WO2019011287A1 - 一种咪唑并异吲哚类衍生物的制备方法 - Google Patents

一种咪唑并异吲哚类衍生物的制备方法 Download PDF

Info

Publication number
WO2019011287A1
WO2019011287A1 PCT/CN2018/095371 CN2018095371W WO2019011287A1 WO 2019011287 A1 WO2019011287 A1 WO 2019011287A1 CN 2018095371 W CN2018095371 W CN 2018095371W WO 2019011287 A1 WO2019011287 A1 WO 2019011287A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
formula
preparation
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/095371
Other languages
English (en)
French (fr)
Inventor
邵启云
徐超
张浩宇
尤凌峰
冯君
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hengrui Medicine Co Ltd, Shanghai Hengrui Pharmaceutical Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Priority to CN201880004456.1A priority Critical patent/CN109983020A/zh
Publication of WO2019011287A1 publication Critical patent/WO2019011287A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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 belongs to the field of medicine and relates to a preparation method of an imidazoisoindole derivative.
  • Indoleamine-pyrrole-2,3-dioxygenase is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds.
  • the alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket.
  • IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan.
  • Fast enzyme which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein.
  • IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack.
  • Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.
  • IDO inhibitors have good application prospects in the pharmaceutical industry as drugs.
  • WO2016169421 discloses a new class of IDO inhibitors whose compounds have the structure shown in formula (I).
  • This class of compounds shows excellent IDO inhibition.
  • the synthesis method of the compound is mainly prepared by reacting a halophenylpyrazole with piperidinyl imidazolium.
  • the method has the disadvantages of complicated operation, high cost, low yield, and difficulty in amplifying production.
  • the invention provides a process for the preparation of a compound of formula I, which comprises the step of reacting a compound of formula II with a compound of formula III.
  • R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group. , aryl and heteroaryl;
  • R 2 is selected from -CH 2 -CH 2 -OR 3 , preferably hydrogen;
  • R 3 is selected from hydrogen or a hydroxy protecting group
  • One of X and Y is a leaving group, and the other is selected from -BF 3 K, -BR a R b , -Sn(R c ) m or -Zn-X',
  • the leaving group is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate, - SR, -SO 2 R;
  • R a and R b are independently selected from -OH, alkyl, alkoxy or optionally substituted C 1 -C 6 mono and diol, or R a and R b are taken together to form a ring, and R c is independently selected from a C 1 -C 6 alkyl group, X' is selected from -Cl, -Br, -I, and R is a C 1 -C 6 alkyl group;
  • n is an integer of 0, 1, 2, 3 or 4
  • m is an integer of 0, 1, 2, 3 or 4.
  • the leaving group is preferably Cl, Br, I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy;
  • X is a leaving group; in certain embodiments, Y is a leaving group.
  • X is a leaving group and Y is selected from the group consisting of BF 3 K and BR a R b ; in certain embodiments, Y is a leaving group and X is selected from the group consisting of BF 3 K and BR a R b .
  • the BR a R b wherein R a and R b are independently selected from -OH, alkyl, alkoxy, or BR a R b is a pinacol boronate frequency, i.e.,
  • the compound of Formula II and the compound of Formula III are preferably subjected to a coupling reaction in the presence of a catalyst, which may include PdL p , PdCl 2 L p , Pd(OAc) 2 L p , Pd 2 (dba) 3 L p , Pd(II) L p , Pd(0), NiCl 2 L p , Ni(COD) 2 L p , NiCl 2 (NEt 3 ) 2 or NiCl 2 (bipy)
  • L is a phosphine-containing ligand or an N-heterocyclic carbene ligand
  • the phosphine-containing ligand may be PPh 3 , dppf, PCy 3 , tBu 3 P, P(OMe) 3 , dppe or dppb, p independent An integer selected from 0, 1, 2, 3 or 4.
  • the catalyst may be Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , palladium carbon, Pd(OAc) 2 , PCy 3 /Pd 2 (dba) 3 , NiCl 2 (dppf), NiCl 2 (PPh 3 ) 2 , Ni ⁇ P(OMe) 3 ⁇ 2 Cl 2 , NiCl 2 (PCy 3 ) 2 , NiCl 2 (dppe), NiCl 2 (dppb), NiCl 2 (NEt 3 2 ) NiCl 2 (bipy), NiCl 2 ⁇ 6H 2 O, NiCl 2 , or Ni(COD) 2 , preferably Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Palladium carbon, Pd(OAc) 2 , PCy 3 /Pd 2 (dba) 3 ,
  • the reaction is carried out in the presence of a basic material, wherein the basic substance is preferably Li 2 CO 3 , Na 2 CO 3 , Ba(OH) 2 , K 3 PO 4 , Cs 2 CO 3 , K 2 or more of CO 3 , TlOH, KF, CsF, Bu 4 NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR, wherein R is independently selected from C 1 ⁇ C 6 alkyl.
  • NaOR, KOR or TlOR can be, for example, NaOMe, NaOEt, KOtBu or TlOEt.
  • the alkaline substance is more preferably one or more of Na 2 CO 3 or K 2 CO 3 .
