WO2019174101A1 - Method for preparing tenofovir - Google Patents

Method for preparing tenofovir Download PDF

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WO2019174101A1
WO2019174101A1 PCT/CN2018/083638 CN2018083638W WO2019174101A1 WO 2019174101 A1 WO2019174101 A1 WO 2019174101A1 CN 2018083638 W CN2018083638 W CN 2018083638W WO 2019174101 A1 WO2019174101 A1 WO 2019174101A1
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compound
formula
reaction
solvent
added
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PCT/CN2018/083638
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叶方国
林海滨
田松川
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安徽华昌高科药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Definitions

  • the invention relates to the field of chemical synthesis, in particular to a preparation method of tenofovir.
  • Tenofovir chemical name (R)-9-(2-phosphomethoxypropyl) adenine (PMPA, formula I), is a novel nucleotide-based reverse transcriptase inhibitor that has been confirmed It has good antiviral activity against HIV and HBV viruses.
  • prodrugs that use tenofovir as an active ingredient in the body, namely tenofovir disoproxil and tenofovir alafenamide. These two prodrugs have a variety of pharmaceutical preparations for sale in the market, and because of their good antiviral activity and safety, they have become important therapeutic drugs in the field of anti-AIDS and anti-hepatitis B.
  • Truvada which contains tenofovir disoproxil developed by Gilead Scientific, has sales of $3.56 billion in 2016; and Genvoya, which developed tenofovir alafenamide, was acquired in 2015. Approved for listing, sales in 2016 have reached $ 1.48 billion.
  • the preparation of tenofovir is basically based on adenine as a raw material, and (R)-(+)-9-(2-hydroxypropyl)adenine is prepared by substitution reaction with (R)-propylene carbonate (Formula XIII). And then synthesized with DESMP (formula VI) by substitution reaction and hydrolysis reaction to obtain tenofovir.
  • Adenine has important biological effects, both biological and chemical. At present, adenosine is mainly obtained by biological fermentation, and then adenine is obtained by enzyme digestion under the catalysis of biological enzyme.
  • An important drawback of biosynthesis is the production of large amounts of wastewater, which is costly in environmentally friendly treatment. The demand for adenine is large, and it is in short supply in the country, causing a sharp rise in prices, which greatly increases the manufacturing cost of tenofovir.
  • the present invention provides a novel method for preparing tenofovir.
  • the method provided has the advantages that the raw materials are cheap and easy to obtain, the process route is short, the conditions are mild and reliable, and the invention is easy to be used for industrial production.
  • the present invention provides the following technical solutions:
  • the present invention provides a compound having the structure shown in Formula XII;
  • the invention also provides the use of the compounds described in the preparation of tenofovir.
  • the invention also provides a preparation method of the compound, wherein the compound represented by the formula XI is prepared by using a compound represented by the formula IV as a raw material; in the presence of a solvent, the action of the organic base, the formula XI The compound is reacted with a compound of formula V to give a compound XII;
  • the solvent is selected from the group consisting of 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran or 2-methyltetrahydrofuran;
  • the organic base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, and N-methylmorpholine;
  • the temperature of the substitution reaction is 50 to 150 ° C, and the amount of the compound represented by the formula V is 0.9 to 1.5 equivalents.
  • the temperature of the substitution reaction is preferably 80 to 120 ° C, more preferably 100 to 110 ° C.
  • the compound of the formula V is preferably used in an amount of from 1.0 to 1.1 equivalents.
  • the method for preparing the compound further comprises the step of purifying, the purified solvent being a beating purification solvent selected from the group consisting of methanol, ethanol, isopropanol, and tert-butanol.
  • the purified solvent being a beating purification solvent selected from the group consisting of methanol, ethanol, isopropanol, and tert-butanol.
  • the invention also provides a preparation method of tenofovir, comprising the following steps:
  • Step 1 using the compound of the formula IV as a starting material, the compound of the formula XI is obtained by a formylation reaction;
  • Step 2 reacting a compound of the formula XI with a compound of the formula V by an organic base in the presence of a solvent to obtain a compound of the formula XII;
  • Step 3 in the presence of a solvent, a compound of the formula XIII undergoes a substitution reaction to obtain a compound of the formula XIV;
  • Step 4 a compound represented by the formula XIV is substituted with a compound of the formula VI, DESMP, and a hydrolysis reaction is carried out under the action of an acid to obtain tenofovir of the formula I;
  • the solvent in the step 2 is selected from the group consisting of 1,4-dioxane, N, N-dimethylformamide, Tetrahydrofuran or 2-methyltetrahydrofuran;
  • the organic base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine;
  • the temperature of the substitution reaction is 50 to 150 ° C, the formula V
  • the compound is shown in an amount of from 0.9 to 1.5 equivalents.
  • the temperature of the substitution reaction is preferably 80 to 120 ° C, more preferably 100 to 110 ° C.
  • the compound of the formula V is preferably used in an amount of from 1.0 to 1.1 equivalents.
  • the compound of the formula XI in the step 2 is reacted with the compound of the formula V to further comprise a purification step, the purified solvent.
  • the solvent is purified for beating and is selected from the group consisting of methanol, ethanol, isopropanol and tert-butanol.
  • the reaction solvent in the step 2 is selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone or N.
  • N-dimethylacetamide the dehydrating agent is selected from trimethyl orthoformate or triethyl orthoformate
  • the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and nitric acid
  • the reaction temperature of the dehydration cyclization is from 0 to 50 ° C. . It is preferably 20 to 30 °C.
  • the step further comprises a step of purifying, the purified solvent is a beating purification solvent, and is selected from the group consisting of methanol and ethanol. , isopropanol, tert-butanol.
  • the solvent in the step 3 is selected from the group consisting of 1,4-dioxane, N, N-dimethylformamide, Tetrahydrofuran or 2-methyltetrahydrofuran; the temperature of the substitution reaction is 80 to 200 °C. It is preferably 90 to 150 ° C, more preferably 100 to 110 ° C.
  • the step 3 after the substitution reaction further comprises a step of purifying
  • the purified solvent is a beating purification solvent, and is selected from the group consisting of methanol and ethanol. Isopropanol, tert-butanol.
  • the solvent in the step 4 is selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone or dimethyl Sulfoxide;
  • the acid is selected from the group consisting of hydrobromic acid, sulfuric acid or hydrochloric acid; and the hydrolysis reaction is carried out at a temperature of 70 to 120 °C. It is preferably 80 to 110 ° C, more preferably 90 to 100 ° C.
  • the invention also provides a preparation method of tenofovir, comprising the following steps:
  • Step 1 using the compound of the formula IV as a starting material, the compound of the formula XI is obtained by a formylation reaction;
  • Step 2 in the presence of a solvent, by the action of an organic base, the compound of the formula XI and the compound of the formula V are substituted and cyclized to obtain a compound of the formula XIII;
  • Step 3 in the presence of a solvent, a compound of the formula XIII undergoes a substitution reaction to obtain a compound of the formula XIV;
  • Step 4 a compound of the formula XIV is substituted with a compound of the formula VI (DESMP), and then hydrolyzed by an acid to obtain tenofovir of the formula I;
  • DESMP compound of the formula VI
  • the solvent in the step 2 is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol or tert-butanol;
  • the organic base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine or N-methylmorpholine;
  • the reaction temperature of the substitution and cyclization is 40 to 120 ° C, preferably 60 to 100 ° C, more preferably 75 ⁇ 85 ° C;
  • the compound D-alaninol represented by the formula V is used in an amount of 0.9 to 1.5 equivalents. It is preferably 1.0 to 1.1 equivalents.
  • the step further comprises a step of purifying, the purified solvent is a beating purification solvent, and is selected from the group consisting of methanol and ethanol. , isopropanol, tert-butanol.
  • the solvent in the step 3 is selected from the group consisting of 1,4-dioxane, N, N-dimethylformamide, Tetrahydrofuran or 2-methyltetrahydrofuran; the temperature of the substitution reaction is 80 to 200 °C. It is preferably 90 to 150 ° C, more preferably 100 to 110 ° C.
  • the step 3 after the substitution reaction further comprises a step of purifying
  • the purified solvent is a beating purification solvent, and is selected from the group consisting of methanol and ethanol. Isopropanol, tert-butanol.
  • the solvent in the step 4 is selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone or dimethyl Sulfoxide;
  • the acid is selected from the group consisting of hydrobromic acid, sulfuric acid or hydrochloric acid; and the hydrolysis reaction is carried out at a temperature of 70 to 120 °C. It is preferably 80 to 110 ° C, more preferably 90 to 100 ° C.
  • the present invention provides a novel method of preparing tenofovir.
  • the method provided has the advantages that the raw materials are cheap and easy to obtain, the process route is short, the conditions are mild and reliable, and it is easy to be used in industrial production.
  • Figure 1 shows a prior art preparation method in the background art
  • Figure 2 shows the preparation method provided by the present invention
  • Figure 3 shows a 1 H NMR chart of Compound XI
  • Figure 4 shows an MS chart of Compound XI
  • Figure 5 shows a 1 H NMR chart of Compound XII
  • Figure 6 shows an MS chart of Compound XII.
  • the invention discloses a preparation method of tenofovir, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
  • the invention provides a method for preparing tenofovir:
  • compound XI is substituted with D-alaninol (formula V) under the action of an organic base to obtain compound XII, which is a new compound not reported;
  • suitable solvent 1,4- Dioxane, N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran;
  • organic base triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine; reaction temperature: 50 -150 ° C, preferably 80-120 ° C, more preferably 100-110 ° C;
  • D-alaninol dosage 0.9-1.5 equivalents, preferably 1.0-1.1 equivalents; pulping purification solvent: methanol, ethanol, isopropanol, tert-butanol .
  • Compound XII is dehydrated and cyclized in a suitable solvent in the presence of an acid to give a compound XIII; suitable solvents: N, N-dimethylformamide, N-methylpyrrolidone, N, N - dimethylacetamide; dehydrating agent: trimethyl orthoformate, triethyl orthoformate; acid: hydrochloric acid, sulfuric acid, nitric acid; reaction temperature: 0-50 ° C, preferably 20-30 ° C, beating purification solvent: methanol, Ethanol, isopropanol, tert-butanol.
  • suitable solvents N, N-dimethylformamide, N-methylpyrrolidone, N, N - dimethylacetamide
  • dehydrating agent trimethyl orthoformate, triethyl orthoformate
  • acid hydrochloric acid, sulfuric acid, nitric acid
  • reaction temperature 0-50 ° C, preferably 20-30 ° C
  • beating purification solvent methanol, E
  • compound XI and D-alaninol (formula V) are simultaneously substituted and cyclized to directly obtain compound XIII;
  • suitable solvents methanol, ethanol, propanol, isopropanol, n-butanol, Tert-butanol; organic base: triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine; reaction temperature: 40-120 ° C, preferably 60-100 ° C, more preferably 75-85 ° C;
  • D- Alanine dosage 0.9-1.5 equivalents, preferably 1.0-1.1 equivalents;
  • a suitable solvent 1,4-dioxane, N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran; ammonia source: Ammonia water, ammonia gas, ammonia methanol solution; reaction temperature: 80-200 ° C, preferably 90-150 ° C, more preferably 100-110 ° C; beating purification solvent: methanol, ethanol, isopropanol, tert-butanol.
  • the present invention provides a novel method of preparing tenofovir.
  • the method provided has the advantages that the raw materials are cheap and easy to obtain, the process route is short, the conditions are mild and reliable, and the invention is easy to be used for industrial production.
