CN103570547B - A kind of Industrialized synthesis method of Salvianic acidA isopropyl ester - Google Patents
A kind of Industrialized synthesis method of Salvianic acidA isopropyl ester Download PDFInfo
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- CN103570547B CN103570547B CN201310470980.7A CN201310470980A CN103570547B CN 103570547 B CN103570547 B CN 103570547B CN 201310470980 A CN201310470980 A CN 201310470980A CN 103570547 B CN103570547 B CN 103570547B
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- isopropyl ester
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- hydrochloric acid
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
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Abstract
The present invention relates to a kind of Industrialized synthesis method of Salvianic acidA isopropyl ester.Under being included in the second hydrochloric acid and reductive agent Zn-Hg existent condition, β-(3,4-dihydroxy phenyl) pyruvic acid and isopropyl ester react in a solvent and generate Salvianic acidA isopropyl ester.β wherein-(3,4-dihydroxy phenyl) pyruvic acid is that (3,4-diacetoxy benzal base) azolactone is hydrolyzed and obtains 2-methyl-4-in the first hydrochloric acid.In method of the present invention, esterification and reductive modification reaction are carried out simultaneously.Eliminate the synthesis of intermediate product Salvianic acidA in synthetic method, simplify technological operation, shorten the production cycle.In addition, 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, further simplify technological operation.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of synthetic method of Salvianic acidA isopropyl ester.
Background technology
21st century, cardiovascular and cerebrovascular diseases has become one of major disease of harm humans life and health, and its lethality rate exceedes tumour and leaps to the first, and chemoprophylaxis and treatment are still main means.Salvianic acidA isopropyl ester is the effect components of effect in compound red sage root formula body, can be used as anti-cardiac-cerebral ischemia and anti-high altitude anoxia one class chemistry new drug is developed, and it is active that it has good anti-cardiac-cerebral ischemia.
Prior art is carry out esterification by Salvianic acidA and Virahol to obtain target compound (I) about the synthetic method of Salvianic acidA isopropyl ester.
Owing to employing unstable compound Salvianic acidA in synthetic route, cause reaction yield low.When carrying out suitability for industrialized production, there is following two problems:
The first, the productive rate of Salvianic acidA isopropyl ester is low, is difficult to satisfy the demands on cost and output;
The second, the Salvianic acidA synthesis existed in process, due to oxidizable, the difficult crystallization of this compound, controls there is remarkable disadvantageous effect to technical process control and product final quality.
Summary of the invention
The object of the present invention is to provide a kind of Salvianic acidA isopropyl ester synthetic method being applicable to suitability for industrialized production.
For this reason, the present invention takes following technical scheme:
An Industrialized synthesis method for Salvianic acidA isopropyl ester, comprises the following steps:
(1) under the second hydrochloric acid (12mol/L) and reductive agent Zn-Hg existent condition, β-(3,4-dihydroxy phenyl) pyruvic acid and Virahol react in a solvent and generate Salvianic acidA isopropyl ester.
Other technologies of the present invention are characterized as:
The second concentration of hydrochloric acid in step (1) is 10-14mol/L.
The mass ratio of described β-(3,4-dihydroxy phenyl) pyruvic acid and Zn-Hg is 1 ﹕ (1.5 ~ 2.5).
Described solvent is Virahol, and the mass ratio of described β-(3,4-dihydroxy phenyl) pyruvic acid and solvent is 1 ﹕ (36 ~ 46).
The temperature of reaction of described step (1) is 70 DEG C-85 DEG C, and the reaction times is 20h-24h.
The mass ratio of described β-(3,4-dihydroxy phenyl) pyruvic acid and the second hydrochloric acid is 1 ﹕ (4 ~ 6).
Further, the Industrialized synthesis method of described Salvianic acidA isopropyl ester is further comprising the steps of: (2) 2-methyl-4-(3,4-diacetoxy benzal base) azolactone is hydrolyzed and obtains β-(3,4-dihydroxy phenyl) pyruvic acid in the first hydrochloric acid.
