CN101812089A

CN101812089A - Adefovir dipivoxil compound and novel preparation method thereof

Info

Publication number: CN101812089A
Application number: CN 201010140637
Authority: CN
Inventors: 陶灵刚
Original assignee: 陶灵刚
Current assignee: Hainan Yongtian Pharmaceutical Institute Co., Ltd.
Priority date: 2010-04-07
Filing date: 2010-04-07
Publication date: 2010-08-25
Anticipated expiration: 2030-04-07
Also published as: CN101812089B

Abstract

The invention aims to provide an adefovir dipivoxil compound and a novel preparation method thereof; the method specifically comprises the following steps that: (2-p-toluenesulfonyloxy ethoxy) diethyl methylphosphonate is hydrolyzed at low temperature, to prepare (2-p-toluenesulfonyloxy ethoxy) methyl phosphonic acid; chloro methyl pivalate is added in to react and prepare an intermediate body (II) under the action of triethylamine; and adenine and the intermediate body (II) react to prepare adefovir dipivoxil under the catalysis of anhydrous potassium carbonate. The invention reduces the introduction of impurities, improves the purity, and lays foundation for industrial production.

Description

A kind of adefovir dipivoxil compound and new preparation method thereof

Technical field

The present invention relates to a kind of adefovir dipivoxil compound, belong to medical technical field.

Background technology

Adefovir ester, chemistry is by name: two (the pivalyl oxygen methoxyl group) phosphatidyl methoxies of 9-[2-[] ethyl] VITAMIN B4, molecular formula C ₂₀H ₃₂N ₅O ₈P, molecular weight 501.47, its structural formula is:

Adefovir is a kind of acyclic nucleotide analogue of single adenosine phosphate, and being phosphorylated to activated meta-bolites under the effect of cell kinase is the Adefovir diphosphate.The Adefovir diphosphate suppresses HBV DNA polymerase (reversed transcriptive enzyme) by following dual mode; The one, with the competition of natural substrate deoxyadenosine triphosphate, the 2nd, cause that the DNA chain extension stops after being incorporated into viral DNA.The Adefovir diphosphate is 0.1 μ M to the inhibition constant (Ki) of HBVDNA polymerase, but to the restraining effect of human DNA polymerase α and γ a little less than, the Ki value is respectively 1.18 μ M and 0.97 μ M.In people's hepatoma cell line of HBV transfected, the concentration (IC50) that Adefovir suppresses 50% viral dna replication is 0.2～2.5uM.Be applicable to that treatment hepatitis B virus active replication and serum amino acid transferring enzyme continue the compensatory adult chronic hepatitis B patient of liver function that raises.

The synthetic route bibliographical information of adefovir ester has a lot, but because selectivity is not strong, major part all is that the chloromethyl pivalate is introduced in final step, therefore 6 bit aminos of VITAMIN B4 also can be participated in reaction, introduced a lot of impurity, bring inconvenience to purification, influenced whole reaction yield simultaneously.The disclosed synthetic route of Chinese patent CN101134765A is:

Chinese patent CN101058588A discloses a kind of synthetic method of Adefovir, and synthetic route is:

The adefovir ester purity that above-mentioned patented method obtains is lower, and is difficult for purifying, and production cost is higher, is difficult for large-scale production.

Summary of the invention

The object of the present invention is to provide a kind of adefovir dipivoxil compound and synthetic method thereof, reduced the introducing of impurity, purity is higher, for suitability for industrialized production is laid a good foundation.

For achieving the above object, the technical scheme of the present invention's solution is as follows:

Adefovir dipivoxil compound and synthetic method thereof shown in a kind of formula (I),

Its synthesis step is:

(1), makes (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid with (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid diethyl ester hydrolysis at low temperatures;

(2) (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid and Chloro methyl pivalate are reacted generation intermediate (II) under the triethylamine effect;

(3) VITAMIN B4 and intermediate (II) react under Anhydrous potassium carbonate catalysis and generate adefovir ester;

In this manual, " low temperature " is meant below the room temperature, is preferably-10 ℃-10 ℃, more preferably about 0 ℃.

In this manual, " about " or " pact " be meant in the scope that those skilled in the art can select and judge according to general knowledge or universal experience, particularly described particular value ± 1 measure unit scope in.For example, be meant 4-6 hour about 5 hours, be meant-1 ℃-1 ℃ about 0 ℃.

