CN108892669B - Method for preparing 2-amino-6-chloropurine - Google Patents
Method for preparing 2-amino-6-chloropurine Download PDFInfo
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Abstract
The invention provides a new process route for preparing 2-amino-6-chloropurine for overcoming the defects of the existing 2-amino-6-chloropurine synthesis process, and the method comprises the following steps: s1: taking guanine as a raw material, adding an oxidant, and carrying out oxidation reaction to obtain a compound shown in a formula A; s2: adding a solvent into the A obtained in the step S1, adding a chlorinating reagent, and performing chlorination reaction to obtain a compound shown as a formula B; s3: and adding a reducing agent into the B obtained in the step S2, and carrying out reduction reaction to obtain a compound shown in the formula C, namely 2-amino-6-chloropurine. The preparation method of 2-amino-6-chloropurine provided by the invention can effectively improve the yield, reduce the production cost, simplify the operation steps, be safer and be more suitable for industrial production.
Description
Technical Field
The invention discloses a method for preparing famciclovir intermediate, in particular to a method for preparing 2-amino-6-chloropurine.
Background
2-amino-6-chloropurine of the formula: c5H4ClN5English name: 2-amino-6-chloropurine, CAS No.: 10310-21-1. Intermediates of famciclovir.
Famciclovir is the second generation open-loop nucleotide anti-herpes virus drug, and is an important variety in the current anti-virus oral drugs. In 1985, Harnden was successfully synthesized and developed by Beecham corporation of Smith Kline in UK, and in 1993, it was first marketed in the UK and then subsequently in the United states, Europe and other countries and regions. Approved for genital herpes in 1995 by the uk and the us under the trade name Famvi. In 1997, treatment of recurrent herpes simplex virus infections (genital herpes and herpes labialis) in HIV patients was approved in the United states for its additional indication, the first oral drug approved in the United states for the treatment of this condition. Clinical studies have demonstrated that famciclovir is the only antiviral drug that reduces post-herpetic neuralgia. Famciclovir has been marketed to date in many countries and regions of the world. Famciclovir has strong inhibitory action not only against herpes virus (including type I and type II), HIV, etc., but also against hepatitis B and C viruses. Has wide market prospect as the main intermediate 2-amino-6-chloropurine of famciclovir.
At present, the synthesis process of 2-amino-6-chloropurine at home and abroad is as follows:
WO93/15075 discloses the preparation of 2-amino-6-chloropurine by direct chlorination followed by hydrolysis of guanine and phosphorus oxychloride in the presence of a phase transfer catalyst. The reaction has low product yield of about 30-42% due to low solubility of guanine, and is not suitable for industrial production due to the use of a large amount of expensive phase transfer catalyst.
Patent WO94/07892 reports that 2,4, 5-triamino-6-chloropyrimidine reacts with triethyl orthoformate to prepare 2-amino-6-chloropurine, the process is simple, the yield is 60% -70%, but the reaction time is long, and the preparation of the 2,4, 5-triamino-6-chloropyrimidine is very difficult, so that the process cannot be industrially produced.
Patent EP0543095A2 reports that guanine reacts with DMF in the presence of chlorinating agent to obtain 2-methylamino-methonimine-6-chloropurine, which then reacts with acetic acid to obtain 2-amino-6-chloropurine, which is then alkalized, recrystallized and purified to obtain 2-amino-6-chloropurine. The synthesis route of the process is as follows:
compared with the former synthesis processes, the synthesis process is relatively reasonable. However, the process can generate a large amount of three wastes, the post-treatment is complicated, the materials are viscous, the suction filtration/centrifugation is difficult, and the requirement on equipment is high.
Disclosure of Invention
The invention aims to overcome the defects of the synthesis processes of the 2-amino-6-chloropurine, provides a novel method for preparing the 2-amino-6-chloropurine, reduces the production cost, simplifies the operation steps, is safer and is more suitable for industrial production.