Described step (2) described reaction is carried out in acetone.
The first concentration of hydrochloric acid described in 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.Eliminate the synthesis of intermediate product Salvianic acidA in synthetic method, simplify technological operation, reduce equipment requirements, improve productive rate, shorten the production cycle, and evaded intermediate Salvianic acidA 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 obtains β-(3,4-dihydroxy phenyl) pyruvic acid in hydrochloric acid soln.Eliminate the intermediate product β-(3 in existing synthetic method, 4-diacetoxy phenyl) the acrylic acid synthesis step of-alpha-acetamido-, simplify technological operation, improve productive rate, shorten the production cycle, be conducive to the industrial production cost reducing Salvianic acidA isopropyl ester.
The present invention designs new synthetic route and prepares Salvianic acidA isopropyl ester, and because synthetic method does not relate to unstable compound Salvianic acidA as synthetic intermediate, and esterification and reduction reaction are carried out simultaneously, decrease reactions steps, improve reaction yield.The method is applicable to the suitability for industrialized production of Salvianic acidA isopropyl ester.It is high that method has compound productive rate, and technological operation and equipment are more simple, and intermediate quality is easier to control, with short production cycle, the features such as production cost is low.
Accompanying drawing explanation
Fig. 1 is the nuclear magnetic resonance map of the Salvianic acidA isopropyl ester that embodiment 1 obtains;
Fig. 2 is the nuclear magnetic resonance map of the Salvianic acidA isopropyl ester that embodiment 2 obtains.
Embodiment
Proposition of the present invention just based on solution Salvianic acidA isopropyl ester by laboratory synthesize move towards plant produced institute must technical solution problem, set up a kind of industrial syntheti c route of Salvianic acidA isopropyl ester.
Salvianic acidA isopropyl ester industrial production process shown in composite structure formula I of the present invention is with β-(3,4-dihydroxy phenyl) pyruvic acid in solvent and dense HCl, carry out esterification and modification Clemmensen with Virahol, reductive agent Zn-Hg and reduce the reaction that simultaneously completes and obtain target product.
In step of the present invention (1), the concentration of the second hydrochloric acid is 10-14mol/L, preferred 12mol/L.
The concentration of the first hydrochloric acid described in step of the present invention (2) is 0.8-1.2mol/L, preferred 1mol/L.
The mass ratio of β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid and Zn-Hg can preferred 1 ﹕ 2.2.
The mass ratio of β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid and solvent can preferred 1 ﹕ 40.
The mass ratio of β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid and the second hydrochloric acid can preferred 1 ﹕ 4.5.
For by 2-methyl-(3,4-diacetoxy benzal base) azolactone directly synthesizes β-(3,4-dihydroxy phenyl) pyruvic acid, inventors performed following optimization Test.
2-methyl-(3 are added in 500mL single port flask, 4-diacetoxy benzal base) azolactone 30g, 30mL acetone, 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 is influence factor, design level of factor table as shown in table 1, carry out orthogonal experiment.After having reacted, be spin-dried for by reactant with rotatory evaporator, cold water washing, suction filtration, dry, obtain white loose shape crystal, weigh, survey fusing point (literature value: m.p.181.4 DEG C), high performance liquid chromatography marker method is identified and is measured product purity, 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-orthogonal results and analysis of (3,4-dihydroxy phenyl) pyruvic acid industry preparation optimization experiment
| 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.
The synthesis of β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid is that (3,4-diacetoxy benzal base) azolactone is raw material to 2-methyl-4-, and in hydrochloric acid soln, hydrolysis obtains β-(3,4-dihydroxy phenyl) pyruvic acid.(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, prepares through Knoevenagel condensation.
The concrete synthetic route of Salvianic acidA isopropyl ester of the present invention as shown in Figure 1.
Specific embodiment is below utilized to be further explained the present invention.
