CN102153462A - Method for synthesizing tanshinol - Google Patents
Method for synthesizing tanshinol Download PDFInfo
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- CN102153462A CN102153462A CN2011100589900A CN201110058990A CN102153462A CN 102153462 A CN102153462 A CN 102153462A CN 2011100589900 A CN2011100589900 A CN 2011100589900A CN 201110058990 A CN201110058990 A CN 201110058990A CN 102153462 A CN102153462 A CN 102153462A
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Abstract
The invention discloses a method for synthesizing tanshinol, which comprises the following steps of: 1) performing Friedel-Crafts acylation reaction on R-tyrosine serving as a raw material and an acylation reagent under the catalytic condition of Lewis acid; 2) performing diazotization reaction on the product in the step 1) and sodium nitrite or potassium nitrite under the catalytic condition of acid; and 3) performing Dakin reaction on the product in the step 2) and a peroxide under the action of alkali to obtain the tanshinol, wherein the reaction equation is shown as (3). In the synthesizing method, the raw materials are easily obtained, the operation is simple, and large-scale industrialized production is suitable.
Description
Technical field
The present invention relates to a kind of synthetic method of Salvianic acidA.
Background technology
Salvianic acidA is one of water-soluble important activity composition of salviamiltiorrhizabung, structure be (
R)-3-(3, the 4-dihydroxy phenyl)-2 hydroxy propanoic acid, its structural formula is seen (I):
In the structure of Salvianic acidA, carboxyl alpha-position carbon atom is a chirality, and natural Salvianic acidA is the R configuration.Bibliographical information, the expansible coronary artery of Salvianic acidA, suppress hematoblastic gathering, improve microcirculation, can dwindle the rat myocardium block scope and alleviate the state of an illness, can suppress the reaction that hydroxy radical qiao, superoxide ion and nitrite anions cause, be good antioxidants etc., ischemic heart diseases such as many clinically injection for treating coronary heart disease with Salvianic acidA, stenocardia have high clinical value.At present, Salvianic acidA is mainly derived from plant, its content in the red sage root only is 5/1000ths, the source of former plant is very limited again, extraction separation complex steps in addition, purification difficult has limited the large-scale application of Salvianic acidA, and the eighties, scholars solved these problems with regard to beginning to explore the synthetic method.
The raceme chemosynthesis of Salvianic acidA, have some reports both at home and abroad, Xue Fen etc. have synthesized Salvianic acidA with chemical process first, because wherein Clemmensen method reducing carbonyl becomes methyne wayward, severe reaction conditions, the reaction scheme relative complex, the synthetic compound is a racemoid, difficult fractionation obtains the pure natural product R configuration of pharmacologically active.Deng Xiling etc. are with 3, and 4-Dihydroxy benzaldehyde and acetyl glycine be through condensation, open loop obtain α-acetamido-
β-(3,4-diacetoxy phenyl) vinylformic acid also obtains the racemoid of Salvianic acidA again through hydrolysis, reduction and salt-forming reaction.Tong Yuanfeng etc. are with 3, and the 4-Dihydroxy benzaldehyde is a starting raw material, through benzyl protection, Darzens reaction, Lewis acid selective opening, NaBH
4Reduction, NaOH hydrolysis, hydrogenation six-step process, but finally do not obtain having optically active single enantiomorph.
Do not see pure up to now as yet
R-(+)-
β-(3, the 4-dihydroxy phenyl) lactic acid (Salvianic acidA) synthetic method report.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of Salvianic acidA.