The specific technical scheme of the invention is as follows:
the method for preparing 2-amino-6-chloropurine is characterized by comprising the following process routes:
the method comprises the following steps:
s1: taking guanine as a raw material, adding an oxidant, and carrying out oxidation reaction to obtain a compound (2-nitro-9H-purine-6-ol) shown in a formula A;
s2: adding a solvent into the A obtained in the step S1, adding a chlorinating reagent, and carrying out chlorination reaction to obtain a compound (6-chloro-2-nitro-9H-purine) shown in the formula B;
s3: and adding a reducing agent into the B obtained in the step S2, and carrying out reduction reaction to obtain a compound shown in the formula C, namely 2-amino-6-chloropurine.
Further, the method specifically comprises the following steps
S1: mixing guanine and a solvent, stirring, controlling the temperature to be below 20 ℃, slowly dripping an oxidant, and controlling the oxidation reaction temperature to be 15-30 ℃, preferably 20-25 ℃; stirring until the guanine reaction is completed, namely the oxidation reaction is finished, filtering and drying to obtain a compound shown as a formula A, wherein the compound shown as the formula A can be directly used for the next reaction;
s2: adding a solvent into the A obtained in the step S1, stirring, cooling to 0-5 ℃, slowly adding the chlorinating agent dropwise, keeping the temperature, stirring, heating, refluxing until the compound A is completely reacted to obtain a chlorination reaction, adding water, washing, and concentrating an organic layer under reduced pressure to obtain a compound shown in a formula B;
s3: and (3) adding the B obtained in the step (S2) into a solvent, stirring, heating to 50 ℃, dropwise adding a reducing agent, heating, refluxing until the reduction reaction is finished, cooling, filtering and drying to obtain a compound shown in the formula (C), namely 2-amino-6-chloropurine.
Further, the solvent in S1 is one or more of N, N-dimethylformamide, N-dimethylacetamide, dichloromethane, and dichloroethane, or 2% to 15% alkaline water, preferably 2% to 15% alkaline water. The alkaline water is prepared from sodium hydroxide/potassium hydroxide and water according to a mass ratio.
S1, the mass ratio of the solvent to the guanine is 1: 3-10
Further, the oxidant S1 is a liquid oxidant, preferably a mixture of one or more of hydrogen peroxide, sodium hypochlorite and peroxyacetic acid, more preferably hydrogen peroxide, and hydrogen peroxide is used as the oxidant, so that the safety is higher than that of sodium hypochlorite and peroxyacetic acid, the three wastes are not generated basically, and the method is relatively environment-friendly.
Further, the molar ratio of the oxidant to the guanine in S1 is 1: 3-1.
Further, the solvent in S2 and S3 is one or more of methanol, ethanol, dichloromethane and dichloroethane, preferably methanol.
S2, the mass ratio of the solvent to the compound A is 2-10: 1
S3, the mass ratio of the solvent to the compound B is 2-5: 1
Further, the chlorinating agent in S2 is one or a mixture of more of phosphorus oxychloride, phosphorus pentachloride, thionyl chloride and chlorine gas, and preferably thionyl chloride, which is much safer than chlorine gas; the generated three wastes are better treated than phosphorus-containing wastewater generated by a phosphorus-containing chlorination reagent, and the cost is low.
Further, the molar ratio of the chlorinating agent in S2 to the compound A is 1-3: 1.
Further, the reducing agent in S3 is one or more of sodium sulfite, glucose, hydroxylamine, sodium borohydride and hydrazine hydrate, preferably hydrazine hydrate, and the yield and quality of the product are higher than those of sodium borohydride due to sodium sulfite and glucose.
Further, the molar ratio of the reducing agent S3 to the compound B is 1-3: 1.
Compared with the prior art, the invention has the beneficial effects that:
1. the oxidation of amino is firstly carried out, the activity of hydroxyl on 6 position is improved, the condition of chlorination reaction is reduced, and the chlorination reaction is better carried out;
2. the solvent adopted by the oxidation reaction of the invention enables guanine to be dissolved, and the reaction system is a homogeneous reaction, so that the reaction is better carried out, and particularly, when 2-15% of alkaline water is used as the solvent, the reaction is safer;
3. the oxidant used in the invention is safe and environment-friendly, and has no by-product;
4. the chlorination reagent used in the invention can obtain a purified product only by distillation after the post-treatment, and does not need to be washed by water. Simple operation and can reduce the generation of waste water.
