CN101570564B - Method for refining tanshinone II A acrylic acid - Google Patents
Method for refining tanshinone II A acrylic acid Download PDFInfo
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- CN101570564B CN101570564B CN2009100268368A CN200910026836A CN101570564B CN 101570564 B CN101570564 B CN 101570564B CN 2009100268368 A CN2009100268368 A CN 2009100268368A CN 200910026836 A CN200910026836 A CN 200910026836A CN 101570564 B CN101570564 B CN 101570564B
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- CN
- China
- Prior art keywords
- tanshinone
- acid
- content
- vinylformic acid
- alkyl chloride
- Prior art date
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- HYXITZLLTYIPOF-UHFFFAOYSA-N 1,6,6-trimethyl-8,9-dihydro-7H-naphtho[1,2-g]benzofuran-10,11-dione Chemical compound O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 title claims abstract description 194
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 title claims abstract description 95
- 238000000034 method Methods 0.000 title claims abstract description 33
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000007670 refining Methods 0.000 title claims abstract description 14
- 238000000746 purification Methods 0.000 claims abstract description 13
- 238000004440 column chromatography Methods 0.000 claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 58
- 239000000047 product Substances 0.000 claims description 48
- 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 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 239000011259 mixed solution Substances 0.000 claims description 25
- 239000012043 crude product Substances 0.000 claims description 22
- 150000001348 alkyl chlorides Chemical class 0.000 claims description 20
- 150000007524 organic acids Chemical class 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- 229960001866 silicon dioxide Drugs 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 239000000284 extract Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- -1 alkyl chloride organic acid Chemical class 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- AZEZEAABTDXEHR-UHFFFAOYSA-M sodium;1,6,6-trimethyl-10,11-dioxo-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-2-sulfonate Chemical compound [Na+].C12=CC=C(C(CCC3)(C)C)C3=C2C(=O)C(=O)C2=C1OC(S([O-])(=O)=O)=C2C AZEZEAABTDXEHR-UHFFFAOYSA-M 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 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 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- 238000012545 processing Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- PQUXFUBNSYCQAL-UHFFFAOYSA-N 1-(2,3-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1F PQUXFUBNSYCQAL-UHFFFAOYSA-N 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 229940047670 sodium acrylate Drugs 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 229930183118 Tanshinone Natural products 0.000 description 5
- ZMQBBPRAZLACCW-UHFFFAOYSA-N acetic acid;dichloromethane Chemical compound ClCCl.CC(O)=O ZMQBBPRAZLACCW-UHFFFAOYSA-N 0.000 description 5
- 238000010812 external standard method Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- JYHBPKNOVQWAPT-UHFFFAOYSA-N chloroform;formic acid Chemical compound OC=O.ClC(Cl)Cl JYHBPKNOVQWAPT-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- GPFHRLLWVCEBRS-UHFFFAOYSA-N dichloromethane;formic acid Chemical compound OC=O.ClCCl GPFHRLLWVCEBRS-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000004237 preparative chromatography Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 238000005842 biochemical reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010262 high-speed countercurrent chromatography Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- WOAHJDHKFWSLKE-UHFFFAOYSA-N 1,2-benzoquinone Chemical compound O=C1C=CC=CC1=O WOAHJDHKFWSLKE-UHFFFAOYSA-N 0.000 description 1
- QSLUMWFISVQCLL-UHFFFAOYSA-N 1,2-dichloroethane;formic acid Chemical compound OC=O.ClCCCl QSLUMWFISVQCLL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- UUAGGCIRJYEZQD-UHFFFAOYSA-N acetic acid;1,2-dichloroethane Chemical compound CC(O)=O.ClCCCl UUAGGCIRJYEZQD-UHFFFAOYSA-N 0.000 description 1
- GGISZLOBBISXOZ-UHFFFAOYSA-N acetic acid;chloroform Chemical compound CC(O)=O.ClC(Cl)Cl GGISZLOBBISXOZ-UHFFFAOYSA-N 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- JRMSIIFHZABOHG-UHFFFAOYSA-N dichloromethane;propanoic acid Chemical compound ClCCl.CCC(O)=O JRMSIIFHZABOHG-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000037324 pain perception Effects 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N para-benzoquinone Natural products O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for refining tanshinone II A acrylic acid, which can improve the content of the tanshinone II A acrylic acid in a coarse product from about 45 to 50 percent to over 96percent finally. The method comprises: a first step, in which the coarse product is initially processed by the method of the invention to make the content of the tanshinone II A acrylic acid reach 80 to 92 percent; and a second step, in which the sample which contains 80 to 92 percent of the tanshinone II A acrylic acid and subjected to initial processing are separated and purified by column chro matography to make the content of the tanshinone II A acrylic acid reach over 96 percent. The method has the advantages of avoiding a bottleneck of prior tanshinone II A derivative purification technology, achieving a tanshinone II A acrylic acid content of over 96 percent, along with simple operation, easy industrialization and high yield.