  • the raw materials, excipients and reagents used in the preparation method of tenofovir provided by the present invention are commercially available.
  • the aqueous phase was extracted once more with 55.0 mL of dichloromethane.
  • the organic phases were combined, concentrated to dryness under reduced pressure at 50 ° C, and then evaporated and evaporated.
  • the crude product was concentrated to dryness, and then 10.0 mL of ethanol was added, and the mixture was beaten for 30 minutes and filtered.
  • the filter cake was dried to give 7.5 g of compound XIII as a yellow solid product with a purity of 98.3% and a yield of 81.5%.
  • the mixture was stirred at 50 ° C for 3 hours. Naturally cool to room temperature and stir for 10 to 12 hours. After filtration, the filter cake was washed with 0.8 kg of water to give a crude product. The obtained crude product and 18 kg of water were added to the reaction vessel, and the mixture was heated to 100-105 ° C, and stirred until the system was dissolved. Naturally cool to 10 ° C and stir for 2 hours. Filtration, the filter cake was washed with 1.0 kg of ice water, and the filter cake was dried to obtain 1.10 kg of Compound I as a white solid with a purity of 99.12% and a yield of 59.2%.
  • reaction was quenched by the addition of water, and extracted three times with dichloromethane, and washed with saturated sodium hydrogen carbonate solution, brine, and distilled water. The organic phase was dried over anhydrous sodium sulfate for 5 hr and filtered over EtOAc. The filtrate was concentrated under reduced pressure to give a crude material. Toluene was added to the crude product, and the mixture was heated to dissolve, and the solid was slowly precipitated.

Abstract

The present invention relates to the field of chemical synthesis, and in particular to a method for preparing tenofovir. The compound provided by the present invention has the structure as shown in formula (XII); and the method for preparing tenofovir based on the compound has the advantages of cheap and readily available raw materials, short process route, mild and reliable conditions, being easily applied to industrial production, etc.

Description

一种替诺福韦的制备方法Preparation method of tenofovir
本申请要求于2018年03月16日提交中国专利局、申请号为201810219215.0、发明名称为“一种替诺福韦的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。The present application claims priority to Chinese Patent Application No. 201101219215.0, the entire disclosure of which is hereby incorporated by reference. In the application.
技术领域Technical field
本发明涉及化学合成领域，特别涉及一种替诺福韦的制备方法。The invention relates to the field of chemical synthesis, in particular to a preparation method of tenofovir.
背景技术Background technique
替诺福韦，化学名为(R)-9-(2-磷酸甲氧基丙基)腺嘌呤(PMPA,式I),是一种新型核苷酸类逆转录酶抑制剂，已被确证对HIV病毒和HBV病毒具有良好的抗病毒活性。目前，已有两种以替诺福韦为体内活性成分的前药上市，即替诺福韦二吡呋酯和替诺福韦艾拉酚胺。这两种前药分别有多种成药制剂在市场销售，由于其良好的抗病毒活性和安全性，在抗艾滋病和抗乙肝领域成为了重要的治疗药物。例如，美国吉利德科学公司开发的含替诺福韦二吡呋酯的Truvada，2016年销售额到达35.6亿美元；而其开发的含替诺福韦艾拉酚胺的Genvoya,2015年才获得批准上市，2016年销售额就已到达14.8亿美元。2017年替诺福韦二吡呋酯在国内已有多家制药公司获得了上市批文。由于全球庞大的艾滋病和乙肝患者，因此对替诺福韦的需求也是巨大的。Tenofovir, chemical name (R)-9-(2-phosphomethoxypropyl) adenine (PMPA, formula I), is a novel nucleotide-based reverse transcriptase inhibitor that has been confirmed It has good antiviral activity against HIV and HBV viruses. At present, there are two prodrugs that use tenofovir as an active ingredient in the body, namely tenofovir disoproxil and tenofovir alafenamide. These two prodrugs have a variety of pharmaceutical preparations for sale in the market, and because of their good antiviral activity and safety, they have become important therapeutic drugs in the field of anti-AIDS and anti-hepatitis B. For example, Truvada, which contains tenofovir disoproxil developed by Gilead Scientific, has sales of $3.56 billion in 2016; and Genvoya, which developed tenofovir alafenamide, was acquired in 2015. Approved for listing, sales in 2016 have reached $ 1.48 billion. In 2017, tenofovir disoproxil has received approvals from several pharmaceutical companies in China. Due to the huge global AIDS and hepatitis B patients, the demand for tenofovir is also huge.
Figure PCTCN2018083638-appb-000001
Figure PCTCN2018083638-appb-000001
替诺福韦的制备基本都是以腺嘌呤为原料，与(R)-碳酸丙烯酯发生取代反应制得(R)-(+)-9-(2-羟丙基)腺嘌呤(式XIII)，再与DESMP(式VI)经取代反应和水解反应合成得到替诺福韦。腺嘌呤具有重要的生物作用，有生物和化学两种合成方法。目前主要采用生物发酵法得到腺苷，再在生物酶的催化作用下进行酶切得到腺嘌呤。生物合成法的重要缺陷就是产生大量的废水，在环保处理上成本高。腺嘌呤市场需求量大，在国内已是供 不应求的局面，造成价格大幅上涨，极大推高了替诺福韦的制造成本。The preparation of tenofovir is basically based on adenine as a raw material, and (R)-(+)-9-(2-hydroxypropyl)adenine is prepared by substitution reaction with (R)-propylene carbonate (Formula XIII). And then synthesized with DESMP (formula VI) by substitution reaction and hydrolysis reaction to obtain tenofovir. Adenine has important biological effects, both biological and chemical. At present, adenosine is mainly obtained by biological fermentation, and then adenine is obtained by enzyme digestion under the catalysis of biological enzyme. An important drawback of biosynthesis is the production of large amounts of wastewater, which is costly in environmentally friendly treatment. The demand for adenine is large, and it is in short supply in the country, causing a sharp rise in prices, which greatly increases the manufacturing cost of tenofovir.
因此，开发非腺嘌呤为原料的替诺福韦制备方法，具有重要意义。有文献报道了以4，6-二羟基嘧啶(式II)和(2R)-羟基丙胺(式V)为原料的合成方法。但是，在这一方法中，化合物IX的氨解反应容易产生磷酰胺杂质，从而在替诺福韦产品中引入了新的杂质，影响了产品质量。Therefore, it is of great significance to develop a preparation method of tenofovir which is not adenine. A synthetic method using 4,6-dihydroxypyrimidine (formula II) and (2R)-hydroxypropylamine (formula V) as a starting material has been reported in the literature. However, in this method, the aminolysis reaction of the compound IX easily causes phosphoramide impurities, thereby introducing new impurities into the tenofovir product, which affects the product quality.
发明内容Summary of the invention
有鉴于此，为了开发非腺嘌呤的制备方法，并克服现有合成方法存在的诸多问题，本发明提供了一种新的制备替诺福韦的方法。所提供的方法具有原料廉价易得，工艺路线短，条件温和可靠，易于用于工业化生产等优点。In view of this, in order to develop a non-adenine preparation method and overcome many problems existing in the prior art synthesis method, the present invention provides a novel method for preparing tenofovir. The method provided has the advantages that the raw materials are cheap and easy to obtain, the process route is short, the conditions are mild and reliable, and the invention is easy to be used for industrial production.
为了实现上述发明目的，本发明提供以下技术方案：In order to achieve the above object, the present invention provides the following technical solutions:
本发明提供了一种化合物，其结构如式XII所示；The present invention provides a compound having the structure shown in Formula XII;
Figure PCTCN2018083638-appb-000002
Figure PCTCN2018083638-appb-000002
本发明还提供了所述的化合物在制备替诺福韦中的应用。The invention also provides the use of the compounds described in the preparation of tenofovir.
本发明还提供了所述的化合物的制备方法，以式Ⅳ所示化合物为原料，通过甲酰化反应制得式XI所示化合物；在溶剂存在的条件下，通过有机碱作用，式XI所示化合物与式V所示化合物发生取代反应，得到化合物XII；The invention also provides a preparation method of the compound, wherein the compound represented by the formula XI is prepared by using a compound represented by the formula IV as a raw material; in the presence of a solvent, the action of the organic base, the formula XI The compound is reacted with a compound of formula V to give a compound XII;
Figure PCTCN2018083638-appb-000003
Figure PCTCN2018083638-appb-000003
在本发明的一些具体实施方案中，所述的化合物的制备方法中所述溶剂选自1,4-二氧六环，N、N-二甲基甲酰胺，四氢呋喃或2-甲基四氢呋喃；所述有机碱选自三乙胺、二异丙基乙胺、吡啶、N-甲基吗啉；所述取代 反应的温度为50～150℃，所述式V所示化合物的用量为0.9～1.5当量。所述取代反应的温度优选80～120℃，更优选100～110℃。所述式V所示化合物的用量优选1.0～1.1当量。In some embodiments of the present invention, the solvent is selected from the group consisting of 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran or 2-methyltetrahydrofuran; The organic base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, and N-methylmorpholine; the temperature of the substitution reaction is 50 to 150 ° C, and the amount of the compound represented by the formula V is 0.9 to 1.5 equivalents. The temperature of the substitution reaction is preferably 80 to 120 ° C, more preferably 100 to 110 ° C. The compound of the formula V is preferably used in an amount of from 1.0 to 1.1 equivalents.
在本发明的一些具体实施方案中，所述的化合物的制备方法中还包括纯化的步骤，所述纯化的溶剂为打浆纯化溶剂，选自甲醇、乙醇、异丙醇、叔丁醇。In some embodiments of the present invention, the method for preparing the compound further comprises the step of purifying, the purified solvent being a beating purification solvent selected from the group consisting of methanol, ethanol, isopropanol, and tert-butanol.
本发明还提供了一种替诺福韦的制备方法，包括如下步骤：The invention also provides a preparation method of tenofovir, comprising the following steps:
步骤1：以式Ⅳ所示化合物为原料，通过甲酰化反应制得式XI所示化合物；Step 1: using the compound of the formula IV as a starting material, the compound of the formula XI is obtained by a formylation reaction;
步骤2：在溶剂存在的条件下，通过有机碱作用，式XI所示化合物与式V所示化合物发生反应，得到式XII所示化合物；Step 2: reacting a compound of the formula XI with a compound of the formula V by an organic base in the presence of a solvent to obtain a compound of the formula XII;
在反应溶剂和酸存在的条件下，式XII所示化合物与脱水剂作用经脱水环化，得到式XIII所示化合物；In the presence of a reaction solvent and an acid, the compound of the formula XII is dehydrated and cyclized with a dehydrating agent to give a compound of the formula XIII;
步骤3：在溶剂存在的条件下，式XIII所示化合物发生取代反应，得到式XIV所示化合物；Step 3: in the presence of a solvent, a compound of the formula XIII undergoes a substitution reaction to obtain a compound of the formula XIV;
步骤4：式XIV所示化合物与式VI所示化合物DESMP发生取代反应，在酸的作用下发生水解反应，得到式I所示替诺福韦；Step 4: a compound represented by the formula XIV is substituted with a compound of the formula VI, DESMP, and a hydrolysis reaction is carried out under the action of an acid to obtain tenofovir of the formula I;
Figure PCTCN2018083638-appb-000004
Figure PCTCN2018083638-appb-000004
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤2中所述溶剂选自1,4-二氧六环,N、N-二甲基甲酰胺，四氢呋喃或2-甲基四氢呋喃；所述有机碱选自三乙胺、二异丙基乙胺、吡啶、N-甲基吗啉；所述取代反应的温度为50～150℃，所述式V所示化合物的用量为0.9～1.5当量。所述取代反应的温度优选80～120℃，更优选100～110℃。所述式V所示化合物的用量优选1.0～1.1当量。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, the solvent in the step 2 is selected from the group consisting of 1,4-dioxane, N, N-dimethylformamide, Tetrahydrofuran or 2-methyltetrahydrofuran; the organic base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine; the temperature of the substitution reaction is 50 to 150 ° C, the formula V The compound is shown in an amount of from 0.9 to 1.5 equivalents. The temperature of the substitution reaction is preferably 80 to 120 ° C, more preferably 100 to 110 ° C. The compound of the formula V is preferably used in an amount of from 1.0 to 1.1 equivalents.
