CN116836137A - Synthetic method of caronic anhydride compound - Google Patents
Synthetic method of caronic anhydride compound Download PDFInfo
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- CN116836137A CN116836137A CN202210291234.0A CN202210291234A CN116836137A CN 116836137 A CN116836137 A CN 116836137A CN 202210291234 A CN202210291234 A CN 202210291234A CN 116836137 A CN116836137 A CN 116836137A
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- anhydride
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- -1 caronic anhydride compound Chemical class 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title claims description 4
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 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 abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- DBIPVNZNXKVLTL-UHFFFAOYSA-N 3-acetyl-2,2-dimethylcyclopropane-1-carboxylic acid Chemical compound CC(=O)C1C(C(O)=O)C1(C)C DBIPVNZNXKVLTL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000005911 haloform reaction Methods 0.000 claims abstract description 3
- 150000008064 anhydrides Chemical class 0.000 claims abstract 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- QKAHKEDLPBJLFD-UHFFFAOYSA-N 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione Chemical compound O=C1OC(=O)C2C1C2(C)C QKAHKEDLPBJLFD-UHFFFAOYSA-N 0.000 claims description 8
- 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 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 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 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 239000007809 chemical reaction catalyst Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 4
- 230000003321 amplification Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 238000004817 gas chromatography Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000005708 Sodium hypochlorite Substances 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 229960004424 carbon dioxide Drugs 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical group [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- VIMXTGUGWLAOFZ-UHFFFAOYSA-N ethyl 2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropane-1-carboxylate Chemical compound CCOC(=O)C1C(C=C(C)C)C1(C)C VIMXTGUGWLAOFZ-UHFFFAOYSA-N 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of a 3, 3-dimethylcyclopropane-1, 2-dicarboxylic anhydride compound (Carlong anhydride I), which takes a 3-acetyl-2, 2-dimethylcyclopropane-1-carboxylic acid compound II as a raw material, utilizes alkali and halogen to generate a haloform reaction to generate an intermediate Carlong acid III, and then carries out a cyclization reaction to generate the Carlong anhydride I. The method has the advantages of easy preparation of raw materials, mild conditions, no metal residues, high production safety, reduced reaction cost, easy amplification and high industrial application value.
Description
Technical Field
The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing a 3, 3-dimethylcyclopropane-1, 2-dimethyl anhydride commonly called Carlong anhydride compound.
Background
Carbonic anhydride (Caronic anhydride) is an important intermediate for synthesizing a novel drug of hepatitis C virus (hepatitis C protease inhibitor), and is also widely applied to the fields of pesticides and other organic synthesis. The structural formulas of the caron anhydride and the hepatitis C protease inhibitor are as follows:
the main methods for synthesizing 3, 3-dimethylcyclopropane-1, 2-dicarboxylic anhydride reported at home and abroad at present are as follows: (1) Patent CN 1805931a describes that the first ethyl chrysanthemate is used as raw material, oxidized by potassium permanganate, then treated by sodium sulfite and concentrated sulfuric acid, hydrolyzed under alkaline condition to obtain 3, 3-dimethylcyclopropane 1, 2-dicarboxylic acid, and then cyclized in acetic anhydride to obtain 3, 3-dimethylcyclopropane-1, 2-dicarboxylic anhydride. (2) Patent CN 101863866B describes that the use of dichlorochrysanthemic acid as raw material is also treated by potassium permanganate oxidation, sodium sulfite and concentrated sulfuric acid, and hydrolyzed and cyclized under alkaline condition to obtain the caronic anhydride. In the methods, firstly, raw materials are prepared more complicated, and oxidation by potassium permanganate can emit a large amount of heat, even has the phenomenon of burning, and has the danger of explosion. Yet another one also generates a lot of manganese residues, which pollute the environment. (3) Patent CN 102070575A describes that, after esterification of compound i, sodium hypochlorite is used to oxidize 3, 3-dimethylcyclopropane 1, 2-dicarboxylic acid, and first, the method uses ester as raw material to react to produce alcohols, which is also considered to be recovered, and then the content of sodium hypochlorite used is low, so that the reaction dosage is large, and sodium hypochlorite is unstable, and is easy to decompose by visible light, and easy to generate danger.