Description
Technical field
The present invention relates to a kind of Tanshinone II A derivative separation purification method, the acrylic acid process for purification of particularly a kind of Tanshinone II A belongs to medical technical field.
Background technology
TANSHINONES is the efficient part that extracts from salviamiltiorrhizabung, and it is the two obedient class quinone ketone compounds that a class has o-quinone or para-quinoid structure.Tanshinone compound meta-bolites in vivo participates in the multiple biochemical reaction of body, and as coenzyme some biochemical reaction is played promotion or interference effect, and shows multiple pharmacological effect, as anticancer, antibiotic, antiviral, the pharmacological action of anti-oxidant and cardiovascular aspect.
Tanshinone II A is one of effective constituent in the Radix Salviae Miltiorrhizae extract, but because its water-soluble extreme difference, be difficult to bring into play pharmacological action, domestic through for many years research, be made into sulfonate sodium, make it have better water solubility, this compound is observed for many years through clinical, have determined curative effect, the advantage that side effect is little is widely used in the treatment of cardio-cerebrovascular diseases.
But because therefore the less stable of sodium tanshinone IIA sulfate must keep when making the prescription of liquid drugs injection acid (pH value is about 5), therefore patient has certain pain perception when injection is used.Its stability is also not ideal enough in addition.
Given this, Chinese patent CN200510095006,200610039929.0 grades disclose a series of soluble derivatives of Tanshinone II A, as ammonium salt, carboxylate salt etc.Wherein, the structural formula of Tanshinone II A sodium acrylate is as follows:
Through preliminary pharmacological screening, proved that the Tanshinone II A sodium acrylate has identical pharmacological action with sodium tanshinone IIA sulfate salt, and certain advantage has been arranged from drug effect.But CN200510095006 only provides the Tanshinone II A synthesis of conjugated carboxylic alkeneacid, the acrylic acid process for purification of Tanshinone II A is not had detailed description.
As everyone knows, the Tanshinone II A derivative is because its special rigid planar structure, in most organic solvents, be difficult to dissolving, Tanshinone II A vinylformic acid is because the character of the impurity that produces in building-up process is very similar to Tanshinone II A vinylformic acid in addition, therefore, find suitable process for purification that the TANSHINONES carboxylic acid derivative is become and to be successfully applied to clinical medicine, have fundamental influence.
Tanshinone II A compounds prior art mainly is a Tanshinone II A sulfonic acid, its process for purification mainly contains: a high-speed countercurrent chromatography (CN00120986.8) b recrystallization method (200610095296.5) c column chromatography (CN200710172251.8) d preparative chromatography etc., for example: Chinese patent 200610095296.5 uses methyl alcohol, water, acetone system recrystallization makes the content of sodium tanshinone IIA sulfate bring up to 99% (unreceipted analytical procedure), and will can only reach 90% (HPLC method) with the refining repeatedly high-content of pure water or methanol acetone water behind the vinylformic acid salify of 80% content.It is acrylic acid refining that the column chromatography system of Chinese patent CN200710172251.8, the especially described moving phase of this patent can't be used for Tanshinone II A.Its chromatogram system of the described high-speed countercurrent chromatography of Chinese patent CN00120986.8 especially moving phase can't to be applied to TANSHINONES acrylic acid refining.Tanshinone II A vinylformic acid uses preparative chromatography purified effect also undesirable.For example: 10 milligrams of Tanshinone II A sodium acrylates (content 80%) are dissolved in 2 ml methanol, and the preparative chromatography sample introduction is collected the peak value flow point, is spin-dried for, and it is 83% that HPLC measures content.
The contriver is refining with recrystallization method to Tanshinone II A vinylformic acid, is 80% Tanshinone II A vinylformic acid with 0.3 gram content, adds 20 milliliters of propyl carbinols, heating for dissolving, and cooling crystallization filters, and oven dry back HPLC mensuration content is 83%.What recrystallization method content was difficult to improve is former because Tanshinone II A vinylformic acid is similar to the solubleness of impurity in solvent, is difficult to improve content with recrystallization method.
