CN103570546B - A kind of Industrialized synthesis method of danshensu norbornene ester - Google Patents
A kind of Industrialized synthesis method of danshensu norbornene ester Download PDFInfo
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- 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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Abstract
The present invention relates to a kind of Industrialized synthesis method of danshensu norbornene ester. Be included under the condition of the second hydrochloric acid, reducing agent Zn-Hg and catalyst existence, β-(3,4-dihydroxy phenyl) pyruvic acid reacts in solvent with borneol and generates danshensu norbornene ester. β-(3,4-dihydroxy phenyl) pyruvic acid is wherein 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. Save the synthetic of the interior intermediate product danshensu of synthetic method, simplified technological operation, shortened 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 solution, has further simplified technological operation.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of prevention and treatment cardiovascular and cerebrovascular diseaseDanshensu norbornene ester synthetic method.
Background technology
21st century, cardiovascular and cerebrovascular disease has become one of major disease of harm humans life and health,Its fatal rate has exceeded tumour and has leapt to the first, and chemoprophylaxis and treatment are still main means. Danshensu iceSheet ester is active ingredient danshensu based on the red sage root and the resulting structure fragment of borneol, utilizes modern medicines designLearn principle of hybridization, the brand-new compound of the structure with treating cerebral ischemia that design is synthetic. In prior artDanshensu norbornene ester synthetic method be all to carry out esterification by danshensu and alcohol to obtain target compound（Ⅰ）。
Owing to having used unsettled compound danshensu in synthetic route, cause reaction yield low. Carry out workWhen industryization is produced, there are following two problems:
The first, the productive rate of danshensu norbornene ester is low, is difficult to satisfy the demands in cost and output;
The second, the danshensu existing in technique is synthetic, due to oxidizable, the difficult crystallization of this compound, to workSkill process control and the control of product final mass have remarkable adverse effect.
Summary of the invention
The object of the present invention is to provide a kind of danshensu 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 danshensu norbornene ester, comprises the following steps:
(1) under the condition existing at the second hydrochloric acid, reducing agent Zn-Hg and catalyst, β-(3,4-dihydroxyPhenyl) pyruvic acid reacts in solvent with borneol and generates danshensu 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 catalyst is solid super-strong acid S2O8 2-/ZrO2、S2O8 2-/TiO2、SO4 2-/Fe2O3、SO4 2-/Al2O3, β-(3,4-dihydroxy phenyl) pyruvic acid and the mole dosage ratio of catalyst be 1 ﹕ (0.03～0.15）。
Described solvent is in benzene,toluene,xylene, oxolane, Isosorbide-5-Nitrae-dioxane and dimethyl sulfoxide (DMSO)One or more mixed liquor, the mass ratio of β-(3,4-dihydroxy phenyl) pyruvic acid and solvent is 1 ﹕（6～16）。
The reaction temperature of step (1) is 65 DEG C-190 DEG C, and the reaction time 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 danshensu norbornene ester is further comprising the steps of: (2) 2-(3,4-diacetoxy benzal base) azolactone is hydrolyzed and obtains β-(3,4-dihydroxy benzenes methyl-4-in the first hydrochloric acidBase) pyruvic 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 syntheticIn method, intermediate product danshensu is synthetic, has simplified technological operation, has reduced equipment requirement, has improved productRate, has shortened the production cycle, and evaded intermediate danshensu in course of reaction, be easy to oxidation, be difficult toPurifying and carry out the problems such as effective mass control.
In addition, in method of the present invention, by 2-methyl-4-, (3,4-diacetoxy benzal base) azolactone is at hydrochloric acidIn solution, hydrolysis directly obtains β-(3,4-dihydroxy phenyl) pyruvic acid. Saved in existing synthetic method inBetween product β-(3,4-diacetoxy phenyl) acrylic acid synthesis step of-alpha-acetamido-, simplified technique behaviourDo, improved productive rate, shortened the production cycle, be conducive to reduce the industrial production cost of danshensu norbornene ester.
