CN114621228B - Preparation method of 2-amino-6-chloropurine - Google Patents
Preparation method of 2-amino-6-chloropurine Download PDFInfo
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Abstract
The invention discloses a preparation method of 2-amino-6-chloropurine, and relates to the technical field of preparation of famciclovir antiviral drug intermediates. The preparation method of the 2-amino-6-chloropurine provided by the invention has the advantages of simpler synthetic route and operation, reduced process difficulty, product yield of 92% or more, simple operation, low process difficulty, contribution to industrial popularization, maximum economic benefit in industrial production, capability of fundamentally solving the problems of high-concentration COD (chemical oxygen demand) wastewater and phosphorus-containing wastewater caused by the prior art, easiness in purifying the product, environment friendliness, and capability of realizing clean production, and the product with the purity of more than 99% can be obtained through two-step refining.
Description
Technical Field
The invention relates to the technical field of preparation of famciclovir antiviral drug intermediates, in particular to a preparation method of 2-amino-6-chloropurine.
Background
Famciclovir (FCV) was the 2 nd generation nucleoside anti-herpes virus drug developed by the company smic, and was first marketed in the united kingdom in 1993. The famciclovir has high bioavailability, good tolerance and small side effect, and occupies nearly 1/3 of antiviral drug market in the first 4 months of the market in the United kingdom. In recent years, the demand for famciclovir has increased dramatically with the spread of viruses.
2-amino-6-chloropurine, also known as 6-chloroguanine, of formula C 5 H 4 ClN 5 White powdery solid, insoluble in water. 2-amino-6-chloropurine is a key intermediate for synthesizing famciclovir, is also an important intermediate for synthesizing purine antiviral drugs such as abacavir, penciclovir and the like, and can be used for synthesizing anticancer, antihypertensive and anti-inflammatory drugs.
Patent EP0543095A2 reports a process for the preparation of 2-amino-6-chloropurine: guanine and phosphorus oxychloride react in dimethylformamide to generate 2-dimethylaminomethylimino-6-chloropurine, and then the 2-amino-6-chloropurine is obtained by hydrolysis, the yield is about 55 percent, however, the preparation method has complex operation and serious three-waste pollution.
Patent WO93/15075 reports that 2-amino-6-chloropurine is prepared by directly chlorinating guanine and phosphorus oxychloride in the presence of a phase transfer catalyst and then hydrolyzing, the yield of 2-amino-6-chloropurine is low, about 30% -42% due to low solubility of guanine, and a large amount of expensive phase transfer catalyst is used, so that the method is not suitable for industrial production.
Patent WO9407892A1 reports that 2,4, 5-triamino-6-chloroguanine is prepared by cyclizing 2,4, 5-triamino-6-chloropyrimidine with triethyl orthoformate, the total yield is about 62%, but the reaction time is long, and the preparation process of 2,4, 5-triamino-6-chloropyrimidine is complex and cannot be industrially produced.
Patent CN108892669B discloses a method for preparing 2-amino-6-chloroguanine, taking guanine as a raw material, adding an oxidant to oxidize 2-amino group of guanine into nitro group, then chloridizing, and finally reducing 2-nitro group to prepare 2-amino-6-chloroguanine, wherein the yield is 58% -81.6%, however, in the process of oxidizing 2-amino group, 6-hydroxy group is inevitably oxidized, and the yield of 2-amino-6-chloropurine is affected.
Patent CN107312003a discloses a synthetic method for preparing high-purity 2-amino-6-chloroguanine, when preparing 2-amino-6-chloroguanine, firstly, guanine and Vilsmeier reagent are reacted to obtain chloro intermediate 2-formamido-6-chloroguanine, then hydrolyzed to obtain 2-amino-6-chloroguanine, however, because Vilsmeier reagent is unstable, the yield of 2-amino-6-chloroguanine is greatly affected, and very high requirements are put forward for process control, so that the industrial production is not facilitated.
