CN103923155B - A kind of preparation method of Crategolic acid - Google Patents
A kind of preparation method of Crategolic acid Download PDFInfo
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Abstract
Do you the invention provides a kind of Crategolic acid (Maslinic? acid) preparation method, raw material Oleanolic Acid successively after the oxidation of oxygenant 2-iodosobenzoic acid, metachloroperbenzoic acid, then through reductive agent NaBH
4reduction, obtain described Crategolic acid.Preparation method of the present invention, raw materials used abundance, reaction conditions gentleness, agents useful for same low price, environmental friendliness, does not exist that heavy metal chromium ion residues problem, synthetic route are short, equipment requirements easily meets, total recovery significantly improves, production cost reduces, applicable suitability for industrialized production.
Description
Technical field
The invention belongs to the technical field of organic chemical synthesis, relate to the preparation method of a kind of Crategolic acid (Maslinicacid).
Background technology
Crategolic acid (maslinicacid, MA) is a kind of Pentacyclic triterpenic acid, is mainly present in the natural phant such as Fructus oleae europaeae, hop, Thinlear Adina Fruit, peppermint, cloves, red date, hawthorn, pomegranate and Salvia japonica Thunb..Recent study shows that Crategolic acid has the effect such as anticancer, anti-oxidant, anti-AIDS, antibacterial, anti-inflammatory, anti-diabetes B, fat-reducing, beauty treatment.Crategolic acid belongs to pentacyclic triterpenoid, and its structure is such as formula shown in (I):
Numata etc. find that Crategolic acid has cytotoxicity for leukemia P-38 tumor cell line, and its inhibit activities is ED50=13.0ug/mL (ChemPharmBull1989,37,648-651).Kim etc. report Crategolic acid all has restraining effect (PlantMed.2000 to non-small cell lung cancer cell strain A549, Ovarian Cancer Cells SK-OV-3, melanoma cell strain SK-MEL-2 cell strain, people's Colon and rectum adenocarcinoma cell strain HCT-15,66,485-486).Wang etc. report Crategolic acid and have cytotoxic activity (ChemPharmBull2006,54,775-778) to human cervical carcinoma cell lines Hela, malignant melanoma cell strain A375, mammary cancer thin strain born of the same parents MCF-7.Oxygenizement plays important role in some degenerative diseases are as the pathologic process such as aging of arteriosclerosis, bioprocess, Montilla etc. find the lipid peroxidation (PlantaMed2003 in blood plasma that Crategolic acid can suppress to be induced by hydroxyl radical free radical, liver plasma membrane, 69,472-474).Xu etc. find that Crategolic acid demonstrates stronger inhibit activities to acquired immune deficiency syndrome (AIDS) associated protein enzyme HIV-1, suppress completely (JNatProd, 1996,59,643-645) HIV-1 protease activity when its concentration is 17.9ug/mL.Braca etc. find that Crategolic acid has stronger inhibit activities to gram-positive microorganism, as being respectively 25 to the minimal inhibitory concentration of staphylococcus epidermidis (S.aureus), suis (S.agalacticae), Candida albicans (C.albicans), 100,25ug/mL (PlantaMed2000,66,768-769).China Medicine University Liu etc. tests the hypoglycemic activity of Crategolic acid for diabetes B animal model KK-Ay mouse.The dosage of KK-Ay mouse oral Crategolic acid 10mg/kg or 30mg/kg every day, takes continuously after 2 weeks and finds that glucose level reduces greatly.Further research finds that the partly cause of Crategolic acid hypoglycemic activity may be the insulin resistant that Crategolic acid reduces KK-Ay mouse, so they think that Crategolic acid may be the natural drug (BiolPharmBull2007 of a very promising treatment diabetes B and obesity, 30,2975-2978).Tyrosine oxidase is enzyme uniquely known at present in Melanin Metabolism, and it is a kind of metalloenzyme of cupric, is synthesized by melanophore, and tyrosinase inhibitor can be used for treatment melanochrome clinically increases dermatoses.Ullah etc. find that Crategolic acid has stronger inhibit activities to tyrosine oxidase, and its IC50 is 1.7uM (PhytotherRes2007,21,1076-1081).Fodder additives plays increasingly important effect in freshwater aquiculture, and they can be improved food conversion ratio, and promotes fish growth.Fern á ndez-Navarro etc. find that in the feed of rainbow trout, add Crategolic acid can promote that it grows, they think that this result of study shows that Crategolic acid can as growth-stimulating factor when being used as fodder additives, promote the synthesis (CompBiochemPhysiolCToxicolPharmacol2006 of protein, 144,130-140).Due to the widespread use of Crategolic acid in medicines and health protection etc., therefore, explore one with natural product cheap and easy to get for starting raw material, and it is significant to be applicable to industrialized synthetic route.
