CN104030923A - Synthesis method of racemic bornyl beta-(3,4-dihydroxyphenyl)-alpha-hydroxypropionate - Google Patents

Abstract

The invention relates to a method for synthesizing danshensubornyl ester. The method comprises using benzyl-protected protocatechualdehyde as an initial raw material, epoxidizing by Darzens, and then catalyzing by palladium catalyst/hydrogen or Raney nickel/hydrogen Reduction can obtain spundanshensubornyl ester. The purity of the product synthesized by the method of the invention can reach 98%, and the yield can reach 48.6%. Moreover, the synthetic method of the present invention has simple and easy-to-obtain raw materials, short route and high yield, and is suitable for large-scale industrial production.

Description

A kind of synthetic method of mixed danshensubornyl ester

technical field

The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of danshensubornyl ester, a medicine that can be used for treating or preventing cardiovascular and cerebrovascular diseases.

Background technique

Hexdanshensu Bornyl Ester, the chemical name is (±)-3′,4′-dihydroxyphenyl-2-hydroxybornyl propionate. Based on the compatibility principle of "drugs", it is designed by combining the active ingredient Danshensu of "Junyao" Danshen and "Shiyao" borneol in the form of ester bonds. Danshensubornyl ester has anti-atherosclerosis, anti-cardiocerebral ischemia, lower blood pressure, improve cardiac diastolic function and so on.

Chinese patent application (publication number: CN1868998A) discloses a reaction of protocatechualdehyde and acetylglycine to obtain 2-methyl-4-(3,4-diacetoxybenzylidene) oxazolone, which is obtained through ring opening Obtain (3,4-diacetoxybenzylidene)-N-acetylacrylic acid, then hydrolyze to obtain β-(3,4-dihydroxyphenyl)pyruvate, and reduce it with zinc amalgam to obtain danshensu, And then esterified with borneol to obtain danshensu bornyl ester. A total of 5 steps of reaction, the total yield is low, about 12%, wherein the use of zinc amalgam as a reducing agent, environmental pollution is large, not easy to industrial production.

Chinese patent application (publication number: CN103570546A) on the basis of Chinese patent application (publication number: CN1868998A), improved process, with β-(3,4-dihydroxyphenyl) pyruvic acid and borneol in solid superacid (S ₂ O ₈ ^2- /ZrO ₂ ), hydrochloric acid, and zinc amalgam in the presence of "one-pot method" to obtain danshensubornyl ester. A total of 3 steps of reaction, the total yield is between 1.2-22.1%, the yield is higher than before, but zinc amalgam is still used as the reducing agent, which causes great environmental pollution and is not easy for industrial production. Other synthetic methods, such as Zhang Qunzheng et al. (Research on the synthesis of β-(3,4-dihydroxyphenyl)-α-hydroxypropionate/bornyl ester, Organic Chemistry, Organic Chemistry, 2009, 29(9), 1466- 1469.) Using 3,4-dihydroxybenzaldehyde as raw material, danshensubornyl ester was obtained by benzyl protection, Darzens epoxidation, Lewis acid ring opening, NaBH ₄ reduction, and catalytic hydrogenation deprotection. The synthetic route is long, the reaction conditions are harsh, the yield is low, and it is not suitable for industrial production; DOI: 10.1021/op4002593) based on the Chinese patent application (publication number: CN1583710A), optimized the synthesis process, and obtained danshensu bornyl ester by reducing β-(3,4-dihydroxyphenyl)pyruvate bornyl ester with Raney nickel , a total of 4 steps of reaction, the total yield reached 47.5%. The process has little pollution and is more suitable for industrial production. In view of the industrial cost problem of this method, the yield still needs to be improved.

Contents of the invention

Aiming at the defects or deficiencies in the prior art, the object of the present invention is to provide a synthetic method of danshensubornyl ester with cheap and easy-to-obtain raw materials, short route, high yield and high purity.

