WO2015188762A1 - 一种抗血管新生化合物及其中间体的制备方法 - Google Patents

一种抗血管新生化合物及其中间体的制备方法 Download PDF

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WO2015188762A1
WO2015188762A1 PCT/CN2015/081236 CN2015081236W WO2015188762A1 WO 2015188762 A1 WO2015188762 A1 WO 2015188762A1 CN 2015081236 W CN2015081236 W CN 2015081236W WO 2015188762 A1 WO2015188762 A1 WO 2015188762A1
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compound
formula
reaction
alkyl
halogen
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侯睿
罗红蓉
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宁波市方昌医药有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to a process for the preparation of a class of neovascular inhibitor compounds and a novel process for the preparation of key intermediates in the process.
  • Angiogenesis is the process of sprouting new blood vessels from existing blood vessels. This process is associated with vascular endothelial cell migration and proliferation.
  • Neovascularization is associated with a variety of major human diseases, such as malignant tumors. It has been found that ocular neovascular diseases, including age-related macular degeneration (AMD), diabetic retinopathy, neovascular glaucoma, etc., are common features of these diseases in the abnormal proliferation of ocular neovascularization (Jin Xiao et al. Advances in the application and mechanism of anti-VEGF drugs in ophthalmic diseases, Chinese and Foreign Medical Care, 2012).
  • AMD age-related macular degeneration
  • neovascular glaucoma etc.
  • macular degeneration is mainly dry and wet.
  • AMD wet macular degeneration
  • Wet macular degeneration will quickly lose vision and be more severe than dryness.
  • photodynamic therapy was improved the efficacy, it is still not ideal.
  • Lucentis vascular endothelial factor antagonist
  • a new vascular endothelial factor antagonist Lucentis
  • Lucentis is a recombinant of a human VEGF subtype monoclonal antibody fragment that reduces neovascularization.
  • the drug was approved by the US FDA for the treatment of wet macular degeneration, and the curative effect was good.
  • the anti-VEGF drugs have therapeutic effects on diabetic retinopathy and neovascular glaucoma.
  • ranibizumab is an antibody drug, the price is extremely high, and it cannot be popularized all over the world. Therefore, the study of small-molecule angiogenesis inhibitors with good efficacy and low price is the focus of fierce competition in the international pharmaceutical industry today.
  • R 1 is selected from H or amino
  • R 3 is selected from H Or C1-2 alkyl
  • R 4 , R 5 , R 6 are each independently selected from halogen, C1-2 alkyl or halogen substituted alkyl
  • R 7 is selected from H or halogen
  • R 2 and R 3 together with the carbon atom to which they are bonded constitute a substituted or unsubstituted five- or six-membered ring containing one N, and the substituent is an alkyl group of C1-3.
  • the compound of the above formula I is obtained from the intermediate compound by reacting with an amine-substituted diazaaromatic compound having an amino-protecting group such as Boc, and further removing the amino-protecting group.
  • the synthetic route is as follows:
  • the present invention provides a novel synthetic process for the preparation of a compound of formula I with a significant increase in yield and a further simplification of the process, as well as a novel process for the synthesis of key intermediates therein.
  • R 1 is selected from H or amino
  • R 3 is selected from H Or C1-2 alkyl
  • R 4 , R 5 , R 6 are each independently selected from halogen, C1-2 alkyl or halogen substituted alkyl
  • R 7 is selected from H or halogen
  • R 2 and R 3 together with the carbon atom to which they are attached constitute an N- or 5-membered ring containing 1 N substituted or unsubstituted by C1-3.
  • the method comprises the step of reacting a compound of formula II with a compound of formula III in the presence of Cs 2 CO 3 in a polar organic solvent to provide a compound of formula I:
  • the compound of formula III is added in an amount of from 1.2 to 1.5 equivalents based on the stoichiometric amount of the compound of formula II; the amount of Cs 2 CO 3 added is from 1.5 to 3 equivalents.
  • the polar organic solvent is not particularly limited as long as it adversely affects the reaction. There may be mentioned DMSO, DMF, and the like.
  • the reaction is preferably carried out at a temperature of from 110 ° C to 120 ° C, most preferably at a temperature of from 115 ° C.
  • R 1 in formula I is H;
  • R 2 is selected from amino or -(CH 2 ) n NHR 8 ; or R 2 , R 3 together with the carbon atom to which they are attached constitutes a C1-3 alkyl group or An unsubstituted five- or six-membered ring containing one N;
  • R 4 , R 5 , and R 6 are the same, and are F, Cl or Br; and
  • R 7 is H.
  • the compound of formula I is a compound of the formula KDR6, V01, V3, V4, V5 or V6:
  • the inventors have found that the amino group in the compound of formula III is not protected, and the compound of formula III is directly reacted with the compound of formula II under certain conditions to unexpectedly increase the yield to about 50%. Moreover, the method has achieved the same success in the amplification reaction.