At present, the source mainly plant extract of Crategolic acid, according to Nisshin Oillio Group Ltd (TheNisshinOillio, Ltd.,) the report (US6740778) of NoriyasuKuno etc., slag charge after utilizing olive fruit to extract oil is for raw material is to extract the technique of Crategolic acid, but because raw material sources are limited, extraction process is complicated, production cost is high, the technique that this plant extraction method prepares Crategolic acid is very limited in practice.
Separately, China Medicine University Wen little An and Sun Hongbin etc. report two similar semi-synthetic route (BioorgMedChemLett2005,15,4944-4948; BioorgMedChemLett2006,16,722-726; CN1634971), as follows:
Two lines are all with the supply of domestic shiploads of merchandiseization, cheap Oleanolic Acid for starting raw material, first the protection of C-28 carboxylic acid benzyl ester are obtained compound 1, then C-3 position hydroxyl PCC are oxidized to carbonyl and obtain compound 2.Article 1, route first the C-3 position carbonyl alkene etherificate of compound 2 is obtained compound 3, and then by compound 3 epoxidation, BH3 reduction obtains compound 5; Article 2 route is by direct for compound 2 metachloroperbenzoic acid (mCPBA) oxidation, introduces a-hydroxyl obtain compound 4 in C-2 position, then obtains compound 5 with NaBH4 reduction; Compound 5 takes off benzyl through Pd/C and obtains Crategolic acid.The total recovery of these two lines is respectively 27.4% and 46.8%, and obvious Article 1 route total recovery is too low, does not have actual application value.The problem of above-mentioned two synthetic routes is: in the reaction of preparation 3-carbonyl olea acid benzyl ester, all employ chromic salts oxygenant PCC, bring heavy metal chromium ion residues problem to undoubtedly product Crategolic acid, not only contaminate environment, and Crategolic acid is as a kind of Medicines and Health Product, be obviously do not allowed heavy metal ion to remain.Secondly, owing to using benzyl as protecting group, therefore need to use expensive catalyst P d/C to carry out hydrogenation when removing this protecting group and take off benzyl, and catalyst P d/C expense is up to 30% of whole production cost.If do not use benzyl whole production cost will be made greatly to reduce as protecting group, be more suitable for suitability for industrialized production.In addition, whole synthetic route is relatively long, and needs when removing benzyl protecting group to use hydrogenation apparatus, higher to equipment requirements.Visible, there is environmental pollution in Crategolic acid synthetic method of the prior art, heavy metal ion is residual, yield is low, high to production unit requirement, high in cost of production problem, is not suitable for suitability for industrialized production.
Summary of the invention
The present invention overcomes the above-mentioned defect that prior art exists, a kind of preparation method of new Crategolic acid is proposed, the method relatively economical, easy to operate, with short production cycle, can industrializing implementation be suitable for, especially productive rate can be solved low, reaction reagent contaminate environment, toxicity are large, expensive, product heavy metal ion remains, and production unit requires high, high in cost of production problem.
In order to solve the problem, the present invention does not use chromic salts oxygenant and benzyl protecting group, adopts following technical scheme:
The preparation method of a kind of Crategolic acid disclosed by the invention, by raw material Oleanolic Acid successively after the oxidation of oxygenant 2-iodosobenzoic acid, metachloroperbenzoic acid, then through the reduction of reductive agent NaBH4, obtains described Crategolic acid.
The reaction scheme of preparation method of the present invention is:
Preparation method of the present invention, comprises the steps:
The first step is oxidized:
Oleanolic Acid is dissolved in the first solvent, adds oxygenant 2-iodosobenzoic acid, at 0-50 DEG C of temperature, reacts 1-3 hour, filters and obtains filtrate, successively through extraction, washing, dry, concentratedly obtain 3-carbonyl Oleanolic Acid;
Second step is oxidized:
Above-mentioned gained 3-carbonyl Oleanolic Acid is dissolved in the second solvent, drip methanolic solution, add oxygenant metachloroperbenzoic acid, at 0-50 DEG C of temperature, react 20-40 hour, successively through extraction, washing, dry, concentratedly obtain 2a-hydroxyl-3-carbonyl Oleanolic Acid;
3rd step reduction:
Above-mentioned gained 2a-hydroxyl-3-carbonyl Oleanolic Acid is dissolved in the 3rd solvent, adds reductive agent NaBH4, at 0-50 DEG C of temperature, react 1-3 hour, successively through extraction, dry, concentrated, then obtain object product as white solid Crategolic acid through silica gel column chromatography.