In conclusion, the existing preparation method of 2-amino-6-chloropurine has the problems of complex process, poor environmental protection, low yield, high process control requirement, inapplicability to industrial production and the like. Based on these problems, how to improve the utilization ratio of atoms in the raw materials, on one hand, the production cost of 2-amino-6-chloropurine can be reduced, and on the other hand, the yield and purity of 2-amino-6-chloropurine can be improved, so that the preparation method of the 2-amino-6-chloropurine which is more environment-friendly is provided, and is an important research content of the technical personnel in the field at present.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide the preparation method of the 2-amino-6-chloropurine, which has the advantages of simpler synthetic route and operation, reduced process difficulty, 92% or more of product yield, simple operation, low process difficulty, contribution to industrial popularization, maximum economic benefit in industrial production, easy purification of the product, environmental friendliness, and capability of obtaining the product with the purity of more than 99% through two-step refining.
In order to achieve the above object, the present invention provides a method for preparing 2-amino-6-chloropurine, comprising the steps of:
s1, sucking dichloroethane in a reaction bottle in vacuum, stirring and adding guanine, and then adding sulfonyl chloride (SO 2 Cl 2 ) Heating to 50-60 ℃, simultaneously slowly dropwise adding N, N' -Dimethylformamide (DMF) at the temperature, keeping the temperature for 3.0-4.5 h, heating to 65-75 ℃ and continuously stirring and refluxing for 9-11 h, cooling to 20-40 ℃, performing filter pressing, weighing to obtain chloride, and transferring mother liquor into a distillation bottle for distillation and application;
s2, adding water into a reaction bottle, starting stirring, cooling to 0-10 ℃, starting vacuum at the temperature, slowly adding chloride in the step S1 into the reaction bottle in batches, controlling the temperature to be not more than 20 ℃, cooling to 0-10 ℃ after the addition, stirring for 30-35 min, taking the material liquid as a standard, standing for 20-30 min, separating liquid, recycling an organic phase at the lower layer, controlling the temperature of an aqueous phase at the upper layer to be 0-10 ℃ to drop liquid caustic soda to enable the pH to be 3.5-4.5, heating to 60-70 ℃, stirring and reacting for 5-6 h, performing pH detection in the heating process, adjusting the pH to 3.5-4.5, slowly dropping a large amount of acid liquor after sampling and sending HPLC detection to be qualified, starting centrifugation after sampling detection to obtain a hydrolyzed wet product, and detecting the hydrolyzed wet product by HPLC, wherein the guanine is not more than 1% and the chloride is <0.5% qualified;
s3, adding water and 30% liquid alkali into a reaction bottle, starting stirring, cooling to 0-10 ℃, slowly adding the hydrolyzed wet product obtained in the step S2, dissolving, adding active carbon, decolorizing for 30-35 min, performing filter pressing, transferring into another reaction bottle, cooling to 0-10 ℃, adding water, dropwise adding acid liquor to pH 7.4-7.6, transferring half of the feed liquid into another reaction bottle, adding water, stirring, heating to 50-60 ℃, preserving heat for 1h, cooling, stirring, and centrifuging to obtain a refined 1 wet product;
s4, adding water into a reaction bottle, controlling the temperature to be 25-35 ℃, adding the refined 1 wet product, stirring for 1h at 25-35 ℃, centrifuging, and weighing to obtain the refined 2 wet product;
s5, transferring the refined 2 wet product into a hot air circulation oven tray, drying (the moisture is less than or equal to 0.5%), and crushing to obtain the product 2-amino-6-chloropurine.
By adopting the scheme, the temperature of rising temperature and refluxing in the step S1 can ensure full conversion of the primarily reacted chloride without maintaining higher temperature, the chloride in the step S1 is a 2-amino-6-chloropurine crude product, the subsequent steps S2, S3 and S4 are required to be refined to prepare the product 2-amino-6-chloropurine in the step S5, after sampling and HPLC detection pass in the step S2, the temperature is reduced to 0-5 ℃, the standard of the qualified 2-amino-6-chloropurine in the sampling and HPLC detection is more than or equal to 95%, the content of guanine raw materials is less than or equal to 1%, the content is less than or equal to 1% by mass, the content is also less than 0.5% by mass in the step S1, and the used liquid alkali in the step S3 is 30% by mass.
