CN101139348A - Method for synthesizing 2-amido-6-chloropurine - Google Patents
Method for synthesizing 2-amido-6-chloropurine Download PDFInfo
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Abstract
The present invention relates to a synthesis method of the 2-amino-6-chlorine purine (1), orderly comprising the following steps: the N, N-dimethylformamide is first added in the phosphorus oxychloride at a low temperature to prepare the mixture solution; then the 1, 2-dichloromethane of the guanine (2) is dropped to react to get the 2-dimethylamino-ene imino-6-chlorine purine (3); the product (3) is dropped into the water; the organic phase is separated and recycled for reuse; the alkali metal hydroxide solution is used for adjusting the pH value of the water phase to be between 3 and 5; the 2- formamide-6-chlorine purine (4) wet material is produced after heating; the product (4) wet material is done with the hydrolysis reaction in the alkali metal hydroxide solution; then the hydrochloric acid is used for adjusting the pH value to get the crude material of the 2-amino-6-chlorine purine (1); finally the fine target product (1) can be got through purification.
Description
Technical field
The present invention relates to the synthetic method of 2-amino-6-chloropurine, 2-amino-6-chloropurine is synthetic antiviral " Famciclovir " important intermediate (Famciclovir), and can be used for the synthetic of anticancer, anti-inflammatory and medicine such as hypotensive.
Background technology
The English name of " Famciclovir " is Famciclovir, its chemical name is 2-[2-(2-amino-9H-purine-9-yl) ethyl]-1, ammediol-diethyl ester is a kind of anti-herpesvirus medicine of high-efficiency low-toxicity, is mainly used in the treatment of zoster and genital herpes.Its structural formula is as follows:
And 2-amino-6-chloropurine is a kind of very important medicine intermediate of synthetic " Famciclovir ".The synthetic route of 2-amino-6-chloropurine is a lot, now disclosed synthetic route is listed below:
One, guanine direct chlorination method
Patent WO93/15075 openly reports, adopt guanine and phosphorus oxychloride under the phase-transfer catalyst tetramethyl ammonium chloride direct chlorination again hydrolysis make 2-amino-6-chloropurine, this route makes product yield very low because of the guanine low-solubility, be about 30%～42%, and use the mass expensive phase-transfer catalyst, unsuitable suitability for industrialized production.
Two, with the pyrimidine derivatives be the synthetic route of raw material
Patent WO94/07892 report adopts 2,4,5-three ammonia-6-chloropyrimide and triethyl orthoformate prepared in reaction 2-amino-6-chloropurine, and yield is 60%70%, technology is simple, but generated time is longer, and preparing 2,4,5-triamino-6-chloropyrimide is difficulty very.
Three, guanine is earlier through amido protecting chlorination again
Patent WO93/15075 and EP0684243A1 report; acidylate in the presence of Glacial acetic acid makes 2 with guanine and acetic anhydride; the 9-diacetylguanine; react under phase-transfer catalyst with phosphoryl chloride behind the washing and drying; hydrolysis deacylated tRNA base makes 2-amino-6-chloropurine again; the yield of this synthetic route can reach 55%～75%, but will use expensive phase-transfer catalyst.
Patent EP0543095A2 report, by guanine and N, dinethylformamide gets 2-dimethylamino methylene imido grpup-6-chloropurine under the chlorizating agent effect, get 2-formamido group-6-chloropurine through acetolysis again, and alkaline hydrolysis then, ammoniacal liquor recrystallizing and refining get 2-amino-6-chloropurine.The total overall reaction process of this synthetic method is as follows:
This synthetic method is compared with aforementioned several synthetic methods, though technology is relatively reasonable, product yield is higher relatively, can reach 60%～70%, but still come with some shortcomings, as by guanine and N, dinethylformamide generates under the chlorizating agent effect in this step reaction of 2-dimethylamino methylene imido grpup-6-chloropurine, because the mode that adopts all raw materials to add together, be unfavorable for N on the one hand, the reaction earlier of dinethylformamide and phosphorus oxychloride generates the active intermediate of carbonium ion, participate in reaction following and guanine then, also cause between guanine and the chlorizating agent easily on the other hand side reaction takes place, thereby make that the product yield of this step reaction is not high, and finally have influence on the yield and the purity of target product 2-amino-6-chloropurine; And after this step reaction finishes,, need carry out post-processing operation such as adjusting of pH value and suction filtration to the reaction solution of this step reaction from reaction solution for intermediate product 2-dimethylamino methylene imino--6-chloropurine (3) is separated, technology compares more complicated; And because the material thickness, suction filtration is also very difficult.Therefore this synthetic method still has improved space.