  • the process of the present invention greatly increases the yield, the synthesis process is simpler, and the cost is greatly reduced, making commercial synthesis of the compound of formula I possible.
  • Compound 21 is obtained by subjecting compound 21 to methyl ether by dropwise addition of boron tribromide;
  • R 4 , R 5 and R 6 are each independently selected from halogen, C1-2 alkyl or halogen substituted alkyl; and R 7 is selected from H or halogen.
  • R 4 , R 5 , and R 6 are the same and are F, Cl or Br; and R 7 is H.
  • the organometallic reagent in the step (1) may be a Grignard reagent; a lithium reagent such as an alkyllithium such as n-butyllithium or the like; zinc cyanide or the like.
  • the zinc powder and the zinc cyanide are subjected to a Grignard reaction in the presence of a palladium catalyst, or a carboxylation reaction is carried out by using n-butyllithium as a lithium reagent and introducing carbon dioxide gas.
  • the palladium catalyst may be: Pd 2 (dba) 3 or the like, and the amount thereof is 0.001-0.1 equivalent, preferably about 0.005 equivalent, based on the amount of the compound 19, in the gram-scale reaction scale of the compound for preparing the V01, the number of conversions (TON, turn) Over number) increased from 4.3 to 200. There is no doubt that TON can be further improved by optimizing the production in the future.
  • the synthesis of the intermediate compound of the formula II is carried out by replacing the chlorinated compound 4 in the original synthesis route with a more active brominated compound 19, thereby further increasing the yield of the carboxylation reaction, and the amount of the catalyst in the Grignard reaction. Significantly reduced (from about 0.23 equivalents to about 0.005 equivalents when synthesizing the V01 compound). Since the preferred palladium catalysts in the reaction are expensive, the improvement in this step contributes significantly to the cost reduction of the overall synthesis process.
  • both lithium reagents and Grignard reagents can be used to convert aryl bromides to the corresponding aryl carboxylic acids or aryl amides, so the use of intermediate 19 instead of intermediate 4 provides more options for the synthetic route of V01. .
  • compound 19 may occur with n-butyllithium bromine - lithium exchange, and subsequently generating compound into the 21 CO 2 gas react.
  • 53% yield of the pure compound 21 was obtained by recrystallization after the reaction.
  • the reaction of the isocyanate in place of CO 2 with compound 19 produces the corresponding amide derivative compound 24.
  • step (1) uses a Grignard reagent to obtain a corresponding cyano-substituted compound 20 from a brominated compound 19 in the presence of a palladium catalyst, and then in a basic condition. Subsequent hydrolysis gives the carboxyl group-substituted compound 21.
  • compound 20 does not need to be purified by chromatography.
  • the crude reaction product can be slurried in petroleum ether, then filtered, dried and purified.
  • step (2) in the step (2), 0.8 to 1.3 equivalents, preferably 1 equivalent of DIPEA, is first added based on the amount of the compound 21 before the dropwise addition of boron tribromide.
  • the yield of step (2) can be as high as 90% or even 98%. And the reaction time is also greatly reduced.
  • compound 19 can be prepared as follows:
  • A is the starting material of compound 13 and compound 14, and the reaction is carried out at 90 ° C to 110 ° C, and concentrated under reduced pressure to obtain crude compound 15
  • step B the reaction is preferably carried out at 240 °C.
  • the reactants are allowed to cool to room temperature (e.g., 25 ° C) at a rate of less than 3 ° C / min, preferably less than 1 ° C / min to give the crystallized compound 16 pure.
  • the pH of the reaction liquid is adjusted to between 5 and 6 with an aqueous solution of glacial hydrochloric acid, and the filter cake is filtered and dried to obtain a crude product of compound 17 which can be directly used for the next reaction.
  • the decarboxylation reaction of step D is refluxed in diphenyl ether for about one hour. The reaction should not be too long. After the reaction was cooled to room temperature, the filter cake was dried and dried to give Compound 18. Compound 18 was used directly in the next reaction without further purification.
  • step E the reaction is carried out by heating to reflux in toluene. After the completion of the reaction, the mixture was kept at 30 ° C or less, and an aqueous ammonia solution was slowly added thereto, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to afford compound 19, and the reaction of the above step 1 was carried out without further purification.
  • the present invention also provides a process for the preparation of a compound of formula II by the process for the preparation of a compound of formula II as described above, and further in accordance with the process of the invention.
  • all the products of each step do not require column purification, which simplifies the process and cost.
  • the key intermediate compound 19 replaces the chlorine substituent of the original process compound 4 with a bromine substituent, so that the amount of the carboxylation catalyst is remarkably lowered, and the yield is remarkably improved.
  • the direct reaction of the compound of the formula II with the compound of the formula III gives the reaction of the compound of the formula I, not only the yield is increased, but also the original two-step reaction is changed to one step, which further simplifies the process and reduces the cost.
  • the present invention will be further illustrated by the following detailed description of the method of synthesizing the compound V01.
