CN104030923B - A kind of synthetic method of DL tanshinol borneol ester - Google Patents
A kind of synthetic method of DL tanshinol borneol ester Download PDFInfo
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- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C67/327—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by elimination of functional groups containing oxygen only in singly bound form
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- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The present invention relates to a kind of synthetic method of DL tanshinol borneol ester; method comprises with the rancinamycin IV of benzyl protection for initial feed; through Darzens epoxidation, then DL tanshinol borneol ester can be obtained through palladium class catalyzer/hydrogen or Raney's nickel/hydrogen catalytic reduction.The product purity adopting method of the present invention to synthesize can reach 98%, and productive rate can reach 48.6%.And synthetic method raw material of the present invention is simple and easy to get, route is short, and productive rate is high, is applicable to large-scale industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of medicine---synthetic method of tanshinol borneol ester that can be used for treating or preventing and treating cardiovascular and cerebrovascular diseases.
Background technology
DL tanshinol borneol ester, chemistry by name (±)-3 ', 4 '-dihydroxy phenyl-2 hydroxy propanoic acid norbornene ester, be the combination principle according to " monarch-make medicine " in medicine effect group's principle of hybridization and Chinese medicine preparation theory, the effective constituent Salvianic acidA of " monarch drug in a prescription " red sage root and " making medicine " borneol are designed with the combination of the form of ester bond.Tanshinol borneol ester has atherosclerosis, anti-cardiac-cerebral ischemia, reduces blood pressure, improves the effects such as cardiac diastolic function.
Chinese patent application (publication number: CN1868998A) discloses one and is obtained by reacting 2-methyl-4-(3 by rancinamycin IV and acetyl glycine; 4-diacetoxy benzal base) azolactone; (3 are obtained through open loop; 4-diacetoxy benzal base)-N-ethanoyl vinylformic acid; hydrolysis obtains β-(3 again; 4-dihydroxy phenyl) pyruvic acid, obtain DL Salvianic acidA with zinc amalgam reduction, then obtain tanshinol borneol ester with borneol esterification.Totally 5 step reactions, overall yield is lower, is about 12%, and wherein use zinc amalgam as reductive agent, environmental pollution is large, not easily suitability for industrialized production.
Chinese patent application (publication number: CN103570546A) is on the basis of Chinese patent application (publication number: CN1868998A), improved technology process, with β-(3,4-dihydroxy phenyl) pyruvic acid and borneol at solid super-strong acid (S
2o
8 2-/ ZrO
2), under the existence of hydrochloric acid, zinc amalgam, " one kettle way " obtains tanshinol borneol ester.Totally 3 step reactions, total recovery is between 1.2-22.1%, and yield increases comparatively before, but still uses zinc amalgam as reductive agent, and environmental pollution is large, not easily suitability for industrialized production.Other synthetic methods; as (β-(3 such as Zhang Qunzheng; 4-dihydroxy phenyl)-alpha-hydroxypropionic acid isopropyl ester/norbornene ester study on the synthesis; organic chemistry, organic chemistry, 2009; 29 (9); 1466-1469.) with 3,4-Dihydroxy benzaldehyde for raw material, through benzyl protection, Darzens epoxidation, Lewis acid open loop, NaBH
4reduction, shortening deprotection obtain tanshinol borneol ester.Synthetic route is longer, severe reaction conditions, and productive rate is lower, is not suitable for suitability for industrialized production; Zheng Xiao sunshine seminar (ImprovedProcessforPilot-ScaleSynthesisofDanshensu (±)-DSS) andItsEnantiomerDerivatives, Org.ProcessRes.Dev., DOI:10.1021/op4002593) on the basis of Chinese patent application (publication number: CN1583710A), optimum synthesis technique, β-(3 are reduced with Raney's nickel, 4-dihydroxy phenyl) pyruvic acid norbornene ester obtains tanshinol borneol ester, totally 4 step reactions, total recovery reaches 47.5%.Process contamination is little, is comparatively applicable to industrial production.The method is in view of industrial cost's problem, and productive rate still has much room for improvement.
