CN113698283A - Preparation method of salvia miltiorrhiza neoketone - Google Patents
Preparation method of salvia miltiorrhiza neoketone Download PDFInfo
- Publication number
- CN113698283A CN113698283A CN202111078711.7A CN202111078711A CN113698283A CN 113698283 A CN113698283 A CN 113698283A CN 202111078711 A CN202111078711 A CN 202111078711A CN 113698283 A CN113698283 A CN 113698283A
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- China
- Prior art keywords
- acid
- formula
- neoketone
- salt
- formate
- Prior art date
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- 241000304195 Salvia miltiorrhiza Species 0.000 title claims abstract description 22
- 235000011135 Salvia miltiorrhiza Nutrition 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- QRYRORQUOLYVBU-VBKZILBWSA-N carnosic acid Chemical compound CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 claims abstract description 80
- XUSYGBPHQBWGAD-PJSUUKDQSA-N Carnosol Chemical compound CC([C@@H]1C2)(C)CCC[C@@]11C(=O)O[C@@H]2C2=C1C(O)=C(O)C(C(C)C)=C2 XUSYGBPHQBWGAD-PJSUUKDQSA-N 0.000 claims abstract description 38
- MMFRMKXYTWBMOM-UHFFFAOYSA-N Carnosol Natural products CCc1cc2C3CC4C(C)(C)CCCC4(C(=O)O3)c2c(O)c1O MMFRMKXYTWBMOM-UHFFFAOYSA-N 0.000 claims abstract description 38
- 235000004654 carnosol Nutrition 0.000 claims abstract description 38
- 239000003054 catalyst Substances 0.000 claims abstract description 27
- 239000007800 oxidant agent Substances 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 16
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims abstract description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims abstract description 13
- 230000001590 oxidative effect Effects 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- -1 peroxyacid salt Chemical class 0.000 claims abstract description 7
- 229910001923 silver oxide Inorganic materials 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 14
- PAFLSMZLRSPALU-UHFFFAOYSA-N Salvianic acid A Natural products OC(=O)C(O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-UHFFFAOYSA-N 0.000 claims description 13
- 238000001953 recrystallisation Methods 0.000 claims description 13
- 229940044170 formate Drugs 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 229930194268 Salvianic acid Natural products 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 239000004280 Sodium formate Substances 0.000 claims description 7
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 7
- 235000019254 sodium formate Nutrition 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 238000006114 decarboxylation reaction Methods 0.000 claims description 6
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 6
- PAFLSMZLRSPALU-MRVPVSSYSA-N (2R)-3-(3,4-dihydroxyphenyl)lactic acid Chemical compound OC(=O)[C@H](O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-MRVPVSSYSA-N 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- 241000207923 Lamiaceae Species 0.000 claims description 5
- 235000017276 Salvia Nutrition 0.000 claims description 5
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 5
- 239000003495 polar organic solvent Substances 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 4
- 238000005899 aromatization reaction Methods 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- SRWMQSFFRFWREA-UHFFFAOYSA-M zinc formate Chemical compound [Zn+2].[O-]C=O SRWMQSFFRFWREA-UHFFFAOYSA-M 0.000 claims description 4
- CBOCVOKPQGJKKJ-UHFFFAOYSA-L Calcium formate Chemical compound [Ca+2].[O-]C=O.[O-]C=O CBOCVOKPQGJKKJ-UHFFFAOYSA-L 0.000 claims description 3
- 239000004281 calcium formate Substances 0.000 claims description 3
- 229940044172 calcium formate Drugs 0.000 claims description 3
- 235000019255 calcium formate Nutrition 0.000 claims description 3
- 150000001844 chromium Chemical class 0.000 claims description 3
- 150000001879 copper Chemical class 0.000 claims description 3
- PQQAOTNUALRVTE-UHFFFAOYSA-L iron(2+);diformate Chemical compound [Fe+2].[O-]C=O.[O-]C=O PQQAOTNUALRVTE-UHFFFAOYSA-L 0.000 claims description 3
- 150000002696 manganese Chemical class 0.000 claims description 3
- 150000002815 nickel Chemical class 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003751 zinc Chemical class 0.000 claims description 3
- 241001529742 Rosmarinus Species 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- 241001072909 Salvia Species 0.000 claims 1
- 235000019395 ammonium persulphate Nutrition 0.000 claims 1
- 150000004675 formic acid derivatives Chemical class 0.000 claims 1
- 235000019394 potassium persulphate Nutrition 0.000 claims 1
