WO2015161781A1 - Method for preparing nucleoside analogue and intermediate thereof - Google Patents

Method for preparing nucleoside analogue and intermediate thereof Download PDF

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Publication number
WO2015161781A1
WO2015161781A1 PCT/CN2015/077078 CN2015077078W WO2015161781A1 WO 2015161781 A1 WO2015161781 A1 WO 2015161781A1 CN 2015077078 W CN2015077078 W CN 2015077078W WO 2015161781 A1 WO2015161781 A1 WO 2015161781A1
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compound
iii
reaction
solvent
toluene
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PCT/CN2015/077078
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French (fr)
Chinese (zh)
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魏用刚
邱关鹏
卢泳华
祝国智
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四川海思科制药有限公司
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Priority to CN201580001778.7A priority Critical patent/CN105531281B/en
Publication of WO2015161781A1 publication Critical patent/WO2015161781A1/en
Priority to HK16105220.3A priority patent/HK1217201A1/en

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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 Table
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a method for preparing a nucleoside analog and an intermediate thereof.
  • the compound of formula (I) is a prodrug of tenofovir, first disclosed in WO2002008241, which inhibits viral polymerase by direct competitive binding to natural deoxyribose substrates for the treatment of HIV and HBV. infection.
  • Compound (I) increases plasma stability, thereby increasing the cumulative concentration of the active metabolite tenofovir in peripheral blood mononuclear cells (PBMCs) and improving the therapeutic effect.
  • PBMCs peripheral blood mononuclear cells
  • the methods for synthesizing compound (I) disclosed at home and abroad mainly include the following:
  • CN1443189A discloses the preparation of a mixture of diastereomers GS-7171 starting from 9-(2-(phosphonomethoxy)propyl]adenine (PMPA), GS-7171 by chromatography or The method of recrystallization is purified to obtain the compound (I), wherein the route of preparing GS-7171 is as follows:
  • WO2013052094 discloses a compound represented by 16 in the preparation route, that is, the compound (I) in the present invention, and the route is as follows:
  • This route employs an alanine isopropyl ester obtained by alkaline relaxation of alanine isopropyl ester salt, and then the isopropyl alanate is stored at a low temperature of -20 ° C.
  • the alanine isopropyl ester hydrochloride is prone to hydrolysis reaction when it is free, and the resulting isopropanol is substituted with the compound 13a to obtain a by-product, and the free alanine isopropyl ester is not stable at room temperature and is easily hydrolyzed. Need to be used now.
  • the present invention can be reacted with the compound (III) using L-alanine isopropyl ester salt, and the free alanine isopropyl ester disclosed in WO2013052094 has the characteristics of reducing the free neutralization reaction and overcoming the free The disadvantage of the stability of isopropyl alanate.
  • the invention relates to a preparation method of a compound represented by the formula (I) and an intermediate thereof, which has high reaction yield, high product purity, simple operation, convenient post-treatment, and is suitable for industrial production.
  • the compound (III) is a key intermediate for obtaining a compound (I) of high purity, and the definition of the substituent in the compound (III) is the same as defined in the specification.
  • the present invention provides a process for the preparation of a compound of formula (III):
  • the compound (IV) is halogenated with a halogenating reagent to form a compound (III);
  • the compound (III) has a diastereomer purity of at least 90% or more;
  • R 1 and R 2 are each independently selected from t-butoxycarbonyl or hydrogen, provided that R 1 and R 2 are not hydrogen at the same time;
  • the halogenating agent is selected from the group consisting of thionyl chloride.
  • the reaction temperature is preferably from 50 ° C to 90 ° C, more preferably from 70 ° C to 90 ° C.
  • the diastereomer purity of the compound (III) is monitored by HPLC during the reaction. After the diastereomer purity is 90% or more, the reaction is stopped, and the reaction time is preferably 48 hours to 96 hours.
  • compound (IV) is halogenated with thionyl chloride to form compound (III);
  • the compound (III) has a diastereomer purity of at least 90% or more;
  • R 1 and R 2 are each independently selected from t-butoxycarbonyl or hydrogen, provided that R 1 and R 2 are not hydrogen at the same time;
  • the reaction temperature is selected from 50 ° C to 110 ° C, preferably from 50 ° C to 90 ° C, further preferably from 70 ° C to 90 ° C;
  • the amount of the thionyl chloride is 3 to 12 times, preferably 5 to 10 times the molar amount of the compound (IV);
  • the reaction concentration of the thionyl chloride is 0.5 to 2 mol / L, preferably 0.8 to 1.5 mol / L;
  • the diastereomer purity of the compound (III) was monitored by HPLC, and after the diastereomer purity was 90% or more, the reaction was stopped, and the reaction time was preferably 48 hours to 96 hours.
  • the invention also provides a preparation method of the compound represented by the formula (I):
  • A is selected from the group consisting of hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid, preferably hydrochloric acid.
  • the compound (III) is substituted with the compound (II) to form the compound (I);
  • reaction may optionally be added with the alkaline reagent triethylamine;
  • the reaction temperature is -30 ° C ⁇ 30 ° C;
  • the diastereomer purity of the compound (I) is at least 90% or more.
  • the mixed solvent volume ratio of toluene to dichloromethane may be any ratio, preferably 1:0.6 to 1:2, more preferably 1:0.6 to 1:1.
  • the amount of the compound (II) is preferably from 1 to 5 times, more preferably from 1 to 3 times, still more preferably from 2 to 3 times the molar amount of the compound (III).
  • the invention also provides another method for preparing the compound of formula (I):
  • diastereomer purity of the compound (I) is at least 90% or more.
  • the mixed solvent volume ratio of toluene to dichloromethane may be any ratio, preferably 1:1 to 1:2, more preferably 1:1 to 1:1.5;
  • the amount of the compound (IX) is 1 times the molar amount of the compound (III).
  • the compound (IX) is an organic
  • the amine can neutralize the hydrochloric acid formed in the reaction to promote the reaction, so the amount of the compound (IX) is more than 1 times the molar amount of the compound (III).
  • the excess compound (IX) is advantageous.
  • Formation of Compound (I), amount of Compound (IX) Preferably, it is 1 to 10 times, more preferably 2 to 7 times, further preferably 3 to 5 times the molar amount of the compound (III);
  • the diastereomer purity of the compound (I) is at least 90% or more.
  • the reaction process is simpler without adding an alkaline reagent such as triethylamine to adjust the pH of the reaction solution system.
  • the present invention provides a process for the preparation of a compound of formula (I), the process comprising the steps of:
  • the acetonitrile solvent, the compound (VIII) is halogenated with thionyl chloride to form the compound (VII), the halogenating agent is selected from the group consisting of thionyl chloride or oxalyl chloride, and the halogenation reaction is selective.
  • Catalyst added, the catalyst is selected from N,N-dimethylformamide;
  • the compound (VI) is reacted with the amino-protecting reagent di-tert-butyl dicarbonate to form the compound (V), and the catalyst 4-dimethylaminopyridine is added to the reaction;
  • the compound (V) is hydrolyzed with an alkaline reagent to form a compound (IV), the solvent is selected from one or a combination of acetonitrile and water, and the alkaline agent is selected from the group consisting of triethylamine and One or a combination of ammonia water;
  • the compound (IV) is halogenated with the halogenating reagent thionyl chloride to form the compound (III), and the diastereomer purity of the compound (III) is 90% or more;
  • the compound (III) is substituted with the compound (II) alanine isopropyl ester to form the compound (I), and the alkaline reagent triethylamine is optionally added.
  • the diastereomer purity of the compound (I) is 90% or more; or
  • the compound (III) is substituted with the compound (IX) alanine isopropyl ester to form the compound (I), and the diastereomer purity of the compound (I) is greater than or equal to 90%;
  • R 1 , R 2 and A are as defined above.
  • a preferred embodiment of the invention a process for the preparation of a compound of formula (I), the process comprising the steps of:
  • halogenation reaction of compound (VIII) with thionyl chloride at 75 ° C to 85 ° C in acetonitrile to form compound (VII), said halogenating agent being selected from the group consisting of thionyl chloride or oxalyl chloride, said The halogenation reaction may be selectively added to the catalyst, the catalyst is selected from N,N-dimethylformamide, and the amount of the thionyl chloride is 4 to 10 times the molar amount of the compound (VIII), and the reaction is carried out for 3 to 4 hours;
  • the compound (V) is hydrolyzed with the alkaline reagent triethylamine to form the compound (IV), and the amount of the triethylamine is the molar amount of the compound (V). 1 to 5 times the amount, the reaction is 10 to 14 hours;
  • the compound (IV) is halogenated with a halogenating reagent, thionyl chloride, at 70 ° C to 90 ° C in a toluene solvent to form a compound (III).
