CN114478296A - Preparation method of dihydrooat alkaloid - Google Patents
Preparation method of dihydrooat alkaloid Download PDFInfo
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- CN114478296A CN114478296A CN202210134512.1A CN202210134512A CN114478296A CN 114478296 A CN114478296 A CN 114478296A CN 202210134512 A CN202210134512 A CN 202210134512A CN 114478296 A CN114478296 A CN 114478296A
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- 229930013930 alkaloid Natural products 0.000 title claims abstract description 56
- 150000003797 alkaloid derivatives Chemical class 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 claims abstract description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 20
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 238000012544 monitoring process Methods 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000000967 suction filtration 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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 238000005809 transesterification reaction Methods 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000003930 superacid Substances 0.000 claims description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000007039 two-step reaction Methods 0.000 abstract description 3
- 238000009835 boiling Methods 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 238000007670 refining Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- QOHGMEYPUKSMST-UHFFFAOYSA-N methyl 2-(4-hydroxyphenyl)propanoate Chemical compound COC(=O)C(C)C1=CC=C(O)C=C1 QOHGMEYPUKSMST-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 230000008569 process Effects 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000003912 environmental pollution Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- -1 methyl p-hydroxy phenyl propionamide benzoate Chemical compound 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- ZOYMZIFAQODIKU-UHFFFAOYSA-N 3-(4-hydroxyphenyl)propanoyl chloride Chemical compound OC1=CC=C(CCC(Cl)=O)C=C1 ZOYMZIFAQODIKU-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000001139 anti-pruritic effect Effects 0.000 description 2
- KIUVQMGRTDPAFR-UHFFFAOYSA-N benzoic acid 2-hydroxy-2-phenylpropanamide Chemical compound C(C1=CC=CC=C1)(=O)O.OC(C(=O)N)(C)C1=CC=CC=C1 KIUVQMGRTDPAFR-UHFFFAOYSA-N 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- MCTRPSAWYSXUSZ-UHFFFAOYSA-N ethyl 2-(4-hydroxyphenyl)propanoate Chemical compound CCOC(=O)C(C)C1=CC=C(O)C=C1 MCTRPSAWYSXUSZ-UHFFFAOYSA-N 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ZDSSCYCDBASEJQ-UHFFFAOYSA-N N-malonylanthranilic acid Chemical compound OC(=O)CC(=O)NC1=CC=CC=C1C(O)=O ZDSSCYCDBASEJQ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- 229940102398 methyl anthranilate Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000037307 sensitive skin Effects 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/02—Sulfur, selenium or tellurium; Compounds thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/02—Sulfur, selenium or tellurium; Compounds thereof
- B01J27/053—Sulfates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0215—Sulfur-containing compounds
- B01J31/0225—Sulfur-containing compounds comprising sulfonic acid groups or the corresponding salts
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/19—Catalysts containing parts with different compositions
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- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/49—Esterification or transesterification
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention discloses a preparation method of dihydro oat alkaloid, which comprises the following steps: s1, preparing p-hydroxy-phenyl propionate, S2, preparing a crude dihydro oat alkaloid product, and S3, preparing a refined dihydro oat alkaloid product, wherein the amine ester exchange catalyst is preferably concentrated sulfuric acid and p-toluenesulfonic acid, which is more favorable for reaction, and although the raw materials have aniline structures and can form aniline salts at low temperature, unstable aniline salts can be liberated when the temperature is higher than 120 ℃, and continue to participate in the reaction, so that the conversion rate of the raw materials is improved; the amine ester exchange solvent is preferably DMSO and sulfolane, the two solvents have high boiling point and good solubility, and meanwhile, the solvent has low toxicity, water solubility and simple post-treatment, and is convenient for refining and purifying the crude dihydrooat alkaloid; meanwhile, the preparation process has short steps, the yield of the two-step reaction is over 80 percent, and the industrial large-scale production is facilitated.
Description
Technical Field
The invention belongs to the technical field of cosmetic preparation, and particularly relates to a preparation method of dihydrooat alkaloid.