  • the solvent of the reaction may be a conventional solvent, and may be, for example, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide, dimethyl ether, isopropanol.
  • the reaction temperature may be from 60 ° C to 150 ° C.
  • the compound of formula (I) in the present invention contains a chiral carbon atom, and the structure of the aforementioned unspecified configuration represents any possibility including, but not limited to, a racemate or an isomer thereof, when obtained by the reaction.
  • the compound of the formula (I) is in the form of a racemate, the isomer form can be further obtained by means of resolution or the like.
  • the compound of Formula I is preferably selected from the following structure:
  • R 3 has the same definition as described above;
  • the compound of formula II is preferably derived from the following structure:
  • the compound of formula III is preferably derived from the following structure:
  • Y and R 3 are the same as described above.
  • the compound of Formula I is preferably selected from the following structure:
  • Another aspect of the invention provides a process for the preparation of a compound of formula Ia, or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound of formula I according to the process of the invention, said method further Including a step of chiral resolution of the compound of formula I, the chiral resolution method is preferably chemical resolution, membrane resolution, chromatographic resolution or capillary electrophoresis resolution,
  • R 1 , R 2 and n are the same as described above.
  • the compound of Formula Ia can be any organic compound.
  • the compound of Formula Ia can be any organic compound.
  • R 3 when R 3 is hydrogen or a hydroxy protecting group, the reaction can proceed smoothly and to obtain the desired product.
  • R 3 is a hydroxy protecting group, a small amount of dehydroxyethyl impurity is easily formed during the process of removing the protecting group, and the impurity has certain pharmacological toxicity, which will have certain influence on the preparation of the compound Ib; when R 3 is In the case of hydrogen, no generation of dehydroxyethyl impurities was detected during the reaction.
  • the preparation method of the imidazoisoindole derivative of the invention has the advantages of safe and simple operation, safer reaction reagent, milder reaction condition, lower cost, suitable for industrial production, and better reaction effects. It has technology and significant social and economic benefits. Among them, the yield of the coupling reaction of the compound II and the compound III is greatly improved, the purity of the product is higher than that of the prior art, the subsequent reaction is easier, the post-treatment operation is reduced, and the industrial scale-up production is more suitable.
  • Alkyl means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl groups and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, pentyl, heptyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, carbonyl group.
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system, preferably a 6 to 10 membered aryl group, Phenyl and naphthyl are more preferred, and phenyl is most preferred.
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane.
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 6 to 10 yuan.
  • the heteroaryl group is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carbonyl group, a -carboxylic acid or a carboxylic acid ester.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycl
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O)n ( Wherein n is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the cycloalkyl ring contains from 3 to 10 ring atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups.
  • Alkoxy means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, and an alkane group.
  • the hydroxy protecting group is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts).
  • the hydroxy protecting group may be a (C 1-10 alkyl or aryl) 3 silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc.; may be a C 1-10 alkyl or substituted alkyl group, preferably an alkoxy or aryl substituted alkyl group, more preferably a C 1-6 alkoxy substituted C a 1-6 alkyl or phenyl substituted C 1-6 alkyl group, most preferably a C 1-4 alkoxy substituted C 1-4 alkyl group, for example: methyl, tert-butyl,
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • reaction solution was cooled to room temperature, 400 mL of water was added, and the mixture was stirred at room temperature for 30 min, filtered, and the filter cake was rinsed with water, and the filter cake was collected, dissolved with 1.2 L of methanol, concentrated hydrochloric acid (40 mL), stirred for 30 min, and concentrated to remove methanol.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明涉及一种咪唑并异吲哚类衍生物的制备方法。具体而言，本发明涉及一种如式I所示的咪唑并异吲哚类衍生物的制备方法，包括将式II所示化合物与式III所示化合物进行反应的步骤。本发明所述的制备方法的产率较现有技术大大提高，产物纯度也更高，更易于后续反应，减少了后处理操作，更加适合工业放大生产。

