CN100457760C - Preparation method of ertabeinan sodium salt - Google Patents

Abstract

A process for preparing Ertapeinan sodium includes such steps as reaction between [4R, 5S, 6S, 8R]-3-[(diphenyl phosphorosoacyl) oxy]-6-(1-hydroxyethyl)-4-methyl-7- oxy-1-azadicyclo [3, 2, 0 hepto-2-ene-2-carboxylate (4-nitrophenyl) methylester and (2S, 4S)-1-(4-nitrobenzyloxycarbonyl)-2-(3-hydroxycarbonylphenylamino formyl) pyrrolidine-4-yl thiol to obtain deprotecting precursor, adding Pd-C catalyst and sodium dicarbonate, and hydrodeprotecting reaction. Its advantages are high output rate and low cost.

Description

The preparation method of ertapenem sodium salt

technical field

The invention relates to a preparation method in the technical field of medicine, in particular to a preparation method of ertapenem sodium salt.

technical background

Ertapenem (ertapenem, MK-0826, L-749,345, trade name INVANZTM) is a new type of broad-spectrum carbapenem antibiotic newly developed by Merck Pharmaceutical Company of the United States. This product was launched in the United States and Europe in November 2001 and April 2002 respectively. It is the only I-β-methylcarbapenem antibiotic for parenteral administration and has a wide range of antibacterial activities, including Gram-positive With negative aerobes and anaerobes.

After searching the literature of the prior art, it is found that the preparation of ertapenem in the prior art is a two-step reaction, such as the preparation method disclosed in US 0,235,817: (1) by (4R, 5S, 6S, 8R)-3- [(Diphenoxyphosphono)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxy Reaction intermediate of acid-(4-nitrophenyl)methyl ester and (2S,4S)-2-[(3-hydroxycarbonyl)phenyl]-carbamoyl)pyrrolidin-4-ylthiol (2) In the case of sodium salt as an alkalizing agent, palladium/charcoal is used as a catalyst to carry out catalytic hydrogen dissociation and protection to obtain ertapenem sodium salt. But this technology has the following disadvantages: 1. The synthesis of required raw materials is cumbersome, and the stability is relatively poor, the reaction steps are long, multi-step crystallization is required in the preparation process, the operation is troublesome, the cost is high, and the experimental operation is inconvenient; 2. The reaction process Reagents used in the process such as solvents, alkalis, etc. are all expensive, making the production cost higher; 3. The reagents required for the post-treatment of the deprotection process are also relatively expensive, so that it is limited in large-scale industrial production.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies of the prior art, to provide a preparation method of ertapenem sodium salt, using the intermediates (4R, 5S, 6S, 8R)-3-[(diphenylphosphonyloxy)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]heptane- (2S,4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-hydroxycarbonylbenzene) as one of the raw materials Carbamoyl) pyrrolidin-4-yl thiol as another raw material, the two-step reaction is carried out by a one-pot method, and the carboxyl group and the protecting group on the secondary ammonia are removed simultaneously in the latter step reaction, the design is reasonable, the operation is convenient, and the production The preparation method has low cost and is applicable to the preparation process of industrialized preparation of ertapenem.

The present invention is realized through the following technical solutions, and the present invention comprises following two-step reaction:

(1) From (4R, 5S, 6S, 8R)-3-[(diphenylphosphonyloxy)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-aza Bicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester and (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(3 -Hydroxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol reaction, condensation to obtain a reaction intermediate, namely [4R, 5S, 6S]-3-[[(3S, 5S]-5-[[(N -p-Nitrobenzyloxycarbonyl-3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7- Oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester);

The (2S, 4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-hydroxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol is prepared by the following method: (1 ) by the reaction of trans-4-hydroxyl L-pyrrolidine and p-nitrobenzyl carbonyl chloride to obtain N-p-nitrobenzyloxycarbonyl-trans-4-hydroxyl-L-pyrrolidine; (2) N-p-nitrobenzyl carbonyl chloride Benzyloxycarbonyl-trans-4-hydroxy L-pyrrolidine is obtained through a one-pot method to obtain thiolactone; (3) react thiolactone with m-aminobenzoic acid to obtain the target compound.

(2) The reaction system in the previous step was not separated, and was directly hydrogenated and deprotected with palladium-charcoal as a catalyst and sodium bicarbonate as an alkalizing agent to obtain ertapenem sodium salt, namely [4R, 5S, 6S]-3 -[[(3S,5S)-5-[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4- Methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt.