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤2中式XI所示化合物与式V所示化合物发生反应后还包括纯化 的步骤，所述纯化的溶剂为打浆纯化溶剂，选自甲醇、乙醇、异丙醇、叔丁醇。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, the compound of the formula XI in the step 2 is reacted with the compound of the formula V to further comprise a purification step, the purified solvent. The solvent is purified for beating and is selected from the group consisting of methanol, ethanol, isopropanol and tert-butanol.
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤2中所述反应溶剂选自N、N-二甲基甲酰胺、N-甲基吡咯烷酮或N、N-二甲基乙酰胺；所述脱水剂选自原甲酸三甲酯或原甲酸三乙酯；所述酸选自盐酸、硫酸、硝酸；所述脱水环化的反应温度：0～50℃。优选20～30℃。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, the reaction solvent in the step 2 is selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone or N. N-dimethylacetamide; the dehydrating agent is selected from trimethyl orthoformate or triethyl orthoformate; the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and nitric acid; and the reaction temperature of the dehydration cyclization is from 0 to 50 ° C. . It is preferably 20 to 30 °C.
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤2脱水环化后还包括纯化的步骤，所述纯化的溶剂为打浆纯化溶剂，选自甲醇、乙醇、异丙醇、叔丁醇。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, after the step of dehydration cyclization, the step further comprises a step of purifying, the purified solvent is a beating purification solvent, and is selected from the group consisting of methanol and ethanol. , isopropanol, tert-butanol.
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤3中所述溶剂选自1,4-二氧六环,N、N-二甲基甲酰胺，四氢呋喃或2-甲基四氢呋喃；所述取代反应的温度为80～200℃。优选90～150℃，更优选100～110℃。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, the solvent in the step 3 is selected from the group consisting of 1,4-dioxane, N, N-dimethylformamide, Tetrahydrofuran or 2-methyltetrahydrofuran; the temperature of the substitution reaction is 80 to 200 °C. It is preferably 90 to 150 ° C, more preferably 100 to 110 ° C.
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤3取代反应后还包括纯化的步骤，所述纯化的溶剂为打浆纯化溶剂，选自甲醇、乙醇、异丙醇、叔丁醇。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, the step 3 after the substitution reaction further comprises a step of purifying, the purified solvent is a beating purification solvent, and is selected from the group consisting of methanol and ethanol. Isopropanol, tert-butanol.
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤4中所述溶剂选自N、N-二甲基甲酰胺、N-甲基吡咯烷酮或或二甲亚砜；所述酸选自氢溴酸、硫酸或盐酸；所述水解反应的温度为70～120℃。优选80～110℃，更优选90～100℃。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, the solvent in the step 4 is selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone or dimethyl Sulfoxide; the acid is selected from the group consisting of hydrobromic acid, sulfuric acid or hydrochloric acid; and the hydrolysis reaction is carried out at a temperature of 70 to 120 °C. It is preferably 80 to 110 ° C, more preferably 90 to 100 ° C.
本发明还提供了一种替诺福韦的制备方法，包括如下步骤：The invention also provides a preparation method of tenofovir, comprising the following steps:
步骤1：以式Ⅳ所示化合物为原料，通过甲酰化反应制得式XI所示化合物；Step 1: using the compound of the formula IV as a starting material, the compound of the formula XI is obtained by a formylation reaction;
步骤2：在溶剂存在的条件下，通过有机碱作用，式XI所示化合物与式V所示化合物发生取代、环化反应，得到式XIII所示化合物；Step 2: in the presence of a solvent, by the action of an organic base, the compound of the formula XI and the compound of the formula V are substituted and cyclized to obtain a compound of the formula XIII;
步骤3：在溶剂存在的条件下，式XIII所示化合物发生取代反应，得到式XIV化合物；Step 3: in the presence of a solvent, a compound of the formula XIII undergoes a substitution reaction to obtain a compound of the formula XIV;
步骤4：式XIV所示化合物与式VI所示化合物(DESMP)发生取代 反应，再在酸的作用下发生水解反应，得到式I所示替诺福韦；Step 4: a compound of the formula XIV is substituted with a compound of the formula VI (DESMP), and then hydrolyzed by an acid to obtain tenofovir of the formula I;
Figure PCTCN2018083638-appb-000005
Figure PCTCN2018083638-appb-000005
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤2中所述溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇或叔丁醇；所述有机碱选自三乙胺、二异丙基乙胺、吡啶或N-甲基吗啉；所述取代、环化的反应温度为40～120℃，优选60～100℃，更优选75～85℃；所述式V所示化合物D-丙氨醇的用量为0.9～1.5当量。优选1.0～1.1当量。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, the solvent in the step 2 is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol or tert-butanol; The organic base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine or N-methylmorpholine; the reaction temperature of the substitution and cyclization is 40 to 120 ° C, preferably 60 to 100 ° C, more preferably 75 ～85 ° C; the compound D-alaninol represented by the formula V is used in an amount of 0.9 to 1.5 equivalents. It is preferably 1.0 to 1.1 equivalents.
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤2环化反应后还包括纯化的步骤，所述纯化的溶剂为打浆纯化溶剂，选自甲醇、乙醇、异丙醇、叔丁醇。In some embodiments of the present invention, in the preparation method of tenofovir provided by the present invention, after the cyclization reaction of step 2, the step further comprises a step of purifying, the purified solvent is a beating purification solvent, and is selected from the group consisting of methanol and ethanol. , isopropanol, tert-butanol.
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤3中所述溶剂选自1,4-二氧六环,N、N-二甲基甲酰胺，四氢呋喃或2-甲基四氢呋喃；所述取代反应的温度为80～200℃。优选90～150℃，更优选100～110℃。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, the solvent in the step 3 is selected from the group consisting of 1,4-dioxane, N, N-dimethylformamide, Tetrahydrofuran or 2-methyltetrahydrofuran; the temperature of the substitution reaction is 80 to 200 °C. It is preferably 90 to 150 ° C, more preferably 100 to 110 ° C.
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤3取代反应后还包括纯化的步骤，所述纯化的溶剂为打浆纯化溶剂，选自甲醇、乙醇、异丙醇、叔丁醇。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, the step 3 after the substitution reaction further comprises a step of purifying, the purified solvent is a beating purification solvent, and is selected from the group consisting of methanol and ethanol. Isopropanol, tert-butanol.
在本发明的一些具体实施方案中，本发明提供的替诺福韦的制备方法中，步骤4中所述溶剂选自N、N-二甲基甲酰胺、N-甲基吡咯烷酮或或二甲亚砜；所述酸选自氢溴酸、硫酸或盐酸；所述水解反应的温度为70～120℃。优选80～110℃，更优选90～100℃。In some embodiments of the present invention, in the method for preparing tenofovir provided by the present invention, the solvent in the step 4 is selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone or dimethyl Sulfoxide; the acid is selected from the group consisting of hydrobromic acid, sulfuric acid or hydrochloric acid; and the hydrolysis reaction is carried out at a temperature of 70 to 120 °C. It is preferably 80 to 110 ° C, more preferably 90 to 100 ° C.
本发明提供了一种新的制备替诺福韦的方法。所提供的方法具有原料 廉价易得，工艺路线短，条件温和可靠，易于用于工业化生产等优点。The present invention provides a novel method of preparing tenofovir. The method provided has the advantages that the raw materials are cheap and easy to obtain, the process route is short, the conditions are mild and reliable, and it is easy to be used in industrial production.
附图说明DRAWINGS
图1示背景技术中现有制备方法；Figure 1 shows a prior art preparation method in the background art;
图2示本发明提供的制备方法；Figure 2 shows the preparation method provided by the present invention;
图3示化合物XI的 1H NMR图； Figure 3 shows a 1 H NMR chart of Compound XI;
图4示化合物XI的MS图；Figure 4 shows an MS chart of Compound XI;
图5示化合物XII的 1H NMR图； Figure 5 shows a 1 H NMR chart of Compound XII;
图6示化合物XII的MS图。Figure 6 shows an MS chart of Compound XII.
具体实施方式detailed description
本发明公开了一种替诺福韦的制备方法，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。The invention discloses a preparation method of tenofovir, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
本发明提拱了一种替诺福韦的制备方法：The invention provides a method for preparing tenofovir:
1)以4，6-二氯-5-氨基嘧啶为原料，通过甲酰化反应得到化合物XI；1) using 4,6-dichloro-5-aminopyrimidine as a starting material, a compound XI is obtained by a formylation reaction;
2)在合适溶剂中，在有机碱的作用下化合物XI与D-丙氨醇(式V)发生取代反应，得到化合物XII,此化合物为未见报道的新化合物；合适溶剂：1,4-二氧六环,N、N-二甲基甲酰胺，四氢呋喃，2-甲基四氢呋喃；有机碱：三乙胺、二异丙基乙胺、吡啶、N-甲基吗啉；反应温度：50-150℃,优选80-120℃，更优选100-110℃；D-丙氨醇用量：0.9-1.5当量，优选1.0-1.1当量；打浆纯化溶剂：甲醇、乙醇、异丙醇、叔丁醇。2) In a suitable solvent, compound XI is substituted with D-alaninol (formula V) under the action of an organic base to obtain compound XII, which is a new compound not reported; suitable solvent: 1,4- Dioxane, N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran; organic base: triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine; reaction temperature: 50 -150 ° C, preferably 80-120 ° C, more preferably 100-110 ° C; D-alaninol dosage: 0.9-1.5 equivalents, preferably 1.0-1.1 equivalents; pulping purification solvent: methanol, ethanol, isopropanol, tert-butanol .
3)在合适的溶剂中，在酸存在下化合物XII与脱水剂作用经脱水环化，得到化合物XIII；合适的溶剂：N、N-二甲基甲酰胺、N-甲基吡咯烷酮、N、N-二甲基乙酰胺；脱水剂：原甲酸三甲酯、原甲酸三乙酯；酸：盐酸、硫酸、硝酸；反应温度：0-50℃,优选20-30℃，打浆纯化溶剂： 甲醇、乙醇、异丙醇、叔丁醇。3) Compound XII is dehydrated and cyclized in a suitable solvent in the presence of an acid to give a compound XIII; suitable solvents: N, N-dimethylformamide, N-methylpyrrolidone, N, N - dimethylacetamide; dehydrating agent: trimethyl orthoformate, triethyl orthoformate; acid: hydrochloric acid, sulfuric acid, nitric acid; reaction temperature: 0-50 ° C, preferably 20-30 ° C, beating purification solvent: methanol, Ethanol, isopropanol, tert-butanol.