Summary of the invention
The present invention is directed to the existing deficiency of above-mentioned EP0543095A2 patent, provide a kind of technology easier rationally, be more suitable in the synthetic method of the 2-of suitability for industrialized production amino-6-chloropurine.2-amino-the 6-chloropurine that adopts this synthetic method to obtain can be used as the intermediate of synthetic antiviral " Famciclovir ".
The technical scheme that realizes the object of the invention is: the synthetic method of a kind of 2-amino-6-chloropurine (1) in turn includes the following steps:
A) guanine (2) is joined 1, in the 2-methylene dichloride, in 20 ℃～30 ℃ N that drip phosphorus oxychloride down, dinethylformamide solution reacts, reaction generates 2-dimethylamino methylene imido grpup-6-chloropurine (3), and this intermediate product (3) need not to separate from reaction solution;
B) reaction solution of the above-mentioned 2-of containing dimethylamino methylene imido grpup-6-chloropurine (3) is splashed in the water that is not higher than 10 ℃ phosphorus oxychloride with decomposing excessive, isolate 1 then, 2-methylene dichloride organic phase, it is 3～5 that water is regulated the pH value with alkali hydroxide soln, reacting by heating gets the wet product of 2-formamido group-6-chloropurine (4);
C) the wet product of above-mentioned 2-formamido group-6-chloropurine (4) are hydrolyzed in alkali hydroxide soln earlier reaction, then with the salt acid for adjusting pH value to neutrality, get 2-amino-6-chloropurine (1) crude product.
D) above-mentioned 2-amino-6-chloropurine (1) crude product is carried out purifying, get 2-amino-6-chloropurine (1) elaboration.
The synthetic method of described 2-amino-6-chloropurine (1) is in step a), and the N of phosphorus oxychloride, dinethylformamide solution preferably are dissolved in N by phosphorus oxychloride in advance under 0 ℃～15 ℃ temperature, dinethylformamide and making.
The synthetic method of described 2-amino-6-chloropurine (1) in step a), the N of phosphorus oxychloride, dinethylformamide solution be in advance by phosphorus oxychloride particularly preferably in being dissolved in N under 0 ℃～10 ℃ the temperature, dinethylformamide and making.
The synthetic method of described 2-amino-6-chloropurine (1) is in step b) and step c), and described alkali hydroxide soln is preferably 5%～15% sodium hydroxide solution.
The synthetic method of described 2-amino-6-chloropurine (1) is in step b) and step c), and described alkali hydroxide soln is 10% sodium hydroxide solution more preferably.
The synthetic method of described 2-amino-6-chloropurine (1) is in step c), the first reaction that in 18 ℃～22 ℃ alkali hydroxide soln, is hydrolyzed of the wet product of described 2-formamido group-6-chloropurine (4), arrive neutrality with the salt acid for adjusting pH value then, get 2-amino-6-chloropurine (1) crude product.
The synthetic method of preferred described 2-amino-6-chloropurine (1) is in step c), the first reaction that in 18 ℃～22 ℃ alkali hydroxide soln, is hydrolyzed of the wet product of described 2-formamido group-6-chloropurine (4), be not higher than under 22 ℃ the condition with the salt acid for adjusting pH value to neutral then, 2-amino-6-chloropurine (1) crude product.
The synthetic method of more preferably described 2-amino-6-chloropurine (1) is in step c), the first reaction that in 18 ℃～℃ alkali hydroxide soln, is hydrolyzed of the wet product of described 2-formamido group-6-chloropurine (4), be not higher than under 10 ℃ the condition with the salt acid for adjusting pH value to neutral then, 2-amino-6-chloropurine (1) crude product.
The synthetic method of preferred described 2-amino-6-chloropurine (1) is in step d), and described 2-amino-6-chloropurine (1) crude product adopts N, and dinethylformamide carries out recrystallization purifying as solvent, gets 2-amino-6-chloropurine (1) elaboration.
In the step a) of above-mentioned 2-amino-6-chloropurine (1) synthetic method, the N of described phosphorus oxychloride, dinethylformamide solution is dissolved in N by phosphorus oxychloride in advance, dinethylformamide and making, help N like this, the reaction earlier of dinethylformamide and phosphorus oxychloride generates the active intermediate of carbonium ion, and then carries out next step reaction with guanine; Preferably under 0 ℃～15 ℃ temperature, be dissolved in N by phosphorus oxychloride in advance, dinethylformamide and making; Especially preferably under 0 ℃～10 ℃ temperature, be dissolved in N by phosphorus oxychloride in advance, dinethylformamide and making; Because under this low temperature, prepare, more help N, the reaction earlier of dinethylformamide and phosphorus oxychloride generates the active intermediate of carbonium ion, and then carry out next step reaction with guanine, otherwise, preparation temperature height is unfavorable for the generation of the active intermediate of carbonium ion, thereby is unfavorable for that also next step and guanine react.