Description

一种咪唑并异吲哚类衍生物的制备方法 技术领域
本发明属于医药领域，涉及一种咪唑并异吲哚类衍生物的制备方法。
背景技术
吲哚胺-吡咯-2,3-双加氧酶(Indoleamine-pyrrole-2,3-dioxygenase，IDO)是一种含铁血红素单体蛋白，由403个氨基酸残基组成，包括两个折叠的α-螺旋结构域，大结构域包含催化口袋，底物可在催化口袋内与IDO发生疏水等作用。IDO是催化色氨酸转化为甲酰犬尿氨酸的酶，广泛分布在人和其他哺乳动物(兔、鼠)除肝脏以外的组织中，是肝脏以外唯一可催化色氨酸分解代谢的限速酶，而色氨酸是细胞维持活化和增殖所必需的氨基酸，也是构成蛋白质不可缺少的重要成分。目前大量研究表明IDO在白血病细胞中较高表达，使局部T细胞增殖受抑，抑制T-细胞介导的免疫反应，使T-细胞活化信号转导受阻，从而介导肿瘤细胞逃逸免疫系统的攻击。已经发现大多数人类肿瘤组成性地表达IDO。因此，IDO是一个具潜力的癌症免疫治疗的靶标。
IDO抑制剂作为药物在医药行业具有良好的应用前景。WO2016169421公开了一类新的IDO抑制剂，其化合物结构如式(I)所示，
Figure PCTCN2018095371-appb-000001
该类化合物显示出了优异的IDO抑制作用。目前该类化合物的合成方法主要是由卤代苯基吡唑与哌啶基咪唑并异吲哚反应制得。该方法存在操作复杂，成本高，收率低，不易于放大生产等缺点。
发明内容
为了克服现有技术的不足，本发明的目的在于提供一种新的咪唑并异吲哚类衍生物的制备方法。
本发明一方面提供了如式I所示化合物的制备方法，包括将式II所示化合物与式III所示化合物反应的步骤。
Figure PCTCN2018095371-appb-000002
其中，R 1相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基和杂芳基；
R 2选自-CH 2-CH 2-OR 3，优选氢；
R 3选自氢或羟基保护基；
X和Y中一个为离去基团，另一个选自-BF 3K、-BR aR b、-Sn(R c) m或-Zn-X’，
其中所述离去基团选自-Cl、-Br、-I、-F、三氟甲磺酰氧基、甲磺酰氧基、苯磺酰氧基、乙酰氧基或磷酸酯基、-SR，-SO 2R；
R a和R b独立地选自-OH、烷基、烷氧基或任意取代的C 1～C 6一元和二元醇，或R a和R b在一起成环，R c独立地选自C 1～C 6烷基，X’选自-Cl、-Br、-I，R为C 1～C 6烷基；
n为0、1、2、3或4的整数，m为0、1、2、3或4的整数。
其中所述离去基团优选Cl、Br、I、三氟甲磺酰氧基、甲磺酰氧基或苯磺酰氧基；
在某些实施方式中，X为离去基团；在某些实施方式中，Y为离去基团。
在某些实施方式中，X为离去基团，Y选自BF 3K和BR aR b；在某些实施方式中，Y为离去基团，X选自BF 3K和BR aR b。
在某些实施方式中，所述BR aR b中R a和R b独立地选自-OH、烷基、烷氧基，或BR aR b为频哪醇硼酸酯，即
Figure PCTCN2018095371-appb-000003
在某些实施方式中，所述式II所示化合物与式III所示化合物优选在催化剂的存在下进行偶联反应，所述的催化剂可以包括PdL p、PdCl 2L p、Pd(OAc) 2L p、Pd 2(dba) 3L p、Pd(II)L p、Pd(0)、NiCl 2L p、Ni(COD) 2L p、NiCl 2(NEt 3) 2或NiCl 2(bipy)，其中L为含膦配体或N-杂环卡宾配体，所述含膦配体可以是PPh 3、dppf、PCy 3、tBu 3P、P(OMe) 3、dppe或dppb，p独立的选自0、1、2、3或4的整数。
