WO2022227117A1

WO2022227117A1 - Method for synthesizing vidarabine monophosphate and use thereof

Info

Publication number: WO2022227117A1
Application number: PCT/CN2021/093193
Authority: WO
Inventors: 韩林; 黄月娜; 王小芳
Original assignee: 海南锦瑞制药有限公司
Priority date: 2021-04-28
Filing date: 2021-05-12
Publication date: 2022-11-03
Also published as: CN113173957A; CN113173957B

Abstract

Disclosed are a method for synthesizing vidarabine monophosphate and the use thereof, which belong to the field of drug synthesis. The synthesis method comprises subjecting 5-iodo-2-((phosphonooxy)methyl)-4-(tosyloxy)tetrahydrofuran-3-yl acetate and tert-butyl(8-hydroxy-9H-purin-6-yl)carbamate to condensation, epoxidation, ring opening and desulfurization reactions in order to synthesize vidarabine monophosphate. The provided method for synthesizing vidarabine monophosphate further simplifies the industrial production steps, improves the total reaction yield, and reduces the industrial production cost. The synthesis method is suitable for the synthesis of vidarabine monophosphate, and the synthesized vidarabine monophosphate is used for preparing vidarabine monophosphate for injection.

Description

Synthetic method and application of adenosine monophosphate arabinoside

technical field

The invention belongs to the field of drug synthesis, and relates to the synthesis and preparation of an antiviral drug, in particular to a synthesis method and application of adenosine monophosphate arabinoside.

Background technique

Adenosine monophosphate [chemical name: 9-(β-D-arabinofuranose) adenine 5'-monophosphate, I] is a nucleotide antiviral drug, and its pharmacological effect is to deoxygenate the virus. Binds to ribonucleotide polymerase, reducing its activity and inhibiting DNA synthesis. After adenosine monophosphate enters cells, it undergoes phosphorylation to generate arabinosine diphosphate (Ara-ADP) and arabinosine triphosphate (Ara-ATP). Antiviral activity is mainly caused by arabinosine triphosphate (Ara-ATP), Ara-ATP competes with deoxyadenosine triphosphate (dATP) to bind to viral DNAP, thereby inhibiting enzyme activity and viral DNA synthesis At the same time, it inhibits the activity of viral nucleotide reductase and inhibits the synthesis of viral DNA, and also inhibits the activity of deoxynucleotidyltransferase at the end of viral DNA, so that Ara-ATP penetrates into the viral DNA and is connected to the 3' of the DNA chain. The end of the -OH position inhibits the continued synthesis of viral DNA, and its chemical formula is:

Adenosine monophosphate is a water-soluble derivative of vidarabine, which has obvious inhibitory activity against various DNA viruses such as type I and type II herpes simplex virus, herpes zoster virus, chickenpox virus, and vaccinia virus; Adenosine monophosphate is also widely used in the treatment of viral hepatitis B in China.

However, the clinical dosage of adenosine monophosphate monophosphate is relatively large, and a synthesis process of adenosine monophosphate monophosphate must be available in order to meet the needs of clinical medication.

There are two main chemical synthesis methods reported in the literature.

The first synthetic route (M.Ikebara, et al. Tetrahedron Let 1972; 28:3695.) uses adenosine monophosphate as a raw material to prepare adenosine monophosphate first, and the latter is phosphorylated to obtain adenosine monophosphate:

The reaction process includes two processes of dephosphorylation and phosphorylation. The steps are long, the yield is low, and the total yield is only 8%; especially, there are many phosphorylation by-products, which brings difficulties to separation and purification.

The second synthetic route (Masakatsu Kaneko, et al.Chem Pharm Bull 1977; 25:1892.) uses adenosine monophosphate as a raw material, is protected and then brominated, and then undergoes reactions such as amination, sulfhydrylation, and hydrogenation to obtain monophosphate. Adenosine Phosphate:

The whole process of this process does not require dephosphorylation and phosphorylation, and the total yield can reach 12%. However, most of the intermediates and final products need to be separated by activated carbon affinity chromatography and ion exchange resin chromatography, and the reaction involves multiple protection and deprotection, which is not conducive to industrial production.

