CN109456329B

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Publication number: CN109456329B
Application number: CN201811375544.0A
Authority: CN
Inventors: 刘超; 葛执信; 李廷义; 苗华明; 蔡亚辉
Original assignee: Dijia Pharmaceutical Group Co ltd; Disha Pharmaceutical Group Co Ltd
Current assignee: Dijia Pharmaceutical Group Co ltd
Priority date: 2018-11-19
Filing date: 2018-11-19
Publication date: 2021-03-09
Anticipated expiration: 2038-11-19
Also published as: CN109456329A

Abstract

The invention relates to a preparation method of famciclovir. The preparation method comprises the steps of taking guanidine nitrate and diethyl malonate as raw materials, performing ring closure reaction under alkaline conditions to obtain 2-amino-4, 6-pyrimidinediol, performing hydroxyl chlorination to obtain 2-amino-4, 6-dichloropyrimidine, and reacting with 2- (2, 2-dimethyl-1, 3-dioxane-5-yl) ethyl-1-amine to generate 6-chloro-substituted benzeneN⁴- (2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine, then reacting with sodium nitrite under an acidic condition to obtain 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidine-4-yl) amino) ethyl) propane-1, 3-diol, and finally carrying out reduction/dechlorination, ring closing and esterification reactions to obtain famciclovir. The invention solves the problems of poor selectivity of the N-alkylation reaction, additional purification of reaction intermediates and the like in the prior art.

Description

Preparation method of famciclovir

Technical Field

The invention relates to a preparation method of famciclovir, belonging to the technical field of medicine.

Background

Famciclovir (Famciclovir, 1), developed by SmithKline Beecham corporation in the 90 s of the 20 th century, is a novel nucleoside-type broad-spectrum antiviral drug and is widely used for diseases such as severe herpes zoster and primary genital herpes. The chemical name is as follows: 2- [2- (2-amino-9H-purin-9-yl) ethyl ] -1, 3-propanediol-diethyl ester, having the chemical structure shown below:

。

the existing famciclovir synthesis methods mainly comprise the following patents: EP 182024, EP 0302644, US 5138057, CN 108314685A, CN 101195622a, CN 100455583C; WO2004/110343, US5917041, CN 101555249B, CN 102924455A, etc.

The synthesis method mainly comprises two main types according to the structural characteristics of famciclovir:

the first type is that 2-amino-6-chloropurine is used as starting material and is respectively connected with different alkane side chains to synthesize famciclovir.

Patents EP 182024, EP 0302644, US 5138057, CN 108314685A, CN 101195622a, CN 100455583C and the like, respectively build different types of alkane side chains around increasing the ratio of N-9/N-7 in the N-alkylation reaction, and the related synthetic routes are as follows:

the step of the route (1-1) is shorter, but the side chain of the raw material esterified substance is not easy to obtain, and the synthesis step is more complicated. The N-7 isomer (about 1/3 in the reaction liquid) generated in the first step of condensation reaction has similar properties with famciclovir, is not easy to remove, needs to be separated by column chromatography technology, is complicated to operate and needs a large amount of organic solvent. Therefore, the method has great difficulty in industrial production.

The route (1-2) has moderate length, easily obtained or synthesized raw materials, mild reaction conditions in each step and no need of special equipment; although the proportion of the N-7 isomer impurity can be reduced to some extent in this route compared with the route (1-1), the impurity still accounts for about 1/6 in the reaction liquid.

In the second category, famciclovir is synthesized by starting with a pyrimidine ring with different substituents, then introducing an alkane side chain at a specific position, and finally closing the ring. As shown in WO2004/110343, US5917041, CN 101555249B, CN 102924455A and the like, the related synthetic routes are as follows:

in the route (2-1), 5-nitrouracil is used as a raw material, and 6 steps of chlorination, N-alkylation, ammonolysis, reduction, ring closing, halogenation and the like are sequentially carried out to prepare 2-amino-9-bromoethyl purine, so that a 9-bit purine substitution product can be generated in a positioned manner, and the generation of an N-7-bit isomer is avoided. Thus, the patent reports a better process for the preparation of famciclovir. However, the patent has long reaction steps and the total yield is 8 percent.

In the 6 th bromination reaction, expensive carbon tetrabromide is used, and the 2-amino-9-bromoethyl purine is unstable and can be condensed by itself (as shown in the formula), so that the purity of the product is reduced.

The route (2-2) takes 2-amino-4, 6-dichloropyrimidine as a raw material, and the famciclovir is synthesized by 6 steps of reactions such as N-alkylation, esterification, diazotization, hydrogenation, ring closure, dechlorination and the like in sequence. The route has longer steps, wherein the material price of the 2-amino-4, 6-dichloropyrimidine is higher; the p-chloroaniline diazonium salt needs to be prepared in situ, has poor stability and safety, and can increase the material cost of a route by using the diazonium salt.

