CN115477576A - Preparation method of caronic acid - Google Patents
Preparation method of caronic acid Download PDFInfo
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- CN115477576A CN115477576A CN202210933921.8A CN202210933921A CN115477576A CN 115477576 A CN115477576 A CN 115477576A CN 202210933921 A CN202210933921 A CN 202210933921A CN 115477576 A CN115477576 A CN 115477576A
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- MSPJNHHBNOLHOC-UHFFFAOYSA-N 3,3-dimethylcyclopropane-1,2-dicarboxylic acid Chemical compound CC1(C)C(C(O)=O)C1C(O)=O MSPJNHHBNOLHOC-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- 238000000034 method Methods 0.000 claims abstract description 27
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000463 material Substances 0.000 claims abstract description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 21
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 18
- 238000007363 ring formation reaction Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000013067 intermediate product Substances 0.000 claims description 3
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 3
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000013590 bulk material Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000001816 cooling Methods 0.000 description 18
- 239000007791 liquid phase Substances 0.000 description 11
- 239000006227 byproduct Substances 0.000 description 9
- 238000010587 phase diagram Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000007086 side reaction Methods 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 4
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000007259 addition reaction Methods 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- -1 ethoxycarbonylmethyl Chemical group 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- ZGHFDIIVVIFNPS-UHFFFAOYSA-N 3-Methyl-3-buten-2-one Chemical compound CC(=C)C(C)=O ZGHFDIIVVIFNPS-UHFFFAOYSA-N 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- VIMXTGUGWLAOFZ-UHFFFAOYSA-N ethyl 2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropane-1-carboxylate Chemical group CCOC(=O)C1C(C=C(C)C)C1(C)C VIMXTGUGWLAOFZ-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- 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
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of medicines, and discloses a preparation method of caronic acid. The method takes a bulk material 3,3-methyl dimethacrylate and methyl chloroacetate as raw materials, and key intermediate diethyl caronate is obtained through reaction; then the caronic acid is obtained through hydrolysis reaction. The method has the advantages of simple and safe operation, cheap and easily obtained materials, mild reaction conditions and industrial advantage.
Description
Technical Field
The invention relates to the technical field of medicines, and relates to a preparation method of caronic acid.
Background
Carronoic acid, also called caronic acid, is originally mainly used for producing hepatitis C protease inhibitor, is an important intermediate for synthesizing 3CL protease inhibitor nemadevir (PF-07321332) at present, and has huge market demand with the development of new coronary epidemic situation, but the current route for synthesizing the caronic acid has certain technical defects.
The general synthetic route for caronic acid is as follows:
the starting material of the route is ethyl chrysanthemate, the number of manufacturers is small, the price is high, potassium permanganate is adopted for oxidation in the first step, the process risk coefficient is high, and a large amount of manganese-containing waste residues are difficult to treat, so that the environmental pollution is caused.
CN102070575A discloses a method for synthesizing caronic acid by a three-step method, wherein in the first step, methyl isobutenone is used as a raw material to perform an addition reaction with (ethoxycarbonylmethyl) dimethyl sulfide ylide. The process is relatively complex, the raw material price is relatively high, the sulfur ylide has strong pungent smell, and the industrial production has large influence on the environment and does not meet the requirement of environmental protection.
Therefore, the method for synthesizing the caronic acid is developed to overcome the defects of the prior art, and has very important significance for realizing industrialization of the medicine.
Disclosure of Invention
In order to overcome the technical problems of high cost for obtaining starting materials, complicated production process, high risk and environmental pollution in the prior art, the invention provides a preparation method of caronic acid, which has the advantages of cheap and easily obtained materials, mild reaction conditions, innovative synthesis of key three-membered rings in the process, industrial advantages and overcoming the technical problems in the prior art.
The specific technical scheme of the invention is as follows:
a preparation method of caronic acid is characterized by comprising the following steps: under the strong alkali condition, carrying out addition cyclization reaction on a compound I and a compound II to obtain a compound III, and synthesizing caronic acid through hydrolysis reaction; the reaction route is as follows:
the method has the advantages of simple and safe operation, cheap and easily obtained materials, mild reaction conditions, innovative synthesis of key three-membered rings in process and industrial advantages.
