CN103570546A - Industrial synthesis method of bornyl tanshinol - Google Patents
Industrial synthesis method of bornyl tanshinol Download PDFInfo
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Abstract
The invention relates to an industrial synthesis method of bornyl tanshinol, which comprises the following step: in the presence of the second hydrochloric acid, a reducing agent Zn-Hg and a catalyst, beta-(3,4-dihydroxylphenyl)pyruvic acid reacts with borneol in a solvent to generate the bornyl tanshinol, wherein the beta-(3,4-dihydroxylphenyl)pyruvic acid is obtained by hydrolyzing 2-methyl-4-(3,4-diacetoxylbenzal)oxazole in the first hydrochloric acid. In the method provided by the invention, esterification and modification reducing reaction are performed at the same time. The synthesis of an intermediate product tanshinol in a synthesis method is omitted, the process operation is simplified, and the production period is shortened. Moreover, since the beta-(3,4-dihydroxylphenyl)pyruvic acid is directly obtained by hydrolyzing 2-methyl-4-(3,4-diacetoxylbenzal)oxazole in the hydrochloric acid solution, the process operation is further simplified.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to the Salvianic acidA norbornene ester synthetic method of a kind of prevention and treatment cardiovascular and cerebrovascular diseases.
Background technology
21st century, cardiovascular and cerebrovascular diseases has become one of major disease of harm humans life and health, and its lethality rate has surpassed tumour and leapt to the first, and chemoprophylaxis and treatment are still main means.Salvianic acidA norbornene ester is effective constituent Salvianic acidA based on the red sage root and the resulting structure fragment of borneol, utilizes modern medicines design science principle of hybridization, the brand-new compound of the structure with treating cerebral ischemia that design is synthetic.Salvianic acidA norbornene ester synthetic method of the prior art is all by Salvianic acidA and alcohol, to carry out esterification to obtain target compound (I).
Owing to having used unsettled compound Salvianic acidA in synthetic route, cause reaction yield low.While carrying out suitability for industrialized production, there are following two problems:
The first, the productive rate of Salvianic acidA norbornene ester is low, is difficult to satisfy the demands in cost and output;
The second, the Salvianic acidA existing in technique is synthetic, due to oxidizable, the difficult crystallization of this compound, technological process control and the control of product final quality is had to remarkable disadvantageous effect.
Summary of the invention
The object of the present invention is to provide a kind of Salvianic acidA norbornene ester synthetic method that is applicable to suitability for industrialized production.
For this reason, the present invention takes following technical scheme:
An Industrialized synthesis method for Salvianic acidA norbornene ester, comprises the following steps:
(1), under the condition existing at the second hydrochloric acid, reductive agent Zn-Hg and catalyzer, β-(3,4-dihydroxy phenyl) pyruvic acid reacts in solvent with borneol and generates Salvianic acidA norbornene ester.
Other technologies of the present invention are characterized as:
The second concentration of hydrochloric acid in step (1) is 10-14mol/L.
Described catalyzer is solid super-strong acid S
2o
8 2-/ ZrO
2, S
2o
8 2-/ TiO
2, SO
4 2-/ Fe
2o
3, SO
4 2-/ Al
2o
3, β-(3,4-dihydroxy phenyl) pyruvic acid is 1 ﹕ (0.03～0.15) with the mole dosage ratio of catalyzer.
Described solvent is one or more the mixed solution in benzene,toluene,xylene, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane and dimethyl sulfoxide (DMSO), and the mass ratio of β-(3,4-dihydroxy phenyl) pyruvic acid and solvent is 1 ﹕ (6～16).
The temperature of reaction of step (1) is 65 ℃-190 ℃, and the reaction times is 24h-28h.
The mol ratio of described β-(3,4-dihydroxy phenyl) pyruvic acid and borneol is 1 ﹕ (0.8～1.2).
Further, the Industrialized synthesis method of described Salvianic acidA norbornene ester is further comprising the steps of: (3,4-diacetoxy benzal base) azolactone is hydrolyzed and obtains β-(3,4-dihydroxy phenyl) pyruvic acid (2) 2-methyl-4-in the first hydrochloric acid.
The described reaction of described step (2) is carried out in acetone.
The first described concentration of hydrochloric acid of step (2) is 0.8-1.2mol/L.