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
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- 238000001308 synthesis method Methods 0.000 abstract description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 abstract 1
- 239000007810 chemical reaction solvent Substances 0.000 description 21
- AIGAZQPHXLWMOJ-UHFFFAOYSA-N Tanshinone I Chemical compound C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 description 17
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 240000007164 Salvia officinalis Species 0.000 description 6
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- 229930183118 Tanshinone Natural products 0.000 description 4
- 239000012935 ammoniumperoxodisulfate Substances 0.000 description 4
- PHFQLYPOURZARY-UHFFFAOYSA-N chromium trinitrate Chemical compound [Cr+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O PHFQLYPOURZARY-UHFFFAOYSA-N 0.000 description 4
- 230000011987 methylation Effects 0.000 description 4
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- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 210000001772 blood platelet Anatomy 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000017858 demethylation Effects 0.000 description 3
- 238000010520 demethylation reaction Methods 0.000 description 3
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- 230000036961 partial effect Effects 0.000 description 3
- 150000004965 peroxy acids Chemical class 0.000 description 3
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- 210000004881 tumor cell Anatomy 0.000 description 3
- HARGZZNYNSYSGJ-UHFFFAOYSA-N 1,2 dihydrotanshinquinone Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)CO1 HARGZZNYNSYSGJ-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- 229910021555 Chromium Chloride Inorganic materials 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- HARGZZNYNSYSGJ-JTQLQIEISA-N Dihydrotanshinone I Chemical compound C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2[C@@H](C)CO1 HARGZZNYNSYSGJ-JTQLQIEISA-N 0.000 description 2
- 102000004300 GABA-A Receptors Human genes 0.000 description 2
- 108090000839 GABA-A Receptors Proteins 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 2
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 2
- FEFAIBOZOKSLJR-UHFFFAOYSA-N Miltirone Chemical compound C1CCC(C)(C)C=2C1=C1C(=O)C(=O)C(C(C)C)=CC1=CC=2 FEFAIBOZOKSLJR-UHFFFAOYSA-N 0.000 description 2
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 2
- 102000004495 STAT3 Transcription Factor Human genes 0.000 description 2
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- YMGFTDKNIWPMGF-QHCPKHFHSA-N Salvianolic acid A Natural products OC(=O)[C@H](Cc1ccc(O)c(O)c1)OC(=O)C=Cc2ccc(O)c(O)c2C=Cc3ccc(O)c(O)c3 YMGFTDKNIWPMGF-QHCPKHFHSA-N 0.000 description 2
- YMGFTDKNIWPMGF-UCPJVGPRSA-N Salvianolic acid A Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C(=C(O)C(O)=CC=1)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 YMGFTDKNIWPMGF-UCPJVGPRSA-N 0.000 description 2
- HYXITZLLTYIPOF-UHFFFAOYSA-N Tanshinone II Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
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- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
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- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 description 2
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- 239000001233 rosmarinus officinalis l. extract Substances 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 229940112950 sage extract Drugs 0.000 description 1
- 235000020752 sage extract Nutrition 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- C07C46/00—Preparation of quinones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
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Abstract
The invention discloses a preparation method of salvia miltiorrhiza neoketone, which comprises the following steps: carnosic acid is used as a raw material, peroxyacid salt or silver oxide is used as an oxidant, salt formed by elements in the fourth period is used as a catalyst, and carnosol can be obtained in high yield through oxidation reaction; the carnosol is heated to react under the catalysis of formate, and the danshenxinone can be obtained in one step. The synthesis method has simple and convenient operation and high yield, avoids using toxic dimethyl sulfate, boron tribromide and trimethylsilyl trifluoromethanesulfonate as reagents, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a preparation method of salvia miltiorrhiza neoketone.