Summary of the invention
The defect existed for prior art or deficiency, the object of the present invention is to provide a kind of starting material cheap and easy to get, route is short, the synthetic method of the DL tanshinol borneol ester that productive rate, purity are higher.
For this reason, the synthetic method of DL tanshinol borneol ester provided by the invention comprises:
Reaction (1): halo benzyl and rancinamycin IV react preparation 3,4-benzyloxy phenyl aldehyde, and described halogenation benzyl is cylite or Benzyl Chloride;
Reaction (2): 3,4-benzyloxy phenyl aldehyde and Mono Chloro Acetic Acid norbornene ester obtain 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester through Darzens epoxidation reaction;
Reaction (3): under catalyzer and hydrogen existence condition, 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester open loop simultaneously debenzylation obtains tanshinol borneol ester.
Preferably, described reaction (1) is carried out in the first organic solvent He under alkaline condition, and reaction (1) is carried out under 20-150 DEG C of condition, described first organic solvent is tetrahydrofuran (THF), dimethyl ethylene glycol, diethyl ethylene glycol, 1,4-dioxane, N, one or more combination in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone and dimethyl sulfoxide (DMSO).
Preferably, described reaction (1) Protocatechuic Aldehyde and the amount of substance of Benzyl Chloride are than being 1:(2 ~ 5).
Preferably, described reaction (2) is carried out in a second organic solvent with under alkaline condition, and described reaction (2) is carried out at 0-50 DEG C; Described second organic solvent is ether, methyl tertiary butyl ether, tetrahydrofuran (THF), dimethyl ethylene glycol, diethyl ethylene glycol, 1,4-dioxane, methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, benzene,toluene,xylene, N, one or more combination in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone and dimethyl sulfoxide (DMSO).
Preferably, described Mono Chloro Acetic Acid norbornene ester and 3,4-benzyloxy phenyl aldehyde to be dissolved in the second organic solvent simultaneously and to be added dropwise in reaction system.
Preferably, the alkali in described reaction (2) is one or more the composition in lithium hydride, sodium hydride, sodium methylate, sodium ethylate, lithium ethoxide, potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium and amylalcohol lithium.
Preferably, the ratio of the Mono Chloro Acetic Acid norbornene ester in described reaction (2) and the amount of substance of 3,4-benzyloxy phenyl aldehyde is 1:(1 ~ 3).
Preferably, the catalyzer in described reaction (3) is one or more the combination in palladium carbon, palladium and palladium hydroxide, or is Raney's nickel.
Preferably, described reaction (3) is carried out in the 3rd organic solvent, and described 3rd organic solvent is one or more the combination in Virahol, ethanol, methyl alcohol, tetrahydrofuran (THF) and methyl tertiary butyl ether.
Further, Mono Chloro Acetic Acid norbornene ester chloroacetyl chloride used in the present invention and borneol react obtained.
In sum, the synthetic method of DL tanshinol borneol ester of the present invention has the following advantages:
(1) adopt cheaper starting materials to be easy to get in the inventive method, reactions steps is short, and aftertreatment is simple, not high to equipment requirements, can carry out large-scale industrial production.
(2) in building-up process of the present invention, do not use industrial chemicals environment to larger pollution, the waste water produced, waste material are convenient to process or are reclaimed, and environmental pollution is little.
(3) adopt synthetic method of the present invention, product yield and purity are all higher, reduce production cost.
To sum up, the synthetic method of a kind of DL tanshinol borneol ester of the present invention for initial feed, through Darzens epoxidation, then can obtain DL tanshinol borneol ester through sodium borohydride reduction with the rancinamycin IV of benzyl protection.Purity reaches more than 98%, and productive rate reaches more than 48.6%.Synthetic method of the present invention, raw material is simple and easy to get, and route is short, and productive rate is high, is applicable to large-scale industrial production.