Compared with prior art, advantage of the present invention is as follows:
In method of the present invention, esterification and modification Clemmensen reduction reaction are carried out simultaneously.Save the synthetic of the interior intermediate product Salvianic acidA of synthetic method, simplified technological operation, reduced equipment requirements, improved productive rate, shortened the production cycle, and evaded intermediate Salvianic acidA and in reaction process, be easy to oxidation, be difficult to purifying and carry out the problems such as virtual mass control.
In addition, in method of the present invention, by 2-methyl-4-, (3,4-diacetoxy benzal base) azolactone is hydrolyzed and directly obtains β-(3,4-dihydroxy phenyl) pyruvic acid in hydrochloric acid soln.Saved the intermediate product β-(3 in existing synthetic method, 4-diacetoxy phenyl) the acrylic acid synthesis step of-alpha-acetamido-, has simplified technological operation, has improved productive rate, shorten the production cycle, be conducive to reduce the industrial production cost of Salvianic acidA norbornene ester.
The present invention designs new synthetic route and prepares Salvianic acidA norbornene ester, and because synthetic method does not relate to unstable compound Salvianic acidA as synthetic intermediate, and esterification and reduction reaction carry out simultaneously, reduced by two reactions steps, improved reaction yield.The method is applicable to the suitability for industrialized production of Salvianic acidA norbornene ester.The features such as it is high that method has compound productive rate, and technological operation and equipment are simpler, and intermediate quality is easier to control, with short production cycle, and production cost is low.
Accompanying drawing explanation
Fig. 1 is the nuclear magnetic resonance spectrum of the obtained Salvianic acidA norbornene ester of embodiment 1;
Fig. 2 is the nuclear magnetic resonance spectrum of the obtained Salvianic acidA norbornene ester of embodiment 2.
Embodiment
Proposition of the present invention just must technical solution problem by the synthetic plant produced institute that moves towards in laboratory based on solving Salvianic acidA norbornene ester, sets up a kind of industrial syntheti c route of Salvianic acidA norbornene ester.
Salvianic acidA norbornene ester industrial production process shown in composite structure formula I of the present invention is with β-(3,4-dihydroxy phenyl) pyruvic acid is in solvent and dense HCl, and that carries out with borneol, reductive agent Zn-Hg that esterification and modification Clemmensen reduction complete simultaneously reacts and obtain target product.β-(3 wherein, 4-dihydroxy phenyl) the synthetic of pyruvic acid is with 3,4-Dihydroxy benzaldehyde is raw material, through Knoevenagel condensation, obtain 2-methyl-4-(3,4-diacetoxy benzal base) azolactone, in hydrochloric acid soln, hydrolysis obtains β-(3,4-dihydroxy phenyl) pyruvic acid.Certainly (3,4-diacetoxy benzal base) azolactone can adopt conventional preparation method to the present invention 2-methyl-4-used, with 3,4-Dihydroxy benzaldehyde, for raw material, through Knoevenagel condensation, prepares.
In step of the present invention (1), the concentration of the second hydrochloric acid is 10-14mol/L, preferably 12mol/L.
The concentration of the first hydrochloric acid that step of the present invention (2) is described is 0.8-1.2mol/L, preferably 1mol/L.
The mole dosage ratio of β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid and catalyzer is 1 ﹕ 0.08 preferably.
The mass ratio of β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid and solvent is 1 ﹕ 12 preferably.
The mol ratio of β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid and borneol is 1 ﹕ 1.1 preferably.
(3,4-diacetoxy benzal base) azolactone can 3, and 4-Dihydroxy benzaldehyde is that prepared using Knoevenagel method of condensing prepares for 2-methyl-4-of the present invention.
Acrylic acid synthetic for saving intermediate product β-(3,4-diacetoxy phenyl)-alpha-acetamido-, contriver has carried out following optimization Test.
In 500mL single port flask, add 2-methyl-(3,4-diacetoxy benzal base) azolactone 30g, with hydrochloric acid volume, (quality of this volume hydrochloric acid is 2-methyl-(3, the multiple of 4-diacetoxy benzal base) azolactone quality), concentration of hydrochloric acid and reaction times are influence factor, the level of factor orthogonal experiment that carries out as shown in table 1, after having reacted, add again 30mL acetone, reflux 4h after being cooled to room temperature.With rotatory evaporator, reactant is spin-dried for, cold water washing, suction filtration, dry, obtain white loose shape crystal, weigh, survey fusing point (literature value: m.p.181.4 ℃), make high performance liquid chromatography.Observation experiment phenomenon, calculates productive rate.