Wherein, preferably, described first solvent is dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) or ethyl acetate.Described first solvent can also be dimethyl formamide, dioxane.
Wherein, described second solvent is methylene dichloride.Described first solvent also comprises chloroform.
Wherein, described 3rd solvent is tetrahydrofuran (THF), methyl alcohol or tetrahydrofuran (THF) and the mixing of methyl alcohol.Described 3rd solvent also comprises ethanol, Virahol, the trimethyl carbinol.
Wherein, the yield of described second step and described 3rd step adds up to 57-63%.
Wherein, the overall yield of reaction (that is, the total recovery of first, second and third step reaction) of described preparation method adds up to 50-58%.
Wherein, in the described the first step, the usage ratio scope of described Oleanolic Acid and described oxygenant 2-iodosobenzoic acid is (1.1-1.5): 1.Preferably, the usage ratio of described Oleanolic Acid and described oxygenant 2-iodosobenzoic acid is (1.2-1.3): 1.
Wherein, in described second step, the usage ratio scope of 3-carbonyl Oleanolic Acid and described oxygenant metachloroperbenzoic acid is (1.0-1.4): 1.Preferably, the usage ratio of 3-carbonyl Oleanolic Acid and described oxygenant metachloroperbenzoic acid is (1.1-1.3): 1.
Wherein, in described second step, the usage ratio scope of 2a-hydroxyl-3-carbonyl Oleanolic Acid and described reductive agent NaBH4 is (3.4-5.0): 1.Preferably, the usage ratio of 2a-hydroxyl-3-carbonyl Oleanolic Acid and described reductive agent NaBH4 is 4.0-4.5: 1.
In the present invention, compared with prior art, whole synthetic route is short, is only 2 steps, and comparatively background technology (5 step) has lacked 2 step reactions, significantly improves the total recovery of reaction scheme.Do not use benzyl protecting group in the present invention, therefore do not need to use expensive Pd/C catalyzer to remove benzyl protecting group compared with background technology; Make that this operational path equipment requirements is low, total recovery is high, production cost is low, be applicable to commercial scale production.
Particularly, in preparation method of the present invention, the first step, Oleanolic Acid, through oxygenant 2-iodosobenzoic acid (2-Iodoxybenzoicacid, IBX) oxidation, obtains 3-carbonyl Oleanolic Acid, yield 88-92%; Second step, 3-carbonyl Oleanolic Acid is oxidized further through metachloroperbenzoic acid (mCPBA, technical grade, purity 70%), obtains 2a-hydroxyl-3-carbonyl Oleanolic Acid; 3rd step, 2a-hydroxyl-3-carbonyl Oleanolic Acid reduces to obtain product Crategolic acid through NaBH4.Compared with background technology, present invention reduces reaction scheme, wherein, second, third step reaction yield adds up to 57-63%, and the total recovery of three-step reaction is 50-58%, is significantly higher than the reaction yield of prior art.Particularly, the reaction formula of preparation method of the present invention is:
Compared with prior art; beneficial effect of the present invention comprises: raw materials used abundance, and reaction conditions is gentle, agents useful for same low price; environmental friendliness; there is not heavy metal chromium ion residues problem, without the need to adding protecting group or Deprotection, synthetic route is short; equipment requirements easily meets; total recovery significantly improves, and production cost, significantly lower than existing technique, is applicable to commercial scale production.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The present invention prepares Crategolic acid by three-step approach, is by raw material Oleanolic Acid successively after the oxidation respectively of specific oxygenant 2-iodosobenzoic acid, oxygenant metachloroperbenzoic acid, then with NaBH
4carry out reduction reaction as reductive agent, obtain described Crategolic acid.Concrete steps comprise:
The preparation of the first step 3-carbonyl Oleanolic Acid
Oleanolic Acid (16g) is dissolved in the dimethyl sulfoxide (DMSO) (DMSO) of 80-160mL, in tetrahydrofuran (THF) (THF) or ethyl acetate, 10.8-14.7g oxygenant 2-iodosobenzoic acid is added 0-50 DEG C of temperature, and react 1-3 hour at this temperature, cross and filter insolubles, filtrate is poured in 200mL water, use 100-200mL extraction into ethyl acetate, water layer uses 100mL extraction into ethyl acetate again, merge organic layer, use saturated sodium carbonate solution successively, saturated common salt solution washing, dry, concentrate to obtain 3-carbonyl Oleanolic Acid crude product 14.1-14.7g, yield 88-92%.