Background
Salvianolic acid (miltione), also known as hypophansquinone, is a fat-soluble component extracted from Salvia officinalis of Labiatae, and 1970 is obtained by separating Salvia miltiorrhiza for the first time. Is the tenth diterpene quinine compound separated from the salvia miltiorrhiza bunge. The molecular formula is shown as follows:
salvianolic acid has wide bioactivity. As central sedatives, partial agonism is achieved on benzodiazepine receptors, and it has been found that most currently widely used central sedatives with good effect have addiction and dependence, while danshenxinone, as a benzodiazepine partial receptor agonist, has a low risk of addiction and dependence (Lee C.M., Wong H., Chui K.Y., et al.Miltiron, a central benzodiazepine receptor partial agonist from a central medicinal tissue of a nuclear tissue of a clinical laboratory Salvia a milirthia militaria.Neurosci.Lett, 1991,127(2): 237-241.). Furthermore, danshenxintong, as an antitumor agent, has an inhibitory effect on STAT3, and is capable of inhibiting the growth of tumor cells and abnormal activation of STAT3 in tumor cells, thereby causing apoptosis of tumor cells, and also enhancing the sensitivity of cytotoxic drugs (Wang X, Morris-nature SL, Lee k. new definitions in the chemistry and biology of the biological activity constraints of tanshenn. med. res. rev.2007,27(1): 133-. As a tanshinone medicine, the danshenxintong can obviously inhibit excessive activation of blood platelets, reduce blood platelet aggregation, reduce the viscosity of blood plasma and whole blood and inhibit thrombosis (Ulmus, Huxiaojie, Wangning, etc. active ingredients in the root of red-rooted salvia for inhibiting the blood platelet aggregation. pharmaceutical science, 1988(11): 830-834.).
The danshenxinone has wide bioactivity, but the content is very low, which restricts the deep research and development of the danshenxinone to a certain extent. Four main tanshinone compounds in salvia are reported: tanshinone IIA, cryptotanshinone, tanshinone I and dihydrotanshinone I, wherein the content of tanshinone IIA is highest and is about 0.1-0.4%; the content of the dihydrotanshinone I is the lowest and is about 0.01-0.04% (blue sky phoenix, king dawn, king Dajie, king light, Liuqing, in Zongyuan. A Messangpo evaluation method determines 4 tanshinone components in salvia miltiorrhiza, Chinese herbal medicines 2012,43(12), 2420-. However, the content of the salvianic acid A neoketone is too low, and the accurate content measurement of the salvianic acid A neoketone is not reported. Through CNKI literature retrieval, a relevant literature (Liu 21180, Yang Huanghao, Li Xianchun, Wang, high performance liquid chromatography-electrospray flight time mass spectrometry analysis of tanshinone compounds in red sage root, journal of mass spectrometry, 2008,29(5), 261 plus 267) is discovered, and the content of tanshinone is estimated to be about 1/5 of tanshinone I, namely about 0.002-0.008% by comparing and analyzing chromatograms of 4 main tanshinone compounds and tanshinone. Obviously, the extraction of the salvianic acid neoketone from the plant is extremely difficult, so that the problem of the source of the salvianic acid neoketone needs to be solved for the intensive research and development of the salvianic acid neoketone.
The sources of the salvia miltiorrhiza neoketone mainly depend on chemical synthesis at present, and the methods comprise total synthesis and semi-synthesis. The known total synthesis method or synthesis path is long, or partial intermediates are expensive and difficult to obtain, so that the total synthesis cost is high; or although the raw material price is not high, the reaction steps are more, the post-treatment is complicated, and the method has a certain distance from the industrial production.