In the step b) of above-mentioned 2-amino-6-chloropurine (1) synthetic method, with alkali hydroxide soln the pH value of water being adjusted to 3～5 so more rational pH value scopes is very crucial synthesis technologic parameters in this step reaction.Because the 2-dimethylamino methylene imido grpup in 2-dimethylamino methylene imido grpup-6-chloropurine (3) only could hydrolysis generate 2-formamido group-6-chloropurine (4) under acidic conditions; Acidity is big more, and hydrolysis is easy more; If acidity excessively a little less than, then the 2-dimethylamino methylene imido grpup in 2-dimethylamino methylene imido grpup-6-chloropurine (3) can not hydrolysis: but if acidity is strong excessively, 6-position chlorine in 2-dimethylamino methylene imido grpup-6-chloropurine (3) is also destroyed, will have by product and generate; Therefore, this step reaction pH value is selected with adjusting extremely important.
In the step b) and step c) of above-mentioned 2-amino-6-chloropurine (1) synthetic method, described alkali hydroxide soln preferably adopts 5%～15% sodium hydroxide solution; More preferably adopt 10% sodium hydroxide solution.Water can further reduce cost with sodium hydroxide solution neutralization cheap and easy to get, is more suitable in suitability for industrialized production.Certainly, in step b) and step c), described alkali hydroxide soln also can adopt potassium hydroxide solution, and only cost is higher slightly.
In the step c) of above-mentioned 2-amino-6-chloropurine (1) synthetic method, the first reaction that in alkali hydroxide soln, is hydrolyzed of the wet product of described 2-formamido group-6-chloropurine (4), hydrolysising reacting temperature is preferably at 18 ℃～22 ℃.Temperature height in strong alkali aqueous solution, though help the 2-formamido group--the 2-formamido group hydrolysis in the 6-chloropurine (4), but 6-position chlorine is wherein also wanted hydrolysis simultaneously, excessive hydrolysis and produce a large amount of guanines as a result, crude product purity influence to product is very big, so will rationally control hydrolysising reacting temperature.Hydrolysis reaction finishes, and the temperature during with the salt acid for adjusting pH value can be lower relatively than hydrolysising reacting temperature, is not higher than 22 ℃ and gets final product, and preferably be not higher than 10 ℃, and this temperature is low more, helps avoiding the hydrolysis of 6-position chlorine more.
In the step d) of above-mentioned 2-amino-6-chloropurine (1) synthetic method, described 2-amino-6-chloropurine (1) crude product preferably adopts N, and dinethylformamide carries out recrystallization purifying as solvent.Because guanine is insoluble to N, dinethylformamide is used N, and dinethylformamide carries out recrystallization as solvent, can obtain the high elaboration of purity, can guarantee that the purity of the elaboration that each batch obtains can reach more than 99%.Certainly, also can adopt disclosed purification process in the prior art, carry out purifying etc. as ammoniacal liquor recrystallization purifying or sodium hydroxide associating gac, but adopt the ammoniacal liquor recrystallization that 2-amino-6-chloropurine (1) crude product is carried out purification process, on the one hand owing to ammonia in the recrystallization liquid can not be discharged fully, cause 2-amino-6-chloropurine (1) from ammoniacal liquor, not separate out fully, thereby can have influence on yield; Also there is big, the high deficiency of environmental pollution on the other hand to equipment requirements; And adopt sodium hydroxide associating gac to carry out purifying, and because the guanine in the crude product is soluble in the alkali, then being difficult for removing the guanine in the crude product, can reach more than 99% so can't guarantee the purity of the elaboration that each batch obtains.
Total overall reaction formula of the present invention is as follows:
Technique effect of the present invention
Because the present invention is by guanine (2) and N, dinethylformamide prepares in the reaction of 2-dimethylamino methylene imido grpup-6-chloropurine (3), and the initial feeding mode that is adopted and the EP0543095A2 patent of disposable all raw materials of input are very different; The present invention is the N for preparing phosphorus oxychloride in advance, and dinethylformamide solution is added to this drips of solution 1 of guanine (2) then, reacts in the 2-dichloroethane solution; After improving like this, help N on the one hand, the reaction earlier of dinethylformamide and phosphorus oxychloride generates the active intermediate of carbonium ion, and then react with guanine, also avoided having higher yield thereby this step is reacted on the other hand because of directly phosphorus oxychloride being splashed in the reaction mixture, producing the shortcoming of side reaction easily with guanine.