Background
Dihydrooat alkaloid, also called hydroxyphenylpropionamide benzoic acid, has rapid anti-inflammatory and antipruritic activities, and is widely applied to skin care products and cosmetics. The product has multiple effects of resisting histamine, oxidation, irritation, inflammation and erythema, and has good effect in relieving itching, irritation and redness of sensitive skin. The product is a powerful natural nonsteroidal anti-inflammatory and antipruritic component, has the potency equivalent to that of hydrocortisone, does not have any side effect of steroid hormone, and has wide market prospect.
At present, for the synthesis of dihydrooat alkaloid, in world patent document WO2005016870, a traditional amide condensation route is adopted, p-hydroxyphenylpropionic acid and anthranilic acid are used as raw materials, N-carbonyldiimidazole is used as a condensing agent, pyridine is used as a deacidification agent to synthesize a target product, the synthesis route is shown as the following formula (i), the total yield of the route is only about 17%, and meanwhile, a large amount of organic wastewater is caused, so that the environmental pollution is serious, and the industrial feasibility is not high;
in chinese patent document CN106511110A, a stepwise synthesis route is adopted, wherein anthranilic acid and p-hydroxybenzaldehyde are used as main raw materials, anthranilic acid and meldrum's acid are condensed to synthesize an intermediate 2- (carboxy acetamido) benzoic acid, then the intermediate is catalyzed by β -alanine catalyst in pyridine solvent to synthesize oat alkaloid, and finally the oat alkaloid is subjected to Pd/C hydrogenation reduction to obtain dihydrooat alkaloid, the synthesis route is shown in formula (ii) below, the total yield of the method is about 60%, but the method has long steps, and pyridine causes problems of a large amount of wastewater which is difficult to treat;
in chinese patent document CN104418764A, p-hydroxy phenyl propionic acid is used as a raw material, a large amount of thionyl chloride is directly used as a chlorination reagent to synthesize p-hydroxy phenyl propionyl chloride, then the p-hydroxy phenyl propionyl chloride reacts with methyl anthranilate under the condition of inorganic base to synthesize methyl p-hydroxy phenyl propionamide benzoate, and the dihydro oat alkaloid is obtained by post-treatment such as hydrolysis, recrystallization and the like; in chinese patent documents CN106631865A and CN112939803A, acetic anhydride is used to protect phenolic hydroxyl group, and then a large amount of thionyl chloride is used to synthesize acyl chloride, which is then reacted with anthranilic acid to synthesize hydroxyphenylpropionamide benzoic acid, and post-treatment such as recrystallization is performed to obtain dihydrooat alkaloid, and the synthetic route is shown in the following formula (iii):
the above synthesis method has the following problems: 1) the acyl chloride is directly prepared by taking p-hydroxyphenylpropionic acid as a raw material, so that a large amount of self-condensation of the p-hydroxyphenylpropionic acid can be caused, and the reaction formula is shown as the following formula (IV); 2) when the acetic anhydride protects the p-hydroxyphenylpropionic acid, intermediate states of mixed anhydride can be generated, the self-condensation of the p-hydroxyphenylpropionic acid can also be caused, the conversion rate is difficult to reach more than 60 percent, and the reaction formula is shown as the following formula (V); 3) the acyl chloride and aniline need to be added with a acid-removing agent for reaction, or aniline itself is used as the acid-removing agent, so that the cost is increased; 4) the use of a large amount of thionyl chloride can cause a large amount of hydrogen chloride and sulfur dioxide waste gas, and cause serious environmental pollution;
in summary, the currently reported synthesis process of the dihydrooat alkaloid has the problems of low yield, long synthesis route, large environmental pollution, unsuitability for industrial production and the like; in view of the above, there is a need to develop a new process for synthesizing dihydroavenanthramide to solve the above problems.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, provides a preparation method of dihydrooat alkaloid, and solves the problems of low yield, long synthesis route, large environmental pollution, unsuitability for industrial production and the like of the existing synthesis process of dihydrooat alkaloid.