  • the diastereomer purity of the compound (III) is greater than or equal to 90%, the amount of the thionyl chloride is 5 to 10 times the molar amount of the compound (IV), and the reaction is carried out for 48 to 96 hours;
  • the compound (III) is substituted with the compound (II) alanine isopropyl ester to form compound (I), and the reaction is selective.
  • the alkaline reagent triethylamine the compound (II) is used in an amount of 1 to 3 times the molar amount of the compound (III), and the reaction is carried out for 1 to 2 hours, and the diastereomer purity of the compound (I) is 90 or more. %;or
  • compound (III) and compound (IX) alanine isopropyl ester are substituted to form compound (I), compound (IX)
  • the amount of the compound (III) is 3 to 5 times the molar amount, and the reaction is carried out for 1 to 2 hours, and the diastereomer purity of the compound (I) is 90% or more;
  • R 1 , R 2 and A are as defined above.
  • the present invention provides a compound of the formula (V), characterized in that:
  • R 1 and R 2 are as defined above.
  • the elements carbon, hydrogen, oxygen, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the elements and carbons, hydrogen, oxygen and sulfur involved in the groups and compounds of the present invention.
  • the nitrogen is optionally further replaced by 1 to 5 of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, and the hydrogen isotopes include ruthenium (H), ruthenium (D, also known as heavy hydrogen), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, nitrogen isotopes include 14 N and 15 N, fluorine isotope 19 F, and chlorine isotopes include 35 Cl and 37 Cl.
  • aromatic solvent means a solvent having an aromatic ring in its molecular structure, and non-limiting examples include benzene, toluene, ethylbenzene, xylene or chlorobenzene.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS), and the external standard is 85% phosphoric acid aqueous solution.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • the external standard is 85% phosphoric acid aqueous solution.
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the room temperature is an optimum temperature of 20 ° C to 30 ° C.
  • M is moles per liter.
  • Boc is a tert-butyloxycarbonyl group.
  • 6-Amino-9-[(2R)-2-(dichlorophosphorylmethoxy)propyl]indole (1B) (crude weight 1.6 kg) was dissolved in dichloromethane (7.0 L), and phenol was added. 725 g, 7.70 mol), cooled to -30 ° C, added triethylamine to adjust pH > 7, and warmed to room temperature overnight. Water (3.0 L) was added to the reaction mixture, and the mixture was separated, and the aqueous layer was extracted with methylene chloride (1.0 L ⁇ 2).
  • 6-Amino-9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]indole (1C) (850 g, 1.93 mol) was dissolved in tetrahydrofuran (4.0 L), and dicarbonic acid was added.
  • Di-tert-butyl ester (1266 g, 5.80 mol) was added to 4-dimethylaminopyridine (47 g, 0.38 mol) in three portions, and the mixture was warmed to reflux for 2 hours. After the reaction mixture was cooled to room temperature, the mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was evaporated to ethyl acetate (3.0L). Drying over sodium sulfate, filtration, and EtOAc (EtOAc) tert-Butylamino-6-ylcarbamate (1D), crude weight 1.4 kg, was used directly in the next reaction.

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Abstract

The present invention relates to a method for preparing a nucleoside analogue and an intermediate thereof, i.e. a method for preparing a compound as shown by formula (I) and an intermediate thereof. The method has the following advantages: a high reaction yield and a high product purity, is convenient to post-process and is suitable for industrial production. Wherein the compound (III) is a key intermediate for making the high-purity compound (I), and the definition of the substituents in the compound (III) is identical to that in the specification.

Description

一种核苷类似物及其中间体的制备方法Preparation method of nucleoside analog and intermediate thereof 技术领域Technical field
本发明涉及一种核苷类似物及其中间体的制备方法。The invention relates to a method for preparing a nucleoside analog and an intermediate thereof.
背景技术Background technique
式(I)所示的化合物是替诺福韦的一种前药，首次公开于WO2002008241，可通过直接竞争性地与天然脱氧核糖底物相结合而抑制病毒聚合酶，用于治疗HIV和HBV感染。The compound of formula (I) is a prodrug of tenofovir, first disclosed in WO2002008241, which inhibits viral polymerase by direct competitive binding to natural deoxyribose substrates for the treatment of HIV and HBV. infection.
Figure PCTCN2015077078-appb-000001
Figure PCTCN2015077078-appb-000001
与替诺福韦酯相比，化合物(I)增加了血浆中的稳定性，从而增加了外周血单核细胞(PBMCs)中活性代谢物替诺福韦的累积浓度，提高了治疗效果。Compared with tenofovir, Compound (I) increases plasma stability, thereby increasing the cumulative concentration of the active metabolite tenofovir in peripheral blood mononuclear cells (PBMCs) and improving the therapeutic effect.
Figure PCTCN2015077078-appb-000002
Figure PCTCN2015077078-appb-000002
目前国内外已公开的合成化合物(I)的方法主要有以下几条：At present, the methods for synthesizing compound (I) disclosed at home and abroad mainly include the following:
1)CN1443189A公开了以9-(2-(膦酰基甲氧基)丙基]腺嘌呤(PMPA)为起始原料，制备非对映异构体混合物GS-7171，GS-7171通过色谱法或者重结晶的方法纯化得到化合物(I)。其中，制备GS-7171路线如下： 1) CN1443189A discloses the preparation of a mixture of diastereomers GS-7171 starting from 9-(2-(phosphonomethoxy)propyl]adenine (PMPA), GS-7171 by chromatography or The method of recrystallization is purified to obtain the compound (I), wherein the route of preparing GS-7171 is as follows:
Figure PCTCN2015077078-appb-000003
Figure PCTCN2015077078-appb-000003
2)WO2013052094公开了制备路线中16所示的化合物即本发明中的化合物(I)，路线如下：2) WO2013052094 discloses a compound represented by 16 in the preparation route, that is, the compound (I) in the present invention, and the route is as follows:
Figure PCTCN2015077078-appb-000004
Figure PCTCN2015077078-appb-000004
该路线采用通过将丙氨酸异丙酯氨酸盐碱性游离后得到丙氨酸异丙酯，然后将丙氨酸异丙酯低温-20℃保存。丙氨酸异丙酯盐酸盐在游离时候容易发生水解反应，生成的异丙醇与化合物13a发生取代反应得到副产物，且游离的丙氨酸异丙酯室温放置稳定性不高，易水解，需要现制现用。This route employs an alanine isopropyl ester obtained by alkaline relaxation of alanine isopropyl ester salt, and then the isopropyl alanate is stored at a low temperature of -20 ° C. The alanine isopropyl ester hydrochloride is prone to hydrolysis reaction when it is free, and the resulting isopropanol is substituted with the compound 13a to obtain a by-product, and the free alanine isopropyl ester is not stable at room temperature and is easily hydrolyzed. Need to be used now.
本发明可采用L-丙氨酸异丙酯盐与化合物(III)反应，与WO2013052094中公开的采用游离的丙氨酸异丙酯，具有减少游离的中和反应的特点，且克服了游离的丙氨酸异丙酯稳定性的缺点。The present invention can be reacted with the compound (III) using L-alanine isopropyl ester salt, and the free alanine isopropyl ester disclosed in WO2013052094 has the characteristics of reducing the free neutralization reaction and overcoming the free The disadvantage of the stability of isopropyl alanate.
目前公开的合成方法中关键中间体[2-(6-氨基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-单磷酸(一苯基PMPA)中的腺嘌呤基团的氨基裸露，该中间体极性大、水溶性好，不易分离纯化。Gland in the key intermediate [2-(6-aminopurine-9-yl)-1-methyl-ethoxy]methyl-phenoxy-monophosphate (monophenyl PMPA) in the currently disclosed synthetic method The amino group of the oxime group is bare, and the intermediate has large polarity and good water solubility, and is difficult to be separated and purified.
发明内容Summary of the invention
本发明涉及一种式(I)所示的化合物及其中间体的制备方法，该方法具有反应产率高产品纯度高，操作简便，后处理方便，适合于工业化生产。其中化合物(III)为制得高纯度的化合物(I)的关键中间体，化合物(III)中取代基的定义与说明书中的定义相同。The invention relates to a preparation method of a compound represented by the formula (I) and an intermediate thereof, which has high reaction yield, high product purity, simple operation, convenient post-treatment, and is suitable for industrial production. Among them, the compound (III) is a key intermediate for obtaining a compound (I) of high purity, and the definition of the substituent in the compound (III) is the same as defined in the specification.