例如，所述催化剂可以是Pd(PPh 3) 2Cl 2、Pd(PPh 3) 4、Pd(dppf)Cl 2、钯碳、Pd(OAc) 2、PCy 3/Pd 2(dba) 3、NiCl 2(dppf)、NiCl 2(PPh 3) 2、Ni{P(OMe) 3} 2Cl 2、NiCl 2(PCy 3) 2、NiCl 2(dppe)，NiCl 2(dppb)，NiCl 2(NEt 3) 2、NiCl 2(bipy)、NiCl 2·6H 2O、NiCl 2，或Ni(COD) 2，优选Pd(PPh 3) 2Cl 2、Pd(PPh 3) 4、Pd(dppf)Cl 2、钯碳、Pd(OAc) 2、 PCy 3/Pd 2(dba) 3，更优选Pd(PPh 3) 2Cl 2。
在某些实施方式中，所述反应在碱性物质存在下反应，其中碱性物质优选Li 2CO 3、Na 2CO 3,Ba(OH) 2、K 3PO 4、Cs 2CO 3、K 2CO 3、TlOH、KF、CsF、Bu 4NF、LiOH、NaOH、KOH、三乙胺、DIPEA、DABCO、NaOR、KOR、TlOR中的一种或多种，其中R独立地选自C 1～C 6烷基。其中NaOR、KOR或TlOR例如可以是NaOMe，NaOEt，KOtBu或TlOEt。所述碱性物质更优选Na 2CO 3或K 2CO 3中的一种或多种。
所述反应的溶剂可以是常规溶剂，例如可以是二甲基甲酰胺、1-甲基-2-吡咯烷酮、四氢呋喃、二氧六环、甲苯、二甲亚砜、二甲基醚、异丙醇、乙醇、水中的一种或多种，优选二甲基甲酰胺、二甲基醚、二氧六环、水中的一种或多种。反应温度可以是60℃～150℃。
应该理解，本发明中式(I)化合物中含有手性碳原子，前述未指明构型的结构代表了任何的可能性，包括但不限于消旋体或者其中任意的异构体，当反应得到的式(I)化合物为消旋体形式时，可以进一步使用拆分等手段得到异构体形式。
在某些实施方式中，所述式I化合物优选自以下结构：
Figure PCTCN2018095371-appb-000004
其中，R 3的定义与前述相同；
所述式II化合物优选自以下结构：
Figure PCTCN2018095371-appb-000005
其中，X的定义与前述相同；
所述式III化合物优选自以下结构：
Figure PCTCN2018095371-appb-000006
其中，Y、R 3的定义与前述相同。
在某些实施方式中，所述式I化合物优选自以下结构：
Figure PCTCN2018095371-appb-000007
本发明另一方面提供了一种如式Ia所示的化合物或其药学上可接受的盐的制备方法，包括根据本发明所述的方法制备如式I所示化合物的步骤，所述方法还包括手性拆分式I所示化合物的步骤，所述手性拆分的方法优选化学拆分、膜拆分、色谱拆分或毛细管电泳拆分，
Figure PCTCN2018095371-appb-000008
其中，R 1、R 2、n的定义与前述相同。
在某些实施方式中，式Ia所示的化合物可以是
Figure PCTCN2018095371-appb-000009
在某些实施方式中，当R 3为氢或羟基保护基时，反应都可顺利进行并得到目标产物。当R 3为羟基保护基时，脱除保护基的过程中容易生成微量的脱羟乙基杂质，该杂质存在一定的药理毒性，这将对化合物Ib制成药物产生一定影响；当R 3为氢时，反应过程中未检测到脱羟乙基杂质的产生。
本发明所述的咪唑并异吲哚类衍生物的制备方法具有操作安全、简单，使用的反应试剂更加安全，反应条件更加温和，成本更低，适合工业化生产等特点，反应效果均优于现有技术，具有显著的社会效益和经济效益。其中，化合物II与化合物III偶联反应的产率大大提高，相比现有技术产物纯度更高，更易于后续反应，减少了后处理操作，也更加适合工业放大生产。