The preparation of second step 2a-hydroxyl-3-carbonyl Oleanolic Acid
The 3-carbonyl Oleanolic Acid crude product the first step obtained is dissolved in the methylene dichloride of 100mL, the methanolic solution (volume percent) of 0.02-0.08% is dripped 0 DEG C of temperature, metachloroperbenzoic acid 10-15g is once dropped into after dropwising, at 0-50 DEG C of thermotonus 20-40 hour, be cooled to 0 degree, drip saturated sodium bicarbonate solution and saturated sodium bisulfite solution, separate organic layer, water layer uses dichloromethane extraction again, merge organic layer, saturated common salt solution washing, organic layer is dry, concentrates to obtain 2a-hydroxyl-3-carbonyl Oleanolic Acid crude product 15-17g.
The preparation of the 3rd step Crategolic acid
2a-hydroxyl-3-carbonyl Oleanolic Acid the crude product obtained by second step is dissolved in the mixed solvent of the tetrahydrofuran (THF) of 200mL, methyl alcohol or tetrahydrofuran (THF) and methyl alcohol, add 3-5g reductive agent NaBH4 0 DEG C of temperature in batches, at 0-50 DEG C of thermotonus 1-3 hour, the hydrochloric acid soln 60-100mL of 5% is dripped under ice bath, add extraction into ethyl acetate, separate organic layer, water layer is extracted with ethyl acetate again, merge organic layer, dry, concentrated, crude product is through silica gel column chromatography (eluent, sherwood oil: tetrahydrofuran (THF); Acetic acid=120: 8: 3) obtain white solid Crategolic acid 8-9.3g.
In above-mentioned reaction, the total 57-63% of second, third step yield, the total recovery of three-step reaction adds up to 50-58%.
Embodiment 1
The first step; Oleanolic Acid (16g) be dissolved in 80mL dimethyl sulfoxide (DMSO) (DMSO), in; 12.7g oxygenant 2-iodosobenzoic acid is added 25 DEG C of temperature; and react 2 hours at this temperature; cross and filter insolubles; filtrate is poured in 200mL water; use 200mL extraction into ethyl acetate; water layer uses 100mL extraction into ethyl acetate again, merges organic layer, uses 100mL saturated sodium carbonate solution successively; 100mL saturated common salt solution washing; drying, concentrates to obtain 3-carbonyl Oleanolic Acid crude product 14.7g, yield 92%.
Second step, the 3-carbonyl Oleanolic Acid crude product that the first step is obtained is dissolved in 100mL methylene dichloride, at the methanolic solution (volume percent) of 0 degree of dropping 0.05%, metachloroperbenzoic acid 12.5g is once dropped into after dropwising, 25 degree of reactions 30 hours, be cooled to 0 DEG C, drip 100mL saturated sodium bicarbonate solution and 100mL saturated sodium bisulfite solution, separate organic layer, water layer adds 100mL dichloromethane extraction again, merge organic layer and use 100mL saturated common salt solution washing, organic layer is dry, concentrate to obtain 2a-hydroxyl-3-carbonyl Oleanolic Acid crude product 17g.
3rd step, 2a-hydroxyl-3-carbonyl Oleanolic Acid the crude product obtained by second step is dissolved in the tetrahydrofuran (THF) of 200mL, add 5g reductive agent NaBH4 at 0 degree in batches, 25 DEG C of thermotonuses 2 hours, the hydrochloric acid soln 80mL of 5% is dripped under ice bath, add 100mL extraction into ethyl acetate, separate organic layer, water layer uses 100mL extraction into ethyl acetate again, merges organic layer, the water washing of 100mL saturated common salt, separate organic layer, organic layer is dry, concentrated, crude product is through silica gel column chromatography (eluent, sherwood oil: tetrahydrofuran (THF); Acetic acid=120: 8: 3) obtain white solid Crategolic acid 9.3g, 1HNMR (DMSO-d6): 12.00 (1H, s, COOH), 5.14 (1H, s, H-12), 4.31-4.35 (1H, m, H-2), 4.2 (1H, d, J=5.0Hz, H-3), 3.29-3.41 (2H, m), 2.70-2.72 (2H, m), 1.07 (3H, s), 0.89 (3H, s), 0.87 (3H, s), 0.85 (6H, s), 0.68 (3H, s), 0.67 (3H, s).