Accompanying drawing explanation
Fig. 1 is DL tanshinol borneol ester mass spectrum prepared by embodiment 1, the DL Salvianic acidA total ion current figure that Fig. 1 (a) is prepared for embodiment 1, Fig. 1 (b) is the mass spectrum at peak 1 in Fig. 1 (a), and Fig. 1 (c) is the mass spectrum at peak 2 in Fig. 1 (a);
Fig. 2 is DL tanshinol borneol ester hydrogen spectrum prepared by embodiment 1;
Fig. 3 is DL tanshinol borneol ester carbon spectrum prepared by embodiment 1;
Fig. 4 is DL tanshinol borneol ester infared spectrum prepared by embodiment 1;
Fig. 5 is DL tanshinol borneol ester chiral column liquid chromatography collection of illustrative plates prepared by embodiment 1.
Embodiment
DL tanshinol borneol ester synthetic route of the present invention is as follows:
In this reaction formula 1 is 3,4-benzyloxy phenyl aldehyde; 2 is Mono Chloro Acetic Acid norbornene ester; 3 is 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester; (I) be tanshinol borneol ester.
The present invention take rancinamycin IV as initial feed, is obtained by reacting DL tanshinol borneol ester through 4 steps.The feature of synthetic route is:
Reaction (1): with two phenolic hydroxyl groups of halogenation benzyl protection rancinamycin IV, obtain 3,4-benzyloxy phenyl aldehyde;
Reaction (2): 3,4-benzyloxy phenyl aldehyde and Mono Chloro Acetic Acid norbornene ester obtain 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester through Darzens epoxidation reaction;
Reaction (3): under catalyzer and hydrogen existence condition, 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester open loop simultaneously debenzylation obtains tanshinol borneol ester.
In the present invention's reaction (1), the first organic solvent used can be tetrahydrofuran (THF), dimethyl ethylene glycol, diethyl ethylene glycol, 1,4-dioxane, N, one or more composition in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone and dimethyl sulfoxide (DMSO).Preferred Isosorbide-5-Nitrae-dioxane, DMF.
One or more composition in alkaline environment available hydrogen sodium oxide, potassium hydroxide, calcium hydroxide, anhydrous sodium carbonate, salt of wormwood, sodium bicarbonate, sodium phosphate, pyridine, DMAP, triethylamine and the diisopropyl ethyl amine of the present invention's reaction needed for (1) adjusts.Preferred sodium carbonate and salt of wormwood.
The temperature of reaction of the present invention's reaction (1) is 20 DEG C ~ 150 DEG C, prioritizing selection 100 DEG C ~ 145 DEG C.Reaction times controls at 1 ~ 8 hour, judges reaction process, preferentially between 2 ~ 4 hours according to TLC.
The present invention reaction (1) in rancinamycin IV be 1:(2 ~ 5 with the ratio of the amount of substance of Benzyl Chloride), prioritizing selection 1:(2 ~ 2.5) between.
Wherein one or more combination below the second organic solvent in the present invention's reaction (2) can be: ether, methyl tertiary butyl ether, tetrahydrofuran (THF), dimethyl ethylene glycol, diethyl ethylene glycol, 1,4-dioxane, methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, benzene,toluene,xylene, N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO).Preferred Virahol and Isosorbide-5-Nitrae-dioxane.
The alkaline environment of the present invention's reaction needed for (2) can use one or more the composition in lithium hydride, sodium hydride, sodium methylate, sodium ethylate, lithium ethoxide, potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium and amylalcohol lithium.Particular methanol sodium and sodium ethylate.