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基或戊基等。更优选的是含有1至6个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基、戊基、庚基等。烷基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷氧基、卤素、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、羰基。
“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元的芳基，更优选苯基和萘基，最优选苯基。芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
“杂芳基”指包含1至4个杂原子，5至14个环原子的杂芳族体系，其中杂原子包括氧、硫和氮。优选为6至10元。杂芳基优选为是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羰基、-羧酸或羧酸酯。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)n(其中n是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，其中1～4个是杂原子，更优选环烷基环包含3至10个环原子。单环环烷基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环环烷基包括螺环、稠环和桥环的杂环基。
“烷氧基”指-O-(烷基)和-O-(未取代的环烷基)，其中烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自为烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羰基、羧酸或羧酸酯。“羟基”指-OH基团。
“羟基保护基”是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，优选烷氧基或芳基取代的烷基，更优选C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基，最优选C 1-4烷氧基取代的C 1-4烷基，例如：甲基，叔丁基，烯丙基，苄基，甲氧基甲基(MOM)，乙氧基乙基，2-四氢吡喃基(THP)等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6烷氧基或 C 6-10芳基氧基)羰基。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
具体实施方式
以下将结合具体实例详细地解释本发明，使得本专业技术人员更全面地理解本发明具体实例仅用于说明本发明的技术方案，并不以任何方式限定本发明。
实施例1
Figure PCTCN2018095371-appb-000010
第一步
将化合物a(177g，0.495mol，根据WO2016169421公开方法制备)溶于1.5L二氯甲烷中，加入300mL 1,4-二氧六环，冰水浴冷却下，滴加浓盐酸(412mL，4.95mol)，升至室温，搅拌反应2小时。反应结束后，向反应液中加入600mL水，萃取分离水相。将氢氧化钠(215g，5.38mol)溶于215mL水中，缓慢滴入上述水相，调节至pH值8～9，水相用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品b 144.8g，产品不经纯化直接进行下一步反应。