In order to solve the problems in the prior art, the invention is realized by the following technical scheme:
a method for preparing dihydro oat alkaloid comprises the following steps:
s1, preparation of p-hydroxy-phenyl propionate: taking p-hydroxyphenylpropionic acid and lower alcohol as raw materials, and carrying out esterification reaction under the action of a catalyst to obtain p-hydroxyphenylpropionate;
s2, preparation of a dihydrooat alkaloid crude product: taking the p-hydroxy-phenyl propionate and the anthranilic acid prepared in the step S1 as raw materials, and obtaining a crude product of the dihydrooat alkaloid after amine ester exchange and quenching treatment;
s3, preparation of a refined dihydrooat alkaloid product: and (5) recrystallizing and drying the crude dihydrooat alkaloid product prepared in the step (S2) to obtain the dihydrooat alkaloid.
Further, in step S1, the ratio of the p-hydroxyphenylpropionic acid to the lower alcohol is 1: (2-3) (W/V); the mass ratio of the p-hydroxyphenylpropionic acid to the catalyst is 1: (0.1-0.11).
Further, in step S1, the lower alcohol is selected from one of methanol, ethanol and isopropanol, and is preferably methanol.
Further, in step S1, the catalyst is selected from one of concentrated sulfuric acid, p-toluenesulfonic acid, polyphosphoric acid, boric acid, and solid super acids.
Further, in step S1, after the raw materials and the catalyst are added, heating and refluxing for 6-8 hours, removing excess lower alcohol after TLC monitoring reaction to obtain brown oily substance, and extracting, washing, drying and concentrating the oily substance to obtain p-hydroxy-phenyl propionate.
Further, in step S2, the amine transesterification catalyst is selected from one of trimethylaluminum, concentrated sulfuric acid, p-toluenesulfonic acid, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and DMAP, and is preferably concentrated sulfuric acid and p-toluenesulfonic acid.
Further, in step S2, the amine transesterification solvent is selected from one of DMSO and sulfolane.
Further, in step S2, the mass ratio of the p-hydroxy-phenyl propionate to the anthranilic acid is 1: (0.5 to 1); the mass ratio of the p-hydroxyphenylpropionate to the catalyst is 1: (0.14-0.2).
Further, in the step S2, adding the reaction raw materials, heating to 130-140 ℃, and carrying out heat preservation reaction for 6-8 hours; then cooling to below 70 ℃, slowly adding water, and stirring for 45-60 min at the temperature of 70-80 ℃; and finally, cooling to below 20 ℃, and performing suction filtration to obtain a crude product of the dihydrooat alkaloid.
Further, in step S3, the recrystallization solvent is selected from one of methanol, ethanol and isopropanol, and is preferably isopropanol.
The preparation process route of the dihydrooat alkaloid is shown as the following formula (VI):
compared with the prior art, the invention has the following advantages:
1) according to the invention, p-hydroxy-phenyl-propionic acid and lower alcohol are used as raw materials, and are subjected to esterification reaction to obtain p-hydroxy-phenyl-propionate, and then are subjected to amine ester exchange with anthranilic acid to obtain dihydro oat alkaloid, so that the process avoids using high-toxicity substances such as thionyl chloride, pyridine and the like, and generates less three wastes; meanwhile, the preparation process has short steps, the yield of the two-step reaction is over 80 percent, and the industrial large-scale production is facilitated;
2) the amine ester exchange catalyst is preferably concentrated sulfuric acid and p-toluenesulfonic acid, which is more favorable for reaction, and although the raw material has an aniline structure and can form aniline salt at low temperature, unstable aniline salt can be liberated at the temperature of more than 120 ℃, and continuously participates in the reaction, so that the conversion rate of the raw material is improved; the amine ester exchange solvent is preferably DMSO and sulfolane, the two solvents have high boiling point and good solubility, and meanwhile, the solvent has low toxicity, water solubility and simple post-treatment, and is convenient for refining and purifying the crude dihydroavenanthramide.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
FIG. 1 is a hydrogen spectrum of a dihydrooat alkaloid produced in accordance with the present invention;
FIG. 2 is an HPLC chromatogram of the dihydrooat alkaloid prepared in the present invention.
Detailed Description
The technical solution in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and all other embodiments obtained by those skilled in the art without any inventive work are within the scope of the present invention.
The conventional reagents and equipment used in the present invention are commercially available unless otherwise specified.
