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CN1168713C - Synthetic route and key intermediates for preparing rhinovirus protease inhibitors - Google Patents

Synthetic route and key intermediates for preparing rhinovirus protease inhibitors Download PDF

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CN1168713C
CN1168713C CNB008118779A CN00811877A CN1168713C CN 1168713 C CN1168713 C CN 1168713C CN B008118779 A CNB008118779 A CN B008118779A CN 00811877 A CN00811877 A CN 00811877A CN 1168713 C CN1168713 C CN 1168713C
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田清平
N·K·奈亚
S·巴布
��Ī������
陶军华
��˹��ŵ��
T·J·莫兰
С��׳
R·小达尼诺
L·J·小米彻尔
÷
T·P·雷马楚克
M·J·梅尔尼克
S·L·本德
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Abstract

The present invention discloses efficient synthetic routes for the preparation of rhinovirus protease inhibitors of formula as well as key intermediates useful in the synthetic routes. These compounds of formula and pharmaceutical compositions containing them are useful in the treatment of patients or hosts infected with one or more picornaviruses.

Description

制备鼻病毒蛋白酶抑制剂的合成路线以及关键的中间体Synthetic route and key intermediates for preparing rhinovirus protease inhibitors

相关的申请资料：Relevant application materials:

本申请涉及美国临时专利申请号60/150,358，其申请日为1999年8月24日。This application is related to US Provisional Patent Application No. 60/150,358, filed August 24,1999.

本申请还涉及美国临时专利申请号60/150,365(律师档案号0125.0027)，其申请日同样为1999年8月24日，发明名称为“制备鼻病毒蛋白酶抑制剂的有效方法，用于制备该抑制剂的关键中间体和连续膜反应器”，发明人为：J.Tao，S.Babu，R.Dagnino，Jr.，Q.Tian，T.Remarchuk，K.McGee，N.Nayyar和T.Moran。上述申请还涉及制备鼻病毒蛋白酶抑制剂的合成路线及其制备中所用的关键中间体。本申请以上述申请为基础并将其引入文中作为参考。This application is also related to U.S. Provisional Patent Application No. 60/150,365 (Attorney Docket No. 0125.0027), also filed on August 24, 1999, entitled "Efficient Process for Preparing Inhibitors of Rhinovirus Protease, for the Preparation of the Inhibitor The key intermediate of agent and continuous membrane reactor", the inventors are: J. Tao, S. Babu, R. Dagnino, Jr., Q. Tian, T. Remarchuk, K. McGee, N. Nayyar and T. Moran. The above application also relates to the synthetic route for preparing the rhinovirus protease inhibitor and the key intermediates used in the preparation. This application is based on the aforementioned application and is incorporated herein by reference.

本发明的技术领域和工业实用性：Technical field and industrial applicability of the present invention:

本发明涉及改进的制备乙基-3-{(5’-甲基异噁唑-3’-羰基)-L-Valψ(COCH2)-L-(4-F-Phe)-L-((S)-吡咯-Ala)}-E-丙酸酯(也称为AG7088)、其类似物及其可药用盐的方法。本发明还包括用于上述方法的一组新的关键中间体。The present invention relates to an improved preparation of ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Valψ(COCH 2 )-L-(4-F-Phe)-L-(( S)-Pyrrole-Ala)}-E-propionate (also known as AG7088), its analogs and pharmaceutically acceptable salts thereof. The present invention also includes a new set of key intermediates for use in the above methods.

发明背景：Background of the invention:

细小核糖核酸病毒是一族可以感染人和其它动物的微小的无包膜的正链含RNA病毒。这些病毒包括人鼻病毒、人脊髓灰质炎病毒、人柯萨奇病毒、人埃可病毒、人和牛肠道病毒、脑心肌炎病毒、脑膜炎病毒、足和口腔病毒、甲肝病毒等。人鼻病毒是普通感冒的主要原因。Picornaviruses are a family of tiny non-enveloped positive-sense RNA-containing viruses that can infect humans and other animals. These viruses include human rhinovirus, human poliovirus, human coxsackievirus, human echovirus, human and bovine enterovirus, encephalomyocarditis virus, meningitis virus, foot and oral cavity virus, hepatitis A virus, etc. Human rhinoviruses are the leading cause of the common cold.

细小核糖核酸病毒的自然成熟需要分解蛋白的3C酶。因此，抑制这些分解蛋白的3C酶的活性代表了一种重要而且有用的治疗和治愈该性质的病毒感染、包括普通感冒的方法。The natural maturation of picornaviruses requires proteolytic 3C enzymes. Therefore, inhibition of the activity of these proteolytic 3C enzymes represents an important and useful approach to the treatment and cure of viral infections of this nature, including the common cold.

最近发现了一些细小核糖核酸病毒3c蛋白酶的酶活性的小分子抑制剂(即抗细小核糖核酸病毒的化合物)。参见，例如美国专利申请号08/850,398，由Webber等人于1997年5月2日递交；美国专利申请号08/991,282，由Dragovich等人于1997年12月16日递交；和美国专利申请号08/991,739，由Webber等人于1997年12月16日递交。这些美国专利申请描述了某些抗细小核糖核酸病毒的化合物及其合成方法，这些申请所公开的内容引入本文作为参考。Several small molecule inhibitors of the enzymatic activity of the picornavirus 3c protease (ie, anti-picornavirus compounds) have recently been discovered. See, e.g., U.S. Patent Application No. 08/850,398, filed May 2, 1997 by Webber et al; U.S. Patent Application No. 08/991,282, filed December 16, 1997 by Dragovich et al; and U.S. Patent Application No. 08/991,739, filed December 16, 1997 by Webber et al. These US patent applications describe certain anti-picornavirus compounds and methods of their synthesis, the disclosures of which are incorporated herein by reference.

最近，在由Dragovich等人于1998年8月28日递交的美国专利申请号60/098,354(’354申请)中公开了一种特别有效的抗细小核糖核酸病毒剂，该申请引入本文作为参考。该申请公开了一组通式I的抗细小核糖核酸病毒剂。其中包括一种特别有前景的化合物，AG7088，该化合物对多种鼻病毒血清型显示极佳的抗病毒特性，目前正在进行人类的临床试验。’354申请还公开了用于合成这些化合物的方法和中间体。例如，其中的一般方法V公开了合成式I化合物的一般方法，该方法包括将通式BB的羧酸与通式P的胺进行形成酰胺的反应以得到最终的产物CC，如下所示。More recently, a particularly potent anti-picornaviral agent is disclosed in U.S. Patent Application No. 60/098,354, filed August 28, 1998 (the '354 application), by Dragovich et al., which application is incorporated herein by reference. This application discloses a group of antipicornavirus agents of general formula I. These include a particularly promising compound, AG7088, which displays excellent antiviral properties against multiple rhinovirus serotypes and is currently in clinical trials in humans. The '354 application also discloses methods and intermediates for the synthesis of these compounds. For example, general method V therein discloses a general method for synthesizing compounds of formula I, which includes reacting a carboxylic acid of general formula BB with an amine of general formula P to form an amide to obtain the final product CC, as shown below.

’354申请还公开了合成通式BB和P的中间体的方法，并教导了进行上述形成酰胺的反应的方法。因此，’354申请教导了从羧酸BB(在以下所述的通式II化合物的范围之内)和通式P的化合物(与以下所述的通式III的化合物相同)合成通式I化合物的适宜方法。同样，Dragovich等人最近的两份出版物也公开了抗细小核糖核酸病毒剂及其适宜的合成方法。参见“不可逆的人鼻病毒3C蛋白酶抑制剂的以结构为基础的设计、合成和生物学评价。3.含酮基亚甲基的肽模拟物的结构活性研究”，Dragovich等，Journal of MedicinalChemistry，ASAP，1999；和“不可逆的人鼻病毒3C蛋白酶抑制剂的以结构为基础的设计、合成和生物学评价。4.掺入P1内酰胺部分作为L-谷酰胺的替代物”，Dragovich等，Journal of MedicinalChemistry，ASAP，1999。上述文章全文引入本文作为参考。The '354 application also discloses methods of synthesizing intermediates of general formula BB and P, and teaches methods of carrying out the amide-forming reactions described above. Thus, the '354 application teaches the synthesis of compounds of general formula I from carboxylic acids BB (within the scope of compounds of general formula II described below) and compounds of general formula P (identical to compounds of general formula III described below) the appropriate method. Likewise, two recent publications by Dragovich et al. disclose antipicornaviral agents and their suitable synthesis. See "Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 3. Structure-Activity Studies of Ketomethylene-Containing Peptidomimetics," Dragovich et al., Journal of Medicinal Chemistry, ASAP, 1999; and "Structure-based design, synthesis, and biological evaluation of an irreversible human rhinovirus 3C protease inhibitor. 4. Incorporation of a P1 lactam moiety as a substitute for L-glutamine", Dragovich et al. , Journal of Medicinal Chemistry, ASAP, 1999. The above article is incorporated herein by reference in its entirety.

但是，仍需要开发用于合成抗细小核糖核酸病毒剂的改进的、更有效的方法和新的中间体。具体地讲，需要改进的合成通式II和III化合物的方法。However, there is still a need to develop improved, more efficient methods and new intermediates for the synthesis of anti-picornaviral agents. In particular, there is a need for improved methods of synthesizing compounds of general formula II and III.

发明概述：Summary of the invention:

本发明涉及制备式I的抗细小核糖核酸病毒剂、例如化合物AG7088的经济、有效的方法以及用于该合成方法的中间体。The present invention relates to an economical and efficient process for the preparation of anti-picornavirus agents of formula I, such as compound AG7088, and intermediates used in the synthetic process.

式I的抗细小核糖核酸病毒剂包括：Anti-picornavirus agents of formula I include:

Figure C0081187700081
Figure C0081187700081

其中R1是H、F、烷基、OH、SH或O-烷基；wherein R is H, F, alkyl, OH, SH or O-alkyl;

R2和R3彼此独立地是H；R 2 and R 3 are H independently of each other;

或 or

其中n是0至5的整数，A1是CH或N，A2和各A3彼此独立地选自C(R41)(R41)、N(R41)、S、S(O)、S(O)2和O，A4是NH或NR41，其中各R41彼此独立地是H或低级烷基，条件是在上述由A1、A2、(A3)n、A4和C＝O形成的环中至多有两个连续的杂原子，并且R2和R3中至少有一个是wherein n is an integer from 0 to 5, A 1 is CH or N, A 2 and each A 3 are independently selected from C(R 41 )(R 41 ), N(R 41 ), S, S(O), S(O) 2 and O, A 4 is NH or NR 41 , wherein each R 41 is independently of each other H or lower alkyl, with the proviso that A 1 , A 2 , (A 3 ) n , A 4 and There are at most two consecutive heteroatoms in the ring formed by C=O, and at least one of R2 and R3 is

Figure C0081187700091
或
Figure C0081187700091
or

R4是 R4 is

Figure C0081187700093
Figure C0081187700093

R5和R6彼此独立地是H、F、烷基、环烷基、杂环烷基、芳基或杂芳基；R and R are independently of each other H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl , or heteroaryl;

R7和R8彼此独立地是H、烷基、环烷基、杂环烷基、芳基、杂芳基、-OR17、-SR17、-NR17R18、-NR19NR17R18或-NR17OR18，其中R17、R18和R19彼此独立地是H、烷基、环烷基、杂环烷基、芳基、杂芳基或酰基，条件是R7和R8中至少有一个是烷基、芳基、杂芳基、-OR17、-SR17、-NR17R18、-NR19NR17R18或-NR17OR18；R 7 and R 8 are independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 17 , -SR 17 , -NR 17 R 18 , -NR 19 NR 17 R 18 or -NR 17 OR 18 , wherein R 17 , R 18 and R 19 are independently of each other H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or acyl, provided that R 7 and R At least one of 8 is alkyl, aryl, heteroaryl, -OR 17 , -SR 17 , -NR 17 R 18 , -NR 19 NR 17 R 18 or -NR 17 OR 18 ;

R9是含有1至3个选自O、N和S的杂原子的5元杂环； R is a 5-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N and S;

Z和Z1彼此独立地是H、F、烷基、环烷基、杂环烷基、芳基、杂芳基、-C(O)R21、-CO2R21、CN、-C(O)NR21R22、-C(O)NR21OR22、-C(S)R21、-C(S)NR21R22、-NO2、-SOR21、-SO2R21、-SO2NR21R22、-SO(NR21)(OR22)、-SONR21、-SO3R21、-PO(OR21)2、-PO(R21)(R22)、-PO(NR21R22)(OR23)、-PO(NR21R22)(NR23R24)、-C(O)NR21NR22R23或-C(S)NR21NR22R23，其中R21、R22、R23和R24彼此独立地是H、烷基、环烷基、杂环烷基、芳基、杂芳基、酰基或硫代酰基，或者其中R21、R22、R23和R24中的任意两个与它们所结合的原子合在一起形成杂环烷基，条件是Z和Z1不同时为H；Z and Z 1 are independently of each other H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C(O)R 21 , -CO 2 R 21 , CN, -C( O)NR 21 R 22 , -C(O)NR 21 OR 22 , -C(S)R 21 , -C(S)NR 21 R 22 , -NO 2 , -SOR 21 , -SO 2 R 21 , - SO 2 NR 21 R 22 , -SO(NR 21 )(OR 22 ), -SONR 21 , -SO 3 R 21 , -PO(OR 21 ) 2 , -PO(R 21 )(R 22 ), -PO( NR 21 R 22 )(OR 23 ), -PO(NR 21 R 22 )(NR 23 R 24 ), -C(O)NR 21 NR 22 R 23 or -C(S)NR 21 NR 22 R 23 , wherein R 21 , R 22 , R 23 and R 24 are independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or thioacyl, or wherein R 21 , R 22 , Any two of R23 and R24 are taken together with the atoms to which they are bound to form a heterocycloalkyl group, provided that Z and Z1 are not H at the same time;

或者Z1和R1与它们所结合的原子合在一起形成环烷基或杂环烷基，其中Z1和R1如上所定义，但不包括不能形成环烷基或杂环烷基的部分；or Z and R taken together with the atoms to which they are bound form a cycloalkyl or heterocycloalkyl, wherein Z and R are as defined above but excluding moieties which cannot form a cycloalkyl or heterocycloalkyl ;

或者Z和Z1与它们所结合的原子合在一起形成环烷基或杂环烷基，其中Z和Z1如上所定义，但不包括不能形成环烷基或杂环烷基的部分。Or Z and Z together with the atoms to which they are bound form a cycloalkyl or heterocycloalkyl, wherein Z and Z are as defined above, excluding moieties which cannot form a cycloalkyl or heterocycloalkyl.