And after this step reaction finishes, need not isolation of intermediate products 2-dimethylamino methylene imido grpup-6-chloropurine (3), just can " one kettle way " directly enter the reaction that next step prepares the wet product of 2-formamido group-6-chloropurine (4).Be that reaction solution directly splashes in the water that is not higher than 10 ℃ and decomposes phosphorus oxychloride; The organic phase Separation and Recovery is utilized, and the water that contains intermediate product (3) adopts a direct step of alkali hydroxide soln that the pH value is adjusted to 3～5 such reasonable range, just can directly make the wet product of 2-formamido group-6-chloropurine (4) through reacting by heating.Benefit after improving like this is embodied in:
(1) owing to need not isolation of intermediate products; Having saved reactions steps must carry out the pH value earlier to reaction solution for isolation of intermediate products (3) in a) and regulate and to make loaded down with trivial details post-processing operation such as its crystallization and then suction filtration;
(2) because with b) water that contains intermediate product (3) in the step adopts a direct step of alkali hydroxide soln to be adjusted to 3～5 so suitable pH value scopes, not only helped the middle 2-dimethylamino methylene imido grpup of 2-dimethylamino methylene imido grpup-6-chloropurine (3) under acidic conditions abundant hydrolysis but also can guarantee that 6-position chlorine wherein is not destroyed; And react after directly heating up and just can make intermediate product (4).Therefore, more reasonable, the easy easy handling again of synthesis technique of this step reaction, and combine compactly with step a), need not the good result that isolation of intermediate products 2-dimethylamino methylene imido grpup-6-chloropurine (3), " one kettle way " make the wet product of 2-formamido group-6-chloropurine (4) thereby reached.
So compared with prior art, this synthetic method is the yield height not only, and more reasonable, easy easy handling again; Thereby be more suitable in suitability for industrialized production.
In addition, this synthetic method is if preferably adopt N, and dinethylformamide carries out recrystallization purifying as solvent to 2-amino-6-chloropurine (1) crude product, also has the high and batch stay-in-grade advantage of purity; Because guanine is insoluble to N, dinethylformamide, thereby can guarantee that the purity of the elaboration that each batch obtains can reach more than 99%.And,, then be difficult for removing the guanine in the crude product because the guanine in the crude product is soluble in the alkali if adopt sodium hydroxide associating gac to carry out purifying, can reach more than 99% so can't guarantee the purity of the elaboration that each batch obtains.
With adopting the ammoniacal liquor recrystallization EP0543095A2 patent that target product 2-amino-6-chloropurine carries out purification process is compared, also had the advantage that environmental pollution is little, equipment requirements is low, can not influence yield.One of shortcoming that EP0543095A2 patent employing ammoniacal liquor recrystallization carries out purification process to target product 2-amino-6-chloropurine is owing to ammonia in the recrystallization liquid can not be discharged fully, 2-amino-6-chloropurine can not be separated out from ammoniacal liquor fully, thereby yield is reduced; Next is that environmental pollution is big, in addition owing to the recovery system that needs deamination and ammonia, to the equipment requirements height.
Show that in sum synthetic method of the present invention has yield height, technology easy rationally easy handling, advantage such as equipment requirements is low, quality is good again, the purity of the finished product can reach 99%, and content is more than or equal to 99%; Environmental pollution is little, is more suitable for and helps suitability for industrialized production.
Embodiment
Among the embodiment, guanine is a technical grade below, is produced by Changzhou Kang Rui chemical industry company limited, and all the other chemical substances or reagent are chemical pure, and all can obtain from normal commercial sources, and N, dinethylformamide abbreviate DMF in the following embodiments as.
Synthesizing of embodiment one 2-amino-6-chloropurine (1)
The synthetic method of 2-amino-6-chloropurine (1) may further comprise the steps successively:
A) preparation of 2-dimethylamino methylene imido grpup-6-chloropurine (3)
In the exsiccant reaction flask, add the N of 40mL, dinethylformamide, Dropwise 35 mL POCl under 0 ℃～10 ℃ conditions earlier
3, be mixed with POCl
3N, dinethylformamide solution, standby; In another exsiccant reaction flask, add 1 of 200mL then, 2-ethylene dichloride and 20g guanine (2) under 20 ℃～30 ℃, drip the N of the above-mentioned phosphorus oxychloride that has prepared, dinethylformamide solution.Dripped off insulated and stirred 1 hour, temperature rising reflux reaction in 5～8 hours finishes then, and cooling makes 2-dimethylamino methylene imido grpup-6-chloropurine (3), and this intermediate product (3) need not to separate from reaction solution, and the reaction solution that contains this intermediate product (3) is standby;
B) preparation of the wet product of 2-formamido group-6-chloropurine (4)
The reaction solution that contains intermediate product 2-dimethylamino methylene imido grpup-6-chloropurine (3) that above-mentioned steps is made in a) splashes into the POCl of decomposing excessive in the 300mL water that is not higher than 10 ℃
3, isolate 1 then, 2-ethylene dichloride organic phase, wherein 1, but the utilization of 2-ethylene dichloride dewatering and recovery, it is 3～5 that water is regulated the pH value with 10% NaOH solution, is warming up to 70 ℃～75 ℃ following insulation reaction 5 hours; Reacted and be cooled to room temperature, suction filtration, the wet product of 2-formamido group-6-chloropurine (4), standby, these wet product needn't be dried;
C) preparation of 2-amino-6-chloropurine (1) crude product
With above-mentioned steps b) in the wet product of 2-formamido group-6-chloropurine (4) of making be added in the NaOH solution of 150mL10%, hydrolysis reaction is 3 hours under 18 ℃～22 ℃ temperature, reacted and remained under the condition that is not higher than 10 ℃, with 1: 1 hydrochloric acid adjust pH was 6.4～7.5, leave standstill, filter, wash, get 2-amino-6-chloropurine (1) crude product, standby;
D) preparation of 2-amino-6-chloropurine (1) elaboration
With above-mentioned steps c) in 2-amino-6-chloropurine (1) crude product DMF recrystallization of making, filter, washing, oven dry, 17.5g 2-amino-6-chloropurine (1) elaboration.