SUMMARY OF THE INVENTION

In order to solve the above deficiencies in the prior art, the present invention aims to provide a method for synthesizing adenosine monophosphate, so as to shorten the synthesis process of adenosine monophosphate, reduce industrial production costs, and improve the total reaction yield. rate purpose.

For achieving the above object, the technical scheme adopted in the present invention is as follows:

A synthetic method of adenosine monophosphate, the synthetic method comprises the following steps:

1) Take 5-iodo-2-((phosphorus carboxy)methyl)-4-(toluenesulfonyl oxo)tetrahydrofuran-3-yl acetate (2) and tert-butyl(8-hydroxy- 9H-purin-6-yl) carbamate (3) is mixed in organic solvent A, add alkali and palladium catalyst to carry out condensation reaction, after filtration and concentration, obtain compound (4) crude product;

2) get the crude product of compound (4) and dissolve it in THF, then add an alkaline solvent to carry out epoxidation reaction, and after the reaction finishes, carry out purification treatment 1 to obtain the crude product of compound (5);

3) get compound (5) crude product and mix in organic solvent B with hydrosulfide, carry out ring-opening reaction, after the reaction finishes, carry out purification treatment II, obtain compound (6) crude product;

4) get compound (6) crude product and be dissolved in lower alcohol, add Raney nickel to carry out desulfurization reaction, promptly obtain monophosphate adenosine arabinophosphate (1), and its total reaction formula is:

As a limitation of the present invention, the organic solvent A is tetrahydrofuran (THF), toluene, N,N-dimethylformamide (DMF) or dimethylsulfoxide (DMSO); the base is carbonate or organic Alkali; the carbonate is sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; the organic base is triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA); the palladium The catalyst is tetrakis (triphenylphosphine) palladium or [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride;

As another limitation of the present invention, the reaction temperature of the condensation reaction is 60-150°C, and the reaction time is 2-10h;

As the third limitation of the present invention, the alkaline solvent is ammonia water or a sodium hydroxide solution with a concentration of 40%; the reaction temperature of the epoxidation reaction is 90-120° C., and the reaction time is 8-12 h;

As the fourth limitation of the present invention, the purification treatment I is to adjust the pH to neutrality with 1N hydrochloric acid, then add ethyl acetate for extraction, retain and concentrate the organic phase, until no solvent is evaporated, to obtain compound (5 )Crude;

As the fifth limitation of the present invention, the hydrosulfide is at least one of potassium hydrosulfide, sodium hydrosulfide and hydrosulfide; the organic solvent B is tetrahydrofuran (THF), dichloromethane (DCM) or Trichloromethane;

As the sixth limitation of the present invention, the reaction temperature of the ring-opening reaction is 40-70 °C, and the reaction time is 5-8 h; the purification treatment II is adding dichloromethane for extraction, adding silica gel, concentrating, and performing column Chromatography, the eluent is petroleum ether with a volume ratio of 13 to 19:1: dichloromethane, and the eluent is collected and concentrated to obtain the crude product of compound (6);

As the seventh limitation of the present invention, the lower alcohol is methanol (MeOH) or ethanol (EtOH); the reaction temperature of the desulfurization reaction is 50-90° C., and the reaction time is 2-5 h;

The present invention also provides an application of the method for synthesizing adenosine monophosphate, the method for synthesizing adenosine monophosphate is used for synthesizing adenosine monophosphate; the obtained adenosine monophosphate is used for preparing injection with adenosine monophosphate.