The contriver is refining with column chromatography to Tanshinone II A vinylformic acid, is 85% treated Tanshinone II A vinylformic acid with 0.1 gram content, is elutriant with ethyl acetate acetate, silica gel is that stationary phase carries out column chromatography, collect red elutriant, be spin-dried for, it is 87% that HPLC measures content.The reason that content is difficult to improve is that the solubleness of Tanshinone II A vinylformic acid in this mixed solution is relatively poor, and more chief reason is that this mixing solutions does not have suitable polarity, and the wash-out of Tanshinone II A vinylformic acid and impurity is not had selectivity.
With impure Tanshinone II A vinylformic acid (content 80%), under ice bath cooling, be solvent and sodium bicarbonate salify with methyl alcohol, obtain the Tanshinone II A sodium acrylate of content 80%, with this sodium salt with methyl alcohol, water, alcohol mixed solvent repeatedly behind the recrystallization HPLC content be 90%, be difficult to improve again.What content was difficult to improve is former because salify rear impurity and the solubleness fairly similar of Tanshinone II A sodium acrylate in pure water solvent are difficult to reach satisfied content with the method for recrystallization.
In addition, because Tanshinone II A vinylformic acid belongs to new compound, pertinent literature does not have the process for purification report yet both at home and abroad.
Summary of the invention
Technical problem
The invention discloses a kind of Promethean Tanshinone II A vinylformic acid process for purification, make this compound refining can reach higher content and can suitability for industrialized production.
Technical scheme
The acrylic acid process for purification of a kind of Tanshinone II A, this method contains following steps:
A, elder generation carry out preliminary treatment with Tanshinone II A vinylformic acid crude product, and the method for preliminary treatment is:
Tanshinone II A vinylformic acid crude product is added 50-150 alkyl chloride doubly and organic acid mixed solution or alkyl chloride at every turn and pure mixed solution extracts 2-3 time, wherein organic acid content in alkyl chloride and organic acid mixed solution is 1-3%, alcohol content in the mixed solution of alkyl chloride and alcohol is 1-10%, filter, united extraction liquid reclaims solvent, add crude product amount 50-200 methyl alcohol or ethanol stirring at room doubly, filter, drying obtains Tanshinone II A vinylformic acid preliminary treatment product;
Or,
With Tanshinone II A vinylformic acid dissolving crude product in 50-200 times of methyl alcohol or ethanol, the ice bath cooling drips down and waits the saturated methanol solution salify of mole sodium bicarbonate, regulates PH to acid with organic acid then, filters, drying obtains Tanshinone II A vinylformic acid preliminary treatment product;
Or,
With silicagel column on the Tanshinone II A vinylformic acid crude product, with alkyl chloride and organic acid mixing solutions is elutriant, wherein the content of organic acid in alkyl chloride and organic acid mixing solutions is 0.2%-2%, carry out column chromatography, collect red elutriant, reclaim elutriant, drying obtains Tanshinone II A vinylformic acid preliminary treatment product;
B, Tanshinone II A vinylformic acid preliminary treatment product are gone up silicagel column, with alkyl chloride and organic acid mixed solution is elutriant, wherein the content of organic acid in alkyl chloride organic acid mixed solution is 0.2-2%, be elutriant with alkyl chloride and pure mixed solution perhaps, wherein the content of alcohol in alkyl chloride and pure mixed solution is 0.2%-10%, carries out column chromatography, collect red elutriant, reclaim solvent, drying obtains refining tanshinone IIA vinylformic acid.
Above-mentioned Tanshinone II A vinylformic acid crude product is a synthetics, and the Tanshinone II A acrylic acid content is lower than 50%; Tanshinone II A vinylformic acid preliminary treatment product its to contain Tanshinone II A vinylformic acid amount be 80%-92%; Its Tanshinone II A acrylic acid content of refining tanshinone IIA vinylformic acid is more than or equal to 96%.
The silica gel specification of using in the exquisite process is preferably the 50-300 order, and usage quantity is 50-500 a times of Tanshinone II A vinylformic acid sample size.
Organic acid preferable formic acid, acetate or propionic acid in the exquisite process.Alcohol is preferably methyl alcohol or ethanol.Preferred methylene dichloride of alkyl chloride or trichloromethane.
