CN117756624A - Process for synthesizing royal jelly acid - Google Patents
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- CN117756624A CN117756624A CN202311724459.1A CN202311724459A CN117756624A CN 117756624 A CN117756624 A CN 117756624A CN 202311724459 A CN202311724459 A CN 202311724459A CN 117756624 A CN117756624 A CN 117756624A
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- QHBZHVUGQROELI-UHFFFAOYSA-N Royal Jelly acid Natural products OCCCCCCCC=CC(O)=O QHBZHVUGQROELI-UHFFFAOYSA-N 0.000 title claims abstract description 31
- QHBZHVUGQROELI-SOFGYWHQSA-N (E)-10-hydroxydec-2-enoic acid Chemical compound OCCCCCCC\C=C\C(O)=O QHBZHVUGQROELI-SOFGYWHQSA-N 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 25
- 230000008569 process Effects 0.000 title claims abstract description 21
- 230000002194 synthesizing effect Effects 0.000 title claims description 12
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 claims abstract description 32
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 230000009467 reduction Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000012320 chlorinating reagent Substances 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- VJRITMATACIYAF-UHFFFAOYSA-N benzenesulfonohydrazide Chemical compound NNS(=O)(=O)C1=CC=CC=C1 VJRITMATACIYAF-UHFFFAOYSA-N 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 2
- 229940067157 phenylhydrazine Drugs 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 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 6
- 239000003377 acid catalyst Substances 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 6
- 238000004821 distillation Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
- KUPHXIFBKAORGY-UHFFFAOYSA-N 2-amino-3-iodo-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(N)=C1I KUPHXIFBKAORGY-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 229940109850 royal jelly Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000012747 synergistic agent Substances 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
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- 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
-
- 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 relates to the technical field of medicine synthesis, and discloses a synthesis process of royal jelly acid, which uses suberic acid as a starting material, and comprises the steps of single esterification, chlorination, reduction, condensation with malonic acid and selective reduction to obtain a target product of royal jelly acid.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a synthesis process of royal jelly acid.
Background
Royal jelly acid, also known as royal jelly acid Chinese name 10-hydroxy-2-decenoic acid, is a specific high-efficiency bioactive substance in royal jelly. Research shows that the royal jelly acid has the functions of resisting bacteria, sterilizing, reducing blood fat, strengthening body and strongly inhibiting various cancer cells such as lymph cancer, breast cancer and the like, can also strengthen the immune function of the body, has obvious curative effect of preventing and treating alopecia and treating acute radiation injury and injury caused by chemical substances, and can be added into cosmetics as a synergistic agent. There are more reports about the synthetic route of royal jelly acid at present, but the synthetic route is either complicated in synthetic steps and low in yield, or the raw material cost is high, the reaction condition is severe, and the method is not suitable for large-scale production.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the royal jelly acid synthesis process which is environment-friendly and safe, has few steps, simple operation, mild conditions, high yield and purity and is suitable for industrial production.
In order to achieve the above object, the present invention provides the following technical solutions. The invention provides a synthesis process of royal jelly acid, which comprises the following steps:
(1) Reacting suberic acid with an alcohol solution, and esterifying one end carboxylic acid group of suberic acid to obtain a monoester compound, wherein the monoester compound is shown in a formula (I);
(2) Mixing a monoester compound with a chlorinating reagent to carry out chlorination reaction, wherein carboxylic acid of the monoester compound is chlorinated to form acyl chloride, reducing a product obtained after the chlorination reaction at low temperature by using a reducing agent, then adding alkali and ethanol for reflux reaction, and finally adding malonic acid for condensation reaction to obtain a compound II, wherein the compound II is shown in a formula (II);
(3) Reducing the compound II by using borohydride, acidifying the reaction solution, and separating and purifying to obtain royal jelly acid shown in a formula (III);
wherein R is an alkyl group, preferably a C1-C4 straight or branched alkyl group.
In some embodiments, R in formula (I) or formula (II) is methyl, ethyl, or isopropyl.
In some embodiments, in the step (1), suberic acid, a solvent and a catalyst are put into a reaction kettle, an alcohol solution is slowly added dropwise at room temperature, stirring is performed for 1-3 hours, reflux is performed for 2-5 hours, cooling is performed, liquid separation is performed, an organic phase is washed with water, and then the organic phase is distilled under reduced pressure to obtain a monoester compound.
In some embodiments, the solvent in the step (1) is at least one of dichloromethane, ethyl acetate, tetrahydrofuran, isopropyl ether and tert-butyl methyl ether, and the solvent is added in an amount of 1 to 10 times of the mass of suberic acid.
In some embodiments, the alcohol solution in the step (1) is one of methanol aqueous solution, ethanol aqueous solution and isopropanol aqueous solution, the concentration is 10-30%, and the addition amount is 1-3 times of mole equivalent of suberic acid.