In step (1), the reaction is to prepare a deprotected precursor, the solution mixing temperature of the two raw materials is maintained at 0°C, and the reaction is carried out in a solvent in the presence of a base, and the amount of the base is 2 to 4 equivalents of the substrate The reaction temperature is between -20°C and -60°C. The solvent for the reaction is a single solvent of acetonitrile, N,N-dimethylformamide and tetrahydrofuran or their mixed solvents. The two raw materials should be mixed at 0°C in solution. The base used can be diisopropylethylamine, diisopropylamine or triethylamine and the like.

In step (2), the reaction is to prepare the target compound [4R, 5S, 6S]-3-[[(3S, 5S)-5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl ]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, The reaction can isolate its reaction intermediate, but the best method is to directly carry out hydrogenation, which avoids the deterioration of the product due to instability, and also reduces the operation. The system of the previous step reaction is poured into a hydrogenation bottle under a nitrogen atmosphere at 0° C., and the pressure of the hydrogen should be between 5 and 20 atmospheres. The amount of sodium bicarbonate used is between 1 and 3 equivalents of the substrate. The amount of the catalyst used is between 0.1 and 0.2 equivalents. The post-treatment of the reaction should first be treated with activated carbon in an ice-water bath and a nitrogen atmosphere, then extracted with ethyl acetate and isoamyl alcohol to remove impurities, and finally evaporated and crystallized in a mixed solvent to obtain the crude product, and then washed to obtain the product. More specifically, after the reaction system is extracted, acetone and propanol are added to remove insoluble matter. The product is precipitated by evaporation and crystallization, and then purified by washing with 95% ethanol and methyl acetate respectively.

The synthetic route of the inventive method is as follows:

In the prior art, (4R, 5S, 6S, 8R)-3-[(diphenoxyphosphono)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-nitrogen Heterobicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester, ertapenem side chain (2S,4S)-1-(4-nitrobenzyloxy Carbonyl)-2-(3-hydroxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol is used as raw material to prepare ertapenem, since the side chain needs to remove the protecting group on the secondary amine during synthesis, The synthesis steps are long, and the post-processing is also troublesome. Furthermore, the last step in the preparation process of ertapenem is to remove the protecting group of the carboxyl group on the bicyclic ring, so that the two protections are divided into two steps to remove, which is obviously defective in the design.

In the present invention, the two protecting groups are designed to be of the same type, and then they are removed in the same step reaction. According to this idea, the side chain with protection on the secondary amine is first synthesized. This method not only shortens the step polymerization of the reaction One step, and the post-treatment is very simple, the generated product is a precipitate, only need to filter and wash the filter cake, which greatly simplifies the operation. In the deprotection process, the present invention adopts the method of evaporative crystallization when finally extracting the product, and then washes to obtain a better effect.

The present invention has the following advantages: 1) while maintaining the yield, the cost is greatly reduced and the operation is simplified; 2) the crystallization refining method is used, which is easy for industrialized production; 3) the source of raw materials is convenient, the yield is increased, and the cost is reduced; 4) The required reagents are cheap and environmentally friendly.

Detailed ways

The following examples are provided in conjunction with the content of the present invention. First, the raw material (2S, 4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-hydroxycarbonylphenylcarbamoyl)pyrrolidin-4-yl Mercaptan, the specific process is as follows:

(1) Preparation of N-p-nitrobenzyloxycarbonyl-trans-4-hydroxyl L-pyrrolidine

Trans-4-hydroxy-L-proline (20g, 153mmol) was dissolved in 100ml of water, potassium carbonate (27.5g, 1.3equ.) was added under stirring, and PNZCl (37.4g, 1.1equ.) was added dropwise in an ice-water bath The toluene solution (35mL) was incubated and stirred for 1h, and the end point of the reaction was monitored by TLC. Separate the water layer, decolorize it with activated carbon, add concentrated hydrochloric acid dropwise in an ice bath until the pH of the system is 2, and keep stirring to avoid agglomeration. After about 1 hour, let it stand for 2 hours, filter it with suction, wash it with an appropriate amount of water, and dry it until constant Weight, to obtain product 45.8g, y=96%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 8.23-8.16 (m, 2H, Ar-H), 7.62-7.56 (m, 2H, Ar-H), 5.26-5.11 (m, 2H, -OCH ₂ -Ar), 4.33-4.17(m, 2H, C-2H and C-4H), 3.52-3.34(m, 2H, C-5H), 2.48(m, 1H, C-3H), 1.99-1.87(m , 1H, C-3H).