The present invention designs new synthetic route and prepares danshensu norbornene ester, because synthetic method does not relate to unstableCompound danshensu is as synthetic intermediate, and esterification and reduction reaction carry out simultaneously, reduced twoReactions steps, has improved reaction yield. The method is applicable to the suitability for industrialized production of danshensu norbornene ester. SideIt is high that method has compound productive rate, and technological operation and equipment are simpler, and intermediate quality is easier to control, rawThe features such as the product cycle is short, and production cost is low.
Brief description of the drawings
Fig. 1 is the nuclear magnetic resoance spectrum of the obtained danshensu norbornene ester of embodiment 1;
Fig. 2 is the nuclear magnetic resoance spectrum of the obtained danshensu norbornene ester of embodiment 2.
Detailed description of the invention
Proposition of the present invention is just based on solving danshensu norbornene ester by the synthetic plant produced institute that moves towards in laboratoryMust technical solution problem, set up a kind of industrial syntheti c route of danshensu norbornene ester.
Danshensu norbornene ester industrial production process shown in composite structure formula of the present invention (I) is with β-(3,4-Dihydroxy phenyl) pyruvic acid in solvent and dense HCl, carry out esterification and change with borneol, reducing agent Zn-HgProperty Clemmensen reduces the reaction that simultaneously completes and obtain target product. Wherein β-(3,4-dihydroxy phenyl)Pyruvic acid synthetic be with 3,4-4-dihydroxy benzaldehyde for raw material, obtain 2-methyl through Knoevenagel condensation(3,4-diacetoxy benzal base) azolactone, in hydrochloric acid solution, hydrolysis obtains β-(3,4-dihydroxy phenyl) to-4-Pyruvic acid. Certainly (3,4-diacetoxy benzal base) azolactone can adopt the present invention 2-methyl-4-usedConventional preparation method,, prepares through Knoevenagel condensation for raw material with 3,4-4-dihydroxy benzaldehyde.
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 described in step of the present invention (2) is 0.8-1.2mol/L, preferably 1mol/L.
Preferably 1 ﹕ of mole dosage ratio of β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid and catalyst0.08。
Preferably 1 ﹕ 12 of the mass ratio of β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid and solvent.
Preferably 1 ﹕ 1.1 of the mol ratio of β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid and borneol.
(3,4-diacetoxy benzal base) azolactone can 3,4-4-dihydroxy benzaldehyde for 2-methyl-4-of the present inventionFor prepared using Knoevenagel method of condensing prepares.
Acrylic acid synthetic for saving intermediate product β-(3,4-diacetoxy phenyl)-alpha-acetamido-, send outA person of good sense has carried out following Optimum Experiment.
To add in 500mL single port flask 2-methyl-(3,4-diacetoxy benzal base) azolactone 30g,With hydrochloric acid volume, (quality of this volume hydrochloric acid is 2-methyl-(3,4-diacetoxy benzal base) azolactone matterThe multiple of amount), concentration of hydrochloric acid and reaction time is influence factor, factor level is as shown in table 1 carry out orthogonalExperiment, after having reacted, adds 30mL acetone after being cooled to room temperature again, adds hot reflux 4h. Use rotary evaporationDevice is spin-dried for reactant, cold water washing, and suction filtration, dry, obtain white loose shape crystal, weigh, survey fusing point(literature value: m.p.181.4 DEG C), makees high performance liquid chromatography. Observation experiment phenomenon, calculates productive rate.