In reaction of the present invention (2), temperature of reaction is 0 DEG C ~ 50 DEG C, and preferably 5 DEG C ~ 30 DEG C, drip the Isosorbide-5-Nitrae-dioxane solution of Mono Chloro Acetic Acid norbornene ester and 3,4-benzyloxy phenyl aldehyde in reaction process, time for adding is 0.25 ~ 2 hour; Reaction times can be controlled in 3 ~ 24 hours, judges reaction process, preferably at 8 ~ 12 hours according to TLC.
In reaction of the present invention (2), the ratio of the amount of substance of Mono Chloro Acetic Acid norbornene ester and 3,4-benzyloxy phenyl aldehyde is 1:(1 ~ 3), preferred 1:(1.2 ~ 1.5).
In reaction of the present invention (3), used catalyst is palladium carbon, palladium, palladium hydroxide and Raney's nickel, preferred palladium carbon or Raney's nickel.
In reaction of the present invention (3), the product reacted in (2) is dissolved in the 3rd organic solvent, 3rd organic solvent is one or more the combination in Virahol, ethanol, methyl alcohol, tetrahydrofuran (THF) and methyl tertiary butyl ether, when reaction is carried out, add catalyzer, pass into hydrogen, pressure remains between 0.1 ~ 2.0MPa, 0.5 ~ 24 hour reaction times.For different catalyzer, consumption, the reaction conditions of its material are different:
Palladium-carbon catalyst (the wet palladium carbon of 5%) and 3-(3,4-benzyloxy phenenyl) mass ratio of glycidic acid norbornene ester is (0.04 ~ 0.3): 1, preferred 0.1:1, reaction pressure is at 0.1 ~ 2.0MPa, preferably 0.1 ~ 1.0MPa, the catalyzed reaction time is 0.5 ~ 24 hour, preferably 0.5 ~ 2 hour;
Palladium and catalyst palladium hydroxide and 3-(3,4-benzyloxy phenenyl) ratio of amount of substance of glycidic acid norbornene ester is (0.01 ~ 0.2): 1, preferred 0.05:1, reaction pressure is at 0.1 ~ 2.0MPa, preferably 0.1 ~ 1.0MPa, the catalyzed reaction time is 0.5 ~ 24 hour, preferably 0.5 ~ 2 hour;
The mass ratio of Raney's nickel catalyst and 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester is (0.04 ~ 0.6): 1, preferred 0.2:1, reaction pressure is at 0.1 ~ 2.0MPa, preferably 0.1 ~ 1.0MPa, the catalyzed reaction time is 1 ~ 24 hour, preferably 1 ~ 4 hour.
Under above-mentioned preferred version, all ultimate yield can be improved.
The recovery of target compound in respectively reacting for the present invention, can adopt following methods to carry out:
After reaction (1) completes, reactant is cooled to room temperature, suction filtration, and filtrate adds in frozen water, and with 0.5mol/LHCl hcl acidifying to pH=4 ~ 5, produce faint yellow solid, suction filtration, obtains 3,4-benzyloxy phenyl aldehyde;
For reaction (2), treat that raw material reaction is complete, pH=4 ~ 5 are regulated with 0.5mol/LHCl, use organic extractant phase again, merge organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure, thick product is through column chromatography purification (silica gel 200 ~ 300 order) or obtain 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester with C1 ~ C4 fatty alcohol/sherwood oil mixing solutions recrystallization;
After reaction (3) completes, filter reactant, concentrating under reduced pressure obtains tanshinol borneol ester.
Mono Chloro Acetic Acid norbornene ester used in the present invention be with chloroacetyl chloride and borneol organic bases as: under the existence of pyridine, DMAP, triethylamine, diisopropyl ethyl amine, obtain by esterification below.
In this reaction formula 2 is Mono Chloro Acetic Acid norbornene ester.
Below the specific embodiment that contriver provides, to be further explained explanation to technical scheme of the present invention.