Due to adopting the above-mentioned technical scheme, compared with the prior art, the present invention has the following beneficial effects:

(1) the synthetic method of the adenosine monophosphate monophosphate provided by the present invention, adopts the small molecule condensation to make the intermediate of monophosphate vidarabine, shortens the process route, simplifies the synthesis steps, and saves the protection group The introduction of , to avoid the formation of other side reactions;

(2) The method for synthesizing adenosine monophosphate monophosphate provided by the present invention improves the total reaction yield of synthesizing adenosine monophosphate arabinophosphate because the synthesis steps are simplified, thereby indirectly reducing the industrial production cost.

(3) The adenosine monophosphate synthesized by the synthetic method of adenosine monophosphate provided by the present invention can not only be used for the preparation of adenosine monophosphate for injection, but also can be prepared into various dosage forms, such as , sprays, ointments, etc., can avoid the local pain and other symptoms caused by adenosine monophosphate injection.

To sum up, the method for synthesizing adenosine monophosphate arabinoside provided by the present invention further simplifies the industrial production steps, improves the overall reaction yield, and reduces the industrial production cost.

The invention is suitable for synthesizing adenosine monophosphate monophosphate, and the synthesized adenosine monophosphate monophosphate is used for preparing adenosine monophosphate monophosphate for injection.

Description of drawings

The present invention will be described in further detail below in conjunction with the accompanying drawings and specific embodiments.

Fig. 1 is the HPLC chart of the adenosine monophosphate arabinoside synthesized in Example 1 of the present invention.

Detailed ways

The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are only used to illustrate and understand the present invention, but not to limit the present invention.

Embodiment 1 A kind of synthetic method of adenosine monophosphate M1

The present embodiment provides a method for synthesizing adenosine monophosphate M1, which comprises the following steps:

1) Weigh 53.6g of 5-iodo-2-((phosphorus carboxy)methyl)-4-(toluenesulfonyloxo)tetrahydrofuran-3-yl acetate (2) and 30g of tert-butyl ( 8-Hydroxy-9H-purin-6-yl)carbamate (3) was mixed in 220ml of THF, 31.8g of sodium carbonate and 5.78g of tetrakis(triphenylphosphine)palladium were added at 70°C, and a condensation reaction was carried out for 8h, The progress of the reaction was monitored by TLC, and the reaction was completed when the UV color developing point of the raw material (2) disappeared. The reaction solution was filtered, the filter cake was washed three times with ethanol, the filtrate was collected and concentrated under reduced pressure until no solvent was evaporated to obtain 39.54 g of compound (4) crude product (yield was 60%), which was directly used in the next step. for:

2) Weigh 39.54g of compound (4) crude product and dissolve it in 130ml of THF, then add 15ml of sodium hydroxide solution with a concentration of 40%, seal and heat up to 90°C, mix and stir for 12h, carry out epoxidation reaction, take a small amount of reaction solution, dilute After injecting into the liquid chromatograph, the material peak of compound (4) disappears, which is the end point of the reaction, adjust the pH to neutrality with 6ml of 1N hydrochloric acid (measured pH=7 by broad-spectrum pH test paper), and then add 300ml of ethyl acetate Extracted three times, retained the combined organic phase, and concentrated all the solvents to obtain 17.09 g of compound (5) crude product (yield was 64%). The reaction formula is:

3) Weigh 17.09g of compound (5) crude product and 2.79g of sodium hydrosulfide to dissolve in 75ml DCM, heat to 50°C and keep stirring for 8h to carry out ring-opening reaction, extract a small amount of reaction solution, inject into liquid chromatograph after dilution, compound ( 5) The material peak disappears, that is, the reaction end point, add 50ml saturated aqueous sodium thiosulfate solution and 200ml dichloromethane for extraction five times, collect the organic phase, concentrate the solvent of three-fifths of the total amount of the reaction solution, then add and react Silica gel with a weight ratio of 1:1 to the total amount of the product was used, concentrated the remaining solvent, carried out column chromatography (200-300 mesh silica gel column), used a mixed solvent of petroleum ether: dichloromethane with a volume ratio of 13:1, collected And the eluent was concentrated to obtain 10.33 g of compound (6) crude product (the yield was 71%), and its reaction formula was:

4) Weigh 10.33g of the crude product of compound (6) and dissolve it in 50ml of MeOH, add 6g of Raney nickel to carry out a desulfurization reaction at 65°C for 3h, extract a small amount of the reaction solution for dilution, inject it into a liquid chromatograph, and the material peak of compound (6) disappears , which is the end point of the reaction, concentrate all the solvents, add 120ml saturated sodium bicarbonate solution and stir until it becomes clear, add 50g activated carbon for decolorization, filter and wash the filter cake, concentrate half of the water under reduced pressure at 50 °C, add acetone with a volume ratio of 5:8 : The mixed solution of cyclohexane was stirred, 10 ml of phosphoric acid was added dropwise until a large amount of solid was precipitated, filtered and dried to obtain 7.85 g of adenosine monophosphate M1(1) (the yield was 83%; the total reaction yield was 22.6%; the purity is 99.7%; ), and its reaction formula is:

Take a small amount of adenosine monophosphate M1, dilute it and inject it into a high performance liquid chromatograph for detection according to the four general chapters of "Chinese Pharmacopoeia" 0512. The measurement results are shown in Figure 1.

Embodiment 2～6 The synthetic method of adenosine monophosphate M2～M6

Embodiments 2 to 6 provide the synthesis methods of adenosine monophosphate M2 to M6, and the synthesis method is roughly the same as the synthesis method of adenosine monophosphate monophosphate provided in Example 1, and the difference is only that some synthetic process parameters are different. , the specific synthesis process parameters are shown in Table 1.

Table 1: Synthesis process parameters of adenosine monophosphate M2～M6

The rest of the process parameters are the same as in Example 1.

Comparative Example 1 Synthetic method of adenosine monophosphate D1

The synthetic method of adenosine monophosphate D1 provided by this comparative example is basically the same as that of Example 1, except that the condensation reaction temperature is 55°C, the reaction is performed for 13 hours, and the reaction progress is monitored by TLC, and the ultraviolet point of the raw material (2) is still there Residual, continue to keep stirring for 3h, TLC monitoring still has raw material (2) remaining, finish the reaction, handle according to the processing mode in Example 1, obtain 17.69g compound (4) (yield is 33%), continue to follow Example 1 The methods in steps 2) to 4) synthesize arabinosine monophosphate, and the obtained arabinosine monophosphate D1 is 4.55 g (the total yield is 13.1%, and the purity is 98.7%).

Comparative Example 2 Synthetic method of adenosine monophosphate D2

The synthetic method of adenosine monophosphate D2 provided by this comparative example is basically the same as that of Example 1, the difference is only that the condensation reaction temperature is 155 ° C, the reaction is performed for 6 h, the progress of the reaction is monitored by TLC, and the ultraviolet point of the raw material (2) disappears, Take a small amount of reaction solution and do liquid chromatograph detection, and compared with the compound (4) obtained in step 1) in Example 1, the polarity is larger than that of compound (4), the molecular weight is 559, and the obtained molecular formula is:

No compound (4) was produced, that is, the synthesis failed.

Comparative Example 3 Synthetic method of adenosine monophosphate D3

The synthetic method of adenosine monophosphate D3 provided in this comparative example is basically the same as that of Example 1, except that the epoxidation reaction temperature is 80 °C, the reaction is performed for 15 h, the reaction progress is monitored by TLC, and the ultraviolet point of compound (4) Exist, no new point is generated, continue to keep stirring for 2h, TLC monitoring still no new point is generated, that is, the synthesis fails.

Comparative example 4 Synthesis method of adenosine monophosphate D4

The synthetic method of adenosine monophosphate D4 provided in this comparative example is basically the same as that of Example 1, except that the epoxidation reaction temperature is 130 ° C, the reaction is performed for 15 h, the reaction progress is monitored by TLC, and the ultraviolet point of compound (4) Disappeared, a new point was generated, and the sample was injected into the liquid chromatograph. The obtained material had a higher peak polarity and a molecular weight of 265. The molecular formula was:

No compound (5) was produced, that is, the synthesis failed.