Further, in step S1, guanine, SO 2 Cl 2 And DMF is used in an amount of from 3mol to 3.5mol to 3mol.
Further, in step S2, when pH detection is performed during the temperature rising process, alkali or sulfuric acid is added dropwise to adjust the pH to 3.5 to 4.5.
Further, in step S2 or step S3, the acid solution is dilute sulfuric acid or dilute hydrochloric acid.
Further, in step S4, when the wet product of 2 is weighed and refined, sampling is also carried out, and the detection standard is that the purity of 2-amino-6-chloropurine is more than 99%.
With the above scheme, the purpose of step S4 is to remove salt from the purified 1 wet product.
Compared with the prior art, the invention has the following beneficial effects:
(1) The 2-amino-6-chloropurine prepared by the preparation method has the advantages of simpler synthetic route and operation, reduced process difficulty, 92% or more of product yield, simple operation and low process difficulty, is favorable for industrial popularization, and ensures that the industrial production has the greatest economic benefit.
(2) POCl is used in the preparation of 2-amino-6-chloropurine in the prior art 3 As a chlorinating agent, the invention adopts SO 2 Cl 2 As a chlorinationThe agent fundamentally solves the problems of high-concentration COD wastewater and phosphorus-containing wastewater caused by the prior art, and the product is easy to purify, is environment-friendly and can realize clean production.
(3) The preparation method of the 2-amino-6-chloropurine provided by the invention does not use a phase transfer catalyst used in the prior art, so that catalyst residues are avoided, the purity of the prepared 2-amino-6-chloropurine product is greatly improved, the product with the purity of more than 99% can be obtained through two-step refining, the production requirement of high-quality products is met, and the method is easy to industrially popularize.
(4) The mother liquor produced by the invention is easy to process and can be recycled, the economy of the reaction is improved, and the method has good economic and social benefits.
Detailed Description
The invention is further described in connection with the following detailed description, in order to make the technical means, the creation characteristics, the achievement of the purpose and the effect of the invention easy to understand.
Example 1
The embodiment provides a preparation method of 2-amino-6-chloropurine, which comprises the following steps:
s1, pumping dichloroethane in a reaction bottle in vacuum, starting stirring, adding 30g (0.2 mol) of guanine, closing a reaction kettle inlet cover, and pumping SO in vacuum 2 Cl 2 81g (0.6 mol) of DMF is prepared, 43.8g (0.6 mol) of DMF is heated to 55 ℃, DMF is slowly added dropwise at the temperature, the temperature is kept for 3.5h and then is raised to 65 ℃, stirring is continued for 9h, the temperature is reduced to 20 ℃, the pressure filtration is carried out, the chloride is obtained by weighing, and the mother liquor is transferred into a distillation bottle for distillation and application;
s2, adding 80-90 mL of distilled water into a reaction bottle, starting stirring, cooling to 5 ℃, starting vacuum at the temperature, slowly adding chloride in the step S1 into the reaction kettle in batches, controlling the temperature to be no more than 15 ℃, cooling to 5 ℃ after the addition is finished, stirring for 32min, taking the material liquid as a standard, standing for 25min, separating liquid, recycling the lower organic phase, controlling the temperature of the upper water phase to be 5 ℃ to drop alkali to pH=3.8, heating to 60 ℃, re-measuring the pH=3.8 in the heating process, if the temperature is not in the range, adjusting the drop alkali or the dilute sulfuric acid to pH=3.8, stirring at 60 ℃ for reacting for 5h, cooling to 5 ℃ after sampling and HPLC detection are qualified, slowly dropping a large amount of dilute sulfuric acid at 5 ℃, starting centrifugation after sampling detection is qualified to obtain a hydrolysis wet product, and detecting the hydrolysis wet product by HPLC, wherein the chloride is less than 0.5%;
s3, adding water and 30% liquid alkali into a reaction bottle, starting stirring, cooling to 5 ℃, slowly adding a hydrolyzed wet product, dissolving, adding active carbon, decolorizing for 30min, performing filter pressing, transferring into another reaction kettle, cooling to 5 ℃, adding 75mL of water, dropwise adding dilute sulfuric acid to pH=7.4, transferring half of the feed liquid into another reaction bottle, adding 85mL of water, stirring, heating to 50 ℃, preserving heat for 1h, cooling, stirring, and centrifuging to obtain a refined 1 wet product;
s4, adding 10mL of water into a reaction bottle, controlling the temperature to be 25 ℃, adding the refined 1 wet product, stirring for 1h at the temperature of 25 ℃, centrifuging, and weighing to obtain a refined 2 wet product, wherein the purity is more than 99 percent;
s5, transferring the refined 2 wet product into a hot air circulation oven tray, drying (moisture is less than 0.5%) and crushing by a crusher to calculate that the yield of the product 2-amino-6-chloropurine is 94%.