To make with extra care back Tanshinone II A vinylformic acid and be dissolved in the methyl alcohol, the ice bath cooling drips the saturated methanol solution salify of equimolar sodium bicarbonate down, stirs, and filters, and reclaims solvent, and drying obtains purified Tanshinone II A sodium acrylate.Content is more than or equal to 96%.
Beneficial effect
The present invention avoids the bottleneck of existing Tanshinone II A derivative purification technique, and the final purifying of Tanshinone II A vinylformic acid is reached more than 96%, is greatly improved through pretreated content in crude product with method of the present invention, brings up to 80-92% from 45-50%.After the processing of two steps, make the content of the finished product bring up to (HPLC method) more than 96%.Simple to operate, be easy to industrialization.Yield is higher, and the refining yield of single step reaches more than 80%.
Specific embodiment
Following examples just are used for method of the present invention is described, and do not limit the scope of the invention:
The preparation of embodiment 1 TANSHINONES vinylformic acid crude product
50g Tanshinone II A (purity 80-90%) is dissolved among the 850ml DMF, drips 100mL POCl under the room temperature
3, dropwising the back and continue stir about 20min, heat temperature raising to 70 ℃ continues stir about 1h, place cooling, reaction solution is poured in the 3L frozen water, the sodium hydroxide solution that begins to add 5mol/L to pH be 5～6, promptly have yellow solid to separate out, filter, filter cake is washed to neutrality, the dry crude product that gets.Add the 400mL ethyl acetate in the crude product, bathe 45 ℃ outward and stir 1h, room temperature is placed and is spent the night, and filters, and solid washs once with sherwood oil again, gets pale brown look solid Tanshinone II A formaldehyde, about 34g, liquid phase relative content 90%.20g Tanshinone II A formaldehyde is dissolved in the 280mL pyridine, add 20g propanedioic acid, 10mL piperidines successively, be heated to 80 ℃, react about 5 hours after, decompression steams solvent, remaining dope is poured in the 1000mL frozen water, and concentrated hydrochloric acid transfers pH nearly 2, promptly has red solid to separate out, filtration, washing, drying, get Tanshinone II A vinylformic acid crude product, about 18g, content are 45% (liquid phase external standard method).
Embodiment 2, the preparation of Tanshinone II A vinylformic acid preliminary treatment product
With 1 gram Tanshinone II A vinylformic acid crude product (HPLC content 50-60%, external standard method about 45%) extracts twice for 150 milliliters with 100: 3 methylene dichloride acetic acid mixed solution, filter merging filtrate, evaporated under reduced pressure behind the recovery solvent, with the solid that obtains with 100 milliliters of stirring at room of methyl alcohol 30 minutes, filter, obtain the product after the 0.3 gram preliminary treatment after the solid oven dry that obtains, yield about 50%, HPLC analyzes, content about about 85%.Methyl alcohol filtrate is reclaimed and to be obtained content behind the solvent is about 20% product, and the yield that calculates after reclaiming is 81%.
Embodiment 3, the preparation of Tanshinone II A vinylformic acid preliminary treatment product
With embodiment 2, extract twice with 100 milliliters of 100: 3 methylene dichloride formic acid mixing solutionss, obtain the product after the 0.28 gram preliminary treatment, HPLC content 83%.The yield that calculates after reclaiming is 80%.
The preparation of embodiment 4 Tanshinone II A vinylformic acid preliminary treatment product
With embodiment 2, extract three times for 80 milliliters with 100: 1 methylene dichloride acetic acid mixed solutions, obtain 0.29 gram product after treatment, content 86%.The yield that calculates after reclaiming is 80%.
Embodiment 5, the preparation of Tanshinone II A vinylformic acid preliminary treatment product
With embodiment 2, extract three times for 50 milliliters with 100: 1 methylene dichloride formic acid mixing solutionss, obtain 0.3 gram product after treatment, content 85%.The yield that calculates after reclaiming is 80%.
Embodiment 6, the preparation of Tanshinone II A vinylformic acid preliminary treatment product
With embodiment 2, extract 2 times for 130 milliliters with 2% propionic acid methylene dichloride mixing solutions, obtain 0.3 gram product after treatment, content 86%.The yield that calculates after reclaiming is 80%.
Embodiment 7, the preparation of Tanshinone I I A vinylformic acid preliminary treatment product
With 1 gram Tanshinone II A vinylformic acid crude product (HPLC content 50-60%, external standard method about 45%) with 50 ml methanol, 0.2 the gram sodium bicarbonate, ice bath stirred 6 hours down, filtered, filtrate is stirred down and is dissolved in the solution adjusting PH of 25 ml methanol to acid with 2.5 gram acetate, filter, the solid oven dry obtains the product after the 0.2 gram preliminary treatment, yield about 35%, HPLC analyzes, about 80% (external standard method about 60%) of content.Obtain content after methyl alcohol filtrate is reclaimed and be about 30% product, the yield that calculates after reclaiming is 80%.