4)在合适溶剂中，化合物XI与D-丙氨醇(式V)同时发生取代、环化反应，直接得到化合物XIII；合适溶剂：甲醇、乙醇、丙醇、异丙醇、正丁醇、叔丁醇；有机碱：三乙胺、二异丙基乙胺、吡啶、N-甲基吗啉；反应温度：40-120℃,优选60-100℃，更优选75-85℃；D-丙氨醇用量：0.9-1.5当量，优选1.0-1.1当量；4) In a suitable solvent, compound XI and D-alaninol (formula V) are simultaneously substituted and cyclized to directly obtain compound XIII; suitable solvents: methanol, ethanol, propanol, isopropanol, n-butanol, Tert-butanol; organic base: triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine; reaction temperature: 40-120 ° C, preferably 60-100 ° C, more preferably 75-85 ° C; D- Alanine dosage: 0.9-1.5 equivalents, preferably 1.0-1.1 equivalents;
5)在合适溶剂中，化合物XIII发生取代反应，得到化合物XIV；合适溶剂：1,4-二氧六环,N、N-二甲基甲酰胺，四氢呋喃，2-甲基四氢呋喃；氨源：氨水、氨气、氨气的甲醇溶液；反应温度：80-200℃,优选90-150℃，更优选100-110℃；打浆纯化溶剂：甲醇、乙醇、异丙醇、叔丁醇。5) In a suitable solvent, the compound XIII is subjected to a substitution reaction to obtain a compound XIV; a suitable solvent: 1,4-dioxane, N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran; ammonia source: Ammonia water, ammonia gas, ammonia methanol solution; reaction temperature: 80-200 ° C, preferably 90-150 ° C, more preferably 100-110 ° C; beating purification solvent: methanol, ethanol, isopropanol, tert-butanol.
6)化合物XIV，与DESMP发生取代反应，再在酸的作用下发生水解反应，得到替诺福韦(式I)。6) Compound XIV, which undergoes a substitution reaction with DESMP, and then undergoes a hydrolysis reaction under the action of an acid to obtain tenofovir (Formula I).
本发明提供了一种新的制备替诺福韦的方法。所提供的方法具有原料廉价易得，工艺路线短，条件温和可靠，易于用于工业化生产等优点。The present invention provides a novel method of preparing tenofovir. The method provided has the advantages that the raw materials are cheap and easy to obtain, the process route is short, the conditions are mild and reliable, and the invention is easy to be used for industrial production.
本发明提供的替诺福韦的制备方法中所用原料、辅料及试剂均可由市场购得。The raw materials, excipients and reagents used in the preparation method of tenofovir provided by the present invention are commercially available.
下面结合实施例，进一步阐述本发明：The present invention is further illustrated below in conjunction with the embodiments:
实施例1 化合物XI的合成Example 1 Synthesis of Compound XI
将1.0kg 4、6-二氯-5-氨基嘧啶加入50L反应釜中，加入8.0L甲酸。降温至0～10℃，滴加3.0L醋酸酐，滴加时控温0～10℃。滴加完后，升温至20～30℃，反应2～3小时。反应完毕，在55℃下减压浓缩至干。加入甲苯带蒸三次，每次使用5.0L甲苯。浓缩干，得到1.16kg粗品。将所得粗品溶解于4.0L甲苯中，升温至90℃，搅拌30分钟。自然降温至20℃，搅拌30分钟。过滤，滤饼烘干得到1.05kg的化合物XI，为类白色固体产品，纯度97.5％，收率89.7％。LC-MS m/z:[M+H] +C 5H 3Cl 2N 3O,计算值:191,193,检测值：191,193； 1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.84(s,1H),8.33(s,1H). 1.0 kg of 4,6-dichloro-5-aminopyrimidine was added to a 50 L autoclave, and 8.0 L of formic acid was added. The temperature was lowered to 0 to 10 ° C, and 3.0 L of acetic anhydride was added dropwise, and the temperature was controlled to be 0 to 10 ° C when added dropwise. After the completion of the dropwise addition, the temperature was raised to 20 to 30 ° C, and the reaction was carried out for 2 to 3 hours. After the reaction was completed, it was concentrated to dryness under reduced pressure at 55 °C. The toluene was added and steamed three times with 5.0 L of toluene each time. It was concentrated to dryness to give 1.16 kg of crude material. The obtained crude product was dissolved in 4.0 L of toluene, heated to 90 ° C, and stirred for 30 minutes. Naturally cool to 20 ° C and stir for 30 minutes. Filtration and drying of the filter cake gave 1.05 kg of compound XI as an off-white solid product with a purity of 97.5% and a yield of 89.7%. LC-MS m / z: [ M + H] + C 5 H 3 Cl 2 N 3 O, Calcd: 191, 193, the detected value: 191,193; 1 H NMR (400MHz , DMSO-d6) δ10.50 (s, 1H ), 8.84 (s, 1H), 8.33 (s, 1H).
实施例2 化合物XII的合成Example 2 Synthesis of Compound XII
2.1将3.8g D-丙氨醇(式V)加入250mL三口瓶中，再加入100.0mL的1,4-二氧六环，搅拌溶清。加入10.0g化合物XI和24.4mL三乙胺。升温至80℃，回流反应20小时。反应完毕，过滤，滤液在55℃下减压浓缩至干。加入40.0mL乙醇带蒸一次。浓缩干得粗品，加入20.0mL乙醇，打浆30分钟。过滤，烘干得到10.0g的化合物XII,为浅黄色固体产品，纯度96.2％，收率83.4％。2.1 3.8 g of D-alaninol (formula V) was added to a 250 mL three-necked flask, and then 100.0 mL of 1,4-dioxane was added and stirred to dissolve. 10.0 g of compound XI and 24.4 mL of triethylamine were added. The temperature was raised to 80 ° C and refluxed for 20 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated to dryness under vacuo. Add 40.0 mL of ethanol to steam once. The crude product was concentrated to dryness, and 20.0 mL of ethanol was added and beaten for 30 minutes. Filtration and drying gave 10.0 g of compound XII as a pale yellow solid product with a purity of 96.2% and a yield of 83.4%.
2.2将3.8g D-丙氨醇加入250mL三口瓶中，再加入100.0mL的1,4-二氧六环，搅拌溶清。加入10.0g化合物XI和24.4mL三乙胺。升温至150℃，回流反应8小时。反应完毕，过滤，滤液在55℃下减压浓缩至干。加入40.0mL乙醇带蒸一次。浓缩干得粗品，加入20.0mL乙醇，打浆30分钟。过滤，烘干得到9.6g的化合物XII,为浅黄色固体产品，纯度96.5％，收率80.0％。2.2 Add 3.8 g of D-alaninol to a 250 mL three-necked flask, add 100.0 mL of 1,4-dioxane, and stir to dissolve. 10.0 g of compound XI and 24.4 mL of triethylamine were added. The temperature was raised to 150 ° C and refluxed for 8 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated to dryness under vacuo. Add 40.0 mL of ethanol to steam once. The crude product was concentrated to dryness, and 20.0 mL of ethanol was added and beaten for 30 minutes. Filtration and drying gave 9.6 g of compound XII as a pale yellow solid product with a purity of 96.5% and a yield of 80.0%.
2.3将3.8g D-丙氨醇加入250mL三口瓶中，再加入100.0mL的1,4-二氧六环，搅拌溶清。加入10.0g化合物XI和29.0mL二异丙基乙胺。升温至100～110℃，回流反应12～14小时。反应完毕，过滤，滤液在55℃下减压浓缩至干。加入40.0mL乙醇带蒸一次。浓缩干得粗品，加入20.0mL乙醇，打浆30分钟。过滤，烘干得到9.78g的化合物XII,为浅黄色固体产品，纯度98.0％，收率81.5％。2.3 Add 3.8 g of D-alaninol to a 250 mL three-necked flask, add 100.0 mL of 1,4-dioxane, and stir to dissolve. 10.0 g of compound XI and 29.0 mL of diisopropylethylamine were added. The temperature was raised to 100 to 110 ° C, and the reaction was refluxed for 12 to 14 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated to dryness under vacuo. Add 40.0 mL of ethanol to steam once. The crude product was concentrated to dryness, and 20.0 mL of ethanol was added and beaten for 30 minutes. Filtration and drying gave 9.78 g of compound XII as a pale yellow solid product with a purity of 98.0% and a yield of 81.5%.
2.4将3.8g D-丙氨醇加入250mL三口瓶中，再加入100.0mL的2-甲基四氢呋喃六环，搅拌溶清。加入10.0g化合物XI和24.4mL三乙胺。升温至100～110℃，回流反应12～14小时。反应完毕，过滤，滤液在55℃下减压浓缩至干。加入40.0mL乙醇带蒸一次。浓缩干得粗品，加入20.0mL乙醇，打浆30分钟。过滤，烘干得到9.66g的化合物XII,为浅黄色固体产品，纯度98.0％，收率80.5％。2.4 Add 3.8 g of D-alaninol to a 250 mL three-necked flask, then add 100.0 mL of 2-methyltetrahydrofuran hexacyclohexane and stir to dissolve. 10.0 g of compound XI and 24.4 mL of triethylamine were added. The temperature was raised to 100 to 110 ° C, and the reaction was refluxed for 12 to 14 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated to dryness under vacuo. Add 40.0 mL of ethanol to steam once. The crude product was concentrated to dryness, and 20.0 mL of ethanol was added and beaten for 30 minutes. Filtration and drying gave 9.66 g of compound XII as a pale yellow solid product with a purity of 98.0% and a yield of 80.5%.
2.5将38g D-丙氨醇加入3.0L四口瓶中，再加入1.0L的1,4-二氧六环，搅拌溶清。加入100.0g化合物XI和244.0mL三乙胺。升温至100～110℃，回流反应12～14小时。反应完毕，过滤，滤液在55℃下减压浓缩至干。加入200.0mL乙醇带蒸一次。浓缩干得粗品，加入200.0mL 乙醇，打浆30分钟。过滤，烘干得到101.7g的化合物XII,为浅黄色固体产品，纯度98.5％，收率84.8％。2.5 38 g of D-alaninol was added to a 3.0 L four-necked flask, and 1.0 L of 1,4-dioxane was added thereto, and the mixture was stirred and dissolved. 100.0 g of compound XI and 244.0 mL of triethylamine were added. The temperature was raised to 100 to 110 ° C, and the reaction was refluxed for 12 to 14 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated to dryness under vacuo. Add 200.0 mL of ethanol to steam once. The crude product was concentrated to dryness, and 200.0 mL of ethanol was added and beaten for 30 minutes. Filtration and drying gave 101.7 g of compound XII as a pale yellow solid product with a purity of 98.5% and a yield of 84.8%.
2.6将380.0g D-丙氨醇加入50L反应釜中，再加入10.0L的1,4-二氧六环，搅拌溶清。加入1.0kg化合物XI和2.44L三乙胺。升温至100～110℃，回流反应12～14小时。反应完毕，过滤，滤液在55℃下减压浓缩至干。加入2.0L乙醇带蒸一次。浓缩干得粗品，加入2.0L乙醇，打浆30分钟。过滤，烘干得到1.0kg的化合物XII,为浅黄色固体产品，纯度98.2％，收率83.3％。LC-MS m/z:[M+H] +C 8H 11ClN 4O 2,计算值:231,检测值：231； 1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.19(s,2H),6.86(s,1H),4.72(s,1H),4.14(s,1H),3.36(d,J＝37.8Hz,2H),1.09(s,3H). 2.6 380.0 g of D-alaninol was added to a 50 L reaction vessel, and 10.0 L of 1,4-dioxane was added thereto, and the mixture was stirred and dissolved. 1.0 kg of compound XI and 2.44 L of triethylamine were added. The temperature was raised to 100 to 110 ° C, and the reaction was refluxed for 12 to 14 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated to dryness under vacuo. Add 2.0 L of ethanol to steam once. The crude product was concentrated to dryness, and 2.0 L of ethanol was added and beaten for 30 minutes. Filtration and drying gave 1.0 kg of compound XII as a pale yellow solid product with a purity of 98.2% and a yield of 83.3%. LC-MS m / z: [ M + H] + C 8 H 11 ClN 4 O 2, Calcd: 231, the detected value: 231; 1 H NMR (400MHz , DMSO-d6) δ9.51 (s, 1H) , 8.19 (s, 2H), 6.86 (s, 1H), 4.72 (s, 1H), 4.14 (s, 1H), 3.36 (d, J = 37.8 Hz, 2H), 1.09 (s, 3H).