Example 2
S1, pumping dichloroethane in a reaction bottle in vacuum, starting stirring, adding 27g (0.18 mol) of guanine, closing the reaction kettle, and pumping SO in vacuum 2 Cl 2 81g (0.6 mol) of DMF is prepared simultaneously with 39.42g (0.54 mol) of DMF, the temperature is raised to 60 ℃, DMF is slowly added dropwise at the temperature, the temperature is kept for 4.5 hours, the temperature is raised to 70 ℃, the temperature is kept for 10 hours after stirring and keeping, the temperature is reduced to 30 ℃, the chloride is obtained through pressure filtration and weighing, and mother liquor is transferred into a distillation bottle for distillation and application;
s2, adding 75-85 mL of distilled water into a reaction bottle, starting stirring, cooling to 10 ℃, starting vacuum at the temperature, slowly adding the chloride in the step S1 into the reaction bottle in batches, controlling the temperature to be no more than 15 ℃, cooling to 10 ℃ after the addition is finished, stirring for 30min, taking the material liquid as a standard, standing for 30min, separating the liquid, recycling the lower organic phase, controlling the temperature of the upper water phase to be 10 ℃ to drop caustic soda to pH=4.5, heating to 65 ℃, re-measuring the pH=4.5 in the heating process, if the temperature is not within the range, adjusting the drop caustic soda or dilute sulfuric acid to pH=4.5, stirring at 65 ℃ for 6h, cooling to 3 ℃ after sampling and HPLC detection is qualified, slowly dropping a large amount of dilute hydrochloric acid at 10 ℃, starting centrifugation after sampling detection is qualified to obtain a hydrolysis wet product, and detecting the hydrolysis wet product by HPLC, wherein the chloride is less than 0.5;
s3, adding water and 30% liquid alkali into a reaction bottle, starting stirring, cooling to 10 ℃, slowly adding a hydrolyzed wet product, dissolving, adding active carbon, decolorizing for 30min, performing filter pressing, transferring into another reaction bottle, cooling to 10 ℃, adding 70mL of water, dropwise adding diluted hydrochloric acid to pH=7.5, transferring half of the feed liquid into another reaction bottle, adding 80mL of water, stirring, heating to 60 ℃, preserving heat for 1h, cooling, stirring, and centrifuging to obtain a refined 1 wet product;
s4, adding 10mL of water into a reaction bottle, controlling the temperature to be 35 ℃, adding the refined 1 wet product, stirring for 1h at the temperature of 35 ℃, centrifuging, weighing to obtain the refined 2 wet product, and sampling and detecting, wherein the purity is more than 99%;
s5, transferring the refined 2 wet product into a hot air circulation oven tray, drying (moisture < 0.5%) and crushing by a crusher, wherein the yield is calculated to be 93%.