Disclosure of Invention
The invention aims to provide a synthesis method of a 3, 3-dimethylcyclopropane-1, 2-dicarboxylic anhydride compound, which has the advantages of easy preparation of raw materials, mild conditions, no metal residues, high production safety, reduced reaction cost, easy amplification and high industrial application value.
The invention provides a synthesis method of a 3, 3-dimethylcyclopropane-1, 2-dicarboxylic anhydride compound I, which takes 3-acetyl-2, 2-dimethylcyclopropane-1-carboxylic acid II as a raw material, utilizes alkali and halogen to generate haloform reaction to generate an intermediate calonic acid III, and then carries out cyclization reaction to generate the calonic anhydride compound I.
The caronic anhydride compound has the following I structure:
the 3-acetyl-2, 2-dimethylcyclopropane-1-carboxylic acid compound has the following II structure:
the caronic acid compound has the following III structure:
in the invention, the preparation method of the caronic anhydride compound I is carried out according to the following reaction route:
the alkali is selected from one of KOH and NaOH.
The halogen is selected from one of bromine and chlorine.
The molar ratio of the alkali to the compound II is 1-20:1, preferably 3-6:1.
the molar ratio of the halogen to the compound II is 1-5:1, preferably 1.2-2:1.
the mass ratio of the acetic anhydride to the compound III is 0.5-5:1, preferably 0.8-1.2:1, more preferably 1:1.
the mass ratio of the sodium acetate to the compound III is 0.01-0.2:1, preferably 0.01-0.05:1, more preferably 0.02:1.
the method comprises the following specific steps:
dissolving alkali in water in ice water bath, then dropwise adding bromine or introducing chlorine, adding 3-acetyl-2, 2-dimethylcyclopropane-1-carboxylic acid compound II in batches after dropwise adding or introducing, continuing to react for 2 hours at room temperature after adding, adding sodium bisulfate aqueous solution after GC analysis, adjusting the pH value to 2 by using concentrated sulfuric acid, precipitating solid Carlong acid III, and drying under reduced pressure. Adding the dried caronic acid III into acetic anhydride, then adding sodium acetate, carrying out reflux reaction for 3 hours, evaporating the residual acetic anhydride at normal pressure, evaporating a crude product caronic anhydride I under reduced pressure, and finally recrystallizing with toluene and petroleum ether to obtain a pure product. The invention has the following advantages:
1. the used reagent is cheap and easy to obtain.
2. High reaction activity, mild reaction condition and high yield.
3. Compared with the traditional method, the method greatly reduces the reaction cost and simplifies the process.
4. No metal residue, environmental friendliness, high production safety, reduced reaction cost, easy amplification and high industrial application value.
Drawings
FIG. 1 shows the nuclear magnetic resonance hydrogen spectrum of the Carbonic acid prepared in example 1
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the caronic anhydride prepared in example 1;
Detailed Description
The following examples further illustrate the invention, but are not intended to limit it. Nuclear magnetic resonance was determined by Bruker400 Nuclear magnetic resonance, and Gas Chromatography (GC) was determined by Agilent 7820 chromatography.
Example 1
Preparation of intermediate III:
under ice-water bath cooling, 20g (500 mmol) of sodium hydroxide is dissolved in 80mL of water, 25g (160 mmol) of bromine is slowly added dropwise to the solution at the temperature below 5 ℃, 15.6g (100 mmol) of compound II is added to the aqueous solution in portions after the dropwise addition, the reaction is stirred at room temperature for 2h after the complete addition, and the reaction of the raw materials is completely stopped by GC analysis. To this was added 100mL of a saturated aqueous solution of sodium hydrogensulfite, which was then acidified with concentrated sulfuric acid (98% by mass), and the pH was adjusted to 2, to precipitate a white solid. Filtration and drying under reduced pressure gave 13.4g of Caronic acid III as a white solid which was used directly in the next reaction. The nuclear magnetic data are as follows:
1 H NMR(400MHz,CD 3 OD) δ1.29 (s, 6H), 2.09 (s, 2H), consistent with the data described in patent CN 102070575 a.
Example 2
13g of Carbonic acid III in example 1 is added into 13g of acetic anhydride, then 0.26g of sodium acetate is added, reflux reaction is carried out for 2h at 150 ℃, the generated acetic acid and the residual acetic anhydride are distilled out under normal pressure, then the product is distilled out under reduced pressure, and the distillate is recrystallized by toluene and petroleum ether (volume ratio is 1:10) to obtain 8.9g of white crystal Carbonic anhydride. The nuclear magnetic data are as follows:
1 H NMR(400MHz,CDCl 3 ) δ1.32 (s, 3H), 1.42 (s, 3H), 2.64 (s, 3H), consistent with the data described in patent CN 102070575A.