The level of factor of table 1 β-(3,4-dihydroxy phenyl) pyruvic acid industry preparation optimization experiment research
Table 2 β-(3,4-dihydroxy phenyl) pyruvic acid industry preparation optimization experiment quadrature results and analysis
| Experiment sequence number | A | B | C | Reaction yield/% |
| 1 | 1 | 1 | 1 | 47.2 |
| 2 | 1 | 2 | 2 | 66.7 |
| 3 | 1 | 3 | 3 | 46.4 |
| 4 | 2 | 1 | 2 | 52.5 |
| 5 | 2 | 2 | 3 | 50.1 |
| 6 | 2 | 3 | 1 | 42.7 |
| 7 | 3 | 1 | 3 | 40.2 |
| 8 | 3 | 2 | 1 | 54.6 |
| 9 | 3 | 3 | 2 | 51.2 |
| K 1 | 160.3 | 139.9 | 144.5 | K=451.6 |
| K 2 | 145.3 | 171.4 | 170.4 | P=22660 |
| K 3 | 146.0 | 140.3 | 136.7 | Q T=477 |
| U | 22708 | 22878 | 22867 | W=23137 |
| Q | 48 | 218 | 207 | ? |
From variance analysis, three factors all have remarkably influenced to reaction yield in selected horizontal extent.Excellent horizontal combination is A
1b
2c
2.
Therefore, β of the present invention-(3,4-dihydroxy phenyl) the synthetic of pyruvic acid can be with 3,4-Dihydroxy benzaldehyde is raw material, through Knoevenagel condensation, obtain 2-methyl-4-(3,4-diacetoxy benzal base) azolactone, in hydrochloric acid soln, hydrolysis obtains β-(3,4-dihydroxy phenyl) pyruvic acid.Certainly (3,4-diacetoxy benzal base) azolactone can adopt conventional preparation method to the present invention 2-methyl-4-used, with 3,4-Dihydroxy benzaldehyde, for raw material, through Knoevenagel condensation, prepares.
Concrete synthetic route of the present invention is as follows:
Below utilize specific embodiment to be further explained the present invention.
Embodiment 1:
(1) 2-methyl-4-(synthesizing of 3,4-diacetoxy benzal base) azolactone
In 500mL there-necked flask, add 3,4-Dihydroxy benzaldehyde 55.2g, ethanoylaminoethanoic acid 56.7g, the acetic anhydride 204.2g of sodium acetate, anhydrous 42.6g and new distillation, 80 ℃ of stirring reaction 5h, are cooled in the backward reaction solution of room temperature and add 150mL frozen water, stir and make to be even emulsion.After cooling, there are a large amount of yellow crystals to separate out, suction filtration, washing, dry, obtain yellow crystals 98.0g, m.p.161.0 ℃～161.4 ℃, yield 80.9%.
(2) β-(3,4-dihydroxy phenyl) pyruvic acid is synthetic
In 500mL single port flask, add 2-methyl-4-(3,4-diacetoxy benzal base) azolactone 30g, 1mol/L the first hydrochloric acid 300mL and acetone 30mL, reflux 10h.After reaction finishes, decompression concentrated solution, steams acetone and the first aqueous hydrochloric acid, after solid is separated out, add 50mL frozen water dispersible solid, decompress filter, frozen water washing, vacuum-drying, obtain faint yellow solid product 13.6g, m.p.161.0 ℃～161.4 ℃, productive rate is 70%.
1H?NMR(400MHz,DMSO)δppm:6.22(s,1H),6.67(d,J=8.4Hz,1H),6.90(dd,J=8Hz,J=2Hz,1H),7.31(d,J=2Hz,1H)。
(3) Salvianic acidA norbornene ester is synthetic
Get β-(3,4-dihydroxy phenyl) pyruvic acid 5.0g (0.026mol), borneol 3.5g (0.023mol), add THF50mL, 12mol/L the second hydrochloric acid 15mL and freshly prepd zinc amalgam 9.00g, water trap and prolong are installed, while being heated to seethe with excitement, are added 0.4g nano solid supper corrosive acid catalyst S
2o
8 2-/ ZrO
2, reacting by heating 22h.After reaction finishes, remove catalysts and solvents, obtain brown oil matter.With appropriate acetic acid ethyl dissolution and move in separating funnel, water (25mL * 2), 4%NaHCO respectively
3the aqueous solution (25mL * 2) and 1.0mol/L hydrochloric acid (25mL * 1) washing.Gained organic phase is through anhydrous Na
2sO
4after dry, ethyl acetate is removed in underpressure distillation, obtains brown color dope, after column chromatography purifying, obtains sundown solid 3.0g, productive rate 39.1%.The Salvianic acidA norbornene ester nmr spectrum that this embodiment makes as shown in Figure 1.
