WO2024193457A1 - 吡咯并三嗪化合物的制备方法 - Google Patents

吡咯并三嗪化合物的制备方法 Download PDF

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WO2024193457A1
WO2024193457A1 PCT/CN2024/081885 CN2024081885W WO2024193457A1 WO 2024193457 A1 WO2024193457 A1 WO 2024193457A1 CN 2024081885 W CN2024081885 W CN 2024081885W WO 2024193457 A1 WO2024193457 A1 WO 2024193457A1
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compound
solvent
reaction
solution
preparation
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PCT/CN2024/081885
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French (fr)
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郑晨光
郭松劲
赵韧
潘睿
王涛
唐平生
金冶华
朱伟
孟艳华
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浙江华海药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • the invention belongs to the field of drug synthesis, and more specifically relates to a method for preparing a pyrrolotriazine compound.
  • Nucleoside drugs are an important class of drugs used clinically to treat viral infections, tumors, and AIDS. Nearly 50% of the antiviral drugs currently in use are nucleoside drugs. Carbon nucleoside pyrrolotriazine amine compounds are often included in the skeleton of nucleoside drugs and play an important role in the research and development of related drugs.
  • Remdesivir is an antiviral drug developed by Gilead Sciences. Its EC 50 value for ARS-CoV and MERS-CoV in HAE cells is 74nM, and its EC 50 value for mouse hepatitis virus in delayed brain tumor cells is 30nM. It is a phosphamide prodrug of the nucleoside GS-441524.
  • Compound 4 is an important intermediate of remdesivir.
  • bromo- or iodo-pyrrolo[2,1-F][1,2,4]triazine-4-amine (compound 2 or compound 5) is reacted with 2,3,5-tribenzyloxy-D-ribonic acid-1,4-lactone (compound 3) to obtain compound 4, and compound 4 is deprotected after the cyano group of the hydroxyl group is replaced to obtain GS-441524.
  • Condition 1 is: compound 2 reacts with compound 3 in tetrahydrofuran at -78°C under the action of n-butyl lithium and TMSCl to obtain compound 4 with a yield of 25%.
  • the yield of this process condition is low, and the product needs to be purified by column chromatography, which is difficult to mass produce.
  • Condition 2 is: reacting under the conditions of 1,2-bis(chlorodimethylsilyl)ethane, NaH, n-BuLi, THF, at -78°C to obtain compound 4 with a yield of 60%.
  • Condition 3 is: compound 5 reacts in TMSCl, PhMgCl, i-PrMgCl ⁇ LiCl, at -20°C to obtain compound 4 with a yield of 40%, but its raw material compound 5 is expensive, the yield is not high, and column chromatography purification is required.
  • CN 101466710B discloses a method for preparing compound 2.
  • 1,3-dibromo-5,5-dimethylhydantoin is added in portions to a dry DMF solution of pyrrolo[2,1-f][1,2,4]triazine-4-ylamine to obtain a crude compound 2.
  • the crude compound 2 is then ground and purified in ethyl acetate to obtain a dibrominated compound 2 containing 2% of the compound 2.
  • the yield is about 50%.
  • This method has the problems of difficult operation, low yield, and low product purity.
  • the purpose of the present invention is to develop a method for preparing carbon nucleoside pyrrolotriazine amine compounds which is more suitable for industrial production.
  • the present invention provides a method for preparing compound 4, comprising the following steps:
  • Step (2) Compound 2 is first reacted with NaH and TMSCl to protect the amino group, and then reacted with compound 3 under the action of n-butyl lithium to obtain compound 4.
  • Step (1) Compound 1 reacts with a bromination reagent to obtain compound 2.
  • the molar ratio of NaH to compound 2 is 0.90:1 to 1.50:1, preferably 1.00:1 to 1.15:1; the molar ratio of n-butyl lithium to compound 2 is 1.30:1 to 3.0:1, preferably 1.50:1 to 2.10:1.
  • the molar ratio of compound 3 to compound 2 is 0.40:1 to 1.20:1, preferably 0.50:1 to 0.80:1, and more preferably 0.55 to 0.60:1.
  • step (2) comprises the following steps: in a first solvent, in the presence of NaH, adding compound 2 at 0 to 30°C for reaction; cooling to -20 to 0°C, adding TMSCl for reaction; cooling again to -100 to -60°C, adding n-butyl lithium for reaction; finally, adding a solution of compound 3 in a second solvent at -100 to -60°C for reaction; obtaining compound 4.
  • the first solvent and the second solvent are each independently selected from one or more of 2-methyltetrahydrofuran, tetrahydrofuran, toluene, and methyl tert-butyl ether, preferably 2-methyltetrahydrofuran;
  • the volume mass ratio of the first solvent to compound 2 is 15:1 to 30:1 L/kg, preferably 17:1 to 22:1 L/kg;
  • the volume mass ratio of the second solvent to compound 3 is 1:1 to 20:1 L/kg; preferably 1.5:1 to 3.5:1 L/kg;
  • the first solvent and the second solvent are the same, more preferably, the first solvent and the second solvent are 2-methyltetrahydrofuran.
  • step (2) further includes the following steps: after the reaction is completed, quenching the reaction system with acid, separating the aqueous phase and the organic phase, washing and concentrating the organic phase, and then recrystallizing.
  • the step of quenching the reaction system with acid comprises: slowly adding the reaction solution into a mixture of an aqueous solution of acid and an organic solvent for quenching; the organic solvent is selected from one or more of 2-methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether or toluene.
  • the organic solvent is 2-methyltetrahydrofuran.
  • the volume mass ratio of the mixed solution to compound 2 is 20:1 to 40:1 L/kg;
  • the volume ratio of the acid aqueous solution to the organic solvent in the mixed solution is 1:1 to 5:1, preferably 3:2 to 3:1;
  • the temperature of the mixed solution is 0-20°C.
  • the acid is selected from one or more of citric acid, tartaric acid, acetic acid, and maleic acid.
  • the acid is citric acid.
  • the concentration of citric acid is 2-30%.
  • the concentration of the citric acid is 5-10%.
  • the washing and concentration of the organic phase comprises washing the separated organic phase with citric acid solution, water, and sodium bicarbonate solution in sequence.
  • the recrystallization solvent is one or more of a halogenated hydrocarbon solvent, an ester solvent and an alkane solvent
  • the halogenated hydrocarbon solvent is dichloromethane or dichloroethane, preferably dichloroethane
  • the ester solvent is one or more of ethyl acetate, propyl acetate and methyl acetate, preferably ethyl acetate
  • the alkane solvent is one or more of n-heptane, hexane, pentane or cyclohexane, preferably n-heptane or cyclohexane.
  • the bromination reagent is dibromohydantoin or NBS; the reaction temperature is -40°C to 10°C, preferably, -25°C to 10°C, and more preferably, -5°C to 10°C.
  • the solvent of the reaction is DMF.
  • step (1) the DMF solution of the bromination reagent is slowly added to the DMF solution of compound 1 to react;
  • the bromination reagent in step (1), is dibromohydantoin, and the molar ratio of dibromohydantoin to compound 1 is 0.4 to 0.8:1, preferably 0.48 to 0.52:1.