Embodiment 1:
The synthesis of (1) 3,4-benzyloxy phenyl aldehyde:
55.2g (0.40mol) rancinamycin IV is dissolved in 600mLN, in dinethylformamide, slowly adds Benzyl Chloride 116.0g (0.92mol), take anhydrous K
2cO
3165.6g (1.2mol) add wherein, stirred at ambient temperature reacts 2 hours, then adds K
2cO
355.2g (0.40mol), 130 DEG C are heated 2 hours, and be cooled to room temperature, suction filtration, filtrate adds in frozen water, uses dilute hydrochloric acid acidifying, produce yellow mercury oxide, suction filtration, and with frozen water washing, obtain 3,4-benzyloxy phenyl aldehyde 122.1g, productive rate is 96%.
(2) synthesis of Mono Chloro Acetic Acid norbornene ester:
400mL methylene dichloride is added in reaction vessel, 77.2g (0.5mol) borneol, 50.5g (0.5mol) triethylamine, chloroacetyl chloride 56.4g (0.5mol) is added at 0 DEG C, stirring at room temperature reacts 3 hours, 200mL water is added in reaction solution, wash with saturated sodium bicarbonate solution 200mL, use dichloromethane extraction 3 times (150mL × 3) again, merge organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains light brown oil thing 106.9g, and productive rate is 93%.
(3) synthesis of 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester:
12.16g (0.225mol) sodium methylate is dissolved in 150ml methyl alcohol, obtains solution one;
Then by 47.7g (0.15mol) 3,4-benzyloxy phenyl aldehyde, 41.5g (0.18mol) Mono Chloro Acetic Acid norbornene ester, be dissolved in 100mL dioxane, obtain solution two;
Afterwards solution one is instilled in solution two in 30mim, stirred overnight at room temperature, reaction solution is added in the frozen water of 100mL, acetic acid is adjusted to neutrality, with methylene dichloride (200mL × 4) extraction, merges organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure, thick product Virahol/sherwood oil recrystallization obtains pale solid 54.6g, and productive rate is 71%.
(4) synthesis of tanshinol borneol ester:
By 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester 25.6g (0.05mol) is dissolved in 300mL tetrahydrofuran (THF), add 5% wet Pd/C2.56g again, pass into hydrogen, react after 1 hour under normal temperature, normal pressure, filter, concentrating under reduced pressure, thick product ethanol/sherwood oil recrystallization obtains faint yellow solid 14.4g, productive rate 86%, purity: 98.1%.
With reference to figure 1-Fig. 5,
ESI-MS,m/z:333.2[M-1]；
1HNMR(600MHz,DMSO-d
6)δ8.69(s，1H),8.62(s，1H),6.60(d,J＝9.6Hz,2H),6.44(d,J＝8.0Hz,1H),5.43(t,J＝6.1Hz,1H),4.72(dd,J＝26.0,9.0Hz,1H),4.14(d,J＝12.8Hz,1H),2.78–2.66(m,2H),2.27–2.14(m,1H),1.85–1.77(m,1H),1.70–1.58(m,2H),1.25–1.12(m,2H),0.86–0.69(m,10H)；
13CNMR(600MHz,DMSO-d
6)δ173.8,173.7,144.8,144.7,143.6,128.0,127.9,119.9,119.9,116.7,115.1,79.01,78.90,74.77,71.85,71.47,48.34,48.23,47.35,47.28,44.52,44.16,44.09,38.419,36.06,35.83,27.95,27.51,27.33,26.58,26.51,25.69,20.06,19.43,18.53,13.41,13.30,13.13；
IR(KBr,cm
-1)3401,2953,1708,1616,1520,1454,1388,1360,1280,1114,1080,995,978,897,852,809,761,704。
Chiral chromatographic column is analyzed: peak 1: peak 2=49.4%:49.1%.