This synthetic method is in guanine, and yield is 78%, and purity is 99%, and fusing point mp is 300 ℃ (decomposition).
Synthesizing of embodiment two 2-amino-6-chloropurines (1)
The synthetic method of 2-amino-6-chloropurine (1) may further comprise the steps:
A) preparation of 2-dimethylamino methylene imido grpup-6-chloropurine (3)
In the exsiccant reaction flask, add the N of 40mL, dinethylformamide, Dropwise 35 mL POCl under 0 ℃～10 ℃ conditions earlier
3, be mixed with POCl
3N, dinethylformamide solution, standby; In another exsiccant reaction flask, add 1 of 200mL then, 2-ethylene dichloride and 20g guanine (2) under 20 ℃～30 ℃, drip the N of the above-mentioned phosphorus oxychloride that has prepared, dinethylformamide solution.Dripped off insulated and stirred 1 hour, temperature rising reflux reaction in 5～8 hours finishes then, and cooling makes 2-dimethylamino methylene imido grpup-6-chloropurine (3), and this intermediate product (3) need not to separate from reaction solution, and the reaction solution that contains this intermediate product (3) is standby;
B) preparation of the wet product of 2-formamido group-6-chloropurine (4)
The reaction solution that contains intermediate product 2-dimethylamino methylene imido grpup-6-chloropurine (3) that above-mentioned steps is made in a) splashes into the POCl of decomposing excessive in the 300mL water that is not higher than 10 ℃
3, isolate 1 then, 2-ethylene dichloride organic phase, wherein 1, but the utilization of 2-ethylene dichloride dewatering and recovery, it is 3～5 that water is regulated the pH value with 10% NaOH solution, is warming up to 70 ℃～75 ℃ following insulation reaction 5 hours; Reacted and be cooled to room temperature, suction filtration, the wet product of 2-formamido group-6-chloropurine (4), standby, these wet product needn't be dried;
C) preparation of 2-amino-6-chloropurine (1) crude product
With above-mentioned steps b) in the wet product of 2-formamido group-6-chloropurine (4) of making be added in the NaOH solution of 150mL 10%, hydrolysis reaction is 3 hours under 18 ℃～22 ℃ temperature, reacted and remained on below 20 ℃, with 1: 1 hydrochloric acid adjust pH was 5～7.5, leave standstill, filter, wash, get 2-amino-6-chloropurine (1) crude product, standby;
D) preparation of 2-amino-6-chloropurine (1) elaboration
With above-mentioned steps c) in 2-amino-6-chloropurine (1) crude product ammoniacal liquor recrystallization of making, filter, washing, oven dry, 17.5g 2-amino-6-chloropurine (1) elaboration.The method of ammoniacal liquor recrystallization is as follows: 2-amino-6-chloropurine (1) crude product room temperature is dissolved in the ammoniacal liquor, remove by filter insolubles, then, below 30 ℃, ammonia is deviate from decompression, along with deviating from of ammonia, the reduction of the concentration of ammonia in the recrystallization liquid, 2-amino-6-chloropurine (1) elaboration is constantly separated out; But because ammonia can not be deviate from fully in the recrystallization liquid, thereby therefore yield can reduce.
This synthetic method is in guanine, and yield is 65%, and purity is 97%, and fusing point mp is 300 ℃ (decomposition).