第二步
将粗品b(144.8g，563mmol)溶于2L乙醇中，依次加入化合物c(94.6g，844mmol)和10％Pd/C 14.5g，升温至75℃，通空气，搅拌反应28小时。反应结束后，过滤除去Pd/C，滤饼用甲醇淋洗，将滤液减压浓缩，真空干燥，得到化合物d 94.4g，产率：48％。
第三步
将化合物d(94.4g，0.27mol)溶于1.2L二氯甲烷中。降温至0℃，加入吡啶(106.8g，1.35mol)，再滴加Tf 2O(99g，0.351mol)。升温至室温，搅拌反应1小时。反应结束后，反应液中加入100mL水，用1M盐酸调节pH值至2，静置分层，分离有机相，水相用二氯甲烷萃取，合并有机相，无水硫酸镁干燥，过滤，滤液减压浓缩，所得残余物柱层析(洗脱剂：DCM:MeOH＝10:1)，得到化合物e 73g，产率：56.1％。
实施例2
Figure PCTCN2018095371-appb-000011
第一步
将化合物e(73g，0.15mol)和化合物f(74.1g，0.23mol，采用“Journal of Medicinal Chemistry,2012,55(18),8091-8109”制备而得)溶于1.1L 1,4-二氧六环和水(V:V＝5:1)的混合溶剂中，依次加入碳酸钠(47.7g，450mmol)和Pd(PPh 3) 2Cl 2(15.8g，22.5mmol)，氩气保护下升温至回流，搅拌反应17小时。反应结束后，反应液冷却至室温，过滤除去催化剂固体，滤液减压浓缩，残余物中加入300mL水，用二氯甲烷萃取，合并有机相，无水硫酸镁干燥，减压浓缩，所得残余物柱层析(洗脱剂：DCM:MeOH＝50:1～20:1)，得到浅棕色固体化合物g 48g，产率：60.7％，HPLC纯度88.1％。
第二步
将化合物g(36g，68.27mmol)溶于400mL甲醇，加入浓盐酸(12mL，136.55mmol)，升温至40℃，搅拌反应2小时。反应液减压浓缩，加入二氯甲烷200mL，加入150mL饱和碳酸钾溶液，搅拌，过滤，滤饼用少量二氯甲烷淋洗，正己烷淋洗，收集滤饼真空干燥，得到浅棕色固体化合物h 20.8g，产率：69％，HPLC纯度92％。
实施例3
Figure PCTCN2018095371-appb-000012
将化合物e(73g，152mmol)和化合物i(72.2g，304mmol，按照CN105189461A公开的方法制备)溶于1500mL 1,4-二氧六环和水(V:V＝5:1)的混合溶剂中，依次加入碳酸钠(48.3g，456mmol)和Pd(dppf)Cl 2(11.1g，15.2mmol)，氩气保护下升温至回流，搅拌反应3小时。反应结束后，反应液冷却至室温，加入400mL水，室温搅拌30min，过滤，滤饼用水淋洗，收集滤饼，用1.2L甲醇分散，加入浓盐酸(40mL)，搅拌30min，浓缩除去甲醇，加入2L水，搅拌30min，过滤，固体用水淋洗，合并水相，用乙酸乙酯反萃(600mL×2)，收集水相，用饱和NaHCO 3溶液调pH至碱性，析出固体，过滤得固体，水洗，真空干燥，得化合物h 41.8g，产率62％，化学纯度：94.4％。
实施例4
将化合物h 11.59g进行手性制备(分离条件：手性制备柱Superchiral S-AS(Chiralway),2cm I.D.*25cm Length,5um；流动相：CO2/MeOH/DEA＝60/40/0.05(v/v)，流速：50mL/min)，收集目标组分，减压浓缩，得到化合物Ib 4.49g，光学纯度：99.6％。
由于已根据其特殊的实施方案描述了本发明，某些修饰和等价变化对于精通此领域的技术人员是显而易见的且包括在本发明的范围内。

