Calquence（阿卡替尼，Acalabrutinib，ACP-196）是一種選擇性Bruton酪胺酸激酶（BTK）共價抑制劑。Calquence與BTK共價結合，從而抑制其活性，並在臨床前研究中證實與其他免疫細胞相互作用很小。Calquence (Acatinib, Acalabrutinib, ACP-196) is a selective Bruton tyrosine kinase (BTK) covalent inhibitor. Calquence binds covalently with BTK, thereby inhibiting its activity, and has demonstrated little interaction with other immune cells in preclinical studies.
Calquence也正在被開發用於治療多種B細胞惡性腫瘤和其他癌症，包括慢性淋巴細胞白血病（CLL）、套細胞淋巴瘤（MCL）、Waldenström巨球蛋白血症（WM）、濾泡性淋巴瘤、瀰漫性大B細胞淋巴瘤和多種骨髓瘤。它也被作為單一療法和實體瘤的組合試驗進行研究。超過35個臨床試驗，涉及40個國家，超過2,500名患者，正在進行或已經完成。Calquence is also being developed to treat a variety of B-cell malignancies and other cancers, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), follicular lymphoma, Diffuse large B-cell lymphoma and multiple myeloma. It has also been studied as a combination trial of monotherapy and solid tumors. More than 35 clinical trials involving more than 2,500 patients in 40 countries are ongoing or completed.
Calquence於2015年9月被美國食品藥品管理局（FDA）授予治療成人患者套細胞淋巴瘤（MCL）的孤兒藥地位。於2016年3月歐洲藥品管理局（EMA）授予Calquence治療CLL、MCL、WM的孤兒藥地位。Calquence於2017年8月被FDA授予突破性治療指定，並於2017年10月31日批准其於用於治療已接受過至少一種療法的套細胞淋巴瘤（MCL）的成人患者。Calquence was granted orphan drug status by the US Food and Drug Administration (FDA) in September 2015 for the treatment of mantle cell lymphoma (MCL) in adult patients. In March 2016, the European Medicines Agency (EMA) granted Calquence the orphan drug status for the treatment of CLL, MCL, and WM. Calquence was granted a breakthrough treatment designation by the FDA in August 2017, and was approved on October 31, 2017 for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one therapy.
國際專利申請WO2013/010868A1公開了Acalabrutinib的合成方法： International patent application WO2013/010868A1 discloses the synthesis method of Acalabrutinib:
化合物XI
是製備阿卡替尼的關鍵中間體，國際專利申請WO2013/010868A1也報導了化合物XI
的合成路線： Compound XI is a key intermediate for the preparation of acatinib. The international patent application WO2013/010868A1 also reported the synthetic route of compound XI :
在WO2013/010868A1中製備化合物VIII的技術方案需要使用昂貴的試劑HATU，導致原料成本很高。同時，製備化合物XI的方法需要-78 °C的溫度並且涉及使用氨氣，不利於放大生產。The technical solution for preparing compound VIII in WO2013/010868A1 requires the use of an expensive reagent HATU, resulting in high raw material costs. Meanwhile, the method of preparing compound XI requires a temperature of -78 °C and involves the use of ammonia gas, which is not conducive to scale-up production.
化合物IV
是合成阿卡替尼的另一個關鍵中間體。文獻Bioorganic & Medicinal Chemistry Letters,2006
,16
, 5217-5211對化合物IV
的合成進行了報導，其合成路線如下圖： Compound IV is another key intermediate in the synthesis of acatinib. The literature Bioorganic & Medicinal Chemistry Letters, 2006 , 16 , 5217-5211 reports on the synthesis of compound IV , and the synthetic route is as follows:
上述合成方案需要使用4-羧基苯硼酸為原料和價格較貴的縮合劑BOP，導致化合物IV
的成本過高。The above synthesis scheme requires the use of 4-carboxyphenylboronic acid as the raw material and the expensive condensing agent BOP, which leads to the high cost of compound IV .