The technical solution used in the present invention is:
A kind of synthetic method of Salvianic acidA may further comprise the steps:
1) with
R-tyrosine is raw material, under lewis acidic catalytic condition, carries out friedel-crafts acylation with acylating reagent, and reaction equation is shown in (1):
R-tyrosine and acylating reagent mol ratio are 1:1.1-1.6,
R-tyrosine and lewis acidic mol ratio are 1:2-6; Lewis acid is aluminum chloride, iron trichloride, tin tetrachloride, zinc dichloride, hydrofluoric acid, spirit of salt, a kind of in the sulfuric acid, and acylating reagent is:
R wherein
1Be C
1～C
5Alkyl, X is chlorine or bromine or iodine;
2) with the product in the step 1) under the acid catalysis condition, carry out diazotization reaction with Sodium Nitrite or potassium nitrite, reaction equation is shown in (2):
The mol ratio of product in the step 1) and Sodium Nitrite or potassium nitrite is 1:1.2-1.6, and wherein acid is hydrochloric acid, sulfuric acid, phosphoric acid, crosses a kind of in chloric acid, the fluoroboric acid;
3) with step 2) in product under the effect of alkali, the Dakin reaction takes place with superoxide, obtain Salvianic acidA, reaction equation is shown in (3):
Wherein, step 2) product in and the mol ratio of superoxide are 1:1.2-1.7, with the mol ratio of alkali be 1:2; Wherein alkali is a kind of in sodium hydroxide, saleratus, salt of wormwood, sodium bicarbonate, yellow soda ash, the triethylamine.
R-tyrosine in the step 1) and acylating reagent mol ratio are 1:1.4, R
1Be the alkyl of C2～C3, X is a chlorine or bromine.
Step 2) in, the mol ratio of the product of used step 1) and Sodium Nitrite or potassium nitrite is 1:1.5, and wherein, acid is sulfuric acid, cross a kind of in the chloric acid.
In the step 3), used step 2) product in and the mol ratio of superoxide are 1:1.5, with the mol ratio of alkali be 1:2, wherein used superoxide is a hydrogen peroxide, wherein alkali is sodium hydroxide or salt of wormwood.
In the step 1), Lewis acid is an aluminum chloride, and acylating reagent is: Acetyl Chloride 98Min..
Step 2) in, acid is sulfuric acid.
In the step 3), superoxide is a hydrogen peroxide, and alkali is sodium hydroxide.
In the step 1), temperature of reaction is 85-90 ℃, and the reaction times is 4-8h.
Step 2) in, temperature of reaction is 85-90 ℃, and the reaction times is 4-8h.
The invention has the beneficial effects as follows: in the synthetic method of the present invention, raw material is easy to get, and is simple to operate, is fit to large-scale industrial production.
Embodiment
The present invention is described further below in conjunction with specific embodiment:
Embodiment 1
(
R)-3-(3-ethanoyl-4-hydroxy phenyl)-2-alanine synthetic:
Get the there-necked flask of 250mL, to wherein adding 175 mL oil of mirbane, at room temperature to wherein adding (7.2 g, 40 mmol) D-tyrosine, add aluminum chloride then, the disposable Acetyl Chloride 98Min. (57.3 mmol) that in reaction system, adds after stirring, reaction system is warmed up to 85～90 ℃ gradually, and reaction 4～8 h pour mixing solutions in the mixing solutions of dense HCl and ice into then, remove organic layer, keep water layer, water layer ethyl acetate extraction 3 times (50 mL * 3), water layer is crystallization at low temperatures, the crystal of separating out is used the 5mol/L recrystallization again, obtain at last compound (
R)-3-(3-ethanoyl-4-hydroxy phenyl)-2-alanine, the beige crystal.M.p 208-214 ℃, the fusing point of product is consistent with the fusing point of known compound; MS (ESI) [M+H]
+M/z 224.2.