正如以下将要讨论的，这些式I的抗细小核糖核酸病毒剂可以通过将通式II的化合物与通式III的化合物进行适当的形成酰胺的反应来合成。本发明的方法不仅减少了合成式III化合物所需的步骤数，而且更为重要的是，还采用了较为便宜的原料和试剂。As will be discussed below, these antipicornavirus agents of formula I can be synthesized by subjecting a compound of formula II to a compound of formula III in an appropriate amide-forming reaction. The method of the present invention not only reduces the number of steps needed to synthesize the compound of formula III, but more importantly, it also uses relatively cheap raw materials and reagents.

通过阅读说明书，可以更全面地理解本发明的这些目的、优点和特点。These objects, advantages and features of the present invention can be more fully understood by reading the specification.

本发明优选实施方案的详细描述：Detailed description of the preferred embodiment of the invention:

在本申请中，使用了如下定义：In this application, the following definitions are used:

根据本领域采用的规则，在本文的结构式中用

Figure C0081187700101
来表示所涉及的部分或取代基与核心或骨架结构的连接点的键。According to the rules adopted in the art, in the structural formulas herein, use
Figure C0081187700101
to indicate the bond at the point of attachment of the moiety or substituent involved to the core or backbone structure.

当化学结构中包含手性碳时，若无指明具体取向，则同时包括两种立体异构体形式。When a chemical structure contains chiral carbons, unless a specific orientation is indicated, both stereoisomeric forms are included.

“烷基”是指碳原子和氢原子的直链或支链的一价饱和和/或不饱和基团，例如甲基(Me)、乙基(Et)、丙基、异丙基、丁基(Bu)、异丁基、叔丁基(t-Bu)、乙烯基、戊烯基、丁烯基、丙烯基、乙炔基、丁炔基、丙炔基、戊炔基、己炔基等，这些基团可以是未取代的(即，仅含碳和氢)或被一个或多个以下所定义的适宜取代基(例如，一个或多个卤素，例如F、Cl、Br或I，优选F和Cl)所取代。“低级烷基”是指在其链中含有1至4个碳原子的烷基。"Alkyl" means a linear or branched monovalent saturated and/or unsaturated group of carbon atoms and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl, butyl Base (Bu), isobutyl, tert-butyl (t-Bu), vinyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl etc., these groups may be unsubstituted (i.e. containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below (e.g. one or more halogens such as F, Cl, Br or I, Preferably F and Cl) are substituted. "Lower alkyl" means an alkyl group having 1 to 4 carbon atoms in the chain.

“环烷基”是指含有3、4、5、6、7、8、9、10、11、12、13或14个碳环原子的非芳香性的一价单环、二环或三环基团，该基团可以是饱和或不饱和的，并且可以是未取代的或被一个或多个以下所定义的适宜取代基所取代，并且该基团可与一个或多个杂环烷基、芳基或杂芳基稠合，这些杂环烷基、芳基或杂芳基本身又可以是未取代的或被一个或多个取代基所取代。环烷基的说明性的例子包括如下基团："Cycloalkyl" means a non-aromatic monovalent monocyclic, bicyclic or tricyclic ring containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon ring atoms group, which may be saturated or unsaturated, and may be unsubstituted or substituted by one or more suitable substituents as defined below, and which may be combined with one or more heterocycloalkyl , aryl or heteroaryl fused, and these heterocycloalkyl, aryl or heteroaryl themselves can be unsubstituted or substituted by one or more substituents. Illustrative examples of cycloalkyl groups include the following groups:

Figure C0081187700111
Figure C0081187700111

Figure C0081187700112
和
Figure C0081187700112
and

“杂环烷基”是指含有3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个环原子、其中包括1、2、3、4或5个选自氮、氧和硫的杂原子的非芳香性的一价单环、二环或三环基团，该基团可以是饱和或不饱和的，并且可以是未取代的或被一个或多个以下所定义的适宜取代基所取代，并且该基团可与一个或多个环烷基、芳基或杂芳基稠合，这些环烷基、芳基或杂芳基本身又可以是未取代的或被一个或多个适宜的取代基所取代。杂环烷基的说明性的例子包括如下基团："Heterocycloalkyl" means containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 ring atoms, including 1, 2, A non-aromatic monovalent monocyclic, bicyclic or tricyclic group of 3, 4 or 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be saturated or unsaturated and may be unsubstituted or substituted by one or more suitable substituents as defined below, and this group may be fused to one or more cycloalkyl, aryl or heteroaryl groups, which cycloalkyl, aryl or heteroaryl A group can itself be unsubstituted or substituted with one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include the following groups:

Figure C0081187700115
和
Figure C0081187700116
Figure C0081187700115
and
Figure C0081187700116

“芳基”是指含有6、10、14或18个碳原子的芳香族一价单环、二环或三环基团，该基团可以是来取代的或被一个或多个以下所定义的适宜取代基所取代，并且该基团可与一个或多个环烷基、杂环烷基或杂芳基稠合，这些环烷基、杂环烷基或杂芳基本身又可以是未取代的或被一个或多个适宜的取代基所取代。芳基的说明性的例子包括如下基团："Aryl" means an aromatic monovalent monocyclic, bicyclic or tricyclic group containing 6, 10, 14 or 18 carbon atoms which may be substituted or replaced by one or more of the following and the group may be fused with one or more cycloalkyl, heterocycloalkyl or heteroaryl groups which themselves may be unidentified Substituted or substituted with one or more suitable substituents. Illustrative examples of aryl groups include the following groups:

和

Figure C0081187700122
and
Figure C0081187700122

“杂芳基”是指含有4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个环原子、其中包括1、2、3、4或5个选自氮、氧和硫的杂原子的芳香性的一价单环、二环或三环基团，该基团可以是未取代的或被一个或多个以下所定义的适宜取代基所取代，并且该基团可与一个或多个环烷基、杂环烷基或芳基稠合，这些环烷基、杂环烷基或芳基本身又可以是未取代的或被一个或多个适宜的取代基所取代。杂芳基的说明性的例子包括如下基团："Heteroaryl" means containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 ring atoms, including 1, 2, 3, 4 Or an aromatic monovalent monocyclic, bicyclic or tricyclic group of 5 heteroatoms selected from nitrogen, oxygen and sulfur, which group may be unsubstituted or substituted by one or more of the following defined and this group may be fused with one or more cycloalkyl, heterocycloalkyl or aryl groups which themselves may be unsubstituted or replaced by a or multiple suitable substituents. Illustrative examples of heteroaryl groups include the following groups:

Figure C0081187700123
Figure C0081187700123

Figure C0081187700131
Figure C0081187700131

Figure C0081187700132
和
Figure C0081187700132
and

“杂环”是指杂芳基或杂环烷基(如上所述，其均可以选择性地被取代)。"Heterocycle" means a heteroaryl or heterocycloalkyl group (both of which may be optionally substituted as described above).

“酰基”是指-C(O)-R基团，其中R是以下所定义的取代基。"Acyl" means a -C(O)-R group where R is a substituent as defined below.

“硫代酰基”是指-C(S)-R基团，其中R是以下所定义的取代基。"Thioacyl" means a -C(S)-R group where R is a substituent as defined below.

“磺酰基”是指-SO2R基团，其中R是以下所定义的取代基。"Sulfonyl" means a -SO2R group where R is a substituent as defined below.

“羟基”是指基团-OH。"Hydroxy" refers to the group -OH.

“氨基”是指基团-NH2。"Amino" refers to the group -NH2 .

“烷基氨基”是指基团-NHRa，其中Ra是烷基。"Alkylamino" refers to the group -NHR a , where R a is alkyl.

“二烷基氨基”是指基团-NRaRb，其中Ra和Rb彼此独立地是烷基。"Dialkylamino" refers to the group -NR a R b , where Ra and R b are independently of each other alkyl.

“烷氧基”是指基团-ORa，其中Ra是烷基。烷氧基的例子包括甲氧基、乙氧基、丙氧基等。"Alkoxy" refers to the group -OR a , where R a is alkyl. Examples of alkoxy include methoxy, ethoxy, propoxy and the like.

“烷氧基羰基”是指基团-C(O)ORa，其中Ra是烷基。"Alkoxycarbonyl" refers to the group -C(O)OR a , where R a is alkyl.

“烷基磺酰基”是指基团-SO2Ra，其中Ra是烷基。"Alkylsulfonyl" refers to the group -SO2Ra where Ra is alkyl.

“烷基氨基羰基”是指基团-C(O)NHRa，其中Ra是烷基。"Alkylaminocarbonyl" refers to the group -C(O)NHR a where R a is alkyl.

“二烷基氨基羰基”是指基团-C(O)NRaRb，其中Ra和Rb彼此独立地是烷基。"Dialkylaminocarbonyl" refers to the group -C(O)NR a R b , where Ra and R b are , independently of each other, alkyl.

“巯基”是指基团-SH。"Mercapto"refers to the group -SH.

“烷硫基”是指基团-SRa，其中Ra是烷基。"Alkylthio" refers to the group -SR a where R a is alkyl.

“羧基”是指基团-C(O)OH。"Carboxy" refers to the group -C(O)OH.

“氨基甲酰基”是指基团-C(O)NH2。"Carbamoyl" refers to the group -C(O) NH2 .

“芳氧基”是指基团-ORc，其中Rc是芳基。"Aryloxy" refers to the group -ORc where Rc is aryl.

“杂芳氧基”是指基团-ORd，其中Rd是杂芳基。"Heteroaryloxy" refers to the group -ORd where Rd is heteroaryl.

“芳硫基”是指基团-SRc，其中Rc是芳基。"Arylthio" refers to the group -SRc where Rc is aryl.

“杂芳硫基”是指基团-SRd，其中Rd是杂芳基。"Heteroarylthio" refers to the group -SRd where Rd is heteroaryl.

“离去基”(Lv)是指可以通过取代反应被置换的任何适宜的基团。本领域普通技术人员可以理解，强酸的任何共轭碱均可以起到离去基的作用。适宜离去基的说明性的例子包括但不仅限于，-F、-Cl、-Br、烷基氯化物、烷基溴化物、烷基碘化物、烷基磺酸酯、烷基苯磺酸酯、烷基对甲苯磺酸酯、烷基甲磺酸酯、三氟甲磺酸酯，以及含有硫酸氢根、硫酸甲酯或磺酸根离子的任何基团。"Leaving group" (Lv) refers to any suitable group that can be displaced by a substitution reaction. Those of ordinary skill in the art will appreciate that any conjugate base of a strong acid can function as a leaving group. Illustrative examples of suitable leaving groups include, but are not limited to, -F, -Cl, -Br, alkyl chlorides, alkyl bromides, alkyl iodides, alkylsulfonates, alkylbenzenesulfonates , alkyl p-toluenesulfonate, alkyl methanesulfonate, triflate, and any group containing bisulfate, methylsulfate, or sulfonate ions.