一種化合物IV
的更簡單高效的合成途徑如下： A simpler and more efficient synthetic route for compound IV is as follows:
然而，上述合成途徑存在若干技術問題： 1）由於2-胺基吡啶的胺基親核性差，化合物I-a
和化合物II
反應形成醯胺鍵，生成化合物III-a
要比預想的困難得多。專利WO2015048689A1和WO2015104722A1報導的產率分別只有65%和45%。 在Tetrahedron Letters2009
,50
, 1986-1988文章中，作者明確指出“When the acylations are attempted with weakly nucleophilic amines, however, they are often met with long reaction times and harsh conditions. …Although there is ample literature precedent for carboxylic acid couplings with 2-aminopyridines, the yields tend to be quite variable and more often than not, require transformation to the acid chloride prior to coupling.”。
嘗試參照專利文獻WO2015/048689A1反應條件製備化合物III-a
，反應結果除生成少量目標化合物III-a
以外，會有大量副產物B
生成。2）芳基溴轉化為對應的硼酸通常涉及與有機鋰試劑或格氏試劑的鹵素-金屬交換，然後與三烷基硼酸酯反應。然而，由於化合物III-a
本身的特殊性，通過鹵素-金屬交換形成對應的有機金屬化合物可能會被醯胺鍵上的酸性質子猝滅，很難生成。 技術問題： 習知技術對合成阿卡替尼中間體化合物IV
和化合物XI
的方法，需要繁瑣的純化和特殊的設備，原料成本高，產率低。需要克服習知技術方案存在的問題，開發一種可用於大規模生產的方案。However, there are several technical problems in the above synthetic route: 1) Due to the poor amine nucleophilicity of 2-aminopyridine, compound Ia and compound II react to form an amide bond, and it is much more difficult than expected to produce compound III-a . The yields reported by patents WO2015048689A1 and WO2015104722A1 are only 65% and 45%, respectively. In the article of Tetrahedron Letters 2009 , 50 , 1986-1988, the author clearly stated that “When the acylations are attempted with weakly nucleophilic amines, however, they are often met with long reaction times and harsh conditions. …Although there is ample literature precedent for carboxylic acid couplings with 2-aminopyridines, the yields tend to be quite variable and more often than not, require transformation to the acid chloride prior to coupling.". Attempt to prepare compound III-a according to the reaction conditions of patent document WO2015/048689A1. In addition to the formation of a small amount of target compound III-a , a large amount of by-product B will be produced as a result of the reaction. 2) The conversion of aryl bromide to the corresponding boric acid usually involves halogen-metal exchange with organolithium reagents or Grignard reagents, followed by reaction with trialkylboronic acid esters. However, due to the particularity of compound III-a itself, the formation of corresponding organometallic compounds through halogen-metal exchange may be quenched by acidic protons on the amide bond, making it difficult to generate. Technical problem: The conventional technology requires a cumbersome purification and special equipment to synthesize the intermediate compound IV and compound XI of acatinib, and the raw material cost is high and the yield is low. It is necessary to overcome the problems of conventional technical solutions and develop a solution that can be used for mass production.
本發明的目的是提供一種低成本且可以放大生產製備阿卡替尼及其中間體式IV
化合物和式XI
化合物的方法。The object of the present invention is to provide a low-cost and scalable method for preparing acartinib and its intermediate compounds of formula IV and XI .
本申請的一個目的是提供化合物IV
的製備方法。An object of the present application is to provide a method for preparing compound IV .
本申請的另一個目的是提供化合物XI
的製備方法。Another object of the present application is to provide a method for preparing compound XI .
本申請的另一個目的是提供阿卡替尼（式XV
化合物）的製備方法。Another object of the present application is to provide a method for preparing acartinib (a compound of formula XV ).
本申請提供了製備式IV
化合物的方法：其中R1係選自C1~20烷基、芳基或取代的芳基，優選為甲基、乙基、正丙基、異丙基和苯基；其中X為Br或I。更優選地，其中R1為異丙基，X為Br。This application provides a method for preparing the compound of formula IV : Wherein R1 is selected from C1-20 alkyl, aryl or substituted aryl, preferably methyl, ethyl, n-propyl, isopropyl and phenyl; wherein X is Br or I. More preferably, wherein R1 is isopropyl and X is Br.