Synthesizing of embodiment three 2-amino-6-chloropurines (1)
The synthetic method of 2-amino-6-chloropurine (1) may further comprise the steps successively:
A) preparation of 2-dimethylamino methylene imido grpup-6-chloropurine (3)
In the exsiccant reaction flask, add the N of 40mL, dinethylformamide, Dropwise 35 mL POCl under 0～10 ℃ of condition earlier
3, be mixed with POCl
3N, dinethylformamide solution, standby; In another exsiccant reaction flask, add 1 of 200mL then, 2-ethylene dichloride and 20g guanine (2) under 20 ℃～30 ℃, drip the N of the above-mentioned phosphorus oxychloride that has prepared, dinethylformamide solution.Dripped off insulated and stirred 1 hour, temperature rising reflux reaction in 5～8 hours finishes then, and cooling makes 2-dimethylamino methylene imido grpup-6-chloropurine (3), and this intermediate product (3) need not to separate from reaction solution, and the reaction solution that contains this intermediate product (3) is standby;
B) preparation of the wet product of 2-formamido group-6-chloropurine (4)
The reaction solution that contains intermediate product 2-dimethylamino methylene imido grpup-6-chloropurine (3) that above-mentioned steps is made in a) splashes into the POCl of decomposing excessive in the 300mL water that is not higher than 10 ℃
3, isolate 1 then, 2-ethylene dichloride organic phase, wherein 1, but the utilization of 2-ethylene dichloride dewatering and recovery, it is 3～5 that water is regulated the pH value with 10% NaOH solution, is warming up to 70 ℃～75 ℃ following insulation reaction 5 hours; Reacted and be cooled to room temperature, suction filtration, the wet product of 2-formamido group-6-chloropurine (4), standby, these wet product needn't be dried;
C) preparation of 2-amino-6-chloropurine (1) crude product
With above-mentioned steps b) in the wet product of 2-formamido group-6-chloropurine (4) of making be added in the NaOH solution of 150mL 10%, hydrolysis reaction is 3 hours under 18 ℃～22 ℃ temperature, reacted and remained on below 20 ℃, with 1: 1 hydrochloric acid adjust pH was 6.5～7.5, leave standstill, filter, wash, get 2-amino-6-chloropurine (1) crude product, standby;
D) preparation of 2-amino-6-chloropurine (1) elaboration
With above-mentioned steps c) in 2-amino-6-chloropurine (1) crude product of making be dissolved in the NaOH solution of 130mL5%, add decolorizing with activated carbon 0.5h, filter.Filtrate adds water to 1000mL, is transferred to neutrality with 5% hydrochloric acid, filter washing dry 2-amino-6-chloropurine 18g.
This synthetic method is in guanine, and yield is 80%, and purity is 95%, and fusing point mp is 300 ℃ (decomposition).
Embodiment four 2-[2-(2-amino-9H-purine-9-yl) ethyl]-1, the preparation of ammediol-diethyl ester
2-amino-the 6-chloropurine (1) that makes with embodiment 1 is raw material and 3-N-PROPYLE BROMIDE-1,1, and the condensation of 1-tricarboxylic acid triethyl gets 2-amino-6-chloro-9-(2,2-diethoxy carbonyl ethyl butyrate-4-yl) purine.Again through with the alcohol sodium solution decarboxylation, do reductive agent reduction, aceticanhydride acidylate, hydrogenation dechlorination with NaBH4 and get 2-[2-(2-amino-9H-purine-9-yl) ethyl]-1, ammediol-diethyl ester, i.e. " Famciclovir ".Concrete preparation method can be referring to Chen Wen China at " chemical reagent " 2006,28 (28): the article of publishing on the 185-186. " Famciclovir synthetic ".
Synthesizing of Comparative Examples 12-amino-6-chloropurine (1)
Concrete synthetic method may further comprise the steps successively:
A) preparation of 2-dimethylamino methylene imido grpup-6-chloropurine (3)
In the exsiccant reaction flask, add 200mL 1,2-ethylene dichloride, 40mLDMF, 20g guanine, then under 20 ℃～30 ℃, Dropwise 35 mL POCl
3, dripped off insulated and stirred 1 hour, then temperature rising reflux 5h, reacted cooling, make 2-dimethylamino methylene imido grpup-6-chloropurine (3), this intermediate product (3) need not to separate from reaction solution, and it is standby to contain this intermediate product 2-dimethylamino methylene imido grpup-6-chloropurine (3) reaction solution;
B) preparation of the wet product of 2-formamido group-6-chloropurine (4)
The above-mentioned reaction solution that contains intermediate product 2-dimethylamino methylene imido grpup-6-chloropurine (3) is splashed into the POCl of decomposing excessive in the 300mL water that is not higher than 10 ℃
3, isolate 1 then, 2-ethylene dichloride organic phase, wherein 1, but the utilization of 2-ethylene dichloride dewatering and recovery, it is 3～5 that water is regulated pH with 10%NaOH solution, is warming up to 70 ℃～75 ℃ following insulation reaction 5 hours; Reacted and be cooled to room temperature, suction filtration, the wet product of 2-formyl radical-6-chloropurine (4), standby, these wet product needn't be dried;
C) preparation of 2-amino-6-chloropurine (1) crude product
The wet product of above-mentioned 2-formyl radical-6-chloropurine (4) are added in the 150mL 10%NaOH solution in 18 ℃～22 ℃ hydrolysis reaction 3 hours, reacted and remained under the condition that is not higher than 10 ℃, transferring pH with 1: 1 hydrochloric acid is 7.5, leave standstill filter wash 2-amino-6-chloropurine (1) crude product, standby;
D) preparation of 2-amino-6-chloropurine (1) elaboration
With above-mentioned 2-amino-6-chloropurine (1) crude product DMF recrystallization, filter, wash, dry, get 15.7g 2-amino-6-chloropurine (1) elaboration.