In some embodiments, the catalyst in step (1) is at least one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, nitric acid, phosphoric acid, in an amount of 0.1% -0.5% by mass of suberic acid.
In some embodiments, in the step (2), the monoester compound of formula (I) and a chlorinating agent are added into a reaction kettle, the temperature is raised to 35-45 ℃ and stirred for 1-5 hours, carboxylic acid of the monoester compound is chlorinated to form acyl chloride, and then the acyl chloride is stirred for 0.5-2 hours in a state of vacuumizing, wherein the chlorinating agent is one or more of thionyl chloride, oxalyl chloride, sulfonyl chloride, phosphorus oxychloride or phosphorus pentachloride, and the chlorinating agent is 1-2 molar equivalents of the monoester compound.
In some embodiments, in the step (2), the temperature is reduced to-5 ℃ to 0 ℃ after the chlorination reaction, a reducing agent is added and stirred for 0.5 to 2 hours, then alkali and ethanol are added, reflux is carried out for 1 to 3 hours, finally malonic acid is added and reacted for 1 to 3 hours, and the compound II is obtained after the reaction is finished.
In some embodiments, the reducing agent in the step (2) is at least one of benzenesulfonyl hydrazide, p-toluenesulfonyl hydrazide and phenylhydrazine, and the adding amount of the reducing agent is 1-2 times of the molar equivalent of the compound of the formula (I).
In some embodiments, the base in step (2) is at least one of triethylamine, diethylamine, tripropylamine, morpholine, 4-dimethylaminopyridine, piperidine, and pyridine, and the amount added is 0.3 to 3 times the molar equivalent of the compound of formula (I).
In some embodiments, in the step (3), adding the compound II, the catalyst and the solvent into a reaction kettle, cooling to-5-0 ℃ under stirring, adding potassium borohydride or sodium borohydride in batches, controlling the temperature to be not more than 10 ℃, keeping the temperature for reaction for 1-5 hours, slowly dropwise adding 15% hydrochloric acid after the reaction is finished to adjust the pH to be 3-4, and separating and purifying to obtain the royal jelly acid.
In some embodiments, the solvent in the step (3) is at least one of tetrahydrofuran, diethyl ether, isopropyl ether and tert-butyl methyl ether, and the addition amount of the solvent is 1-10 times of the mass of the compound II.
In some embodiments, the catalyst in the step (3) is at least one of aluminum trichloride, zinc chloride, zinc iodide, copper bromide and ferric trichloride, and the addition amount of the catalyst is 0.5-2 times of the molar equivalent of the compound II.
The technical scheme has the following beneficial effects:
the invention uses suberic acid as the initial raw material, carries out monoesterification, then chloridization and reduction, condenses with malonic acid, and then carries out selective reduction to obtain the target product royal jelly acid, which has the advantages of simple process operation, low cost raw material, mild reaction condition, environment protection and safety, suitability for industrial production, high yield and high HPLC purity of more than 99 percent. Has great industrial prospect. The invention discovers that the oil-water two-phase reaction is adopted in the step (1) and the reflux time is controlled, so that the bi-esterification byproducts can be avoided; the combination of hydrazine as a reducing agent with an amine as a base in step (2) allows highly selective dehydrogenation to form olefinic bonds at specific positions and all in the (E) configuration; step (3) uses a combination of a salt catalyst and an alkali metal borohydride as a catalyst to reduce the terminal ester group of compound II to a hydroxyl group with high selectivity.
Description of the terms
It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or terminal that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or terminal. Without further limitation, an element defined by the statement "comprising … …" or "comprising … …" does not exclude the presence of additional elements in a process, method, article or terminal device comprising the element. Further, herein, "greater than," "less than," "exceeding," and the like are understood to not include the present number; "above", "below", "within" and the like are understood to include this number.
As used herein, "room temperature" and "normal temperature" refer to ambient temperatures ranging from about 10deg.C to about 40deg.C. In some embodiments, "room temperature" or "ambient temperature" refers to a temperature from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" or "ambient temperature" refers to a temperature from about 25 ℃ to about 30 ℃; in still other embodiments, "room temperature" or "normal temperature" refers to 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, and the like.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
Detailed Description
In order to describe the technical content, constructional features, achieved objects and effects of the technical solution in detail, the following description is made in detail with reference to specific embodiments.
The preparation method of the alcohol aqueous solution comprises the following steps:
for example: 2645ml 10% ethanol configuration: 264.5g of ethanol (5.74 mol,1 molar equivalent) were weighed out,
then adding water to dilute to 2645ml, namely the total volume of the prepared 10% ethanol water solution is 2645ml.