The factor level of Optimal Experimental research is prepared in table 1 β-(3,4-dihydroxy phenyl) pyruvic acid industry
The orthogonal results and analysis of Optimal Experimental is prepared in table 2 β-(3,4-dihydroxy phenyl) pyruvic acid industry
| 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 |
| K1 | 160.3 | 139.9 | 144.5 | K=451.6 |
| K2 | 145.3 | 171.4 | 170.4 | P=22660 |
| K3 | 146.0 | 140.3 | 136.7 | QT=477 |
| U | 22708 | 22878 | 22867 | W=23137 |
| Q | 48 | 218 | 207 |
From variance analysis, three factors all have remarkable shadow to reaction yield in selected horizontal extentRing. Excellent horizontal combination is A1B2C2。
Therefore the synthetic of, β of the present invention-(3,4-dihydroxy phenyl) pyruvic acid can be with 3,4-dihydroxy benzenes firstAldehyde is raw material, through Knoevenagel condensation obtain 2-methyl-4-(3,4-diacetoxy benzal base) azolactone,In hydrochloric acid solution, hydrolysis obtains β-(3,4-dihydroxy phenyl) pyruvic acid. Certainly the present invention's 2-methyl used(3,4-diacetoxy benzal base) azolactone can adopt conventional preparation method to-4-, with 3,4-dihydroxy benzenes firstAldehyde is raw material, prepares through Knoevenagel condensation.
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 3,4-4-dihydroxy benzaldehyde 55.2g, acetylaminoacetic acid 56.7g, nothingThe acetic anhydride 204.2g of water acetic acid sodium 42.6g and new distillation, 80 DEG C of stirring reaction 5h, are cooled to room temperature backwardIn reactant liquor, add 150mL frozen water, stir and make to be even emulsion. After cooling, there are a large amount of yellow crystals to analyseGo out, suction filtration, washing, dry, obtain yellow crystals 98.0g, m.p.161.0 DEG C～161.4 DEG C, yield 80.9%.
(2) synthesizing of β-(3,4-dihydroxy phenyl) pyruvic acid
To add in 500mL single port flask 2-methyl-4-(3,4-diacetoxy benzal base) azolactone 30g,1mol/L the first hydrochloric acid 300mL and acetone 30mL, add hot reflux 10h. After reaction finishes, reduced pressure concentrationSolution, steams acetone and the first aqueous hydrochloric acid solution, after solid is separated out, adds 50mL frozen water dispersing solid,Decompress filter, frozen water washing, vacuum drying, obtains 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) danshensu norbornene ester is synthetic
Get β-(3,4-dihydroxy phenyl) pyruvic acid 5.0g (0.026mol), borneol 3.5g (0.023mol), addTHF50mL, 12mol/L the second hydrochloric acid 15mL and freshly prepd zinc amalgam 9.00g, install water knockout drum andCondenser pipe, adds 0.4g nano solid supper corrosive acid catalyst S while being heated to seethe with excitement2O8 2-/ZrO2, add thermal response22h. After reaction finishes, remove catalysts and solvents, obtain brown oil matter. Molten with appropriate ethyl acetateSeparate and move in separatory funnel, respectively water (25mL × 2), 4%NaHCO3The aqueous solution (25mL × 2)Wash with 1.0mol/L hydrochloric acid (25mL × 1). Gained organic phase is through anhydrous Na2SO4After dry, decompressionEthyl acetate is removed in distillation, obtains brown color dope, after column chromatography purifying, obtains sundown solid 3.0g,Productive rate 39.1%. The danshensu 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 25.0kg3,4-4-dihydroxy benzaldehyde, 25.0kg acetoglycocoll and20.0kg anhydrous sodium acetate, 87.5kg acetic anhydride, logical Steam Heating stirs. Stirring reaction at 80 DEG C4.5h, is then warming up to 100 DEG C and continues to stir 1h. Steam off, water flowing cooling, treats that temperature in the kettle is down to55 DEG C, open drain hole, approximately there is 100L feed liquid. After being cooled to room temperature, there is yellow solid to separate out, add 2The frozen water of times material liquid volume stirs and evenly mixs, after in centrifuge, filter centrifugal, water wash twice on the rocks during this time,The yellow solid obtaining 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
To add in the glass reactor of the 500L pool 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. Decompression is steamedHeat up in a steamer concentrated material to certain volume, open drain hole blowing. Be cooled to solid and separate out completely, centrifuge fromThe heart takes off liquid, adds during this time water wash several times, puts into 60 DEG C of drying rooms dry after dehydration, obtains faint yellow solidProduct 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-dihydroxyBase phenyl) pyruvic acid, (3,4-diacetoxy benzal base) azolactone obtains 3.2kg to 25kg raw material 2-methyl-4-Product, in 15 hours reaction time, the production cycle is 6 days.