实施例3 化合物XIII的合成Example 3 Synthesis of Compound XIII
3.1将10.0g化合物XII加入500mL三口反应瓶中，再加入80.0mL的N、N-二甲基甲酰胺，搅拌溶清。降温至0～10℃，加入45.0mL的原甲酸三甲酯和7.20mL浓盐酸。在0～10℃下，搅拌反应44～48小时。反应完毕，在70℃下减压浓缩至干。加入100.0mL的二氯甲烷和100.0mL的水，搅拌10分钟，静置分层。水相再用55.0mL的二氯甲烷萃取一次。合并有机相，在50℃下减压浓缩至干，加入20.0mL乙醇带蒸一次。浓缩干得粗品，加入10.0mL乙醇，打浆30分钟，过滤。滤饼烘干得到7.5g的化合物XIII,为黄色固体产品，纯度98.3％，收率81.5％。3.1 10.0 g of compound XII was added to a 500 mL three-neck reaction flask, and 80.0 mL of N,N-dimethylformamide was added thereto, and the mixture was stirred and dissolved. The temperature was lowered to 0 to 10 ° C, and 45.0 mL of trimethyl orthoformate and 7.20 mL of concentrated hydrochloric acid were added. The reaction was stirred at 0 to 10 ° C for 44 to 48 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure at 70 °C. 100.0 mL of dichloromethane and 100.0 mL of water were added, stirred for 10 minutes, and allowed to stand for stratification. The aqueous phase was extracted once more with 55.0 mL of dichloromethane. The organic phases were combined, concentrated to dryness under reduced pressure at 50 ° C, and then evaporated and evaporated. The crude product was concentrated to dryness, and then 10.0 mL of ethanol was added, and the mixture was beaten for 30 minutes and filtered. The filter cake was dried to give 7.5 g of compound XIII as a yellow solid product with a purity of 98.3% and a yield of 81.5%.
3.2将10.0g化合物XII加入500mL三口反应瓶中，再加入80.0mL的N、N-二甲基甲酰胺，搅拌溶清。加入45.0mL的原甲酸三甲酯和7.20mL浓盐酸。升温至40～50℃下，搅拌反应6～8小时。反应完毕，在70℃下减压浓缩至干。加入100.0mL的二氯甲烷和100.0mL的水，搅拌10分钟，静置分层。水相再用55.0mL的二氯甲烷萃取一次。合并有机相，在50℃下减压浓缩至干，加入20.0mL乙醇带蒸一次。浓缩干得粗品，加入10.0mL乙醇，打浆30分钟，过滤。滤饼烘干得到6.9g的化合物XIII,为黄色固体产品，纯度97.3％，收率75.0％。3.2 Add 10.0 g of compound XII to a 500 mL three-neck reaction flask, add 80.0 mL of N,N-dimethylformamide, and stir to dissolve. 45.0 mL of trimethyl orthoformate and 7.20 mL of concentrated hydrochloric acid were added. The temperature was raised to 40 to 50 ° C, and the reaction was stirred for 6 to 8 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure at 70 °C. 100.0 mL of dichloromethane and 100.0 mL of water were added, stirred for 10 minutes, and allowed to stand for stratification. The aqueous phase was extracted once more with 55.0 mL of dichloromethane. The organic phases were combined, concentrated to dryness under reduced pressure at 50 ° C, and then evaporated and evaporated. The crude product was concentrated to dryness, and then 10.0 mL of ethanol was added, and the mixture was beaten for 30 minutes and filtered. The filter cake was dried to give 6.9 g of compound XIII as a yellow solid product with a purity of 97.3% and a yield of 75.0%.
3.3将10.0g化合物XII加入500mL三口反应瓶中，再加入80.0mL 的N、N-二甲基甲酰胺，搅拌溶清。加入45.0mL的原甲酸三甲酯和7.20mL浓盐酸。在20～30℃下，搅拌反应14～18小时。反应完毕，在70℃下减压浓缩至干。加入100.0mL的二氯甲烷和100.0mL的水，搅拌10分钟，静置分层。水相再用55.0mL的二氯甲烷萃取一次。合并有机相，在50℃下减压浓缩至干，加入20.0mL乙醇带蒸一次。浓缩干得粗品，加入10.0mL乙醇，打浆30分钟，过滤。滤饼烘干得到7.85g的化合物XIII,为黄色固体产品，纯度98.6％，收率85.4％。3.3 Add 10.0 g of compound XII to a 500 mL three-neck reaction flask, add 80.0 mL of N,N-dimethylformamide, and stir to dissolve. 45.0 mL of trimethyl orthoformate and 7.20 mL of concentrated hydrochloric acid were added. The reaction was stirred at 20 to 30 ° C for 14 to 18 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure at 70 °C. 100.0 mL of dichloromethane and 100.0 mL of water were added, stirred for 10 minutes, and allowed to stand for stratification. The aqueous phase was extracted once more with 55.0 mL of dichloromethane. The organic phases were combined, concentrated to dryness under reduced pressure at 50 ° C, and then evaporated and evaporated. The crude product was concentrated to dryness, and then 10.0 mL of ethanol was added, and the mixture was beaten for 30 minutes and filtered. The filter cake was dried to give 7.85 g of compound XIII as a yellow solid product with a purity of 98.6% and a yield of 85.4%.
3.4将10.0g化合物XII加入500mL三口反应瓶中，再加入80.0mL的N-甲基吡咯烷酮，搅拌溶清。加入45.0mL的原甲酸三甲酯和7.20mL浓盐酸。在20～30℃下，搅拌反应14～18小时。反应完毕，在70℃下减压浓缩至干。加入100.0mL的二氯甲烷和100.0mL的水，搅拌10分钟，静置分层。水相再用55.0mL的二氯甲烷萃取一次。合并有机相，在50℃下减压浓缩至干，加入20.0mL乙醇带蒸一次。浓缩干得粗品，加入10.0mL乙醇，打浆30分钟，过滤。滤饼烘干得到7.6g的化合物XIII,为黄色固体产品，纯度98.6％，收率83.2％。3.4 10.0 g of compound XII was added to a 500 mL three-neck reaction flask, and then 80.0 mL of N-methylpyrrolidone was added and stirred to dissolve. 45.0 mL of trimethyl orthoformate and 7.20 mL of concentrated hydrochloric acid were added. The reaction was stirred at 20 to 30 ° C for 14 to 18 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure at 70 °C. 100.0 mL of dichloromethane and 100.0 mL of water were added, stirred for 10 minutes, and allowed to stand for stratification. The aqueous phase was extracted once more with 55.0 mL of dichloromethane. The organic phases were combined, concentrated to dryness under reduced pressure at 50 ° C, and then evaporated and evaporated. The crude product was concentrated to dryness, and then 10.0 mL of ethanol was added, and the mixture was beaten for 30 minutes and filtered. The filter cake was dried to give 7.6 g of compound XIII as a yellow solid product with a purity of 98.6% and a yield of 83.2%.
3.5将100.0g化合物XII加入5.0L四口反应瓶中，再加入800.0mL的N、N-二甲基甲酰胺，搅拌溶清。加入450.0mL的原甲酸三甲酯和72.0mL浓盐酸。在20～30℃下，搅拌反应14～18小时。反应完毕，在70℃下减压浓缩至干。加入1.0L的二氯甲烷和1.0L的水，搅拌10分钟，静置分层。水相再用550.0mL的二氯甲烷萃取一次。合并有机相，在50℃下减压浓缩至干，加入200.0mL乙醇带蒸一次。浓缩干得粗品，加入100.0mL乙醇，打浆30分钟，过滤。滤饼烘干得到82.1g的化合物XIII,为黄色固体产品，纯度98.4％，收率89.3％。3.5 100.0 g of compound XII was added to a 5.0 L four-neck reaction flask, and then 800.0 mL of N,N-dimethylformamide was added, and the mixture was stirred and dissolved. 450.0 mL of trimethyl orthoformate and 72.0 mL of concentrated hydrochloric acid were added. The reaction was stirred at 20 to 30 ° C for 14 to 18 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure at 70 °C. 1.0 L of dichloromethane and 1.0 L of water were added, stirred for 10 minutes, and allowed to stand for separation. The aqueous phase was extracted once more with 550.0 mL of dichloromethane. The organic phases were combined, concentrated to dryness under reduced pressure at 50 &lt The crude product was concentrated to dryness, and then 100.0 mL of ethanol was added, and the mixture was beaten for 30 minutes and filtered. The filter cake was dried to give 82.1 g of compound XIII as a yellow solid product with a purity of 98.4% and a yield of 89.3%.
3.6将1.0kg化合物XII加入50L反应釜中，再加入8.0L的N、N-二甲基甲酰胺，搅拌溶清。加入4.5L的原甲酸三甲酯和720.0mL浓盐酸。在20～30℃下，搅拌反应14～18小时。反应完毕，在70℃下减压浓缩至干。加入10.0L的二氯甲烷和10.0L的水，搅拌10分钟，静置分层。水相再用5.5L的二氯甲烷萃取一次。合并有机相，在50℃下减压浓缩至干，加入2.0L乙醇带蒸一次。浓缩干得粗品，加入1.0L乙醇，打浆 30分钟，过滤。滤饼烘干得到805.9g的化合物XIII,为黄色固体产品，纯度98.1％，收率87.6％。LC-MS m/z:[M+H] +C 8H 9ClN 4O,计算值:213,检测值：213； 1H NMR(400MHz,DMSO-d6)δ8.73(s,2H),5.03(s,1H),4.74(s,1H),3.76(d,J＝35.6Hz,2H),1.09(s,3H). 3.6 1.0 kg of the compound XII was placed in a 50 L reaction vessel, and then 8.0 L of N,N-dimethylformamide was added thereto, and the mixture was stirred and dissolved. 4.5 L of trimethyl orthoformate and 720.0 mL of concentrated hydrochloric acid were added. The reaction was stirred at 20 to 30 ° C for 14 to 18 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure at 70 °C. 10.0 L of dichloromethane and 10.0 L of water were added, stirred for 10 minutes, and allowed to stand for stratification. The aqueous phase was extracted once more with 5.5 L of dichloromethane. The organic phases were combined, concentrated to dryness under reduced pressure at 50 ° C, and then evaporated and evaporated. The crude product was concentrated to dryness. The filter cake was dried to obtain 805.9 g of compound XIII as a yellow solid product, purity 98.1%, yield 87.6%. LC-MS m / z: [ M + H] + C 8 H 9 ClN 4 O, Calcd: 213, the detected value: 213; 1 H NMR (400MHz , DMSO-d6) δ8.73 (s, 2H), 5.03 (s, 1H), 4.74 (s, 1H), 3.76 (d, J = 35.6 Hz, 2H), 1.09 (s, 3H).