For this reason, the synthetic method of the mixed danshensubornyl ester provided by the invention comprises:

Reaction (1): 3,4-dibenzyloxybenzaldehyde is prepared by reacting benzyl halide with protocatechualdehyde, and the benzyl halide is benzyl bromide or benzyl chloride;

Reaction (2): 3,4-dibenzyloxybenzaldehyde and bornyl chloroacetate were epoxidized by Darzens to obtain bornyl 3-(3,4-dibenzyloxyphenyl)glycidyl propionate;

Reaction (3): In the presence of catalyst and hydrogen, bornyl 3-(3,4-dibenzyloxyphenyl)glycidate is ring-opened and debenzylated simultaneously to obtain bornyl danshensu.

Preferably, the reaction (1) is carried out in the first organic solvent and under alkaline conditions, and the reaction (1) is carried out at 20-150°C, the first organic solvent is tetrahydrofuran, dimethylethylene di Alcohol, diethyl glycol, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide one or a combination of two or more.

Preferably, the ratio of protocatechualdehyde to benzyl chloride in the reaction (1) is 1: (2-5).

Preferably, the reaction (2) is carried out in a second organic solvent under alkaline conditions, and the reaction (2) is carried out at 0-50°C; the second organic solvent is ether, methyl tert-butyl Dimethyl ether, tetrahydrofuran, dimethyl glycol, diethyl glycol, 1,4-dioxane, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, benzene, toluene , xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide, or a combination of two or more.

Preferably, the bornyl chloroacetate and 3,4-dibenzyloxybenzaldehyde are simultaneously dissolved in the second organic solvent and added dropwise to the reaction system.

Preferably, the base in the reaction (2) is one of lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, lithium ethoxide, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide and lithium pentoxide or a combination of two or more.

Preferably, the ratio of the amount of bornyl chloroacetate to 3,4-dibenzyloxybenzaldehyde in the reaction (2) is 1:(1-3).

Preferably, the catalyst in the reaction (3) is one or a combination of two or more of palladium carbon, palladium acetate and palladium hydroxide, or Raney nickel.

Preferably, the reaction (3) is carried out in a third organic solvent, and the third organic solvent is one or a combination of two or more of isopropanol, ethanol, methanol, tetrahydrofuran and methyl tert-butyl ether .

Further, the bornyl chloroacetate used in the present invention is prepared by reacting chloroacetyl chloride with borneol.

In summary, the synthetic method of danshensubornyl ester of the present invention has the following advantages:

(1) The raw materials used in the method of the present invention are cheap and easy to obtain, the reaction steps are short, the aftertreatment is simple, the requirements for equipment are not high, and large-scale industrial production can be carried out.

(2) In the synthesis process of the present invention, chemical raw materials that have relatively large pollution to the environment are not used, and the generated waste water and waste materials are easy to process or recycle, and have little environmental pollution.

(3) Adopt synthetic method of the present invention, product yield and purity are all higher, have reduced production cost.

In summary, a kind of synthetic method of DSB of the present invention takes benzyl-protected protocatechualdehyde as the initial raw material, undergoes Darzens epoxidation, and then reduces it with sodium borohydride to obtain DSB ester. The purity reaches more than 98%, and the yield reaches more than 48.6%. The synthesis method of the invention has simple and easy-to-obtain raw materials, short route and high yield, and is suitable for large-scale industrial production.

Description of drawings

Fig. 1 is the mass spectrum of the spundanshensu bornyl ester prepared in Example 1, and Fig. 1 (a) is the total ion chromatogram of the spundanshensu prepared in Example 1, and Fig. 1 (b) is peak 1 in Fig. 1 (a) The mass spectrogram, Fig. 1 (c) is the mass spectrogram of peak 2 in Fig. 1 (a);

Fig. 2 is the hydrogen spectrum of the mixed danshensubornyl ester prepared by embodiment 1;

Fig. 3 is the carbon spectrum of the mixed danshensubornyl ester prepared in embodiment 1;

Fig. 4 is the infrared spectrum of slurried danshensu bornyl ester prepared in embodiment 1;

Fig. 5 is the liquid chromatogram of the chiral column of danshensubornyl ester prepared in Example 1.