  • the compounds of the formula I according to the invention can be reacted in a similar manner with the corresponding aminodiazabenzene compounds by the intermediate compound of the formula II to give the target compound.
  • the V01 compound was synthesized according to the following synthetic route:
  • test conditions are as follows:
  • the loss of yield is mainly due to the side reaction in step 2.
  • the main impurities were identified as residual 15, 16a and 16b from decarboxylation.
  • the loading of the catalyst palladium can be significantly reduced by using the substrate 19.
  • the number of conversions (TON) increased from 4.3 to 200. Without a doubt, by optimizing in the future TON can be further improved in scale-up production.
  • the yield increased from 62% to 82%.
  • the reaction liquid is poured into water to precipitate the product, and most of the impurities can be removed.
  • purifying with petroleum ether a product having a purity of ⁇ 99.5% can be obtained.
  • reaction time was reduced to about 6 hours. After purification, the only impurity in product 9 detected by HPLC was unreacted starting material 21.
  • the DIPEA was not added in the reaction, and the yield of the step was increased to about 60%.
  • the impurities remaining in the product include compound 24 (0.58%) derived from the impurity 21 brought from in the raw material 9, 32 (0.11%, whose structure is as follows) which may be coupled by 9 and 10, and the other two structures are unknown. Impurities (0.13%, 0.06%).
  • the organic phase was washed successively with water (2.5 L) and brine (1.2 L). Further, activated carbon (57 g) and anhydrous sodium sulfate (270 g) were added to the organic phase, and stirred for 2 hours, followed by filtration. The filtrate was concentrated to 450 ml under reduced pressure at 45 ° C, methanol (180 ml) was added, and the mixture was heated to reflux, followed by n-heptane (1.8 L).
  • reaction solution was cooled to 25 ° C, and stirred for 3 hours, then filtered, and the filtered cake was washed with ethyl acetate (200 mL) and dried under vacuum at 45 ° C for 16 hours to give white solid V01 (63 g, yield 49%, purity 99.5%).

Abstract