Royal jelly acid HPLC detection method
Chromatographic column Xtime C18 column (4.6. Times.250 mm,5 um) mobile phase methanol 0.1% formic acid=60:40, detection wavelength 210nm, column temperature 30C, +sample injection amount 5. Mu.1, chromatographic run time 30minv.
Example 1: process for synthesizing royal jelly acid, compound shown in formula (III)
S1, 1000g of suberic acid, 4000g of ethyl acetate and 1g of sulfuric acid are put into a reaction kettle, 1840ml of 20% methanol aqueous solution is slowly added dropwise at room temperature, the mixture is stirred for 2h under heat preservation, the mixture is refluxed for 3h, the temperature is reduced, the mixture is separated, an organic phase is washed once by water, and the solvent is removed by reduced pressure distillation to obtain 1017.8g of a compound of formula (I), and the yield is: 94.2%;
s2, adding 1017.8g of a compound shown in the formula (I) and 707.7g of thionyl chloride into a reaction kettle, heating to 40 ℃, stirring for 3 hours, and stirring for 1 hour in a vacuumizing state; cooling to 0 ℃, adding 1007g of p-toluenesulfonyl hydrazide, stirring for 1h, adding 547.2g of triethylamine and 2000ml of ethanol, refluxing for 2h, finally adding 562.7g of malonic acid, reacting for 2h, removing the solvent by reduced pressure distillation after the reaction is finished, adding 3000ml of ethyl acetate to the residue, dissolving, washing with water, separating liquid, drying the organic phase, removing the solvent by reduced pressure to obtain 1072.8g of colorless oily compound of formula (II), and obtaining the yield: 92.6%;
s3, adding 1072.8g of a compound shown in a formula (II), 682.5g of zinc chloride and 4000g of tetrahydrofuran into a reaction kettle, cooling to 0 ℃ under stirring, adding 324g of potassium borohydride in batches, controlling the temperature to be not more than 10 ℃, after the addition, carrying out heat preservation reaction for 2 hours, slowly dropwise adding 15% hydrochloric acid to adjust ph=3-4 after the reaction is finished, separating liquid, drying an organic phase, removing a solvent under reduced pressure to obtain a white solid, and recrystallizing with petroleum ether to obtain 907.4g of royal jelly acid shown in a formula (III), wherein the yield is: 97.3%, HPLC:99.3%.
Example 2:
s1, 1000g of suberic acid, 5000g of tetrahydrofuran and 1g of p-toluenesulfonic acid are put into a reaction kettle, 2645ml of 20% ethanol water solution is slowly added dropwise at room temperature, the mixture is stirred for 3 hours under heat preservation, the mixture is refluxed for 3 hours, the temperature is reduced, the mixture is separated, an organic phase is washed once by water, and the solvent is removed by reduced pressure distillation to obtain 1115.8g of a compound of the formula (I), and the yield is: 96.1%;
s2, adding 1115.8g of a compound shown in the formula (I) and 722g of thionyl chloride into a reaction kettle, heating to 40 ℃, stirring for 4 hours, and stirring for 1 hour in a vacuumizing state; cooling to 0 ℃, adding 1130.1g of p-toluenesulfonyl hydrazide, stirring for 1.5h, then adding 670g of triethylamine and 2000ml of ethanol, refluxing for 2h, finally adding 574.1g of malonic acid, reacting for 3h, removing the solvent by reduced pressure distillation, adding 3000ml of ethyl acetate to the residue, dissolving, washing with water, separating liquid, drying the organic phase, removing the solvent by reduced pressure to obtain 1188.9g of colorless oily compound of formula (II), and obtaining the yield: 94.4%;
s3, adding 1188.9g of a compound shown in a formula (II), 694.4g of aluminum trichloride and 4000g of tetrahydrofuran into a reaction kettle, cooling to 0 ℃ under stirring, adding 309g of potassium borohydride in batches, controlling the temperature to be not more than 10 ℃, after the addition, carrying out heat preservation reaction for 4 hours, slowly dropwise adding 15% hydrochloric acid to adjust ph=3-4 after the reaction is finished, separating liquid, drying an organic phase, removing a solvent under reduced pressure to obtain a white solid, and recrystallizing with petroleum ether to obtain 954.4g of royal jelly acid shown in a formula (III), wherein the yield is: 98.4%, HPLC:99.2%.
While the embodiments have been described above, other variations and modifications will occur to those skilled in the art once the basic inventive concepts are known, and it is therefore intended that the foregoing description be regarded as illustrative rather than limiting, and that it is intended that all such modifications and variations be regarded as being included within the scope of the invention, whether they are to be regarded as equivalent structures or equivalent processes using the teachings of this invention, or whether they are directed to or directed to other relevant technology.