典型的保护基、试剂和溶剂，例如但不仅限于下表1中所列的那些，在文中和权利要求中采用如下缩写。本领域技术人员可以理解，表中所列的化合物可以互换使用；例如，在“试剂和溶剂”下所列的化合物可以用作保护基等。此外，其它可能的保护基、试剂和溶剂是本领域技术人员已知的；这些均包括在本发明的范围内。Typical protecting groups, reagents and solvents, such as but not limited to those listed in Table 1 below, are used in the text and claims as follows abbreviated. It will be appreciated by those skilled in the art that the compounds listed in the tables may be used interchangeably; for example, the compounds listed under "Reagents and Solvents" may be used as protecting groups, etc. Furthermore, other possible protecting groups, reagents and solvents are known to those skilled in the art; these are included within the scope of the present invention.

表1Table 1

                           保护基Protecting group

Ada                        金刚烷乙酰基Ada adamantane acetyl

Alloc                      烯丙氧羰基Alloc Allyloxycarbonyl

Allyl                      烯丙基酯Allyl Allyl Ester

Boc                        叔丁氧羰基Boc tert-butoxycarbonyl

Bzl                        苄基Bzl Benzyl

Cbz                        苄氧羰基Cbz Benzyloxycarbonyl

Fmoc                       芴基甲氧羰基Fmoc Fluorenylmethoxycarbonyl

OBzl                       苄酯OBzl Benzyl Ester

OEt                        乙酯OEt ethyl ester

OMe                        甲酯OMe Methyl Ester

Tos(Tosyl)                 对甲苯磺酰基Tos(Tosyl) p-Toluenesulfonyl

Trt                        三苯基甲基Trt Triphenylmethyl

                           试剂和溶剂Reagents and Solvents

ACN                        乙腈ACN Acetonitrile

AcOH                      乙酸AcOH Acetic Acid

Ac.sub.2 0                乙酸酐Ac.sub.2 0 Acetic anhydride

AdacOH                    金刚烷乙酸AdacOH adamantane acetic acid

AIBN                      2，2-偶氮二异丁腈AIBN 2,2-azobisisobutyronitrile

Alloc-Cl                  烯丙氧基羰酰氯Alloc-Cl Allyloxycarbonyl Chloride

BHT                       2，6-二-叔丁基-4-甲基苯酚BHT 2,6-di-tert-butyl-4-methylphenol

Boc.sub.2 0               二碳酸二叔丁酯Boc.sub.2 0 di-tert-butyl dicarbonate

CDI                       1，1’-羰基二咪唑CDI 1,1’-Carbonyldiimidazole

DIEA                      二异丙基乙基胺DIEA Diisopropylethylamine

DIPEA                     N，N-二异丙基乙基胺DIPEA N,N-Diisopropylethylamine

DMA                       二甲基乙酰胺DMA Dimethylacetamide

DMF                       N，N-二甲基甲酰胺DMF N,N-Dimethylformamide

DMSO                      二甲亚砜DMSO Dimethyl Sulfoxide

EDTA                      乙二胺四乙酸EDTA ethylenediaminetetraacetic acid

Et.sub.3N                 三乙胺Et.sub.3N Triethylamine

EtOAc                     乙酸乙酯EtOAc Ethyl acetate

FDH                       甲酸脱氢酶FDH formate dehydrogenase

FmocOSu                   9-芴基甲氧基羰基N-羟基琥珀酰亚胺酯FmocOSu 9-Fluorenylmethoxycarbonyl N-hydroxysuccinimide ester

HATU                      N-[(二甲基氨基)-1H-1，2，3-三唑并[4，5-b]吡HATU N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine

                          啶基亚甲基]-N-甲基甲铵六氟磷酸盐N-氧化物                                                       

HOBT                      1-羟基苯并三唑HOBT 1-Hydroxybenzotriazole

HF                        氢氟酸HF Hydrofluoric Acid

LDH                       乳酸脱氢酶LDH lactate dehydrogenase

LiHMDS                    双三甲基硅烷基氨基锂LiHMDS Lithium bistrimethylsilylamide

MeOH                      甲醇MeOH Methanol

Mes(Mesyl)                甲磺酰基Mes(Mesyl) Methylsulfonyl

MTBE                      叔丁基甲基醚MTBE tert-butyl methyl ether

NAD                       烟酰胺腺嘌呤二核苷酸NAD Nicotinamide Adenine Dinucleotide

NADH                      过氧化氢氧化还原酶NADH Hydrogen peroxide oxidoreductase

NaHMDS                    双三甲基硅烷基氨基钠NaHMDS Sodium Bistrimethylsilylamide

NMP                       1-甲基-2-吡咯烷酮NMP 1-Methyl-2-pyrrolidone

nin.                      茚三酮nin. ninhydrin

i-PrOH                      异丙醇i-PrOH Isopropanol

Pip                         哌啶Pip Piperidine

PPL                         脂酶PPL Lipase

pTSA                        对甲苯磺酸一水合物pTSA p-toluenesulfonic acid monohydrate

Pyr                         吡啶Pyr Pyridine

TEA                         三乙胺TEA Triethylamine

TET                         三亚乙基四胺TET Triethylenetetramine

TFA                         三氟乙酸TFA Trifluoroacetic acid

THF                         四氢呋喃THF Tetrahydrofuran

Triflate(Tf)                三氟甲磺酰基Triflate(Tf) Trifluoromethanesulfonyl

术语“适宜的有机部分”是指本领域技术人员可以通过例如常规的试验来判断的、不会对本发明化合物的抑制活性产生不利影响的任何有机部分。适宜的有机部分的说明性的例子包括但不仅限于，羟基、烷基、氧代基团、环烷基、杂环烷基、芳基、杂芳基、酰基、磺酰基、巯基、烷硫基、烷氧基、羧基、氨基、烷基氨基、二烷基氨基、氨基甲酰基、芳硫基、杂芳硫基等。The term "suitable organic moiety" refers to any organic moiety that a person skilled in the art can judge by, for example, routine testing, which does not adversely affect the inhibitory activity of the compounds of the present invention. Illustrative examples of suitable organic moieties include, but are not limited to, hydroxy, alkyl, oxo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, sulfonyl, mercapto, alkylthio , alkoxy, carboxyl, amino, alkylamino, dialkylamino, carbamoyl, arylthio, heteroarylthio, etc.

术语“取代基”或“适宜的取代基”指本领域技术人员可以通过例如常规的试验来判断的任何适宜的取代基。适宜取代基的说明性的例子包括羟基、卤素、氧代基团、烷基、酰基、磺酰基、巯基、烷硫基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、羧基、氨基、烷基氨基、二烷基氨基、氨基甲酰基、芳氧基、杂芳氧基、芳硫基、杂芳硫基等。The term "substituent" or "suitable substituent" refers to any suitable substituent that can be judged by those skilled in the art, for example, by routine experimentation. Illustrative examples of suitable substituents include hydroxy, halogen, oxo, alkyl, acyl, sulfonyl, mercapto, alkylthio, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, carboxyl group, amino group, alkylamino group, dialkylamino group, carbamoyl group, aryloxy group, heteroaryloxy group, arylthio group, heteroarylthio group, etc.

术语“选择性取代的”用来表示指定的基团是未取代的或被一个或多个适宜的取代基所取代，如果对选择性的取代基进行了明确指定，则该术语表示该基团是未取代的或被指定的取代基所取代的。正如以上所定义的，各基团均可以是未取代或取代的(即，它们是选择性取代的)，除非另有说明(例如，指明该基团是未取代的)。The term "optionally substituted" is used to indicate that the specified group is unsubstituted or substituted with one or more suitable substituents, and if an optional substituent is specified, the term indicates that the group is unsubstituted or substituted with a designated substituent. As defined above, each group can be unsubstituted or substituted (ie, they are optionally substituted), unless otherwise stated (eg, it is indicated that the group is unsubstituted).

“前药”是指可以在生理条件下或通过溶剂分解或代谢转化成具有药物活性的特定化合物的化合物。"Prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis or metabolism into a specific compound with pharmaceutical activity.

“药物活性代谢物”是指通过代谢在体内产生的特定化合物的药理学活性产物。"Pharmaceutically active metabolite" refers to the pharmacologically active product of a particular compound produced in vivo by metabolism.

“溶剂化物”是指指定化合物的可药用溶剂化物，其保留了该化合物的生物学效力。溶剂化合物的例子包括本发明化合物与水、异丙醇、乙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸或乙醇胺的结合物。"Solvate" refers to a pharmaceutically acceptable solvate of a given compound, which retains the biological effectiveness of the compound. Examples of solvent compounds include combinations of compounds of the invention with water, isopropanol, ethanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine.

“可药用盐”是指保留了指定化合物的游离酸或碱的生物学效力并且在生物学或其它方面没有不利影响的盐。可药用盐的例子包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1，4-二酸盐、己炔-1，6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、乙醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐。"Pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acid or base of the specified compound and has no adverse effects, biological or otherwise. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloric acid Salt, hydrobromide, hydroiodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propyne salt, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne- 1,6-diacid salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, orthobenzoate Diformate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartaric acid salt, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate.

本发明还提供了包括本申请中所列的合成步骤之一的合成方法。当一个合成步骤至少是最终合成方法的一部分时，则合成方法包含了该合成步骤。因此，合成方法可以仅有一个合成步骤，或者还含有与之有关的附加合成步骤。该合成方法可以含有很少的附加合成步骤，或者可以含有很多附加的合成步骤。The present invention also provides a synthetic method comprising one of the synthetic steps listed in this application. A synthetic method comprises a synthetic step when that synthetic step is at least part of a final synthetic method. Thus, a synthetic method may have only one synthetic step, or may contain additional synthetic steps associated therewith. The synthetic method may contain few additional synthetic steps, or may contain many additional synthetic steps.

如果由本发明的方法制得的式I的抗细小核糖核酸病毒剂是碱，则可以通过本领域已知的任何适宜方法制备所需的盐，包括将游离碱用无机酸例如盐酸；氢溴酸；硫酸；硝酸；磷酸等处理，或用有机酸例如乙酸；马来酸；琥珀酸；扁桃酸；富马酸；丙二酸；丙酮酸；草酸；乙醇酸；水杨酸；吡喃糖基酸，例如葡糖醛酸或半乳糖醛酸；α-羟基酸，例如柠檬酸或酒石酸；氨基酸，例如天冬氨酸或谷氨酸；芳香族酸，例如苯甲酸或肉桂酸；磺酸，例如对甲苯磺酸或乙磺酸等处理。If the antipicornavirus agent of formula I prepared by the method of the present invention is a base, the desired salt can be prepared by any suitable method known in the art, including dissolving the free base with a mineral acid such as hydrochloric acid; hydrobromic acid ; sulfuric acid; nitric acid; phosphoric acid, etc., or treatment with organic acids such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; Acids such as glucuronic acid or galacturonic acid; alpha-hydroxy acids such as citric acid or tartaric acid; amino acids such as aspartic acid or glutamic acid; aromatic acids such as benzoic acid or cinnamic acid; sulfonic acids, Such as p-toluenesulfonic acid or ethanesulfonic acid treatment.

如果由本发明的方法制得的式I的抗细小核糖核酸病毒剂是酸，则可以通过本领域已知的任何适宜方法制备所需的盐，包括将游离酸用无机或有机碱例如胺(伯、仲或叔)；碱金属或碱土金属氢氧化物等处理。适宜的盐的说明性的例子包括从氨基酸例如甘氨酸和精氨酸；氨；伯、仲和叔胺以及和环状的胺例如哌啶、吗啉和哌嗪衍生的有机盐；以及从钠、钙、钾、镁、锰、铁、铜、锌、铝和锂衍生的无机盐。If the antipicornavirus agent of formula I prepared by the method of the present invention is an acid, the desired salt can be prepared by any suitable method known in the art, including treating the free acid with an inorganic or organic base such as an amine (primary , secondary or tertiary); alkali metal or alkaline earth metal hydroxide treatment. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary and tertiary amines and cyclic amines such as piperidine, morpholine and piperazine; Inorganic salts derived from calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

当化合物、其盐或溶剂化物是固体时，本领域技术人员可以理解，本发明的方法中所用的式I化合物以及中间体、其盐和溶剂化物可以以不同的晶型存在，所有这些均包括在本发明和指定的分子式的范围内。When the compound, its salt or solvate is solid, those skilled in the art will understand that the compound of formula I used in the method of the present invention and the intermediate, its salt and solvate can exist in different crystal forms, all of which include Within the scope of the invention and the specified formulae.

式I的抗细小核糖核酸病毒剂以及本发明的方法中所用的中间体可以以单个的立体异构体、消旋体和/或旋光对映体的混合物和/或非对映体的形式存在。所有这些单个的立体异构体、消旋体及其混合物均包括在本发明的范围内。但是，优选本发明的方法中所用的中间体化合物是光学纯的形式。The antipicornavirus agents of formula I and the intermediates used in the methods of the invention may exist as individual stereoisomers, racemates and/or mixtures of optical antipodes and/or diastereomers . All such individual stereoisomers, racemates and mixtures thereof are included within the scope of the present invention. However, it is preferred that the intermediate compounds used in the process of the invention are in optically pure form.