Detailed ways

The synthesis route of danshensubornyl ester of the present invention is as follows:

1 in this reaction formula is 3,4-dibenzyloxybenzaldehyde; 2 is bornyl chloroacetate; 3 is 3-(3,4-dibenzyloxyphenyl) bornyl glycidate; (I ) is Danshensubornyl ester.

The invention uses protocatechuic aldehyde as an initial raw material, and obtains spundanshensubornyl ester through four steps of reaction. The characteristics of the synthetic route are:

Reaction (1): protect the two phenolic hydroxyl groups of protocatechualdehyde with benzyl halide to obtain 3,4-dibenzyloxybenzaldehyde;

Reaction (2): 3,4-dibenzyloxybenzaldehyde and bornyl chloroacetate were epoxidized by Darzens to obtain bornyl 3-(3,4-dibenzyloxyphenyl)glycidyl propionate;

Reaction (3): In the presence of catalyst and hydrogen, bornyl 3-(3,4-dibenzyloxyphenyl)glycidate is ring-opened and debenzylated simultaneously to obtain bornyl danshensu.

The first organic solvent used in reaction (1) of the present invention can be THF, dimethyl glycol, diethyl glycol, 1,4-dioxane, N,N-dimethylformamide, One or more of N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide. Preference is given to 1,4-dioxane, N,N-dimethylformamide.

The required alkaline environment of reaction (1) of the present invention can be sodium hydroxide, potassium hydroxide, calcium hydroxide, anhydrous sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, pyridine, 4-dimethylaminopyridine, three One or more combinations of ethylamine and diisopropylethylamine are adjusted. Sodium carbonate and potassium carbonate are preferred.

The reaction temperature of the reaction (1) of the present invention is 20°C to 150°C, preferably 100°C to 145°C. The reaction time is controlled within 1-8 hours, and the reaction progress is judged according to TLC, preferably between 2-4 hours.

The ratio of the amount of protocatechualdehyde to benzyl chloride in the reaction (1) of the present invention is 1:(2-5), preferably 1:(2-2.5).

The second organic solvent in the reaction (2) of the present invention can be one of the following or a combination of more than two: ether, methyl tert-butyl ether, tetrahydrofuran, dimethyl glycol, diethyl glycol, 1,4-Dioxane, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, benzene, toluene, xylene, N,N-dimethylformamide, N,N-di Methylacetamide, N-methylpyrrolidone, dimethylsulfoxide. Preference is given to isopropanol and 1,4-dioxane.

The basic environment required for the reaction (2) of the present invention can be one of lithium hydride, sodium hydride, sodium methylate, sodium ethylate, lithium ethylate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide and lithium pentoxide or a combination of two or more. Sodium methoxide and sodium ethoxide are preferred.

In the reaction (2) of the present invention, the reaction temperature is 0°C to 50°C, preferably 5°C to 30°C. During the reaction, 1,4-dibenzyl chloroacetate and 3,4-dibenzyloxybenzaldehyde are added dropwise. The dropwise addition time of the oxyhexane solution is 0.25-2 hours; the reaction time can be controlled within 3-24 hours, and the reaction progress can be judged according to TLC, preferably within 8-12 hours.

In the reaction (2) of the present invention, the ratio of the amount of bornyl chloroacetate to 3,4-dibenzyloxybenzaldehyde is 1:(1-3), preferably 1:(1.2-1.5).

The catalyst used in the reaction (3) of the present invention is palladium carbon, palladium acetate, palladium hydroxide and Raney nickel, preferably palladium carbon or Raney nickel.

In reaction (3) of the present invention, the product in reaction (2) is dissolved in the 3rd organic solvent, and the 3rd organic solvent is a kind of in Virahol, ethanol, methyl alcohol, THF and methyl tert-butyl ether Or a combination of two or more, when the reaction is in progress, add catalyst, feed hydrogen, keep the pressure between 0.1-2.0MPa, and the reaction time is 0.5-24 hours. For different catalysts, the amount of substances and reaction conditions are different:

The mass ratio of palladium carbon catalyst (5% wet palladium carbon) to 3-(3,4-dibenzyloxyphenyl) glycidic acid bornyl ester is (0.04～0.3):1, preferably 0.1:1, the reaction The pressure is 0.1-2.0 MPa, preferably 0.1-1.0 MPa, and the catalytic reaction time is 0.5-24 hours, preferably 0.5-2 hours;