在具體實施方案中，每個反應步驟的反應條件詳述如下：In a specific embodiment, the reaction conditions of each reaction step are detailed as follows:
由式I
化合物和式II
化合物合成式III
化合物：許多已知方法和偶聯劑用於由羧酸和胺形成醯胺，例如通過醯鹵或使用EDCI、HATU等縮合劑。然而，因為化合物II
的低親核性質，醯胺的形成很困難（Tetrahedron Letters,2009
,50,
1986-1988）。在檢索到的文獻報導中，由化合物II
通過醯胺化反應製備化合物III
的產率都不高（(a) Tetrahedron,2008
,64
, 6230-6237; (b) J. Org. Chem.2002
,67
, 8832-8841; (c) J. Med.Chem.2007
,50
, 1850-1864）。 在許多試驗失敗後，意外地發現使用特別的羧酸活化試劑可以高產率的獲得醯胺化合物III
。活化試劑係選自N,N'-羰基二咪唑、甲磺醯氯、對甲苯磺醯氯或對硝基苯磺醯氯。有機溶劑係選自N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、乙腈、四氫呋喃、甲基四氫呋喃、甲苯、二甲苯、1,4-二氧六環、二甲亞碸、N-甲基吡咯烷酮、環丁碸、二氯甲烷中的一種或多種，優選地，有機溶劑選自四氫呋喃、甲苯或1,4-二氧六環。Synthesis of compound of formula III from compound of formula I and compound of formula II : Many known methods and coupling agents are used to form amides from carboxylic acids and amines, for example by halides or using EDCI, HATU and other condensing agents. However, because of the low nucleophilic nature of compound II , the formation of amides is difficult (Tetrahedron Letters, 2009 , 50, 1986-1988). In the literature reports retrieved, the yield of compound III prepared from compound II through the amidation reaction is not high ((a) Tetrahedron, 2008 , 64 , 6230-6237; (b) J. Org. Chem. 2002 , 67 , 8832-8841; (c) J. Med. Chem. 2007 , 50 , 1850-1864). After many tests failed, it was unexpectedly found that the use of special carboxylic acid activating reagent can obtain the amide compound III in high yield. The activation reagent is selected from N,N'-carbonyldiimidazole, mesylate chloride, p-toluenesulfonyl chloride or p-nitrobenzenesulfonyl chloride. The organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, toluene, xylene, 1,4-dioxane, dioxane One or more of formazan, N-methylpyrrolidone, cyclobutane, and methylene chloride. Preferably, the organic solvent is selected from tetrahydrofuran, toluene, or 1,4-dioxane.
由式III
化合物合成式IV
化合物：化合物III
在有機金屬試劑的存在下與三烷基硼酸酯反應生成化合物IV
。有機金屬試劑係選自丁基鋰、乙基鋰、戊基鋰、苯基鋰、甲基鋰、環己基鋰、異丙基氯化鎂及異丙基溴化鎂中的一種或多種。R1為C1~20烷基、芳基或取代的芳基，優選地R1為甲基、乙基、正丙基、異丙基或苯基，更優的R1為異丙基，金屬有機試劑為正丁基鋰。 對反應物、有機金屬試劑和烷基硼酸進行了篩選。由於化合物III
的醯胺鍵上的氫原子可能會與有機鋰或格任亞（Grignard）試劑反應，或醯胺鍵上的質子可能猝滅生產的芳基鋰或芳基格任亞試劑，因此製備了兩種氮原子保護了的III-a
化合物嘗試進行反應。結果總結在下表中：
通常，鋰鹵交換反應從鹵素-金屬交換開始，通過將芳基鹵代物與有機金屬試劑混合，然後加入三烷基硼酸酯。如上表所示，使用化合物III-a
進行該反應，產率都不是很高（序號1-5）。化合物III-a
的醯胺鍵上的氫原子在鹵素-金屬交換發生之前與有機金屬試劑反應或通過提供質子淬滅芳基鋰或芳基格任亞試劑，使反應不能很好的進行。出人意料地發現，改變反應物的加入順序可以高產率地得到化合物IV
。通過在低溫下將有機鋰加入到化合物III-a
和三烷基硼酸酯的混合物中獲得了意想不到的高產率（序號8）。Synthesis of compound of formula IV from compound of formula III : Compound III reacts with trialkyl borate in the presence of an organometallic reagent to produce compound IV . The organometallic reagent is one or more selected from butyl lithium, ethyl lithium, pentyl lithium, phenyl lithium, methyl lithium, cyclohexyl lithium, isopropyl magnesium chloride, and isopropyl magnesium bromide. R1 is C1~20 alkyl, aryl or substituted aryl, preferably R1 is methyl, ethyl, n-propyl, isopropyl or phenyl, more preferably R1 is isopropyl, the metal organic reagent is N-butyl lithium. The reactants, organometallic reagents and alkylboronic acid were screened. Since the hydrogen atom on the amide bond of Compound III may react with organolithium or Grignard reagents, or the protons on the amide bond may quench the produced aryllithium or arylgrenion