In conclusion, the existing first-class route has the inevitable defects of poor selectivity of N-alkylation reaction and generation of more N-7 site isomer impurities, and column chromatography or additional purification operation is often needed to ensure that the quality of a final product is not influenced in order to remove the impurities, so that the problems of yield reduction, cost increase, complex operation and the like are inevitably caused, and the industrial production is not facilitated. Although the second route can avoid the generation of N-7 isomer impurities, the route (2-1) has the defects of long steps, low yield, high price of carbon tetrabromide and unstable intermediate 2-amino-9-bromoethyl purine; the route (2-2) has the defects of longer steps, higher material price of the material 2-amino-4, 6-dichloropyrimidine, existing preparation of the p-chloroaniline diazonium salt, potential safety hazard and the like.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: based on the problems in the route, the preparation method of famciclovir is provided to solve the problems in the route that the selectivity of N-alkylation reaction is poor, reaction intermediates need extra purification, the process operation is complicated, the intermediates are unstable, the use of diazonium salt has potential safety hazard and the production cost of products is high.

Technical scheme

The technical scheme of the invention is as follows: a preparation method of famciclovir comprises the steps of taking guanidine nitrate and diethyl malonate as raw materials, performing ring closure reaction under alkaline conditions to obtain 2-amino-4, 6-pyrimidinediol, performing hydroxyl chlorination to obtain 2-amino-4, 6-dichloropyrimidine, and reacting with 2- (2, 2-dimethyl-1, 3-dioxane-5-yl) ethyl-1-amine to generate 6-chloro-substituted benzeneN⁴- (2- (2, 2-dimethyl-1, 3-dioxane-5-yl) ethyl) pyrimidine-2, 4-diamine, then reacting with sodium nitrite under an acidic condition to obtain 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidine-4-yl) amino) ethyl) propane-1, 3-diol, and finally synthesizing reduction/dechlorination, ring closing and esterification by using a one-pot method to obtain famciclovir. The synthetic route of the technical scheme is as follows:

the preparation method of famciclovir comprises the following steps:

first step preparation of 2-amino-4, 6-pyrimidinediol, a compound of formula 5:

taking guanidine nitrate and diethyl malonate as initial raw materials shown in formula 6, heating, dehydrating and ring-closing in an alcohol solution of organic base to synthesize 2-amino-4, 6-pyrimidinediol, decompressing and concentrating after the reaction is finished, adding water into the residue to dissolve, and then acidifying by using a dilute hydrochloric acid solution to obtain the compound shown in formula 5. Wherein the feeding molar ratio of guanidine nitrate, diethyl malonate and organic alkali is 1: 1-1.2: 2-3, preferably 1: 1.04: 2.5; the reaction temperature is 60-100 ℃, and preferably 60-80 ℃; the organic base is selected from common strong bases such as sodium methoxide, sodium ethoxide and the like; the alcohol solution is C1-C4 alcohol, and is specifically selected from methanol, ethanol, tert-butyl alcohol and the like; the reaction time is 0.5-12 h; the acidification endpoint was pH = 6.

The second step is 2-amino-4, 6-dichloropyrimidine preparation:

mixing 2-amino-4, 6-pyrimidinediol with a chlorinating reagent to prepare a compound 2-amino-4, 6-dichloropyrimidine shown in a formula 4, taking a solution with a volume ratio of dichloromethane to methanol of 10:1 as a developing agent, pouring a reaction solution into ice water for quenching after detecting that no 2-amino-4, 6-dichloropyrimidine remains as a raw material by a TLC (thin-layer chromatography) method, and separating out a solid product. The chlorination reagent is selected from thionyl chloride, phosphorus oxychloride and the like, and the dosage of the chlorination reagent is 1-5 times of the molar weight of the 2-amino-4, 6-pyrimidinediol; the reaction solvent is selected from aprotic solvents such as 1, 2-dichloroethane or no solvent; the reaction temperature is 60-100 ℃, and preferably 70-90 ℃; when the product is filtered, the filter cake is sufficiently washed so as not to influence the quality of the product during drying and the next reaction, and the pH value of the effluent is preferably 7.

The third step of 6-chloro-N⁴Preparation of- (2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine:

the compound 6-chloro-substituted pyridine of the formula 3 is prepared by taking 2-amino-4, 6-dichloropyrimidine and 2- (2, 2-dimethyl-1, 3-dioxane-5-yl) ethyl-1-amine as raw materials in the presence of an acid-binding agentN⁴- (2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine. Wherein the feeding molar ratio of the 2-amino-4, 6-dichloropyrimidine to the 2- (2, 2-dimethyl-1, 3-dioxane-5-yl) ethyl-1-amine is 1: 1-2, preferably 1:1 to 1.1; the acid-binding agent is selected from inorganic bases such as sodium carbonate and potassium carbonate, and the feeding molar quantity of the acid-binding agent is usually 1-2 times of that of 2-amino-4, 6-dichloropyrimidine; the reaction solvent is selected from polar aprotic solvents such as acetonitrile, N-dimethylformamide and the like; the reaction temperature is 60-100 ℃, and preferably 70-90 ℃; the reaction time is 18-22 h.