Preferably, the preparation method specifically comprises the following steps:
(1) Adding methyl chloroacetate, 3,3-methyl dimethacrylate and a solvent into a reaction vessel, adding strong base, stirring uniformly, carrying out addition cyclization reaction to obtain an intermediate product of diethyl caronate, and removing the solvent after the reaction is finished; the reaction route is as follows:
under the action of strong alkali, the alpha-carbon on the methyl chloroacetate (II) loses proton to generate stable carbanion; then, the carbon-carbon double bond of 3,3-methyl dimethacrylate (I) is subjected to addition reaction to obtain a new carbanion, the negative charge of the carbanion attacks alpha-carbon by an intramolecular SN2 mechanism, and chloride ions leave to form a ternary ring structure. The specific reaction mechanism is as follows:
(2) Adding water into the obtained material, heating for hydrolysis reaction, and extracting to obtain white solid caronic acid after the reaction is finished; the reaction route is as follows:
preferably, in the step (1), the temperature of the addition cyclization reaction is-20 to 10 ℃.
More preferably, in the step (1), the temperature of the addition cyclization reaction is from-10 to-0.5 ℃.
Based on theoretical research and experiments, the team of the invention discovers that when the reaction temperature is higher than 10 ℃, side reaction is increased, and methyl chloroacetate (the compound in the formula II) is easy to generate side reaction with strong base to generate the compound by-product in the formula V. Based on this, the invention controls the temperature of addition cyclization reaction between-10 ℃ and-0.5 ℃, can obtain higher reaction rate, simultaneously controls and reduces the formation of by-products, and improves the reaction conversion rate and the product purity.
Preferably, in step (1), the strong base is one of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide and potassium tert-butoxide; the solvent is one of methanol, ethanol, isopropanol and tert-butanol corresponding to strong base.
More preferably, in step (1), the strong base is sodium methoxide; the solvent is methanol.
Based on theoretical research and experiments, the team of the invention finds that when the strong base is sodium methoxide and the corresponding reaction solvent is methanol, ester exchange reaction does not occur in the reaction process because the two raw materials (the compound shown in the formula I and the compound shown in the formula II) are methyl ester, the conversion rate is high, and the number of byproducts is small. Also, the choice of sodium methoxide can improve the product purity compared to sodium hydroxide, because: sodium hydroxide has too low solubility in organic solvents, the reaction is slow, the required reaction time is longer, the temperature conditions are more severe, and more by-products, such as compound V, are produced.
Preferably, in the step (2), the extraction is carried out by dropping hydrochloric acid to adjust the pH value to precipitate crystals.
More preferably, in the step (2), hydrochloric acid is added dropwise to adjust the pH to 0 to 1, and crystals are precipitated.
Based on product property research and experiments, the team of the invention finds that after the hydrolysis reaction is finished, the pH value of the solution is controlled to directly obtain the caronic acid product, no additional operations such as extraction are needed, the highest yield of the product can be obtained by controlling the pH value to be 0-1, and when the pH value is too high, the caronic acid is partially dissolved in the solution and can not be separated out, so that the yield is reduced.
According to the invention, the operation of the step (2) is to directly add water into the material obtained in the step (1), heat up for hydrolysis reaction, adjust the pH value to 0-1 to obtain the caronic acid in the second step, and synthesize the caronic acid by adopting a one-pot method, the intermediate diethyl caronic acid in the first step does not need any separation, extraction and purification operation, and the method has the characteristics of simple operation and high yield, and is less in industrial amplification equipment requirement, convenient to operate, easy to amplify and produce.
Compared with the prior art, the invention has the following advantages:
1. the invention provides a new synthesis method of caronic acid, which has the innovation point that alpha-carbon on methyl chloroacetate (II) loses protons under the action of strong alkali to generate stable carbanions, the stable carbanions and carbon-carbon double bonds on 3,3-methyl dimethacrylate (I) are subjected to addition reaction to obtain new carbanions, and negative charges of the carbanions attack alpha-carbon by an intramolecular SN2 mechanism and leave chloride ions to form a key three-membered ring structure in caronic acid molecules.
2. The method synthesizes diethyl caronate by using 3,3-methyl dimethacrylate (I) and methyl chloroacetate (II) to synthesize caronic acid, and further synthesize caronic acid, and has the characteristics of cheap and easily obtained starting materials, mild conditions, simple process, safety, environmental protection and easy industrialization.
3. The method for synthesizing the caronic acid by the one-pot method has the characteristics of simple operation, high yield and easy industrialization.