Claims (10)
1. The synthesis process of royal jelly acid is characterized by comprising the following steps:
(1) Reacting suberic acid with an alcohol solution under an acid catalyst, and esterifying a carboxylic acid group at one end of suberic acid to obtain a monoester compound, wherein the monoester compound is shown as a formula (I);
(2) Mixing monoester compound (I) with a chlorinating reagent for chlorination reaction, condensing the product after the chlorination reaction with a reducing agent at low temperature, adding alkali and an alcohol solvent for reflux reduction, and finally adding malonic acid for condensation reaction to obtain a compound II shown as a formula (II);
(3) Reducing the compound II by using alkali metal borohydride, acidifying the reaction solution, and separating and purifying to obtain the royal jelly acid shown in a formula (III):
wherein R is alkyl, preferably C1-C4 straight or branched alkyl.
2. The process for synthesizing royal jelly acid according to claim 1, characterized in that in the step (1), suberic acid, a solvent and a catalyst are put into a reaction kettle, an alcohol solution is slowly dropped at room temperature, the dropping is completed, stirring is carried out for 1-3 hours, reflux is carried out for 2-5 hours, cooling is carried out, liquid separation is carried out, an organic phase is washed with water, and then the organic phase is distilled under reduced pressure to obtain a monoester compound.
3. The process for synthesizing royal jelly acid of claim 2, wherein the solvent in the step (1) is at least one of dichloromethane, ethyl acetate, tetrahydrofuran, isopropyl ether and tert-butyl methyl ether, and the solvent is added in an amount of 1 to 10 times the mass of suberic acid.
4. The process for synthesizing the royal jelly acid according to claim 2, characterized in that the alcohol solution in the step (1) is one of a methanol aqueous solution, an ethanol aqueous solution and an isopropyl alcohol aqueous solution, the concentration of the alcohol solution is 10-30%, and the addition amount of the alcohol solution is 1-3 times of the molar equivalent of the suberic acid; the catalyst in the step S1 in the step (1) is at least one of sulfuric acid, p-toluenesulfonic acid and methanesulfonic acid, and the dosage of the catalyst is 0.1-0.5% of the mass of suberic acid.
5. The process for synthesizing royal jelly acid according to claim 1, characterized in that in the step (2), monoester compound of formula (I) and thionyl chloride are added into a reaction kettle, the temperature is raised to 35-45 ℃ and stirred for 1-5h, carboxylic acid of monoester compound is chlorinated to form acyl chloride, and then stirred for 0.5-2h in a vacuum state, in the step (2), the temperature is reduced to-5-0 ℃ after the chlorination reaction, a reducing agent is added and stirred for 0.5-2h, then alkali and ethanol are added, reflux is carried out for 1-3h, malonic acid is finally added and reacted for 1-3h, and the compound II is obtained after the reaction is completed.
6. The process for synthesizing royal jelly acid of claim 1, characterized in that the reducing agent in the step (2) is at least one of benzenesulfonyl hydrazide, p-toluenesulfonyl hydrazide and phenylhydrazine, and the addition amount of the reducing agent is 1-2 times of the molar equivalent of the compound of formula (I); the chlorinating agent is one or more of thionyl chloride, oxalyl chloride, sulfonyl chloride, phosphorus oxychloride or phosphorus pentachloride, and the chlorinating agent is 1-2 molar equivalents of monoester compound.
7. The process for synthesizing royal jelly acid of claim 1, wherein the base in the step (2) is at least one of triethylamine, diethylamine, tripropylamine, morpholine, 4-dimethylaminopyridine, piperidine and pyridine, and the addition amount thereof is 0.3 to 1 time of molar equivalent of the compound of formula (I).
8. The process for synthesizing the royal jelly acid according to claim 1, characterized in that in the step (3), a compound II, a catalyst and a solvent are added into a reaction kettle, the temperature is reduced to-5-0 ℃ under stirring, alkali metal borohydride is added in batches, the temperature is controlled to be not more than 10 ℃, the reaction is carried out for 1-5 hours under heat preservation, 15% hydrochloric acid is slowly added dropwise after the reaction is finished to adjust the pH value to be 3-4, and the royal jelly acid is obtained through separation and purification.
9. The process for synthesizing royal jelly acid of claim 1, wherein the solvent in the step (3) is at least one of tetrahydrofuran, diethyl ether, isopropyl ether and tert-butyl methyl ether, the addition amount of which is 1 to 10 times the mass of the compound II, and the alkali metal borohydride is potassium borohydride or sodium borohydride.
10. The process for synthesizing royal jelly acid of claim 1, wherein the catalyst in the step (3) is at least one of aluminum trichloride, zinc chloride, iodine, copper bromide and ferric trichloride, and the addition amount thereof is 0.5 to 2 times of the molar equivalent of the compound II.
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