Embodiment 1:
(1) the 2-methyl-4-(synthesis of 3,4-diacetoxy benzal base) azolactone
3,4-Dihydroxy benzaldehyde 55.2g is added, ethanoylaminoethanoic acid 56.7g in 500mL there-necked flask, the acetic anhydride 204.2g of sodium acetate, anhydrous 42.6g and new distillation, 80 DEG C of stirring reaction 5h, add 150mL frozen water after being cooled to room temperature in reaction solution, stir and make in even emulsion.A large amount of yellow crystals is had to separate out after cooling, suction filtration, washing, dry, obtain yellow crystals 98.0g, m.p.161.0 DEG C ~ 161.4 DEG C, yield 80.9%.
(2) synthesis of β-(3,4-dihydroxy phenyl) pyruvic acid
2-methyl-4-(3,4-diacetoxy benzal base) azolactone 30g, 1mol/L first hydrochloric acid 300mL and acetone 30mL, reflux 10h is added in 500mL single port flask.After reaction terminates, decompression concentrated solution, steams acetone and aqueous hydrochloric acid, after solid is separated out, add 50mL frozen water dispersible solid, decompress filter, frozen water washs, vacuum-drying, obtain faint yellow solid product 13.6g, m.p.161.0 DEG C ~ 161.4 DEG C, productive rate is 70%.
1HNMR(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) synthesis of Salvianic acidA isopropyl ester
β-(3,4-dihydroxy phenyl) pyruvic acid 5.5g, Virahol 240mL, the second hydrochloric acid 30mL and freshly prepd zinc amalgam 12g, reflux 20h is added in 500mL single port flask.Reaction terminates rear removing zinc amalgam and excessive Virahol, and residue viscous fluid pours separating funnel into after appropriate acetic acid ethyl dissolution, uses water (30mL × 2) respectively, saturated NaHCO
3(20mL × 1) washs.Separate organic layer, anhydrous Na
2sO
4dry 2h, filters, revolves steaming, obtain viscous brown liquid 5.4g, productive rate 80.66%.
The Salvianic acidA isopropyl ester nmr spectrum that this embodiment obtains as shown in Figure 1.
Embodiment 2:
(1) the 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 DEG C, is then warming up to 100 DEG C and continues to stir 1h.Steam off, water flowing is lowered the temperature, and treats that temperature in the kettle is down to 55 DEG C, opens drain hole, about have 100L feed liquid.Have yellow solid to separate out after being cooled to room temperature, add the frozen water stirring and evenly mixing of 2 times of material liquid volumes, after filter centrifugation in centrifuges, period water wash twice on the rocks, the yellow solid obtained is dry 8h in 60 DEG C of drying rooms, obtains product 45.0kg, yield 81.7%.
(2) production of β-(3,4-dihydroxy phenyl) pyruvic acid
2-methyl-4-(3,4-diacetoxy benzal base) azolactone 25kg, 25L acetone and 1mol/L first hydrochloric acid 250L, logical steam heating, stirring and refluxing reaction 10h is added in the glass reactor of the 500L pool.Underpressure distillation concentrates material to certain volume, opens drain hole blowing.Be cooled to solid to separate out completely, take off liquid at centrifuge, period adds water wash several times, puts into 60 DEG C of drying rooms dry, obtain faint yellow solid product 9.0kg, productive rate 55.7% after dehydration.The production cycle of this step is 2 days.
Method disclosed in ZL200410026205.3 and ZL20060042787.3 is adopted to prepare β-(3,4-dihydroxy phenyl) pyruvic acid, (3,4-diacetoxy benzal base) azolactone can only obtain 3.2kg product to 25kg raw material 2-methyl-4-, and the production cycle is 6 days.
(3) production of Salvianic acidA isopropyl ester
20kg β-(3,4-dihydroxy phenyl) pyruvic acid, 800L Virahol, 90L second hydrochloric acid (14mol/L), 44kg brand-new is added for zinc amalgam, reflux 22h in the pool glass still of 1000L.After reaction terminates, Filtration of catalyst, pressure reducing and steaming solvent, obtains brown oil material, is dissolved in ethyl acetate.Use water, 4%NaHCO respectively
3the aqueous solution and 1.0mol/L salt acid elution.Gained organic phase is through anhydrous Na
2sO
4after drying, decompression removing ethyl acetate, obtains brown color dope, after purification by column chromatography, obtains β-(3,4-dihydroxy phenyl)-alpha-hydroxypropionic acid isopropyl 16.7kg, yield 68.2%.The Salvianic acidA isopropyl ester nmr spectrum that industrial production obtains as shown in Figure 2.And the production cycle of this step is 3 days.