The method obtains the novel salvia miltiorrhiza ketone through seven steps of reaction (see: Huang W.G., Li Y.F., Lu W. & Aisa H.A.Total synthesis of national company, 2006,42(6), 665-. From the above reaction conditions, the grignard reaction (step d) which has strict requirements for anhydrous and oxygen-free operation and the toxic hydrogen chloride (step c) are used, and the method can be only used for preparing the salvia miltiorrhiza neoketone in a laboratory and has large pollution to the environment.
Currently, the research is mostly semi-synthetic methods, and the representative work is to obtain the compound danshenxintong by methylation, rearrangement and demethylation using the natural product carnosol as the raw material (see: Luis J.G., Andres L.S., Fletcher W.Q., et al.Rearrangerment of methyl 11,12-di-O-methyl-6, 7-dihydrocarnosate in basic medium. easy synthesis of magnesium. journal of the Chemical Society, Perkin Transactions 1,1996 (2207) -2211.).
The starting material carnosol for this reaction is expensive and its preparation is protected by PCT patent (a process for producing carnosol from carnosic acid using hydrogen peroxide or a peracid application No. 200880112717.8). The reagents hydrogen peroxide and peracid used in the reaction have certain potential safety hazards, and the solvents glacial acetic acid used in the reaction have high irritation and are not environment-friendly, so that the mass preparation of the raw materials is not easy.
During the experiment for preparing the salvianic acid neoketone by the carnosol, the reaction has the following defects: dimethyl sulfate and boron tribromide are used as reagents for methylation and demethylation in the reactions, the dimethyl sulfate is a highly toxic organic compound, and the boron tribromide has strong corrosivity, relatively high price and great environmental pollution, and is not beneficial to industrial production of the salvia miltiorrhiza neoketone. ② the total yield of the reaction is not high, only about 20 percent. Wherein, the lactone ring is not easy to open in the step a, the methylation is incomplete, and the carboxyl in the step b is easy to aromatize in the rearrangement process, so that the decarboxylation in the step c is incomplete. Several intermediates of the reaction basically need to be purified by column chromatography, so that the whole operation process is relatively complicated and is not easy to realize industrial production.
Recently, Salvia miltiorrhiza neoketone is obtained by decarboxylation aromatization one-step reaction by adding Lewis acid into carnosic acid as a raw material (see: preparation methods of Salvia miltiorrhiza neoketone and dehydroSalvia miltiorrhiza neoketone, patent application No. 201810006572.9; Li, C.J.; Xia, F.; Zhang, W., et al.Semisynthesis of millitron, 1, 2-dehydromillitron, Saliger from carnosic acid and cycloxities of the hair derivative. tetrahedron Letters 59(2018)2607 TfTf.), but the Lewis acid trimethylsilyl Trifluoromethanesulfonate (TMSO) is a liquid flammable reagent, reacts with water, is not easy to store, has severe skin corrosiveness (class 1B), can cause severe eye injury (class 1), and the final product needs to be purified by silica gel column chromatography, thereby limiting the industrial degree.
Disclosure of Invention
The invention aims to provide a preparation method of salvia miltiorrhiza neoketone, which solves the problems.
The invention realizes the purpose through the following technical scheme: a preparation method of salvianic acid neoketone is characterized by comprising the steps of taking carnosic acid as a raw material, taking salt formed by elements in the fourth period as a catalyst and taking peroxoate or silver oxide as an oxidant in a water-containing polar organic solvent system to obtain carnosol, wherein the reaction is as shown in a formula (1):
compared with the prior art, the reaction has the advantages that the reaction efficiency is greatly improved, the yield can reach more than 90%, the peroxyacid salt or the silver oxide is used as an oxidant, the reaction environment is mild and safe, the potential safety hazard caused by using hydrogen peroxide and peracid is avoided, in addition, glacial acetic acid with strong irritation is abandoned, the environment is very friendly, and the industrial production is easier.