实施例4 化合物XIII的合成Example 4 Synthesis of Compound XIII
4.1将5.7g D-丙氨醇加入500mL三口反应瓶中，再加入100.0mL的乙醇，搅拌溶清。加入15.0g化合物XI和37.0mL三乙胺。升温至40～60℃，反应2天。反应完毕，关闭加热，降温至10℃。搅拌30分钟后，过滤。滤饼烘干得到13.5g的化合物XIII，为黄色固体产品，纯度99.1％，收率81.3％。4.1 Add 5.7 g of D-alaninol to a 500 mL three-neck reaction flask, add 100.0 mL of ethanol, and stir to dissolve. 15.0 g of compound XI and 37.0 mL of triethylamine were added. The temperature was raised to 40 to 60 ° C and the reaction was carried out for 2 days. After the reaction is completed, the heating is turned off and the temperature is lowered to 10 °C. After stirring for 30 minutes, it was filtered. The filter cake was dried to give 13.5 g of compound XIII as a yellow solid product with a purity of 99.1% and a yield of 81.3%.
4.2将5.7g D-丙氨醇加入500mL三口反应瓶中，再加入100.0mL的乙醇，搅拌溶清。加入15.0g化合物XI和37.0mL三乙胺。升温至100～120℃，密封反应7～9小时。反应完毕，关闭加热，降温至10℃。搅拌30分钟后，过滤。滤饼烘干得到12.6g的化合物XIII，为黄色固体产品，纯度94.0％，收率75.9％。4.2 Add 5.7 g of D-alaninol to a 500 mL three-neck reaction flask, add 100.0 mL of ethanol, and stir to dissolve. 15.0 g of compound XI and 37.0 mL of triethylamine were added. The temperature was raised to 100 to 120 ° C, and the reaction was sealed for 7 to 9 hours. After the reaction is completed, the heating is turned off and the temperature is lowered to 10 °C. After stirring for 30 minutes, it was filtered. The filter cake was dried to give 12.6 g of compound XIII as a yellow solid product, purity 94.0%, yield 75.9%.
4.3将5.7g D-丙氨醇加入500mL三口反应瓶中，再加入100.0mL的乙醇，搅拌溶清。加入15.0g化合物XI和37.0mL三乙胺。升温至75～85℃，回流反应15～17小时。反应完毕，关闭加热，降温至10℃。搅拌30分钟后，过滤。滤饼烘干得到14.0g的化合物XIII，为黄色固体产品，纯度98.7％，收率84.3％。4.3 Add 5.7 g of D-alaninol to a 500 mL three-neck reaction flask, add 100.0 mL of ethanol, and stir to dissolve. 15.0 g of compound XI and 37.0 mL of triethylamine were added. The temperature was raised to 75 to 85 ° C, and the reaction was refluxed for 15 to 17 hours. After the reaction is completed, the heating is turned off and the temperature is lowered to 10 °C. After stirring for 30 minutes, it was filtered. The filter cake was dried to obtain 14.0 g of compound XIII as a yellow solid product, purity 98.7%, yield 84.3%.
4.3将5.7g D-丙氨醇加入500mL三口反应瓶中，再加入100.0mL的异丙醇，搅拌溶清。加入15.0g化合物XI和37.0mL三乙胺。升温至75～85℃，回流反应15～17小时。反应完毕，关闭加热，降温至10℃。搅拌30分钟后，过滤。滤饼烘干得到13.7g的化合物XIII，为黄色固体产品，纯度98.7％，收率82.5％。4.3 Add 5.7 g of D-alaninol to a 500 mL three-neck reaction flask, add 100.0 mL of isopropanol, and stir to dissolve. 15.0 g of compound XI and 37.0 mL of triethylamine were added. The temperature was raised to 75 to 85 ° C, and the reaction was refluxed for 15 to 17 hours. After the reaction is completed, the heating is turned off and the temperature is lowered to 10 °C. After stirring for 30 minutes, it was filtered. The filter cake was dried to obtain 13.7 g of compound XIII as a yellow solid product, purity 98.7%, yield 82.5%.
4.3将5.7g D-丙氨醇加入500mL三口反应瓶中，再加入100.0mL的乙醇，搅拌溶清。加入15.0g化合物XI和43.5mL二异丙基乙胺。升温至75～85℃，回流反应15～17小时。反应完毕，关闭加热，降温至 10℃。搅拌30分钟后，过滤。滤饼烘干得到13.0g的化合物XIII，为黄色固体产品，纯度98.7％，收率78.3％。4.3 Add 5.7 g of D-alaninol to a 500 mL three-neck reaction flask, add 100.0 mL of ethanol, and stir to dissolve. 15.0 g of compound XI and 43.5 mL of diisopropylethylamine were added. The temperature was raised to 75 to 85 ° C, and the reaction was refluxed for 15 to 17 hours. After the reaction is completed, the heating is turned off and the temperature is lowered to 10 °C. After stirring for 30 minutes, it was filtered. The filter cake was dried to obtain 13.0 g of compound XIII as a yellow solid product, purity 98.7%, yield 78.3%.
4.4将57.0g D-丙氨醇加入5.0L三口反应瓶中，再加入1.0L的乙醇，搅拌溶清。加入150.0g化合物XI和370.0mL三乙胺。升温至75～85℃，回流反应15～17小时。反应完毕，关闭加热，降温至10℃。搅拌30分钟后，过滤。滤饼烘干得到145.0g的化合物XIII，为黄色固体产品，纯度99.3％，收率87.3％。4.4 57.0 g of D-alaninol was added to a 5.0 L three-neck reaction flask, and then 1.0 L of ethanol was added thereto, and the mixture was stirred and dissolved. 150.0 g of compound XI and 370.0 mL of triethylamine were added. The temperature was raised to 75 to 85 ° C, and the reaction was refluxed for 15 to 17 hours. After the reaction is completed, the heating is turned off and the temperature is lowered to 10 °C. After stirring for 30 minutes, it was filtered. The filter cake was dried to give 145.0 g of Compound XIII as a yellow solid product with a purity of 99.3% and a yield of 87.3%.
4.5将570g D-丙氨醇加入50L反应釜中，再加入10.0L的乙醇，搅拌溶清。加入1.5kg化合物XI和3.7L三乙胺。升温至75～85℃，回流反应15～17小时。反应完毕，关闭加热，降温至10℃。搅拌30分钟后，过滤。滤饼烘干得到1.47kg的化合物XIII，为黄色固体产品，纯度99.0％，收率88.5％。LC-MS m/z:[M+H] +C 8H 9ClN 4O,计算值:213,检测值：213； 1H NMR(400MHz,DMSO-d6)δ8.73(s,2H),5.03(s,1H),4.74(s,1H),3.76(d,J＝35.6Hz,2H),1.09(s,3H). 4.5 Add 570 g of D-alaninol to a 50 L reactor, add 10.0 L of ethanol, and stir to dissolve. 1.5 kg of compound XI and 3.7 L of triethylamine were added. The temperature was raised to 75 to 85 ° C, and the reaction was refluxed for 15 to 17 hours. After the reaction is completed, the heating is turned off and the temperature is lowered to 10 °C. After stirring for 30 minutes, it was filtered. The filter cake was dried to give 1.47 kg of compound XIII as a yellow solid product with a purity of 99.0% and a yield of 88.5%. LC-MS m / z: [ M + H] + C 8 H 9 ClN 4 O, Calcd: 213, the detected value: 213; 1 H NMR (400MHz , DMSO-d6) δ8.73 (s, 2H), 5.03 (s, 1H), 4.74 (s, 1H), 3.76 (d, J = 35.6 Hz, 2H), 1.09 (s, 3H).
实施例5 化合物XIV的合成Example 5 Synthesis of Compound XIV
5.1将12.0g化合物XIII加入500mL闷罐中，再加入60.0mL的1,4-二氧六环和60.0mL氨水。升温至80～90℃，密封反应16～18小时。反应完毕，关闭加热。在60℃下减压浓缩至干，加入30.0mL异丙醇带蒸一次。浓缩干得粗品，加入30.0mL乙醇，打浆30分钟。过滤，滤饼烘干得到9.5g的化合物XIV，为黄色固体产品，纯度96.2％，收率87.1％。5.1 12.0 g of compound XIII was added to a 500 mL tank, followed by 60.0 mL of 1,4-dioxane and 60.0 mL of aqueous ammonia. The temperature was raised to 80 to 90 ° C, and the reaction was sealed for 16 to 18 hours. After the reaction is completed, the heating is turned off. It was concentrated to dryness under reduced pressure at 60 ° C, and then was added with 30.0 mL of isopropyl alcohol. The crude product was concentrated to dryness, and 30.0 mL of ethanol was added and beaten for 30 minutes. Filtration and drying of the filter cake gave 9.5 g of compound XIV as a yellow solid product with a purity of 96.2% and a yield of 87.1%.
5.2将12.0g化合物XIII加入500mL闷罐中，再加入60.0mL的1,4-二氧六环和60.0mL氨水。升温至180～200℃，密封反应1～2小时。反应完毕，关闭加热。在60℃下减压浓缩至干，加入30.0mL异丙醇带蒸一次。浓缩干得粗品，加入30.0mL乙醇，打浆30分钟。过滤，滤饼烘干得到9.26g的化合物XIV，为黄色固体产品，纯度94.1％，收率84.9％。5.2 12.0 g of compound XIII was added to a 500 mL tank, followed by 60.0 mL of 1,4-dioxane and 60.0 mL of aqueous ammonia. The temperature was raised to 180 to 200 ° C, and the reaction was sealed for 1 to 2 hours. After the reaction is completed, the heating is turned off. It was concentrated to dryness under reduced pressure at 60 ° C, and then was added with 30.0 mL of isopropyl alcohol. The crude product was concentrated to dryness, and 30.0 mL of ethanol was added and beaten for 30 minutes. Filtration and drying of the filter cake gave 9.26 g of compound XIV as a yellow solid product with a purity of 94.1% and a yield of 84.9%.
5.3将12.0g化合物XIII加入500mL闷罐中，再加入60.0mL的1,4-二氧六环和60.0mL氨水。升温至100～110℃，密封反应6～8小时。反应完毕，关闭加热。在60℃下减压浓缩至干，加入30.0mL异丙醇带蒸 一次。浓缩干得粗品，加入30.0mL乙醇，打浆30分钟。过滤，滤饼烘干得到10.2g的化合物XIV，为黄色固体产品，纯度95.8％，收率93.5％。5.3 12.0 g of compound XIII was added to a 500 mL tank, followed by 60.0 mL of 1,4-dioxane and 60.0 mL of aqueous ammonia. The temperature was raised to 100 to 110 ° C, and the reaction was sealed for 6 to 8 hours. After the reaction is completed, the heating is turned off. It was concentrated to dryness under reduced pressure at 60 ° C, and then was then evaporated and then evaporated. The crude product was concentrated to dryness, and 30.0 mL of ethanol was added and beaten for 30 minutes. Filtration and drying of the filter cake gave 10.2 g of compound XIV as a yellow solid product with a purity of 95.8% and a yield of 93.5%.
5.4将120.0g化合物XIII加入2.0L加压反应釜中，再加入600.0mL的1,4-二氧六环和600.0mL氨水。升温至100～110℃，密封反应6～8小时。反应完毕，关闭加热。在60℃下减压浓缩至干，加入300.0mL异丙醇带蒸一次。浓缩干得粗品，加入300.0mL乙醇，打浆30分钟。过滤，滤饼烘干得到104.2g的化合物XIV，为黄色固体产品，纯度96.1％，收率95.6％。5.4 120.0 g of compound XIII was added to a 2.0 L pressurized autoclave, followed by 600.0 mL of 1,4-dioxane and 600.0 mL of aqueous ammonia. The temperature was raised to 100 to 110 ° C, and the reaction was sealed for 6 to 8 hours. After the reaction is completed, the heating is turned off. It was concentrated to dryness under reduced pressure at 60 ° C, and was added once with 300.0 mL of isopropyl alcohol. The crude product was concentrated to dryness, and 300.0 mL of ethanol was added and beaten for 30 minutes. Filtration and drying of the filter cake gave 104.2 g of compound XIV as a yellow solid product with a purity of 96.1% and a yield of 95.6%.