  • the post-treatment step of the reaction includes a step of recrystallizing and purifying the product with glacial acetic acid.
  • the recovery comprises: combining the aqueous phases treated with acid after the reaction in step (2) (for example, the aqueous phase quenched with acid and the aqueous phase washed with acid), controlling the temperature at ⁇ 30°C, adding alkali to adjust the pH value to alkaline, filtering, slurrying the filter cake with water, filtering, and drying the filter cake.
  • the base is sodium hydroxide or potassium hydroxide.
  • the pH value is adjusted to 7-14.
  • step (3) the pH value is adjusted to 7-9.
  • step (3) the pH value is adjusted to 11-13.
  • Another aspect of the present invention provides a method for preparing compound 2, comprising step (1): reacting compound 1 with a brominating agent to obtain compound 2, and after the reaction is completed, recrystallizing and purifying the product with glacial acetic acid,
  • the bromination reagent is dibromohydantoin or NBS, and the reaction temperature is -40°C to 10°C; preferably, -25°C to 10°C, and more preferably, -5°C to 10°C.
  • the reaction solvent in step (1) is DMF.
  • step (1) preferably, the DMF solution of the bromination reagent is slowly added to the DMF solution of compound 1 to carry out the reaction.
  • the bromination reagent is dibromohydantoin
  • the molar ratio of dibromohydantoin to compound 1 is 0.4 to 0.8:1, preferably 0.48 to 0.52:1.
  • the method of the present invention has high selectivity for preparing compound 2, and the purity and yield of compound 2 in the obtained crude product of compound 2 are relatively high.
  • a high-purity product can be obtained after being refined with acetic acid;
  • the method of the present invention is used to prepare compound 4.
  • the raw materials and reagents are low in price and used in small amounts.
  • step (2) the protection and lithium halide exchange are staged reactions with high conversion rate.
  • the amount of ribonucleolactone used is small, and the post-treatment is simple. After washing with citric acid to remove compound 1, the product can be directly crystallized to obtain the product with high yield and high quality.
  • Compound 1 can be recovered.
  • the entire route has low cost and is more conducive to industrial production.
  • Figure 2 refers to the HPLC detection spectrum of the crude compound 2 prepared by the method in CN 101466710B.
  • the peaks with retention times of 4.589, 9.952, 10.454 and 17.777 are residual raw materials, 5-isomers, compound 2 and dibrominated impurities, respectively.
  • FIG3 is a HPLC detection spectrum of crude compound 2 in Example 1.
  • FIG4 is a HPLC detection spectrum of the refined product of Compound 2 in Example 3.
  • % is weight/weight (w/w) percentage unless otherwise stated.
  • any numerical value such as a concentration or a range of concentrations stated herein, is to be understood as being modified in all instances by the term "about.”
  • the term "about” is intended to limit the numerical value it modifies, indicating that such a value may vary within a certain range.
  • the term “about” should be understood to mean a larger range including the stated value, as well as a range including the range of plus or minus 10% of the stated value when significant figures are taken into account.
  • acetic acid acetic acid, glacial acetic acid and glacial acetic acid represent the same meaning.
  • the sodium hydrogen reagent can be a sodium hydrogen reagent commonly used in the art.
  • the mass percentage of NaH in the sodium hydrogen reagent used in the embodiment of the present invention is 60%, and it is dispersed in mineral oil.
  • the feed amount is the amount of the reagent used, which is not converted into the amount of the effective ingredient.
  • the n-butyl lithium reagent used in the present invention may be a commonly used n-butyl lithium reagent in the art.
  • the n-butyl lithium reagent used in the embodiment of the present invention is preferably a n-butyl lithium hexane solution with a molar concentration of 2.5 M.
  • the feed amount is the amount of reagent used, which is not converted into the amount of effective ingredient.
  • the bromination reagent in the present invention can be a bromination reagent commonly used in the art, for example, dibromohydantoin or NBS.
  • dibromohydantoin is used, because its bromination efficiency is higher, the amount of reagent used is less, and the isomers produced are less, which is more conducive to purification and separation, and the product purity and yield are higher.
  • the bromination reagent is dibromohydantoin.
  • the DMF solution of dibromohydantoin is slowly added to the DMF solution of compound 1 for reaction.
  • the mass percentage concentration of the DMF solution of dibromohydantoin is 10% to 50%, preferably 20 to 25% (e.g., 20%, 23%, 25% or any value or range therebetween); the mass percentage concentration of the DMF solution of compound 1 is 10% to 50%, preferably 20 to 25% (e.g., 20%, 23%, 25% or any value or range therebetween).
  • the selectivity of the reaction of the method of the present invention is good, and the purity and yield of the reaction solution are high.
  • the post-treatment is simple, and a high-purity product can be obtained by refining with glacial acetic acid.
  • the reagent equivalent used in the method of the present invention is less, and the amount of solvent used is less, which is conducive to post-treatment.
  • the recovery process of compound 1 is shown in Figure 1.
  • the quenched aqueous phase and the citric acid washing aqueous phase in step (2) are mixed, and the pH value is adjusted to alkaline by adding alkali to recover compound 1.
  • the recovery rate can reach 35.1%.
  • the yield of compound 4 can reach 75.7% by preparing compound 4 in two steps from compound 1.
  • the acid used for post-treatment in the present invention can be one or more of citric acid, tartaric acid, acetic acid, and maleic acid.
  • citric acid is used.
  • the citric acid used can be a citric acid aqueous solution with a concentration of 2 to 30%, such as 2%, 5%, 10%, 15%, 20%, 30% or any value or range thereof.
  • the sodium bicarbonate solution used for post-treatment can be a sodium bicarbonate aqueous solution with a mass percentage concentration of 2 to 20%, such as 5%, 7%, 10%, 15%, or 20%.
  • the sodium sulfite aqueous solution used for post-treatment in step (1) can be a sodium sulfite aqueous solution with a concentration of 2 to 30%, for example, 2%, 5%, 10%, 15%, 20%, 30% or any value or range therebetween.
  • the aqueous sodium hydroxide solution used for post-treatment in step (1) can be an aqueous sodium hydroxide solution with a concentration of 2 to 100%, for example, 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 80%, 100% or any value or range thereof.
  • the post-reaction treatment step comprises: heating up after the reaction is completed to evaporate most of the solvent; adding water to cool down, treating with aqueous sodium sulfite solution and aqueous sodium hydroxide solution in sequence, collecting the solid, and recrystallizing with glacial acetic acid.
  • the temperature is raised to 70-100°C (e.g., 70-80°C, 80-90°C, 90-100°C), water is added to cool the temperature to 0-30°C (e.g., 0-10°C, 10-20°C or 20-30°C), and an aqueous sodium sulfite solution is slowly added dropwise to quench; an aqueous sodium hydroxide solution is slowly added dropwise; filtering, the wet filter cake is slurried with water; filtering, the filter cake is dried; the dry product is crystallized with glacial acetic acid, filtered, the wet filter cake is slurried with water; filtering, and the filter cake is dried to obtain compound 2.