本发明公开了一种式I所示抗血管新生化合物的制备方法。所述方法包括在极性有机溶剂中，使式II化合物在Cs2CO3的存在下与式III化合物反应得到式I化合物的步骤。根据本发明的方法，不对式III化合物中的氨基进行保护，在一定条件下直接使式III化合物与式II化合物反应，大大提高了收率，合成方法更加简单，成本也大大降低，使式I化合物的酉业化合成成为可能。同时还公开了制备其中间体式II化合物的方法。

Description

一种抗血管新生化合物及其中间体的制备方法 技术领域
本发明涉及用于制备一类新生血管抑制剂类化合物的工艺方法以及该方法中的关键中间体的新制备方法。
背景技术
新生血管(angiogenesis)，是从已有血管发芽生成新血管的过程。这一过程与血管内皮细胞迁移和增殖相关。新生血管与多种人类重大疾病有关，如恶性肿瘤。目前发现，眼部血管新生性疾病，包括年龄相关性黄斑变性(AMD)、糖尿病视网膜病变、新生血管性青光眼等，这类疾病的共同特点都在于眼部新生血管的异常增生(金晓等，抗VEGF药物在眼科疾病中的应用及机制研究进展，中外医疗，2012年)。
其中，黄斑变性主要有干性和湿性两种，湿性黄斑变性(AMD)的特点是，脉络膜的新生血管进入视网膜下以及继而发生的出血、渗出及水肿等病理变化。湿性黄斑变性将迅速丧失视力，较干性更为严重。目前，在湿性黄斑变性的治疗方面已有较好的进展。早期的激光烧烁止血被血管内皮因子拮抗剂所代替，但因后者效果不佳，很快被光动力疗法所取代。光动力疗法虽然提高了疗效，但仍不理想。近年又出现了新的血管内皮因子拮抗剂——雷珠单抗(Lucentis)，是一种人源性VEGF亚型单克隆抗体片段的重组体，可减少新生血管生成。2006年，该药物被美国FDA批准用于治疗湿性黄斑变性，疗效良好；同时，目前也发现该类抗VEGF药物对糖尿病视网膜病变、新生血管性青光眼有治疗作用。但由于雷珠单抗为抗体药，价格极高，它还不能在全世界普及。因此，研究疗效良好、价格低廉的小分子新生血管抑制剂药物是当今国际制药界激烈竞争的焦点。
本申请人最新开发了一种新型抑制新生血管的化合物并已向中国专利局递交了发明专利申请No.201410125752.0，该专利申请的全文通过引 用并入本文。该申请中公开了一种式I化合物：
Figure PCTCN2015081236-appb-000001
其中，X为C，Y为N；
R1选自H或氨基；R2选自H、氨基或-(CH2)nNHR8，其中，n＝1-3，R8为H或C1-2的烷基；R3选自H或C1-2烷基；R4、R5、R6分别独立选自卤素、C1-2的烷基或卤素取代烷基；R7选自H或卤素；
或者，R2、R3与其相连的碳原子共同构成取代或非取代的含1个N的五元或六元环，取代基为C1-3的烷基。
并公开了一种用于制备优选的式I化合物的中间体化合物10：
Figure PCTCN2015081236-appb-000002
由该中间体化合物通过与带有氨基保护基(如Boc)的胺基取代的二氮杂芳香化合物反应，并进一步脱去氨基保护基，从而得到上述式I化合物。
上述合成反应以合成V01化合物为例，
Figure PCTCN2015081236-appb-000003
其合成路线如下：
Figure PCTCN2015081236-appb-000004
在上述合成路线中，共涉及11步反应，总收率仅约0.58％，特别是最后两步，使用了Boc保护的22来成醚键，然后在酸性条件脱Boc保护得到V01，总收率仅为约10％，极大地制约了该工艺方法的商业化。其它缺陷主要还在于其中化合物4、5、11、12以及终产物V01均需要通过柱层析纯化；步骤4中的钯催化剂费用昂贵以及其配体需要高负载量。可见，该方法并不适于商业化生产。因此需要成本进一步降低，工艺进一步简化的适于商业化生产的合成工艺方法。
发明内容
针对以上问题，本发明提供一种产率显著提高、工艺进一步简化的制备式I化合物的新的合成工艺方法以及合成其中关键中间体的新工艺方法。
根据本发明的第一方面，提供一种制备式I化合物的方法，
Figure PCTCN2015081236-appb-000005
其中，X为C，Y为N；
R1选自H或氨基；R2选自H、氨基或-(CH2)nNHR8，其中，n＝1-3，R8为H或C1-2的烷基；R3选自H或C1-2烷基；R4、R5、R6分别独立选自卤素、C1-2的烷基或卤素取代烷基；R7选自H或卤素；
或者，R2、R3与其相连的碳原子共同构成被C1-3的烷基取代的或非取代的含1个N的五元或六元环，
其中，所述方法包括在极性有机溶剂中，使式II化合物在Cs2CO3的存在下与式III化合物反应得到式I化合物的步骤：
Figure PCTCN2015081236-appb-000006
根据优选的实施方式，基于式II化合物的化学当量，式III化合物的加入量为1.2～1.5当量；Cs2CO3的加入量为1.5～3当量。
所述极性有机溶剂没有特别的限制，只要对反应产生不利影响即可。可列举的有：DMSO、DMF等。
所述反应优选在110℃～120℃，最优选在115℃的温度下进行。
优选地，式I中R1为H；R2选自氨基或-(CH2)nNHR8；或者，R2、R3与其相连的碳原子共同构成被C1-3的烷基取代的或非取代的含1个N的五元或六元环；R4、R5、R6相同，为F、Cl或Br；和R7为H。
更优选地，所述式I化合物为如下式KDR6、V01、V3、V4、V5或V6的化合物：
Figure PCTCN2015081236-appb-000007
Figure PCTCN2015081236-appb-000008