5.5将1.2kg化合物XIII加入50L加压反应釜中，再加入6.0L的1,4-二氧六环和6.0L氨水。升温至100～110℃，密封回流反应6～8小时。反应完毕，关闭加热。在60℃下减压浓缩至干，加入3.0L异丙醇带蒸一次。浓缩干得粗品，加入3.0L乙醇，打浆30分钟。过滤，滤饼烘干得到1.05kg的化合物XIV，为黄色固体产品，纯度95.2％，收率96.3％。LC-MS m/z:[M+H] +C 8H 11N 5O,计算值:194,检测值：194； 1H NMR(400MHz,DMSO-d6)δ8.11(d,J＝20.4Hz,2H),7.19(s,2H),5.11(s,1H),4.56(s,1H),3.70(d,J＝40.2Hz,2H),1.44(s,3H). 5.5 1.2 kg of compound XIII was added to a 50 L pressurized reactor, followed by 6.0 L of 1,4-dioxane and 6.0 L of aqueous ammonia. The temperature was raised to 100 to 110 ° C, and the reflux reaction was sealed for 6 to 8 hours. After the reaction is completed, the heating is turned off. It was concentrated to dryness under reduced pressure at 60 ° C, and then was added with 3.0 L of isopropyl alcohol. The crude product was concentrated to dryness, added with 3.0 L of ethanol, and beaten for 30 minutes. Filtration and drying of the filter cake gave 1.05 kg of compound XIV as a yellow solid product with a purity of 95.2% and a yield of 96.3%. LC-MS m / z: [ M + H] + C 8 H 11 N 5 O, Calcd: 194, the detected value: 194; 1 H NMR (400MHz , DMSO-d6) δ8.11 (d, J = 20.4 Hz, 2H), 7.19 (s, 2H), 5.11 (s, 1H), 4.56 (s, 1H), 3.70 (d, J = 40.2 Hz, 2H), 1.44 (s, 3H).
实施例6 化合物I的合成Example 6 Synthesis of Compound I
在氮气保护下，向50L反应釜内加入1.25kg化合物XIV、6.0kg DMF和0.73kg异丙醇镁。升温至65℃，搅拌反应1小时。降温至45～55℃，向反应釜中分批缓慢滴加DESMP(式VI)，加完后45～55℃保温搅拌10小时。HPLC检测确定反应完成，减压浓缩DMF及异丙醇。向浓缩物中加入6.25kg浓盐酸，升温至90℃，搅拌反应10小时。反应结束后，降温至10-15℃，搅拌20-30分钟。过滤，滤饼用1.0kg稀盐酸溶液洗涤，滤饼弃去。滤液转移至反应釜中，加入2.0kg二氯甲烷，搅拌15分钟，静置30分钟。分液，收集水相，减压浓缩盐酸。向浓缩物中加入7.5kg水，升温至40℃，搅拌至溶清。缓慢滴加40％NaOH水溶液调节pH值至3.0。滴加完后，50℃，保温搅拌3小时。自然降温至室温，搅拌10～12小时。过滤，滤饼用0.8kg水洗涤，得粗品。向反应釜内加 入所得粗品和18kg水，升温至100-105℃，搅拌至体系溶清。自然降温至10℃，搅拌2小时。过滤，滤饼用1.0kg冰水洗涤，滤饼烘干得1.10kg化合物I，为白色固体，纯度99.12％，收率59.2％。Under a nitrogen atmosphere, 1.25 kg of compound XIV, 6.0 kg of DMF and 0.73 kg of magnesium isopropoxide were added to a 50 L autoclave. The temperature was raised to 65 ° C, and the reaction was stirred for 1 hour. The temperature was lowered to 45-55 ° C, and DESMP (formula VI) was slowly added dropwise to the reaction kettle in portions, and the mixture was stirred at 45 to 55 ° C for 10 hours after the addition. The completion of the reaction was confirmed by HPLC, and DMF and isopropyl alcohol were concentrated under reduced pressure. 6.25 kg of concentrated hydrochloric acid was added to the concentrate, the temperature was raised to 90 ° C, and the reaction was stirred for 10 hours. After the reaction is completed, the temperature is lowered to 10-15 ° C and stirred for 20-30 minutes. After filtration, the filter cake was washed with 1.0 kg of dilute hydrochloric acid solution, and the filter cake was discarded. The filtrate was transferred to a reaction vessel, and 2.0 kg of dichloromethane was added thereto, and the mixture was stirred for 15 minutes and allowed to stand for 30 minutes. The liquid was separated, the aqueous phase was collected, and hydrochloric acid was concentrated under reduced pressure. 7.5 kg of water was added to the concentrate, and the temperature was raised to 40 ° C, and stirred until it was dissolved. The pH was adjusted to 3.0 by slowly adding 40% aqueous NaOH solution. After the dropwise addition was completed, the mixture was stirred at 50 ° C for 3 hours. Naturally cool to room temperature and stir for 10 to 12 hours. After filtration, the filter cake was washed with 0.8 kg of water to give a crude product. The obtained crude product and 18 kg of water were added to the reaction vessel, and the mixture was heated to 100-105 ° C, and stirred until the system was dissolved. Naturally cool to 10 ° C and stir for 2 hours. Filtration, the filter cake was washed with 1.0 kg of ice water, and the filter cake was dried to obtain 1.10 kg of Compound I as a white solid with a purity of 99.12% and a yield of 59.2%.
对比例1 化合物VIII的合成Comparative Example 1 Synthesis of Compound VIII
向反应瓶中加入4,6-二氯-5-硝基嘧啶(1.93g，10mmol)和20mL N,N-二甲基甲酰胺，室温搅拌至溶解。降温至0～5℃，分批加入2.8g叔丁醇钾(2.5eq,易吸潮，分批加料时注意)，同时滴加(R)-1-氨基-2-(二乙氧基磷酰甲氧基)丙烷(2.93g,13mmol)的DMF溶液。缓慢升至室温，搅拌5～7小时。确认反应完成后，加入水淬灭反应，用二氯甲烷萃取三次，分别用饱和碳酸氢钠溶液、盐水、蒸馏水洗涤。有机相用无水硫酸钠干燥5小时，用布氏漏斗过滤。滤液减压浓缩得粗品。向粗品中加入甲苯，升温溶解，缓慢加温析出固体。用布氏漏斗过滤，滤饼减压干燥得到类白色固体(R)-4-{N-[2-(二乙氧基磷酰甲氧基)丙基]氨基}-5-硝基-6-氯嘧啶(VIII)2.98g，收率为78.2％。4,6-Dichloro-5-nitropyrimidine (1.93 g, 10 mmol) and 20 mL of N,N-dimethylformamide were added to the reaction flask, and stirred at room temperature until dissolved. Cool down to 0 ~ 5 ° C, add 2.8g potassium t-butoxide (2.5 eq, easy to absorb moisture, pay attention to batch feeding), while adding (R)-1-amino-2-(diethoxyphosphorus) A solution of acyloxy)propane (2.93 g, 13 mmol) in DMF. Rin slowly to room temperature and stir for 5-7 hours. After confirming the completion of the reaction, the reaction was quenched by the addition of water, and extracted three times with dichloromethane, and washed with saturated sodium hydrogen carbonate solution, brine, and distilled water. The organic phase was dried over anhydrous sodium sulfate for 5 hr and filtered over EtOAc. The filtrate was concentrated under reduced pressure to give a crude material. Toluene was added to the crude product, and the mixture was heated to dissolve, and the solid was slowly precipitated. Filtration with a Buchner funnel, and the filter cake was dried under reduced pressure to give an off-white solid (R)-4-{N-[2-(diethoxyphosphorylmethoxy)propyl]amino}-5-nitro-6 -Chloropyrimidine (VIII) 2.98 g, yield 78.2%.
对比例2 化合物IX的合成Comparative Example 2 Synthesis of Compound IX
向反应瓶中加入(R)-4-{N-[2-(二乙氧基磷酰甲氧基)丙基]氨基}-5-硝基-6-氯嘧啶(VIII)(1.90g，5mmol)、保险粉(2.18g,1.25eq)、甲醇25mL和蒸馏水25mL。升温至50-60℃，搅拌反应6小时。减压浓缩至体积一半，用二氯甲烷萃取3次。合并有机相，水洗，浓缩至干。加入甲酸25mL，升温至150-170℃(高温，注意烫伤)，保温反应3小时。TLC确认反应完全后，降温至70-80℃，加入活性炭，保温搅拌30分钟。趁热过滤，滤液加压浓缩。浓缩物加入到水和甲醇的混合液中，搅拌打浆1小时。用布氏漏斗过滤，滤饼减压干燥得到淡黄色固体(R)-1-(6-氯嘌呤-9-基)-2-(二乙氧基磷酰甲氧基)丙烷(IX)1.3g，收率为73.3％。To the reaction flask was added (R)-4-{N-[2-(diethoxyphosphorylmethoxy)propyl]amino}-5-nitro-6-chloropyrimidine (VIII) (1.90 g, 5 mmol), insurance powder (2.18 g, 1.25 eq), methanol 25 mL, and distilled water 25 mL. The temperature was raised to 50-60 ° C, and the reaction was stirred for 6 hours. It was concentrated to a half volume under reduced pressure and extracted three times with dichloromethane. The organic phases were combined, washed with water and concentrated to dry. Add 25 mL of formic acid, raise the temperature to 150-170 ° C (high temperature, pay attention to burns), and keep the reaction for 3 hours. After confirming the completion of the reaction by TLC, the temperature was lowered to 70-80 ° C, activated carbon was added, and the mixture was stirred under heat for 30 minutes. The mixture was filtered while hot, and the filtrate was concentrated under pressure. The concentrate was added to a mixture of water and methanol, and the mixture was beaten for 1 hour. Filtration with a Buchner funnel, and the filter cake was dried under reduced pressure to give a pale yellow solid (R)-1-(6-chloropurin-9-yl)-2-(diethoxyphosphorylmethoxy)propane (IX) 1.3 g, the yield was 73.3%.
对比例3 化合物X的合成Comparative Example 3 Synthesis of Compound X
向耐压瓶中加入(R)-1-(6-氯嘌呤-9-基)-2-(二乙氧基磷酰甲氧基)丙烷(V)(1.8g，5mmol)和饱和的氨气甲醇溶液25mL，密封搅拌反应16小时。减压浓缩至干。浓缩物悬浮于用蒸馏水中，加热溶解。加入活性炭，搅拌30分钟，趁热过滤。滤液冷却结晶5小时，用布氏漏斗过滤，滤饼减压干燥得到类白色固体(R)-1-(6-氨基嘌呤-9-基)-2-(二乙氧基磷酰甲氧基)丙烷(VI)1.42g，收率为83.2％，纯度94.7％。(R)-1-(6-Chloropurin-9-yl)-2-(diethoxyphosphorylmethoxy)propane (V) (1.8 g, 5 mmol) and saturated ammonia were added to a pressure bottle. 25 mL of a methanol solution was stirred and stirred for 16 hours. Concentrate to dryness under reduced pressure. The concentrate was suspended in distilled water and dissolved by heating. Add activated carbon, stir for 30 minutes, and filter while hot. The filtrate was cooled and crystallized for 5 hours, filtered through a Buchner funnel, and the filter cake was dried under reduced pressure to give an off-white solid (R)-1-(6-aminopurin-9-yl)-2-(diethoxyphosphorylmethoxy) Propane (VI) 1.42 g, yield 83.2%, purity 94.7%.