Embodiment 2
(
R)-3-(3-butyryl radicals-4-hydroxy phenyl)-2-alanine synthetic:
Get the there-necked flask of 250mL, to wherein adding 175 mL oil of mirbane, at room temperature to wherein adding (7.2 g, 40 mmol) D-tyrosine, add aluminum chloride then, the disposable butyryl chloride (57.3 mmol) that in reaction system, adds after stirring, reaction system is warmed up to 85～90 ℃ gradually, and reaction 4～8 h pour mixing solutions in the mixing solutions of dense HCl and ice into then, remove organic layer, keep water layer, water layer ethyl acetate extraction 3 times (50 mL * 3), water layer is crystallization at low temperatures, the crystal of separating out is used the 5mol/L recrystallization again, obtain at last compound (
R)-3-(3-butyryl radicals-4-hydroxy phenyl)-2-alanine.(4.6 g, productive rate 42%), solid.The product mass spectrum is consistent with the mass spectrum of known compound.
Embodiment 3
(
R)-3-(3-caproyl-4-hydroxy phenyl)-2-alanine synthetic:
Get the there-necked flask of 250mL, to wherein adding 88 mL oil of mirbane, at room temperature to wherein adding (3.6 g, 20 mmol) D-tyrosine, add aluminum chloride then, the disposable Acetyl Chloride 98Min. (2 mL, 29 mmol) that adds in reaction system after stirring is warmed up to 85～90 ℃ gradually with reaction system, reaction 4～8 h, then mixing solutions is poured in the mixing solutions of dense HCl and ice, removed organic layer, keep water layer, water layer ethyl acetate extraction 3 times (25 mL * 3), water layer is crystallization at low temperatures, and the crystal of separating out is used the 5mol/L recrystallization again, obtain at last compound (
R)-3-(3-caproyl-4-hydroxy phenyl)-2-alanine (2.5 g, productive rate 44.8%).The product mass spectrum is consistent with the mass spectrum of known compound.
Embodiment 4
(
R)-3-(3-ethanoyl-4-hydroxy phenyl)-2-alanine synthetic
Get the there-necked flask of 250mL, to wherein adding 175 mL oil of mirbane, at room temperature to wherein adding (7.2 g, 40 mmol) D-tyrosine, add tin tetrachloride then, the disposable Acetyl Chloride 98Min. (57.3 mmol) that in reaction system, adds after stirring, reaction system is warmed up to 85～90 ℃ gradually, and reaction 4～8 h pour mixing solutions in the mixing solutions of dense HCl and ice into then, remove organic layer, keep water layer, water layer ethyl acetate extraction 3 times (50 mL * 3), water layer is crystallization at low temperatures, the crystal of separating out is used the 5mol/L recrystallization again, obtain at last compound (
R)-3-(3-ethanoyl-4-hydroxy phenyl)-2-alanine.(4.2 g, productive rate 46%).The product mass spectrum is consistent with the mass spectrum of known compound.
Embodiment 5
(
R)-3-(3-ethanoyl-4-hydroxy phenyl)-2-alanine synthetic
Get the there-necked flask of 250mL, to wherein adding 175 mL oil of mirbane, at room temperature to wherein adding (7.2 g, 40 mmol) D-tyrosine, add spirit of salt then, the disposable Acetyl Chloride 98Min. (4 mL, 57.3 mmol) that in reaction system, adds after stirring, reaction system is warmed up to 85～90 ℃ gradually, reaction 4～8 h pour mixing solutions in the mixing solutions of dense HCl and ice into then, remove organic layer, keep water layer, water layer ethyl acetate extraction 3 times (50 mL * 3), water layer is crystallization at low temperatures, and the crystal of separating out is used the 5mol/L recrystallization again, obtain product (3.8 g, productive rate 44.6%) at last.The product mass spectrum is consistent with the mass spectrum of known compound.