具体而言，本发明提供一种式(III)所示的化合物的制备方法：In particular, the present invention provides a process for the preparation of a compound of formula (III):
Figure PCTCN2015077078-appb-000005
Figure PCTCN2015077078-appb-000005
50℃～110℃和甲苯溶剂中，化合物(IV)与卤代试剂发生卤代反应生成化合物(III)；In a solvent of 50 ° C to 110 ° C and a toluene solvent, the compound (IV) is halogenated with a halogenating reagent to form a compound (III);
Figure PCTCN2015077078-appb-000006
Figure PCTCN2015077078-appb-000006
其中，化合物(III)的非对映异构体纯度至少大于等于90％；Wherein the compound (III) has a diastereomer purity of at least 90% or more;
R1和R2各自独立选自叔丁氧基羰基或氢，条件是R1和R2不同时为氢；R 1 and R 2 are each independently selected from t-butoxycarbonyl or hydrogen, provided that R 1 and R 2 are not hydrogen at the same time;
所述的卤代试剂选自二氯亚砜。The halogenating agent is selected from the group consisting of thionyl chloride.
本发明优选方案，反应温度优选50℃～90℃，进一步优选70℃～90℃。In a preferred embodiment of the invention, the reaction temperature is preferably from 50 ° C to 90 ° C, more preferably from 70 ° C to 90 ° C.
本发明优选方案，反应期间，通过HPLC监控化合物(III)的非对映异构体纯度，非对映异构体纯度大于等于90％后，停止反应，反应时间优选48小时～96小时。In a preferred embodiment of the present invention, the diastereomer purity of the compound (III) is monitored by HPLC during the reaction. After the diastereomer purity is 90% or more, the reaction is stopped, and the reaction time is preferably 48 hours to 96 hours.
本发明优选方案，一种式(III)所示的化合物的制备方法：According to a preferred embodiment of the present invention, a method for preparing a compound represented by the formula (III):
Figure PCTCN2015077078-appb-000007
Figure PCTCN2015077078-appb-000007
甲苯溶剂中，化合物(IV)与二氯亚砜发生卤代反应生成化合物(III)； In the toluene solvent, compound (IV) is halogenated with thionyl chloride to form compound (III);
Figure PCTCN2015077078-appb-000008
Figure PCTCN2015077078-appb-000008
其中，化合物(III)的非对映异构体纯度至少大于等于90％；Wherein the compound (III) has a diastereomer purity of at least 90% or more;
R1和R2各自独立选自叔丁氧基羰基或氢，条件是R1和R2不同时为氢；R 1 and R 2 are each independently selected from t-butoxycarbonyl or hydrogen, provided that R 1 and R 2 are not hydrogen at the same time;
反应温度选自50℃～110℃，优选50℃～90℃，进一步优选70℃～90℃；The reaction temperature is selected from 50 ° C to 110 ° C, preferably from 50 ° C to 90 ° C, further preferably from 70 ° C to 90 ° C;
二氯亚砜的用量为化合物(IV)的摩尔量的3～12倍，优选5～10倍；The amount of the thionyl chloride is 3 to 12 times, preferably 5 to 10 times the molar amount of the compound (IV);
二氯亚砜的反应浓度为0.5～2mol/L，优选0.8～1.5mol/L；The reaction concentration of the thionyl chloride is 0.5 to 2 mol / L, preferably 0.8 to 1.5 mol / L;
反应期间，通过HPLC监控化合物(III)的非对映异构体纯度，非对映异构体纯度大于等于90％后，停止反应，反应时间优选48小时～96小时。During the reaction, the diastereomer purity of the compound (III) was monitored by HPLC, and after the diastereomer purity was 90% or more, the reaction was stopped, and the reaction time was preferably 48 hours to 96 hours.
本发明同时提供一种式(I)所示的化合物的制备方法：The invention also provides a preparation method of the compound represented by the formula (I):
Figure PCTCN2015077078-appb-000009
Figure PCTCN2015077078-appb-000009
-50℃～30℃和甲苯与二氯甲烷的混合溶剂中，化合物(III)与化合物(II)发生取代反应生成化合物(I)；-50 ° C ~ 30 ° C and a mixed solvent of toluene and dichloromethane, compound (III) and compound (II) substitution reaction to form compound (I);
Figure PCTCN2015077078-appb-000010
Figure PCTCN2015077078-appb-000010
其中，所述的A选自盐酸、甲磺酸、对甲苯磺酸或苯磺酸，优选盐酸。Wherein A is selected from the group consisting of hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid, preferably hydrochloric acid.
本发明优选方案，一种式(I)所示的化合物的制备方法：A preferred embodiment of the invention, a method for preparing a compound of formula (I):
Figure PCTCN2015077078-appb-000011
Figure PCTCN2015077078-appb-000011
甲苯与二氯甲烷的混合溶剂中，化合物(III)与化合物(II)发生取代反应生成化合物(I)； In a mixed solvent of toluene and dichloromethane, the compound (III) is substituted with the compound (II) to form the compound (I);
Figure PCTCN2015077078-appb-000012
Figure PCTCN2015077078-appb-000012
其中，A的定义如前所述；Wherein, the definition of A is as described above;
反应可选择性的加入碱性试剂三乙胺；The reaction may optionally be added with the alkaline reagent triethylamine;
反应的温度为-30℃～30℃；The reaction temperature is -30 ° C ~ 30 ° C;
化合物(I)的非对映异构体纯度至少大于等于90％。The diastereomer purity of the compound (I) is at least 90% or more.
本发明优选方案，甲苯与二氯甲烷的混合溶剂体积比可以为任何比例，优选1:0.6～1:2，更优选1:0.6～1:1。In a preferred embodiment of the present invention, the mixed solvent volume ratio of toluene to dichloromethane may be any ratio, preferably 1:0.6 to 1:2, more preferably 1:0.6 to 1:1.
本发明优选方案，化合物(II)的用量优选地为化合物(III)的摩尔量的1～5倍，更优选1～3倍，进一步优选2～3倍。In a preferred embodiment of the present invention, the amount of the compound (II) is preferably from 1 to 5 times, more preferably from 1 to 3 times, still more preferably from 2 to 3 times the molar amount of the compound (III).
本发明同时提供另外一种制备式(I)所示的化合物方法：The invention also provides another method for preparing the compound of formula (I):
Figure PCTCN2015077078-appb-000013
Figure PCTCN2015077078-appb-000013
-40℃～30℃和甲苯与二氯甲烷的混合溶剂中，化合物(III)与化合物(IX)发生取代反应生成化合物(I)；-40 ° C ~ 30 ° C and a mixed solvent of toluene and dichloromethane, compound (III) and compound (IX) substitution reaction to form compound (I);
Figure PCTCN2015077078-appb-000014
Figure PCTCN2015077078-appb-000014
其中化合物(I)的非对映异构体纯度至少大于等于90％。Wherein the diastereomer purity of the compound (I) is at least 90% or more.
本发明优选方案，甲苯与二氯甲烷的混合溶剂体积比可以为任何比例，优选1:1～1:2，更优选1:1～1:1.5；Preferably, the mixed solvent volume ratio of toluene to dichloromethane may be any ratio, preferably 1:1 to 1:2, more preferably 1:1 to 1:1.5;
理论分析，化合物(IX)的用量为化合物(III)的摩尔量的1倍，考虑到反应中有氢氯酸生成，氢氯酸的存在不利于反应进行，而化合物(IX)为一种有机胺，可中和反应中生成的氢氯酸，从而促进反应的进行，故化合物(IX)的用量为大于化合物(III)的摩尔量1倍，一般的讲，过量的化合物(IX)有利于化合物(I)的生成，化合物(IX)的用量 优选地为化合物(III)的摩尔量的1～10倍，更优选2～7倍，进一步优选3～5倍；Theoretical analysis, the amount of the compound (IX) is 1 times the molar amount of the compound (III). Considering the formation of hydrochloric acid in the reaction, the presence of hydrochloric acid is not conducive to the reaction, and the compound (IX) is an organic The amine can neutralize the hydrochloric acid formed in the reaction to promote the reaction, so the amount of the compound (IX) is more than 1 times the molar amount of the compound (III). In general, the excess compound (IX) is advantageous. Formation of Compound (I), amount of Compound (IX) Preferably, it is 1 to 10 times, more preferably 2 to 7 times, further preferably 3 to 5 times the molar amount of the compound (III);
化合物(I)的非对映异构体纯度至少大于等于90％。该方法中，反应过程无需加入碱性试剂如三乙胺调节反应液体系的pH值，操作更简单。The diastereomer purity of the compound (I) is at least 90% or more. In this method, the reaction process is simpler without adding an alkaline reagent such as triethylamine to adjust the pH of the reaction solution system.