Preferably, the carnosic acid is derived from an extract of a plant belonging to the genus Salvia of the family Labiatae, or from an extract of another plant belonging to the family Labiatae, such as rosemary, etc., and the purity of the carnosic acid is not limited, but the product obtained by reacting more than or equal to 50% of the raw materials can be purified by recrystallization, avoiding column chromatography.
Preferred polar organic solvents in the present invention are methanol, ethanol, isopropanol, butanol and acetonitrile. The formula (1) can react at room temperature and in a heating state, and the heating temperature is less than or equal to 100 ℃.
As a preferable mode of the present invention, the salt formed by the fourth period element includes a chromium salt, a manganese salt, a nickel salt, a copper salt and a zinc salt. Wherein the chromium salt comprises chromium acetate, chromium sulfate, chromium nitrate, and chromium chloride; manganese salt comprises manganese sulfate, manganese chloride, and manganese acetate; the nickel salt comprises nickel sulfate, nickel chloride, nickel bromide and nickel iodide; the copper salt comprises copper carbonate, copper sulfate, copper nitrate, copper chloride and copper acetate; the zinc salt includes zinc nitrate, zinc chloride, zinc sulfate, and zinc acetate.
Preferably, the peroxyacid salts include potassium persulfate, ammonium persulfate, and potassium and ammonium peroxodisulfate.
In the present invention, the amount of the catalyst used in the formula (1) is preferably 0.5% or more and the amount of the oxidizing agent used is preferably 50% or more, based on the molar ratio of the raw materials.
As the optimization of the invention, the obtained carnosol can generate decarboxylation and aromatization reaction under the catalysis and heating condition of formate, and the product is recrystallized to obtain the salvia miltiorrhiza neoketone, wherein the reaction is as shown in formula (2):
the reaction can prepare the salvia miltiorrhiza neoketone by only one step, is promoted by the nucleophilic substitution reaction of formate, and greatly improves the reaction efficiency compared with the existing literature for preparing the salvia miltiorrhiza neoketone by four steps of methylation, rearrangement reaction, demethylation and oxidation reaction of carnosol.
As a preferred aspect of the present invention, the formate includes sodium formate, ammonium formate, calcium formate, iron formate, zinc formate.
In the present invention, the amount of formate in the formula (2) is preferably 10% or more based on the raw material in terms of molar ratio.
In the reaction of the formula (2), the reaction is preferably carried out under heating, but the side reactions are significantly increased when the temperature exceeds 150 ℃, and the heating temperature is preferably controlled to 50 to 150 ℃, preferably 70 to 140 ℃, and more preferably 100 to 120 ℃.
Preferably, in the reaction of formula (2), the presence of formate is an irreplaceable reaction condition, and the reaction cannot be promoted by using other organic salts or inorganic salts, and the catalytic reaction mechanism is illustrated by sodium formate here as follows: firstly, the formate attacks the electron-deficient center on a lactone ring to break the inner ester bond of carnosol to form formate, and the formate is isomerized at high temperature to remove formyloxy; subsequently, the o-diphenol is oxidized into quinone, and then decarboxylation, isomerization and oxidation are carried out to form the danshenxinone.
Preferably, in the reaction of formula (2), the purity of the raw material is not limited, and the raw material can be purified carnosol or a crude intermediate which is not processed in the first step of reaction, wherein the content of the carnosol is 10-90%, but the danshenxineon product prepared by reacting the high-purity carnosol is beneficial to direct recrystallization, and the yield and the purity are higher.
Compared with the prior art, the invention has the following beneficial effects: the invention provides a novel synthesis method of salvia miltiorrhiza neoketone, which can obtain the salvia miltiorrhiza neoketone by only two steps of reactions, has high yield, low cost, safe preparation process, environmental protection and no need of column chromatography, and is suitable for industrial production.