This synthetic method is in guanine, and yield is 70%, and purity is 99%, and content is more than or equal to 99%, and fusing point mp is 300 ℃ (decomposition).
Synthesizing of Comparative Examples 22-amino-6-chloropurine (1)
Concrete synthetic method may further comprise the steps successively:
A) preparation of 2-dimethylamino methylene imido grpup-6-chloropurine (3)
In the exsiccant reaction flask, add 200mL 1,2-ethylene dichloride, 40mLDMF, 20g guanine, then under 20～30 ℃, Dropwise 35 mL POCl
3, dripping off insulated and stirred 1 hour, temperature rising reflux 5h has reacted cooling then, and reaction solution splashes in the 300mL water that is not higher than 10 ℃, tells organic phase recovery set usefulness, and it is 7～8 that water is transferred pH with 10%NaOH.Suction filtration gets 2-dimethylamino methylene imido grpup-6-chloropurine (3) then, and wet product needn't be dried.
B) preparation of the wet product of 2-formamido group-6-chloropurine (4)
The acetum of wet product of above-mentioned 2-dimethylamino methylene imido grpup-6-chloropurine (3) and 100mL12% is mixed in 70 ℃ of reaction 1h down, and phenomenon is to dissolve afterwards earlier to separate out in the reaction process.Reacted and be cooled to room temperature, suction filtration, the wet product of 2-formamido group-6-chloropurine (4), wet product needn't be dried.
C) preparation of 2-amino-6-chloropurine (1) crude product
Above-mentioned 2-formamido group-6-chloropurine (4) crude product is added in the 150mL10%NaOH solution in 20 ℃ of following hydrolysis reaction 3h, and having reacted at 20 ℃ is 7.5 with 1: 1 hydrochloric acid accent pH down, static, filter, wash 2-amino-6-chloropurine (1) crude product.
D) preparation of 2-amino-6-chloropurine (1) elaboration
Under 20 ℃, above-mentioned 2-amino-6-chloropurine (1) crude product is dissolved in the NaOH solution of 130mL5%, adds decolorizing with activated carbon 0.5h, filters.Filtrate adds water to 1000mL, is transferred to neutrality with 5% hydrochloric acid, filter, wash, dry 2-amino-6-chloropurine 16g.
This synthetic method is in guanine, and yield is 71%, and purity is 99%, and fusing point mp is 300 ℃ (decomposition).
Embodiment 1 compares with Comparative Examples 1, because the change of feeding mode in the step a) has improved final yield; Embodiment 3 compares with Comparative Examples 2, because step a) and step b) have been carried out more rational improvement and simplification, promptly change feeding mode and do not separate intermediate product 2-dimethylamino methylene imido grpup-6-chloropurine (3), but " one kettle way " directly enters the reaction of the wet product of next step preparation 2-formamido group-6-chloropurine (4), so not only obtained higher yield, and the easy easy handling again rationally of technology, be more suitable for and help suitability for industrialized production.
Claims (9)
1. the synthetic method of a 2-amino-6-chloropurine (1) in turn includes the following steps:
A) guanine (2) is joined 1, in the 2-methylene dichloride, in 20 ℃～30 ℃ N that drip phosphorus oxychloride down, dinethylformamide solution reacts, reaction generates 2-dimethylamino methylene imido grpup-6-chloropurine (3), and this intermediate product (3) need not to separate from reaction solution;
B) reaction solution of the above-mentioned 2-of containing dimethylamino methylene imido grpup-6-chloropurine (3) is splashed in the water that is not higher than 10 ℃ phosphorus oxychloride with decomposing excessive, isolate 1 then, 2-methylene dichloride organic phase, it is 3～5 that water is regulated the pH value with alkali hydroxide soln, reacting by heating gets the wet product of 2-formamido group-6-chloropurine (4);
C) the wet product of above-mentioned 2-formamido group-6-chloropurine (4) are hydrolyzed in alkali hydroxide soln earlier reaction, then with the salt acid for adjusting pH value to neutrality, get 2-amino-6-chloropurine (1) crude product.