本领域技术人员通常可以理解，光学纯的化合物是对映体纯的化合物。本文所用的术语“光学纯”是指化合物含有至少足够量的单个对映体以得到具有所需的药理学活性的化合物。优选“光学纯”是指化合物含有至少90％的单个异构体(80％对映体过量(以下称为“e.e.”))，更优选至少95％(90％e.e.)，仍更优选至少97.5％(95％e.e.)，首选至少99％(98％e.e.)。优选由本发明的方法形成的式I的抗细小核糖核酸病毒剂是光学纯的。It is generally understood by those skilled in the art that an optically pure compound is an enantiomerically pure compound. As used herein, the term "optically pure" means that a compound contains at least sufficient amounts of the individual enantiomers to give the compound the desired pharmacological activity. Preferably "optically pure" means that the compound contains at least 90% of the individual isomers (80% enantiomeric excess (hereinafter "e.e.")), more preferably at least 95% (90% e.e.), still more preferably at least 97.5% % (95% e.e.), preferably at least 99% (98% e.e.). Preferably the antipicornaviral agent of formula I formed by the method of the invention is optically pure.

本发明涉及制备式I的抗细小核糖核酸病毒剂的方法：The present invention relates to the method for the anti-picornavirus agent of preparation formula I:

Figure C0081187700181
Figure C0081187700181

其中R1是H、F、烷基、OH、SH或O-烷基；wherein R is H, F, alkyl, OH, SH or O-alkyl;

R2和R3彼此独立地是H；R 2 and R 3 are H independently of each other;

或

Figure C0081187700192
or
Figure C0081187700192

其中n是0至5的整数，A1是CH或N，A2和各A3彼此独立地选自C(R41)(R41)、N(R41)、S、S(O)、S(O)2和O，A4是NH或NR41，其中各R41彼此独立地是H或低级烷基，条件是在上述由A1、A2、(A3)n、A4和C＝O形成的环中至多有两个连续的杂原子，并且R2和R3中至少有一个是wherein n is an integer from 0 to 5, A 1 is CH or N, A 2 and each A 3 are independently selected from C(R 41 )(R 41 ), N(R 41 ), S, S(O), S(O) 2 and O, A 4 is NH or NR 41 , wherein each R 41 is independently of each other H or lower alkyl, with the proviso that A 1 , A 2 , (A 3 ) n , A 4 and There are at most two consecutive heteroatoms in the ring formed by C=O, and at least one of R2 and R3 is

或

Figure C0081187700194
or
Figure C0081187700194

R4是 R4 is

R5和R6彼此独立地是H、F、烷基、环烷基、杂环烷基、芳基或杂芳基；R and R are independently of each other H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl , or heteroaryl;

R7和R8彼此独立地是H、烷基、环烷基、杂环烷基、芳基、杂芳基、-OR17、-SR17、-NR17R18、-NR19NR17R18或-NR17OR18，其中R17、R18和R19彼此独立地是H、烷基、环烷基、杂环烷基、芳基、杂芳基或酰基，条件是R7和R8中至少有一个是烷基、芳基、杂芳基、-OR17、-SR17、-NR17R18、-NR19NR17R18或-NR17OR18；R 7 and R 8 are independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 17 , -SR 17 , -NR 17 R 18 , -NR 19 NR 17 R 18 or -NR 17 OR 18 , wherein R 17 , R 18 and R 19 are independently of each other H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or acyl, provided that R 7 and R At least one of 8 is alkyl, aryl, heteroaryl, -OR 17 , -SR 17 , -NR 17 R 18 , -NR 19 NR 17 R 18 or -NR 17 OR 18 ;

R9是含有1至3个选自O、N和S的杂原子的5元杂环； R is a 5-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N and S;

Z和Z1彼此独立地是H、F、烷基、环烷基、杂环烷基、芳基、杂芳基、-C(O)R21、-CO2R21、CN、-C(O)NR21R22、-C(O)NR21OR22、-C(S)R21、-C(S)NR21R22、-NO2、-SOR21、-SO2R2R21、-SO2NR21R22、-SO(NR21)(OR22)、-SONR21、-SO3R21、-PO(OR21)2、-PO(R21)(R22)、-PO(NR21R22)(OR23)、-PO(NR21R22)(NR23R24)、-C(O)NR21NR22R23或-C(S)NR21NR22R23，其中R21、R22、R23和R24彼此独立地是H、烷基、环烷基、杂环烷基、芳基、杂芳基、酰基或硫代酰基，或者其中R21、R22、R23和R24中的任意两个与它们所结合的原子合在一起形成杂环烷基，条件是Z和Z1不同时为H；Z and Z 1 are independently of each other H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C(O)R 21 , -CO 2 R 21 , CN, -C( O)NR 21 R 22 , -C(O)NR 21 OR 22 , -C(S)R 21 , -C(S)NR 21 R 22 , -NO 2 , -SOR 21 , -SO 2 R 2 R 21 , -SO 2 NR 21 R 22 , -SO(NR 21 )(OR 22 ), -SONR 21 , -SO 3 R 21 , -PO(OR 21 ) 2 , -PO(R 21 )(R 22 ), - PO(NR 21 R 22 )(OR 23 ), -PO(NR 21 R 22 )(NR 23 R 24 ), -C(O)NR 21 NR 22 R 23 or -C(S)NR 21 NR 22 R 23 , wherein R 21 , R 22 , R 23 and R 24 are independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or thioacyl, or wherein R 21 , R 22. Any two of R 23 and R 24 are combined with the atoms they are bound to form a heterocycloalkyl group, provided that Z and Z 1 are not H at the same time;

或者Z1和R1与它们所结合的原子合在一起形成环烷基或杂环烷基，其中Z1和R1如上所定义，但不包括不能形成环烷基或杂环烷基的部分；or Z and R taken together with the atoms to which they are bound form a cycloalkyl or heterocycloalkyl, wherein Z and R are as defined above but excluding moieties which cannot form a cycloalkyl or heterocycloalkyl ;

或者Z和Z1与它们所结合的原子合在一起形成环烷基或杂环烷基，其中Z和Z1如上所定义，但不包括不能形成环烷基或杂环烷基的部分。Or Z and Z together with the atoms to which they are bound form a cycloalkyl or heterocycloalkyl, wherein Z and Z are as defined above, excluding moieties which cannot form a cycloalkyl or heterocycloalkyl.

本发明公开了式I化合物可以通过将式II化合物和式III化合物进行形成酰胺的反应来制备：The present invention discloses that the compound of formula I can be prepared by reacting the compound of formula II and the compound of formula III to form an amide:

形成酰胺的反应可以通过任何适宜的方法、试剂和反应条件来完成。优选可以采用’354申请中所公开的各种方法。例如，可将式II化合物与式III化合物在HATU、DIPEA、CH3CN和H2O的存在下反应生成所需的式I化合物。可以采用任何适宜的纯化方法来进一步纯化式I化合物。The amide forming reaction can be accomplished by any suitable method, reagents and reaction conditions. Preferably, the various methods disclosed in the '354 application can be used. For example, a compound of formula II can be reacted with a compound of formula III in the presence of HATU, DIPEA, CH3CN and H2O to yield the desired compound of formula I. Compounds of formula I may be further purified by any suitable purification method.

更优选通过包括如下步骤的酰胺形成反应来制备式I化合物：More preferably the compound of formula I is prepared by an amide forming reaction comprising the following steps:

(a)将式II化合物与式IIIA化合物在N-甲基吗啉的存在下反应形成反应混合物；然后(a) reacting the compound of formula II with the compound of formula IIIA in the presence of N-methylmorpholine to form a reaction mixture; then

(b)向反应混合物中加入式Lv-X的化合物形成式I化合物，其中X是任何适宜的卤化物。(b) adding a compound of formula Lv-X to the reaction mixture to form a compound of formula I, wherein X is any suitable halide.

优选地，采用更优选的酰胺形成反应的制备式I化合物的方法，采用以下公开的某些或全部试剂和反应条件。因此，优选将式II化合物和式IIIA化合物在任何适宜的容器中在DMF中混合。适宜的容器优选是单颈烧瓶，然后将其用任何适宜的隔膜覆盖并用温度探针覆盖。在向反应混合物中加入N-甲基吗啉之前，用氮气将适宜的容器净化。更优选将N-甲基吗啉通过注射器一次性加入并将反应混合物冷却至约-5℃至5℃。更优选将反应混合物冷却至约0℃。然后向反应混合物中加入式Lv-X化合物的溶液。更优选式Lv-X化合物的溶液是式Lv-X化合物的DMF溶液。仍更优选式Lv-X化合物是CDMT。将式Lv-X化合物的溶液通过任何适宜的方法加入到反应混合物中以使反应混合物保持在恒定的温度。例如，可以将式Lv-X化合物的溶液用注射器滴加到反应混合物中。在式Lv-X化合物加料结束后，将反应混合物升温至约室温。通过薄层色谱(以下称为”TLC)监测式II化合物的消失来监测反应的进程。当反应至少是基本结束时，可以通过向反应混合物中缓慢加入水形成浆液使式I化合物从溶液中析出沉淀。然后可以通过本领域技术人员已知的任何适宜方法从浆液中分离出式I化合物。例如，可以通过过滤从浆液中分离出式I化合物。可以采用本领域技术人员已知的任何适宜的纯化方法来纯化式I化合物。更优选将式I化合物通过重结晶进行纯化。Preferably, methods of preparing compounds of formula I employ more preferred amide forming reactions employing some or all of the reagents and reaction conditions disclosed below. Thus, it is preferred to mix the compound of formula II and the compound of formula IIIA in DMF in any suitable vessel. A suitable vessel is preferably a single-necked flask, which is then covered with any suitable septum and covered with a temperature probe. A suitable container was purged with nitrogen prior to adding N-methylmorpholine to the reaction mixture. More preferably, N-methylmorpholine is added in one shot via syringe and the reaction mixture is cooled to about -5°C to 5°C. More preferably the reaction mixture is cooled to about 0°C. A solution of the compound of formula Lv-X is then added to the reaction mixture. More preferably the solution of the compound of formula Lv-X is a solution of the compound of formula Lv-X in DMF. Still more preferably the compound of formula Lv-X is CDMT. The solution of the compound of formula Lv-X is added to the reaction mixture by any suitable method to maintain the reaction mixture at a constant temperature. For example, a solution of a compound of formula Lv-X can be added dropwise to the reaction mixture using a syringe. After the addition of the compound of formula Lv-X is complete, the reaction mixture is allowed to warm to about room temperature. The progress of the reaction is monitored by thin layer chromatography (hereinafter referred to as "TLC) to monitor the disappearance of the compound of formula II. When the reaction is at least substantially complete, the compound of formula I can be precipitated from solution by slowly adding water to the reaction mixture to form a slurry Precipitation. The compound of formula I can then be isolated from the slurry by any suitable method known to those skilled in the art. For example, the compound of formula I can be isolated from the slurry by filtration. Any suitable method known to those skilled in the art can be used Purification methods are used to purify the compound of formula I. More preferably, the compound of formula I is purified by recrystallization.

本发明还公开了合成式III化合物及其酸加成盐的两种方法。在这两种方法中，第二种方法是目前优选的方法，因为该方法在工业规模上可以产生更大的成本有效性。The invention also discloses two methods for synthesizing the compound of formula III and its acid addition salt. Of these two methods, the second method is currently the preferred method as it can yield greater cost-effectiveness on an industrial scale.

在这两种方法中，第一种方法是从式V化合物制备式IV化合物及其酸加成盐。Of these two methods, the first method is the preparation of compounds of formula IV and acid addition salts thereof from compounds of formula V.

本领域技术人员可以看出，式IV化合物是式III化合物的亚属。It will be apparent to those skilled in the art that compounds of formula IV are a subgenus of compounds of formula III.

式V化合物可以从市售的N-Boc L谷氨酸γ-苄酯制备。可以采用任何适宜的方法来制备式V化合物。优选采用美国专利申请号08/991,739中公开的方法。美国专利申请号08/991,739全文引入本文作为参考。The compound of formula V can be prepared from commercially available N-Boc L glutamic acid γ-benzyl ester. Compounds of formula V may be prepared by any suitable method. Preferably, the method disclosed in US Patent Application No. 08/991,739 is used. US Patent Application No. 08/991,739 is incorporated herein by reference in its entirety.