Embodiment 2:
This embodiment difference from Example 1 is:
(1) synthesis of 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester:
Sodium methylate 12.2g (0.225mol) is dissolved in 150mL methyl alcohol, obtains solution one;
By 3,4-benzyloxy phenyl aldehyde 47.7g (0.15mol), Mono Chloro Acetic Acid norbornene ester 48.4g (0.21mol), be dissolved in 200mL dioxane, obtain solution two;
In 1 hour, solution two is instilled in solution one, maintain temperature of reaction at 5-10 DEG C, after dripping, be slowly warming up to room temperature, stirring is spent the night, reaction solution is added in the frozen water of 200mL, hydrochloric acid is adjusted to neutrality, with methylene dichloride (200mL × 4) extraction, merges organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure, thick product ethanol/sherwood oil recrystallization obtains pale solid 37.6g, and productive rate is 75%.
(2) synthesis of tanshinol borneol ester:
By 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester 25.6g (0.05mol) is dissolved in 300mL Virahol, add 5% wet Pd/C2.56g again, pass into hydrogen, react under normal temperature, normal pressure after 1.5 hours, filter, concentrating under reduced pressure, thick product ethanol/sherwood oil recrystallization obtains faint yellow solid 13.2g, productive rate 79%.
Embodiment 3:
This embodiment difference from Example 1 is:
(1) synthesis of 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester:
Sodium tert-butoxide 21.6g (0.225mol) is dissolved in the 150mL trimethyl carbinol, obtains solution one;
By 3,4-benzyloxy phenyl aldehyde 47.7g (0.15mol), Mono Chloro Acetic Acid norbornene ester 34.6g (0.15mol), be dissolved in 150mL dioxane, obtain solution two;
In 1 hour, solution two is instilled in solution one, maintain temperature of reaction at 5-10 DEG C, after dripping, be slowly warming up to room temperature, stirring is spent the night, reaction solution is added in the frozen water of 200mL, hydrochloric acid is adjusted to neutrality, with methylene dichloride (200mL × 4) extraction, merges organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure, thick product ethanol/sherwood oil recrystallization obtains pale solid 49.2g, and productive rate is 64%.
(2) synthesis of tanshinol borneol ester:
By 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester 25.6g (0.05mol) is dissolved in 300mL ethanol, add 5% wet Pd/C2.56g again, pass into hydrogen, react under normal temperature, normal pressure after 1 hour, filter, concentrating under reduced pressure, thick product ethanol/sherwood oil recrystallization obtains faint yellow solid 13.5g, productive rate 81%.
Embodiment 4:
This embodiment difference from Example 3 is:
The synthesis of tanshinol borneol ester:
By 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester 5.12g (0.01mol) is dissolved in 30mL ethanol, add palladium 0.22g again, pass into hydrogen, react under normal temperature, normal pressure after 2 hours, filter, concentrating under reduced pressure, thick product ethanol/sherwood oil recrystallization obtains faint yellow solid 2.71g, productive rate 83%.
Embodiment 5:
This embodiment difference from Example 3 is:
By 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester 5.12g (0.01mol) is dissolved in 30mL ethanol, add palladium hydroxide 0.14g again, pass into hydrogen, react under normal temperature, normal pressure after 2 hours, filter, concentrating under reduced pressure, thick product ethanol/sherwood oil recrystallization obtains faint yellow solid 2.64g, productive rate 79%.
Embodiment 6:
(1) synthesis of 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester:
Potassium tert.-butoxide 12.6g (0.113mol) is dissolved in the 75mL trimethyl carbinol, obtains solution one;
By 3,4-benzyloxy phenyl aldehyde 25.5g (0.08mol), Mono Chloro Acetic Acid norbornene ester 20.8g (0.09mol), be dissolved in 100mL dioxane, obtain solution two;
In 1 hour, by solution two in room temperature instillation solution one, stirred overnight at room temperature, added by reaction solution in the frozen water of 200mL, hydrochloric acid is adjusted to neutrality, extract with methylene dichloride (100mL × 4), merge organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure, thick product ethanol/sherwood oil recrystallization obtains pale solid 17.4g, and productive rate is 65%.