5. In the whole reaction process, the used raw and auxiliary materials are cheap and easy to obtain, the production cost of the product is reduced, and the competitiveness of an enterprise is improved.
6. The whole reaction system has mild conditions and simple and convenient operation, and is suitable for industrial production.
7. The preparation method of the invention enables the yield of the 2-amino-6-chloropurine to reach 81.6 percent, and greatly improves the yield compared with the yield of the synthesis process of the 2-amino-6-chloropurine in the prior art.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1
100g of 2% alkaline water and 15g of guanine are added into a reactor, stirring is started, the temperature is controlled below 20 ℃, 3.5g of hydrogen peroxide is slowly dripped, and after dripping is finished, the temperature is controlled at 20 ℃ and stirring is carried out for about 1.2 hours. Until the reaction of the raw material guanine is finished, filtering and drying after the reaction is finished to obtain A16 g, which is directly used for the next reaction.
And (3) putting the product A in the previous step into a reactor, adding 50g of methanol, stirring and cooling to 0-5 ℃, slowly dropwise adding 12g of thionyl chloride, keeping the temperature and stirring for 20min after dropwise adding, heating and carrying out reflux reaction until the raw materials react completely, and carrying out reduced pressure concentration to obtain 16.8g of B.
Putting the B into a reaction bottle, adding methanol, stirring, heating to about 50 ℃, dropwise adding 10g of hydrazine hydrate, heating for reflux reaction after dropwise adding is finished until the raw materials are reacted, cooling, filtering and drying,
the product C, i.e., 11.9g of 2-amino-6-chloropurine, was obtained in an overall yield of 70% and a purity of 99.8%.
Example 2
100g of 10% alkaline water and 15g of guanine are added into a reactor, stirring is started, the temperature is controlled below 20 ℃, 10g of sodium hypochlorite is slowly dripped, and after dripping is finished, stirring is carried out for about 1.5 hours at the temperature of 30 ℃. Until the reaction of the raw material guanine was completed, after the reaction was completed, the mixture was filtered and dried to obtain 15.2g of A, which was used directly in the next reaction.
And (3) putting the product A in the step into a reactor, adding 60g of methanol, stirring and cooling to 0-5 ℃, slowly dropwise adding 15g of thionyl chloride, keeping the temperature and stirring for 20min after dropwise adding, heating and carrying out reflux reaction until the raw materials react completely, and carrying out reduced pressure concentration to obtain 15.8g of B.
Putting the B into a reaction bottle, adding methanol, stirring, heating to about 50 ℃, dropwise adding 20g of hydrazine hydrate, heating for reflux reaction after dropwise adding is finished until the raw materials are reacted, cooling, filtering and drying,
the product C, i.e., 2-amino-6-chloropurine, was obtained in 12.8g, yield 75.8% and purity 99.9%.
Example 3
Adding 100g of 15% alkaline water and 15g of guanine into a reactor, starting stirring, controlling the temperature below 20 ℃, slowly dropwise adding 10g of hydrogen peroxide, and controlling the temperature at 20 ℃ and stirring for about 2 hours after dropwise adding. Until the reaction of the raw material guanine was completed, the reaction was filtered and dried to obtain 17.2g of A, which was used directly in the next reaction.
And (3) putting the product A in the step into a reactor, adding 50g of methanol, stirring and cooling to 0-5 ℃, slowly dropwise adding 12g of thionyl chloride, keeping the temperature and stirring for 20min after dropwise adding, heating and carrying out reflux reaction until the raw materials react completely, and carrying out reduced pressure concentration to obtain 17g of B.
Putting the B into a reaction bottle, adding methanol, stirring, heating to about 50 ℃, dropwise adding 20g of hydrazine hydrate, heating for reflux reaction after dropwise adding is finished until the raw materials are reacted, cooling, filtering and drying,
13.8g of the product C, i.e. 2-amino-6-chloropurine, was obtained in a yield of 81.6% and a purity of 99.7%.