As embodiment preferred of the present invention, step (1) concrete operations are: (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid diethyl ester and acetonitrile are mixed stirring, be cooled to 0 ℃, add bromotrimethylsilane again, adopt oil bath to be heated to reflux state, backflow 10-20 hour, preferred about 15 hours, evaporated under reduced pressure solvent then, in resistates, add entry, with sodium hydroxide solution conditioned reaction system pH is 7.5, uses ethyl acetate extraction 2-3 time again, and it is 3 that the water of merging is regulated the pH value with hydrochloric acid soln, and then use ethyl acetate extraction, use anhydrous sodium sulfate drying, the concentrating under reduced pressure solvent gets oily matter (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid to dry.

As embodiment preferred of the present invention, step (2) concrete operations are: (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid and DMF are mixed, drip triethylamine and Chloro methyl pivalate, stirring at room reaction about 24 hours leaches insolubles, in reactant, add entry then, with ethyl acetate extraction 2-3 time, merge organic phase, respectively water, the saturated sodium-chloride water solution washing, use anhydrous sodium sulfate drying, filter, the concentrating under reduced pressure solvent adds isopropyl ether to dry, stir, freezing, separate out solid, filter, 40 ℃ of following vacuum-dryings, get the off-white color product.

As embodiment preferred of the present invention, step (3) concrete operations are: VITAMIN B4 is suspended among the DMF, stir and add Anhydrous potassium carbonate down, reaction system is warming up to about 100 ℃, slowly add intermediate (II) then, continue stirring reaction then about 8 hours, after question response liquid is cooled to room temperature, the elimination solid, filtrate decompression is concentrated into drying, add acetone in the residue: the mixed solvent and the gac of sherwood oil (1/5v/v), reflux half an hour heat filtering, filtrate is cooled to room temperature, left standstill 12 hours, and filtered, get the adefovir ester product.

The inventor has selected above-mentioned new synthetic route through research in many ways, has effectively reduced the introducing of impurity, has improved degree of purity of production, for suitability for industrialized production is laid a good foundation.

Embodiment

Below further explain and describe content of the present invention by embodiment, but this embodiment is not to be construed as limiting the scope of the invention.

Synthesizing of embodiment 1 adefovir ester

(1) (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid diethyl ester and the 1500ml acetonitrile with 366g (1mol) joins in three mouthfuls of reaction flasks of 3L, mix, be cooled to 0 ℃, add 375ml (3mol) bromotrimethylsilane, adopt oil bath to be heated to reflux state then, refluxed 15 hours, evaporated under reduced pressure solvent then, the water that in resistates, adds 1000ml, with the pH=7.5 of the sodium hydroxide solution conditioned reaction system of 2mol/L, use the ethyl acetate extraction 2 times of 400ml respectively, water is regulated pH=3 with the 2mol/L hydrochloric acid soln, use the ethyl acetate extraction of 500ml then, use anhydrous sodium sulfate drying, the concentrating under reduced pressure solvent obtains oily matter (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid 276g to dry, it can be directly used in the next step, yield 89%.

(2) intermediate (II) is synthetic

In three mouthfuls of reaction flasks, add the DMF of 1000ml and (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid of 155g (0.5mol), drip the 140ml triethylamine and add 300g (2mol) Chloro methyl pivalate, stirring at room reaction 24 hours leaches insolubles, adds entry 2500ml then in reactant, use the 500ml ethyl acetate extraction respectively three times, merge organic phase, respectively water, the saturated sodium-chloride water solution washing is spent the night with anhydrous sodium sulfate drying, filter, the concentrating under reduced pressure solvent adds the 500ml isopropyl ether to dry, stirs, freezing, separate out solid, filter, 40 ℃ of following vacuum-dryings, get off-white color product 247g, yield 92%.

(3) adefovir ester is synthetic

In the there-necked flask of 1000ml, the VITAMIN B4 of 54g (0.4mol) is suspended among the DMF of 600ml, stir the Anhydrous potassium carbonate that adds 55.4g (0.4mol) down, reaction system is warming up to about 100 ℃, the intermediate (II) that slowly adds 214g (0.4mol) then adds the back and continued stirring reaction 8 hours, and question response liquid is cooled to room temperature, the elimination solid, filtrate decompression is concentrated dried, the acetone of adding 600ml in the residue: the mixed solvent of sherwood oil (1/5v/v) and gac 10g, reflux half an hour, heat filtering, filtrate is cooled to room temperature, leaves standstill 12 hours, filters, get adefovir ester product 152g, yield 72%.