D) above-mentioned 2-amino-6-chloropurine (1) crude product is carried out purifying, get 2-amino-6-chloropurine (1) elaboration.
2. the synthetic method of 2-amino-6-chloropurine according to claim 1 (1), it is characterized in that: in step a), the N of phosphorus oxychloride, dinethylformamide solution are dissolved in N by phosphorus oxychloride in advance under 0 ℃～15 ℃ temperature, dinethylformamide and making.
3. the synthetic method of 2-amino-6-chloropurine according to claim 2 (1), it is characterized in that: in step a), the N of phosphorus oxychloride, dinethylformamide solution are dissolved in N by phosphorus oxychloride in advance under 0 ℃～10 ℃ temperature, dinethylformamide and making.
4. the synthetic method of 2-amino-6-chloropurine according to claim 1 (1) is characterized in that: in step b) and step c), described alkali hydroxide soln is 5%～15% sodium hydroxide solution.
5. the synthetic method of 2-amino-6-chloropurine according to claim 4 (1) is characterized in that: in step b) and step c), described alkali hydroxide soln is 10% sodium hydroxide solution.
6. the synthetic method of 2-amino-6-chloropurine according to claim 1 (1), it is characterized in that: in step c), the first reaction that in 18 ℃～22 ℃ alkali hydroxide soln, is hydrolyzed of the wet product of described 2-formamido group-6-chloropurine (4), arrive neutrality with the salt acid for adjusting pH value then, get 2-amino-6-chloropurine (1) crude product.
7. the synthetic method of 2-amino-6-chloropurine according to claim 6 (1), it is characterized in that: in step c), the first reaction that in 18 ℃～22 ℃ alkali hydroxide soln, is hydrolyzed of the wet product of described 2-formamido group-6-chloropurine (4), be not higher than under 22 ℃ the condition with the salt acid for adjusting pH value to neutral then, 2-amino-6-chloropurine (1) crude product.
8. the synthetic method of 2-amino-6-chloropurine according to claim 7 (1), it is characterized in that: in step c), the first reaction that in 18 ℃～22 ℃ alkali hydroxide soln, is hydrolyzed of the wet product of described 2-formamido group-6-chloropurine (4), be not higher than under 10 ℃ the condition with the salt acid for adjusting pH value to neutral then, 2-amino-6-chloropurine (1) crude product.
9. according to the synthetic method of any one described 2-amino-6-chloropurine (1) of claim 1～8, it is characterized in that: in step d), described 2-amino-6-chloropurine (1) crude product adopts N, dinethylformamide carries out recrystallization purifying as solvent, gets 2-amino-6-chloropurine (1) elaboration.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107312003A (en) * | 2017-07-07 | 2017-11-03 | 浙江工业大学 | A kind of synthetic method for preparing the chlorine guanine of 2 amino of high-purity 6 |
| CN108084184A (en) * | 2017-12-25 | 2018-05-29 | 中山市得高行知识产权中心（有限合伙） | A kind of synthetic method of 2- amido-6-chloropurines |
| CN108892669A (en) * | 2018-08-01 | 2018-11-27 | 江苏八巨药业有限公司 | A method of preparing 2- amido-6-chloropurine |
| CN114437071A (en) * | 2022-01-12 | 2022-05-06 | 甘肃欣睿泽医药科技有限公司 | Process for preparing purine derivatives |
| CN114621228A (en) * | 2022-04-19 | 2022-06-14 | 杭州丰禾生物技术有限公司 | Preparation method of 2-amino-6-chloropurine |
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2007
- 2007-09-27 CN CNB2007101336490A patent/CN100549013C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107312003A (en) * | 2017-07-07 | 2017-11-03 | 浙江工业大学 | A kind of synthetic method for preparing the chlorine guanine of 2 amino of high-purity 6 |
| CN108084184A (en) * | 2017-12-25 | 2018-05-29 | 中山市得高行知识产权中心（有限合伙） | A kind of synthetic method of 2- amido-6-chloropurines |
| CN108892669A (en) * | 2018-08-01 | 2018-11-27 | 江苏八巨药业有限公司 | A method of preparing 2- amido-6-chloropurine |
| CN114437071A (en) * | 2022-01-12 | 2022-05-06 | 甘肃欣睿泽医药科技有限公司 | Process for preparing purine derivatives |
| CN114621228A (en) * | 2022-04-19 | 2022-06-14 | 杭州丰禾生物技术有限公司 | Preparation method of 2-amino-6-chloropurine |
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