Embodiment 2:
(1) 2-methyl-4-(production of 3,4-diacetoxy benzal base) azolactone
In the reactor of 500L, add 25.0kg3,4-Dihydroxy benzaldehyde, 25.0kg acetyl glycine and 20.0kg sodium acetate, anhydrous, 87.5kg acetic anhydride, logical steam heating stirs.Stirring reaction 4.5h at 80 ℃, is then warming up to 100 ℃ and continues to stir 1h.Steam off, water flowing cooling, treats that temperature in the kettle is down to 55 ℃, opens drain hole, approximately has 100L feed liquid.After being cooled to room temperature, have yellow solid to separate out, add the frozen water stirring and evenly mixing of 2 times of material liquid volumes, after in whizzer, filter centrifugal, during water wash twice on the rocks, the yellow solid obtaining is dry 8h in 60 ℃ of drying rooms, obtains product 45.0kg, yield 81.7%.
(2) production of β-(3,4-dihydroxy phenyl) pyruvic acid
In the glass reactor of the 500L pool, add 2-methyl-4-(3,4-diacetoxy benzal base) azolactone 25kg, 25L acetone and 1mol/L the first hydrochloric acid 250L, logical steam heating, stirring and refluxing reaction 10h.The concentrated material of underpressure distillation, to certain volume, is opened drain hole blowing.Be cooled to solid and separate out completely, at whizzer centrifugal dewatering, during add water wash several times, after dehydration, put into 60 ℃ of drying rooms dry, obtain faint yellow solid product 9.0kg, productive rate 55.7%.The production cycle of this step is 2 days.
Adopt ZL200410026205.3 and the disclosed method of ZL20060042787.3 to prepare β-(3,4-dihydroxy phenyl) pyruvic acid, (3,4-diacetoxy benzal base) azolactone obtains 3.2kg product to 25kg raw material 2-methyl-4-, in 15 hours reaction times, the production cycle is 6 days.
(3) production of Salvianic acidA norbornene ester
In the glass still of the pool of 500L, add β-(3,4-dihydroxy phenyl) pyruvic acid, 17kg borneol, 270L tetrahydrofuran (THF), 110L the second hydrochloric acid (12mol/L), 50kg new system of 20kg for zinc amalgam and 2.4kg nano solid supper corrosive acid catalyst S
2o
8 2-/ ZrO
2react reflux 12h.After reaction finishes, remove catalysts and solvents, obtain brown oil matter, be dissolved in ethyl acetate.Difference water, 4%NaHCO
3the aqueous solution and 1.0mol/L salt acid elution.Gained organic phase is through anhydrous Na
2sO
4after dry, ethyl acetate is removed in decompression, obtains brown color dope, after column chromatography purifying, obtains β-(3,4-dihydroxy phenyl)-alpha hydroxy borneol propionate 10.7kg, yield 31.5%.The production cycle of this step is 3 days.The Salvianic acidA norbornene ester nmr spectrum that this embodiment makes as shown in Figure 2.
Adopt the disclosed method of ZL20060042787.3 to implement the preparation of Salvianic acidA norbornene ester, 20kg raw material β-(3,4-dihydroxy phenyl) pyruvic acid can only obtain 1.3kg, Salvianic acidA norbornene ester, and the low and long reaction time of productive rate, the production cycle is 6 days.
Embodiment 3:
This embodiment is as different from Example 2: the solvent in step (3) is toluene.Finally obtain β-(3,4-dihydroxy phenyl)-alpha hydroxy borneol propionate 3.4kg, yield 9.5%.
Embodiment 4:
This embodiment is as different from Example 2: the solvent in step (3) is dimethylbenzene.Finally obtain β-(3,4-dihydroxy phenyl)-alpha hydroxy borneol propionate 0.9kg, yield 2.6%.
Embodiment 5:
This embodiment is as different from Example 2: the solvent in step (3) is Isosorbide-5-Nitrae-dioxane.Finally obtain β-(3,4-dihydroxy phenyl)-alpha hydroxy borneol propionate 1.3kg, yield 3.8%.
Embodiment 6:
This embodiment is as different from Example 2: the solvent in step (3) is dimethyl sulfoxide (DMSO).Finally obtain β-(3,4-dihydroxy phenyl)-alpha hydroxy borneol propionate 2.1kg, yield 5.6%.