Ultimate analysis (C ₂₀H ₃₂N ₅O ₈P)

Theoretical value: C:47.90%; H:6.43%; N:13.97%; O:25.52%; P:6.18%.

Measured value: C:47.58%; H:6.46%; N:13.99%; O:25.48%; P:6.30%.

IR(KBr，cm ^-1)：3367.22，3276.83，3121.46，2981.16，2935.11，2874.33，1758.20，1685.11，1605.40，1572.65，1481.47，1263.26，1136.18，1025.45，967.29。

¹H?NMR(CDCl ₃)δ：8.385(s，1H)，7.962(s，1H)，6.580(brs，2H)，5.705-5.655(m，4H)，4.405(t，J＝5.2Hz，2H)，3.966(t，J＝5.2Hz，2H)，3.880(d，J＝7.6Hz，2H)，1.215(s，18H)。

¹³C NMR (CDCl ₃) δ: 152.742 (1 CH), 149.715 (1 quaternary carbon), 119.248 (1 quaternary carbon), 155.821 (1 quaternary carbon), 141.085 (1 CH), 43.172 (1 CH ₂), 71.220 (d, J=9.5Hz, 1 CH ₂), 65.398 (d, J=165.7Hz, 1 CH ₂), 81.543 (d, J=6.4Hz, 2 CH ₂), 176.566 (2 quaternary carbons), 38.533 (2 quaternary carbons), 26.642 (6 CH ₃).

³¹P NMR (CDCl ₃) δ: 21.734 (1 P).

MS(EI，M+)：MS(ESI)，[M+1]+503，[M+K]+541，[2M+1]+1003，[2M+Na]+1025，[2M+K]+1040。

Should be understood that the synthetic method that the application provides is not limited thereto.Those skilled in the art can under spirit of the present invention instructs, for example select similar raw material according to content disclosed by the invention, change reaction conditions or time a little, and these selections and change are also within the scope of the invention.

Claims

1. the adefovir dipivoxil compound shown in the formula (I),

The steps include:

2. adefovir ester according to claim 1 and synthetic method thereof, it is characterized in that step (1) is: (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid diethyl ester and acetonitrile are mixed stirring, be cooled to 0 ℃, add bromotrimethylsilane again, adopt oil bath to be heated to reflux state, refluxed about 15 hours, evaporated under reduced pressure solvent then, in resistates, add entry, with sodium hydroxide solution conditioned reaction system pH is 7.5, use ethyl acetate extraction 2-3 time again, it is 3 that the water that merges is regulated the pH value with hydrochloric acid soln, and then uses ethyl acetate extraction, uses anhydrous sodium sulfate drying, the concentrating under reduced pressure solvent gets oily matter (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid to dry.

3. according to the synthetic method of the described adefovir ester of claim 1-2, it is characterized in that step (2) is: (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid and DMF are mixed, drip triethylamine and add Chloro methyl pivalate, stirring reaction leached insolubles about 24 hours under the room temperature, in reactant, add entry then, with ethyl acetate extraction 2-3 time, merge organic phase, respectively water, the saturated sodium-chloride water solution washing, use anhydrous sodium sulfate drying, filter, the concentrating under reduced pressure solvent adds isopropyl ether to dry, stir, freezing, separate out solid, filter, 40 ℃ of following vacuum-dryings, get the off-white color product.

4. according to the synthetic method of the described adefovir ester of claim 1-3, it is characterized in that step (3) is: VITAMIN B4 is suspended among the DMF, stir and add Anhydrous potassium carbonate down, reaction system is warming up to about 100 ℃, slowly adds intermediate (II) then, continue stirring reaction then about 8 hours, after question response liquid is cooled to room temperature, the elimination solid is concentrated into drying with filtrate decompression, adds acetone in the residue; The mixed solvent and the gac of sherwood oil (1/5v/v) reflux half an hour, heat filtering, and filtrate is cooled to room temperature, leaves standstill 12 hours, filters, and gets the adefovir ester product.