Example 1
A method for preparing dihydro oat alkaloid comprises the following steps:
s1, preparation of methyl p-hydroxyphenylpropionate: sequentially adding 50g of p-hydroxyphenylpropionic acid (1.0 eq), 150mL of methanol and 5g of concentrated sulfuric acid into a 250mL three-necked bottle, heating and refluxing for 6-8 h, removing excessive methanol after TLC monitoring reaction to obtain a brown oily substance, adding 100mL of dichloromethane into the oily substance, then adding 50mL of water, separating an organic phase, sequentially drying the organic phase with a saturated sodium bicarbonate solution and anhydrous magnesium sulfate, concentrating to obtain 53g of oily substance, wherein the HPLC purity is higher than 98%, recrystallizing the oily substance with an ethanol/water mixed solvent to obtain 48g of quasi-white crystal powder (methyl p-hydroxyphenylpropionate), the melting point is 38-39 ℃, and the yield is 89.2%;
s2, preparation of a dihydrooat alkaloid crude product: adding methyl p-hydroxyphenylpropionate (30g, 1.0eq), DMSO (100mL, 3.3V), anthranilic acid (23g, 1.0eq) and p-toluenesulfonic acid (5g, 0.17X) into a 250mL three-neck flask, heating to 130-140 ℃, and carrying out heat preservation reaction for 6-8 hours; then cooling to below 70 ℃, slowly adding 200-400 mL of water, and stirring for 45-60 min at the temperature of 70-80 ℃; finally, cooling to below 20 ℃, and performing suction filtration to obtain 60g of a crude dihydrooat alkaloid product;
s3, preparation of a refined dihydrooat alkaloid product: recrystallizing the coarse dihydrooat alkaloid product prepared in the step S2 with isopropanol, and drying to obtain 43g of dihydrooat alkaloid; the yield thereof was found to be 90%.
Performing nuclear magnetic resonance and HPLC analysis on the prepared dihydrooat alkaloid, wherein the hydrogen spectrum is shown in figure 1:
1H NMR(400MHz，DMSO)δppm 2.61-2.65(m，2H)，2.80-2.85(m，2H)，6.63-6.67(m，2H)，7.02-7.05(m，2H)，7.10-7.15(m，1H)，7.55-7.59(m，1H)，7.95-7.97(m，1H)，8.47-8.49(m，1H)，9.15(s，1H)，11.11(s，1H)，13.59(s，1H)；
the HPLC spectrum is shown in figure 2: the retention time is 10.483min, and the purity is 99.73%.
Example 2
A method for preparing dihydro oat alkaloid comprises the following steps:
s1, preparation of ethyl p-hydroxyphenylpropionate: adding p-hydroxyphenylpropionic acid (50g, 1.0eq), anhydrous ethanol 150mL and concentrated sulfuric acid 5g into a 250mL three-necked bottle in sequence, heating and refluxing for 6-8 h, removing excessive ethanol after TLC monitoring reaction is finished to obtain brown oily matter, adding petroleum ether into the oily matter for extraction, drying with saturated sodium bicarbonate solution and anhydrous magnesium sulfate in sequence, and concentrating to obtain oily matter 53.1g, wherein the HPLC purity is 99.6% and the yield is 91.5%;
s2, preparation of a dihydrooat alkaloid crude product: adding ethyl p-hydroxyphenylpropionate (50g, 1.0eq), sulfolane (100mL, 2V), anthranilic acid (35g, 1.0eq) and concentrated sulfuric acid (5g, 0.17X) into a 250mL three-necked bottle, heating to 130-140 ℃, and carrying out heat preservation reaction for 6-8 hours; then cooling to below 70 ℃, slowly adding 200-400 mL of water, and stirring for 45-60 min at the temperature of 70-80 ℃; finally, cooling to below 20 ℃, and performing suction filtration to obtain 100g of a crude product of the dihydrooat alkaloid;
s3, preparation of a refined dihydrooat alkaloid product: recrystallizing the crude dihydrooat alkaloid product prepared in the step S2 with isopropanol, and drying to obtain 61g of dihydrooat alkaloid; the yield was 83% and the HPLC purity was 99.1%.