Embodiment 7:
This embodiment is as different from Example 2: the catalyzer in step (3) is S
2o
8 2-/ TiO
2.Finally obtain β-(3,4-dihydroxy phenyl)-alpha hydroxy borneol propionate 1.5kg, yield 4.0%.
Embodiment 8:
This embodiment is as different from Example 2: the catalyzer in step (3) is SO
4 2-/ Fe
2o
3.Finally obtain β-(3,4-dihydroxy phenyl)-alpha hydroxy borneol propionate 3.3kg, yield 9.2%.
Embodiment 9:
This embodiment is as different from Example 2: the catalyzer in step (3) is SO
4 2-/ Al
2o
3.Finally obtain β-(3,4-dihydroxy phenyl)-alpha hydroxy borneol propionate 2.8kg, yield 7.9%.
Claims (9)
1. an Industrialized synthesis method for Salvianic acidA norbornene ester, is characterized in that, comprises the following steps:
(1), under the condition existing at the second hydrochloric acid, reductive agent Zn-Hg and catalyzer, β-(3,4-dihydroxy phenyl) pyruvic acid reacts in solvent with borneol and generates Salvianic acidA norbornene ester.
2. the Industrialized synthesis method of Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, the second concentration of hydrochloric acid in step (1) is 10-14mol/L.
3. the Industrialized synthesis method of Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, described catalyzer is solid super-strong acid S
2o
8 2-/ ZrO
2, S
2o
8 2-/ TiO
2, SO
4 2-/ Fe
2o
3, SO
4 2-/ Al
2o
3, described β-(3,4-dihydroxy phenyl) pyruvic acid is 1 ﹕ (0.03～0.15) with the mole dosage ratio of catalyzer.
4. the Industrialized synthesis method of Salvianic acidA norbornene ester as claimed in claim 1, it is characterized in that, described solvent is benzene,toluene,xylene, tetrahydrofuran (THF), 1, the mixed solution of one or more in 4-dioxane and dimethyl sulfoxide (DMSO), the mass ratio of β-(3,4-dihydroxy phenyl) pyruvic acid and solvent is 1 ﹕ (6～16).
5. the Industrialized synthesis method of Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, the temperature of reaction of step (1) is 65 ℃-190 ℃, and the reaction times is 24h-28h.
6. the Industrialized synthesis method of Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, the mol ratio of described β-(3,4-dihydroxy phenyl) pyruvic acid and borneol is 1 ﹕ (0.8～1.2).
7. the Industrialized synthesis method of Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, the Industrialized synthesis method of described Salvianic acidA norbornene ester is further comprising the steps of:
(2) (3,4-diacetoxy benzal base) azolactone is hydrolyzed and obtains β-(3,4-dihydroxy phenyl) pyruvic acid 2-methyl-4-in the first hydrochloric acid.
8. the Industrialized synthesis method of Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, the described reaction of described step (2) is carried out in acetone.
9. the Industrialized synthesis method of Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, the first described concentration of hydrochloric acid of step (2) is 0.8-1.2mol/L.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108047048A (en) * | 2017-12-30 | 2018-05-18 | 苏州沪云肿瘤研究中心股份有限公司 | A kind of benzenpropanoic acid ester type compound and its preparation method and application |
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| CN1868998A (en) * | 2006-05-15 | 2006-11-29 | 西北大学 | Beta-(3,4) dihydroxy phenyl-alpha hydroxy borneol propionate, its synthesis method and use |
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| CN1868998A (en) * | 2006-05-15 | 2006-11-29 | 西北大学 | Beta-(3,4) dihydroxy phenyl-alpha hydroxy borneol propionate, its synthesis method and use |
| WO2007131446A1 (en) * | 2006-05-15 | 2007-11-22 | Northwest University | Substituted beta-phenyl-alpha-hydroxy propanoic acid, synthesis method and use thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047048A (en) * | 2017-12-30 | 2018-05-18 | 苏州沪云肿瘤研究中心股份有限公司 | A kind of benzenpropanoic acid ester type compound and its preparation method and application |
| CN108047048B (en) * | 2017-12-30 | 2021-01-12 | 苏州沪云肿瘤研究中心股份有限公司 | Phenylpropanoate compound and preparation method and application thereof |
| US11767286B2 (en) | 2017-12-30 | 2023-09-26 | Suzhou Pharmavan Co., Ltd | Phenylpropionate compound, preparation method for same, and applications thereof |
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