Fourth step preparation of 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol:

the acidic reagent is mixed with 6-chloro-N⁴Crude 2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine is thoroughly mixed with stirring, followed by the addition of sodium nitrite solution to prepare the compound of formula 2,2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol. Wherein the feeding amount of the sodium nitrite is 6-chlorine-N⁴1 to 3 times, preferably 1 to 2 times, the molar amount of the- (2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine; the acid reagent is selected from organic acids such as formic acid, glacial acetic acid and the like or inorganic acids such as diluted hydrochloric acid, diluted nitric acid and the like, and the molar amount of the acid reagent is the raw material 6-chloro-N⁴3 to 4 times the molar amount of the- (2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine; the reaction temperature is 60-100 ℃, and the preferable temperature is 60-80 ℃; the reaction time is 1-5 h.

Fifth step preparation of famciclovir, the compound of formula 1:

the reaction of the step is carried out in three stages:

in the first stage, 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidine-4-yl) amino) ethyl) propane-1, 3-diol is used as a raw material, ethyl acetate is used as a solvent, and dechlorination and nitroso reduction are completed under the action of an ammonium formate/palladium carbon system; after detecting that no raw material 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol remains by TLC (dichloromethane/methanol =4:1, V/V), filtering out palladium carbon and ammonium salt, drying the filtrate, filtering out solid again, and keeping the filtrate;

the feeding amount of the ammonium formate is 4-10 times, preferably 5-6 times of the molar amount of the raw material glycol; the specification of the palladium-carbon is selected from different models such as 3%, 5%, 10% and the like, preferably 5%, and the feeding amount of the palladium-carbon is 0.05-0.1 time of the mass of the raw material 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol; the reaction temperature is 20-100 ℃, and preferably 60-80 ℃; (ii) a The drying agent is selected from conventional drying reagents such as anhydrous sodium sulfate, anhydrous magnesium sulfate and the like;

in the second stage, triethyl orthoformate and glacial acetic acid are added into the filtrate obtained in the first step for reaction, and the construction of purine rings is completed through ring closure;

the molar ratio of the raw material 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol to triethyl orthoformate and glacial acetic acid is 1: 1-1.5: 1 to 1.5; the reaction temperature is 0-50 ℃, and the preferable temperature is 25-35 ℃; the reaction time is 12-24 h;

and in the third stage, adding an excessive acid-binding agent into the reaction liquid in the second step, adding 4-dimethylaminopyridine and acetic anhydride, and carrying out esterification reaction to generate famciclovir.

The acid-binding agent is selected from organic bases such as triethylamine, pyridine and the like; in the stage, the feeding molar ratio of the raw material 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidine-4-yl) amino) ethyl) propane-1, 3-diol to the acid-binding agent, 4-dimethylaminopyridine and acetic anhydride is 1: 3-6: 0.05-0.15: 5-8, preferably 1: 3-3.5: 0.05-0.1: 6; the reaction temperature is 10-40 ℃, and the preferable temperature is 20-30 ℃; the reaction temperature is 1-4 h.

The invention has the beneficial effects that the preparation method of famciclovir is provided, and the problems of poor selectivity of N-alkylation reaction, extra purification of reaction intermediates, complex process operation, unstable intermediates, potential safety hazard in use of diazonium salt, high production cost of products and the like which are commonly existed in the current route are solved. The method synthesizes famciclovir by taking guanidine nitrate and diethyl malonate as starting raw materials, has mild reaction conditions in each step, is safe and simple to operate, adopts large chemical products as materials and reagents required by the reaction, is easy to synthesize, has low production cost, and is convenient for industrial production.

In the technical scheme of the invention, the dihydroxyl of the alkane side chain (namely, 2- (2, 2-dimethyl-1, 3-dioxane-5-yl) ethyl-1-amine) in the reaction in the step 3 is protected by propylidene, so that the generation of a byproduct ether in the alkylation reaction can be avoided, and the selectivity and the atom economy of the reaction are improved; and the propylidene protection can be synchronously removed in the next nitrosation reaction without additional protection removal operation. In the reaction of the 4 th step, sodium nitrite is used as a raw material to introduce nitroso, so that the use of p-chloroaniline diazonium salt (which is prepared as before) in the route (2-4) is replaced. The sodium nitrite has the advantages of low price, stable property, high safety and the like, so that the reaction operation in the step is simple, and the introduction of impurities such as parachloroaniline and the like as by-products is avoided. Finally, a one-pot reaction is adopted, firstly, palladium carbon/ammonium formate is subjected to catalytic transfer hydrogenation to complete 6-chlorine removal and nitroso reduction, palladium carbon and ammonium salt are filtered out from reaction liquid, the reaction liquid is dried and then directly subjected to ring closure reaction with added triethyl orthoformate and glacial acetic acid to complete construction of an imidazole ring, then an appropriate amount of acid-binding agent such as triethylamine and acetic anhydride is added into the reaction liquid, and the reaction is continued to complete esterification of hydroxyl, so that famciclovir is finally prepared; the feeding and reaction mode can bring the greatest advantage to the simplicity of operation and is extremely suitable for industrial production.