Example 3
A method for preparing dihydro oat alkaloid comprises the following steps:
s1, preparation of methyl p-hydroxyphenylpropionate: sequentially adding p-hydroxyphenylpropionic acid (50g, 1.0eq), methanol (100 mL) and concentrated sulfuric acid (4.75 g) into a 250mL three-necked bottle, heating and refluxing for 6-8 h, removing excessive methanol after TLC monitoring reaction is finished to obtain brown oily matter, adding dichloromethane (100 mL) into the oily matter, then adding 50mL water, separating out an organic phase, sequentially drying the organic phase with saturated sodium bicarbonate solution and anhydrous magnesium sulfate, concentrating to obtain oily matter (53 g), wherein the HPLC purity is higher than 98%, recrystallizing the oily matter with an ethanol/water mixed solvent to obtain 48g of quasi-white crystal powder (methyl p-hydroxyphenylpropionate), the melting point is 38-39 ℃, and the yield is 89.2%;
s2, preparation of a dihydrooat alkaloid crude product: adding methyl p-hydroxyphenylpropionate (30g, 1.0eq), DMSO (100mL, 3.3V), anthranilic acid (26g, 1.0eq) and p-toluenesulfonic acid (4.8g, 0.17X) into a 250mL three-neck flask, heating to 130-140 ℃, and carrying out heat preservation reaction for 6-8 h; then cooling to below 70 ℃, slowly adding 200-400 mL of water, and stirring for 45-60 min at the temperature of 70-80 ℃; finally, cooling to below 20 ℃, and performing suction filtration to obtain 63g of a dihydrooat alkaloid crude product;
s3, preparation of a refined dihydrooat alkaloid product: recrystallizing the coarse dihydrooat alkaloid product prepared in the step S2 with isopropanol, and drying to obtain 44g of dihydrooat alkaloid; the yield was 91.9% and the purity was 99.65%.
Comparative example 1
The preparation method of dihydroavenanthramides is substantially the same as in example 1, except that in step S2, the temperature is raised to 100 ℃ for the incubation reaction.
As a result, it was found that the yield of dihydroavenanthramide was 65% and the HPLC purity was 89%. The aniline salt is formed by the reaction raw materials at low temperature, and does not participate in subsequent reaction, so that the product yield is low.
Comparative example 2
The preparation method of dihydroavenanthramides is substantially the same as in example 1, except that in step S2, the temperature is raised to 110 ℃ for the incubation reaction.
As a result, it was found that the yield of the dihydroavenanthramide was 70% and the HPLC purity was 90%. The aniline salt is formed by the reaction raw materials at low temperature, and does not participate in subsequent reaction, so that the product yield is low.
Comparative example 3
The preparation method of dihydroavenanthramides is essentially the same as in example 1, except that in step S2, the temperature is raised to 160 ℃ for the incubation reaction.
As a result, it was found that the yield of the obtained dihydroavenanthramide was 85% and the HPLC purity was 92%. This is because methyl p-hydroxyphenylpropionate is partially self-polymerized under high temperature conditions, resulting in a low yield of the product.
Comparative example 4
The preparation method of dihydroavenanthramides is substantially the same as in example 1, except that in step S2, the temperature is raised to 170 ℃ for the incubation reaction.
As a result, it was found that the yield of the dihydroavenanthramide was 80% and the HPLC purity was 91%. This is because methyl p-hydroxyphenylpropionate is partially self-polymerized under high temperature conditions, resulting in a lower yield of the product and the self-condensation reaction is more severe at higher temperatures.
In conclusion, the method takes the p-hydroxyphenylpropionic acid and the lower alcohol as raw materials, the p-hydroxyphenylpropionic acid ester is obtained through esterification, and then the p-hydroxyphenylpropionic acid ester and the anthranilic acid are subjected to amine ester exchange to obtain the dihydrooat alkaloid, so that the process avoids using high-toxicity substances such as thionyl chloride, pyridine and the like, and generates less three wastes; meanwhile, the preparation process has short steps, the yield of the two-step reaction is over 80 percent, and the industrial large-scale production is facilitated.
Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that: any person skilled in the art can modify or easily conceive the technical solutions described in the foregoing embodiments or equivalent substitutes for some technical features within the technical scope of the present disclosure; such modifications, changes or substitutions do not depart from the spirit and scope of the embodiments of the present invention, and they should be construed as being included therein.