The ratio of the amount of palladium acetate and palladium hydroxide catalyst to 3-(3,4-dibenzyloxyphenyl) glycidic acid bornyl ester is (0.01～0.2):1, preferably 0.05:1, and the reaction pressure At 0.1-2.0MPa, preferably 0.1-1.0MPa, the catalytic reaction time is 0.5-24 hours, preferably 0.5-2 hours;

The mass ratio of Raney nickel catalyst to 3-(3,4-dibenzyloxyphenyl)bornyl glycidate is (0.04～0.6):1, preferably 0.2:1, and the reaction pressure is 0.1～2.0MPa, It is preferably 0.1-1.0 MPa, and the catalytic reaction time is 1-24 hours, preferably 1-4 hours.

Under the above-mentioned preferred scheme, the final yield can be improved.

For the recovery of target compound in each reaction of the present invention, can adopt following method to carry out:

After reaction (1) is completed, the reactant is cooled to room temperature, filtered with suction, the filtrate is added to ice water, acidified with 0.5mol/L HCl hydrochloric acid to pH=4~5, a light yellow solid is produced, filtered with suction to obtain 3,4-dibenzyloxy benzaldehyde;

For reaction (2), after the reaction of the raw materials is completed, adjust the pH to 4~5 with 0.5mol/L HCl, then extract with the organic phase, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the crude product is subjected to column chromatography Purify (silica gel 200-300 mesh) or recrystallize with C1-C4 fatty alcohol/petroleum ether mixed solution to obtain bornyl 3-(3,4-dibenzyloxyphenyl)glycidate;

After the reaction (3) was completed, the reactant was filtered and concentrated under reduced pressure to obtain bornyl danshensu.

Bornyl chloroacetate used in the present invention is based on chloroacetyl chloride and borneol in the presence of organic bases such as: pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, according to the following esterification Response gets.

2 in this reaction formula is bornyl chloroacetate.

The following are specific examples provided by the inventors to further explain the technical solutions of the present invention.

Example 1:

(1) Synthesis of 3,4-dibenzyloxybenzaldehyde:

Dissolve 55.2g (0.40mol) of protocatechualdehyde in 600mL of N,N-dimethylformamide, slowly add 116.0g (0.92mol) of benzyl chloride, and weigh 165.6g (1.2mol) of anhydrous K ₂ CO ₃ ) into it, stirred at room temperature for 2 hours, then added K ₂ CO ₃ 55.2g (0.40mol), heated at 130°C for 2 hours, cooled to room temperature, filtered with suction, added the filtrate to ice water, acidified with dilute hydrochloric acid, and produced a yellow precipitate , filtered with suction and washed with ice water to obtain 122.1 g of 3,4-dibenzyloxybenzaldehyde with a yield of 96%.

(2) Synthesis of Bornyl Chloroacetate:

Add 400mL of dichloromethane, 77.2g (0.5mol) of borneol, 50.5g (0.5mol) of triethylamine into the reaction vessel, add 56.4g (0.5mol) of chloroacetyl chloride at 0°C, and stir the reaction at room temperature for 3 hours. Add 200mL of water to the solution, wash with 200mL of saturated sodium bicarbonate solution, and extract 3 times with dichloromethane (150mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 106.9g of light brown oil , the yield was 93%.

(3) Synthesis of 3-(3,4-dibenzyloxyphenyl)bornyl glycidate:

Dissolve 12.16g (0.225mol) of sodium methoxide in 150ml of methanol to obtain solution 1;

Next, 47.7g (0.15mol) of 3,4-dibenzyloxybenzaldehyde and 41.5g (0.18mol) of bornyl chloroacetate were dissolved in 100mL of dioxane to obtain solution 2;

After that, solution 1 was dropped into solution 2 within 30 mm, stirred at room temperature overnight, the reaction solution was added to 100 mL of ice water, acetic acid was adjusted to neutrality, extracted with dichloromethane (200 mL×4), the organic phases were combined, and anhydrous Dry over sodium sulfate, concentrate under reduced pressure, and recrystallize the crude product from isopropanol/petroleum ether to obtain 54.6 g of off-white solid with a yield of 71%.