在常规的反应路线设计中，通常会考虑先对式III中R2和/或R3中的氨基进行保护后再与式II化合物进行成醚反应，然后在酸性条件下脱保护而得到最终式I化合物。例如在中国专利申请No.201410125752.0中的实施例中均采用这种合成路线。然而这两步反应的总收率仅为约10％左右，使式I化合物无法大量商业化合成。
经反复实验，本发明人发现不对式III化合物中的氨基进行保护，在一定条件下直接使式III化合物与式II化合物反应，出乎意料地将收率提高到约50％。而且在放大反应中，该方法也取得了同样的成功。本发明的方法大大提高了收率，合成方法更加简单，成本也大大降低，使式I化合物的商业化合成成为可能。
根据本发明的第二方面，提供一种制备中间体式II化合物的方法，所述方法包括以下步骤：
(1)使化合物19与有机金属试剂反应得到化合物21；
(2)通过滴加三溴化硼使化合物21脱甲醚得到化合物9；和
(3)和使化合物9与式IV化合物在HATU(2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯，(1-[Bis(dimethylamino)methylene]-1H-1，2，3-triazolo[4，5-b]pyridinium 3-oxid hexafluorophosphate))存在下反应得到式II化合物，
Figure PCTCN2015081236-appb-000009
其中，R4、R5、R6分别独立选自卤素、C1-2的烷基或卤素取代烷基；R7选自H或卤素。
优选地，R4、R5、R6相同，为F、Cl或Br；R7为H。
步骤(1)中的有机金属试剂可为格氏试剂；锂试剂，例如烷基锂，如正丁基锂等；氰化锌等。优选地，步骤(1)在钯催化剂的存在下，锌粉和氰化锌进行格氏反应，或者以正丁基锂为锂试剂并通入二氧化碳气进行羧化反应。其中钯催化剂可为：Pd2(dba)3等，其用量以化合物19的量计为0.001-0.1当量，优选为约0.005当量在制备V01化合物的克级反应规模中，转换数(TON，turn over number)从4.3增长到200。毫无疑问，通过优化在将来的放大生产中可以进一步提高TON。
在本发明中，中间体式II化合物的合成采用活性更高的溴代化合物19代替了原合成路线中的氯代化合物4，使羧化反应的产率进一步提高，而格氏反应中的催化剂用量大大降低(在合成V01化合物时，由原来的约0.23当量降低至约0.005当量)。因为反应中优选的钯催化剂价格高昂，因此，这步反应的改进对整个合成工艺的成本降低贡献巨大。
此外，锂试剂和格氏试剂均可用来将芳基溴代物转换为相应的芳基羧酸或者芳基酰胺，因此使用中间体19来替代中间体4为V01的合成路线提供了更多的选择。
Figure PCTCN2015081236-appb-000010
例如根据一种实施方式，化合物19可以与正丁基锂发生溴-锂交换，并与随后通入的CO2气体发生反应生成化合物21。在多次克级规模实验中，反应后通过重结晶得到53％收率的纯品化合物21。根据另一种实施方式，用异氰酸酯代替CO2与化合物19反应则可生成相应的酰胺衍生物化合物24。
根据本发明的优选实施方式，步骤(1)采用格氏试剂在钯催化剂的存在下，由溴代化合物19得到相应的氰基取代化合物20，再在碱性条件 下水解得到羧基取代的化合物21。在该实施方式中，化合物20不需通过色谱柱纯化。优选地，反应粗产物可在石油醚中打浆，然后过滤、干燥而纯化。
根据本发明的一种优选实施方式，在步骤(2)中，在滴加三溴化硼之前，基于化合物21的量先加入0.8～1.3当量，优选1当量的DIPEA。在该优选实施方式中，步骤(2)的收率可高达90％以上，甚至达到98％。而且反应时间也大大减少。
根据一种实施方式，化合物19可按照以下步骤制备：
A以化合物13和化合物14为起始反应物，在90℃～110℃进行反应，减压浓缩后得到化合物15粗品
B化合物15粗品在二苯醚中加热至220℃～250℃下反应得到化合物16；
C化合物16在碱性水溶液中水解得到化合物17；
D化合物17经加热脱羧反应得到化合物18；和
E化合物18与三溴氧磷反应得到化合物19。
根据优选的实施方式，步骤B中，优选在240℃下进行反应。反应结束后使反应物以低于3℃/分钟，优选低于1℃/分钟的速度降温至室温(如25℃)以便直接得到结晶的化合物16纯品。
优选地，步骤C的反应结束后，用冰盐酸水溶液将反应液的pH值调至5～6之间，过滤并干燥滤饼，得到化合物17的粗品，可直接用于下一步反应。
优选，步骤D的脱羧反应在二苯醚中回流约1小时。该反应不宜时间过长。反应结束降温至室温过滤并干燥滤饼即得到化合物18。化合物18不需进一步纯化而直接用于下一步反应。
优选，步骤E中，在甲苯中加热至回流进行反应。当反应结束后，保持在30℃以下，缓慢加入氨水溶液，用乙酸乙酯萃取，将有机层减压浓缩得到化合物19，不需进一步纯化可直接进行上述步骤1的反应。
本发明还提供采用上述制备中间体式II化合物的方法制备式II化合物，并进而根据本发明的方法制备终产物式I化合物的合成方法。在该方 法中，所有各步的产物均不需色谱柱纯化，简化了工艺和成本。关键中间体化合物19以溴取代基代替原工艺化合物4的氯取代基，使羧化反应催化剂用量显著降低，收率明显提高。最后由式II与式III化合物直接反应得到式I化合物的反应，不仅收率提高了，而且将原来的两步反应变为1步，进一步简化了工艺，降低了成本。以上这些主要改进，使本发明合成式I化合物的合成工艺能够用于工业化生产。