Compared with other existing routes, the technical scheme has the advantages that: (1) the route completely avoids the generation of N-7 isomer impurities, and greatly improves the atom economy; (2) the materials used in each step of reaction are easy to obtain or prepare, the price is low, and the production cost of famciclovir is reduced; (3) the reaction conditions in each step are mild, the requirements on production equipment are not high, and the industrial production is facilitated; (4) in the fourth step, sodium nitrite is used for replacing diazonium salt to carry out nitrosation reaction, so that the safety coefficient is high; (5) and the fifth step adopts a one-pot method to telescope the multi-step reaction into one step, thereby simplifying the operation and shortening the production period of famciclovir.

The specific implementation mode is as follows:

for a better understanding of the present invention, reference will now be made to the following examples, which are set forth to illustrate, but are not to be construed as the limit of the present invention.

Example 1

First step, synthesis of 2-amino-4, 6-pyrimidinediol

Controlling the temperature to be 5 ℃, adding 30.52g (0.25 mol) of guanidine nitrate and 100ml of methanol into a 500ml four-mouth bottle, starting stirring, slowly dropping 250ml of 2.5M sodium methoxide methanol solution after the solid is completely dissolved, and keeping the temperature and stirring for 0.5 h; 41.64g (0.26 mol) of diethyl malonate was then slowly dropped into the reaction flask, and after dropping, the temperature was raised to reflux reaction for 6 hours. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a white solid. Adding 60ml of drinking water into a reaction bottle to dissolve solids, and adjusting the pH value of the system to 6 by using 10% dilute hydrochloric acid solution, so that a large amount of solids are separated out; suction filtration, leaching with drinking water, drying by pressing, and air-blast drying the wet cake at 60 ℃ to constant weight to obtain 29.74g of white-like product, wherein the yield of the step is 93.6%, and the HPLC purity is 99.2%.

Example 2

First step, synthesis of 2-amino-4, 6-pyrimidinediol

Controlling the temperature to be 5 ℃, putting 30.52g (0.25 mol) of guanidine nitrate and 100ml of absolute ethyl alcohol into a 500ml four-mouth bottle, starting stirring, slowly dropping 250ml of 2.5M sodium methoxide ethanol solution after the solid is completely dissolved, preserving the temperature and stirring for 0.5 h; 41.64g (0.26 mol) of diethyl malonate was then slowly dropped into the reaction flask, and after dropping, the temperature was raised to 65 ℃ to react for 6 hours. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a white solid. Adding 60ml of drinking water into a reaction bottle to dissolve solids, and adjusting the pH value of the system to 6 by using 10% dilute hydrochloric acid solution, so that a large amount of solids are separated out; and (3) carrying out suction filtration, leaching with drinking water, drying by pressing, and carrying out forced air drying on the wet cake at 60 ℃ to constant weight to obtain 30.56g of white-like product, wherein the yield of the step is 96.10%, and the HPLC purity is 99.7%.

Example 3

First step, synthesis of 2-amino-4, 6-pyrimidinediol

Controlling the temperature to be 5 ℃, adding 30.52g (0.25 mol) of guanidine nitrate and 100ml of absolute ethyl alcohol into a 500ml four-mouth bottle, starting stirring, slowly dropping 250ml of 2.5M ethanol solution of sodium ethoxide after all solids are dissolved, and keeping the temperature and stirring for 0.5 h; 41.64g (0.26 mol) of diethyl malonate was then slowly dropped into the reaction flask, and after the dropping, the temperature was raised to reflux reaction for 4 hours. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a white solid. Adding 60ml of drinking water into a reaction bottle to dissolve solids, and adjusting the pH value of the system to 6 by using 10% dilute hydrochloric acid solution, so that a large amount of solids are separated out; suction filtration, leaching with drinking water, drying by pressing, and air-blast drying the wet cake at 60 ℃ to constant weight to obtain 28.78g of white-like product, wherein the yield of the step is 90.59%, and the HPLC purity is 99.7%.

Example 4

Second step, synthesis of 2-amino-4, 6-dichloropyrimidine

28.00g (0.22 mol) of 2-amino-4, 6-pyrimidinediol and 80ml (1.1 mol) of thionyl chloride are put into a 250ml four-necked flask at room temperature, and the temperature is raised until reflux reaction is carried out for 4 hours. After the reaction is finished, the heating is closed, the temperature is reduced to room temperature, and then the reaction liquid is slowly poured into ice water for quenching. At this time, a large amount of solid is separated out, the filtration is carried out, and the filter cake is rinsed by drinking water until the pH value is 7. The wet cake was air-dried at 60 ℃ to constant weight to give 33.45g of pale yellow product, 92.7% yield and 99.1% purity by HPLC.