4. The caronic acid is obtained by a method of controlling the pH value crystallization, and the complex operations of extraction, washing and the like in the conventional technology are avoided.
Drawings
FIG. 1 is a liquid phase diagram of caronic acid from example 1.
FIG. 2 is a Caronic acid LC-MS spectrum of example 1.
FIG. 3 is a liquid phase diagram of caronic acid from example 2.
FIG. 4 is a liquid phase diagram of Caronic acid of comparative example 2.
FIG. 5 is a liquid phase diagram of Caronic acid of comparative example 1.
FIG. 6 is a liquid phase diagram of Caronic acid of comparative example 3.
Detailed Description
The present invention will be further described with reference to the following examples, but the present invention is not limited thereto.
General examples
A preparation method of caronic acid specifically comprises the following steps:
(1) Adding methyl chloroacetate, 3,3-methyl dimethacrylate and a solvent into a reaction vessel, adding strong base, stirring uniformly, carrying out addition cyclization reaction to obtain an intermediate product of diethyl caronate, and removing the solvent after the reaction is finished; the reaction route is as follows:
(2) Adding water into the obtained material, heating for hydrolysis reaction, and extracting to obtain white solid caronic acid after the reaction is finished; the reaction route is as follows:
preferably, in the step (1), the temperature of the addition cyclization reaction is-20 to 10 ℃.
More preferably, the temperature of the addition cyclization reaction is from-10 to-0.5 ℃.
Preferably, in the step (1), the strong base is one of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide and potassium tert-butoxide; the solvent is one of methanol, ethanol, isopropanol and tert-butanol corresponding to strong base.
More preferably, in step (1), the strong base is sodium methoxide and the solvent is methanol.
Preferably, in the step (2), the extraction is carried out by dropping hydrochloric acid to adjust the pH value to precipitate crystals.
More preferably, in the step (2), hydrochloric acid is added dropwise to adjust the pH to 0 to 1, and crystals are precipitated.
Example 1
Adding 50g of methyl chloroacetate (II) and 105ml of 30% sodium methoxide methanol solution into a reaction bottle, uniformly mixing and stirring, cooling to 0 ℃, dropwise adding 50g of 3,3-methyl dimethacrylate (I), and controlling the temperature to be-10 to-0.5 ℃. After the dripping is finished, the temperature range is kept for continuous reaction for 4 hours, after the reaction is finished, the feed liquid is decompressed and concentrated to be dry, and the obtained material is directly used for the next step. The reaction route is as follows:
200ml of water is added into the obtained material, the mixture is heated to 65 ℃, and the reflux reaction is carried out for 2 hours. After the reaction is finished, cooling to 0-20 ℃, dropwise adding concentrated hydrochloric acid, adjusting the pH = 0-1, cooling to 0-5 ℃, preserving the temperature for 2h, filtering, and drying to obtain a white solid. The reaction route is as follows:
59.6g of the product, carbazolonic acid white solid (theoretical yield 69.3 g), yield 86%. The liquid phase spectrum of the caronic acid is shown in figure 1, and the LC-MS spectrum is shown in figure 2. The retention time of 5.025min is the peak emergence time of the caronic acid, and the purity of the caronic acid is 99.8 percent.
Example 2
Adding 25g of methyl chloroacetate (II) and 110ml of 30% sodium ethoxide ethanol solution into a reaction bottle, mixing and stirring uniformly, cooling to 0 ℃, dropwise adding 25g of 3,3-methyl dimethacrylate (I), and controlling the temperature to be-10 to-0.5 ℃. After the dripping is finished, the temperature range is kept for continuous reaction for 4 hours, after the reaction is finished, the feed liquid is decompressed and concentrated to be dry, and the obtained material is directly used for the next step. The reaction route is as follows:
200ml of water is added into the obtained material, the mixture is heated to 65 ℃, and the reflux reaction is carried out for 2 hours. After the reaction is finished, cooling to 0-20 ℃, dropwise adding concentrated hydrochloric acid, adjusting the pH = 0-1, cooling to 0-5 ℃, preserving the temperature for 2h, filtering, and drying to obtain a white solid. The reaction route is as follows:
the product, caronic acid, is a white solid 28.1g (theoretical yield 34.7 g), yield 81%, purity 99.2%. The liquid phase diagram of caronic acid is shown in figure 3.