(3) production of danshensu norbornene ester
In the glass still of the pool of 500L, add 20kg β-(3,4-dihydroxy phenyl) pyruvic acid, 17kg borneol,270L oxolane, 110L the second hydrochloric acid (12mol/L), 50kg new system are for zinc amalgam and 2.4kg nanometerSolid super acid catalyst S2O8 2-/ZrO2React, add hot reflux 12h. After reaction finishes, remove and urgeAgent and solvent, obtain brown oil matter, is dissolved in ethyl acetate. Water, 4%NaHCO respectively3The aqueous solutionWith 1.0mol/L salt acid elution. Gained organic phase is through anhydrous Na2SO4After dry, ethyl acetate is removed in decompression,Obtain brown color dope, after column chromatography purifying, obtain β-(3,4-dihydroxy phenyl)-α-hydracrylate borneolEster 10.7kg, yield 31.5%. The production cycle of this step is 3 days. The danshensu ice that this embodiment makesSheet ester nmr spectrum as shown in Figure 2.
Adopt the disclosed method of ZL20060042787.3 to implement the preparation of danshensu norbornene ester, 20kg raw materialβ-(3,4-dihydroxy phenyl) pyruvic acid can only obtain 1.3kg, danshensu norbornene ester, low and reaction time of productive rateLong, 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 obtainβ-(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. ?Obtain eventually 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). FinallyObtain 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 catalyst in step (3) is S2O8 2-/TiO2. ?Obtain eventually 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 catalyst in step (3) is SO4 2-/Fe2O3. ?Obtain eventually 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 catalyst in step (3) is SO4 2-/Al2O3. ?Obtain eventually β-(3,4-dihydroxy phenyl)-alpha hydroxy borneol propionate 2.8kg, yield 7.9%.
Claims (7)
1. an Industrialized synthesis method for danshensu norbornene ester, is characterized in that, comprises the following steps:
(1) under the condition existing at the second hydrochloric acid, reducing agent Zn-Hg and catalyst, β-(3,4-dihydroxyPhenyl) pyruvic acid reacts in solvent with borneol and generates danshensu norbornene ester;
Described the second concentration of hydrochloric acid is 10-14mol/L;
Described catalyst is solid super-strong acid S2O8 2-/ZrO2；
Described solvent is oxolane, and the mass ratio of β-(3,4-dihydroxy phenyl) pyruvic acid and solvent is 1 ﹕(6～16)。
2. the Industrialized synthesis method of danshensu norbornene ester as claimed in claim 1, is characterized in that,Described catalyst is solid super-strong acid S2O8 2-/ZrO2, described β-(3,4-dihydroxy phenyl) pyruvic acid and catalysisThe mole dosage ratio of agent is 1 ﹕ (0.03～0.15).
3. the Industrialized synthesis method of danshensu norbornene ester as claimed in claim 1, is characterized in that,The reaction temperature of step (1) is 65 DEG C-190 DEG C, and the reaction time is 24h-28h.
4. the Industrialized synthesis method of danshensu 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).
5. the Industrialized synthesis method of danshensu norbornene ester as claimed in claim 1, is characterized in that,The Industrialized synthesis method of described danshensu norbornene ester is further comprising the steps of:
(2) (3,4-diacetoxy benzal base) azolactone is hydrolyzed and obtains 2-methyl-4-in the first hydrochloric acidβ-(3,4-dihydroxy phenyl) pyruvic acid.
6. the Industrialized synthesis method of danshensu norbornene ester as claimed in claim 5, is characterized in that,The described reaction of described step (2) is carried out in acetone.
7. the Industrialized synthesis method of danshensu norbornene ester as claimed in claim 5, is characterized in that,The first described concentration of hydrochloric acid of step (2) is 0.8-1.2mol/L.
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| Title |
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| 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 * |
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