Example 5

Second step, synthesis of 2-amino-4, 6-dichloropyrimidine

28.00g (0.22 mol) of 2-amino-4, 6-pyrimidinediol and 80ml (0.86 mol) of phosphorus oxychloride are put into a 250ml four-mouth bottle at room temperature, and the temperature is increased to 80 ℃ for reaction for 4 hours. After the reaction is finished, the heating is closed, the temperature is reduced to room temperature, and then the reaction liquid is slowly poured into ice water for quenching. At this time, a large amount of solid is separated out, the filtration is carried out, and the filter cake is rinsed by drinking water until the pH value is 7. The wet cake was air dried at 60 ℃ to constant weight to give 32.66g of pale yellow product, 90.5% yield and 88.9% purity by HPLC.

Example 6

Second step, synthesis of 2-amino-4, 6-dichloropyrimidine

28.00g (0.22 mol) of 2-amino-4, 6-pyrimidinediol, 100ml of 1, 2-dichloroethane and 20ml (0.28 mol) of phosphorus oxychloride are put into a 250ml four-mouth bottle at room temperature, and the temperature is increased until the reflux reaction is carried out for 6 hours. After the reaction is finished, the heating is closed, the temperature is reduced to room temperature, and then the reaction liquid is slowly poured into ice water for quenching. At this time, a large amount of solid is separated out, the filtration is carried out, and the filter cake is rinsed by drinking water until the pH value is 7. The wet cake was air-dried at 60 ℃ to constant weight to give 32.98g of pale yellow product, 91.4% yield and 99.3% purity by HPLC.

Example 7

The third step, 6-chloro-N⁴Synthesis of- (2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine

29.51g (0.18 mol) of 2-amino-4, 6-dichloropyrimidine, 37.32g (0.27 mol) of potassium carbonate, 30.25g (0.19 mol) of 2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl-1-amine and 600ml of DMF were put into a 1000ml four-necked flask at room temperature, stirred, heated to 80 ℃ and reacted for 18 hours while maintaining the temperature. And (3) after the reaction is finished, closing heating, cooling to room temperature, performing suction filtration, and performing reduced pressure concentration to remove DMF (dimethyl formamide) to obtain brown yellow thick oil, wherein the yield of the step is 100%, and the next step of reaction is directly carried out.

Example 8

29.51g (0.18 mol) of 2-amino-4, 6-dichloropyrimidine, 37.32g (0.27 mol) of potassium carbonate, 30.25g (0.19 mol) of 2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl-1-amine and 600ml of acetonitrile were put into a 1000ml four-necked flask at room temperature, stirred, heated to reflux and reacted for 20 hours while maintaining the temperature. And after the reaction is finished, closing heating, cooling to room temperature, performing suction filtration, and performing reduced pressure concentration to remove acetonitrile to obtain brown yellow thick oil, wherein the yield of the step is 100 percent, and the step is directly put into the next step for reaction.

Example 9

29.51g (0.18 mol) of 2-amino-4, 6-dichloropyrimidine, 28.62g (0.27 mol) of sodium carbonate, 30.25g (0.19 mol) of 2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl-1-amine and 600ml of DMF were put into a 1000ml four-necked flask at room temperature, stirred, heated to 80 ℃ and reacted for 22 hours while maintaining the temperature. And (3) after the reaction is finished, closing heating, cooling to room temperature, performing suction filtration, and performing reduced pressure concentration to remove DMF (dimethyl formamide) to obtain brown yellow thick oil, wherein the yield of the step is 100%, and the next step of reaction is directly carried out.

Example 10

Fourth step, Synthesis of 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol

Controlling the temperature at 0 ℃ to react with 6-chlorine-N⁴- (2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine (0.18 mol) and 150ml of 25% glacial acetic acid solution are sequentially put into a 500ml four-mouth bottle, stirred and mixed uniformly, then 100ml of 25% sodium nitrite aqueous solution (0.36 mol) is slowly dripped, and the temperature is raised to 80 ℃ for reaction for 1h after dripping. After the reaction is finished, cooling the reaction solution to 0 ℃, adjusting the pH to be =7 by using a 10% sodium hydroxide solution, performing reduced pressure concentration until no flowing liquid exists, repeatedly extracting the product for 2 times by using 150ml of n-butyl alcohol, and combining organic phases; drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness to obtain orange thick oil, which is crude product of 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidine-4-yl) amino) ethyl) propane-1, 3-diol.

