base is 1:1.05;
the organic solvent is one or a mixture of two of 1,4 dioxane and n-hexane, and the mass volume ratio of the compound 1 to the solvent is 1g: (5-7) mL;
the reaction temperature is 70 ℃, and the reaction time is 12-16 hours.
4. The process of claim 1, wherein in step (1), propylene oxide is added at a flow rate of 30 to 120mL/h.
5. The process of claim 4, wherein in step (1), propylene oxide is added at a flow rate of 50 to 100mL/h.
6. The process of claim 1, wherein in step (2), the equivalent ratio of compound 1 to base is 1: (2-6), wherein the base is an inorganic base;
the solvent for the reaction is a mixed solution of an organic solvent and water;
the reaction temperature is 40-90 ℃, and the reaction time is 1-4 hours.
7. The method of claim 6, wherein in step (2), the equivalent ratio of compound 1 to base is 1: (3.36-4.48), wherein the alkali is sodium hydroxide;
the organic solvent is one or a mixture of two of 1,4 dioxane and n-hexane;
the reaction temperature is 70-80 ℃ and the reaction time is 2 hours.
8. The method of claim 1, further comprising the following purification steps after the reaction of step (2) is completed: extracting with water and dichloromethane, separating, collecting water phase, adjusting pH to 1-2, extracting with methyl tert-butyl ether, separating, collecting organic phase, concentrating, and distilling under reduced pressure to obtain 2-methylcyclopropyl carboxylic acid.
9. The method of any one of claims 1-8, wherein R 1 Is ethyl, R 2 Is ethyl, R 3 Is ethyl.
10. The method of claim 9, wherein the propylene oxide isCompound 2 is2-methylcyclopropanecarboxylic acid is +.>
Alternatively, the propylene oxide isCompound 2 is->2-methylcyclopropanecarboxylic acid is +.>
Alternatively, the propylene oxide isCompound 2 is->2-methylcyclopropanecarboxylic acid is +.>
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311472803.2A CN117567266A (en) | 2023-11-07 | 2023-11-07 | Method for preparing 2-methylcyclopropyl carboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311472803.2A CN117567266A (en) | 2023-11-07 | 2023-11-07 | Method for preparing 2-methylcyclopropyl carboxylic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117567266A true CN117567266A (en) | 2024-02-20 |
Family
ID=89859832
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311472803.2A Pending CN117567266A (en) | 2023-11-07 | 2023-11-07 | Method for preparing 2-methylcyclopropyl carboxylic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117567266A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101466691A (en) * | 2006-06-08 | 2009-06-24 | 伊莱利利公司 | Substituted carboxamides as group I metabotropic receptor antagonists |
| CN103429582A (en) * | 2011-03-04 | 2013-12-04 | 莱西肯医药有限公司 | MST1 kinase inhibitors and method of use thereof |
-
2023
- 2023-11-07 CN CN202311472803.2A patent/CN117567266A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101466691A (en) * | 2006-06-08 | 2009-06-24 | 伊莱利利公司 | Substituted carboxamides as group I metabotropic receptor antagonists |
| CN103429582A (en) * | 2011-03-04 | 2013-12-04 | 莱西肯医药有限公司 | MST1 kinase inhibitors and method of use thereof |
Non-Patent Citations (2)
| Title |
|---|
| BARTON, LISA M. 等: "Electrochemical borylation of carboxylic acids", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA》, vol. 118, no. 34, 17 August 2021 (2021-08-17), pages 1 - 7 * |
| DELHAYE, LAURENT 等: "A Short and Efficient Synthesis of (R, R)-2-Methylcyclopropanecarboxylic Acid", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》, vol. 11, no. 4, 13 June 2007 (2007-06-13), pages 689 - 692 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CZ278978B6 (en) | Diethers used in the preparation of ziegler-natt catalysts | |
| US8134034B2 (en) | Recovery of bis(diarylphenol) ligands during the production of isopulegol | |
| EP2059493B1 (en) | Recovery of phenol ligands during the production of isopulegol | |
| CN102336723B (en) | Preparation method of L-chloperastine fendizoic acid | |
| CN117567266A (en) | Method for preparing 2-methylcyclopropyl carboxylic acid | |
| CN106674112A (en) | Synthetic methods of 7-azaspiro[3,5]-nonane-2-ol and hydrochloride compound thereof | |
| EP0270724A1 (en) | Preparation of alkyl trifluoroacetoacetate | |
| CA1157037A (en) | Cis-6-undecene-1-chloride and a method for the preparation thereof | |
| CN102391083B (en) | Method for synthesizing decyl acetal aldehyde | |
| CN105622350B (en) | A kind of synthetic method of RV | |
| CN114409505A (en) | Preparation method of posaconazole intermediate | |
| US7388103B2 (en) | Cyclopentane carboxylate compounds, process and intermediates for preparing the same and use thereof | |
| CN112209825B (en) | Synthetic method of 3-ethoxy-4-ethoxycarbonylphenylacetic acid | |
| RU2797603C1 (en) | Method of obtaining 1-bromomethyl-4-chloromethylbenzene | |
| Croft et al. | Convenient synthesis of medium-ring cis-1, 2-dichlorocycloalkanes | |
| CN111039849B (en) | Preparation method of carbazole ring-containing compound | |
| JPH0549657B2 (en) | ||
| JP2697198B2 (en) | Method for producing 2-hydroxy-3,3,3-trifluoropropionitrile | |
| CN111470959A (en) | Industrial production process of melonal | |
| JP2808788B2 (en) | Method for producing α-perfluoroalkyl acrylonitrile | |
| CN115872935A (en) | Synthesis method of 1, 3-dialkyl imidazole dicyanamide salt ionic liquid | |
| RU1213723C (en) | Dialkydicyclohexyl-18-crown-6 as extracting agents of potassium, mercury, iron, lead, indium, thallium, gallium and strontium from solutions | |
| JP3892137B2 (en) | Tetrakis (fluoroaryl) borate ether complex and method for producing the same | |
| CN116903493A (en) | Method for synthesizing polysubstituted o-phenylphenol compound through nucleophilic reaction ring opening of dibenzofuran | |
| CN117903202A (en) | Water-compatible temperature-sensitive ionic liquid and application thereof in preparation of 5-hydroxymethylfurfural |
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 |