  • 70-100°C e.g., 70-80°C, 80-90°C, 90-100°C
  • water is added to cool the temperature to 0-30°C (e.g., 0-10°C, 10-20°C or 20-30°C)
  • step (2) a first solvent (2-methyltetrahydrofuran, tetrahydrofuran, toluene, methyl tert-butyl ether) and sodium hydrogen are added to a reaction kettle; then compound 2 is added (for example, added in batches), and the reaction is carried out at 0 to 30° C. (for example, 0 to 10° C., 10 to 20° C., 20 to 30° C. or any value or range therein) until there are no obvious bubbles.
  • a first solvent (2-methyltetrahydrofuran, tetrahydrofuran, toluene, methyl tert-butyl ether) and sodium hydrogen are added to a reaction kettle; then compound 2 is added (for example, added in batches), and the reaction is carried out at 0 to 30° C. (for example, 0 to 10° C., 10 to 20° C., 20 to 30° C. or any value or range therein) until there are no obvious bubbles.
  • step (2) the temperature is lowered to -20 to 0°C (e.g., -20 to -15°C, -15 to -5°C, -5 to 0°C, or any value or range therein), the temperature is controlled to be ⁇ -5°C, TMSCl is slowly added dropwise, and after the addition is completed, the reaction is kept warm for a period of time, e.g., 0.5 to 2 hours.
  • -20 to 0°C e.g., -20 to -15°C, -15 to -5°C, -5 to 0°C, or any value or range therein
  • TMSCl is slowly added dropwise, and after the addition is completed, the reaction is kept warm for a period of time, e.g., 0.5 to 2 hours.
  • step (2) the internal temperature is lowered to -100 to -60°C (e.g., -100 to -90°C, -90 to -75°C, -75 to -60°C or any value or range therein), and n-butyl lithium is added dropwise.
  • the reaction is maintained at -90 to -75°C (e.g., -100 to -9 0°C, -90 to -75°C, -75 to -60°C or any value or range therein) for a period of time, e.g., 0.5 to 2 hours.
  • step (2) the temperature in the reaction kettle is controlled at -90 to -75°C (e.g., -100 to -90°C, -90 to -75°C, -75 to -60°C or any value or range therein), and a solution of a second solvent for compound 3 (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, toluene, methyl tert-butyl ether) is added dropwise; after the addition is completed, the temperature is kept at -90 to -75°C (e.g., -100 to -90°C, -90 to -75°C, -75 to -60°C or any value or range therein) for a period of time, e.g., 0.5 to 2 hours.
  • a second solvent for compound 3 e.g., 2-methyltetrahydrofuran, tetrahydrofuran, toluene, methyl tert-butyl ether
  • step (2) after the reaction is completed, the reaction solution is added dropwise to a mixture of a pre-cooled citric acid aqueous solution and an organic solvent (e.g., 2-methyltetrahydrofuran or toluene) to quench. After quenching, the mixture is allowed to stand for stratification, and the organic phase is washed with a citric acid solution, water, and a sodium bicarbonate solution in sequence.
  • an organic solvent e.g., 2-methyltetrahydrofuran or toluene
  • the post-treatment may be to remove all or part of the solvent by evaporation under reduced pressure, and after cooling, a halogenated hydrocarbon solvent (e.g., dichloromethane) or an ester solvent (e.g., ethyl acetate) is added to dissolve the residue; the above solution is added dropwise to an alkane solvent (e.g., n-heptane or cyclohexane) to precipitate a solid; the filter cake is rinsed with an alkane solvent (e.g., n-heptane or cyclohexane), and dried to obtain compound 4.
  • a halogenated hydrocarbon solvent e.g., dichloromethane
  • an ester solvent e.g., ethyl acetate
  • step (2) the reaction solution is added dropwise to a pre-cooled mixture of citric acid aqueous solution and 2-methyltetrahydrofuran to quench, and the solvent is evaporated under reduced pressure and then recrystallized with ethyl acetate and n-heptane.
  • the organic solvent in the first solvent, the second solvent and the post-treatment mixed solution is the same, for example, all are 2-methyltetrahydrofuran.
  • the recovery in step (3) comprises: combining the aqueous phase treated with acid after the reaction in step (2), controlling the temperature at ⁇ 30°C, adding alkali to adjust the pH value to alkaline, filtering, slurrying the filter cake with water, filtering, and drying the filter cake.
  • the method of the present invention firstly makes the amino group on the compound 2 under the action of NaH and TMS, and then uses n-butyl lithium to carry out lithium halogen exchange, and the protection and lithiation are carried out in stages, so that the reaction is more complete and the conversion rate is higher.
  • the compound 3 does not need to be excessive in large quantities, the organic impurities generated by the reaction are reduced, column chromatography is not required for post-reaction treatment, the amount of butyl lithium used is small, the time required for low-temperature control of the reaction is short, the operation is simple, the energy consumption is low, and it is conducive to industrial production.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Me-THF (150L) and sodium hydrogen (1.48kg) were added to the reactor in turn and stirred ( ⁇ 0.5h); Compound 2 (7.5kg) was added in batches; after addition, the mixture was kept at 20 ⁇ 30°C and stirred ( ⁇ 1h) until no obvious bubbles were observed; the mixture was cooled to -15 ⁇ -5°C, the temperature was controlled to ⁇ -5°C, and TMSCl (4.6kg) was slowly added dropwise ( ⁇ 1h); after addition, the mixture was kept at -15 ⁇ -5°C and stirred for 0.5h; the internal temperature was lowered to -90 ⁇ -75°C, and n-butyllithium (19.1kg) was added dropwise ( ⁇ 1h); after addition, the mixture was kept at -90 ⁇ -75°C and stirred for 0.5h; the internal temperature was controlled at -90 ⁇ -75°C, and a solution of compound 3 (8.8kg) in Me-THF (30L) was added dropwise; after addition, the mixture was kept at -90 ⁇ -75
  • the quenched aqueous phase and the citric acid washed aqueous phase in step 2 were mixed, cooled to 0-10°C and stirred; the temperature was controlled to ⁇ 25°C, and 30% sodium hydroxide solution was added dropwise until the pH value was 12-13; stirring was continued for 0.5h, and the pH value was re-measured to be 12-13; filtration was performed, and the filter cake was slurried with water (10L); filtration was performed, and the filter cake was vacuum dried at 50-55°C to obtain compound 1, 1.51kg of white powder, with a recovery rate of 32.0% and a purity of 99.5%.
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Me-THF (940 L) and sodium hydrogen (9.3 kg) were added to the reactor in turn and stirred ( ⁇ 0.5 h); Compound 2 (47.0 kg) was added in batches; after addition, the temperature was kept at 20-30 ° C and stirred until there were no obvious bubbles; the temperature was lowered to -20--10 ° C, the temperature was controlled at ⁇ -10 ° C, and TMSCl (24.0 kg) was slowly added dropwise ( ⁇ 1 h); after addition, the temperature was kept at -15--5 °C, stirred for ⁇ 0.5h; the internal temperature dropped to -90 ⁇ -75°C, and n-butyl lithium (120.0kg) was added dropwise ( ⁇ 1h); after the addition, the temperature was kept at -90 ⁇ -75°C and stirred for 0.5h; the internal temperature was controlled at -90 ⁇ -75°C, and a solution of compound 3 (55.4kg) in Me-THF (150L) was added dropwise; after the addition, the temperature was kept at -90 ⁇ ⁇ -75
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • the quenched aqueous phase and the citric acid washed aqueous phase in step 2 were mixed, cooled to 0-10°C and stirred; the temperature was controlled to ⁇ 30°C, and 30% sodium hydroxide solution was added dropwise until the pH value was 11-13; stirring was continued for 0.5h, and the pH value was re-measured to be 11-13; filtration was performed, and the filter cake was slurried with water (100mL); filtration was performed, and the filter cake was vacuum dried at 50-60°C to obtain compound 1, 23.5g of white powder, with a recovery rate of 35.1% and a purity of 99.6%.