Embodiment 8, the preparation of Tanshinone II A vinylformic acid preliminary treatment product
With embodiment 7, the dissolve with methanol crude product with 100 milliliters is adjusted to acidity with formic acid, obtains 0.16 gram, the product of HPLC content 84%, and the yield that calculates after reclaiming is 80%.
Embodiment 9, the preparation of Tanshinone II A vinylformic acid preliminary treatment product
With embodiment 7, with 200 milliliters of dissolve with ethanol crude products, be adjusted to acidity with propionic acid, obtain 0.12 gram, the product of HPLC content 87%, the yield that calculates after reclaiming is 80%.
Embodiment 10, the preparation of Tanshinone II A vinylformic acid preliminary treatment product
With 1 gram Tanshinone II A vinylformic acid crude product (HPLC content 50-60%, external standard method about 45%) be elutriant with the methylene dichloride acetic acid mixed solution, the ratio of acetate and methylene dichloride is 1: 100, column chromatography silica gel (200-300 order, about 50 grams) is a stationary phase, carries out column chromatography, collect about 250 milliliters of red elutriant, obtain the product of about 0.38 gram after the preliminary treatment after being spin-dried for, HPLC detection level scope is 80-92%, and yield is 80%.
Embodiment 11, the preparation of Tanshinone II A vinylformic acid preliminary treatment product
With embodiment 10, be elutriant with 100: 0.5 methylene dichloride acetic acid mixed solutions, obtain the product of 0.32 gram preliminary treatment, content is 85-92%, yield is 70%.
Embodiment 12, the preparation of Tanshinone II A vinylformic acid preliminary treatment product
With embodiment 10, be elutriant with 100: 1 trichloromethane formic acid mixing solutionss, obtain the product of 0.38 gram after the preliminary treatment, it is 82-92% that HPLC detects each flow point content range, yield 80%
Embodiment 13, the preparation of Tanshinone II A vinylformic acid preliminary treatment product
With embodiment 10, be elutriant with 100: 0.5 trichloromethane formic acid mixing solutionss, obtain the product of 0.32 gram preliminary treatment, content is 86-92%, yield is 71%.
Embodiment 14, the exquisite product preparation of Tanshinone II A vinylformic acid
Take by weighing 50 gram silica gel (100-200 order), the dress post, last 0.1 gram content is about 85% the Tanshinone II A vinylformic acid through preliminary treatment, with ratio is that 150: 1 trichloromethane methanol mixed solution is the elutriant wash-out, collect about 150 milliliters of red elutriant, be spin-dried for and obtain 0.02 gram approximately, HPLC analyzes content about 96%, all the other flow points reclaim, and the yield that calculates after reclaiming is 85%.
Embodiment 15, the exquisite product preparation of Tanshinone II A vinylformic acid
Take by weighing 50 gram silica gel (100-200 order), the dress post, last 0.1 gram content is about 86% the Tanshinone II A vinylformic acid through preliminary treatment, with ratio is that 200: 1 trichloromethane acetic acid mixed solution is that elutriant carries out wash-out, collect about 150 milliliters of red elutriant, be spin-dried for and obtain about 0.02 gram Tanshinone II A vinylformic acid, HPLC analyzes content about 98%, all the other flow points reclaim, and the yield that calculates after reclaiming is 83%.
Embodiment 16, the exquisite product preparation of Tanshinone II A vinylformic acid
With embodiment 15, be that elutriant carries out wash-out with trichloromethane formic acid mixing solutions, obtaining 0.02 gram content is 97.5% product, the yield that calculates after reclaiming is 84%.
Embodiment 17, the exquisite product preparation of Tanshinone II A vinylformic acid
Take by weighing 50 gram silica gel (100-200 order), the dress post, last 0.1 gram content is about 86% treated Tanshinone II A vinylformic acid, with ratio is that 100: 1 methylene dichloride acetic acid mixed solution is that elutriant carries out wash-out, collects about 150 milliliters of red elutriant, is spin-dried for, obtain about 0.02 gram Tanshinone II A vinylformic acid, HPLC analyzes content and is about 97%, and all the other flow points reclaim, and the yield that calculates after reclaiming is 86%.