From the comparison of example 1, it can be seen that when the strong base used was sodium ethoxide and the reaction solvent was ethanol, the yield was low, presumably because, when the strong base was sodium methoxide and the corresponding reaction solvent was methanol, transesterification did not occur during the reaction because both raw materials (the compound of formula I and the compound of formula II) were methyl esters, the conversion was high, and the by-products were few.
Example 3
Adding 10g of methyl chloroacetate (II), 6g of sodium hydroxide and 20ml of methanol into a reaction bottle, uniformly mixing and stirring, cooling to 0 ℃, dropwise adding 10g of 3,3-methyl dimethacrylate (I), and controlling the temperature to be 0-10 ℃. After the dripping is finished, the temperature range is kept for continuous reaction for 6 hours, after the reaction is finished, the feed liquid is decompressed and concentrated to be dry, 40ml of water is added into the obtained material, the temperature is heated to 65 ℃, and the reflux reaction is carried out for 2 hours. After the reaction is finished, cooling to 0-20 ℃, dropwise adding concentrated hydrochloric acid, adjusting the pH = 0-1, cooling to 0-5 ℃, preserving the temperature for 2h, filtering, and drying to obtain 1.5g (theoretical yield 13.9 g) of white solid caronic acid, wherein the yield is 11% and the purity is 14.7%.
Comparing example 1, it can be seen that when the strong base used was sodium hydroxide, the yield was lower and the purity was lower. Based on theoretical research and experiments, the team of the invention discovers that the solubility of sodium hydroxide in a solvent is too low, the reaction is very slow, side reaction occurs, and a compound of the formula V is generated as a byproduct, so that if the sodium hydroxide is used as strong base for addition cyclization reaction in industrial production, the reaction time needs to be properly prolonged and the reaction temperature needs to be increased, and the aim of improving the industrial efficiency of the caronic acid can be fulfilled.
Comparative example 1
Adding 10g of methyl chloroacetate (II) and 21ml of 30% sodium methoxide methanol solution into a reaction bottle, uniformly mixing and stirring, cooling to 0 ℃, dropwise adding 3,3-methyl dimethacrylate (I) 10g, and controlling the temperature to be 0-10 ℃. After the dripping is finished, the temperature range is kept for continuous reaction for 4 hours, after the reaction is finished, the feed liquid is decompressed and concentrated to be dry, 40ml of water is added into the obtained material, the temperature is heated to 65 ℃, and the reflux reaction is carried out for 2 hours. After the reaction is finished, cooling to 0-20 ℃, dropwise adding concentrated hydrochloric acid, adjusting the pH to be = 0-1, cooling to 0-5 ℃, preserving the heat for 2 hours, filtering and drying to obtain 10.5g (theoretical yield is 13.9 g) of white solid Carron acid, wherein the yield is 76% and the purity is 96.7%. The liquid phase diagram of caronic acid is shown in figure 5.
Comparing example 1, it can be seen that when the reaction temperature is greater than-0.5 ℃, the amount of the obtained diethyl caronate intermediate is reduced and the yield is lowered. The reason is presumed to be that the temperature is too high, so that methyl chloroacetate is liable to undergo a side reaction with a strong base to produce the compound of formula V as a by-product.
Comparative example 2
Adding 10g of methyl chloroacetate (II) and 21ml of 30% sodium methoxide methanol solution into a reaction bottle, uniformly mixing and stirring, cooling to 10 ℃, dropwise adding 10g of 3,3-methyl dimethacrylate (I), and controlling the temperature to be 10-20 ℃. After the dripping is finished, the temperature range is kept for continuous reaction for 3 hours, after the reaction is finished, the feed liquid is decompressed and concentrated to be dry, 40ml of water is added into the obtained material, the temperature is heated to 65 ℃, and the reflux reaction is carried out for 2 hours. After the reaction is finished, cooling to 0-20 ℃, dropwise adding concentrated hydrochloric acid, adjusting the pH = 0-1, cooling to 0-5 ℃, preserving the temperature for 2h, filtering, and drying to obtain 9.1g (theoretical yield 13.9 g) of white solid caronic acid, wherein the yield is 66% and the purity is 40.0%. The liquid phase diagram of caronic acid is shown in figure 4.
Comparing example 1 with comparative example 1, it can be seen that when the reaction temperature is greater than 10 ℃, the obtained intermediate of diethyl caronate is reduced, the yield is reduced, and the purity is reduced. Presumably, the reason is that the temperature is too high, which makes methyl chloroacetate susceptible to side reactions with strong bases, resulting in the formation of the compound of formula V as a by-product.