具体实施方式
本发明教导的目的和/或方案将以优选实施方式的形式给出。对这些实施方式的说明是用于更好地理解本发明，而非限制可行的其他实施方式，这些其他实施方式可由对本发明的实践得知。
以下通过详述合成化合物V01的方法来进一步说明本发明。本发明式I的化合物均可用中间体式II化合物以类似方法与相应的氨基二氮杂苯化合物反应得到目标化合物。
实施例：合成化合物V01
Figure PCTCN2015081236-appb-000011
按照以下合成路线合成V01化合物：
Figure PCTCN2015081236-appb-000012
除使用TLC来监控的反应外，其余所有反应过程的监测都使用此高效液相色谱法。并且该方法同时用来检测中间体以及终产物的纯度。
检测条件如下：
Figure PCTCN2015081236-appb-000013
A化合物16的制备
Figure PCTCN2015081236-appb-000014
将化合物14(230g，1.87mol)和乙氧基甲叉丙二酸二乙酯13(414g，1.92mol)混合物在60分钟内逐渐加热升温至90-110℃。当HPLC检测到化合物14峰面积≤0.5％时，将反应混合物降温至50℃，减压浓缩得粗品15。
将二苯醚(0.77L)加热到240℃左右，随后加入粗品15，反应物加热回流5小时左右。当HPLC监测到15的峰面积≤15％时，反应物缓慢降温至25℃。将反应混合物过滤，滤饼用石油醚洗涤(3×200mL)，真空干燥得化合物16(188g，收率：41％)。
化合物16：1H NMR(400MHZ，d6-DMSO)δ1.28(t，J＝6.8Hz，3H)，3.85(s，3H)，4.21(q，J＝6.8Hz，2H)，6.98(d，J＝9.6Hz，1H)，7.00(s，1H)， 8.05(d，J＝9.6Hz，1H)，8.47(s，1H)。
收率的损失主要是由于步骤2中的副反应导致的。主要杂质鉴定为残留的15、16a以及脱羧产生的16b。
Figure PCTCN2015081236-appb-000015
B化合物18的制备
Figure PCTCN2015081236-appb-000016
将化合物16(235g，0.95mol)悬浮于氢氧化钠水溶液中(2N，3.5L)，并加热回流1-1.5h。当TLC监测不到化合物16后(乙酸乙酯∶石油醚＝10∶1)，反应液加入活性炭脱色，然后过滤，滤液用冰盐酸水溶液(2N，大约3.5L)调pH至5～6之间。然后将产生的悬浊液过滤，滤饼用水洗涤(2×500mL)。50℃下真空干燥得到粗品17(228g)。
将粗品17(150g，0.69mol)缓慢地加入到沸腾的二苯醚(1.5L)中。反应液在240℃左右回流1h。当TLC监测不到化合物17后(乙酸乙酯∶甲醇＝10∶1)，反应混合物降温到25℃，过滤，滤饼用石油醚洗涤(2×100mL)，真空干燥得到化合物18(117g，收率98％)。
化合物18：1H NMR(400MHz，d6-DMSO)δ3.83(s，3H)，5.94(d，J＝7.2Hz，1H)，6.89(d，J＝9.2Hz，1H)，6.90(s，1H)，7.80(d，J＝7.2Hz，1H)，7.98(d，J＝9.2Hz，1H)，11.52(br，1H)。
C化合物19的制备
Figure PCTCN2015081236-appb-000017
向三溴氧磷的甲苯溶液中(2M，1.5L)加入化合物18(150g，0.86mol)。反应液加热回流3小时。当TLC检测不到反应物18后(乙酸乙酯∶甲醇＝10∶1)，将反应液降温至室温。然后在保持反应液温度≤30℃下，缓慢加入氨水溶液(1.5L)。混合溶液用乙酸乙酯(2×2.0L)萃取。合并有机层，用饱和食盐水(1.0L)洗涤，无水硫酸钠干燥，然后减压浓缩得到化合物19(134g，三步总收率为71％)
化合物19：1H NMR(400MHz，d6-DMSO)δ3.94(s，3H)，7.42(d，J＝9.2Hz，1H)，7.44(s，1H)，7.76(d，J＝4.4Hz，1H)，8.05(d，J＝9.2Hz，1H)，8.64(d，J＝4.4Hz，1H)。
D制备化合物20
Figure PCTCN2015081236-appb-000018
向化合物19(100g，0.42mol)的N，N-二甲基乙酰胺溶液中加入锌粉(4.1g，63mmol)，氰化锌(39.4g，0.34mol)，dppf(11.6g，21mmol)，以及Pd2(dba)3(1.92g，2.1mmol)。反应体系用氮气置换空气3次，然后在85℃和氮气保护下搅拌18h。TLC监测到反应物19反应完全后(石油醚∶乙酸乙酯＝3∶1)，将反应物倒入水(2.0L)中并室温搅拌1h，过滤。滤饼用二氯甲烷(1.5L)溶解，然后再过滤，滤液用饱和食盐水(500mL)洗涤，无水硫酸钠(100g)干燥，减压浓缩得粗品产物。粗品在石油醚(300mL)中打浆1小时，然后过滤，滤饼在50℃下真空干燥，得到褐色固体20(63g，收率为82％)。
化合物20：1H NMR(400MHz，d6-DMSO)δ3.96(s，3H)，7.52(d，J＝2.4Hz，1H)，7.55(d，J＝9.2Hz，1H)，7.94(d，J＝4.4Hz，1H)，8.01(d，J＝9.2Hz，1H)，9.02(d，J＝4.4Hz，1H)。