本发明的方法包括如下步骤：Method of the present invention comprises the steps:

(a)将式V化合物用双(三甲基硅烷基)氨基化物和溴乙腈进行氰基甲基化生成式VI化合物；(a) carrying out cyanomethylation of the compound of formula V with bis(trimethylsilyl)amide and bromoacetonitrile to generate the compound of formula VI;

Figure C0081187700222
Figure C0081187700222

(b)将式VI化合物依次进行还原、环化和脱保护生成式VII化合物；然后(b) reducing, cyclizing and deprotecting the compound of formula VI successively to generate the compound of formula VII; then

Figure C0081187700231
Figure C0081187700231

(c)通过将化合物与SO3-吡啶复合物反应将式VII化合物氧化和烯化生成反应混合物，然后将反应混合物与式VIII的正膦反应。(c) Oxidation and olefination of the compound of formula VII by reacting the compound with SO 3 -pyridine complex to form a reaction mixture, and then reacting the reaction mixture with a phosphorane of formula VIII.

Figure C0081187700232
Figure C0081187700232

如上所述，根据本发明，从N-Boc谷氨酸γ-苄酯制备式V化合物可以通过本领域已知的任何适宜的方法来进行。As mentioned above, according to the present invention, the preparation of the compound of formula V from γ-benzyl N-Boc glutamate can be carried out by any suitable method known in the art.

此外，式V化合物的氰基甲基化可以用任何适宜的方法、试剂和反应条件来完成。优选以下所公开的方法并且使用全部或某些试剂或反应条件。因此，优选将式V化合物在氮气氛下用至少5个小时的时间于-70℃下滴加到搅拌中的NaHMDS的THF溶液中，然后与溴乙腈混合。Furthermore, cyanomethylation of compounds of formula V can be accomplished using any suitable method, reagents and reaction conditions. The methods disclosed below are preferred and employ all or some of the reagents or reaction conditions. Therefore, preferably, the compound of formula V is added dropwise to a stirred THF solution of NaHMDS at -70° C. under a nitrogen atmosphere for at least 5 hours, and then mixed with bromoacetonitrile.

按照该方法将式V化合物用双(三甲基硅烷基)氨基化物和溴乙腈氰基甲基化可以以5∶1的比例生成式VI化合物及其差向异构体。但是，该化合物可以通过任何适宜的方法纯化。优选将式VI化合物通过过滤然后在研磨后进行色谱分离来纯化。在这些优选的条件下，可以以60％的总收率得到非对映体纯度＞99％的式VI化合物。Cyanomethylation of the compound of formula V with bis(trimethylsilyl)amide and bromoacetonitrile according to this procedure yields the compound of formula VI and its epimers in a 5:1 ratio. However, the compound can be purified by any suitable method. The compound of formula VI is preferably purified by filtration followed by chromatography after trituration. Under these preferred conditions, the compound of formula VI can be obtained in an overall yield of 60% with diastereomeric purity >99%.

将式VI化合物转化成式VII化合物的步骤(b)的三步还原、环化和脱保护反应可以用任何适宜的试剂和反应条件来完成。优选采用以下公开的方法，使用全部或某些试剂和反应条件。因此，优选通过向式VI化合物的四氢呋喃/甲醇溶液中加入氯化钴(II)六水合物将式VI化合物还原。将所得溶液冷却至0℃，然后在至少7小时的时间内分批加入硼氢化钠。然后向粗产物的甲醇溶液中加入对甲苯磺酸一水合物并在室温下反应至少约18小时。除去溶剂后，将残余物溶于乙酸乙酯并洗涤。可以使用任何适宜的洗涤试剂。优选的洗涤试剂是饱和碳酸氢钠。然后向粗产物中加入甲醇的水溶液。更优选使用2.5％的甲醇溶液。可以通过任何适宜的方法从溶液中分离出粗产物。例如，可以通过过滤并将滤液在旋转蒸发仪上浓缩分离出粗产物。然后将产物溶于乙酸乙酯，干燥，过滤然后浓缩得到式VII化合物的粗品。更优选将产物用硫酸镁干燥。粗品式VII化合物可以通过任何适宜的纯化方法进一步纯化。更优选将式VII的粗品化合物通过用1∶1乙酸乙酯和己烷研磨进行纯化。The three-step reduction, cyclization and deprotection reactions of the step (b) of converting the compound of formula VI to the compound of formula VII can be accomplished with any suitable reagents and reaction conditions. Preferably, the methods disclosed below are employed, using all or some of the reagents and reaction conditions. Therefore, it is preferred to reduce the compound of formula VI by adding cobalt(II) chloride hexahydrate to a solution of the compound of formula VI in tetrahydrofuran/methanol. The resulting solution was cooled to 0°C and sodium borohydride was added portionwise over a period of at least 7 hours. To the methanol solution of the crude product was then added p-toluenesulfonic acid monohydrate and reacted at room temperature for at least about 18 hours. After removing the solvent, the residue was dissolved in ethyl acetate and washed. Any suitable washing reagent can be used. A preferred washing agent is saturated sodium bicarbonate. An aqueous solution of methanol was then added to the crude product. More preferably a 2.5% solution in methanol is used. The crude product can be separated from solution by any suitable means. For example, the crude product can be isolated by filtration and concentration of the filtrate on a rotary evaporator. The product is then dissolved in ethyl acetate, dried, filtered and concentrated to give the crude compound of formula VII. More preferably the product is dried over magnesium sulfate. The crude compound of formula VII can be further purified by any suitable purification method. More preferably, the crude compound of formula VII is purified by trituration with 1:1 ethyl acetate and hexanes.

如果采用以上公开的优选的三步还原、环化和脱保护反应，可以以至少约95％的总收率得到纯净的式VII化合物。If the preferred three-step reduction, cyclization and deprotection reactions disclosed above are employed, the pure compound of formula VII can be obtained in an overall yield of at least about 95%.

在采用SO3-吡啶复合物和式VIII的正膦将式VIII化合物氧化和烯化生成式IV的反应中，可以采用任何适宜的方法、试剂和反应条件。优选采用以下公开的方法和全部或某些试剂和反应条件。因此，优选将三乙胺加入到式VIII化合物和甲基亚砜的溶液中。将所得溶液冷却至约5℃，然后加入三氧化硫-吡啶复合物。将反应液于大约5℃下搅拌至少约15分钟。移走用于将溶液冷却至约5℃的冷却浴后，将反应液继续搅拌至少约1小时。然后加入(乙氧羰基亚甲基三苯基)-正膦并将反应混合物在室温下搅拌至少约3小时。然后，用乙酸乙酯终止反应并萃取。更优选通过加入饱和盐水终止反应。然后将合并的有机相洗涤，干燥，过滤然后浓缩得到粗品式IV化合物。更优选将合并的有机相用饱和盐水洗涤然后用硫酸镁干燥。In the reaction of oxidizing and olefinizing the compound of formula VIII to formula IV by using SO 3 -pyridine complex and the phosphorane of formula VIII, any suitable method, reagent and reaction condition can be used. Preferably, the methods and all or some of the reagents and reaction conditions disclosed below are employed. Therefore, triethylamine is preferably added to a solution of the compound of formula VIII and methyl sulfoxide. The resulting solution was cooled to about 5°C and the sulfur trioxide-pyridine complex was added. The reaction was stirred at about 5°C for at least about 15 minutes. After removing the cooling bath used to cool the solution to about 5°C, the reaction was stirred for at least about 1 hour. (Ethoxycarbonylmethylenetriphenyl)-phosphorane was then added and the reaction mixture was stirred at room temperature for at least about 3 hours. Then, the reaction was quenched with ethyl acetate and extracted. More preferably, the reaction is terminated by adding saturated brine. The combined organic phases are then washed, dried, filtered and concentrated to give the crude compound of formula IV. More preferably, the combined organic phases are washed with saturated brine and then dried over magnesium sulfate.

可将式IV化合物通过任何适宜的方法进行纯化。优选采用色谱纯化和研磨的方法。如果采用优选的纯化方法，可以达到55％至60％的收率。Compounds of formula IV may be purified by any suitable method. Chromatographic purification and trituration are preferred. If the preferred purification method is used, a yield of 55% to 60% can be achieved.

本发明所公开的制备式IV化合物及其酸加成盐的第二种方法包括如下步骤：The second method for preparing the compound of formula IV and its acid addition salt disclosed by the present invention comprises the following steps:

(a)将式IX化合物用溴乙腈进行双阴离子烷基化反应生成式X化合物；(a) the compound of formula IX is subjected to double anion alkylation reaction with bromoacetonitrile to generate the compound of formula X;

Figure C0081187700251
Figure C0081187700251

(b)将式X化合物氢化生成式XI的胺；(b) hydrogenating the compound of formula X to generate an amine of formula XI;

Figure C0081187700252
Figure C0081187700252

(c)将式XI的胺与Et3N反应生成式XII的内酰胺酯；(c) reacting an amine of formula XI with Et 3 N to generate a lactam ester of formula XII;

Figure C0081187700253
Figure C0081187700253

(d)将式XII的内酰胺酯通过适宜的还原方法还原生成式XIII的化合物；(d) reducing the lactam ester of formula XII to generate a compound of formula XIII by a suitable reduction method;

(e)通过将式XIII化合物与式XV化合物反应将其氧化和烯化，生成式XIV化合物；然后(e) oxidizing and olefinating a compound of formula XIII by reacting it with a compound of formula XV to produce a compound of formula XIV; then

Figure C0081187700262
Figure C0081187700262

(f)将式XIV化合物转化成式IV化合物。(f) converting a compound of formula XIV to a compound of formula IV.

此外，本领域技术人员可以理解，以上公开的方法可用于制备式XIV化合物。具体地讲，步骤(a)-(e)公开了制备式XIV化合物的方法。In addition, those skilled in the art will understand that the methods disclosed above can be used to prepare compounds of formula XIV. In particular, steps (a)-(e) disclose processes for the preparation of compounds of formula XIV.

式IX化合物可以通过本领域已知的任何适宜方法进行制备。例如，N-Boc L-(+)-谷氨酸二甲酯可以从市售的L-谷氨酸二甲酯盐酸盐或市售的L-谷氨酸5-甲酯按照文献中的方法制备。参见，例如Shimamoto等，J.Org.Chem.1991，56，4167和Duralski等，Tetrahedron Lett.1998，30，3585。这些参考文献全文引入本文作为参考。Compounds of formula IX may be prepared by any suitable method known in the art. For example, N-Boc L-(+)-dimethyl glutamate can be obtained from commercially available dimethyl L-glutamate hydrochloride or commercially available 5-methyl L-glutamate according to literature Method preparation. See, eg, Shimamoto et al., J. Org. Chem. 1991, 56, 4167 and Duralski et al., Tetrahedron Lett. 1998, 30, 3585. These references are incorporated herein by reference in their entirety.

优选地，双阴离子烷基化反应采用以下公开的方法和全部或某些试剂和反应条件进行制备。因此，优选将式IX化合物首先溶于THF形成溶液，然后将其在氩气氛下于-78℃滴加到搅拌中的LiHMDS的溶液中。将所得混合物于大约-78℃下搅拌2小时，然后在1小时内滴加新蒸馏的溴乙腈。将反应混合物于大约-78℃下继续搅拌2小时。然后终止反应。更优选通过加入0.5M HCl和H2O终止反应。分出所形成的水层并用甲基叔丁基醚进一步萃取。将合并的有机萃取液洗涤，干燥然后过滤。更优选将有机萃取液用饱和碳酸氢钠和盐水洗涤然后用硫酸镁干燥。减压蒸除溶剂。Preferably, the dianion alkylation reaction is prepared using the methods disclosed below and all or some of the reagents and reaction conditions. Therefore, it is preferred to dissolve the compound of formula IX in THF first to form a solution, and then add it dropwise to the stirring LiHMDS solution at -78°C under an argon atmosphere. The resulting mixture was stirred at about -78°C for 2 hours, then freshly distilled bromoacetonitrile was added dropwise over 1 hour. The reaction mixture was stirred for an additional 2 hours at approximately -78°C. The reaction was then terminated. More preferably the reaction is terminated by adding 0.5M HCl and H2O . The resulting aqueous layer was separated and further extracted with methyl tert-butyl ether. The combined organic extracts were washed, dried and filtered. More preferably the organic extract is washed with saturated sodium bicarbonate and brine then dried over magnesium sulfate. The solvent was evaporated under reduced pressure.

式IX化合物可以通过本领域已知的任何适宜方法氢化成式XI的胺。优选在5％Pd/C的存在下进行氢化反应。更优选按照以下公开的使用某些或全部试剂和反应条件的方法进行氢化反应。根据该优选的氢化方法，将式IX化合物溶于HOAc并和5％Pd/C一起在50psi的氢气压力下振摇3天。然后将混合物用硅藻土过滤。然后可以将滤液减压蒸发并将残余物反复从甲基叔丁基醚中蒸发。Compounds of formula IX can be hydrogenated to amines of formula XI by any suitable method known in the art. The hydrogenation reaction is preferably carried out in the presence of 5% Pd/C. More preferably, the hydrogenation reaction is carried out as disclosed below using some or all of the reagents and reaction conditions. According to the preferred hydrogenation procedure, the compound of formula IX was dissolved in HOAc and shaken with 5% Pd/C under 50 psi hydrogen pressure for 3 days. The mixture was then filtered through celite. The filtrate can then be evaporated under reduced pressure and the residue evaporated repeatedly from methyl tert-butyl ether.