Example 3
S1, pumping dichloroethane in a reaction bottle in vacuum, starting stirring, adding 30g (0.2 mol) of guanine, closing a reaction kettle, and pumping SO in vacuum 2 Cl 2 94.5g (0.7 mol) of DMF is prepared simultaneously with 43.8g (0.6 mol) of DMF, the temperature is raised to 50 ℃, DMF is slowly added dropwise at the temperature, after 4.0h of heat preservation, the temperature is raised to 75 ℃, stirring and heat preservation are continued for 11h, the temperature is reduced to 40 ℃, the pressure filtration is carried out, the chloride is obtained by weighing, and the mother liquor is transferred into a distillation bottle for distillation and application;
s2, adding 75-85 mL of distilled water into a reaction bottle, starting stirring, cooling to 0 ℃, starting vacuum at the temperature, slowly adding the chloride in the step S1 into the reaction bottle in batches, controlling the temperature to be not more than 10 ℃, cooling to 0 ℃ after the addition is finished, stirring for 35min, taking the material liquid as a standard, standing for 20min, separating the liquid, recycling the lower organic phase, controlling the temperature of the upper water phase to be 0 ℃ to drop caustic soda to pH=3.5, heating to 70 ℃, re-measuring the pH=3.5 in the heating process, if the temperature is not in the range, adjusting the drop caustic soda or dilute sulfuric acid to pH=3.5, stirring at 70 ℃ for reacting for 5.5h, sampling, sending HPLC to be qualified, cooling to 0 ℃, slowly dropping a large amount of dilute hydrochloric acid at 0 ℃, centrifuging to obtain a hydrolyzed wet product after the sampling is qualified, detecting the hydrolyzed wet product by HPLC, and the chloride is less than 0.5%;
s3, adding water and 30% liquid alkali into a reaction bottle, starting stirring, cooling to 0 ℃, slowly adding a hydrolyzed wet product, dissolving, adding active carbon, decolorizing for 35min, performing filter pressing, transferring into another reaction bottle, cooling to 0 ℃, adding 70mL of water, dropwise adding diluted hydrochloric acid to pH=7.6, transferring half of the feed liquid into another reaction bottle, adding 80mL of water, stirring, heating to 50 ℃, preserving heat for 1h, cooling, stirring, and centrifuging to obtain a refined 1 wet product;
s4, adding 10mL of water into a reaction bottle, controlling the temperature to be 30 ℃, adding the refined 1 wet product, stirring for 1h at the temperature of 30 ℃, centrifuging, weighing to obtain the refined 2 wet product, and sampling and detecting, wherein the purity is more than 99%;
s5, transferring the refined 2 wet product into a hot air circulation oven tray, drying (moisture < 0.5%) and crushing by a crusher, wherein the yield is calculated to be 92%.
While the fundamental and principal features of the invention and advantages of the invention have been shown and described, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (4)
1. A method for preparing 2-amino-6-chloropurine, which is characterized by comprising the following steps:
s1, pumping dichloroethane into a reaction bottle in vacuum, stirring and adding guanine, and then adding SO 2 Cl 2 Heating to 50-60 ℃, simultaneously slowly dropwise adding DMF at the temperature, keeping the temperature for 3.0-4.5 h, heating to 65-75 ℃, continuously stirring and refluxing for 9-11 h, cooling to 20-40 ℃, press-filtering, weighing to obtain chloride, and transferring mother liquor into a distillation bottle for distillation and application;