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Test solution Use diluent to prepare a solution containing the test sample at a concentration of 0.5 mg/mL.
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Test sample solution Use diluent to prepare a solution containing the test sample at a concentration of 0.5 mg/mL.
  • Steps Inject 1 injection of blank solution and 1 injection of test solution according to the chromatographic conditions, and record the chromatographic process.

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Abstract

本发明属于药物合成领域，更具体地涉及吡咯并三嗪化合物的制备方法，具体为：化合物2先通过和NaH、TMSCl反应保护氨基，再在正丁基锂作用下和化合物3反应得到化合物4，化合物2可由化合物1和溴化试剂反应得到，化合物1可回收。本发明方法操作简单，成本低，更有利于工业化生产。

Description

吡咯并三嗪化合物的制备方法 技术领域
本发明属于药物合成领域，更具体地涉及吡咯并三嗪化合物的制备方法。
背景技术
核苷类药物是临床上用于治疗病毒感染、肿瘤、艾滋病的一类重要的药物，目前在使用的抗病毒药物中近50％是核苷类药物。碳核苷吡咯并三嗪胺类化合物经常包含于核苷类药物的骨架之中，在相关药物研发中扮演着重要的角色。
瑞德西韦(Remdesivir)，是吉利德化学研发的抗病毒药物，其在HAE细胞中，对ARS-CoV和MERS-CoV的EC50值为74nM，在延迟脑肿瘤细胞中，对鼠肝炎病毒的EC50值为30nM，它是核苷GS-441524的一种磷酰胺类前药。
化合物4为瑞德西韦的重要中间体。J.Med.Chem.2017,60,1648-1661中公开GS-441524的制备方法中，使用溴代或碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺(化合物2或化合物5)与2,3,5-三苄氧基-D-核糖酸-1,4-内酯(化合物3)反应得到化合物4，化合物4经过羟基的氰基取代后脱除保护基得到GS-441524。
J.Med.Chem.2017,60,1648-1661中公开化合物4的3种制备条件，条件一为：化合物2在正丁基锂和TMSCl作用下，在四氢呋喃中和化合物3在-78℃下反应得到化合物4，收率25％，该工艺条件收率低，产物需要柱层析纯化，难以大规模生产；条件二为：在1,2-双(氯二甲基硅基)乙烷,NaH,n-BuLi,THF,-78℃条件下反应，得到化合物4，收率60％，该条件下虽然收率较高，但是所使用的试剂1,2-双(氯二甲基硅基)乙烷价格昂贵，市场上无商业化供应，无法实现工业化生产；条件三为：化合物5在TMSCl、PhMgCl、i-PrMgCl·LiCl、-20℃反应得到化合物4，收率40％，但是其原料化合物5价格昂贵，收率不高，需要柱层析纯化。
CN 101466710B中公开化合物2的制备方法，在-20℃下，将1，3-二溴-5，5-二甲基乙内酰脲按份添加至吡咯并[2，1-f][1，2，4]三嗪-4-基胺的无水DMF溶液中反应得到粗制的化合物2，经在乙酸乙酯中研磨纯化，得到含2％的二溴代的化合物2，收率约为50％，该方法存在操作困难，收率低，产品纯度不高的问题。
考虑到碳核苷吡咯并三嗪胺类化合物在核苷类药物中的重要性，有必要开发适合工业化生产该类化合物的制备方法。
发明内容
本发明的目的在于开发更适合工业化生产的碳核苷吡咯并三嗪胺类化合物的制备方法。
本发明一方面提供化合物4的制备方法，包括以下步骤：
步骤(2)：化合物2先通过和NaH、TMSCl反应保护氨基，再在正丁基锂作用下和化合物3反应得到化合物4，
在本发明的一些实施方式中，还包括以下步骤：
步骤(1)：化合物1和溴化试剂反应得到化合物2，
在本发明的一些实施方式中，还包括以下步骤：
步骤(3)：回收化合物1。
在本发明的一些实施方式中，步骤(2)中，NaH和化合物2的摩尔比为0.90:1～1.50:1，优选为1.00:1～1.15:1；正丁基锂和化合物2的摩尔比为1.30:1～3.0:1，优选为1.50:1～2.10:1。
在本发明的一些实施方式中，步骤(2)中，化合物3和化合物2的摩尔比为0.40:1～1.20:1，优选为0.50:1～0.80:1，更优选为0.55～0.60:1。
在本发明的一些实施方式中，步骤(2)包括以下步骤：在第一溶剂中，NaH存在下，在0～30℃加入化合物2反应；降温至-20～0℃，加入TMSCl进行反应；再降温至-100～-60℃，加入正丁基锂进行反应；最后在-100～-60℃加入化合物3在第二溶剂中的溶液进行反应；得到化合物4。
在本发明的一些实施方式中，步骤(2)中，所述第一溶剂和第二溶剂各自独立地选自2-甲基四氢呋喃、四氢呋喃、甲苯、甲基叔丁基醚中的一种或多种，优选地为2-甲基四氢呋喃；所述第一溶剂和化合物2的体积质量比为15:1～30:1L/kg，优选地为17:1～22:1L/kg；所述第二溶剂和化合物3的体积质量比为1:1～20:1L/kg；优选地为1.5:1～3.5:1L/kg；优选地，所述第一溶剂和第二溶剂相同，更优选地，所述第一溶剂和第二溶剂为2-甲基四氢呋喃。
在本发明的一些实施方式中，步骤(2)中，还包括以下步骤：反应完成后以酸淬灭反应体系，分离水相和有机相，将有机相洗涤浓缩后，进行重结晶。
在本发明的一些实施方式中，步骤(2)中，所述以酸淬灭反应体系的步骤包括：将的反应液缓慢加入酸的水溶液和有机溶剂的混合液中淬灭；所述有机溶剂选自2-甲基四氢呋喃、甲基叔丁基醚、乙醚或甲苯中的一种或多种。
在本发明的一些实施方式中，所述有机溶剂为2-甲基四氢呋喃。
在本发明的一些实施方式中，所述混合液和化合物2的体积质量比为20:1～40:1L/kg；
在本发明的一些实施方式中，混合液中所述酸水溶液和有机溶剂的体积比为1:1～5:1，优选地为3:2～3:1；