式XI的胺与Et3N的反应可以用任何适宜的条件来完成。优选采用以下公开的方法和全部或某些试剂和反应条件。因此，优选将式XI的胺溶于1∶1 MeOH/THF混合物，然后向溶液中加入Et3N。将所得混合物于大约45℃下搅拌约10小时或者直至原料消失。可以通过1HNMR监测原料的存在。蒸除溶剂后，加入甲基叔丁基醚。然后滤出沉淀。向用水稀释的滤液中加入0.5M HCl。分相后，将水相用乙酸乙酯萃取。将合并的有机相洗涤，干燥，过滤然后浓缩。更优选将合并的有机相用盐水洗涤然后用硫酸镁干燥。可将有机相在旋转蒸发仪上浓缩。经快速色谱分离得到式XII的内酰胺酯。The reaction of amines of formula XI with Et3N can be accomplished using any suitable conditions. Preferably, the methods and all or some of the reagents and reaction conditions disclosed below are employed. Thus, it is preferred to dissolve the amine of formula XI in a 1:1 MeOH/THF mixture and then add Et3N to the solution. The resulting mixture was stirred at about 45°C for about 10 hours or until the starting material disappeared. The presence of starting material can be monitored by1HNMR . After distilling off the solvent, methyl tert-butyl ether was added. The precipitate was then filtered off. To the filtrate diluted with water was added 0.5M HCl. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed, dried, filtered and concentrated. More preferably the combined organic phases are washed with brine and dried over magnesium sulfate. The organic phase can be concentrated on a rotary evaporator. The lactam ester of formula XII is obtained by flash chromatography.

可以采用任何适宜的还原方法将式XII的内酰胺酯转化成式XIII化合物。优选使用LiBH4作为还原剂。更优选采用以下公开的方法或该方法的一部分，以及任何或全部试剂和反应条件。因此，更优选地，将LiBH4加入到搅拌中的式XII内酰胺酯的THF溶液中。将LiBH4分数次在氩气氛下于0℃加入。将反应混合物于0℃搅拌10分钟，然后升温至室温并继续搅拌2小时。然后终止反应。更优选通过在冰浴冷却下滴加0.5M HCl来终止反应。将溶液用乙酸乙酯和H2O稀释。相分离后，可将水相用乙酸乙酯萃取。将合并的有机层洗涤，干燥，过滤然后浓缩。更优选将合并的有机相用盐水洗涤并用硫酸镁干燥。可将有机相在旋转蒸发仪上浓缩。快速色谱分离得到式XII化合物。Lactam esters of formula XII may be converted to compounds of formula XIII by any suitable reduction method. Preference is given to using LiBH4 as reducing agent. More preferably, the method or part thereof, and any or all of the reagents and reaction conditions disclosed below are employed. Therefore, more preferably, LiBH4 is added to a stirred THF solution of the lactam ester of formula XII. LiBH4 was added in portions at 0 °C under argon atmosphere. The reaction mixture was stirred at 0 °C for 10 minutes, then allowed to warm to room temperature and stirring was continued for 2 hours. The reaction was then terminated. More preferably the reaction is terminated by dropwise addition of 0.5M HCl under ice-bath cooling. The solution was diluted with ethyl acetate and H2O . After phase separation, the aqueous phase can be extracted with ethyl acetate. The combined organic layers were washed, dried, filtered and concentrated. More preferably the combined organic phases are washed with brine and dried over magnesium sulfate. The organic phase can be concentrated on a rotary evaporator. Flash chromatography provides the compound of formula XII.

可以采用任何适宜的氧化和烯化方法从式XIII化合物制备式XIV化合物。优选采用以下公开的方法或该方法的一部分，以及全部或某些试剂和反应条件。因此，根据本发明，将苯甲酸、(乙氧羰基亚甲基三苯基)正膦和DMSO加入到式XIII化合物的二氯甲烷溶液中。向该溶液中分数次加入Dess-Martin periodinane，然后将反应混合物在室温下搅拌至少5小时直至式XIII化合物基本消失。可以通过1H NMR监测式XIII化合物的存在。加入饱和碳酸氢钠溶液，然后将混合物搅拌30分钟生成沉淀。滤出沉淀，然后将滤液的有机相分离，洗涤然后浓缩得到粗品式XIV化合物。更优选将滤液用盐水洗涤然后在旋转蒸发仪上浓缩。可以采用任何适宜的方法纯化粗品式XIV化合物。更优选将粗品式XIV化合物通过快速色谱纯化然后溶于乙酸乙酯。然后逐渐向搅拌的溶液中加入过量的己烷生成沉淀。滤出沉淀然后干燥得到式XIV化合物。更优选将沉淀在真空烘箱中干燥至少约12小时。Compounds of formula XIV may be prepared from compounds of formula XIII by any suitable oxidation and olefination methods. Preferably, the method or a part thereof, and all or some of the reagents and reaction conditions disclosed below are employed. Thus, according to the invention, benzoic acid, (ethoxycarbonylmethylenetriphenyl)phosphorane and DMSO are added to a solution of the compound of formula XIII in dichloromethane. To this solution was added Dess-Martin periodinane in portions, and the reaction mixture was stirred at room temperature for at least 5 hours until the compound of formula XIII had substantially disappeared. The presence of compounds of formula XIII can be monitored by1H NMR. Saturated sodium bicarbonate solution was added, and the mixture was stirred for 30 minutes to form a precipitate. The precipitate is filtered off and the organic phase of the filtrate is separated, washed and concentrated to give the crude compound of formula XIV. More preferably the filtrate is washed with brine and then concentrated on a rotary evaporator. The crude compound of formula XIV may be purified by any suitable method. More preferably the crude compound of formula XIV is purified by flash chromatography and then dissolved in ethyl acetate. Excess hexane was then gradually added to the stirred solution to form a precipitate. The precipitate is filtered off and dried to give the compound of formula XIV. More preferably, the precipitate is dried in a vacuum oven for at least about 12 hours.

提供以下实施例仅仅是为了说明本发明，不应将其看作是对所附权利要求所定义的本发明保护范围的限定。The following examples are provided only to illustrate the present invention and should not be considered as limiting the protection scope of the present invention defined by the appended claims.

实施例：Example:

以下说明了用于制备式I化合物的属于式II和式III范围内的两种化合物之间的酰胺形成反应的实施例。具体地讲，以下反应方案1中所描述的实施例说明了用于制备蛋白酶抑制剂AG7088的1和2之间的反应。An example of an amide forming reaction between two compounds falling within the scope of formula II and formula III for the preparation of a compound of formula I is illustrated below. Specifically, the example described below in Reaction Scheme 1 illustrates the reaction between 1 and 2 for the preparation of the protease inhibitor AG7088.

                     反应方案1Reaction scheme 1

以下实施例公开了包括在式IV化合物范围之内的化合物1的制备。第一个实施例(如以下反应方案2中所示)说明了以上公开的使用氰基甲基化反应的路线。第二个实施例(如以下反应方案3中所示)说明了用于制备同样化合物的第二种更优选的经济上有效的路线。The following examples disclose the preparation of Compound 1 included within the scope of compounds of Formula IV. The first example (shown in Reaction Scheme 2 below) illustrates the route disclosed above using a cyanomethylation reaction. The second example (shown below in Reaction Scheme 3) illustrates a second more preferred economically efficient route for the preparation of the same compound.

                    反应方案2Reaction scheme 2

                    反应方案3Reaction Scheme 3

Figure C0081187700311
Figure C0081187700311

4的制备(反应方案2)Preparation of 4 (Reaction Scheme 2)

将3(1.0kg，2.34mol，1.0当量)的THF(8.0L)溶液用5小时的时间在氮气氛下于-70℃滴加到搅拌中的NaHMDS的THF溶液(1M的THF溶液，2.96L，1.28当量)中。将所得溶液于-70℃搅拌0.5小时，然后用25分钟的时间滴加新蒸馏的溴乙腈(320mL，2.0当量)。将反应混合物于-70℃继续搅拌1小时直至原料3消失。加入饱和氯化铵溶液(7.0L)终止反应，用甲基叔丁基醚(24L)萃取。将有机相用盐水(3×6.0L)洗涤。减压蒸除溶剂得到深棕色的油(1.5kg)。将该粗产物溶于二氯甲烷(8.0L)然后通过硅胶(600g)和活性碳(250g)的床。将滤饼用二氯甲烷(4.0L)漂洗后，将滤液在旋转蒸发仪上浓缩得到浅棕色的油(1.28Kg)，然后将其溶于乙酸乙酯(2.5L)。在剧烈搅拌下向形成的溶液中加入过量的己烷(14.5L)，在30分钟内有白色固体析出。将该浆液用冰水浴冷却并搅拌4.5小时，然后过滤得到浅棕色固体状的4(662g，60％)：1H NMR(CDCl3)δ1.46(s，3H)，1.49(s，9H)，1.59(s，3H)，1.75-1.95(m，1H)，2.15-2.31(m，1H)，2.55-3.15(m，3H)，3.36(d，J＝10.8Hz，1H)，3.62-4.10(m，3H)，4.13-4.32(m，3H)，4.70(m，1H)，7.15-7.42(m，5H)。A THF (8.0L) solution of 3 (1.0kg, 2.34mol, 1.0eq) was added dropwise to a THF solution of NaHMDS (1M THF solution, 2.96L , 1.28 equivalents). The resulting solution was stirred at -70 °C for 0.5 h, then freshly distilled bromoacetonitrile (320 mL, 2.0 equiv) was added dropwise over 25 min. The reaction mixture was stirred at -70°C for an additional 1 hour until starting material 3 disappeared. The reaction was quenched by adding saturated ammonium chloride solution (7.0 L), and extracted with methyl tert-butyl ether (24 L). The organic phase was washed with brine (3 x 6.0 L). The solvent was evaporated under reduced pressure to give a dark brown oil (1.5 kg). The crude product was dissolved in dichloromethane (8.0 L) and passed through a bed of silica gel (600 g) and activated carbon (250 g). After rinsing the filter cake with dichloromethane (4.0 L), the filtrate was concentrated on a rotary evaporator to give a light brown oil (1.28 Kg), which was then dissolved in ethyl acetate (2.5 L). To the resulting solution was added excess hexane (14.5 L) with vigorous stirring, and a white solid precipitated within 30 minutes. The slurry was cooled in an ice-water bath and stirred for 4.5 hours, then filtered to give 4 (662 g, 60%) as a light brown solid: 1 H NMR (CDCl 3 ) δ 1.46 (s, 3H), 1.49 (s, 9H) , 1.59(s, 3H), 1.75-1.95(m, 1H), 2.15-2.31(m, 1H), 2.55-3.15(m, 3H), 3.36(d, J=10.8Hz, 1H), 3.62-4.10 (m, 3H), 4.13-4.32 (m, 3H), 4.70 (m, 1H), 7.15-7.42 (m, 5H).

6的制备(反应方案3)Preparation of 6 (Reaction Scheme 3)

化合物6从L-谷氨酸二甲酯盐酸盐(可从Lancaster购买到)或L-谷氨酸5-甲酯(可从Aldrich购买到)按照文献中的方法制备。Compound 6 was prepared from L-glutamic acid dimethyl ester hydrochloride (available from Lancaster) or L-glutamic acid 5-methyl ester (available from Aldrich) according to literature methods.