(4) Synthesis of Danshensu Bornyl Ester:

Dissolve 25.6 g (0.05 mol) of bornyl 3-(3,4-dibenzyloxyphenyl) glycidate in 300 mL of tetrahydrofuran, then add 2.56 g of 5% wet Pd/C, pass in hydrogen, and After reacting under normal pressure for 1 hour, filter and concentrate under reduced pressure, the crude product was recrystallized with ethanol/petroleum ether to obtain 14.4 g of a light yellow solid with a yield of 86% and a purity of 98.1%.

Referring to Figure 1-Figure 5,

ESI-MS, m/z: 333.2[M-1];

¹ H NMR (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);

¹³ C NMR (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, 48.334, 478.2 ,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 chromatography column analysis: peak 1: peak 2 = 49.4%: 49.1%.

Example 2:

This embodiment differs from Embodiment 1 in that:

(1) Synthesis of 3-(3,4-dibenzyloxyphenyl)bornyl glycidate:

Dissolve 12.2 g (0.225 mol) of sodium methoxide in 150 mL of methanol to obtain solution 1;

Dissolve 47.7g (0.15mol) of 3,4-dibenzyloxybenzaldehyde and 48.4g (0.21mol) of bornyl chloroacetate in 200mL of dioxane to obtain solution 2;

Within 1 hour, drop solution 2 into solution 1, keep the reaction temperature at 5-10°C, after the dropwise addition, slowly warm up to room temperature, stir overnight, add the reaction solution into 200mL of ice water, adjust the hydrochloric acid to neutral, Extracted with dichloromethane (200mL×4), combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized the crude product with ethanol/petroleum ether to obtain 37.6g of off-white solid with a yield of 75%.

(2) Synthesis of Danshensu Bornyl Ester:

Dissolve 25.6 g (0.05 mol) of bornyl 3-(3,4-dibenzyloxyphenyl) glycidate in 300 mL of isopropanol, add 2.56 g of 5% wet Pd/C, and blow in hydrogen. After reacting at room temperature and pressure for 1.5 hours, it was filtered and concentrated under reduced pressure. The crude product was recrystallized with ethanol/petroleum ether to obtain 13.2 g of a light yellow solid with a yield of 79%.

Example 3:

This embodiment differs from Embodiment 1 in that:

(1) Synthesis of 3-(3,4-dibenzyloxyphenyl)bornyl glycidate:

Dissolve 21.6 g (0.225 mol) of sodium tert-butoxide in 150 mL of tert-butanol to obtain solution 1;

Dissolve 47.7g (0.15mol) of 3,4-dibenzyloxybenzaldehyde and 34.6g (0.15mol) of bornyl chloroacetate in 150mL of dioxane to obtain solution 2;

Within 1 hour, drop solution 2 into solution 1, keep the reaction temperature at 5-10°C, after the dropwise addition, slowly warm up to room temperature, stir overnight, add the reaction solution into 200mL of ice water, adjust the hydrochloric acid to neutral, Extract with dichloromethane (200 mL×4), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and recrystallize the crude product with ethanol/petroleum ether to obtain 49.2 g of off-white solid, with a yield of 64%.

(2) Synthesis of Danshensu Bornyl Ester:

Dissolve 25.6 g (0.05 mol) of bornyl 3-(3,4-dibenzyloxyphenyl) glycidate in 300 mL of ethanol, then add 2.56 g of 5% wet Pd/C, pass in hydrogen, and After reacting under normal pressure for 1 hour, it was filtered and concentrated under reduced pressure. The crude product was recrystallized from ethanol/petroleum ether to obtain 13.5 g of light yellow solid with a yield of 81%.