In above-mentioned reaction, second, third step yield adds up to 63%, three step total recoverys 58%.
Embodiment 2
The first step; Oleanolic Acid (16g) is dissolved in the tetrahydrofuran (THF) (THF) of 120mL; 14.7g oxygenant 2-iodosobenzoic acid is added at 0 degree; and react 3 hours at this temperature; cross and filter insolubles; filtrate is poured in 200mL water; use 200mL extraction into ethyl acetate; water layer uses 100mL extraction into ethyl acetate again, merges organic layer, uses 100mL saturated sodium carbonate solution successively; 100mL saturated common salt solution washing; drying, concentrates to obtain 3-carbonyl Oleanolic Acid crude product 14.4g, yield 90%.
Second step, the 3-carbonyl Oleanolic Acid crude product the first step obtained is dissolved in the methylene dichloride of 100mL, at the methanolic solution (volume percent) of 0 degree of dropping 0.02%, metachloroperbenzoic acid 15g is once dropped into after dropwising, 0 degree of reaction 40 hours, be cooled to 0 degree, drip 100mL saturated sodium bicarbonate solution and 100mL saturated sodium bisulfite solution, separate organic layer, water layer adds 100mL dichloromethane extraction again, merge organic layer and use 100mL saturated common salt solution washing, organic layer is dry, concentrate to obtain 2a-hydroxyl-3-carbonyl Oleanolic Acid crude product 16g.
3rd step, 2a-hydroxyl-3-carbonyl Oleanolic Acid the crude product obtained by second step is dissolved in the mixed solvent of the isopyknic tetrahydrofuran (THF) of 200mL and methyl alcohol, add 4g reductive agent NaBH4 at 0 degree in batches, 0 degree of reaction 3 hours, the hydrochloric acid soln 100mL of 5% is dripped under ice bath, add 100mL extraction into ethyl acetate, separate organic layer, water layer uses 100mL extraction into ethyl acetate again, merges organic layer, the water washing of 100mL saturated common salt, separate organic layer, organic layer is dry, concentrated, crude product is through silica gel column chromatography (eluent, sherwood oil: tetrahydrofuran (THF); Acetic acid=120: 8: 3) obtain white solid Crategolic acid 8.8g, 1HNMR (DMSO-d6): 12.00 (1H, s, COOH), 5.14 (1H, s, H-12), 4.31-4.35 (1H, m, H-2), 4.2 (1H, d, J=5.0Hz, H-3), 3.29-3.41 (2H, m), 2.70-2.72 (2H, m), 1.07 (3H, s), 0.89 (3H, s), 0.87 (3H, s), 0.85 (6H, s), 0.68 (3H, s), 0.67 (3H, s).
In above-mentioned reaction, second, third step yield adds up to 61%, three step total recoverys 55%.
Embodiment 3
The first step, Oleanolic Acid (16g) is dissolved in the ethyl acetate of 160mL, adds 10g oxygenant 2-iodosobenzoic acid at 50 degree; and react 1 hour at this temperature, cross and filter insolubles, filtrate is poured in 200mL water; use 100mL extraction into ethyl acetate; water layer uses 100mL extraction into ethyl acetate again, merges organic layer, uses 100mL saturated sodium carbonate solution successively; 100mL saturated common salt solution washing; drying, concentrates to obtain 3-carbonyl Oleanolic Acid crude product 14.1g, yield 88%.
Second step, the 3-carbonyl Oleanolic Acid crude product the first step obtained is dissolved in the methylene dichloride of 100mL, at the methanolic solution (volume percent) of 0 degree of dropping 0.08%, metachloroperbenzoic acid 10g is once dropped into after dropwising, 50 degree of reactions 20 hours, be cooled to 0 degree, drip 100mL saturated sodium bicarbonate solution and 100mL saturated sodium bisulfite solution, separate organic layer, water layer adds 100mL dichloromethane extraction again, merge organic layer and use 100mL saturated common salt solution washing, organic layer is dry, concentrate to obtain 2a-hydroxyl-3-carbonyl Oleanolic Acid crude product 15g.