Example 4
150g of 5% alkaline water and 15g of guanine are added into a reactor, stirring is started, the temperature is controlled below 20 ℃, 10g of hydrogen peroxide is slowly dripped, and after the dripping is finished, the temperature is controlled at 20 ℃ and stirring is carried out for about 1 hour. Until the reaction of the raw material guanine was completed, after the reaction was completed, A17.1g was obtained by filtration and drying, and was used directly in the next reaction.
And (3) putting the product A in the previous step into a reactor, adding 100g of dichloroethane, stirring and cooling to 0-5 ℃, slowly dropwise adding 16g of phosphorus oxychloride, keeping the temperature and stirring for 20min after dropwise adding, heating and carrying out reflux reaction until the raw materials react completely, adding water for washing, and carrying out reduced pressure concentration on an organic layer to obtain 14.2g of B.
Putting the B into a reaction bottle, adding methanol, stirring, heating to about 50 ℃, dropwise adding 15g of hydrazine hydrate, heating for reflux reaction after dropwise adding is finished until the raw materials are reacted, cooling, filtering and drying,
the product C, i.e., 11.2g of 2-amino-6-chloropurine, was obtained in 66.7% yield and 99.7% purity.
Example 5
100g of N, N-dimethylformamide and 15g of guanine are put into a reactor, stirring is started, the temperature is controlled below 20 ℃, 10g of sodium hypochlorite is slowly dripped, and after the dripping is finished, the temperature is controlled at 30 ℃ and stirring is carried out for about 2 hours. Until the reaction of the raw material guanine is completed, after the reaction is completed, A13 g is obtained by filtration and drying and is directly used for the next reaction.
And (3) putting the product A in the previous step into a reactor, adding 50g of ethanol, stirring, cooling to 0-5 ℃, slowly dropwise adding 12g of phosphorus oxychloride, keeping the temperature and stirring for 20min after dropwise adding, heating, carrying out reflux reaction until the raw materials react completely, and carrying out reduced pressure concentration to obtain 13.5g of B.
Adding B into a reaction bottle, adding 40g of ethanol, stirring, heating to about 50 ℃, dropwise adding 10g of sodium sulfite, heating to perform reflux reaction after dropwise adding is finished, cooling, filtering, drying,
the product C, i.e., 9.8g of 2-amino-6-chloropurine, was obtained in 58% yield and 98.5% purity.
Example 6
100g of dichloromethane and 15g of guanine are put into a reactor, stirring is started, 10g of peroxyacetic acid is slowly dripped into the reactor at the temperature of below 20 ℃, and after dripping is finished, the reactor is stirred for about 1.5 hours at the temperature of 15 ℃. Until the reaction of the raw material guanine is finished, filtering and drying after the reaction is finished to obtain A16 g, which is directly used for the next reaction.
And (2) putting the product A in the previous step into a reactor, adding 50g of dichloromethane, stirring and cooling to 0-5 ℃, slowly dropwise adding 25g of phosphorus pentachloride, keeping the temperature and stirring for 20min after dropwise adding, heating and carrying out reflux reaction until the raw materials are reacted completely, and concentrating under reduced pressure to obtain 16.5g of B16.
Adding B into a reaction bottle, adding 60g of dichloromethane, stirring, heating to about 50 ℃, dropwise adding 20g of glucose, heating after dropwise adding, carrying out reflux reaction until the raw materials are reacted, cooling, filtering, drying,
10.5g of the product C, i.e. 2-amino-6-chloropurine, was obtained with a yield of 62.1% and a purity of 98.8%.
Example 7
100g of dichloroethane and 15g of guanine are added into a reactor, stirring is started, 10g of peroxyacetic acid is slowly dripped into the reactor at the temperature of below 20 ℃, and after dripping is finished, the reactor is stirred for about 2 hours at the temperature of 25 ℃. Until the reaction of the raw material guanine is finished, after the reaction is finished, the raw material guanine is filtered and dried to obtain A15.7g which is directly used for the next reaction.
And (3) putting the product A in the step into a reactor, adding 50g of dichloroethane, stirring, cooling to 0-5 ℃, introducing 10g of chlorine, stirring for 20min at a constant temperature after dropwise addition, heating, carrying out reflux reaction until the raw materials react completely, and concentrating under reduced pressure to obtain 15.6g of B.