通过使用底物19可以明显地降低催化剂钯的负载量。在克级反应规模中，转换数(TON)从4.3增长到200。毫无疑问，通过优化在将来的 放大生产中可以进一步提高TON。另外，虽然降低了配体的使用量，但是收率却从62％增加到了82％。在后处理过程中，反应液倒入水中析出产品，可以除去大部分的杂质。最后通过使用石油醚打浆纯化，可得到纯度≥99.5％的产物。
E化合物21的制备
Figure PCTCN2015081236-appb-000019
室温下，向化合物20(220g，1.12mol)的乙二醇(3.3L)和水(150mL)溶液中加入氢氧化钠固体(383g，9.46mol)。反应混合物加热到100℃并搅拌3h。当TLC监测到反应物20反应完全且薄层板上只有一个点时(石油醚∶乙酸乙酯＝3∶1)，反应液降温至室温。加入盐酸水溶液(2N，大约5L)调节pH至4，然后过滤，滤饼在50℃下真空干燥得到黄色固体21(190g，收率为78％)。
化合物21：1H NMR(400MHz，d6-DMSO)δ3.93(s，3H)，7.36(dd，J1 2＝2.4Hz，9.2Hz，1H)，7.61(d，J＝2.4Hz，1H)，7.75(d，J＝4.4Hz，1H)，8.60(d，J＝9.2Hz，1H)，8.94(d，J＝4.4Hz，1H)。
F制备化合物9
Figure PCTCN2015081236-appb-000020
向化合物21(100g，0.49mol)的二氯甲烷(1.0L)溶液中加入DIPEA(81mL，0.49mol)。混合物冷却到0℃，然后缓慢滴加三溴化硼(183mL，2.0mol)，在滴加过程中保持反应物温度低于10℃。滴加完毕后，将反应液温度升至25℃。当HPLC监测到反应物21峰面积＜＝5.0％时(一般反应6h)，向反应液中加入水(2.0L)，然后缓慢加入饱和碳酸钠溶液(将近300 mL)调节pH至2～3，过滤，滤饼在50℃下真空干燥12小时得到黄色固体9(91.3g，收率：98％，纯度：96.8％)。
本反应时间降低到了6小时左右。纯化后，HPLC检测到产物9中唯一的杂质就是未反应的原料21。
G化合物10的制备
Figure PCTCN2015081236-appb-000021
向化合物9(100g，0.53mol)的DMF(1.0L)溶液中加入HATU(241g，0.63mol)以及间三氟甲基苯胺(102g，0.63mol)。25℃下搅拌16后，IPC监测到反应物9的峰面积＜＝20％后，向反应液中加入水(3.0L)，然后缓慢加入饱和碳酸氢钠溶液调节pH至7～8之间，过滤，滤饼依次用水(0.5L)和石油醚(0.5L)洗涤。然后在25℃下将滤饼溶解在乙酸乙酯(5.9L)中，加入活性炭(29g)并加热回流1h，反应液过滤，滤液在45℃下减压旋浓缩到300mL。然后缓慢加入石油醚(900mL)。混合物慢慢降温到25℃，再搅拌1小时，随后过滤，滤饼用石油醚(100mL)洗涤，在45℃下真空干燥12小时得白色固体10(61g，产率为59％，纯度为99.4％)。
为了减少化合物9聚合的可能性，反应中未加入DIPEA，使本步收率提高到了60％左右。
通过对粗品进行重结晶，产物纯度能提高到99.1％。产物中残留的杂质包括由原料9中带来的杂质21所衍生所得的化合物24(0.58％)，可能由9与10偶联产生的32(0.11％，其结构如下)和其他两个结构未知杂质(0.13％，0.06％)。
Figure PCTCN2015081236-appb-000022
H V01的制备
Figure PCTCN2015081236-appb-000023
向化合物10(100g，0.30mol)的DMSO(1.0L)溶液中加入化合物22(58g，0.45mol)以及Cs2CO3(294g，0.09mol)。反应液在115℃下搅拌18h。当IPC监测到反应物10的峰面积＜＝3.0％时，将反应液冷却至25℃，然后加入乙酸乙酯(2.0L)和活性炭(57g)，搅拌30分钟，然后过滤，滤饼用乙酸乙酯(4.5L)洗涤。合并滤液，向其中加入水(2.5L)，并搅拌1小时。有机相依次用水(2.5L)和饱和食盐水(1.2L)洗涤。再向有机相中加入活性炭(57g)，无水硫酸钠(270g)，并搅拌2小时，之后过滤。滤液于45℃下减压浓缩到450ml，加入甲醇(180ml)，此混合溶液加热至回流，随后加入正庚烷(1.8L)。将反应液冷却至25℃，并搅拌3小时，之后过滤，滤饼用乙酸乙酯(200mL)洗涤，在45℃下真空干燥16小时得白色固体V01(63g，产率为49％，纯度为99.5％)。
以上已经通过优选的实施例描述了本发明的实施方式，但本领域的技术人员应理解，可以在这些实施方式中进行改变而不背离本发明的原理和精神，本发明的范围由权利要求及其等同物限定。

Claims (14)

  1. 一种制备式I化合物的方法，
    Figure PCTCN2015081236-appb-100001
    其中，X为C，Y为N；R1选自H或氨基；R2选自H、氨基或-(CH2)nNHR8，其中，n＝1-3，R8为H或C1-2的烷基；R3选自H或C1-2烷基；R4、R5、R6分别独立选自卤素、C1-2的烷基或卤素取代烷基；R7选自H或卤素；
    或者，R2、R3与其相连的碳原子共同构成被C1-3的烷基取代的或非取代的含1个N的五元或六元环，