Claims (10)

  1. 一种如式I所示化合物的制备方法，包括将式II所示化合物与式III所示化合物反应的步骤，
    Figure PCTCN2018095371-appb-100001
    其中，R 1相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基和杂芳基；
    R 2选自-CH 2-CH 2-OR 3；
    R 3选自氢或羟基保护基，优选氢；
    X和Y中一个为离去基团，另一个选自-BF 3K、-BR aR b、-Sn(R c) m或-Zn-X’，
    其中所述离去基团选自-Cl、-Br、-I、-F、三氟甲磺酰氧基、甲磺酰氧基、苯磺酰氧基、乙酰氧基或磷酸酯基、-SR，-SO 2R；
    R a和R b独立地选自-OH、烷基、烷氧基或任意取代的C 1～C 6一元和二元醇，或R a和R b在一起成环，R c独立地选自C 1～C 6烷基，X’选自-Cl、-Br、-I，R为C 1～C 6烷基；
    n为0、1、2、3或4的整数，m为0、1、2、3或4的整数。
  2. 根据权利要求1所述的制备方法，其特征在于，所述反应在催化剂的存在下进行，所述的催化剂优选自PdL p、PdCl 2L p、Pd(OAc) 2L p、Pd 2(dba) 3L p、Pd(II)L p、Pd(0)、NiCl 2L p、Ni(COD) 2L p、NiCl 2(NEt 3) 2或NiCl 2(bipy)，
    其中L为含膦配体或N-杂环卡宾配体，所述含膦配体优选自PPh 3、dppf、PCy 3、tBu 3P、P(OMe) 3、dppe或dppb，
    p独立的选自0、1、2、3或4的整数，
    所述的催化剂更优选Pd(PPh 3) 2Cl 2、Pd(PPh 3) 4、Pd(dppf)Cl 2、钯碳、Pd(OAc) 2、PCy 3/Pd 2(dba) 3，最优选Pd(PPh 3) 2Cl 2。
  3. 根据权利要求1所述的制备方法，其特征在于，所述反应在碱性物质存在下进行反应，其中碱性物质优选Li 2CO 3、Na 2CO 3、Ba(OH) 2、K 3PO 4、Cs 2CO 3、K 2CO 3、TlOH、KF、CsF、Bu 4NF、LiOH、NaOH、KOH、三乙胺、DIPEA、DABCO、NaOR、 KOR、TlOR中的一种或多种，其中R独立地选自C 1～C 6烷基，所述碱性物质更优选Na 2CO 3或K 2CO 3中的一种或多种。
  4. 根据权利要求1所述的制备方法，其特征在于，所述反应的溶剂为二甲基甲酰胺、1-甲基-2-吡咯烷酮、四氢呋喃、二氧六环、甲苯、二甲亚砜、二甲基醚、异丙醇、乙醇、水中的一种或多种，优选二甲基甲酰胺、二甲基醚、二氧六环、水中的一种或多种。
  5. 根据权利要求1所述的制备方法，其特征在于，X为离去基团，Y选自-BF 3K或-BR aR b，其中所述离去基团选自-Cl、-Br、-I、三氟甲磺酰氧基、甲磺酰氧基、苯磺酰氧基，所述BR aR b优选R a和R b独立地选自-OH、烷基、烷氧基，或BR aR b为频哪醇硼酸酯。
  6. 根据权利要求1所述的制备方法，其特征在于，所述式I化合物为
    Figure PCTCN2018095371-appb-100002
  7. 根据权利要求1所述的制备方法，其特征在于，所述式II化合物为
    Figure PCTCN2018095371-appb-100003
  8. 一种如式Ia所示的化合物或其药学上可接受的盐的制备方法，包括根据权利要求1-7任意一项的方法制备如式I所示化合物的步骤，所述方法还包括手性拆分式I所示化合物的步骤，所述手性拆分的方法优选化学拆分、膜拆分、色谱拆分或毛细管电泳拆分，
    Figure PCTCN2018095371-appb-100004
    其中，R 1、R 2、n的定义如权利要求1所述。
  9. 根据权利要求8所述的制备方法，其特征在于，所述式Ia化合物为
    Figure PCTCN2018095371-appb-100005
  10. 根据权利要求1至5任意一项所述的制备方法，其特征在于，所述式I化合物为
    Figure PCTCN2018095371-appb-100006
PCT/CN2018/095371 2017-07-13 2018-07-12 一种咪唑并异吲哚类衍生物的制备方法 Ceased WO2019011287A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880004456.1A CN109983020A (zh) 2017-07-13 2018-07-12 一种咪唑并异吲哚类衍生物的制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710568648.2 2017-07-13
CN201710568648 2017-07-13

Publications (1)