本发明提供一种式(I)所示的化合物的制备方法，所述的方法包括以下步骤：The present invention provides a process for the preparation of a compound of formula (I), the process comprising the steps of:
a.乙腈溶剂中，化合物(VIII)与二氯亚砜发生卤代反应生成化合物(VII)，所述的卤代试剂选自二氯亚砜或草酰氯，所述的卤代反应可选择性地加入催化剂，催化剂选自N,N-二甲基甲酰胺；a. The acetonitrile solvent, the compound (VIII) is halogenated with thionyl chloride to form the compound (VII), the halogenating agent is selected from the group consisting of thionyl chloride or oxalyl chloride, and the halogenation reaction is selective. Catalyst added, the catalyst is selected from N,N-dimethylformamide;
b.二氯甲烷溶剂中，化合物(VII)与苯酚在碱性试剂三乙胺的作用下发生取代反应生成化合物(VI)；b. In a dichloromethane solvent, compound (VII) and phenol are substituted by the action of the alkaline reagent triethylamine to form compound (VI);
c.四氢呋喃溶剂中，化合物(VI)与氨基保护试剂二碳酸二叔丁酯反应生成化合物(V)，反应中加入催化剂4-二甲氨基吡啶；c. In the tetrahydrofuran solvent, the compound (VI) is reacted with the amino-protecting reagent di-tert-butyl dicarbonate to form the compound (V), and the catalyst 4-dimethylaminopyridine is added to the reaction;
d.溶剂中，化合物(V)与碱性试剂发生水解反应生成化合物(IV)，所述的溶剂选自乙腈和水中的一种或其组合，所述的碱性试剂选自三乙胺和氨水中的一种或其组合；d. In the solvent, the compound (V) is hydrolyzed with an alkaline reagent to form a compound (IV), the solvent is selected from one or a combination of acetonitrile and water, and the alkaline agent is selected from the group consisting of triethylamine and One or a combination of ammonia water;
e.甲苯溶剂中，化合物(IV)与卤代试剂二氯亚砜发生卤代反应生成化合物(III)，化合物(III)的非对映异构体纯度大于等于90％；e. In the toluene solvent, the compound (IV) is halogenated with the halogenating reagent thionyl chloride to form the compound (III), and the diastereomer purity of the compound (III) is 90% or more;
f.二氯甲烷和甲苯的混合溶剂中，化合物(III)与化合物(II)丙氨酸异丙酯盐发生取代反应生成化合物(I)，反应可选择性的加入碱性试剂三乙胺，化合物(I)的非对映异构体纯度大于等于90％；或者f. In a mixed solvent of dichloromethane and toluene, the compound (III) is substituted with the compound (II) alanine isopropyl ester to form the compound (I), and the alkaline reagent triethylamine is optionally added. The diastereomer purity of the compound (I) is 90% or more; or
g.二氯甲烷和甲苯的混合溶剂中，化合物(III)与化合物(IX)丙氨酸异丙酯发生取代反应生成化合物(I)，化合物(I)的非对映异构体纯度大于等于90％；g. In a mixed solvent of dichloromethane and toluene, the compound (III) is substituted with the compound (IX) alanine isopropyl ester to form the compound (I), and the diastereomer purity of the compound (I) is greater than or equal to 90%;
Figure PCTCN2015077078-appb-000015
Figure PCTCN2015077078-appb-000015
其中，R1、R2和A的定义如如前所述。Wherein R 1 , R 2 and A are as defined above.
本发明的一种优选方案，一种式(I)所示的化合物的制备方法，所述的方法包括以下步骤：A preferred embodiment of the invention, a process for the preparation of a compound of formula (I), the process comprising the steps of:
a.在75℃～85℃下和乙腈中，化合物(VIII)与二氯亚砜发生卤代反应生成化合物(VII)，所述的卤代试剂选自二氯亚砜或草酰氯，所述的卤代反应可选择性地加入催化剂，催化剂选自N,N-二甲基甲酰胺，二氯亚砜的用量为化合物(VIII)的摩尔量的4～10倍，反应3～4小时；a. halogenation reaction of compound (VIII) with thionyl chloride at 75 ° C to 85 ° C in acetonitrile to form compound (VII), said halogenating agent being selected from the group consisting of thionyl chloride or oxalyl chloride, said The halogenation reaction may be selectively added to the catalyst, the catalyst is selected from N,N-dimethylformamide, and the amount of the thionyl chloride is 4 to 10 times the molar amount of the compound (VIII), and the reaction is carried out for 3 to 4 hours;
b.在-30℃～室温下和二氯甲烷中，化合物(VII)与苯酚在碱性试剂三乙胺的作用下发生取代反应生成化合物(VI)，苯酚的用量为化合物(VII)的摩尔量的2～3倍，三乙胺的用量为化合物(VII)的摩尔量的6～10倍，反应10～14小时；b. At -30 ° C ~ room temperature and dichloromethane, the compound (VII) and phenol are substituted under the action of the alkaline reagent triethylamine to form compound (VI), the amount of phenol is the mole of compound (VII) 2 to 3 times the amount, triethylamine is used in an amount of 6 to 10 times the molar amount of the compound (VII), and the reaction is carried out for 10 to 14 hours;
c.在60℃～70℃下和四氢呋喃中，化合物(VI)与氨基保护试剂二碳酸二叔丁酯反应生成化合物(V)，反应中加入二碳酸二叔丁酯的用量为化合物(VI)的摩尔量的2～4倍，催化剂4-二甲氨基吡啶的用量为化合物(VI)的摩尔量的0.2～0.5倍，反应2～4小时；c. Compound (VI) is reacted with aminoprotective reagent di-tert-butyl dicarbonate at 60 ° C to 70 ° C in tetrahydrofuran to form compound (V). The amount of di-tert-butyl dicarbonate added in the reaction is compound (VI). 2 to 4 times the molar amount, the catalyst 4-dimethylaminopyridine is used in an amount of 0.2 to 0.5 times the molar amount of the compound (VI), and the reaction is carried out for 2 to 4 hours;
d.在50℃～60℃下和乙腈-水的混合溶剂中，化合物(V)与碱性试剂三乙胺发生水解反应生成化合物(IV)，三乙胺的用量为化合物(V)的摩尔量的1～5倍，反应10～14小时；d. In a mixed solvent of acetonitrile-water at 50 ° C to 60 ° C, the compound (V) is hydrolyzed with the alkaline reagent triethylamine to form the compound (IV), and the amount of the triethylamine is the molar amount of the compound (V). 1 to 5 times the amount, the reaction is 10 to 14 hours;
e.在70℃～90℃下和甲苯溶剂中，化合物(IV)与卤代试剂二氯亚砜发生卤代反应生成化合物(III)，化合物(III)的非对映异构体纯度大于等于90％，二氯亚砜的的用量为化合物(IV)的摩尔量的5～10倍，反应48～96小时；e. The compound (IV) is halogenated with a halogenating reagent, thionyl chloride, at 70 ° C to 90 ° C in a toluene solvent to form a compound (III). The diastereomer purity of the compound (III) is greater than or equal to 90%, the amount of the thionyl chloride is 5 to 10 times the molar amount of the compound (IV), and the reaction is carried out for 48 to 96 hours;
f.在-30℃～30℃下和二氯甲烷与甲苯的混合溶剂中，化合物(III)与化合物(II)丙氨酸异丙酯盐发生取代反应生成化合物(I)，反应可选择性的加入碱性试剂三乙胺，化合物(II)的用量为化合物(III)的摩尔量的1～3倍，反应1～2小时，化合物(I)的非对映异构体纯度大于等于90％；或者f. In the mixed solvent of dichloromethane and toluene at -30 ° C to 30 ° C, the compound (III) is substituted with the compound (II) alanine isopropyl ester to form compound (I), and the reaction is selective. Adding the alkaline reagent triethylamine, the compound (II) is used in an amount of 1 to 3 times the molar amount of the compound (III), and the reaction is carried out for 1 to 2 hours, and the diastereomer purity of the compound (I) is 90 or more. %;or
g.在-40℃～30℃下和二氯甲烷与甲苯的混合溶剂中，化合物(III)与化合物(IX)丙氨酸异丙酯发生取代反应生成化合物(I),化合物(IX)的用量为化合物(III)的摩尔量的3～5倍，反应1～2小时，化合物(I)的非对映异构体纯度大于等于90％； g. In the mixed solvent of dichloromethane and toluene at -40 ° C to 30 ° C, compound (III) and compound (IX) alanine isopropyl ester are substituted to form compound (I), compound (IX) The amount of the compound (III) is 3 to 5 times the molar amount, and the reaction is carried out for 1 to 2 hours, and the diastereomer purity of the compound (I) is 90% or more;
Figure PCTCN2015077078-appb-000016
Figure PCTCN2015077078-appb-000016
其中，R1、R2和A的定义如如前所述。Wherein R 1 , R 2 and A are as defined above.