The above-described embodiments represent only embodiments of the present invention, but are not to be construed as limiting the scope of the patent of the invention, it being noted that several variations and modifications can be made by a person skilled in the art without departing from the inventive concept.
Claims (9)
1. A synthetic method of a caronic anhydride compound is characterized in that:
3-acetyl-2, 2-dimethylcyclopropane-1-carboxylic acid (compound II) is used as a raw material, a haloform reaction is carried out by utilizing alkali and halogen to generate an intermediate calonic acid (compound III), and then a cyclization reaction is carried out to generate calonic anhydride I.
2. The method for synthesizing a caron anhydride compound according to claim 1, wherein: the reaction formula is as follows:
3. the method for synthesizing a caron anhydride compound according to claim 1, wherein: the alkali is selected from one or two of KOH and NaOH; the molar ratio of the alkali to the compound II is 1-20:1, preferably 3-6:1.
4. the method for synthesizing a caron anhydride compound according to claim 1, characterized in that: the halogen is selected from one or two of bromine and chlorine; the molar ratio of the halogen to the compound II is 1-5:1, preferably 1.2-2:1, a step of; the halogen is one or two of chlorine and bromine.
5. A process for the synthesis of a caron anhydride compound according to any one of claims 1 to 4, characterized in that: the synthesis process of the intermediate is carried out in an aqueous solution, 50-200L of water is used for every 100mmol of compound II; the reaction is carried out for 1 to 12 hours, preferably 2 to 10 hours.
6. The method for synthesizing a caron anhydride compound according to claim 1, characterized in that: the cyclization reaction is carried out in a solvent, wherein the solvent is acetic anhydride, and the mass ratio of the acetic anhydride to the compound III is 0.5-5:1, preferably 0.8-1.2:1, more preferably 1:1.
7. the method for synthesizing a caron anhydride compound according to claim 1, characterized in that: the cyclization reaction catalyst is sodium acetate, and the mass ratio of the sodium acetate to the compound III is 0.01-0.2:1, preferably 0.01-0.05:1, more preferably 0.02:1.
8. the method for synthesizing a caron anhydride compound according to claim 1 or 6 or 7, characterized in that: the reaction temperature of the cyclization reaction is 110-200 ℃, preferably 120-150 ℃ for 1-12 hours, preferably 2-10 hours.
9. The synthetic method of a caron anhydride compound according to claim 1 or 2, characterized in that: the method specifically comprises the following steps:
dissolving alkali in water in ice water bath, then dropwise adding bromine and/or introducing chlorine, adding a compound II after dropwise adding and/or introducing, continuing to react for 1-12 hours, preferably 2-10 hours at room temperature after adding, adding sodium bisulfate aqueous solution, then adjusting the pH value to 1-2 with concentrated sulfuric acid to precipitate solid Caronic acid III, and drying under reduced pressure; adding the dried caronic acid III into acetic anhydride, then adding sodium acetate, and carrying out reflux reaction for 1-12h, preferably 2-10h at 110-200 ℃ (preferably 120-150 ℃); evaporating the residual acetic anhydride at normal pressure, then evaporating the crude product of the caronic anhydride I at reduced pressure, and finally recrystallizing with toluene and petroleum ether (volume ratio is 1:10) to obtain a pure product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210291234.0A CN116836137A (en) | 2022-03-23 | 2022-03-23 | Synthetic method of caronic anhydride compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202210291234.0A CN116836137A (en) | 2022-03-23 | 2022-03-23 | Synthetic method of caronic anhydride compound |
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| Publication Number | Publication Date |
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| CN116836137A true CN116836137A (en) | 2023-10-03 |
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| CN202210291234.0A Pending CN116836137A (en) | 2022-03-23 | 2022-03-23 | Synthetic method of caronic anhydride compound |
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| Country | Link |
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- 2022-03-23 CN CN202210291234.0A patent/CN116836137A/en active Pending
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