Adding 100ml of acetone into the crude product, pulping at 25 ℃ for 3h, then performing suction filtration and pressure drying, placing at 40 ℃ and drying under reduced pressure to constant weight to obtain 45.17g of orange-colored product, wherein the combined yield of the two steps is 91.12%, and the HPLC purity is 98.6%.

Example 11

Controlling the temperature at 0 ℃ to react with 6-chlorine-N⁴- (2- (2, 2-dimethyl-1, 3)-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine (0.18 mol) and 230ml of 10% diluted hydrochloric acid solution are sequentially put into a 500ml four-neck flask, stirred and mixed uniformly, then 100ml of 25% sodium nitrite aqueous solution (0.36 mol) is slowly dripped, and after dripping is finished, the temperature is controlled at 60 ℃ for reaction for 3 hours. After the reaction is finished, cooling the reaction solution to 0 ℃, adjusting the pH to be =7 by using a 10% sodium hydroxide solution, performing reduced pressure concentration until no flowing liquid exists, repeatedly extracting the product for 2 times by using 150ml of n-butyl alcohol, and combining organic phases; drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness to obtain orange thick oil, which is crude product of 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidine-4-yl) amino) ethyl) propane-1, 3-diol.

Adding 100ml of acetone into the crude product, pulping at 25 ℃ for 3h, then performing suction filtration and pressure drying, placing at 40 ℃ and drying under reduced pressure to constant weight to obtain 44.82g of orange-colored product, wherein the combined yield of the two steps is 90.38%, and the HPLC purity is 98.3%.

Example 12

Controlling the temperature at 0 ℃ to react with 6-chlorine-N⁴- (2- (2, 2-dimethyl-1, 3-dioxane-5-yl) ethyl) pyrimidine-2, 4-diamine (0.18 mol) and 230ml of 10% dilute nitric acid solution are sequentially put into a 500ml four-mouth bottle, stirred and mixed uniformly, then 100ml (0.36 mol) of 25% sodium nitrite aqueous solution is slowly dripped, and the temperature is controlled at 60 ℃ for reaction for 3 hours after dripping. After the reaction is finished, cooling the reaction solution to 0 ℃, adjusting the pH to be =7 by using a 10% sodium hydroxide solution, performing reduced pressure concentration until no flowing liquid exists, repeatedly extracting the product for 2 times by using 150ml of n-butyl alcohol, and combining organic phases; drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness to obtain orange thick oil, which is crude product of 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidine-4-yl) amino) ethyl) propane-1, 3-diol.

Adding 100ml of acetone into the crude product, pulping at 25 ℃ for 3h, then performing suction filtration and pressure drying, placing at 40 ℃ and drying under reduced pressure to constant weight to obtain 44.96g of orange-colored product, wherein the combined yield of the two steps is 90.66%, and the HPLC purity is 98.2%.

Example 13

Fifth step, Synthesis of famciclovir

Putting 35.00g of 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol (0.13 mol), 350.00g of ethyl acetate, 49.16g (0.78 mol) of ammonium formate and 3.50g of 5% palladium-carbon into a four-mouth reaction bottle, heating to 65 ℃, and carrying out heat preservation reaction for 22 hours; after the reaction, the solution was filtered, and then 20.00g of anhydrous sodium sulfate was added to the mother liquor, stirred for 0.5h, and the mother liquor was retained after the filtration. 22.23g (0.15 mol) of triethyl orthoformate and 9.00g (0.15 mol) of glacial acetic acid are added into the mother liquor, and the mixture is reacted for 20 hours at the temperature of 30 ℃; and after the reaction is finished, adding 43.51g (0.43 mol) of triethylamine and 1.47g (0.012 mol) of DMAP into a reaction bottle, controlling the temperature to be 30 ℃, dropwise adding 79.64g (0.78 mol) of acetic anhydride, continuously reacting for 1.5h after the dropwise adding is finished, continuously quenching for 1h after the pH value is regulated to be =7 by 10% sodium carbonate solution, standing and separating at 25 ℃, keeping an ethyl acetate phase, and concentrating under reduced pressure to obtain an off-white solid, so that 38.02g of crude famciclovir is obtained, wherein the yield of the step is 91.01%.

Adding 60.00g of n-butanol into the crude product, heating to reflux, slowly cooling and crystallizing after the solid is completely dissolved, growing crystals for 2 hours at 25 ℃, carrying out suction filtration, drying by pressing, placing the wet product at 60 ℃ and carrying out forced air drying to constant weight to obtain 34.96g of white crystalline powder, wherein the yield of the step is 92.12%, and the quality of the finished product meets the USP quality standard.