Drawings
FIG. 1 is a schematic diagram of the reaction mechanism of carnosol in the presence of formate to convert danshenxinone according to the present invention.
Detailed Description
The invention will be further described with reference to the accompanying figure 1:
example 1
In a 500ml three-necked flask, 3.32g of carnosic acid was added, 250ml of 60% acetonitrile was added as a reaction solvent, 1.4g of potassium persulfate as an oxidizing agent and 0.2g of manganese chloride as a catalyst were added, respectively, and the reaction was carried out at 40 ℃ for 5 hours, followed by recrystallization to obtain 3.0g of carnosol with a yield of 90.9%. Putting 3.0g carnosol into a 500ml three-necked bottle, adding 200ml dioxane as a reaction solvent, 0.55g sodium formate as a catalyst, heating to react at 115 ℃ for 10 hours, and recrystallizing with methanol/acetic acid to obtain 2.27g danshenxintong with 88.7% yield. The total yield is 80.6%.
Example 2
In a 1000ml three-necked flask, 9.49g of rosemary extract with a carnosic acid content of 70% was added, 500ml of 40% ethanol was added as a reaction solvent, 4.2g of ammonium peroxodisulfate as an oxidizing agent and 1.0g of manganese acetate as a catalyst were added, and the mixture was reacted at 80 ℃ for 10 hours, followed by recrystallization to obtain 6.01g of carnosol with a yield of 91.1%. Putting 6.01g carnosol into a 500ml three-necked bottle, adding 200ml dimethylformamide as a reaction solvent and 1.2g ammonium formate as a catalyst, heating and reacting at 85 ℃ for 12 hours, and recrystallizing with ethanol/formic acid to obtain 4.72g of danshenxinone with a yield of 91.9%. The total yield was 83.7%.
Example 3
Adding 16.6g of sage extract with the carnosic acid content of 20% into a 1000ml three-necked bottle, adding 500ml of 5% butanol as a reaction solvent, respectively adding 5.6g of ammonium persulfate as an oxidant and 0.5g of zinc acetate as a catalyst, reacting at 55 ℃ for 8 hours, and recrystallizing to obtain 3.04g of carnosol with the yield of 92.1%. Putting 3.04g carnosol into a 500ml three-necked bottle, adding 200ml dimethyl sulfoxide reaction solvent and 2.6g iron formate as a catalyst, heating and reacting at 140 ℃ for 5 hours, and recrystallizing with methanol to obtain 2.41g danshenxintong with the yield of 92.9%. The total yield is 85.6%.
Example 4
In a 500ml three-necked flask, 4.25g of carnosic acid was charged, 230ml of 80% isopropyl alcohol was added as a reaction solvent, 3.8g of potassium peroxodisulfate as an oxidizing agent and 1.7g of chromium nitrate as a catalyst were added, and the mixture was reacted at 90 ℃ for 24 hours. The isopropanol was evaporated under reduced pressure and recrystallized to give carnosol 4.01g with a yield of 94.9%. Putting 4.01g carnosol into a 500ml three-necked bottle, adding 200ml toluene as a reaction solvent and 6.1g zinc formate as a catalyst, heating and reacting at 110 ℃ for 6 hours, and recrystallizing the product with isopropanol to obtain 3.22g of danshenxinone, wherein the yield is 94.0%. The total yield is 89.2%.
Example 5
Adding 33.2g of carnosic acid into a 5000ml three-necked bottle, adding 2600ml of 95% butanol as a reaction solvent, respectively adding 23.1g of silver oxide as an oxidant and 2.8g of manganese sulfate as a catalyst, reacting at 100 ℃ for 6 hours, and recrystallizing to obtain 31.3g of carnosol with the yield of 94.8%. 31.3g carnosol is put into a 5000ml three-necked bottle, 2000ml dimethylformamide is added as a reaction solvent, 28g sodium formate is used as a catalyst, the mixture is heated and reacted for 6 hours at the temperature of 130 ℃, and 24.83g of salvia miltiorrhiza neoketone is obtained by recrystallization through acetic acid, and the yield is 92.8%. The total yield was 88.0%.