在本发明的一些实施方式中，所述混合液的温度为0～20℃。
在本发明的一些实施方式中，步骤(2)中，所述酸选自柠檬酸、酒石酸、醋酸、马来酸中的一种或多种。
在本发明的一些实施方式中，所述酸为柠檬酸。
在本发明的一些实施方式中，所述柠檬酸的浓度为2～30％。
在本发明的一些实施方式中，所述柠檬酸的浓度5～10％。
在本发明的一些实施方式中，步骤(2)中，所述有机相洗涤浓缩包括将分离的有机相依次用柠檬酸溶液、水、碳酸氢钠溶液洗涤。
在本发明的一些实施方式中，步骤(2)中，所述重结晶的溶剂为卤代烃类溶剂、酯类溶剂和烷烃类溶剂中的一种或多种，所述卤代烃类溶剂为二氯甲烷、二氯乙烷，优选为二氯乙烷；所述酯类溶剂为乙酸乙酯、乙酸丙酯、乙酸甲酯中的一种或多种，优选为乙酸乙酯；所述烷烃类溶剂为正庚烷、己烷、戊烷或环己烷中的一种或多种；优选地为正庚烷或环己烷。
在本发明的一些实施方式中，步骤(1)中，所述溴化试剂为二溴海因或NBS；所述反应的温度为-40℃～10℃，优选地，为-25℃～10℃，更优选地，为-5℃～10℃。
在本发明的一些实施方式中，所述反应的溶剂为DMF。
在本发明的一些实施方式中，步骤(1)中，将所述溴化试剂的DMF溶液缓慢加入化合物1的DMF溶液进行反应；
在本发明的一些实施方式中，步骤(1)中，所述溴化试剂为二溴海因，其和化合物1的摩尔比为0.4～0.8:1，优选地为0.48～0.52:1。
在本发明的一些实施方式中，步骤(1)中，所述反应的后处理步骤中包括以冰乙酸重结晶纯化产物的步骤。
在本发明的一些实施方式中，步骤(3)中，所述回收包括：将步骤(2)中，反应后以酸处理过的水相(例如包括酸淬灭的水相和酸洗涤的水相)合并，将温度控制在≤30℃，加入碱调节pH值至碱性，过滤，滤饼用水打浆，过滤，滤饼烘干。
在本发明的一些实施方式中，步骤(3)中，所述碱为氢氧化钠或氢氧化钾。在本发明的一些实施方式中，步骤(3)中，所述pH值调节至7～14。
在本发明的一些实施方式中，步骤(3)中，所述pH值调节至7～9。
在本发明的一些实施方式中，步骤(3)中，所述pH值调节至11～13。
本发明另一方面提供一种化合物2的制备方法，包含步骤(1)：化合物1和溴化试剂反应得到化合物2，反应完毕后以冰乙酸重结晶纯化产物，
在本发明的一些实施方式中，步骤(1)中，溴化试剂为二溴海因或NBS，反应的温度为-40℃～10℃；优选地，为-25℃～10℃，更优选地，为-5℃～10℃。
在本发明的一些实施方式中，步骤(1)中反应溶剂为DMF。
在本发明的一些实施方式中，步骤(1)中，优选地，将所述溴化试剂的DMF溶液缓慢加入化合物1的DMF溶液进行反应。
在本发明的一些实施方式中，溴化试剂为二溴海因，其和化合物1的摩尔比为0.4～0.8:1，优选地为0.48～0.52:1。
有益效果：
本发明方法制备化合物2反应选择性高，得到的化合物2的粗产品中化合物2的纯度和产率较高，通过醋酸精制后可得到高纯度的产品；
本发明方法制备化合物4，原料和试剂价格低，用量较少，步骤(2)中保护和锂卤交换分段反应，转化率高，核糖酸内酯使用当量少，后处理简便，柠檬酸洗涤去除化合物1后可直接析晶得到产物，产率高，质量高。
化合物1可回收。
整条路线成本低，更有利于工业化生产。
附图说明
图1工艺流程图。
图2参考CN 101466710B中方法所制备化合物2粗品HPLC检测图谱，保留时间4.589、9.952、10.454和17.777的峰分别为残留原料、5-位异构体、化合物2和二溴代杂质。
图3实施例1中化合物2粗品HPLC检测图谱。
图4实施例3化合物2精制品HPLC检测图谱。
具体实施方式
以下具体实施方式为本发明的进一步详细说明。
在本文中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所用实验室操作步骤均为相应领域内广泛使用的常规步骤。
术语和说明：
当描述本发明的化合物、组合物、方法和工艺时，除非另外指示，否则下列术语具有下列含义。另外，除非使用的上下文另外明确规定，否则如本文所用，单数形式“一”和“所述”包括相应的复数形式。
术语“具有”、“包含”和“包括”应解释为开放式的，表明存在所列举的要素但不排除未列举的任何其他一个或多个要素的存在、出现或添加。
本文叙述的所有范围包括列举两个值之间的范围的那些端点。不管是否指出，本文所列举的所有值包括用于测量该值的给定技术的预期实验误差、技术误差和仪器误差的程度。
在本文中，如无另外说明，％是重量/重量(w/w)的百分数。
除非另有说明，否则任何数值，例如本文所述的浓度或浓度范围，应理解为在所有情况下均由术语“约”修饰。
在本文中，除非另有说明，术语“约”旨在限定其修饰的数值，表示这样的值可在一定范围内变化。当没有记载范围(例如误差范围或图表或数据表中给出的平均值的标准偏差)时，术语“约”应理解为表示包含所记载的值的较大范围，以及在考虑有效数字的情况下，通过四舍五入到该数字而包括的范围，以及包含所记载值的加减10％比例的范围。
本发明实施例中所用的原料或试剂除特别说明之外，均市售可得。诸如采购自以下公司：

本发明中使用的缩写具有本领域常规含义，例如以下缩写的含义如下：
本发明乙酸、醋酸、冰醋酸、冰乙酸代表相同的含义。
NaH
本发明中，钠氢试剂可以是本领域常用的钠氢试剂。本发明实施例中使用的钠氢试剂中NaH的质量百分含量为60％，分散在矿物油中。投料量为使用的试剂用量，未换算为有效成分用量。
正丁基锂
本发明中使用的正丁基锂试剂，可以是本领域常用的正丁基锂试剂，本发明实施例中使用的正丁基锂试剂优选为摩尔浓度为2.5M的正丁基锂正己烷溶液。投料量为使用的试剂用量，未换算为有效成分用量。
溴化试剂
本发明中溴化试剂可以是本领域常用的溴化试剂，例如可以是二溴海因或NBS，优选地使用二溴海因，其溴化的效率更高，使用的试剂量当量较少，产生的异构体较少，更有益于纯化分离，产物纯度和收率更高。
在本发明的一些优选实施方式中，步骤(1)中，溴化试剂为二溴海因。
在本发明的一些优选实施方式中，将二溴海因的DMF溶液缓慢加入化合物1的DMF溶液进行反应。在本发明的一些实施方式中，二溴海因的DMF溶液的质量百分浓度为10％～50％，优选地为20～25％(例如20％、23％、25％或其间任意数值或范围)；化合物1的DMF溶液的质量百分浓度为10％～50％，优选地为20～25％(例如20％、23％、25％或其间任意数值或范围)。