s2, adding water into a reaction bottle, starting stirring, cooling to 0-10 ℃, starting vacuum at the temperature, adding the chloride in the step S1 into the reaction bottle, controlling the temperature to be not more than 20 ℃, cooling to 0-10 ℃ after the addition is finished, stirring for 30-35 min, standing for 20-30 min, separating the liquid, recycling the lower organic phase, controlling the temperature of the upper aqueous phase to be 0-10 ℃ to drop caustic soda to enable the pH to be 3.5-4.5, heating to 60-70 ℃, stirring and reacting for 5-6 h, performing pH detection in the heating process, adjusting the pH to 3.5-4.5, slowly dropping a large amount of acid liquor after sampling and HPLC detection is qualified, starting centrifugation after sampling detection is qualified to obtain a hydrolysis wet product, detecting the guanine by HPLC, and enabling the guanine to be less than or equal to 1%, wherein the chloride is <0.5% to be qualified;
s3, adding water and 30% liquid alkali into a reaction bottle, starting stirring, cooling to 0-10 ℃, slowly adding the hydrolyzed wet product obtained in the step S2, dissolving, adding active carbon, decolorizing for 30-35 min, performing filter pressing, transferring into another reaction bottle, cooling to 0-10 ℃, adding water, dropwise adding acid liquor to pH 7.4-7.6, transferring half of the feed liquid into another reaction bottle, adding water, stirring and heating to 50-60 ℃, preserving heat for 1h, cooling, stirring, and centrifuging to obtain a refined 1 wet product;
s4, adding water into a reaction bottle, controlling the temperature to be 25-35 ℃, adding the refined 1 wet product, stirring for 1h at 25-35 ℃, centrifuging, and weighing to obtain the refined 2 wet product;
s5, drying the refined 2 wet product, and crushing to obtain a product 2-amino-6-chloropurine;
in step S1, guanine, SO 2 Cl 2 And DMF is used in an amount of from 3mol to 3.5mol to 3mol.
2. The method for producing 2-amino-6-chloropurine according to claim 1, wherein in step S2, when pH detection is performed during temperature rising, alkali or sulfuric acid is added dropwise to adjust pH to 3.5 to 4.5.
3. The method for preparing 2-amino-6-chloropurine according to claim 1, wherein in step S2 or step S3, the acid solution is dilute sulfuric acid or dilute hydrochloric acid.
4. The method for producing 2-amino-6-chloropurine according to claim 1, wherein step S4 is performed by sampling and detecting the 2-amino-6-chloropurine when the 2-wet product is weighed and refined, wherein the purity of the 2-amino-6-chloropurine is greater than 99%.
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| CA2076886C (en) * | 1991-11-22 | 2002-06-11 | Masami Igi | Method for production of 2-amino-6-halogenopurine and synthesis intermediate therefor |
| ATE364607T1 (en) * | 2001-04-05 | 2007-07-15 | Sumitomo Chemical Co | METHOD FOR PRODUCING 2,6-DIHALOGENOPURINES |
| CN100549013C (en) * | 2007-09-27 | 2009-10-14 | 常州工程职业技术学院 | The synthetic method of 2-amino-6-chloropurine |
| 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 |
| CN110713490A (en) * | 2018-07-12 | 2020-01-21 | 浙江医药股份有限公司新昌制药厂 | Preparation method of penciclovir |
| CN108892669B (en) * | 2018-08-01 | 2020-04-21 | 江苏八巨药业有限公司 | Method for preparing 2-amino-6-chloropurine |
| CN111592542A (en) * | 2020-06-15 | 2020-08-28 | 上海凌凯医药科技有限公司 | Method for synthesizing 2-amino-6-chloropurine |
| CN112961198B (en) * | 2021-02-24 | 2022-03-25 | 南京欧信医药技术有限公司 | Preparation method of purine nucleotide intermediate |
| CN113292564B (en) * | 2021-05-10 | 2022-04-19 | 上海凌凯医药科技有限公司 | Synthetic method of 2-amino-6-chloropurine |
| CN113234077B (en) * | 2021-05-11 | 2022-03-08 | 上海凌凯医药科技有限公司 | Synthesis method of 2-amino-6-chloropurine |
| CN113292507B (en) * | 2021-06-25 | 2022-07-19 | 潍坊奥通药业有限公司 | Preparation method of 2-amino-6-chloroguanine and intermediate thereof |
| CN114031620A (en) * | 2021-11-30 | 2022-02-11 | 湖北省宏源药业科技股份有限公司 | Production method of high-purity 2-amino-6-chloroguanine |
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