Example 6
In a 5000ml three-necked flask, 33.2g of carnosic acid was charged, 2600ml of 90% methanol was added as a reaction solvent, 14.6g of ammonium peroxodisulfate as an oxidizing agent and 2.1g of chromium chloride as a catalyst, respectively, and reacted at 60 ℃ for 10 hours, followed by recrystallization to obtain 30.8g of carnosol with a yield of 93.3%. 30.8g of carnosol is put into a 5000ml three-necked bottle, 2000ml of ethylene glycol is added as a reaction solvent, 15g of calcium formate is used as a catalyst, the mixture is heated and reacted for 3 hours at the temperature of 150 ℃, and 24.2g of danshenxinone is obtained by recrystallization of formic acid, wherein the yield is 91.9%. The total yield is 85.7%.
Example 7
Adding 33.2g of carnosic acid into a 5000ml three-necked bottle, adding 2300ml of 50% acetonitrile serving as a reaction solvent, respectively adding 12.6g of silver oxide serving as an oxidant and 2.1g of nickel sulfate serving as a catalyst, reacting at 50 ℃ for 9 hours, and recrystallizing to obtain 30.1g of carnosol with the yield of 90.7%. 30.1g carnosol is put into a 5000ml three-necked bottle, 2500ml dimethylformamide is added as a reaction solvent, 26g sodium formate is used as a catalyst, the mixture is heated and reacted for 7 hours at the temperature of 130 ℃, and 22.9g of danshenxinone is obtained by methanol/formic acid recrystallization, wherein the yield is 89.0%. The total yield is 80.7%.
Example 8
In a 5000ml three-necked bottle, 33.2g of carnosic acid was added, 2400ml of 15% isopropanol was added as a reaction solvent, 21.7g of ammonium persulfate was added as an oxidizing agent, 1.6g of zinc chloride was added as a catalyst, the reaction was carried out at 95 ℃ for 3 hours, and 29.9g of carnosol was obtained by recrystallization, with a yield of 90.6%. Putting 29.9g carnosol into a 5000ml three-necked bottle, adding 2500ml tetrahydrofuran as a reaction solvent and 30g ammonium formate as a catalyst, heating and reacting at 70 ℃ for 24 hours, and recrystallizing with ethanol/acetic acid to obtain 23.5g danshenxinone with a yield of 92.0%. The total yield was 83.4%.
Example 9
In a 5000ml three-necked flask, 33.2g of carnosic acid was added, 2500ml of 50% acetonitrile was added as a reaction solvent, 17.9g of potassium persulfate as an oxidizing agent and 0.9g of copper chloride as a catalyst were added, and the mixture was reacted at 50 ℃ for 8 hours, followed by recrystallization to obtain 31.2g of carnosol with a yield of 94.5%. 31.2g of carnosol is put into a 5000ml three-necked bottle, 2500ml of dimethylformamide is added as a reaction solvent, 27g of zinc formate is added as a catalyst, the mixture is heated and reacted for 24 hours at the temperature of 70 ℃, and the mixture is recrystallized by ethanol to obtain 24.7g of danshenxinone, wherein the yield is 92.6%. The total yield is 87.5%.
Example 10
In a 5000ml three-necked flask, 33.2g carnosic acid, 2200ml of 70% acetonitrile as a reaction solvent, 29.3g ammonium peroxodisulfate as a reaction solvent, 3.6g nickel bromide as a catalyst were added, and the mixture was reacted at 80 ℃ for 5 hours, followed by recrystallization to obtain 29.9g carnosol with a yield of 90.6%. Putting 29.9g carnosol into a 5000ml three-necked bottle, adding 2500ml dimethylformamide as a reaction solvent and 12.8g sodium formate as a catalyst, heating to react at 120 ℃ for 4 hours, and recrystallizing with isopropanol/acetic acid to obtain 22.6g of danshenxinone with a yield of 88.5%. The total yield is 80.2%.