(2) Preparation of N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2,2,1]heptan-3-one

N-p-nitrobenzyloxycarbonyl-trans-4-hydroxy L-pyrrolidine (12.4g, 40mmol) was dissolved in THF (250mL), and DIPEA (17.3mL, 2.5equiv. ) and diphenylphosphinyl chloride (8mL, 1.05equiv.), incubated for 40min, and then reacted at room temperature for 20min. The temperature was then lowered to -12°C, and pyridine (3.4 g, 1.1 equiv.) and methanesulfonyl chloride (3.7 ml, 1.2 equiv.) were added sequentially. It was incubated for another 40 minutes, and then reacted at room temperature for 20 minutes. Sodium sulfide (Na ₂ S·9H ₂ O, 11.5 g, 1.2 equiv.) was dissolved in 20 mL of water, and added into the system under vigorous stirring. Stir overnight at room temperature, extract with toluene, wash the organic phase with 10% dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine successively, remove the toluene by rotary evaporation to obtain a crude product, and recrystallize with acetic acid to obtain a light green solid (9.9 g, y = 80%).

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.23(d, J=8.6Hz, 2H), 7.54(d, J=8.6Hz, 2H), 5.31(d, J=13.7Hz, 1H), 5.21(d , J=13.7Hz, 1H), 4.62-4.70(m, 1H, C-2H), 4.15-4.19(m, 1H, C-4H), 3.85-3.90(m, 1H, C-5H), 3.67- 3.72 (m, 1H, C-5H), 2.11-2.27 (m, 2H, C-3H).

(3) Preparation of (2S, 4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3-hydroxycarbonyl)-phenylcarbamoyl]-pyrrolidin-4-ylthiol

Add acetic acid (50 mL) to N-protected thiolactone (8.0 g, 30 mmol) and m-aminobenzoic acid (4.3 g, 36 mmol), and stir at room temperature overnight. After filtering, the filter cake was washed with appropriate amount of acetic acid and ether, and dried to obtain the product (12.6 g, y=96%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 12.80 (br, 1H, -COOH), 10.28 (d, J=8.8Hz, 1H, -NH), 8.25-7.39 (m, 8H, Ar-H) , 5.27-4.99 (m, 2H, -OCH ₂ ), 4.41-4.29 (m, 1H, C-2H), 4.04-3.90 (m, 1H, C-4H), 3.42-3.11 (m, 2H, C- 5H), 2.73-2.66(m, 1H, C-3H), 1.90-1.80(m, 1H, C-3H).

Example 1

[4R, 5S, 6S]-3-[[(3S, 5S)-5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R) Preparation of -1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt

(4R, 5S, 6S, 8R)-3-[(diphenoxyphosphono)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2 .0] Hept-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester (2, 0.595 g, 1 mmol) dissolved in N-methylpyrrolidone + N, N-dimethylformamide (( 10mL, v/v=3:1), add (2S,4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl) at 0°C under stirring ) Pyrrolidin-4-ylthiol (0.445g, 1 equiv.) in N-methylpyrrolidone+N,N-dimethylformamide (10mL, v/v=3:1) solution, transferred to -40°C After 10 min, diisopropylethylamine (0.38 mL, 2.2 equiv.) was added rapidly, stirred vigorously, and the reaction was completed in 4 h.

Add 20 mL of deionized water treated with ultrasound and nitrogen bubbling to the hydrogenation bottle, add anhydrous sodium bicarbonate (84 mg, 1 equiv.), 10% palladium/carbon (0.29 g, 0.2 equiv.) in a nitrogen atmosphere at 0 ° C The above reaction solution was poured down, and incubated at 20atm for 5h.

The palladium/charcoal was filtered off, the filtrate was treated with activated carbon in an ice-water bath and a nitrogen atmosphere, and then extracted twice with cold ethyl acetate (50mL*2) and isoamyl alcohol (50mL*2) successively, and the obtained liquid was added to 50 mL each of acetone and propanol was allowed to stand, filtered, the filtrate was concentrated to 10 mL, filtered, the solids were washed with 95% ethanol and methyl acetate, and dried in vacuo to obtain ertapenem sodium salt (0.33 g, y=66.2%).

m.p.: 261-263°C (dec.)