本发明提供一种式(V)所示的化合物，其特征在于：The present invention provides a compound of the formula (V), characterized in that:
Figure PCTCN2015077078-appb-000017
Figure PCTCN2015077078-appb-000017
其中，R1和R2的定义如前所述。Wherein R 1 and R 2 are as defined above.
本发明的详细说明：Detailed description of the invention:
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.
本发明所述基团和化合物中所涉及的元素碳、氢、氧、氮或卤素均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫或氮任选进一步被1至5个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，氮的同位素包括14N和15N，氟的同位素19F，氯的同位素包括35Cl和37Cl。The elements carbon, hydrogen, oxygen, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the elements and carbons, hydrogen, oxygen and sulfur involved in the groups and compounds of the present invention. Or the nitrogen is optionally further replaced by 1 to 5 of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, and the hydrogen isotopes include ruthenium (H), ruthenium (D, also known as heavy hydrogen),氚 (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, nitrogen isotopes include 14 N and 15 N, fluorine isotope 19 F, and chlorine isotopes include 35 Cl and 37 Cl.
“芳烃类溶剂”是指分子结构中含有芳环的溶剂，非限制性实施例包括苯、甲苯、乙苯、二甲苯或氯苯等。The "aromatic solvent" means a solvent having an aromatic ring in its molecular structure, and non-limiting examples include benzene, toluene, ethylbenzene, xylene or chlorobenzene.
"可选择性地"意味着随后所描述地事件或环境可以但不必发生，包括该事件或环境发生或不发生的场合。例如，“卤代反应可选择性地加入催化剂”意味着催化剂可以加入反应但不必须加入反应。 "Optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "halogenation reaction can be selectively added to the catalyst" means that the catalyst can be added to the reaction without necessarily adding to the reaction.
具体实施方式detailed description
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)，外标为85％磷酸水溶液。The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS), and the external standard is 85% phosphoric acid aqueous solution.
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
实施例中无特殊说明，反应在氮气氛下进行。Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.
实施例中无特殊说明，溶液是指水溶液。Unless otherwise stated in the examples, the solution means an aqueous solution.
实施例中无特殊说明，反应的温度为室温。There is no particular description in the examples, and the reaction temperature is room temperature.
室温为最适宜的温度，为20℃～30℃。The room temperature is an optimum temperature of 20 ° C to 30 ° C.
M为摩尔每升。M is moles per liter.
Boc为叔丁基氧基羰基。Boc is a tert-butyloxycarbonyl group.
实施例1：Example 1:
[(1R)-2-[6-[二(叔丁基氧羰基)氨基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-单磷酸(化合物1)[(1R)-2-[6-[Di(tert-Butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (Compound 1)
[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphinic acid[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphinic acid
Figure PCTCN2015077078-appb-000018
Figure PCTCN2015077078-appb-000018
Figure PCTCN2015077078-appb-000019
Figure PCTCN2015077078-appb-000019
第一步：6-氨基-9-[(2R)-2-(二氯磷酰基甲氧基)丙基]嘌呤(1B)First step: 6-amino-9-[(2R)-2-(dichlorophosphorylmethoxy)propyl]indole (1B)
9-[2-(dichlorophosphorylmethoxy)propyl]purin-6-amine9-[2-(dichlorophosphorylmethoxy)propyl]purin-6-amine
Figure PCTCN2015077078-appb-000020
Figure PCTCN2015077078-appb-000020
将[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]磷酸(PMPA，Tenofovir)(1kg,3.48mol)溶于乙腈(5.0L)中，室温下滴加二氯亚砜(1.65kg,13.92mol)，升温至回流反应4小时。将反应液冷却至室温，减压浓缩得到黄色固体状的目标产物6-氨基-9-[(2R)-2-(二氯磷酰基甲氧基)丙基]嘌呤(1B)，粗品重量1.60kg，直接投下一步反应。[[(1R)-2-(6-Aminofluoren-9-yl)-1-methylethoxy]methyl]phosphoric acid (PMPA, Tenofovir) (1 kg, 3.48 mol) was dissolved in acetonitrile (5.0 L) Further, thionyl chloride (1.65 kg, 13.92 mol) was added dropwise at room temperature, and the mixture was heated to reflux for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced vacuoielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel Kg, directly cast the next reaction.
第二步：6-氨基-9-[(2R)-2-(二苯氧基磷酰基甲氧基)丙基]嘌呤(1C)Second step: 6-amino-9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]pyrene (1C)
9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-amine9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-amine
Figure PCTCN2015077078-appb-000021
Figure PCTCN2015077078-appb-000021
将6-氨基-9-[(2R)-2-(二氯磷酰基甲氧基)丙基]嘌呤(1B)(粗品重量1.6kg)溶于二氯甲烷(7.0L)中，加入苯酚(725g,7.70mol),冷却至-30℃,加入三乙胺调节pH>7，升温至室温反应过夜。反应液中加入水(3.0L),萃取分层，水相再用二氯甲烷(1.0L×2)萃取，合并有机相，加入无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩残余物加入4M盐酸水溶液(3.0L)，充分搅拌，然后加入乙酸乙酯(1.0L×2)萃取，水相冷却至0℃，加入氨水调节pH>7，然后加入乙酸乙酯(2.0L×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到黄色固体状的目标产物6-氨基-9-[(2R)-2-(二苯氧基磷酰基甲氧基)丙基]嘌呤(1C)(850g,两步总产率55.8％)。6-Amino-9-[(2R)-2-(dichlorophosphorylmethoxy)propyl]indole (1B) (crude weight 1.6 kg) was dissolved in dichloromethane (7.0 L), and phenol was added. 725 g, 7.70 mol), cooled to -30 ° C, added triethylamine to adjust pH > 7, and warmed to room temperature overnight. Water (3.0 L) was added to the reaction mixture, and the mixture was separated, and the aqueous layer was extracted with methylene chloride (1.0 L×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, Add 4M aqueous hydrochloric acid (3.0 L), stir well, then add ethyl acetate (1.0 L × 2) for extraction, the aqueous phase is cooled to 0 ° C, add aqueous ammonia to adjust pH > 7, then add ethyl acetate (2.0 L × 2) The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated Base] 嘌呤 (1C) (850 g, two-step total yield 55.8%).
1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.87(s,1H),7.34–7.26(m,4H),7.21– 7.13(m,4H),7.10–7.05(m,2H),5.86(s,2H),4.35(dd,1H),4.19–4.10(m,2H),4.08–3.98(m,1H),3.90(dd,1H),1.25(d,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (s, 1H), 7.87 (s, 1H), 7.34 - 7.26 (m, 4H), 7.21 - 7.13 (m, 4H), 7.10 - 7.05 (m, 2H) ), 5.86 (s, 2H), 4.35 (dd, 1H), 4.19 - 4.10 (m, 2H), 4.08 - 3.98 (m, 1H), 3.90 (dd, 1H), 1.25 (d, 3H).
第三步：N-叔丁基氧基-N-[9-[(2R)-2-(二苯氧基磷酰基甲氧基)丙基]嘌呤-6-基]氨基甲酸叔丁酯(1D)Third step: N-tert-butoxy-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]indol-6-yl]carbamic acid tert-butyl ester ( 1D)
Tert-butyl N-tert-butoxycarbonyl-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-yl]carbamateTert-butyl N-tert-butoxycarbonyl-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-yl]carbamate
Figure PCTCN2015077078-appb-000022
Figure PCTCN2015077078-appb-000022
将6-氨基-9-[(2R)-2-(二苯氧基磷酰基甲氧基)丙基]嘌呤(1C)(850g,1.93mol)溶于四氢呋喃(4.0L)中，加入二碳酸二叔丁酯(1266g,5.80mol)，分三批加入4-二甲氨基吡啶(47g,0.38mol)，升温至回流反应2小时。反应液冷却至室温后减压浓缩除去四氢呋喃，浓缩残余物加入到乙酸乙酯(3.0L)中溶解，然后加入0.24M盐酸水溶液(2.5L×1)洗涤，萃取分层，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到黑色油状的目标产物N-叔丁基氧基-N-[9-[(2R)-2-(二苯氧基磷酰基甲氧基)丙基]嘌呤-6-基]氨基甲酸叔丁酯(1D)，粗品重量1.4kg，直接用于下一步反应。6-Amino-9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]indole (1C) (850 g, 1.93 mol) was dissolved in tetrahydrofuran (4.0 L), and dicarbonic acid was added. Di-tert-butyl ester (1266 g, 5.80 mol) was added to 4-dimethylaminopyridine (47 g, 0.38 mol) in three portions, and the mixture was warmed to reflux for 2 hours. After the reaction mixture was cooled to room temperature, the mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was evaporated to ethyl acetate (3.0L). Drying over sodium sulfate, filtration, and EtOAc (EtOAc) tert-Butylamino-6-ylcarbamate (1D), crude weight 1.4 kg, was used directly in the next reaction.