The foregoing illustrates and describes the principles, general features, and advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed.
Claims (12)
1. A preparation method of salvia miltiorrhiza neoketone comprises the following steps:
1) carnosic acid is prepared in a polar organic solvent containing water by taking salt formed by elements in the fourth period as a catalyst and one or two of peroxonate and silver oxide as an oxidant to obtain carnosol, wherein the reaction is as shown in formula (1):
2) dissolving the obtained carnosol in a corresponding solvent, performing decarboxylation and aromatization reactions under the catalysis and heating conditions of formate, and recrystallizing the product to obtain the salvia miltiorrhiza neoketone, wherein the reaction is as shown in formula (2):
2. the method for preparing salvianic acid neoketone according to claim 1, wherein the method for preparing carnosol comprises the following steps:
(1) providing raw material carnosic acid;
(2) providing an aqueous polar organic solvent;
(3) salt is used as a catalyst, and the salt is formed by the fourth period element;
(4) one or two of peroxoate and silver oxide are used as an oxidant;
(5) reacting at the temperature of less than or equal to 100 ℃. .
3. The method for preparing salvianic acid neoketone as claimed in claim 2, wherein the method for preparing salvianic acid neoketone comprises the following steps:
(1) providing raw material carnosol;
(2) formate is used as a catalyst;
(3) reacting at the temperature of less than or equal to 150 ℃, wherein the reaction comprises decarboxylation, aromatization and recrystallization.
4. The method of claim 2, wherein the carnosic acid is derived from the extract of Salvia of Labiatae, or from other Labiatae such as rosemary, and the purity of carnosic acid is not limited, but 50% is advantageous for the reaction and post-treatment.
5. The method for preparing salvianic acid A neoketone as claimed in claim 1, wherein the amount of the catalyst in formula (1) is more than 0.5% of the raw material, and the amount of the oxidant is more than 50% of the raw material; the consumption of the formate in the formula (2) is more than 10% of the raw material.
6. The method of claim 2, wherein the aqueous polar organic solvent of formula (1) comprises methanol, ethanol, acetic acid, isopropanol, ethylene glycol, butanol and acetonitrile; the solvent of formula (2) is selected from one of methanol, ethanol, isopropanol, acetic acid, acetonitrile, DMF, DMSO or any mixture of the above solvents.
7. The method of claim 2, wherein the reaction of formula (1) is carried out at room temperature and under heating at 100 ℃.
8. The method of claim 2, wherein the salt of the fourth period element of formula (1) comprises a chromium salt, a manganese salt, a nickel salt, a copper salt, and a zinc salt.
9. The method of claim 2, wherein the peroxyacid salt of formula (1) comprises potassium persulfate, ammonium persulfate, potassium peroxydisulfate, or ammonium peroxydisulfate.
10. The method according to claim 3, wherein the formate salt of formula (2) comprises sodium formate, ammonium formate, calcium formate, iron formate, zinc formate.
11. The method for preparing salvianic acid A neoketone as claimed in claim 3, wherein the temperature of the formula (2) is 50-150 ℃ during the heating reaction.
12. The method for preparing salvianic acid A neoketone as claimed in claim 1, wherein the solvent for recrystallization of the product of formula (2) is selected from an alcohol solvent and an acid solvent, or a combination of the alcohol solvent and the acid solvent, wherein the alcohol solvent comprises methanol, ethanol, isopropanol; the acid solvent comprises formic acid and acetic acid.
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| MASAHIRO TADA ET AL.: "Syntheses of Carnosic Acid and Carnosol, Anti-oxidants in Rosemary, from Pisiferic Acid, the Major Constituent of Sawara", 《CHEM. PHARM. BULL.》, vol. 58, no. 1, pages 27 - 29 * |
| 杨保津: "丹参的活性成分", 中成药, no. 03, pages 36 - 37 * |
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