Embodiment 18, the exquisite product preparation of Tanshinone II A vinylformic acid
With embodiment 17, be that 100: 1 methylene dichloride formic acid mixing solutions is that elutriant carries out wash-out with ratio, collect 150 milliliters of red elutriants, be spin-dried for, obtain the product of content 97%, the yield that calculates after reclaiming is 86%.
Embodiment 19, the exquisite product preparation of Tanshinone II A vinylformic acid
With embodiment 17, be that elutriant carries out wash-out with 100: 1 ethylene dichloride acetic acid mixed solutions, collect red elutriant, be spin-dried for, obtain content and be 96% Tanshinone II A vinylformic acid 0.02 gram, the yield that calculates after reclaiming is 75%.
Embodiment 20, the exquisite product preparation of Tanshinone II A vinylformic acid
With embodiment 17, be the moving phase wash-out with ethylene dichloride formic acid (100: 1), obtain content and be 96% product 0.02 gram, the yield that calculates after reclaiming is 78%.
The preparation of embodiment 21, Tanshinone II A sodium acrylate
Crossing content that post obtains and be 96% exquisite product 0.5 of Tanshinone II A propylene restrains, be dissolved in 250 ml methanol, drip the saturated methanol solution salify of equimolar sodium bicarbonate in the ice bath cooling, drip off and stirred 5 hours, filter, filtrate being spin-dried for obtains about 0.5 gram of Tanshinone II A sodium acrylate, and the HPLC detection level is 96%.
Claims (3)
1. acrylic acid process for purification of Tanshinone II A, this method contains following steps:
A, elder generation carry out preliminary treatment with Tanshinone I I A vinylformic acid crude product, and the method for preliminary treatment is:
Tanshinone I I A vinylformic acid crude product is added 50-150 alkyl chloride doubly and organic acid mixed solution or alkyl chloride at every turn and pure mixed solution extracts 2-3 time, wherein organic acid content in alkyl chloride and organic acid mixed solution is 1-3%, alcohol content in the mixed solution of alkyl chloride and alcohol is 1-10%, filter, united extraction liquid reclaims solvent, add crude product amount 50-200 methyl alcohol or ethanol stirring at room doubly, filter, drying obtains Tanshinone I I A vinylformic acid preliminary treatment product;
Or,
With Tanshinone II A vinylformic acid dissolving crude product in 50-200 times of methyl alcohol or ethanol, ice bath cools off to drip down and waits the saturated methanol solution salify of mole sodium bicarbonate, and is extremely acid with organic acid for adjusting pH then, filters, drying obtains Tanshinone I I A vinylformic acid preliminary treatment product;
Or,
With silicagel column on the Tanshinone I I A vinylformic acid crude product, with alkyl chloride and organic acid mixing solutions is elutriant, wherein the content of organic acid in alkyl chloride and organic acid mixing solutions is 0.2%-2%, carry out column chromatography, collect red elutriant, reclaim elutriant, drying obtains Tanshinone I I A vinylformic acid preliminary treatment product;
B, Tanshinone I I A vinylformic acid preliminary treatment product are gone up silicagel column, with alkyl chloride and organic acid mixed solution is elutriant, wherein the content of organic acid in alkyl chloride organic acid mixed solution is 0.2-2%, be elutriant with alkyl chloride and pure mixed solution perhaps, wherein the content of alcohol in alkyl chloride and pure mixed solution is 0.2%-10%, carries out column chromatography, collect red elutriant, reclaim solvent, drying obtains refining tanshinone IIA vinylformic acid;
Wherein, alkyl chloride is methylene dichloride or trichloromethane; Organic acid is a formic acid, acetate or propionic acid; Alcohol is methyl alcohol or ethanol.
2. the acrylic acid process for purification of a kind of Tanshinone I I A according to claim 1 is characterised in that Tanshinone II A vinylformic acid crude product is a synthetics, and its Tanshinone II A acrylic acid content is lower than 50%; Its Tanshinone I of Tanshinone II A vinylformic acid preliminary treatment product I A acrylic acid content is 80%-92%; Its Tanshinone I of refining tanshinone II A vinylformic acid I A acrylic acid content is more than or equal to 96%.
3. the acrylic acid process for purification of a kind of Tanshinone II A according to claim 1 is characterized in that the silica gel specification is the 50-300 order, and usage quantity is 50-500 a times of Tanshinone II A vinylformic acid sample size.
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