Putting B into a reaction bottle, adding 50g of dichloroethane, stirring and heating to about 50 ℃, dropwise adding 5g of sodium borohydride, heating and refluxing after dropwise adding until the raw materials react completely, cooling, filtering and drying,
10.6g of the product C, i.e., 2-amino-6-chloropurine, was obtained in 62.7% yield and 99.5% purity.
Claims (10)
1. The method for preparing 2-amino-6-chloropurine is characterized by comprising the following process routes:
the method comprises the following steps:
s1: taking guanine as a raw material, mixing the guanine and a solvent, stirring, controlling the temperature to be below 20 ℃, slowly dripping an oxidant, and controlling the oxidation reaction temperature to be 15-30 ℃; stirring until the guanine reaction is completed, namely the oxidation reaction is finished, filtering and drying to obtain a compound shown as a formula A, wherein the compound shown as the formula A can be directly used for the next reaction;
s2: adding a solvent into the A obtained in the step S1, stirring, cooling to 0-5 ℃, slowly adding the chlorinating agent dropwise, keeping the temperature, stirring, heating, refluxing until the compound A is completely reacted to obtain a chlorination reaction, adding water, washing, and concentrating an organic layer under reduced pressure to obtain a compound shown in a formula B;
s3: adding the B obtained in the step S2 into a solvent, stirring, heating to 50 ℃, dropwise adding a reducing agent, heating, refluxing until the reduction reaction is finished, cooling, filtering and drying to obtain a compound shown in a formula C, namely 2-amino-6-chloropurine;
s1, the solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, dichloromethane and dichloroethane, or 2-15% alkaline water;
s1, the oxidant is a liquid oxidant and comprises one or more of hydrogen peroxide, sodium hypochlorite and peroxyacetic acid;
the solvent in S2 and S3 is one or more of methanol, ethanol, dichloromethane and dichloroethane;
s2, the chlorinating agent is one or a mixture of more of phosphorus oxychloride, phosphorus pentachloride, thionyl chloride and chlorine;
s3 the reducing agent is one or more of sodium sulfite, glucose, hydroxylamine, sodium borohydride and hydrazine hydrate.
2. The method for producing 2-amino-6-chloropurine according to claim 1, wherein the oxidation reaction temperature of S1 is 20 to 25 ℃.
3. The method of claim 1, wherein the solvent of S1 is 2% to 15% aqueous base.
4. The method for preparing 2-amino-6-chloropurine according to claim 1, wherein the oxidant S1 is hydrogen peroxide.
5. The method for preparing 2-amino-6-chloropurine according to claim 1, wherein the molar ratio of the oxidant to guanine in S1 is 1:3 to 1.
6. The process for preparing 2-amino-6-chloropurine according to claim 1, wherein the solvent used in S2 or S3 is methanol.
7. The process for producing 2-amino-6-chloropurine according to claim 1, wherein the chlorinating reagent S2 is thionyl chloride.
8. The method for preparing 2-amino-6-chloropurine according to claim 1, wherein the molar ratio of the chlorinating reagent S2 to the compound A is 1-3: 1.
9. The method for producing 2-amino-6-chloropurine according to claim 1, wherein the reducing agent of S3 is hydrazine hydrate.
10. The method for producing 2-amino-6-chloropurine according to claim 1, wherein the molar ratio of the reducing agent S3 to the compound B is 1 to 3: 1.
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| 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 |
| 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 |
| 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 |
| CN114621228B (en) * | 2022-04-19 | 2023-06-30 | 杭州丰禾生物技术有限公司 | Preparation method of 2-amino-6-chloropurine |
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| 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 |
| CN101899045A (en) * | 2010-04-15 | 2010-12-01 | 中国人民解放军第二军医大学 | 9-substituted-2-amino-6-guanidyl purine compounds as well as preparation method and application thereof |
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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 |
| 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 |
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| 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 |
| CN101899045A (en) * | 2010-04-15 | 2010-12-01 | 中国人民解放军第二军医大学 | 9-substituted-2-amino-6-guanidyl purine compounds as well as preparation method and application thereof |
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