Publication Number Publication Date
WO2019011287A1 true WO2019011287A1 (zh) 2019-01-17

Family

ID=65001843

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/095371 Ceased WO2019011287A1 (zh) 2017-07-13 2018-07-12 一种咪唑并异吲哚类衍生物的制备方法

Country Status (3)

Country Link
CN (1) CN109983020A (zh)
TW (1) TW201908321A (zh)
WO (1) WO2019011287A1 (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102083429A (zh) * 2008-04-24 2011-06-01 新联基因股份公司 Ido抑制剂
WO2016169421A1 (zh) * 2015-04-21 2016-10-27 江苏恒瑞医药股份有限公司 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10087191B2 (en) * 2015-06-16 2018-10-02 Jiangsu Hengrui Medicine Co., Ltd. Piperidine derivative and preparation method and pharmaceutical use thereof
TW201815793A (zh) * 2016-10-21 2018-05-01 江蘇恆瑞醫藥股份有限公司 一種咪唑並異吲哚類衍生物的遊離鹼的結晶形式及其製備方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102083429A (zh) * 2008-04-24 2011-06-01 新联基因股份公司 Ido抑制剂
WO2016169421A1 (zh) * 2015-04-21 2016-10-27 江苏恒瑞医药股份有限公司 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用

Also Published As

Publication number Publication date
CN109983020A (zh) 2019-07-05
TW201908321A (zh) 2019-03-01

Similar Documents

Publication Publication Date Title
CN108047261B (zh) 一种克立硼罗的制备方法
WO2009096202A1 (ja) ハロ多環芳香族化合物及びその製造方法
CN104402862B (zh) 艾立替尼的制备方法
Jiang et al. Synthesis of indolylpyrimidines via cross-coupling of indolylboronic acid with chloropyrimidines: Facile synthesis of meridianin D
CN104276994B (zh) 3,3′‑双取代氧化吲哚与3‑烯键氧化吲哚拼接衍生物及其制备方法及应用
CN107573327B (zh) 吲唑-甲酰胺-吡啶酮衍生物及其制备方法和用途
CN110183445B (zh) 莫西沙星及其衍生物的合成方法
CN103922992B (zh) 一种抗癌活性吲哚酮衍生物、合成方法及其用途
WO2019011287A1 (zh) 一种咪唑并异吲哚类衍生物的制备方法
CN102746226B (zh) 吖啶衍生物及其制备方法和应用
CN103626828A (zh) 一种抗肿瘤活性的熊果酸化学修饰物及其制备方法
CN107814757B (zh) 一种合成多取代吡咯衍生物的方法
CN107892669B (zh) 一种通过借氢反应合成喹啉衍生物的方法
CN109983019B (zh) 一种咪唑并异吲哚类衍生物的制备方法
CN110305142A (zh) 一种6β-羟基吗啡衍生物的立体选择性合成方法
CN113321675B (zh) 手性3-亚甲基吲哚啉化合物及其制备方法
CN104072495A (zh) 天然产物生物碱Aaptamine的制备方法
CN104327053A (zh) 氘代克里唑蒂尼及其衍生物、制备方法及应用
KR20100054627A (ko) 바이나프톨 알데히드 유도체 및 그의 제조방법
RU2554937C1 (ru) СПОСОБ ПОЛУЧЕНИЯ АНТРА[2,3-b]ФУРАН-3-КАРБОНОВОЙ КИСЛОТЫ
CN102786527A (zh) N1取代3,4-二氢嘧啶-2-酮修饰尾式卟啉化合物及制备方法
CN101643450B (zh) 一种多取代2,3-二氢-4(1h)-嘧啶硫酮的合成方法
CN110590641B (zh) 一种3-羟基异吲哚-1-酮系列化合物的绿色制备方法
CN121537397A (zh) 一种芳杂稠环类化合物及其制备方法与应用
CN107236004A (zh) 二氢杨梅素环磷酰胺衍生物及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18832067

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18832067

Country of ref document: EP

Kind code of ref document: A1