由图2和图3的对比可以看出，本发明方法反应的选择性好，反应液的纯度和产率高。后处理简单，通过冰乙酸精制可以得到高纯度的产品。本发明方法使用的试剂当量较少，溶剂用量较少，有利于后处理。
回收化合物1
化合物1的回收流程参考图1，将步骤(2)中的淬灭水相和柠檬酸洗涤水相混合，加碱调节pH值至碱性后回收化合物1。回收率可达35.1％。基于回收率，从化合物1制备化合物4两步反应，化合物4的收率可达75.7％。
酸
本发明中用于后处理的酸可以是柠檬酸、酒石酸、醋酸、马来酸中的一种或多种。优选地使用柠檬酸。所使用的柠檬酸使用柠檬酸溶液可以是浓度为2～30％的柠檬酸水溶液，例如2％、5％、10％、15％、20％、30％或其间任意数值或范围的柠檬酸水溶液。
碳酸氢钠溶液
本发明中步骤(2)中，用于后处理的碳酸氢钠溶液可以是质量百分比浓度为2～20％的碳酸氢钠水溶液，例如5％、7％、10％、15％、20％的碳酸氢钠水溶液。
亚硫酸钠水溶液
本发明中，步骤(1)中用于后处理的亚硫酸钠水溶液可以是浓度为2～30％的亚硫酸钠水溶液，例如2％、5％、10％、15％、20％、30％或其间任意数值或范围的亚硫酸钠水溶液。
氢氧化钠水溶液
本发明中，步骤(1)中用于后处理的氢氧化钠水溶液可以是浓度为2～100％的氢氧化钠水溶液，例如2％、5％、10％、15％、20％、30％、40％、50％、60％、80％、100％或其间任意数值或范围的氢氧化钠水溶液。
在本发明的一些实施方式中，步骤(1)中，反应后处理步骤包括：反应完毕后升温蒸去大部分溶剂；加水降温后依次用亚硫酸钠水溶液和氢氧化钠水溶液处理后，收集固体，用冰乙酸重结晶。
在本发明的一些实施方式中，反应完毕后升温至70～100℃(例如70～80℃、80～90℃、90～100℃)，加水降温至0～30℃(例如0～10℃、10～20℃或20～30℃)，缓慢滴加亚硫酸钠水溶液淬灭；缓慢滴加氢氧化钠水溶液；过滤，湿滤饼用水打浆；过滤，滤饼烘干；干品用冰乙酸析晶，过滤，湿滤饼用水打浆；过滤，滤饼烘干，得到化合物2。
在本发明的一些实施方式中，步骤(2)中，反应釜中加入第一溶剂(2-甲基四氢呋喃、四氢呋喃、甲苯、甲基叔丁基醚)和钠氢；再加入化合物2(例如分批加入)，在0～30℃(例如0～10℃、10～20℃、20～30℃或其中任意数值或范围)反应至无明显气泡。
本发明的一些实施方式中，步骤(2)中，降温至-20～0℃(例如-20～-15℃、-15～-5℃、-5～0℃或其中任意数值或范围)，控温≤-5℃，缓慢滴加TMSCl，滴毕，保温反应一段时间，例如0.5～2h。
本发明的一些实施方式中，步骤(2)中，将內温降至-100～-60℃(例如-100～-90℃、-90～-75℃、-75～-60℃或其中任意数值或范围)，滴加正丁基锂；滴毕，保温-90～-75℃(例如-100～-9 0℃、-90～-75℃、-75～-60℃或其中任意数值或范围)反应一段时间，例如0.5～2h。
在本发明的一些实施方式中，步骤(2)中，控制反应釜內温-90～-75℃(例如-100～-90℃、-90～-75℃、-75～-60℃或其中任意数值或范围)，滴加化合物3的第二溶剂(例如2-甲基四氢呋喃、四氢呋喃、甲苯、甲基叔丁基醚)的溶液；滴毕，保温-90～-75℃(例如-100～-90℃、-90～-75℃、-75～-60℃或其中任意数值或范围)反应一段时间，例如0.5～2h。
在本发明的一些实施方式中，步骤(2)中，反应完毕后，将反应液滴加至预冷至柠檬酸水溶液和有机溶剂(例如2-甲基四氢呋喃或甲苯)的混合液中淬灭。淬灭后静置分层，有机相依次用柠檬酸溶液、水、碳酸氢钠溶液洗涤。步骤(2)中，后处理可以减压蒸除全部或部分溶剂，冷却后，加入卤代烃类溶剂(例如二氯甲烷)或酯类溶剂(例如乙酸乙酯)溶解残留物；将上述溶液滴加烷烃类溶剂(例如正庚烷或环己烷)中，析出固体；过滤，滤饼用烷烃类溶剂(例如正庚烷或环己烷)淋洗，烘干，得到化合物4。
在本发明的一些实施方式中，步骤(2)中，将反应液滴加至预冷至柠檬酸水溶液和2-甲基四氢呋喃的混合液中淬灭，减压蒸除溶剂后以乙酸乙酯和正庚烷重结晶。
优选地，第一溶剂、第二溶剂和后处理混合液中的有机溶剂相同，例如均为2-甲基四氢呋喃。
在本发明的一些实施方式中，步骤(3)中所述回收包括：将步骤(2)中，反应后以酸处理过的的水相合并，将温度控制在≤30℃，加入碱调节pH值至碱性，过滤，滤饼用水打浆，过滤，滤饼烘干。
本发明的方法先使在NaH和TMS作用下化合物2上的氨基，再使用正丁基锂进行锂卤交换，保护与锂化分段进行，反应更为充分，转化率较高，后续糖苷化反应中化合物3无需大量过量，反应产生的有机物杂质减少，反应后处理无需柱层析，丁基锂用量较少，反应需要低温控制的时间较少，操作简便，能耗少，有利于工业化生产。
实施例1：
步骤1：化合物2的制备
氮气保护下，向反应釜内加入化合物1(4.0kg)，加入DMF(13.3kg)，降温至-5～5℃；滴加二溴海因(4.26kg)的DMF(15.2kg)溶液，控温-5℃～10℃；加料完毕，-5℃～10℃保温反应～2h；升温至70～80℃，减压蒸去大部分溶剂；加入水(100L)，降至0～10℃；缓慢滴加10％亚硫酸钠水溶液(4.0kg)淬灭；再缓慢滴加30％氢氧化钠水溶液(15kg)；保温0～10℃搅拌～1h，过滤，湿滤饼用水(30L)打浆；过滤，滤饼烘干；干品用冰乙酸(32L)析晶，过滤，湿滤饼用水(30L)打浆；过滤，滤饼烘干，得到化合物2，白色粉末，5.7kg，产率90％，纯度99.4％。
步骤2：化合物4的制备
氮气保护下，依次将Me-THF(150L)和钠氢(1.48kg)投入反应釜，搅拌(～0.5h)；分批加入化合物2(7.5kg)；加毕，保温20～30℃，搅拌(～1h)，至无明显气泡；降温至-15～-5℃，控温≤-5℃，缓慢(～1h)滴加TMSCl(4.6kg)；滴毕，保温-15～-5℃，搅拌0.5h；內温降至-90～-75℃，滴加(～1h)正丁基锂(19.1kg)；滴毕，保温-90～-75℃搅拌0.5h；控制內温-90～-75℃，滴加化合物3(8.8kg)的Me-THF(30L)溶液；滴毕，保温-90～-75℃，搅拌0.5h；搅拌下，将反应液滴加至预冷至0～10℃的10％柠檬酸水溶液(180L)和2-甲基四氢呋喃(60L)的混合液中；淬灭结束，搅拌(～1h)，静置1h，分液，有机相依次用10％柠檬酸溶液(150L)、水(100L)、7％碳酸氢钠溶液(50L)洗涤；减压蒸干溶剂，冷却至10～30℃；加入乙酸乙酯(7.5L)溶解残留物；将上述溶液滴加至预冷至0～5℃的正庚烷(220L)中，析出淡黄色固体；过滤，滤饼用正庚烷淋洗，放入烘箱30～40℃真空烘干，得到化合物4，淡黄色粉末10.5kg，产率54％，纯度95.6％。