Comparative Example 5 Synthetic method of adenosine monophosphate D5

The synthetic method of adenosine monophosphate D5 provided in this comparative example is basically the same as that of Example 1, the difference is only that the temperature of the ring-opening reaction is room temperature, the reaction is performed for 10 h, the progress of the reaction is monitored by TLC, and the ultraviolet point of compound (5) exists, No new spots were generated, and the temperature was kept stirring for 5 h. If no new spots were generated by TLC monitoring, the synthesis failed.

The synthetic method of comparative example 6 adenosine monophosphate D6

The synthetic method of adenosine monophosphate D6 provided in this comparative example is basically the same as that of Example 1, the difference is that the temperature of the ring-opening reaction is 80 °C, the reaction is performed for 5 h, the progress of the reaction is monitored by TLC, and the ultraviolet point of compound (5) disappears , a new point is generated, which is quite different from compound (6) in polarity. The molecular weight measured by sampling and sending to the liquid phase is 413, and the molecular formula is:

If no compound (6) is produced, the synthesis fails.

The synthetic method of comparative example 7 adenosine monophosphate D7

The synthetic method of adenosine monophosphate D7 provided by this comparative example is basically the same as that of Example 1, the difference is only that the eluent used in step 4) is a mixed solution of petroleum ether with a volume ratio of 10:1: dichloromethane Elution, all impurities were eluted together with adenosine monophosphate D7, which could not achieve the purpose of separation by column chromatography. The obtained arabinosine monophosphate D7 8.79g (yield 93%; purity 90.6%) .

Comparative example 8 Synthesis method of adenosine monophosphate D8

The synthetic method of adenosine monophosphate D8 provided by this comparative example is basically the same as that of Example 1, except that the eluent used in step 4) is a mixed solution of petroleum ether with a volume ratio of 22:1: dichloromethane After 48 hours of elution, adenosine monophosphate D8 still could not be eluted, and the separation purpose of column chromatography could not be achieved. The polarity of the eluent was gradually increased to 19:1, and adenosine monophosphate was eluted. The obtained Adenosine monophosphate D8 6.99 g (74% yield; 20.17% overall yield; 95.3% purity).

Comparative Example 9 Synthetic method of adenosine monophosphate D9

This comparative example adopts the Chinese invention patent whose application number is 200410015563.4 to synthesize adenosine monophosphate D9, and the method steps are:

(1) Preparation of 2-oxo-p-toluenesulfonyl ester-5-phosphate adenosine (II)

Add 34.7 g of 5-AMP to a mixed solution of 150 ml of dioxane and 350 ml of 1N sodium hydroxide; after dissolving, add 22.8 g of finely ground p-toluenesulfonyl chloride to the solution, and stir at 0°C After 15 hours of reaction, 35 ml of 6N hydrochloric acid was added to adjust the pH to 4.0. The precipitated crystals were collected by filtration to obtain 46.4 g of crystalline powder II.

(2) Preparation of 8-bromo-2-oxo-p-toluenesulfonyl ester-5-phosphate adenosine (III)

In 240 ml of 2M sodium acetate (pH4) solution, add 46 g of II, and cool to 0-5°C. To this solution was then added dropwise 19 ml of bromine, maintaining 0-5°C. Stir at this temperature for 18 hours. 28 g of sodium bisulfite was added to the reaction solution at 0 to 5°C. After stirring for 15 minutes, the pH was adjusted to 4.0 with 5N sodium hydroxide (about 90-100 mL). It was evaporated to dryness under reduced pressure, and the obtained solid was directly used in the next reaction.