(2) synthesis of tanshinol borneol ester:
By 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester 15.4g (0.03mol) is dissolved in 100mL ethanol, add palladium and palladium hydroxide mixed catalyst, wherein palladium 0.24g again, palladium hydroxide 0.14g, pass into hydrogen, react under normal temperature, normal pressure after 2 hours, filter, concentrating under reduced pressure, thick product ethanol/sherwood oil recrystallization obtains faint yellow solid 8.32g, productive rate 83%.
Claims (6)
1. a synthetic method for DL tanshinol borneol ester, is characterized in that, this synthetic method comprises:
Reaction (1): halogenation benzyl and rancinamycin IV react preparation 3,4-benzyloxy phenyl aldehyde, and described halogenation benzyl is cylite or Benzyl Chloride;
Reaction (2): 3,4-benzyloxy phenyl aldehyde and Mono Chloro Acetic Acid norbornene ester obtain 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester through Darzens epoxidation reaction;
Reaction (3): under catalyzer and hydrogen existence condition, 3-(3,4-benzyloxy phenenyl) glycidic acid norbornene ester open loop simultaneously debenzylation obtains tanshinol borneol ester;
Described reaction (2) is carried out in a second organic solvent with under alkaline condition, and described reaction (2) is carried out at 0 DEG C-50 DEG C; Described second organic solvent is Isosorbide-5-Nitrae-dioxane;
Described Mono Chloro Acetic Acid norbornene ester and 3,4-benzyloxy phenyl aldehyde to be dissolved in the second organic solvent simultaneously and to be added dropwise in reaction system;
Alkali in described reaction (2) is one or more the composition in lithium hydride, sodium hydride, sodium methylate, sodium ethylate, lithium ethoxide, potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium and amylalcohol lithium;
The ratio of the amount of substance of the Mono Chloro Acetic Acid norbornene ester in described reaction (2) and 3,4-benzyloxy phenyl aldehyde is 1:(1 ~ 3).
2. the synthetic method of DL tanshinol borneol ester as claimed in claim 1, it is characterized in that, described reaction (1) is carried out in the first organic solvent He under alkaline condition, and reaction (1) is carried out under 20 DEG C of-150 DEG C of conditions, described first organic solvent is tetrahydrofuran (THF), dimethyl ethylene glycol, diethyl ethylene glycol, 1,4-dioxane, N, one or more combination in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone and dimethyl sulfoxide (DMSO).
3. the synthetic method of DL tanshinol borneol ester as claimed in claim 1, is characterized in that, described reaction (1) Protocatechuic Aldehyde is 1:(2 ~ 5 with the amount of substance ratio of Benzyl Chloride).
4. the synthetic method of DL tanshinol borneol ester as claimed in claim 1, it is characterized in that, the catalyzer in described reaction (3) is one or more the combination in palladium carbon, palladium and palladium hydroxide, or is Raney's nickel.
5. the synthetic method of DL tanshinol borneol ester as claimed in claim 1, it is characterized in that, described reaction (3) is carried out in the 3rd organic solvent, and described 3rd organic solvent is one or more the combination in Virahol, ethanol, methyl alcohol, tetrahydrofuran (THF) and methyl tertiary butyl ether.
6. the synthetic method of DL tanshinol borneol ester as claimed in claim 1, is characterized in that, described Mono Chloro Acetic Acid norbornene ester chloroacetyl chloride and borneol react obtained.
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| dl-丹参素的合成;童元峰等;《中国药物化学杂志》;20070430;第17卷(第2期);92-94 * |
| β-(3,4-二羟基苯基)-α-羟基丙酸异丙酯/冰片酯合成研究;张群正等;《有机化学》;20091231;第29卷(第9期);1466-1469 * |
| 丹参素衍生物的合成;孙举等;《合成化学》;20101231;第18卷(第2期);215-218 * |
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