步骤3：化合物1的回收
将步骤2中淬灭水相和柠檬酸洗涤水相混合，降温至0～10℃搅拌；控温≤25℃，滴加30％氢氧化钠溶液至pH＝12～13；继续搅拌0.5h，复测pH＝12～13；过滤，滤饼用水(10L)打浆；过滤，滤饼50～55℃真空烘干，得到化合物1，白色粉末1.51kg，回收率32.0％，纯度99.5％。
实施例2：
步骤1：化合物2的制备
氮气保护下，向反应釜内加入化合物1(120kg)，加入DMF(400kg)，降温至-10～0℃；滴加二溴海因(130.5kg)的DMF(460kg)溶液，控温-10℃～0℃；加料完毕，-10℃～0℃保温反应～2h；升温至80～90℃，减压蒸去大部分溶剂；加入水(2400L)，降至0～10℃；缓慢滴加10％亚硫酸钠水溶液(120kg)淬灭；缓慢滴加30％氢氧化钠水溶液(450kg)；过滤，湿滤饼用水(1000L)打浆；过滤，滤饼烘干；干品用冰乙酸(670L)析晶，过滤，湿滤饼用水(1000L)打浆；过滤，滤饼烘干，得到化合物2，白色粉末，173.6kg，产率91％，纯度99.3％。
步骤2：化合物4的制备
氮气保护下，依次将Me-THF(940L)和钠氢(9.3kg)投入反应釜，搅拌(～0.5h)；分批加入化合物2(47.0kg)；加毕，保温20～30℃，搅拌至无明显气泡；降温至-20～-10℃，控温≤-10℃，缓慢(～1h)滴加TMSCl(24.0kg)；滴毕，保温-15～-5℃，搅拌～0.5h；內温降至-90～-75℃，滴加(～1h)正丁基锂(120.0kg)；滴毕，保温-90～-75℃搅拌0.5h；控制內温-90～-75℃，滴加化合物3(55.4kg)的Me-THF(150L)溶液；滴毕，保温-90～-75℃，搅拌～0.5h；搅拌下，将反应液滴加至预冷至0～10℃的10％柠檬酸水溶液(1100L)和2-甲基四氢呋喃(420L)的混合液中；淬灭结束，搅拌(～1h)，静置1h，分液，有机相依次用10％柠檬酸溶液(660L)、10％柠檬酸溶液(420L)、水(450L)、7％碳酸氢钠溶液(330L)洗涤；减压蒸除部分溶剂(剩余溶液～200L)，冷却至10～30℃；加入二氯甲烷(45L)溶解残留物；将上述溶液滴加至预冷至-10～0℃的正庚烷(1400L)中，析出淡黄色固体；过滤，滤饼用正庚烷(50L)淋洗，放入烘筒30～40℃真空烘干，得到化合物4，淡黄色粉末58.7kg，产率52％，纯度94.0％。
步骤3：化合物1的回收
将步骤2中淬灭水相和柠檬酸洗涤水相混合，降温至0～10℃搅拌；控温≤30℃，加入氢氧化钠固体至pH＝11～13；继续搅拌0.5h，复测pH＝11～13；过滤，滤饼用水(100L)打浆；过滤，滤饼50～55℃真空烘干，得到化合物1，白色粉末9.8kg，回收率33.1％，纯度99.5％。
实施例3：
步骤1：化合物2的制备
氮气保护下，向反应瓶内加入化合物1(160g)，加入DMF(530g)，降温至-5～5℃；滴加NBS(216.8g)的DMF(600g)溶液，控温-5℃～10℃；加料完毕，-5℃～10℃保温反应2个小时；升温至70～80℃，减压蒸去大部分溶剂；加入水(1L)，降至0～10℃；缓慢滴加10％亚硫酸钠水溶液(40g)淬灭；缓慢滴加30％氢氧化钠水溶液(100g)；过滤，湿滤饼用水(300mL)打浆；过滤，滤饼烘干；干品用冰乙酸(260mL)析晶，过滤，湿滤饼用水(300mL)打浆；过滤，滤饼烘干，得到化合物2，白色粉末216.1g，产率85％，纯度99.5％。
步骤2：化合物4的制备
氮气保护下，依次将THF(2100mL)和钠氢(21.0g)投入反应瓶，搅拌(～0.5h)；分批加入化合物2(106.5g)；加毕，保温20～30℃，搅拌至无明显气泡；降温至-15～-5℃，控温≤-5℃，缓慢滴加TMSCl(65.2g)；滴毕，保温-15～-5℃，搅拌0.5h；继续降温至-90～-75℃，滴加正丁基锂(272g)；滴毕，保温-90～-75℃搅拌0.5h；控制內温-90～-75℃，滴加化合物3(167.4g)的THF(320mL)溶液；滴毕，保温-90～-75℃，搅拌0.5h；搅拌下，将反应液滴加至预冷至0～10℃的10％柠檬酸水溶液(1500mL)和甲苯(1000mL)的混合液中；淬灭结束，搅拌(～1h)，静置1h，分液，有机相依次用10％柠檬酸溶液(1500mL)、10％柠檬酸溶液(1000mL)、水(1000mL)、7％碳酸氢钠溶液(700mL)洗涤；减压蒸去部分溶剂(剩余反应液～300mL)，冷却至10～30℃；将上述溶液滴加至预冷至0～5℃的环己烷(3000mL)中，析出淡黄色固体；过滤，滤饼用环己烷(200mL)淋洗，放入烘箱30～40℃真空烘干，得到化合物4，淡黄色粉末132.7g，产率48％，纯度95.1％。
步骤3：化合物1的回收
将步骤2中淬灭水相和柠檬酸洗涤水相混合，降温至0～10℃搅拌；控温≤30℃，滴加30％氢氧化钠溶液至pH＝11～13；继续搅拌0.5h，复测pH＝11～13；过滤，滤饼用水(100mL)打浆；过滤，滤饼50～60℃真空烘干，得到化合物1，白色粉末23.5g，回收率35.1％，纯度99.6％。
实施例4：
化合物2有关物质检测方法：
仪器：高效液相色谱仪配备紫外检测器
色谱柱：WatersCSH Fluoro-Phenyl 150*4.6mm,3.5μm
流动相A：0.1％全氟丁酸水溶液:乙腈＝99:1(％V/V)
流动相B：0.1％全氟丁酸水溶液:乙腈＝55:45(％V/V)
检测波长：280nm                   流速：1.0mL/min
进样体积：10μL                    柱温：45℃
运行时间：40min
梯度：
溶液配制
溶液1：三氟乙酸:水:乙腈＝0.1:70:30(V/V/V)
稀释液：溶液1:水＝20:80(％V/V)
空白溶液：稀释液
供试品溶液：用稀释液配制成含供试品浓度为0.5mg/mL的溶液
进样程序
步骤：按照色谱条件分别进样空白溶液1针，供试品溶液1针，记录色谱过程。
计算：面积归一化法。
实施例5：
化合物4有关物质检测方法：
仪器：高效液相色谱仪配备紫外检测器
色谱柱：WatersMS C18 150*4.6mm,3.5μm
流动相A：0.1％三氟乙酸水溶液
流动相B：0.1％三氟乙酸乙腈溶液
检测波长：235nm                  流速：1.0mL/min