(3) Preparation of 8-hydroxy-N,3-diacetyl-2-oxo-p-toluenesulfonyl ester-5-phosphate adenosine (IV)

80 ml of acetic acid and 80 ml of acetic anhydride were added to the reaction product of the previous step, and the reaction was stirred and refluxed for 2 hours. After cooling to room temperature, 60 mL of methanol was added. Evaporate dry. Add ethanol and evaporate to dryness; then add ethanol and evaporate to dryness. The residue was dissolved by heating with as little water as possible, cooled to 5°C with stirring, and allowed to stand overnight. Filter, wash with a small amount of water, and vacuum dry to obtain 60.2 g of solid.

(4) Preparation of 5-phosphate 8,2-epoxyadenosine (V)

In the reaction kettle, 60 grams of IV was suspended in 300 ml of ethanol, and ammonia gas was passed through to saturation at 0 to 5 °C, and the reaction was stirred at 65 to 70 °C for 20 hours after sealing. After cooling to room temperature, the steel kettle was placed in a dry ice-methanol bath (or ice-salt bath) for 2 hours. The precipitated solid was collected by filtration and washed with cold methanol to obtain 35 g of V, which could be used for the next reaction.

(5) Preparation of adenosine monophosphate (I)

Dissolve 35 g of V with 240 ml of pyridine, put it in a steel kettle, add 5 g of Dowex 50x4; pass dry hydrogen sulfide to saturation. After sealing, heat at 95-100°C for 15 hours. Excess hydrogen sulfide was driven off by nitrogen, and the reaction solution was concentrated to dryness under reduced pressure. The residue was dissolved in 600 ml of water, and the insoluble matter was filtered off. 20 grams of Raney nickel was added to the filtrate, and the reaction was refluxed for 2.5 hours; 6 grams of Raney nickel was added, and the reaction was refluxed for 0.5 hours, and 4 grams of Raney nickel was added, and the reaction was refluxed for 0.5 hours. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure to 200 ml, adjusted to pH 2.5 with 37% hydrochloric acid, seed crystals were added, cooled to 5° C. with stirring, and left overnight. Filter, wash with a small amount of water, and vacuum dry to obtain 7.2 grams of adenosine monophosphate (I) white solid, and the total reaction formula is:

Application Example Preparation method of adenosine monophosphate monophosphate for injection

Adenosine monophosphate 100g

Mannitol 40g

5% sodium hydroxide solution appropriate amount

Add water for injection to 2000ml to make 1000 sticks.

Preparation method: randomly select 100 g of adenosine monophosphate M5 synthesized in Example 5, add 40 g of mannitol to dissolve in 1500 ml of water for injection, adjust pH=7, make up for water for injection to 2000 ml, fill, and place the qualified product in the filling. In the freeze-drying box, pre-freeze at -50°C for 2 hours, vacuumize the box to 25Pa, slowly raise the temperature at 2°C/hour for sublimation until the product temperature reaches -5°C, further heat up for desorption drying, equilibrate at 40°C for 1 hour, Press the full stopper. The freeze-dried products are crimped, inspected by light, labelled and packaged.

Experimental Example Stability test of adenosine monophosphate monophosphate for injection

accelerated test

Adenosine monophosphate for injection prepared in the above application example was placed under the conditions of temperature 40 ℃ ± 2 ℃ and relative humidity 75% ± 5% for 6 months, after sampling analysis, the analysis results of each index were consistent with 0. Compared with the previous month, the content decreased slightly, and the related substances increased slightly, but they were all within the proposed limits, and other test indicators did not change significantly. The lower quality is basically stable, and the measurement results are shown in Table 2.

Table 2: Accelerated test results of adenosine monophosphate for injection

Long term trial

The adenosine monophosphate for injection prepared in the above application example was placed for 24 months under the conditions of a temperature of 25 ° C ± 2 ° C and a relative humidity of 60 ± 10%. After sampling and analysis, the analysis results of various indicators were the same as Compared with 0 months, the content decreased slightly and the related substances increased slightly, but they were all within the proposed limits. There was no significant change in other monitoring indicators, indicating that the quality of this product was basically stable under the conditions of long-term testing. The test results are shown in Table 3. .