Claims (10)
1. A preparation method of dihydro oat alkaloid is characterized by comprising the following steps:
s1, preparation of p-hydroxyphenylpropionate: taking p-hydroxyphenylpropionic acid and lower alcohol as raw materials, and carrying out esterification reaction under the action of a catalyst to obtain p-hydroxyphenylpropionic ester;
s2, preparation of a dihydrooat alkaloid crude product: taking the p-hydroxy-phenyl propionate and the anthranilic acid prepared in the step S1 as raw materials, and obtaining a crude product of the dihydrooat alkaloid after amine ester exchange and quenching treatment;
s3, preparation of a refined dihydrooat alkaloid product: and (5) recrystallizing and drying the crude dihydrooat alkaloid product prepared in the step (S2) to obtain the dihydrooat alkaloid.
2. The method of claim 1, wherein in step S1, the ratio of the p-hydroxyphenylpropionic acid to the lower alcohol is 1: (2-3) (W/V); the mass ratio of the p-hydroxyphenylpropionic acid to the catalyst is 1: (0.1-0.11).
3. The method of claim 1, wherein in step S1, the lower alcohol is selected from the group consisting of methanol, ethanol and isopropanol.
4. The method of claim 1, wherein in step S1, the catalyst is selected from the group consisting of concentrated sulfuric acid, p-toluenesulfonic acid, polyphosphoric acid, boric acid, and solid superacids.
5. The method for preparing dihydrooat alkaloid according to claim 1, wherein in step S1, after the raw material and the catalyst are added, the temperature is raised and the reflux reaction is carried out for 6-8 h, after the TLC monitoring reaction is finished, the excess lower alcohol is removed to obtain brown oily matter, and the oily matter is extracted, washed, dried and concentrated to obtain p-hydroxy-phenyl propionate.
6. The method of claim 1, wherein in step S2, the amine transesterification catalyst is selected from one of trimethylaluminum, concentrated sulfuric acid, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, DMAP.
7. The method of claim 1, wherein in step S2, the amine transesterification solvent is selected from one of DMSO and sulfolane.
8. The method of claim 6, wherein in step S2, the mass ratio of the p-hydroxy-phenyl propionate to the anthranilic acid is 1: (0.5 to 1); the mass ratio of the p-hydroxy-phenyl propionate to the catalyst is 1: (0.14-0.2).
9. The method for preparing dihydroavenanthramide according to claim 1, wherein in step S2, the temperature is raised to 130-140 ℃ after the reaction raw materials are added, and the reaction is carried out for 6-8 hours under the condition of heat preservation; then cooling to below 70 ℃, slowly adding water, and stirring for 45-60 min at the temperature of 70-80 ℃; and finally, cooling to below 20 ℃, and performing suction filtration to obtain a crude product of the dihydrooat alkaloid.
10. The method of claim 1, wherein in step S3, the recrystallization solvent is selected from one of methanol, ethanol, and isopropanol.
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|---|---|---|---|---|
| EP0333522A2 (en) * | 1988-03-18 | 1989-09-20 | MITSUI TOATSU CHEMICALS, Inc. | Catechol derivatives and pharmaceutical preparations containing same |
| WO2005016870A1 (en) * | 2003-08-14 | 2005-02-24 | Smithkline Beecham Corporation | 2-substituted benzoic acid derivatives as hm74a receptor agonists |
| CN104418764A (en) * | 2013-09-11 | 2015-03-18 | 上海伊明化学科技有限公司 | Method for synthesizing 4-hydroxy benzenepropionamido benzoic acid |
| CN109553550A (en) * | 2018-12-29 | 2019-04-02 | 上海克琴科技有限公司 | A kind of method of synthesizing dihydro oat alkaloid |
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| EP0333522A2 (en) * | 1988-03-18 | 1989-09-20 | MITSUI TOATSU CHEMICALS, Inc. | Catechol derivatives and pharmaceutical preparations containing same |
| WO2005016870A1 (en) * | 2003-08-14 | 2005-02-24 | Smithkline Beecham Corporation | 2-substituted benzoic acid derivatives as hm74a receptor agonists |
| CN104418764A (en) * | 2013-09-11 | 2015-03-18 | 上海伊明化学科技有限公司 | Method for synthesizing 4-hydroxy benzenepropionamido benzoic acid |
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