Embodiment 6
(
RSynthesizing of)-3-(3-ethanoyl-4-hydroxy phenyl)-2 hydroxy propanoic acid
Get the three-necked bottle of 25 ml; take by weighing (R)-3-(3-ethanoyl-4-hydroxy phenyl)-2-alanine (2 g; 9 mmol) to wherein adding an amount of water it is dissolved; the aqueous solution (14%) of the vitriol oil for preparing is joined in the reaction system; with ice bath the temperature of reaction system is remained on 0～5 ℃, in reaction system, add NaNO this moment
2(0.96 g, 14 mmol)) saturated aqueous solution, return to room temperature then, react 30 min, be warming up to 50 ℃, TLC monitors reaction, after question response finishes, with the mixing solutions extraction of ethyl acetate and ether 3 times, organic phase anhydrous Na
2The SO4 drying, the silicagel column separation obtains product (800 mg, productive rate 40%), oily liquids.Product mass spectrum, nuclear magnetic spectrogram are consistent with mass spectrum, the nuclear magnetic spectrogram of known compound.
Embodiment 7
(
RSynthesizing of)-3-(3-ethanoyl-4-hydroxy phenyl)-2 hydroxy propanoic acid
Get the three-necked bottle of 25 ml; take by weighing (R)-3-(3-ethanoyl-4-hydroxy phenyl)-2-alanine (2 g; 9 mmol) to wherein adding an amount of water it is dissolved; to cross chloric acid in right amount joins in the reaction system; with ice bath the temperature of reaction system is remained on 0～5 ℃, in reaction system, add NaNO this moment
2(0.96 g, 14 mmol)) saturated aqueous solution, return to room temperature then, react 30 min, be warming up to 50 ℃, TLC monitors reaction, after question response finishes, with the mixing solutions extraction of ethyl acetate and ether 3 times, organic phase anhydrous Na
2SO
4Drying, the silicagel column separation obtains product (760 mg, productive rate 38%), oily liquids.The product mass spectrum is consistent with the mass spectrum of known compound.
Embodiment 8
R-(+)-
βSynthesizing of-(3, the 4-dihydroxy phenyl) lactic acid (Salvianic acidA):
Get 25ml single port flask; take by weighing (80 mg; 0.36 mmol) (R)-3-(3-ethanoyl-4-hydroxy phenyl)-2 hydroxy propanoic acid; add the suitable quantity of water dissolving; to wherein adding the 5mol/L NaOH aqueous solution; pH is transferred to about 12-13, the temperature of reaction system is reduced to 0 ℃, add 30% H of about 1.8 mL then with ice bath
2O
2(17.6 mmol) continues reaction 1 h under ice bath, then temperature of reaction system risen to room temperature, and TLC monitors reaction, after question response finishes, adds saturated Na in system
2SO
3,Is 3 with the dilute hydrochloric acid souring soln to pH, the mixed solution extraction of usefulness ethyl acetate and ether 3 times, organic phase anhydrous Na
2SO
4Dry.Silicagel column separates, and obtains product (25 mg, productive rate 35%), and oily liquids is used FeCl
3Color spray shows green (the material FeCl that contains adjacent two phenolic hydroxyl groups
3It is green that color spray shows).MS (ESI) [M-H]
-M/z 197.1, and its Rf value is all identical with the Salvianic acidA that extracts from plant with specific optical rotation.
Embodiment 9
R-(+)-
βSynthesizing of-(3, the 4-dihydroxy phenyl) lactic acid (Salvianic acidA):
Get 25ml single port flask; take by weighing (80 mg; 0.36 mmol) (R)-3-(3-ethanoyl-4-hydroxy phenyl)-2 hydroxy propanoic acid; add the suitable quantity of water dissolving; to wherein adding the 5mol/L NaOH aqueous solution; pH is transferred to about 12-13, the temperature of reaction system is reduced to 0 ℃, add a certain amount of Na then with ice bath
2O
2(17.6 mmol) continues reaction 1 h under ice bath, then temperature of reaction system risen to room temperature, and TLC monitors reaction, after question response finishes, adds saturated Na in system
2SO
3,Is 3 with the dilute hydrochloric acid souring soln to pH, the mixed solution extraction of usefulness ethyl acetate and ether 3 times, organic phase anhydrous Na
2SO
4Dry.Silicagel column separates, and obtains product (20 mg, productive rate 31%), oily liquids.Its Rf value is all identical with the Salvianic acidA that extracts from plant with specific optical rotation.