Table 3: Long-term test results of adenosine monophosphate for injection

According to the regulations on the validity period of drugs in "Pharmaceutics", the validity period of this product can be tentatively set to 24 months.

It should be noted that the above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art can still The technical solutions described in the above embodiments are modified, or some technical features thereof are equivalently replaced. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

A method for synthesizing adenosine monophosphate, characterized in that: the method for synthesizing comprises the following steps:

1) Take 5-iodo-2-((phosphorus carboxy)methyl)-4-(toluenesulfonyl oxo)tetrahydrofuran-3-yl acetate (2) and tert-butyl(8-hydroxy- 9H-purin-6-yl) carbamate (3) is mixed in organic solvent A, add alkali and palladium catalyst to carry out condensation reaction, after filtration and concentration, obtain compound (4) crude product;

2) get compound (4) crude product and dissolve it in tetrahydrofuran, then add basic solvent to carry out epoxidation reaction, after the reaction finishes, carry out purification treatment 1 to obtain compound (5) crude product;

3) get compound (5) crude product and mix in organic solvent B with hydrosulfide, carry out ring-opening reaction, after the reaction finishes, carry out purification treatment II, obtain compound (6) crude product;

4) get compound (6) crude product and be dissolved in lower alcohol, add Raney nickel to carry out desulfurization reaction, promptly obtain monophosphate adenosine arabinophosphate (1), and its total reaction formula is:
The method for synthesizing adenosine monophosphate according to claim 1, wherein the organic solvent A is tetrahydrofuran, toluene, N,N-dimethylformamide or dimethyl sulfoxide; the alkali It is carbonate or organic base; the carbonate is sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; the organic base is triethylamine or N,N-diisopropylethylamine; the palladium The catalyst is tetrakistriphenylphosphine palladium or [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium.
The method for synthesizing adenosine monophosphate adenosine monophosphate according to claim 1, characterized in that: the reaction temperature of the condensation reaction is 60～150°C, and the reaction time is 2～10h.
The method for synthesizing adenosine monophosphate according to any one of claims 1 to 3, wherein the alkaline solvent is ammonia water or a sodium hydroxide solution with a concentration of 40%; the epoxidation The reaction temperature of the reaction is 90-120° C., and the reaction time is 8-12 h.
The method for synthesizing adenosine monophosphate according to any one of claims 1 to 3, wherein the purification treatment I is to adjust pH to neutrality with 1N hydrochloric acid, and then add ethyl acetate for extraction, The organic phase was retained and concentrated until no more solvent was evaporated to obtain the crude product of compound (5).
The method for synthesizing adenosine monophosphate according to any one of claims 1 to 3, wherein the hydrosulfide is at least one of potassium thiocyanate, sodium hydrosulfide and hydrosulfide ; The organic solvent B is tetrahydrofuran, dichloromethane or chloroform.
The method for synthesizing adenosine monophosphate according to any one of claims 1 to 3, characterized in that: the reaction temperature of the ring-opening reaction is 40-70° C., and the reaction time is 5-8 h; Purification treatment II is adding dichloromethane for extraction, adding silica gel with a weight ratio of 1 to 1.5:1 to the total amount of reactants, concentrating, and performing column chromatography, and the eluent is petroleum with a volume ratio of 13 to 19:1. Ether: dichloromethane, collect and concentrate the eluent to obtain the crude product of compound (6).
The method for synthesizing adenosine monophosphate according to any one of claims 1 to 3, wherein the lower alcohol is methanol or ethanol; the reaction temperature of the desulfurization reaction is 50-90° C. The time is 2 to 5h.
An application of the method for synthesizing adenosine monophosphate according to any one of claims 1 to 8, wherein the method for synthesizing adenosine monophosphate is used for synthesizing adenosine monophosphate glucoside; the obtained arabinosine monophosphate is used to prepare arabinosine monophosphate for injection.