reagents, so Two III-a compounds protected by nitrogen atoms were prepared to try the reaction. The results are summarized in the following table: Generally, the lithium halogen exchange reaction starts with halogen-metal exchange, by mixing an aryl halide with an organometallic reagent, and then adding a trialkyl borate. As shown in the above table, the reaction was carried out using compound III-a , and the yield was not very high (serial numbers 1-5). The hydrogen atom of the amide bond of the compound III-a reacts with the organometallic reagent before the halogen-metal exchange occurs or quenches the aryllithium or arylgrenia reagent by providing protons, so that the reaction does not proceed well. Surprisingly, it was found that changing the order of addition of the reactants can give compound IV in high yield. By adding organolithium to the mixture of compound III-a and trialkyl borate at a low temperature, an unexpectedly high yield is obtained (No. 8).
由式IV
化合物合成式XIV-a
或XIV-b
化合物：式IV
化合物與醇反應生成式XIV-a
或XIV-b
化合物。其中，醇係選自甲醇、乙醇、丙醇、異丙醇或頻哪醇。更優選地，醇係甲醇或頻哪醇。R1是C1~20的烷基、芳基或取代的芳基，優選為甲基、乙基、丙基、異丙基或苯基。Synthesis of compounds of formula XIV-a or XIV-b from compounds of formula IV : A compound of formula IV reacts with an alcohol to form a compound of formula XIV-a or XIV-b . Among them, the alcohol is selected from methanol, ethanol, propanol, isopropanol or pinacol. More preferably, the alcohol is methanol or pinacol. R1 is C1-20 alkyl, aryl or substituted aryl, preferably methyl, ethyl, propyl, isopropyl or phenyl.
本申請提供了製備式XI
化合物的方法：在具體實施方案中，每個反應步驟的反應條件詳述如下：This application provides a method for preparing the compound of formula XI : In a specific embodiment, the reaction conditions of each reaction step are detailed as follows:
本申請提供了製備式XI
化合物的方法：This application provides a method for preparing the compound of formula XI :
由式VI
化合物與式VII
化合物反應合成式VIII
化合物：首先化合物V
與草醯氯反應得到醯氯化合物VI
，醯氯化合物VI
與化合物VII
或其鹽反應得到化合物VIII
。其中，草醯氯相對於式V
化合物的當量為0.8~10。更優選地，草醯氯相對於式V
化合物的當量為1.5~3。式VIII
化合物的掌性雜質不大於2％。更優選地，式VIII
化合物的掌性雜質不大於0.5％。 BOP、PyBOP、HBTU、TBTU、EDCI等偶聯試劑的常見問題是價格高，原子經濟性低。該類反應一般會生成大量副產物。由於外消旋化問題，醯氯方法通常不用於掌性純胺基酸合成醯胺。本發明發展了一種使用草醯氯製備醯氯中間體，同時外消旋化被很好地抑制的實驗方案。The compound of formula VIII is synthesized from the reaction of compound of formula VI with compound of formula VII : First, compound V is reacted with oxalyl chloride to obtain compound chlorinated compound VI , and compound chlorinated compound VI is reacted with compound VII or a salt thereof to obtain compound VIII . Among them, the equivalent of oxalyl chloride to the compound of formula V is 0.8 to 10. More preferably, the equivalent of oxalochloride to the compound of formula V is 1.5~3. The palm impurities of the compound of formula VIII are not more than 2%. More preferably, the palm impurities of the compound of formula VIII are no more than 0.5%. The common problems of coupling reagents such as BOP, PyBOP, HBTU, TBTU, EDCI, etc. are high price and low atom economy. Such reactions generally generate large amounts of by-products. Due to racemization problems, the acetyl chloride method is generally not used to synthesize amide with palm pure amino acids. The present invention develops an experimental scheme for preparing chloroform intermediates using oxalochloride, while racemization is well suppressed.