Embodiment 10
R-(+)-
βSynthesizing of-(3, the 4-dihydroxy phenyl) lactic acid (Salvianic acidA):
Get 25ml single port flask, take by weighing (80 mg, 0.36 mmol) (R)-3-(3-ethanoyl-4-hydroxy phenyl)-2 hydroxy propanoic acid, add the suitable quantity of water dissolving, to wherein adding a certain amount of NaCO
3The aqueous solution transfers to about 12-13 with pH, with ice bath the temperature of reaction system is reduced to 0 ℃, adds 30% H of about 1.8 mL then
2O
2(17.6 mmol) continues reaction 1 h under ice bath, then temperature of reaction system risen to room temperature, and reaction is spent the night.TLC monitors reaction, after question response finishes, adds saturated Na in system
2SO
3,Is 3 with the dilute hydrochloric acid souring soln to pH, the mixed solution extraction of usefulness ethyl acetate and ether 3 times, organic phase anhydrous Na
2SO
4Dry.Silicagel column separates, and obtains product (22 mg, productive rate 32%), oily liquids.Its Rf value is all identical with the Salvianic acidA that extracts from plant with specific optical rotation.
In R-(+)-β-(3, the 4-dihydroxy phenyl) lactic acid (Salvianic acidA) synthetic, utilize TLC monitoring reaction.
In the synthetic method of the present invention, raw material is easy to get, and is simple to operate, is fit to large-scale industrial production.
Claims (9)
1. the synthetic method of a Salvianic acidA may further comprise the steps:
1) with
R-tyrosine is raw material, under lewis acidic catalytic condition, carries out friedel-crafts acylation with acylating reagent, and reaction equation is shown in (1):
R-tyrosine and acylating reagent mol ratio are 1:1.1-1.6,
R-tyrosine and lewis acidic mol ratio are 1:2-6; Lewis acid is a kind of in aluminum chloride, iron trichloride, tin tetrachloride, zinc dichloride, hydrofluoric acid, spirit of salt, the sulfuric acid, and acylating reagent is:
R wherein
1Be C
1～C
5Alkyl, X is chlorine or bromine or iodine;
2) with the product in the step 1) under the acid catalysis condition, carry out diazotization reaction with Sodium Nitrite or potassium nitrite, reaction equation is shown in (2):
The mol ratio of product in the step 1) and Sodium Nitrite or potassium nitrite is 1:1.2-1.6, and wherein acid is hydrochloric acid, sulfuric acid, phosphoric acid, crosses a kind of in chloric acid, the fluoroboric acid;
3) with step 2) in product under the effect of alkali, the Dakin reaction takes place with superoxide, obtain Salvianic acidA, reaction equation is shown in (3):
Wherein, step 2) product in and the mol ratio of superoxide are 1:1.2-1.7, with the mol ratio of alkali be 1:2, wherein alkali is a kind of in sodium hydroxide, saleratus, salt of wormwood, sodium bicarbonate, yellow soda ash, the triethylamine.
2. the synthetic method of a kind of Salvianic acidA according to claim 1 is characterized in that: in the step 1)
R-tyrosine and acylating reagent mol ratio are 1:1.4, R
1Be C
2～C
3Alkyl, X is a chlorine or bromine.
3. the synthetic method of a kind of Salvianic acidA according to claim 1 is characterized in that: step 2) in, the mol ratio of the product of used step 1) and Sodium Nitrite or potassium nitrite is 1:1.5, wherein, acid is sulfuric acid, cross a kind of in the chloric acid.
4. the synthetic method of a kind of Salvianic acidA according to claim 1, it is characterized in that: in the step 3), used step 2) product in and the mol ratio of superoxide are 1:1.5, with the mol ratio of alkali be 1:2, wherein used superoxide is a hydrogen peroxide, and wherein alkali is sodium hydroxide or salt of wormwood.