7的制备(反应方案3)Preparation of 7 (Reaction Scheme 3)

将N-Boc L-(+)-谷氨酸二甲酯(6，10g，36.3mmol，1当量)的THF(100mL)溶液于-78℃及氩气氛下滴加到搅拌中的LiHMDS溶液(77mL，1M的THF溶液，77.0mmol，2.1当量)中。将形成的深色混合物于-78℃搅拌2小时，然后用1小时的时间滴加新蒸馏的溴乙腈(13.1g，109.0mmol，3当量)。将反应混合物于-78℃继续搅拌2小时，并通过TLC分析证实原料(6)的消失。加入HCl(120mL，0.5M)和H2O(200mL)终止反应。分层，将水层用甲基叔丁基醚萃取(3×200mL)。将合并的有机萃取液用饱和碳酸氢钠(2×250mL)和盐水(2×250mL)洗涤，用硫酸镁干燥然后过滤。减压蒸除溶剂得到棕色的油(15.2g)。经快速硅胶色谱(3∶1己烷/乙酸乙酯)得到无色的油(7，6.67g，10.8mmol，58％)：1H NMR(CDCl3)δ1.46(s，9H)，2.12-2.24(m，2H)，2.77-2.82(m，2H)，2.85-2.91(m，1H)，3.78(s，3H)，3.79(s，3H)，4.32-4.49(m，1H)，5.13(d，J＝6.0Hz，1H)；13CNMR(CDCl3)δ19.4，28.6，34.3，38.6，49.8，53.1，80.9，117.5，155.9，172.4，172.8；HRMS m/z 314.1481(C12H22N2O4的计算值，314.1486)。A THF (100 mL) solution of N-Boc L-(+)-dimethylglutamate (6, 10 g, 36.3 mmol, 1 equiv.) was added dropwise to a stirred LiHMDS solution at -78° C. under an argon atmosphere ( 77mL, 1M solution in THF, 77.0mmol, 2.1 equivalents). The resulting dark mixture was stirred at -78°C for 2 hours, then freshly distilled bromoacetonitrile (13.1 g, 109.0 mmol, 3 equiv) was added dropwise over 1 hour. The reaction mixture was stirred for an additional 2 hours at -78°C, and analysis by TLC confirmed the disappearance of starting material (6). The reaction was quenched by adding HCl (120 mL, 0.5M) and H2O (200 mL). The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (3 x 200 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 250 mL) and brine (2 x 250 mL), dried over magnesium sulfate and filtered. The solvent was distilled off under reduced pressure to give a brown oil (15.2 g). Flash chromatography on silica gel (3:1 hexane/ethyl acetate) gave a colorless oil (7, 6.67 g, 10.8 mmol, 58%): 1 H NMR (CDCl 3 ) δ 1.46 (s, 9H), 2.12 -2.24(m, 2H), 2.77-2.82(m, 2H), 2.85-2.91(m, 1H), 3.78(s, 3H), 3.79(s, 3H), 4.32-4.49(m, 1H), 5.13 (d, J=6.0Hz, 1H); 13 CNMR (CDCl 3 ) δ19.4, 28.6, 34.3, 38.6, 49.8, 53.1, 80.9, 117.5, 155.9, 172.4, 172.8; HRMS m/z 314.1481 (C 12 H Calcd for 22 N2O4 , 314.1486) .

8的制备(反应方案3)Preparation of 8 (Reaction Scheme 3)

将化合物7(4.60g，14.6mmol)溶于HOAc(120mL)并和5％Pd/C(20g)一起在氢气氛(50psi)下振摇3天。将混合物用硅藻土过滤。将滤液减压蒸发并将残余物反复从甲基叔丁基醚中蒸发得到浅粉红色固体(8，8.32g)，将其直接用于随后的步骤。1H NMR(CD3OD)δ1.47(s，9H)，1.85-2.10(m，4H)，2.60-2.62(m，1H)，2.92-2.96(m，2H)，3.74(s，3H)，3.77(s，3H)，4.22-4.26(m，1H)；注：实验证实，不到5％的Pd/C就可以使反应完全，即1g的5％Pd/C就可以有效地将2g的7还原。Compound 7 (4.60 g, 14.6 mmol) was dissolved in HOAc (120 mL) and shaken with 5% Pd/C (20 g) under hydrogen atmosphere (50 psi) for 3 days. The mixture was filtered through celite. The filtrate was evaporated under reduced pressure and the residue was evaporated repeatedly from methyl tert-butyl ether to give a pale pink solid (8, 8.32g) which was used directly in the next step. 1 H NMR (CD 3 OD) δ1.47(s, 9H), 1.85-2.10(m, 4H), 2.60-2.62(m, 1H), 2.92-2.96(m, 2H), 3.74(s, 3H) , 3.77 (s, 3H), 4.22-4.26 (m, 1H); Note: Experiments have confirmed that less than 5% Pd/C can make the reaction complete, that is, 1g of 5% Pd/C can effectively convert 2g 7 restore.

9的制备(反应方案3)Preparation of 9 (Reaction Scheme 3)

将粗品8溶于1∶1 MeOH/THF(40mL)并向溶液中加入Et3N(7mL)。将形成的混合物于45℃搅拌10小时直至通过1H NMR监测到原料消失。在旋转蒸发仪上蒸除溶剂后，加入甲基叔丁基醚(200mL)，有白色固体析出。过滤除去固体沉淀。将滤液用200mL H2O稀释，然后加入0.5M HCl(5mL)。相分离，将水相用乙酸乙酯(4×200mL)萃取。将合并的有机相用盐水(2×700mL)洗涤，用硫酸镁干燥，过滤然后在旋转蒸发仪上浓缩得到浅棕色的油。经快速色谱得到白色固体(9，2.5g，8.74mmol，60％)：1H NMR(CDCl3)δ1.37(s，9H)，1.75-1.80(m，2H)，2.04-2.09(m，1H)，2.39-2.42(m，2H)，3.25-3.29(m，2H)，3.67(s，3H)，4.23-4.26(m，1H)，5.47(d，J＝8.0Hz，1H)，6.29(s，1H)；13C NMR(CDCl3)δ28.5，28.6，34.5，38.5，40.7，52.7，52.8，80.3，156.1，173.3，180.0；HRMS m/z286.1564(C13H22N2O5的计算值，286.1587)。Crude 8 was dissolved in 1:1 MeOH/THF (40 mL) and Et3N (7 mL) was added to the solution. The resulting mixture was stirred at 45°C for 10 hours until disappearance of starting material as monitored by1H NMR. After the solvent was evaporated on a rotary evaporator, methyl tert-butyl ether (200 mL) was added, and a white solid precipitated out. The solid precipitate was removed by filtration. The filtrate was diluted with 200 mL H2O , then 0.5M HCl (5 mL) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (4 x 200 mL). The combined organic phases were washed with brine (2 x 700 mL), dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give a light brown oil. Flash chromatography gave a white solid (9, 2.5 g, 8.74 mmol, 60%): 1 H NMR (CDCl 3 ) δ 1.37 (s, 9H), 1.75-1.80 (m, 2H), 2.04-2.09 (m, 1H), 2.39-2.42(m, 2H), 3.25-3.29(m, 2H), 3.67(s, 3H), 4.23-4.26(m, 1H), 5.47(d, J=8.0Hz, 1H), 6.29 (s, 1H); 13 C NMR (CDCl 3 ) δ28.5, 28.6, 34.5, 38.5, 40.7, 52.7, 52.8, 80.3, 156.1, 173.3, 180.0; HRMS m/z 286.1564 (C 13 H 22 N 2 Calculated for O 5 , 286.1587).

从4制备5(反应方案2)Preparation of 5 from 4 (Scheme 2)

向4(400g，0.85mol，1当量)的四氢呋喃(3.0L)溶液中加入氯化钴(II)六水合物(200g，0.85mol，1当量)的甲醇(3.0L)溶液。将所得溶液冷却至0℃并在7小时的时间内分批加入硼氢化钠(130g，3.51mol，4.4当量)。将反应混合物升温至室温并搅拌20小时，同时用TLC监测原料(4)是否消失。将反应液冷却至0℃并通过加入1.0MHCl(14L)和乙酸乙酯(12L)终止反应。分相并向水相中加入2.0kg氯化钠和4.0L乙酸乙酯。分相，将有机相合并，用盐水(1×3.0L)洗涤，在旋转蒸发仪上浓缩得到粗品物质(440g)，将其直接用于随后的水解反应。向粗品物质(440g，1当量)的甲醇(800mL)溶液中加入对甲苯磺酸一水合物(4.0g，0.015当量)。将反应液室温搅拌过夜。在旋转蒸发仪上蒸除溶剂并将残余物溶于乙酸乙酯(2.0L)，用饱和碳酸氢钠(2×100mL)洗涤。将合并的水相用乙酸乙酯(2×200mL)萃取。合并所有的有机相，在旋转蒸发仪上浓缩得到275g粗产物，向其中加入2.5％甲醇(20mL)的(780mL)溶液并室温搅拌过夜。过滤除去颗粒状的固体(手性辅剂)然后将滤液在旋转蒸发仪上浓缩。将残余物溶于乙酸乙酯(1.5L)，用硫酸镁干燥，过滤然后浓缩得到粘稠的油。将该油通过用1∶1乙酸乙酯(1L)和己烷(1L)研磨得到白色固体状5(104g，从4的总收率为47％)。To a solution of 4 (400 g, 0.85 mol, 1 eq) in tetrahydrofuran (3.0 L) was added a solution of cobalt(II) chloride hexahydrate (200 g, 0.85 mol, 1 eq) in methanol (3.0 L). The resulting solution was cooled to 0°C and sodium borohydride (130 g, 3.51 mol, 4.4 equiv) was added portionwise over a period of 7 hours. The reaction mixture was warmed to room temperature and stirred for 20 hours while monitoring the disappearance of starting material (4) by TLC. The reaction was cooled to 0 °C and quenched by adding 1.0M HCl (14 L) and ethyl acetate (12 L). The phases were separated and 2.0 kg sodium chloride and 4.0 L ethyl acetate were added to the aqueous phase. The phases were separated and the organic phases were combined, washed with brine (1 x 3.0 L), and concentrated on a rotary evaporator to give crude material (440 g), which was used directly in the subsequent hydrolysis reaction. To a solution of the crude material (440 g, 1 equiv) in methanol (800 mL) was added p-toluenesulfonic acid monohydrate (4.0 g, 0.015 equiv). The reaction was stirred overnight at room temperature. The solvent was evaporated on a rotary evaporator and the residue was dissolved in ethyl acetate (2.0 L), washed with saturated sodium bicarbonate (2 x 100 mL). The combined aqueous phases were extracted with ethyl acetate (2 x 200 mL). All organic phases were combined and concentrated on a rotary evaporator to obtain 275 g of crude product, to which a solution of 2.5% methanol (20 mL) (780 mL) was added and stirred overnight at room temperature. Particulate solids (chiral adjuvant) were removed by filtration and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate (1.5 L), dried over magnesium sulfate, filtered and concentrated to a viscous oil. The oil was triturated with 1:1 ethyl acetate (1 L) and hexanes (1 L) to afford 5 (104 g, 47% overall yield from 4) as a white solid.

从9制备5(反应方案3)Preparation of 5 from 9 (Scheme 3)

0℃及氩气氛下，向搅拌中的9(1.75g，6.10mmol)的THF(40mL)溶液中分数次加入LiBH4(270mg，12.2mmol，2当量)。将反应混合物于0℃搅拌10分钟，然后升温至室温并继续搅拌2小时。通过在冰浴冷却下滴加0.5M HCl(24mL)终止反应(注：观察到有气体生成)。将溶液用乙酸乙酯(100mL)和H2O(50mL)稀释。分相，将水层用乙酸乙酯(6×150mL)萃取。将合并的有机相用硫酸镁干燥，过滤然后在旋转蒸发仪上浓缩得到浅棕色的油。经快速色谱得到白色固体(5，1.308g，5.06mmol，83％)：1H NMR(CDCl3)δ1.46(s，9H)，1.61-1.67(m，1H)，1.82-1.91(m，1H)，1.94-2，00(m，1H)，2.43-2.48(m，1H)，2.49-2.55(m，1H)，3.32-3.34(m，3H)，3.58-3.66(m，2H)，3.68-3.79(m，2H)，5.47(d，J＝7.0Hz，1H)，6.24(s，1H)；13C NMR(CDCl3)δ28.8，32.9，38.4，40.8，51.5，66.3，79.8，157.0，181.3；HRMS m/z 258.1652(C13H22N2O5的计算值，258.1650)。To a stirred solution of 9 (1.75 g, 6.10 mmol) in THF (40 mL) was added LiBH4 (270 mg, 12.2 mmol, 2 eq) in portions at 0 °C under argon atmosphere. The reaction mixture was stirred at 0 °C for 10 minutes, then allowed to warm to room temperature and stirring was continued for 2 hours. The reaction was quenched by the dropwise addition of 0.5M HCl (24 mL) under ice-bath cooling (note: gas evolution was observed). The solution was diluted with ethyl acetate (100 mL) and H2O (50 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (6 x 150 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give a light brown oil. Flash chromatography gave a white solid (5, 1.308 g, 5.06 mmol, 83%): 1 H NMR (CDCl 3 ) δ 1.46 (s, 9H), 1.61-1.67 (m, 1H), 1.82-1.91 (m, 1H), 1.94-2, 00(m, 1H), 2.43-2.48(m, 1H), 2.49-2.55(m, 1H), 3.32-3.34(m, 3H), 3.58-3.66(m, 2H), 3.68-3.79 (m, 2H), 5.47 (d, J=7.0Hz, 1H), 6.24 (s, 1H); 13 C NMR (CDCl 3 ) δ28.8, 32.9, 38.4, 40.8, 51.5, 66.3, 79.8 , 157.0 , 181.3; HRMS m/z 258.1652 (calcd for C13H22N2O5 , 258.1650 ) .