Comparative example 3
Adding 10g of methyl chloroacetate (II) and 21ml of 30% sodium methoxide methanol solution into a reaction bottle, uniformly mixing and stirring, cooling to 30 ℃, dropwise adding 10g of 3,3-methyl dimethacrylate (I), and controlling the temperature to be 30-40 ℃. After the dripping is finished, the temperature range is kept for continuous reaction for 3 hours, after the reaction is finished, the feed liquid is decompressed and concentrated to be dry, 40ml of water is added into the obtained material, the temperature is heated to 65 ℃, and the reflux reaction is carried out for 2 hours. After the reaction is finished, cooling to 0-20 ℃, dropwise adding concentrated hydrochloric acid, adjusting the pH to be = 0-1, cooling to 0-5 ℃, preserving the temperature for 2h, filtering, and drying to obtain 1.7g (theoretical yield is 13.9 g) of white solid caronic acid, wherein the yield is 9.4%. The results are shown in the liquid phase diagram of FIG. 6, and the caronic acid main product is not available.
Comparing example 1 with comparative examples 1-2, it can be seen that when the reaction temperature is greater than 10 ℃, the obtained diethylcaronate intermediate is reduced, the yield is reduced, and the purity is reduced. Presumably, the reason is that the temperature is too high, which makes methyl chloroacetate susceptible to side reactions with strong bases, resulting in the formation of the compound of formula V as a by-product.
The embodiment shows that the method for preparing the caronic acid has the advantages of simple and safe operation, cheap and easily obtained materials, mild reaction conditions, environmental protection, innovative synthesis of key three-membered rings in process and industrial advantages. The liquid phase atlas verifies that the caronic acid has high purity, high yield, good economic benefit and easy industrialized production.
The raw materials and equipment used in the invention are common raw materials and equipment in the field if not specified; the methods used in the present invention are conventional in the art unless otherwise specified.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, alterations and equivalents of the above embodiments according to the technical spirit of the present invention are still within the protection scope of the technical solution of the present invention.
Claims (8)
1. A preparation method of caronic acid is characterized by comprising the following steps: under the strong alkali condition, carrying out addition cyclization reaction on a compound I and a compound II to obtain a compound III, and synthesizing caronic acid through hydrolysis reaction; the reaction route is as follows:
2. the method of claim 1, comprising the steps of:
(1) Adding methyl chloroacetate, 3,3-methyl dimethacrylate and a solvent into a reaction vessel, adding strong base, stirring uniformly, carrying out addition cyclization reaction to obtain an intermediate product of diethyl caronate, and removing the solvent after the reaction is finished; the reaction route is as follows:
(2) Adding water into the obtained material, heating for hydrolysis reaction, and extracting to obtain white solid caronic acid after the reaction is finished; the reaction route is as follows:
3. the process according to claim 2, wherein the temperature of the addition cyclization reaction in the step (1) is from-20 to 10 ℃.
4. The process according to claim 3, wherein the temperature of the addition cyclization reaction is from-10 to-0.5 ℃.
5. The method according to claim 2, wherein in the step (1), the strong base is one of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide and potassium tert-butoxide; the solvent is one of methanol, ethanol, isopropanol and tert-butanol corresponding to strong base.
6. The method according to claim 5, wherein in the step (1), the strong base is sodium methoxide; the solvent is methanol.
7. The method according to claim 2, wherein the extraction in the step (2) is carried out by adjusting pH by adding hydrochloric acid dropwise to precipitate crystals.
8. The process according to claim 7, wherein in the step (2), hydrochloric acid is added dropwise to adjust the pH to 0 to 1 to precipitate crystals.
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| CN102070575A (en) * | 2010-12-28 | 2011-05-25 | 上海北卡医药技术有限公司 | New synthesis method of caronic anhydride |
| CN114456065A (en) * | 2021-12-23 | 2022-05-10 | 上海璨谊生物科技有限公司 | Synthesis method of carinic acid diester compound and carinic acid derivative |
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| CN102070575A (en) * | 2010-12-28 | 2011-05-25 | 上海北卡医药技术有限公司 | New synthesis method of caronic anhydride |
| CN114456065A (en) * | 2021-12-23 | 2022-05-10 | 上海璨谊生物科技有限公司 | Synthesis method of carinic acid diester compound and carinic acid derivative |
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