1H NMR (400MHz, dioxane as reference at d=3.75) δ:d 7.86(s, 1H), 7.71(d, 1H, J=7.2Hz), 7.65(d, 1H, J=8.0Hz), 7.47(t , 1H, J=8.0Hz), 4.60(t, 1H, J=8.4Hz), 4.23～4.17(m, 2H), 4.05(m, 1H), 3.80(dd, 1H, J=12.8, 6.8Hz) , 3.47～3.42(m, 2H), 3.31(m, 1H), 3.00(m, 1H), 2.20(m, 1H), 1.27(d, 3H, J=6.4Hz), 1.17(d, 3H, J =6.8Hz)

MS (ESI): 476.0 (M+1), 498.1 (M+Na).

Example 2

[4R, 5S, 6S]-3-[[(3S, 5S)-5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R) Preparation of -1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt

(4R, 5S, 6S, 8R)-3-[(diphenoxyphosphono)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2 .0] Hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (2, 0.595g, 1mmol) was dissolved in N-methylpyrrolidone+N,N-dimethylformamide (10mL , v/v=3:1), add (2S,4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl) at 0°C under stirring The solution of pyrrolidin-4-ylthiol (0.445g, 1 equiv.) in N-methylpyrrolidone+N,N-dimethylformamide (10mL, v/v=3:1) was transferred to -20℃ In the cold bath, diisopropylethylamine (0.38 mL, 2.2 equiv.) was added rapidly after 10 min, stirred vigorously, and the reaction was completed in 4 h.

Add 20 mL of deionized water treated with ultrasound and nitrogen bubbling to the hydrogenation bottle, add anhydrous sodium bicarbonate (84 mg, 1 equiv.), 10% palladium/carbon (0.29 g, 0.2 equiv.) in a nitrogen atmosphere at 0 ° C The above reaction solution was poured down and incubated at 18.5atm for 7h.

The palladium/charcoal was filtered off, the filtrate was treated with activated carbon in an ice-water bath and a nitrogen atmosphere, and then extracted twice with cold ethyl acetate (50mL*2) and isoamyl alcohol (50mL*2) successively, and the obtained liquid was added to 50 mL each of acetone and propanol, let stand, filter, concentrate the filtrate to 10 mL, filter, disperse the solid in methanol, centrifuge after ultrasonic treatment, and vacuum dry Deltapenem sodium salt (0.30 g, y=60.0%) .

Example 3

(4R, 5S, 6S, 8R)-3-[(diphenoxyphosphono)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2 .0] Hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (2, 0.595g, 1mmol) was dissolved in N-methylpyrrolidone+N,N-dimethylformamide (10mL , v/v=3:1), add (2S,4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl) at 0°C under stirring The solution of pyrrolidin-4-ylthiol (0.445g, 1 equiv.) in N-methylpyrrolidone+N,N-dimethylformamide (10mL, v/v=3:1) was transferred to -60℃ In the cold bath, diisopropylethylamine (0.38 mL, 2.2 equiv.) was added rapidly after 10 min, stirred vigorously, and the reaction was completed in 8 h.

Add 20 mL of deionized water treated with ultrasound and nitrogen bubbling into the hydrogenation bottle, add anhydrous sodium bicarbonate (0.25 g, 3 equiv.), 10% palladium/carbon (0.15 g, 0.1 equiv.) The above reaction solution was poured under the atmosphere, and kept at 20atm for 11h.

The palladium/carbon was filtered off, the filtrate was treated with activated carbon in an ice-water bath and a nitrogen atmosphere, and then extracted twice with cold ethyl acetate (50mL*2) and isoamyl alcohol (50mL*2) successively, and the water phase was adjusted with acetic acid pH = 7.5, add 50 mL each of acetone and propanol to the obtained liquid, let stand, filter, concentrate the filtrate to 10 mL, filter, wash the solid with 95% ethanol and methyl acetate, and dry in vacuum to obtain Ertapenem sodium salt ( 0.23 g, y=46.2%).

Example 4

(4R, 5S, 6S, 8R)-3-[(diphenoxyphosphono)oxy]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2 .0] Hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (2, 0.595g, 1mmol) was dissolved in N-methylpyrrolidone+N,N-dimethylformamide (10mL , v/v=3:1), add (2S,4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl) at 0°C under stirring The solution of pyrrolidin-4-ylthiol (0.445g, 1 equiv.) in N-methylpyrrolidone+N,N-dimethylformamide (10mL, v/v=3:1) was transferred to -40℃ In the cold bath, diisopropylethylamine (0.38 mL, 2.2 equiv.) was added rapidly after 10 min, stirred vigorously, and the reaction was completed in 4 h.