从5制备1Prepare 1 from 5

方法A(反应方案2)Method A (Reaction Scheme 2)

向5(50.0g，0.184mol，1当量)的甲基亚砜(500mL)溶液中加入三乙胺(116mL)。将所得溶液用冰浴冷却至5℃，然后加入三氧化硫-吡啶复合物(132g)。将反应液在该温度下搅拌15分钟。移走冷却浴，将反应液继续搅拌1小时。一次性加入(乙氧羰基亚甲基三苯基)-正膦(112g)并将反应液室温搅拌3小时。通过加入饱和盐水(3.0L)终止反应，用乙酸乙酯(3×1.5L)萃取。将合并的有机相用饱和盐水(3×1.5L)洗涤，用硫酸镁干燥，过滤然后浓缩得到深红色的油。将该油通过色谱法纯化，然后用乙酸乙酯(60mL)和过量的己烷(240mL)研磨。得到白色固体状的1(36.0g，60％)。To a solution of 5 (50.0 g, 0.184 mol, 1 eq) in methyl sulfoxide (500 mL) was added triethylamine (116 mL). The resulting solution was cooled to 5°C with an ice bath, and then sulfur trioxide-pyridine complex (132 g) was added. The reaction was stirred at this temperature for 15 minutes. The cooling bath was removed and the reaction was stirred for an additional 1 hour. (Ethoxycarbonylmethylenetriphenyl)-phosphorane (112 g) was added in one portion and the reaction was stirred at room temperature for 3 hours. The reaction was quenched by adding saturated brine (3.0 L), extracted with ethyl acetate (3 x 1.5 L). The combined organic phases were washed with saturated brine (3 x 1.5 L), dried over magnesium sulfate, filtered and concentrated to give a dark red oil. The oil was purified by chromatography, then triturated with ethyl acetate (60 mL) and excess hexane (240 mL). 1 was obtained as a white solid (36.0 g, 60%).

方法B(反应方案3)Method B (Reaction Scheme 3)

向5(1.0g，3.87mmol，1当量)的二氯甲烷(80mL)溶液中加入苯甲酸(1.89g，15.5mmol，4当量)、(乙氧羰基亚甲基三苯基)正膦(5.39g，15.5mmol，4当量)和DMSO(4.8mL)。向该溶液中分数次加入Dess-Martin periodinane(4.1g，9.17mmol，2.5当量)，然后将反应混合物室温搅拌5小时直至原料5消失。加入饱和碳酸氢钠，将该混合物搅拌30分钟。有白色固体析出，滤出该固体。将滤液的有机相分离，用盐水(250mL)洗涤然后在旋转蒸发仪上浓缩得棕色的油，将其通过快速色谱纯化得到浅棕色的泡沫(0.956g)。将该泡沫溶于乙酸乙酯(3mL)。向搅拌的溶液中逐渐加入过量的己烷(12mL)，有白色固体析出。将该固体过滤然后在真空烘箱中干燥过夜得到1(0.69g，2.11mmol，55％)。手性HPLC：97％纯，98％de和100％E异构体；1H NMR(CDCl3)δ1.22(t，J＝7.2Hz，3H)，1.38(s，9H)，1.53-1.58(m，1H)，1.66-1.84(m，1H)，1.85-2.00(m，1H)，2.30-2.50(m，2H)，3.20-3.37(m，2H)，4.13(q，J＝7.2Hz，2H)，4.20-4.35(m，1H)，5.13(d，J＝7.5Hz，1H)，5.68(s，1H)，5.90(dd，J＝1.8，15.6Hz，1H)，6.80(dd，J＝5.1，15.6Hz，1H)；HRMS m/z 326.1846(C16H26N2O6的计算值，326.1840)。To a solution of 5 (1.0 g, 3.87 mmol, 1 eq) in dichloromethane (80 mL) was added benzoic acid (1.89 g, 15.5 mmol, 4 eq), (ethoxycarbonylmethylenetriphenyl)phosphorane (5.39 g, 15.5 mmol, 4 equiv) and DMSO (4.8 mL). To this solution was added Dess-Martin periodinane (4.1 g, 9.17 mmol, 2.5 equiv) in portions, and the reaction mixture was stirred at room temperature for 5 hours until starting material 5 disappeared. Saturated sodium bicarbonate was added and the mixture was stirred for 30 minutes. A white solid precipitated which was filtered off. The organic phase of the filtrate was separated, washed with brine (250 mL) and concentrated on a rotary evaporator to a brown oil which was purified by flash chromatography to give a light brown foam (0.956 g). The foam was dissolved in ethyl acetate (3 mL). To the stirred solution was gradually added excess hexane (12 mL), and a white solid precipitated out. The solid was filtered and dried in a vacuum oven overnight to afford 1 (0.69 g, 2.11 mmol, 55%). Chiral HPLC: 97% pure, 98% de and 100% E isomers; 1 H NMR (CDCl 3 ) δ 1.22 (t, J=7.2Hz, 3H), 1.38 (s, 9H), 1.53-1.58 (m, 1H), 1.66-1.84(m, 1H), 1.85-2.00(m, 1H), 2.30-2.50(m, 2H), 3.20-3.37(m, 2H), 4.13(q, J=7.2Hz , 2H), 4.20-4.35(m, 1H), 5.13(d, J=7.5Hz, 1H), 5.68(s, 1H), 5.90(dd, J=1.8, 15.6Hz, 1H), 6.80(dd, J = 5.1 , 15.6 Hz, 1H); HRMS m/z 326.1846 (calcd for C16H26N2O6 , 326.1840 ) .

从1和2制备AG7088(反应方案1)。AG7088 was prepared from 1 and 2 (Scheme 1).

将751mg化合物1在单颈圆底烧瓶中溶于DCM(10mL/g的1)然后用隔膜覆盖。然后将烧瓶用氮气净化，然后在将溶液搅拌的同时通过注射器加入1.4mL TFA。用5％MeOH的DCM溶液通过TLC监测反应的进程，直至约4小时后原料消失。在压力＜50mTorr@45℃下真空蒸除溶剂和过量的TFA。将产物化合物1A立即用于下述步骤。751 mg of compound 1 was dissolved in DCM (10 mL/g of 1) in a single neck round bottom flask and covered with a septum. The flask was then purged with nitrogen, and then 1.4 mL of TFA was added via syringe while the solution was stirred. The progress of the reaction was monitored by TLC with 5% MeOH in DCM until the starting material disappeared after about 4 hours. Solvent and excess TFA were evaporated under vacuum at pressure <50 mTorr @ 45°C. The product Compound 1A was used immediately in the following steps.

将化合物1A和2在覆盖有隔膜并且装有温度探针的单颈圆底烧瓶中溶于DMF(7mL/g的2)。将烧瓶用氮气净化。将所得溶液分成两份。通过注射器向第一份中加入1.6mL N-甲基吗啉然后冷却至0℃±5℃。在第二份溶液中溶解281mg CDMT。然后将该CDMT溶液通过注射器滴加到第一份溶液中，保持反应温度为0℃±5℃。然后将所得反应混合物升温至室温。通过TLC(7∶3∶1己烷∶EtOAc∶IPA)监测反应约1小时直至化合物2消失。反应结束后，通过向反应混合物中缓慢加入水使产物AG7088从溶液中析出。将形成的浆液过滤得到＞85％的化合物AG7088的白色颗粒状结晶，纯度＞97％。然后可将该产物通过溶于热的MeOH∶EtOAc 1∶1中然后缓慢加入己烷(2体积)进行重结晶。Compounds 1A and 2 were dissolved in DMF (7 mL/g of 2) in a single-neck round bottom flask covered with a septum and equipped with a temperature probe. The flask was purged with nitrogen. The resulting solution was divided into two portions. Add 1.6 mL of N-methylmorpholine to the first portion via syringe and cool to 0°C ± 5°C. Dissolve 281 mg CDMT in the second solution. Then the CDMT solution was added dropwise to the first solution through a syringe, keeping the reaction temperature at 0°C±5°C. The resulting reaction mixture was then allowed to warm to room temperature. The reaction was monitored by TLC (7:3:1 hexanes:EtOAc:IPA) for about 1 hour until compound 2 disappeared. After the reaction was complete, the product AG7088 was precipitated out of solution by slowly adding water to the reaction mixture. The resulting slurry was filtered to yield >85% white granular crystals of compound AG7088 with a purity of >97%. The product can then be recrystallized by dissolving in hot MeOH:EtOAc 1:1 followed by slow addition of hexanes (2 vol).

应当理解，以上描述是用于示范和解释的，其目的是为了说明本发明及其优选的实施方案。通过常规的实验，本领域技术人员可确认出可以进行的不背离本发明精神的明显的修饰和改变。因此，本发明不是由以上说明书而是由下列权利要求所定义的。It should be understood that the foregoing description is exemplary and explanatory, and is intended to illustrate the invention and its preferred embodiments. Through routine experimentation, those skilled in the art can ascertain that obvious modifications and changes can be made without departing from the spirit of the invention. Accordingly, the invention is defined not by the foregoing description but by the following claims.

Claims (4)

1.合成式IA′化合物或其酸加成盐的方法：1. the method for synthetic formula IA ' compound or its acid addition salt: 包括如下步骤：Including the following steps: 步骤A：制备式IV′化合物：Step A: Preparation of compound of formula IV': 包括：include: (a)用双(三甲基硅烷基)氨基钠和溴乙腈进行式V′化合物的氰基甲基化反应生成式VI′化合物；(a) carry out the cyanomethylation reaction of formula V' compound with two (trimethylsilyl) sodium amide and bromoacetonitrile to generate formula VI' compound; (b)将式VI′化合物依次进行还原、环化和脱保护生成式VII′化合物；然后(b) reducing, cyclizing and deprotecting the compound of formula VI' successively to generate the compound of formula VII'; then
Figure C008118770003C1
Figure C008118770003C1
 (c)通过将化合物与SO3-吡啶复合物反应，然后将形成的反应混合物与Ph3P＝CHCO2Et反应将式VII′化合物氧化和烯化；(c) oxidation and olefination of the compound of formula VII' by reacting the compound with a SO 3 -pyridine complex and then reacting the resulting reaction mixture with Ph 3 P=CHCO 2 Et; 步骤B：将式IV′化合物脱保护生成式IVA′化合物：Step B: deprotecting the compound of formula IV' to generate the compound of formula IVA': 和 and 步骤C：将式II′化合物和式IVA′化合物进行形成酰胺的反应Step C: reacting a compound of formula II' and a compound of formula IVA' to form an amide 2.合成抗细小核糖核酸病毒的化合物的方法，包括：2. A method for synthesizing an anti-picornavirus compound, comprising: (a)将式IX′化合物用溴乙腈进行双阴离子烷基化反应制备式X′化合物；(a) carrying out the double anion alkylation reaction of the compound of formula IX' with bromoacetonitrile to prepare the compound of formula X';
Figure C008118770004C1
Figure C008118770004C1
 (b)将式X′化合物氢化生成式XI′的胺；(b) hydrogenating the compound of formula X' to generate the amine of formula XI'; (c)将式XI′化合物与Et3N反应生成式XII′的内酰胺酯；(c) reacting the compound of formula XI' with Et 3 N to generate the lactam ester of formula XII';
Figure C008118770004C3
Figure C008118770004C3
 (d)将式XII′的内酰胺酯还原生成式XIII′化合物：(d) reduction of lactam esters of formula XII' to generate compounds of formula XIII':
Figure C008118770004C4
和
Figure C008118770004C4
and (e)将式XIII′化合物通过与Ph3P＝CHCO2Et反应进行氧化，然后烯化生成式XIV′化合物。(e) Oxidation of the compound of formula XIII' by reaction with Ph 3 P=CHCO 2 Et followed by olefination to give the compound of formula XIV'.
Figure C008118770005C1
Figure C008118770005C1
 3.权利要求2所述的合成抗细小核糖核酸病毒的化合物的方法，该方法还包括：3. the method for the compound of synthetic anti-picornavirus described in claim 2, the method also comprises: 将式XIV′化合物转化成式IV′化合物。Compounds of formula XIV' are converted to compounds of formula IV'.
Figure C008118770005C2
Figure C008118770005C2
 4.权利要求3所述的合成抗细小核糖核酸病毒的化合物的方法，该方法还包括：4. the method for the compound of synthetic anti-picornavirus described in claim 3, this method also comprises: 步骤A：将式IV′化合物脱保护生成式IVA′化合物：Step A: deprotecting the compound of formula IV' to generate the compound of formula IVA':
Figure C008118770005C3
Figure C008118770005C3
 和and 步骤C：将式II′化合物和式IVA′化合物进行形成酰胺的反应。Step C: A compound of formula II' and a compound of formula IVA' are subjected to an amide forming reaction.
Figure C008118770005C4
Figure C008118770005C4
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