5. the synthetic method of a kind of Salvianic acidA according to claim 1, it is characterized in that: in the step 1), Lewis acid is an aluminum chloride, and acylating reagent is: Acetyl Chloride 98Min..
6. the synthetic method of a kind of Salvianic acidA according to claim 1 is characterized in that: step 2) in, acid is sulfuric acid.
7. the synthetic method of a kind of Salvianic acidA according to claim 1, it is characterized in that: in the step 3), superoxide is a hydrogen peroxide, and alkali is sodium hydroxide.
8. the synthetic method of a kind of Salvianic acidA according to claim 1, it is characterized in that: in the step 1), temperature of reaction is 85-90 ℃, and the reaction times is 4-8h.
9. the synthetic method of a kind of Salvianic acidA according to claim 1 is characterized in that: step 2) in, temperature of reaction is 85-90 ℃, the reaction times is 4-8h.
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| CN2011100589900A CN102153462A (en) | 2011-03-12 | 2011-03-12 | Method for synthesizing tanshinol |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863328A (en) * | 2012-05-15 | 2013-01-09 | 北京华素制药股份有限公司 | Synthesis method of tanshinol |
| CN102924265A (en) * | 2012-10-30 | 2013-02-13 | 中国人民解放军第四军医大学 | Asymmetric synthesis method of (+)-tanshinol |
| CN103288630A (en) * | 2012-02-27 | 2013-09-11 | 上海交通大学 | Synthesizing method of Salvianic acid A sodium |
| CN105294666A (en) * | 2014-06-19 | 2016-02-03 | 常州喜鹊医药有限公司 | Tanshinol derivative and preparation method therefor and pharmaceutical application thereof |
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| CN101012163A (en) * | 2006-11-03 | 2007-08-08 | 上海朗萨医药科技有限公司 | Method of preparing high purity Danshensu |
| CN101838195A (en) * | 2009-03-17 | 2010-09-22 | 天津天士力制药股份有限公司 | Chemical resolution preparation method for optical pure Beta-3, 4-dyhydroxyophenyl lactic acid |
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2011
- 2011-03-12 CN CN2011100589900A patent/CN102153462A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012163A (en) * | 2006-11-03 | 2007-08-08 | 上海朗萨医药科技有限公司 | Method of preparing high purity Danshensu |
| CN101838195A (en) * | 2009-03-17 | 2010-09-22 | 天津天士力制药股份有限公司 | Chemical resolution preparation method for optical pure Beta-3, 4-dyhydroxyophenyl lactic acid |
Non-Patent Citations (1)
| Title |
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| DAVID E.BOGUCKI，ET AL.: "A non-enzymatic synthesis of (S)-(-)-rosmarinic acid and a study of a biominetic route to (+)-rabdosiin", 《CANADIAN JOURNAL OF CHEMISTRY》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288630A (en) * | 2012-02-27 | 2013-09-11 | 上海交通大学 | Synthesizing method of Salvianic acid A sodium |
| CN102863328A (en) * | 2012-05-15 | 2013-01-09 | 北京华素制药股份有限公司 | Synthesis method of tanshinol |
| CN102924265A (en) * | 2012-10-30 | 2013-02-13 | 中国人民解放军第四军医大学 | Asymmetric synthesis method of (+)-tanshinol |
| CN102924265B (en) * | 2012-10-30 | 2015-09-09 | 中国人民解放军第四军医大学 | The method of asymmetric synthesis of (+)-Salvianic acidA |
| CN105294666A (en) * | 2014-06-19 | 2016-02-03 | 常州喜鹊医药有限公司 | Tanshinol derivative and preparation method therefor and pharmaceutical application thereof |
| CN105294666B (en) * | 2014-06-19 | 2018-04-03 | 常州喜鹊医药有限公司 | A kind of Danshensu derivatives and preparation method thereof and medical applications |
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Application publication date: 20110817 |