1H NMR(400MHz,CDCl3)δ8.83(s,1H),8.17(s,1H),7.37–7.28(m,4H),7.25–7.13(m,6H),4.48–4.39(m,1H),4.28(dd,1H),4.15(dd,1H),4.09–4.00(m,1H),4.01–3.91(m,1H),1.51–1.39(m,18H),1.22(d,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 8.83 (s, 1H), 8.17 (s, 1H), 7.37 - 7.28 (m, 4H), 7.25 - 7.13 (m, 6H), 4.48 - 4.39 (m, 1H) ), 4.28 (dd, 1H), 4.15 (dd, 1H), 4.09 - 4.00 (m, 1H), 4.01 - 3.91 (m, 1H), 1.51 - 1.39 (m, 18H), 1.22 (d, 3H).
第四步：[(1R)-2-[6-[二(叔丁基氧羰基)氨基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-单磷酸(化合物1)Fourth step: [(1R)-2-[6-[bis(tert-butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (Compound 1)
[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphinic acid[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphinic acid
Figure PCTCN2015077078-appb-000023
Figure PCTCN2015077078-appb-000023
将N-叔丁基氧基-N-[9-[(2R)-2-(二苯氧基磷酰基甲氧基)丙基]嘌呤-6-基]氨基甲酸 叔丁酯(1D)(粗品1.4kg)溶于乙腈(3.2L)和水(0.8L，乙腈：水(v:v)＝4:1)中，加入三乙胺(979g,9.67mol)，升温至50℃反应过夜。反应液冷却至室温，减压浓缩除去乙腈，浓缩残余物中加入0.5％的氨水溶液(5L)，充分搅拌，然后用乙酸乙酯(1.5L×3)萃取分层，水相冷却0℃，滴加3M盐酸水溶液调节pH＝1～3，然后用二氯甲烷(3L×2)萃取，合并二氯甲烷相，无水硫酸钠干燥，过滤，滤液减压浓缩得到暗红色油状的目标产物[(1R)-2-[6-[二(叔丁基氧羰基)氨基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-单磷酸(化合物1)(850g,两步总产率78％)。N-tert-Butoxy-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]indol-6-yl]carbamic acid tert-Butyl ester (1D) (crude 1.4 kg) was dissolved in acetonitrile (3.2 L) and water (0.8L, acetonitrile: water (v:v) = 4:1), and triethylamine (979 g, 9.67 mol) was added. The temperature was raised to 50 ° C and allowed to react overnight. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove acetonitrile. <RTI ID=0.0>> 3M hydrochloric acid aqueous solution was added dropwise to adjust the pH = 1 to 3, and then extracted with dichloromethane (3 L × 2). The methylene chloride phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the desired product as a dark red oil. (1R)-2-[6-[bis(tert-butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (Compound 1) ( 850 g, total yield of 78% in two steps).
1H NMR(400MHz,CDCl3)δ12.53(s,1H),8.81(s,1H),8.59(s,1H),7.29–7.19(m,4H),7.02(m,1H),4.43(d,1H),4.23(dd,1H),3.91(m,2H),3.66–3.61(m,1H),1.42(s,18H),1.09(d,3H)。 1 H NMR (400MHz, CDCl 3 ) δ12.53 (s, 1H), 8.81 (s, 1H), 8.59 (s, 1H), 7.29-7.19 (m, 4H), 7.02 (m, 1H), 4.43 ( d, 1H), 4.23 (dd, 1H), 3.91 (m, 2H), 3.66 - 3.61 (m, 1H), 1.42 (s, 18H), 1.09 (d, 3H).
31P NMR(162MHz,CDCl3)δ15.05。 31 P NMR (162 MHz, CDCl 3 ) δ 15.05.
实施例2Example 2
6-氨基-9-[(2R)-2-[[氯(苯氧基)膦酰基]甲氧基]异丙基]嘌呤(化合物2)6-Amino-9-[(2R)-2-[[chloro(phenoxy)phosphonyl]methoxy]isopropyl]anthracene (Compound 2)
9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine
Figure PCTCN2015077078-appb-000024
Figure PCTCN2015077078-appb-000024
将[(1R)-2-[6-[二(叔丁基氧羰基)氨基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-单磷酸(化合物1)(200g,0.355mol)溶于甲苯(2.0L)中，加入二氯亚砜(422g,3.55mol)，升温至90℃反应时间48小时后，反应期间，通过HPLC监控化合物2的非对映异构体纯度，非对映异构体纯度大于等于90％后，停止反应。反应液减压蒸馏得到黄色固体状的标题产物6-氨基-9-[(2R)-2-[[氯(苯氧基)膦酰基]甲氧基]异丙基]嘌呤(化合物2)，粗品150g，直接用于下一步反应。[(1R)-2-[6-[Di(tert-Butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (Compound 1 (200 g, 0.355 mol) dissolved in toluene (2.0 L), added with thionyl chloride (422 g, 3.55 mol), and warmed to 90 ° C for 48 hours. After the reaction, the diastereomer of compound 2 was monitored by HPLC. The purity of the isomer, and the purity of the diastereomer is 90% or more, and the reaction is stopped. The reaction mixture was evaporated under reduced pressure to give the title compound 6-amino-9-[(2.sup. The crude product was 150 g and used directly in the next reaction.
实施例3Example 3
6-氨基-9-[(2R)-2-[[氯(苯氧基)膦酰基]甲氧基]异丙基]嘌呤(化合物2)6-Amino-9-[(2R)-2-[[chloro(phenoxy)phosphonyl]methoxy]isopropyl]anthracene (Compound 2)
9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine
Figure PCTCN2015077078-appb-000025
Figure PCTCN2015077078-appb-000025
将[(1R)-2-[6-[二(叔丁基氧羰基)氨基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-单磷酸(化合物1)(1500g,2.66mol)溶于甲苯(15.0L)中，加入二氯亚砜(1582.7g,13.3mol)，升温至90℃反应时间48小时，反应期间，通过HPLC监控化合物2的非对映异构体纯度，非对映异构体纯度大于等于90％后，停止反应。反应液减压蒸馏得到黄色固体状的标题产物6-氨基-9-[(2R)-2-[[氯(苯氧基)膦酰基]甲氧基]异丙基]嘌呤(化合物2)，粗品1015g，直接用于下一步反应。[(1R)-2-[6-[Di(tert-Butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (Compound 1 (1500 g, 2.66 mol) was dissolved in toluene (15.0 L), thionyl chloride (1582.7 g, 13.3 mol) was added, and the temperature was raised to 90 ° C for 48 hours. During the reaction, the diastereomeric reaction of compound 2 was monitored by HPLC. The purity of the isomer, and the purity of the diastereomer is 90% or more, and the reaction is stopped. The reaction mixture was evaporated under reduced pressure to give the title compound 6-amino-9-[(2.sup. The crude product was 1015 g and used directly for the next reaction.
实施例4Example 4
(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]氨基]丙酸异丙酯(化合物3)(2S)-2-[[[(1R)-2-(6-aminofluoren-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino]amino]propanoate Propyl ester (compound 3)
Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoateIsopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate
Figure PCTCN2015077078-appb-000026
Figure PCTCN2015077078-appb-000026
L-丙氨酸异丙酯盐酸盐(52.5g,0.314mol)溶于二氯甲烷(200mL)溶液中，然后将6-氨基-9-[(2R)-2-[[氯(苯氧基)膦酰基]甲氧基]异丙基]嘌呤(化合物2)(粗品60g)的甲苯(300mL)溶液加入到反应液中，加入完毕，冷却至-25℃，滴加三乙胺(31.8g，0.314mol)，滴完后继续搅拌反应1小时后结束反应。向反应液中加入10％磷酸二氢钠水溶液(400mL)，充分搅拌萃取分层，有机相中加入15％碳酸氢钾水溶液(170mL)萃取分层后，有机相依次用用去离子水(150mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]氨基]丙酸异丙酯(化合物3)的粗品。L-alanine isopropyl ester hydrochloride (52.5 g, 0.314 mol) was dissolved in dichloromethane (200 mL), then 6-amino-9-[(2R)-2-[[chloro(phenoxy) A solution of the phosphonyl]methoxy]isopropyl]indole (Compound 2) (crude 60g) in toluene (300 mL) was added to the reaction mixture. After the addition was completed, the mixture was cooled to -25 ° C, and triethylamine (31.8) was added dropwise. g, 0.314 mol), the reaction was stirred for 1 hour after the completion of the dropwise addition, and the reaction was terminated. A 10% aqueous solution of sodium dihydrogen phosphate (400 mL) was added to the reaction mixture, and the mixture was thoroughly stirred and extracted. The organic phase was extracted with a 15% aqueous solution of potassium hydrogencarbonate (170 mL), and the organic phase was applied with deionized water (150 mL). ×1) Washing, drying over anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure to give (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethyl A crude product of oxy]methyl-phenoxy-phosphino]amino]propionic acid isopropyl ester (Compound 3).