Example 4:

This embodiment differs from embodiment 3 in that:

Synthesis of Danshensubornyl Ester:

Dissolve 5.12g (0.01mol) of bornyl 3-(3,4-dibenzyloxyphenyl)epoxypropionate in 30mL of ethanol, then add 0.22g of palladium acetate, pass in hydrogen, and react under normal temperature and pressure After 2 hours, it was filtered and concentrated under reduced pressure. The crude product was recrystallized from ethanol/petroleum ether to obtain 2.71 g of a light yellow solid with a yield of 83%.

Example 5:

This embodiment differs from embodiment 3 in that:

Dissolve 5.12g (0.01mol) of bornyl 3-(3,4-dibenzyloxyphenyl)epoxypropionate in 30mL of ethanol, then add 0.14g of palladium hydroxide, pass in hydrogen, and After reacting for 2 hours, it was filtered and concentrated under reduced pressure. The crude product was recrystallized from ethanol/petroleum ether to obtain 2.64 g of a light yellow solid with a yield of 79%.

Embodiment 6:

(1) Synthesis of 3-(3,4-dibenzyloxyphenyl)bornyl glycidate:

Dissolve 12.6 g (0.113 mol) of potassium tert-butoxide in 75 mL of tert-butanol to obtain solution 1;

Dissolve 25.5g (0.08mol) of 3,4-dibenzyloxybenzaldehyde and 20.8g (0.09mol) of bornyl chloroacetate in 100mL of dioxane to obtain solution 2;

Within 1 hour, drop solution 2 into solution 1 at room temperature, stir overnight at room temperature, add the reaction solution into 200 mL of ice water, adjust to neutral with hydrochloric acid, extract with dichloromethane (100 mL×4), combine the organic phases, Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and recrystallize the crude product from ethanol/petroleum ether to obtain 17.4 g of off-white solid with a yield of 65%.

(2) Synthesis of Danshensu Bornyl Ester:

Dissolve 15.4 g (0.03 mol) of bornyl 3-(3,4-dibenzyloxyphenyl) glycidate in 100 mL of ethanol, then add palladium acetate and palladium hydroxide mixed catalyst, wherein palladium acetate 0.24 g, 0.14 g of palladium hydroxide was fed with hydrogen, reacted at room temperature and pressure for 2 hours, filtered, concentrated under reduced pressure, and the crude product was recrystallized with ethanol/petroleum ether to obtain 8.32 g of a light yellow solid with a yield of 83%.

Claims (10)

1. a synthetic method for DL Salvianic acidA norbornene ester, is characterized in that, this synthetic method comprises:

Reaction (1): halogenation benzyl reacts preparation 3,4-benzyloxy phenyl aldehyde with rancinamycin IV, 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 Salvianic acidA norbornene ester.

2. the synthetic method of DL Salvianic acidA norbornene 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 ℃ of-150 ℃ of conditions, described the first organic solvent is tetrahydrofuran (THF), dimethyl ethylene glycol, diethyl ethylene glycol, 1,4-dioxane, N, the combination of one or more in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone and dimethyl sulfoxide (DMSO).

3. the synthetic method of DL Salvianic acidA norbornene 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 Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, described reaction (2) is carried out in the second organic solvent He under alkaline condition, and described reaction (2) is carried out at 0 ℃-50 ℃; Described the 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).

5. the synthetic method of DL Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, described Mono Chloro Acetic Acid norbornene ester and 3,4-benzyloxy phenyl aldehyde are dissolved in the second organic solvent simultaneously and are added dropwise in reaction system.

6. the synthetic method of DL Salvianic acidA norbornene ester as claimed in claim 1, it is characterized in that, 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.

7. the synthetic method of DL Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, 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).

8. the synthetic method of DL Salvianic acidA norbornene ester as claimed in claim 1, 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.

9. the synthetic method of DL Salvianic acidA norbornene ester as claimed in claim 1, it is characterized in that, described reaction (3) is carried out in the 3rd organic solvent, and described the 3rd organic solvent is one or more the combination in Virahol, ethanol, methyl alcohol, tetrahydrofuran (THF) and methyl tertiary butyl ether.

10. the synthetic method of DL Salvianic acidA norbornene ester as claimed in claim 1, is characterized in that, described Mono Chloro Acetic Acid norbornene ester reacts and makes with borneol with chloroacetyl chloride.