Example 14

Fifth step, Synthesis of famciclovir

Putting 35.00g of 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol (0.13 mol), 350.00g of ethyl acetate, 49.16g (0.78 mol) of ammonium formate and 1.75g of 10% palladium-carbon into a four-mouth reaction bottle, heating to 65 ℃, and carrying out heat preservation reaction for 12 hours; after the reaction, the solution was filtered, and then 20.00g of anhydrous sodium sulfate was added to the mother liquor, stirred for 0.5h, and the mother liquor was retained after the filtration. 22.23g (0.15 mol) of triethyl orthoformate and 9.00g (0.15 mol) of glacial acetic acid are added into the mother liquor, and the mixture is reacted for 20 hours at the temperature of 30 ℃; and after the reaction is finished, adding 43.51g (0.43 mol) of triethylamine and 1.47g (0.012 mol) of DMAP into a reaction bottle, controlling the temperature to be 25 ℃, dropwise adding 79.64g (0.78 mol) of acetic anhydride, continuously reacting for 2h after dropwise adding, continuously quenching for 1h after adjusting the pH to be =7 by using a 10% sodium carbonate solution, standing and separating at 25 ℃, keeping an ethyl acetate phase, and concentrating under reduced pressure to obtain a white-like solid, thus obtaining 38.51g of crude famciclovir, wherein the yield of the step is 92.23%.

Adding 60.00g of n-butanol into the crude product, heating to reflux, slowly cooling and crystallizing after the solid is completely dissolved, growing the crystals for 2 hours at 25 ℃, filtering, pressing to dry, placing the wet product at 60 ℃ and drying by air blast until the weight is constant to obtain 34.67g of white crystal powder, wherein the yield in the step is 90.02%, and the quality of the finished product meets the USP quality standard.

Example 15

Fifth step, Synthesis of famciclovir

Putting 35.00g of 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol (0.13 mol), 350.00g of ethyl acetate, 49.16g (0.78 mol) of ammonium formate and 3.50g of 10% palladium-carbon into a four-mouth reaction bottle, heating to 65 ℃, and carrying out heat preservation reaction for 5 hours; after the reaction, the reaction solution was filtered, and then 20.00g of anhydrous magnesium sulfate was added to the mother solution, followed by stirring for 0.5 hour, and the mother solution was again filtered and retained. 22.23g (0.15 mol) of triethyl orthoformate and 9.00g (0.15 mol) of glacial acetic acid are added into the mother liquor, and the mixture is reacted for 20 hours at the temperature of 30 ℃; and after the reaction is finished, adding 34.00g (0.43 mol) of pyridine and 1.47g (0.012 mol) of DMAP (dimethyl methylacetate) into a reaction bottle, controlling the temperature to be 20 ℃, dropwise adding 79.64g (0.78 mol) of acetic anhydride, continuously reacting for 2.5h after finishing dropwise adding, continuously quenching for 1h after adjusting the pH to be =7 by using 10% sodium carbonate solution, standing and separating at 25 ℃, keeping an ethyl acetate phase, and concentrating under reduced pressure to obtain an off-white solid to obtain 39.38g of crude famciclovir, wherein the yield of the step is 94.32%.

Adding 60.00g of n-butanol into the crude product, heating to reflux, slowly cooling and crystallizing after the solid is completely dissolved, growing the crystals for 2 hours at 25 ℃, performing suction filtration, drying by pressing, placing the wet product at 60 ℃ and drying by air blasting until the weight is constant to obtain 35.73g of white crystal powder, wherein the yield in the step is 90.73%, and the quality of the finished product meets the USP quality standard.

Claims

1. A method for preparing famciclovir, which is characterized by comprising the following steps:

first step preparation of 2-amino-4, 6-pyrimidinediol, a compound of formula (5):

taking guanidine nitrate and diethyl malonate in a formula (6) as starting materials, heating, dehydrating and ring-closing to synthesize 2-amino-4, 6-pyrimidinediol in an alcohol solution of organic base, concentrating under reduced pressure after the reaction is finished, adding water to the residue to dissolve the residue, and then acidifying the reaction solution with dilute hydrochloric acid to obtain a compound in a formula (5), wherein the organic base is selected from sodium methoxide and sodium ethoxide, the alcohol solution is a solution of C1-C4 alcohol, the reaction temperature is 60-100 ℃, and the feeding molar ratio of the guanidine nitrate to the diethyl malonate to the organic base is 1: 1-1.2: 2-3;

the second step is 2-amino-4, 6-dichloropyrimidine preparation:

mixing 2-amino-4, 6-pyrimidinediol with a chlorinating agent to prepare a compound 2-amino-4, 6-dichloropyrimidine shown as a formula (4), taking a mixed solvent with a volume ratio of dichloromethane to methanol of 10:1 as a developing agent, pouring a reaction liquid into ice water for quenching after detecting that no 2-amino-4, 6-dichloropyrimidine remains as a raw material by a TLC method, and precipitating a solid product, wherein the chlorinating agent is selected from thionyl chloride and phosphorus oxychloride, and the reaction solvent is selected from an aprotic solvent or no solvent; the reaction temperature is 60-100 ℃;