将化合物3粗品加入到乙腈(12mL)与甲苯(108mL)的混合溶剂(乙腈/甲苯(v/v)＝1:9)中，室温搅拌6小时后，固体充分析出，过滤，滤饼用甲苯(200mL)洗涤，滤饼干燥得到纯化的产品化合物3(30g，产率35％，HPLC纯度为95.10％，手性HPLC非对映异构体纯度96.04％)。The crude compound 3 was added to a mixed solvent of acetonitrile (12 mL) and toluene (108 mL) (acetonitrile / toluene (v / v) = 1:9), and the mixture was stirred at room temperature for 6 hours, and then the solid was analyzed and filtered, and the cake was filtered. (200 mL) was washed and the filter cake was dried to give purified product Compound 3 (30 g, yield 35%, HPLC purity 95.10%, chiral HPLC diastereomer purity 96.04%).
根据需要，若要得到更高非对映异构体纯度的化合物3，可继续进行如下操作：将化合物3(30g)加入到乙腈(120mL)中，升温至回流1小时，然后自然冷却至常温搅拌6小时后，固体充分析出，过滤，滤饼用乙腈(40mL)洗涤，滤饼干燥得到纯 化的产品化合物3(15g，HPLC纯度为99.40％，手性HPLC非对映异构体纯度为99.79％)。If desired, to obtain a higher diastereomeric purity of Compound 3, the following operation can be continued: Compound 3 (30 g) is added to acetonitrile (120 mL), warmed to reflux for 1 hour, and then naturally cooled to ambient temperature. After stirring for 6 hours, the solid was analyzed and filtered, and the filter cake was washed with acetonitrile (40 mL). Compound 3 (15 g, HPLC purity 99.40%, chiral HPLC diastereomer purity 99.79%).
1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.99(s,1H),7.19(m,2H),7.10(m,1H),7.00(m,2H),6.18(bs,2H),5.01(m,1H),4.33(dd,1H),4.12(m,3H),3.88(m,2H),3.67(m,1H),1.28(d,3H),1.22(m,9H)。 1 H NMR (400MHz, CDCl 3 ) δ8.33 (s, 1H), 7.99 (s, 1H), 7.19 (m, 2H), 7.10 (m, 1H), 7.00 (m, 2H), 6.18 (bs, 2H), 5.01 (m, 1H), 4.33 (dd, 1H), 4.12 (m, 3H), 3.88 (m, 2H), 3.67 (m, 1H), 1.28 (d, 3H), 1.22 (m, 9H) ).
31P NMR(162MHz,CDCl3)δ22.5。 31 P NMR (162 MHz, CDCl 3 ) δ 22.5.
实施例5Example 5
(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]氨基]丙酸异丙酯(化合物3)(2S)-2-[[[(1R)-2-(6-aminofluoren-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino]amino]propanoate Propyl ester (compound 3)
Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoateIsopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate
Figure PCTCN2015077078-appb-000027
Figure PCTCN2015077078-appb-000027
L-丙氨酸异丙酯(232.5g,1.78mol)溶于二氯甲烷(1000mL)溶液中，冷却至-25℃，然后将6-氨基-9-[(2R)-2-[[氯(苯氧基)膦酰基]甲氧基]异丙基]嘌呤(化合物2)(粗品149g)的甲苯(600mL)溶液加入到反应液中，加入完毕，继续搅拌反应1小时后结束反应。向反应液中加入10％磷酸二氢钠水溶液(1.2L)，充分搅拌萃取分层，有机相中加入15％碳酸氢钾水溶液(0.5L)萃取分层后，有机相依次用用去离子水(0.5L×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]氨基]丙酸异丙酯(化合物3)的粗品。L-alanine isopropyl ester (232.5 g, 1.78 mol) was dissolved in dichloromethane (1000 mL), cooled to -25 ° C, then 6-amino-9-[(2R)-2-[[chlorine A solution of (phenoxy)phosphono]methoxy]isopropyl]indole (Compound 2) (crude 149 g) in toluene (600 mL) was added to the reaction mixture, and after the addition was completed, the reaction was further stirred for 1 hour, and then the reaction was completed. 10% aqueous sodium dihydrogen phosphate solution (1.2 L) was added to the reaction solution, and the mixture was thoroughly stirred and extracted. The organic phase was extracted with 15% aqueous potassium hydrogencarbonate solution (0.5 L), and the organic phase was sequentially treated with deionized water. (0.5L × 1) washing, drying with anhydrous sodium sulfate, filtration, and the filtrate was concentrated under reduced pressure to give (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-yl A crude product of isopropyl-ethoxy]methyl-phenoxy-phosphino]amino]propanoate (Compound 3).
将化合物3粗品加入到乙腈(40mL)与甲苯(360mL)的混合溶剂(乙腈/甲苯(v/v)＝1:9)中，室温搅拌6小时后，固体充分析出，过滤，滤饼用甲苯(400mL)洗涤，滤饼干燥得到纯化的产品化合物3(120g，产率71％，HPLC纯度为99.39％，手性HPLC非对映异构体纯度96.05％)。The crude compound 3 was added to a mixed solvent of acetonitrile (40 mL) and toluene (360 mL) (acetonitrile / toluene (v / v) = 1:9), and the mixture was stirred at room temperature for 6 hours, and then the solid was analyzed and filtered. (400 mL) was washed and the filter cake was dried to give purified product Compound 3 (120 g, yield 71%, HPLC purity: 99.39%, chiral HPLC diastereomer purity 96.05%).
根据需要，若要得到更高非对映异构体纯度的化合物3，可继续进行如下操作：将化合物3加入到乙腈(600mL)中，升温至回流1小时，然后自然冷却至常温搅拌6小时后，固体充分析出，过滤，滤饼用乙腈(200mL)洗涤，滤饼干燥得到纯化的产品化合物3(102g，HPLC纯度为99.86％，手性HPLC非对映异构体纯度为98.98％)。 If desired, to obtain a higher diastereomeric purity of Compound 3, the following operation can be continued: Compound 3 is added to acetonitrile (600 mL), warmed to reflux for 1 hour, and then naturally cooled to room temperature for 6 hours. After that, the solid was taken up and filtered, filtered, washed with acetonitrile (200 mL), and filtered to give purified product compound 3 (102 g, HPLC purity: 99.86%, chiral HPLC diastereomer purity: 98.98%).
实施例6Example 6
(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]氨基]丙酸异丙酯(化合物3)(2S)-2-[[[(1R)-2-(6-aminofluoren-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino]amino]propanoate Propyl ester (compound 3)
Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoateIsopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate
Figure PCTCN2015077078-appb-000028
Figure PCTCN2015077078-appb-000028
L-丙氨酸异丙酯(1742g,13.3mol)溶于二氯甲烷(7.0L)溶液中，冷却至-25℃，然后将6-氨基-9-[(2R)-2-[[氯(苯氧基)膦酰基]甲氧基]异丙基]嘌呤(化合物2)(粗品1015g)的甲苯(6.0L)溶液加入到反应液中，加入完毕，继续搅拌反应1小时后结束反应。向反应液中加入10％磷酸二氢钠水溶液(9.0L)，充分搅拌萃取分层，有机相中加入15％碳酸氢钾水溶液(3.75L)萃取分层后，有机相依次用用去离子水(3.75L×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]氨基]丙酸异丙酯(化合物3)的粗品。L-Alanine isopropyl ester (1742 g, 13.3 mol) was dissolved in dichloromethane (7.0 L), cooled to -25 ° C, then 6-amino-9-[(2R)-2-[[chlorine A solution of (phenoxy)phosphono]methoxy]isopropyl]indole (Compound 2) (crude 1015 g) in toluene (6.0 L) was added to the reaction mixture, and the mixture was stirred. 10% aqueous sodium dihydrogen phosphate solution (9.0 L) was added to the reaction solution, and the mixture was thoroughly stirred and extracted. The organic phase was extracted with 15% aqueous potassium hydrogencarbonate solution (3.75 L), and the organic phase was sequentially treated with deionized water. (3.75 L × 1) Wash, dry over anhydrous sodium sulfate, filtered, and then filtrated to give (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl A crude product of isopropyl-ethoxy]methyl-phenoxy-phosphino]amino]propanoate (Compound 3).