3rd step, 2a-hydroxyl-3-carbonyl Oleanolic Acid the crude product that second step is obtained be dissolved in the methyl alcohol of 200mL mixed in, add 3g reductive agent NaBH4 at 0 degree in batches, 50 degree of reactions 1 hour, the hydrochloric acid soln 60mL of 5% is dripped under ice bath, add 100mL extraction into ethyl acetate, separate organic layer, water layer uses 100mL extraction into ethyl acetate again, merges organic layer, the water washing of 100mL saturated common salt, separate organic layer, organic layer is dry, concentrated, crude product is through silica gel column chromatography (eluent, sherwood oil: tetrahydrofuran (THF); Acetic acid=120: 8: 3) obtain white solid Crategolic acid 8g, 1HNMR (DMSO-d6): 12.00 (1H, s, COOH), 5.14 (1H, s, H-12), 4.31-4.35 (1H, m, H-2), 4.2 (1H, d, J=5.0Hz, H-3), 3.29-3.41 (2H, m), 2.70-2.72 (2H, m), 1.07 (3H, s), 0.89 (3H, s), 0.87 (3H, s), 0.85 (6H, s), 0.68 (3H, s), 0.67 (3H, s).
In above-mentioned reaction, second, third step yield adds up to 57%, three step total recoverys 50%.
Claims (6)
1. a preparation method for Crategolic acid, is characterized in that, raw material Oleanolic Acid successively after the oxidation of oxygenant 2-iodosobenzoic acid, metachloroperbenzoic acid, then through reductive agent NaBH
4reduction, obtain described Crategolic acid; The reaction scheme of described preparation method is:
The preparation method of described Crategolic acid comprises the steps:
The first step is oxidized
Oleanolic Acid is dissolved in the first solvent, adds oxygenant 2-iodosobenzoic acid, at 0-50 DEG C of temperature, reacts 1-3 hour, filters and obtains filtrate, successively through extraction, washing, dry, concentratedly obtain 3-carbonyl Oleanolic Acid;
Second step is oxidized
Above-mentioned gained 3-carbonyl Oleanolic Acid is dissolved in the second solvent, drip methanolic solution, add oxygenant metachloroperbenzoic acid, at 0-50 DEG C of temperature, react 20-40 hour, successively through extraction, washing, dry, concentratedly obtain 2 Alpha-hydroxy-3-carbonyl Oleanolic Acids;
3rd step reduction
Above-mentioned gained 2 Alpha-hydroxy-3-carbonyl Oleanolic Acid is dissolved in the 3rd solvent, adds reductive agent NaBH
4, at 0-50 DEG C of temperature, react 1-3 hour, successively through extraction, dry, concentrated, then obtain object product as white solid Crategolic acid through silica gel column chromatography.
2. the preparation method of Crategolic acid as claimed in claim 1, it is characterized in that, described first solvent is dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) or ethyl acetate; Described second solvent is methylene dichloride; Described 3rd solvent is the mixture of tetrahydrofuran (THF), methyl alcohol or tetrahydrofuran (THF) and methyl alcohol.
3. the preparation method of Crategolic acid as claimed in claim 1, is characterized in that, the yield of described second step and described 3rd step adds up to 57-63%; The overall yield of reaction of described preparation method is 50-58%.
4. the preparation method of Crategolic acid as claimed in claim 1, it is characterized in that, in the described the first step, the usage ratio of described Oleanolic Acid and described oxygenant 2-iodosobenzoic acid is weight ratio (1.1-1.5): 1.
5. the preparation method of Crategolic acid as claimed in claim 1, it is characterized in that, in described second step, the usage ratio of described 3-carbonyl Oleanolic Acid and described oxygenant metachloroperbenzoic acid is weight ratio (1.0-1.4): 1.
6. the preparation method of Crategolic acid as claimed in claim 1, is characterized in that, in described second step, and described 2 Alpha-hydroxy-3-carbonyl Oleanolic Acids and described reductive agent NaBH
4usage ratio be weight ratio (3.4-5.0): 1.
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| CN101619088A (en) * | 2009-08-04 | 2010-01-06 | 上海朴颐生物科技有限公司 | Maslinic acid derivative as well as preparation and application thereof |
| CN101974064A (en) * | 2010-11-19 | 2011-02-16 | 南京师范大学 | Method for synthesizing crataegolic acid |
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| CN101619088A (en) * | 2009-08-04 | 2010-01-06 | 上海朴颐生物科技有限公司 | Maslinic acid derivative as well as preparation and application thereof |
| CN101974064A (en) * | 2010-11-19 | 2011-02-16 | 南京师范大学 | Method for synthesizing crataegolic acid |
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