进样体积：10μL                   柱温：45℃
运行时间：40min
梯度：
溶液配制
稀释液：乙腈:水＝50:50(％V/V)
空白溶液：稀释液
供试品溶液：用稀释液配制成含供试品浓度为0.5mg/mL的溶液。
进样程序
步骤：按照色谱条件分别进样空白溶液1针，供试品溶液1针，记录色谱过程。
计算：面积归一化法。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本请所附权利要求书。
上述较佳案例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的学者能够了解本发明的内容，并不能以此限制本发明的保护范围。凡是根据本发明精神实质所做的等效变化或修饰，都应涵盖本发明的保护范围之内。

Claims (14)

  1. 化合物4的制备方法，其特征在于，包括以下步骤：
    步骤(2)：化合物2先通过和NaH、TMSCl反应保护氨基，再在正丁基锂作用下和化合物3反应得到化合物4，
  2. 根据权利要求1所述的制备方法，其特征在于，还包括以下步骤：
    步骤(1)：化合物1和溴化试剂反应得到化合物2，
  3. 根据权利要求2所述的制备方法，其特征在于，还包括以下步骤：
    步骤(3)：回收化合物1。
  4. 根据权利要求1～3中任一项所述的制备方法，其特征在于，
    步骤(2)中，NaH和化合物2的摩尔比为0.90:1～1.50:1，优选为1.00:1～1.15:1；正丁基锂和化合物2的摩尔比为1.30:1～3.0:1，优选为1.50:1～2.10:1。
  5. 根据权利要求4所述的制备方法，其特征在于，步骤(2)中，化合物3和化合物2的摩尔比为0.40:1～1.20:1，优选为0.50:1～0.80:1，更优选为0.55～0.60:1。
  6. 根据权利要求4所述的制备方法，其特征在于，步骤(2)包括以下步骤：在第一溶剂中，NaH存在下，在0～30℃加入化合物2反应；降温至-20～0℃，加入TMSCl进行反应；再降温至-100～-60℃，加入正丁基锂进行反应；最后在-100～-60℃加入化合物3在第二溶剂中的溶液进行反应；得到化合物4。
  7. 根据权利要求6所述的制备方法，其特征在于，步骤(2)中，所述第一溶剂和第二溶剂各自独立地选自2-甲基四氢呋喃、四氢呋喃、甲苯、甲基叔丁基醚中的一种或多种，优选地为2-甲基四氢呋喃；所述第一溶剂和化合物2的体积质量比为15:1～30:1L/kg，优选地为17:1～22:1L/kg；所述第二溶剂和化合物3的体积质量比为1:1～20:1L/kg；优选地为1.5:1～3.5:1L/kg；优选地，所述第一溶剂和第二溶剂相同，更优选地，所述第一溶剂和第二溶剂为2-甲基四氢呋喃。
  8. 根据权利要求4所述的制备方法，其特征在于，还包括以下步骤：反应完成后以酸淬灭反应体系，分离水相和有机相，将有机相洗涤浓缩后，进行重结晶。
  9. 根据权利要求8所述的制备方法，其特征在于，所述以酸淬灭反应体系的步骤包括：将的反应液缓慢加入的酸的水溶液和有机溶剂的混合液中淬灭；所述有机溶剂选自2-甲基四氢呋喃、甲基叔丁基醚、乙醚或甲苯中的一种或多种，优选地，所述有机溶剂为2-甲基四氢呋喃；优选地，所述混合液和化合物2的体积质量比为20:1～40:1L/kg；优选地，混合液中所述酸的水溶液和有机溶剂的体积比为1:1～5:1，优选地为3:2～3:1；优选地，所述混合液的温度为0～20℃。
  10. 根据权利要求8所述的制备方法，其特征在于，所述酸选自柠檬酸、酒石酸、醋酸、马来酸中的一种或多种，优选地，所述酸为柠檬酸；优选地，所述柠檬酸的浓度为2～30％，更优选地，为5％～10％；所述有机相洗涤浓缩包括将分离的有机相依次用柠檬酸溶液、水、碳酸氢钠溶液洗涤。
  11. 根据权利要求8所述的制备方法，其特征在于，所述重结晶的溶剂为卤代烃类溶剂、酯类溶剂和烷烃类溶剂中的一种或多种，所述卤代烃类溶剂为二氯甲烷、二氯乙烷，优选为二氯乙烷；所述酯类溶剂为乙酸乙酯、乙酸丙酯、乙酸甲酯中的一种或多种，优选为乙酸乙酯；所述烷烃类溶剂为正庚烷、己烷、戊烷或环己烷中的一种或多种；优选地为正庚烷或环己烷。
  12. 根据权利要求2所述的制备方法，其特征在于，步骤(1)中，所述溴化试剂为二溴海因或NBS；所述反应的温度为-40℃～10℃，优选地，为-25℃～10℃，更优选地，为-5℃～10℃；
    优选地，所述反应的溶剂为DMF；
    更优选地，将所述溴化试剂的DMF溶液缓慢加入化合物1的DMF溶液进行反应；
    优选地，所述溴化试剂为二溴海因，其和化合物1的摩尔比为0.4～0.8:1，优选地为0.48～0.52:1。
    优选地，所述反应的后处理步骤中包括以冰乙酸重结晶纯化产物的步骤。
  13. 根据权利要求3所述的制备方法，其特征在于，所述回收包括：将步骤(2)中，反应后以酸处理过的的水相合并，将温度控制在≤30℃，加入碱调节pH值至碱性，过滤，滤饼用水打浆，过滤，滤饼烘干。优选地，所述碱为氢氧化钠或氢氧化钾，优选地，所述pH值调节至pH＝11～13。
  14. 一种化合物2的制备方法，其特征在于，化合物1和溴化试剂反应得到化合物2，反应完毕后以冰乙酸重结晶纯化产物，优选地，所述溴化试剂为二溴海因
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DUSTIN SIEGEL, HON C. HUI, EDWARD DOERFFLER, MICHAEL O. CLARKE, KWON CHUN, LIJUN ZHANG, SEAN NEVILLE, ERNEST CARRA, WILLARD LEW, B: "Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1- f ][triazin-4-amino] Adenine C -Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 60, no. 5, 9 March 2017 (2017-03-09), US , pages 1648 - 1661, XP055489271, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b01594 *

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