preparing a compound 6-chloro-substituted benzene of a formula (3) by taking 2-amino-4, 6-dichloropyrimidine and 2- (2, 2-dimethyl-1, 3-dioxane-5-yl) ethyl-1-amine as raw materials in the presence of an acid-binding agentN⁴- (2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine, in whichThe feeding molar ratio of the 2-amino-4, 6-dichloropyrimidine to the 2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl-1-amine is 1: 1-2, wherein the acid-binding agent is selected from sodium carbonate and potassium carbonate, the feeding molar weight of the acid-binding agent is 1-2 times of that of 2-amino-4, 6-dichloropyrimidine, the reaction solvent is selected from acetonitrile and N, N-dimethylformamide, and the reaction temperature is 60-100 ℃;

fourth step preparation of 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol, a compound of formula (2):

the acidic reagent is mixed with 6-chloro-N⁴The crude 2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine is thoroughly mixed with stirring and subsequently a solution of sodium nitrite is added to prepare the compound 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol of formula (2), wherein the amount of sodium nitrite charged is 6-chloro-N⁴1 to 3 times of the molar amount of the- (2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl) pyrimidine-2, 4-diamine, wherein the acidic reagent is selected from formic acid, glacial acetic acid or dilute hydrochloric acid, and dilute nitric acid, and the molar amount of the acidic reagent is the raw material 6-chloro-N⁴3 to 4 times of the molar weight of the- (2- (2, 2-dimethyl-1, 3-dioxane-5-yl) ethyl) pyrimidine-2, 4-diamine, the reaction temperature is 60 to 100 ℃, and the reaction time is 1 to 5 hours;

fifth step preparation of famciclovir, a compound of formula (1):

the reaction of the step is carried out in three stages:

in the first stage, 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidine-4-yl) amino) ethyl) propane-1, 3-diol is used as a raw material, ethyl acetate is used as a solvent, and dechlorination and nitroso reduction are completed under the action of an ammonium formate/palladium carbon system; taking a mixed solvent with the volume ratio of dichloromethane to methanol being 4:1 as a developing solvent, filtering palladium carbon and ammonium salt after detecting that no raw material 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidine-4-yl) amino) ethyl) propane-1, 3-diol remains by a TLC method, drying the filtrate, filtering solids again, and keeping the filtrate;

the feeding amount of ammonium formate is 4-10 times of the molar amount of the raw material 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol, and the feeding amount of palladium carbon is 0.05-0.1 time of the mass of the raw material 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol; the reaction temperature is 60-80 ℃; the drying agent is selected from anhydrous sodium sulfate and anhydrous magnesium sulfate;

the molar ratio of the raw material 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol to triethyl orthoformate and glacial acetic acid is 1: 1-1.5: 1 to 1.5; the reaction temperature is 25-35 ℃;

and in the third stage, adding an excessive acid-binding agent into the reaction liquid in the second step, adding 4-dimethylaminopyridine and acetic anhydride, and performing esterification reaction to generate famciclovir, wherein the acid-binding agent is selected from triethylamine and pyridine, and the feeding molar ratio of the raw material 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidine-4-yl) amino) ethyl) propane-1, 3-diol to the acid-binding agent, 4-dimethylaminopyridine and acetic anhydride is 1: 3-3.5: 0.05-0.1: 6; the reaction temperature is 20-30 ℃.

2. The method for preparing famciclovir according to claim 1, wherein the molar ratio of guanidine nitrate, diethyl malonate and organic base in the first step is 1: 1.04: 2.5.

3. the method for preparing famciclovir according to claim 1, wherein the reaction temperature in the first step is 60-80 ℃, after the reaction is completed, the reaction solution is concentrated under reduced pressure, water is added into the residue for dissolution, and then the reaction solution is acidified by dilute hydrochloric acid to have pH = 6.

4. The method of claim 1, wherein the alcohol in the first step is selected from the group consisting of methanol, ethanol, and t-butanol.

5. The preparation method of famciclovir according to claim 1, wherein the amount of the second chlorinating agent is 1-5 times of the molar amount of 2-amino-4, 6-pyrimidinediol.

6. The method of claim 1, wherein the solvent for the second step is selected from 1, 2-dichloroethane, and the reaction temperature is selected from 70-90 ℃.

7. The method of claim 1, wherein the molar ratio of 2-amino-4, 6-dichloropyrimidine to 2- (2, 2-dimethyl-1, 3-dioxan-5-yl) ethyl-1-amine fed in the third step is 1:1 to 1.1.

8. The preparation method of famciclovir according to claim 1, wherein the third reaction temperature is 70-90 ℃.

9. The method of claim 1, wherein the ammonium formate is fed in the first stage of the fifth step in an amount of 5 to 6 times the molar amount of the raw material 2- (2- ((2-amino-6-chloro-5-nitrosopyrimidin-4-yl) amino) ethyl) propane-1, 3-diol.