Add 20 mL of deionized water treated with ultrasound and nitrogen bubbling into the hydrogenation bottle, add anhydrous sodium bicarbonate (0.17 g, 2 equiv.), 10% palladium/carbon (0.29 g, 0.2 equiv.) The above reaction solution was poured under the atmosphere, and kept at 20atm for 5h.

The palladium/carbon was filtered off, the filtrate was treated with activated carbon in an ice-water bath and a nitrogen atmosphere, and then extracted twice with cold ethyl acetate (50mL*2) and isoamyl alcohol (50mL*2) successively, and the water phase was adjusted with acetic acid pH = 7.5, add 50 mL each of acetone and propanol to the obtained liquid, let stand, filter, concentrate the filtrate to 10 mL, filter, wash the solid with 95% ethanol and methyl acetate, and dry in vacuum to obtain Ertapenem sodium salt ( 0.31 g, y=62.2%).

Among the above examples, the reaction time is short and the yield is high in Example 1, which is the preferred reaction route. The invention has reasonable design, convenient operation and low production cost.

Claims (8)

1, a kind of preparation method of ertabeinan sodium salt is characterized in that, comprises following two-step reaction:

(1)) by (4R, 5S, 6S, 8R)-and 3-[(diphenyl phosphine oxide acyl) oxygen]-6-(1-hydroxyethyl)-4-methyl-7-oxygen-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxylic acid (4-nitrophenyl) methyl esters and (2S, 4S)-1-(4-nitro carbobenzoxy-(Cbz))-2-(3-hydroxycarbonyl group phenyl amino formyl radical) tetramethyleneimine-4-base thiol reactant, condensation obtains [4R, 5S, 6S]-3-[[(3S, 5S)-5-[[(N-is to nitro carbobenzoxy-(Cbz)-3-carboxyl phenyl) amino] carbonyl]-the 3-pyrrolidyl] sulfenyl]-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxylic acid (4-nitrophenyl) methyl esters);

(2) the previous step reaction system is without separation; directly carry out the hydrogenation deprotection as catalyzer, sodium bicarbonate as basifier and make ertabeinan sodium salt with palladium-charcoal; i.e. [4R; 5S; 6S]-3-[[(3S, 5S)-the 5-[[(3-carboxyl phenyl) amino] carbonyl]-the 3-pyrrolidyl] sulfenyl]-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxylic acid list sodium salt.

2, the preparation method of ertabeinan sodium salt according to claim 1, it is characterized in that, in the step (1), the solution mixing temperature of two kinds of raw materials remains on 0 ℃, in the presence of alkali, be reflected in the solvent and carry out, the consumption of alkali is between 2～4 equivalents of substrate, and temperature of reaction is between-20 ℃～-60 ℃.

3, the preparation method of ertabeinan sodium salt according to claim 2 is characterized in that, alkali is diisopropyl ethyl amine, diisopropylamine or triethylamine.

4, the preparation method of ertabeinan sodium salt according to claim 1 is characterized in that, in the step (2), directly carries out hydrogenation, the system of back reaction impouring hydrogenation bottle under the nitrogen atmosphere in the time of 0 ℃, and the pressure of hydrogen is between 5～20 normal atmosphere.

5, the preparation method of ertabeinan sodium salt according to claim 1 is characterized in that, in the step (2), the consumption of sodium bicarbonate is between 1～3 equivalent of substrate.

6, the preparation method of ertabeinan sodium salt according to claim 1 is characterized in that, in the step (2), between catalyst consumption 0.1～0.2 equivalent.

7, the preparation method of ertabeinan sodium salt according to claim 1, it is characterized in that, in the step (2), the aftertreatment of reaction: at first under ice-water bath and nitrogen atmosphere, use activated carbon treatment, carry out abstraction impurity removal with ethyl acetate and primary isoamyl alcohol again, evaporative crystallization gets crude product in mixed solvent at last, again by wash product.

8, the preparation method of ertabeinan sodium salt according to claim 7, it is characterized in that, reaction system adds acetone and propyl alcohol and removes insolubles after extracting, product is that the mode by evaporative crystallization makes it to separate out, then respectively with 95% ethanol and ritalin washing carrying out purifying.