    其中，所述方法包括在极性有机溶剂中，使式II化合物在Cs2CO3的存在下与式III化合物反应得到式I化合物的步骤：
    Figure PCTCN2015081236-appb-100002
  2. 根据权利要求1所述的方法，基于式II化合物的化学当量，式III化合物的加入量为1.2～1.5当量；Cs2CO3的加入量为1.5～3当量。
  3. 根据权利要求1所述的方法，其中式I中R1为H；R2选自氨基或-(CH2)nNHR8；或者，R2、R3与其相连的碳原子共同构成被C1-3的烷基取代的或非取代的含1个N的五元或六元环；R4、R5、R6相同，为F、 Cl或Br；和R7为H。
  4. 根据权利要求1所述的方法，其中式I化合物为选自如下式KDR6、V01、V3、V4、V5和V6的化合物：
    Figure PCTCN2015081236-appb-100003
  5. 一种制备中间体式II化合物的方法，
    Figure PCTCN2015081236-appb-100004
    所述方法包括以下步骤：
    Figure PCTCN2015081236-appb-100005
    (1)使化合物19与有机金属试剂反应得到化合物21；
    (2)通过滴加三溴化硼使化合物21脱甲醚得到化合物9；和
    (3)和使化合物9与式IV化合物在2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(HATU)存在下反应得到式II化合物，
    其中，R4、R5、R6分别独立选自卤素、C1-2的烷基或卤素取代烷基；R7选自H或卤素；优选地R4、R5、R6相同，为F、Cl或Br；R7为H。
  6. 根据权利要求5所述的方法，其中步骤(1)在钯催化剂的存在下，以锌粉和氰化锌进行反应，或者以正丁基锂为锂试剂并通入二氧化碳气进行羧化反应。
  7. 根据权利要求6所述的方法，其中钯催化剂的用量以化合物19的量计为0.001～0.1当量，优选为约0.005当量。
  8. 根据权利要求5所述的方法，在步骤(2)中，在滴加三溴化硼之前，基于化合物21的量先加入0.5～2当量，优选1当量的DIPEA。
  9. 根据权利要求5所述的方法，其中化合物19按照以下步骤制备：
    A以化合物13和化合物14为起始反应物，在90℃～110℃进行反应，减压浓缩后得到化合物15粗品
    B化合物15粗品在二苯醚中加热至220℃～250℃，优选240℃下反应得到化合物16；
    C化合物16在碱性水溶液中水解得到化合物17；
    D化合物17经加热脱羧反应得到化合物18；和
    E化合物18与三溴氧磷反应得到化合物19。
  10. 根据权利要求9所述的方法，其中步骤B中，反应结束后使反应物以低于3℃/分钟，优选低于1℃/分钟的速度降温至室温获得结晶的化合物16。
  11. 根据权利要求9所述的方法，其中步骤C的反应结束后，用冰 盐酸水溶液将反应液的pH值调至5～6之间，过滤并干燥滤饼，得到化合物17的粗品，直接用于下一步反应。
  12. 根据权利要求9所述的方法，其中步骤D的脱羧反应在二苯醚中回流约1小时。
  13. 根据权利要求9所述的方法，其中步骤E中，在甲苯中加热至回流进行反应；当反应结束后，保持在30℃以下，缓慢加入氨水溶液，用乙酸乙酯萃取，将有机层减压浓缩得到化合物19，不需进一步纯化可直接进行上述步骤1的反应。
  14. 一种制备式I化合物的方法，
    Figure PCTCN2015081236-appb-100006
    其中，X为C，Y为N；R1为H；R2选自氨基或-(CH2)nNHR8；或者，R2、R3与其相连的碳原子共同构成被C1-3的烷基取代的或非取代的含1个N的五元或六元环；R4、R5、R6相同，为F、Cl或Br；和R7为H，
    其中，所述方法包括在极性有机溶剂中，使式II化合物在Cs2CO3的存在下与式III化合物反应得到式I化合物的步骤：
    Figure PCTCN2015081236-appb-100007
    且其中，所述式II化合物根据权利要求5-13中任意一项所述的方法制备。
PCT/CN2015/081236 2014-06-13 2015-06-11 一种抗血管新生化合物及其中间体的制备方法 WO2015188762A1 (zh)

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* Cited by examiner, † Cited by third party
Title
HARMANGE, J.C. ET AL.: "Naphthamides as Novel and Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: Design, Synthesis, and Evaluation", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 6, 7 March 2008 (2008-03-07), pages 1649 - 1667, XP002668409 *

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