Adopt method disclosed in ZL200410026205.3 to implement the preparation of Salvianic acidA isopropyl ester, 20kg raw material β-(3,4-dihydroxy phenyl) pyruvic acid can only obtain 4.6kg product, and the production cycle is 6 days.
Claims (8)
1. an Industrialized synthesis method for Salvianic acidA isopropyl ester, is characterized in that, comprises the following steps:
(1) under the second hydrochloric acid and reductive agent Zn-Hg existent condition, β-(3,4-dihydroxy phenyl) pyruvic acid and Virahol react in a solvent and generate Salvianic acidA isopropyl ester; Described second concentration of hydrochloric acid is 10-14mol/L.
2. the Industrialized synthesis method of Salvianic acidA isopropyl ester as claimed in claim 1, it is characterized in that, the mass ratio of described β-(3,4-dihydroxy phenyl) pyruvic acid and reductive agent Zn-Hg is 1 ﹕ (1.5 ~ 2.5).
3. the Industrialized synthesis method of Salvianic acidA isopropyl ester as claimed in claim 1, it is characterized in that, described solvent is Virahol, and the mass ratio of described β-(3,4-dihydroxy phenyl) pyruvic acid and solvent is 1 ﹕ (36 ~ 46).
4. the Industrialized synthesis method of Salvianic acidA isopropyl ester as claimed in claim 1, it is characterized in that, the temperature of reaction of described step (1) is 70 DEG C-85 DEG C, and the reaction times is 20h-24h.
5. the Industrialized synthesis method of Salvianic acidA isopropyl ester as claimed in claim 1, it is characterized in that, the mass ratio of described β-(3,4-dihydroxy phenyl) pyruvic acid and the second hydrochloric acid is 1 ﹕ (4 ~ 6).
6. the Industrialized synthesis method of Salvianic acidA isopropyl ester as claimed in claim 1, it is characterized in that, further, the Industrialized synthesis method of described Salvianic acidA isopropyl ester is further comprising the steps of: 2-methyl-4-(3,4-diacetoxy benzal base) azolactone is hydrolyzed and obtains β-(3,4-dihydroxy phenyl) pyruvic acid in the first hydrochloric acid.
7. the Industrialized synthesis method of Salvianic acidA isopropyl ester as claimed in claim 6, it is characterized in that, (3,4-diacetoxy benzal base) azolactone is hydrolyzed the reaction obtaining β-(3,4-dihydroxy phenyl) pyruvic acid in the first hydrochloric acid to carry out 2-methyl-4-in acetone.
8. the Industrialized synthesis method of Salvianic acidA isopropyl ester as claimed in claim 7, it is characterized in that, the first described concentration of hydrochloric acid is 0.8-1.2mol/L.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1583710A (en) * | 2004-06-03 | 2005-02-23 | 西安交通大学 | Beta (3,4-dihydroxyphenyl)-alpha-hydroxyisopropyl propionate and its synthesis |
| 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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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1583710A (en) * | 2004-06-03 | 2005-02-23 | 西安交通大学 | Beta (3,4-dihydroxyphenyl)-alpha-hydroxyisopropyl propionate and its synthesis |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 丹参素的合成;邓喜玲等;《中国医药工业杂志》;20050910;第36卷(第9期);第523-524页 * |
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Effective date of registration: 20230714 Address after: 710069 No. 229 Taibai North Road, Shaanxi, Xi'an Patentee after: NORTHWEST University Address before: 710065, No. two, No. 18, Xi'an, Shaanxi Patentee before: XI'AN SHIYOU University Patentee before: NORTHWEST University |