将化合物3粗品加入到乙腈(0.24L)与甲苯(2.16L)的混合溶剂(乙腈/甲苯(v/v)＝1:9)中，室温搅拌6小时后，固体充分析出，过滤，滤饼用甲苯(3.0L)洗涤，滤饼干燥得到纯化的产品化合物3(700g，产率55％，HPLC纯度为97.97％，手性HPLC非对映异构体纯度94.28％)。The crude compound 3 was added to a mixed solvent of acetonitrile (0.24 L) and toluene (2.16 L) (acetonitrile/toluene (v/v) = 1:9), and the mixture was stirred at room temperature for 6 hours, and the solid was analyzed, filtered, and filtered. After washing with toluene (3.0 L), the cake was dried to give purified product compound 3 (700 g, yield 55%, HPLC purity 97.97%, chiral HPLC diastereomer purity 94.28%).
根据需要，若要得到更高非对映异构体纯度的化合物3，可继续进行如下操作：将化合物3加入到乙腈(3.5L)中，升温至回流1小时，然后自然冷却至常温搅拌6小时后，固体充分析出，过滤，滤饼用乙腈(500mL)洗涤，滤饼干燥得到纯化的产品化合物3(500g，手性HPLC分析显示非对映异构体纯度99.29％)。 If desired, to obtain a higher diastereomeric purity of Compound 3, the following operation can be continued: Compound 3 is added to acetonitrile (3.5 L), heated to reflux for 1 hour, and then naturally cooled to room temperature with stirring 6 After an hour, the solid was taken up and filtered, filtered, washed with acetonitrile (500 mL).

Claims (8)

  1. 一种式(III)所示的化合物的制备方法：A method for preparing a compound represented by formula (III):
    Figure PCTCN2015077078-appb-100001
    Figure PCTCN2015077078-appb-100001
    其特征在于50℃～110℃和甲苯溶剂中，化合物(IV)与卤代试剂发生卤代反应生成化合物(III)；It is characterized in that the compound (IV) is halogenated with a halogenated reagent to form a compound (III) in a solvent of 50 ° C to 110 ° C and a toluene solvent;
    Figure PCTCN2015077078-appb-100002
    Figure PCTCN2015077078-appb-100002
    其中，化合物(III)的非对映异构体纯度至少大于等于90％；Wherein the compound (III) has a diastereomer purity of at least 90% or more;
    R1和R2各自独立选自叔丁氧基羰基或氢，条件是R1和R2不同时为氢；R 1 and R 2 are each independently selected from t-butoxycarbonyl or hydrogen, provided that R 1 and R 2 are not hydrogen at the same time;
    所述的卤代试剂选自二氯亚砜。The halogenating agent is selected from the group consisting of thionyl chloride.
  2. 根据权利要求1所述的方法，其特征在于：The method of claim 1 wherein:
    反应的温度为70℃～90℃。The reaction temperature is from 70 ° C to 90 ° C.
  3. 根据权利要求1所述的方法，其特征在于：The method of claim 1 wherein:
    反应的时间为48小时～96小时。The reaction time is from 48 hours to 96 hours.
  4. 一种式(I)所示的化合物的制备方法：A method for preparing a compound represented by the formula (I):
    Figure PCTCN2015077078-appb-100003
    Figure PCTCN2015077078-appb-100003
    其特征在于-50℃～30℃和甲苯与二氯甲烷的混合溶剂中，化合物(III)与化合物(II)发生取代反应生成化合物(I)； The compound (III) is substituted with the compound (II) to form the compound (I) in a mixed solvent of -50 ° C to 30 ° C and toluene and dichloromethane;
    Figure PCTCN2015077078-appb-100004
    Figure PCTCN2015077078-appb-100004
    其中，所述的A选自盐酸、甲磺酸、对甲苯磺酸或苯磺酸。Wherein A is selected from the group consisting of hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid.
  5. 根据权利要求4所述的方法，其特征在于：The method of claim 4 wherein:
    反应可选择性的加入碱性试剂三乙胺；The reaction may optionally be added with the alkaline reagent triethylamine;
    反应的温度为-30℃～30℃；The reaction temperature is -30 ° C ~ 30 ° C;
    化合物(I)的非对映异构体纯度至少大于等于90％。The diastereomer purity of the compound (I) is at least 90% or more.
  6. 一种式(I)所示的化合物的制备方法：A method for preparing a compound represented by the formula (I):
    Figure PCTCN2015077078-appb-100005
    Figure PCTCN2015077078-appb-100005
    其特征在于-40℃～30℃和甲苯与二氯甲烷的混合溶剂中，化合物(III)与化合物(IX)发生取代反应生成化合物(I)；The compound (III) is substituted with the compound (IX) to form the compound (I) in a mixed solvent of -40 ° C to 30 ° C and toluene and dichloromethane;
    Figure PCTCN2015077078-appb-100006
    Figure PCTCN2015077078-appb-100006
    化合物(I)的非对映异构体纯度至少大于等于90％。The diastereomer purity of the compound (I) is at least 90% or more.
  7. 一种式(I)所示的化合物的制备方法，其特征在于所述的方法包括以下步骤：A method for preparing a compound represented by the formula (I), characterized in that the method comprises the steps of:
    a.乙腈溶剂中，化合物(VIII)与二氯亚砜发生卤代反应生成化合物(VII)，所述的卤代试剂选自二氯亚砜或草酰氯，所述的卤代反应可选择性地加入催化剂，催化剂选自N,N-二甲基甲酰胺；a. The acetonitrile solvent, the compound (VIII) is halogenated with thionyl chloride to form the compound (VII), the halogenating agent is selected from the group consisting of thionyl chloride or oxalyl chloride, and the halogenation reaction is selective. Catalyst added, the catalyst is selected from N,N-dimethylformamide;
    b.二氯甲烷溶剂中，化合物(VII)与苯酚在碱性试剂三乙胺的作用下发生取代反应生成化合物(VI)；b. In a dichloromethane solvent, compound (VII) and phenol are substituted by the action of the alkaline reagent triethylamine to form compound (VI);
    c.四氢呋喃溶剂中，化合物(VI)与氨基保护试剂二碳酸二叔丁酯反应生成化合物(V)，反应中加入催化剂4-二甲氨基吡啶； c. In the tetrahydrofuran solvent, the compound (VI) is reacted with the amino-protecting reagent di-tert-butyl dicarbonate to form the compound (V), and the catalyst 4-dimethylaminopyridine is added to the reaction;
    d.溶剂中，化合物(V)与碱性试剂发生水解反应生成化合物(IV)，所述的溶剂选自乙腈和水中的一种或其组合，所述的碱性试剂选自三乙胺和氨水中的一种或其组合；d. In the solvent, the compound (V) is hydrolyzed with an alkaline reagent to form a compound (IV), the solvent is selected from one or a combination of acetonitrile and water, and the alkaline agent is selected from the group consisting of triethylamine and One or a combination of ammonia water;
    e.甲苯溶剂中，化合物(IV)与卤代试剂二氯亚砜发生卤代反应生成化合物(III)，化合物(III)的非对映异构体纯度大于等于90％；e. In the toluene solvent, the compound (IV) is halogenated with the halogenating reagent thionyl chloride to form the compound (III), and the diastereomer purity of the compound (III) is 90% or more;
    f.二氯甲烷和甲苯的混合溶剂中，化合物(III)与化合物(II)丙氨酸异丙酯盐发生取代反应生成化合物(I)，反应可选择性的加入碱性试剂三乙胺，化合物(I)的非对映异构体纯度大于等于90％；或者f. In a mixed solvent of dichloromethane and toluene, the compound (III) is substituted with the compound (II) alanine isopropyl ester to form the compound (I), and the alkaline reagent triethylamine is optionally added. The diastereomer purity of the compound (I) is 90% or more; or
    g.二氯甲烷和甲苯的混合溶剂中，化合物(III)与化合物(IX)丙氨酸异丙酯发生取代反应生成化合物(I)，化合物(I)的非对映异构体纯度大于等于90％；g. In a mixed solvent of dichloromethane and toluene, the compound (III) is substituted with the compound (IX) alanine isopropyl ester to form the compound (I), and the diastereomer purity of the compound (I) is greater than or equal to 90%;
    Figure PCTCN2015077078-appb-100007
    Figure PCTCN2015077078-appb-100007
    其中，R1和R2的定义如权利要求1所述；Wherein R 1 and R 2 are as defined in claim 1;
    A的定义如权利要求4所述。The definition of A is as set forth in claim 4.
  8. 一种式(V)所示的化合物，其特征在于：A compound of the formula (V) characterized by:
    Figure PCTCN2015077078-appb-100008
    Figure PCTCN2015077078-appb-100008
    其中，R1和R2的定义如权利要求1所述。 Wherein R 1 and R 2 are as defined in claim 1.
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