对比例4Comparative example 4
室温下，向反应瓶中加入4.0g化合物XIV、20mL NMP和10.6g异丙醇镁。搅拌下，加热至70℃，先混和液中滴加10.0g DESMP(式VI)。搅拌反应10小时。降温至20℃，用醋酸调节pH值至6-7。加入100mL乙酸乙酯，剧烈搅拌，升温至50℃。趁热过滤，滤液减压浓缩蒸除乙酸乙酯。剩余溶液转入反应瓶中，加入7.5g溴化钠。降温至0℃，滴加12.0g三甲基氯硅烷。滴加完后，升温至75℃，搅拌反应16小时。降温至室温，加入40mL水，用乙酸乙酯萃取两次。水相降温至5℃，用40％的氢氧化钠溶液调节pH值至3.0。搅拌2小时，用布氏漏斗过滤，滤饼用冰水洗涤，在65o真空干燥C下真空干燥得到3.2g化合物I，收率51.0％，纯度98.4％。4.0 g of compound XIV, 20 mL of NMP and 10.6 g of magnesium isopropoxide were added to the reaction flask at room temperature. With stirring, the mixture was heated to 70 ° C, and 10.0 g of DESMP (formula VI) was added dropwise to the first mixed solution. The reaction was stirred for 10 hours. The temperature was lowered to 20 ° C, and the pH was adjusted to 6-7 with acetic acid. 100 mL of ethyl acetate was added, stirred vigorously, and the temperature was raised to 50 °C. The mixture was filtered while hot, and the filtrate was concentrated and evaporated to ethyl acetate. The remaining solution was transferred to a reaction flask and 7.5 g of sodium bromide was added. The temperature was lowered to 0 ° C, and 12.0 g of trimethylchlorosilane was added dropwise. After the completion of the dropwise addition, the temperature was raised to 75 ° C, and the reaction was stirred for 16 hours. After cooling to room temperature, 40 mL of water was added and extracted twice with ethyl acetate. The aqueous phase was cooled to 5 ° C and the pH was adjusted to 3.0 with 40% sodium hydroxide. After stirring for 2 hours, it was filtered with a Buchner funnel, and the filter cake was washed with ice water, and dried under vacuum at 65 ° C under vacuum to give 3.2 g of Compound I, yield 51.0%, purity 98.4%.
实施例7Example 7
比较结果见表1、表2。The comparison results are shown in Table 1 and Table 2.
表1 生产成本比较Table 1 Comparison of production costs
Figure PCTCN2018083638-appb-000006
Figure PCTCN2018083638-appb-000006
Figure PCTCN2018083638-appb-000007
Figure PCTCN2018083638-appb-000007
注： *示与对比例相比具有显著差异(P＜0.05)； #示与对比例相比具有极显著差异(P＜0.01). Note: * There is a significant difference compared with the comparative example (P<0.05);# shows a significant difference compared with the comparative example (P<0.01).
表2 化合物I的制备比较Table 2 Comparison of preparation of compound I
组别Group 收率(％)Yield (%) 纯度(％)purity(%)
实施例6Example 6 59.259.2 99.1299.12
对比例4Comparative example 4 51.0％51.0% 98.40％98.40%
注： *示与对比例相比具有显著差异(P＜0.05)； #示与对比例相比具有极显著差异(P＜0.01)。 Note: *There is a significant difference compared with the comparative example (P<0.05);# shows a very significant difference compared with the comparative example (P<0.01).
以上对本发明所提供的一种替诺福韦的制备方法进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。The preparation method of tenofovir provided by the present invention is described in detail above. The principles and embodiments of the present invention have been described with reference to specific examples, and the description of the above embodiments is only to assist in understanding the method of the present invention and its core idea. It should be noted that those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the invention.

Claims (10)

  1. 化合物，其特征在于，结构如式XII所示；a compound characterized by having the structure shown in Formula XII;
    Figure PCTCN2018083638-appb-100001
    Figure PCTCN2018083638-appb-100001
  2. 根据权利要求1所述的化合物在制备替诺福韦中的应用。Use of a compound according to claim 1 for the preparation of tenofovir.
  3. 根据权利要求1所述的化合物的制备方法，其特征在于，以式Ⅳ所示化合物为原料，通过甲酰化反应制得式XI所示化合物；在溶剂存在的条件下，通过有机碱作用，式XI所示化合物与式V所示化合物发生取代反应，得到化合物XII；The method for preparing a compound according to claim 1, wherein a compound of the formula XI is obtained by a formylation reaction using a compound represented by the formula IV; and an organic base is used in the presence of a solvent. The compound of formula XI is substituted with a compound of formula V to give compound XII;
    Figure PCTCN2018083638-appb-100002
    Figure PCTCN2018083638-appb-100002
  4. 根据权利要求3所述的制备方法，其特征在于，所述溶剂选自1,4-二氧六环，N、N-二甲基甲酰胺，四氢呋喃或2-甲基四氢呋喃；所述有机碱选自三乙胺、二异丙基乙胺、吡啶、N-甲基吗啉；所述取代反应的温度为50～150℃，所述式V所示化合物的用量为0.9～1.5当量。The preparation method according to claim 3, wherein the solvent is selected from the group consisting of 1,4-dioxane, N, N-dimethylformamide, tetrahydrofuran or 2-methyltetrahydrofuran; It is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, and N-methylmorpholine; the temperature of the substitution reaction is 50 to 150 ° C, and the amount of the compound represented by the formula V is 0.9 to 1.5 equivalents.
  5. 一种替诺福韦的制备方法，其特征在于，包括如下步骤：A method for preparing tenofovir, comprising the steps of:
    步骤1：以式Ⅳ所示化合物为原料，通过甲酰化反应制得式XI所示化合物；Step 1: using the compound of the formula IV as a starting material, the compound of the formula XI is obtained by a formylation reaction;
    步骤2：在溶剂存在的条件下，通过有机碱作用，式XI所示化合物与式V所示化合物发生反应，得到式XII所示化合物；Step 2: reacting a compound of the formula XI with a compound of the formula V by an organic base in the presence of a solvent to obtain a compound of the formula XII;
    在反应溶剂和酸存在的条件下，式XII所示化合物与脱水剂作用经脱水环化，得到式XIII所示化合物；In the presence of a reaction solvent and an acid, the compound of the formula XII is dehydrated and cyclized with a dehydrating agent to give a compound of the formula XIII;
    步骤3：在溶剂存在的条件下，式XIII所示化合物发生取代反应，得到式XIV所示化合物；Step 3: in the presence of a solvent, a compound of the formula XIII undergoes a substitution reaction to obtain a compound of the formula XIV;
    步骤4：式XIV所示化合物与式VI所示化合物DESMP发生取代反应，在酸的作用下发生水解反应，得到式I所示替诺福韦；Step 4: a compound represented by the formula XIV is substituted with a compound of the formula VI, DESMP, and a hydrolysis reaction is carried out under the action of an acid to obtain tenofovir of the formula I;
    Figure PCTCN2018083638-appb-100003
    Figure PCTCN2018083638-appb-100003
  6. 根据权利要求5所述的制备方法，其特征在于，步骤2中所述溶剂选自1,4-二氧六环,N、N-二甲基甲酰胺，四氢呋喃或2-甲基四氢呋喃；所述有机碱选自三乙胺、二异丙基乙胺、吡啶、N-甲基吗啉；所述取代反应的温度为50～150℃，所述式V所示化合物的用量为0.9～1.5当量。The preparation method according to claim 5, wherein the solvent in the step 2 is selected from the group consisting of 1,4-dioxane, N, N-dimethylformamide, tetrahydrofuran or 2-methyltetrahydrofuran; The organic base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, and N-methylmorpholine; the temperature of the substitution reaction is 50 to 150 ° C, and the amount of the compound represented by the formula V is 0.9 to 1.5. equivalent.
  7. 根据权利要求5或6所述的制备方法，其特征在于，步骤3中所述反应溶剂选自N、N-二甲基甲酰胺、N-甲基吡咯烷酮或N、N-二甲基乙酰胺；所述脱水剂选自原甲酸三甲酯或原甲酸三乙酯；所述酸选自盐酸、硫酸、硝酸；所述脱水环化的反应温度：0～50℃。The preparation method according to claim 5 or 6, wherein the reaction solvent in the step 3 is selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone or N,N-dimethylacetamide. The dehydrating agent is selected from trimethyl orthoformate or triethyl orthoformate; the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and nitric acid; and the reaction temperature of the dehydration cyclization is from 0 to 50 °C.
  8. 一种替诺福韦的制备方法，其特征在于，包括如下步骤：A method for preparing tenofovir, comprising the steps of:
    步骤1：以式Ⅳ所示化合物为原料，通过甲酰化反应制得式XI所示化合物；Step 1: using the compound of the formula IV as a starting material, the compound of the formula XI is obtained by a formylation reaction;
    步骤2：在溶剂存在的条件下，通过有机碱作用，式XI所示化合物与式V所示化合物发生取代、环化反应，得到式XIII所示化合物；Step 2: in the presence of a solvent, by the action of an organic base, the compound of the formula XI and the compound of the formula V are substituted and cyclized to obtain a compound of the formula XIII;
    步骤3：在溶剂存在的条件下，式XIII所示化合物发生取代反应，得到式XIV化合物；Step 3: in the presence of a solvent, a compound of the formula XIII undergoes a substitution reaction to obtain a compound of the formula XIV;
    步骤4：式XIV所示化合物与式VI所示化合物DESMP发生取代反应，再在酸的作用下发生水解反应，得到式I所示替诺福韦；Step 4: The compound represented by the formula XIV is substituted with the compound DESMP of the formula VI, and then hydrolyzed by the action of an acid to obtain tenofovir of the formula I;
    Figure PCTCN2018083638-appb-100004
    Figure PCTCN2018083638-appb-100004
    Figure PCTCN2018083638-appb-100005
    Figure PCTCN2018083638-appb-100005
  9. 根据权利要求8所述的制备方法，其特征在于，步骤2中所述溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇或叔丁醇；所述有机碱选自三乙胺、二异丙基乙胺、吡啶或N-甲基吗啉；所述取代、环化的反应温度为40～120℃，所述式V所示化合物D-丙氨醇的用量为0.9～1.5当量。The preparation method according to claim 8, wherein the solvent in the step 2 is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol or tert-butanol; and the organic base is selected from the group consisting of triethylamine. , diisopropylethylamine, pyridine or N-methylmorpholine; the reaction temperature of the substitution and cyclization is 40 to 120 ° C, and the amount of the compound D-alaninol represented by the formula V is 0.9 to 1.5. equivalent.
  10. 根据权利要求5至9任一项所述的制备方法，其特征在于，步骤3中所述溶剂选自1,4-二氧六环,N、N-二甲基甲酰胺，四氢呋喃或2-甲基四氢呋喃；所述取代反应的温度为80～200℃。The preparation method according to any one of claims 5 to 9, wherein the solvent in the step 3 is selected from the group consisting of 1,4-dioxane, N, N-dimethylformamide, tetrahydrofuran or 2- Methyltetrahydrofuran; the temperature of the substitution reaction is 80 to 200 °C.
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