由式VIII
化合物合成式X
化合物：式VIII
化合物與脫水試劑反應，得到式IX
化合物。化合物IX
與溴化試劑反應，得到式X
化合物。其中溶劑係選自N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、乙腈、四氫呋喃、甲基四氫呋喃、甲苯、二甲苯、二氧六環、二甲基亞碸、N-甲基吡咯烷酮、環丁碸及二氯甲烷中的一種或多種；脫水試劑係選自三氯氧磷或五氯化磷。Synthesis of compound of formula X from compound of formula VIII : The compound of formula VIII is reacted with a dehydrating reagent to obtain the compound of formula IX . Compound IX is reacted with a bromination reagent to obtain a compound of formula X. The solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, toluene, xylene, dioxane, dimethyl sulfoxide , N-methylpyrrolidone, cyclobutane and one or more of dichloromethane; dehydration reagent is selected from phosphorus oxychloride or phosphorus pentachloride.
由式X
化合物合成式XI
化合物：通過使式X
化合物與氨水在有機溶劑中反應製備化合物XI
。溶劑係選自N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、乙腈、異丙醇、叔丁醇、四氫呋喃、甲基四氫呋喃、甲苯、二甲苯、二氧六環、二甲基亞碸、N-甲基吡咯烷酮、環丁碸及二氯甲烷中的一種或多種。更優選地，溶劑係異丙醇。Synthesis of compound of formula XI from compound of formula X : Compound XI is prepared by reacting the compound of formula X with ammonia water in an organic solvent. The solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, isopropanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, toluene, xylene, dioxane One or more of cyclo, dimethyl sulfoxide, N-methylpyrrolidone, cyclobutane and dichloromethane. More preferably, the solvent is isopropyl alcohol.
本申請提供了一種製備阿卡替尼（式XV
化合物）的方法： This application provides a method for preparing acatinib (compound of formula XV ):
本發明的合成途徑，提供了一種製備阿卡替尼、中間體IV
和中間體XI
的合成方法，該合成途徑成本低，可用於放大生產。The synthetic route of the present invention provides a synthetic method for preparing acatinib, intermediate IV and intermediate XI . The synthetic route has low cost and can be used for scale-up production.
以下通過實施例來描述本申請的實施方式，本領域的技術人員應當認識到，這些具體的實施例僅表明為了達到本申請的目的而選擇的實施技術方案，並不是對技術方案的限制。根據本申請的教示，結合習知技術對本申請技術方案的改進是顯然的，均屬於本申請保護的範圍。The following describes the implementation of the present application through examples. Those skilled in the art should recognize that these specific examples only show implementation technical solutions selected for the purpose of the present application, and do not limit the technical solutions. According to the teachings of the present application, it is obvious that the improvement of the technical solution of the present application in combination with the conventional technology belongs to the protection scope of the present application.
實施例中採用的實施條件可以根據具體要求做進一步調整，未註明的實施條件通常為常規實驗中的條件。其中，在以下實施例中用到的化學試劑均為市售的化學試劑。實施例 1 將2.0 g對溴苯甲酸（化合物I-a）、1.11 g三乙胺加入反應瓶中，加入16 mL的1,4-二氧六環，滴加甲基磺醯氯1.25 g，升溫至40 °C攪拌2 h。加入1.35 g的4-二甲胺基吡啶和1.41 g鄰胺基吡啶，加完後升溫至60 °C反應3 h。加入20 mL的水淬滅反應，用20 mL的乙酸乙酯萃取兩次，合併有機相，減壓蒸餾除去溶劑，用正庚烷/乙酸乙酯通過矽膠管柱層析純化，獲得產物，產率69%。 化合物III-a
核磁資料如下：1
H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.40 (dd,J
= 4.8, 1.1 Hz, 1H), 8.18 (d,J
= 8.4 Hz, 1H), 8.03-7.93 (m, 2H), 7.91-7.81 (m, 1H), 7.77-7.67 (m, 2H), 7.26-7.11 (m, 1H).實施例 2 將20.0 g對溴苯甲酸（化合物I-a）、19.34 g 的N,N-羰基二咪唑加入反應瓶中，加入200 mL甲苯，升溫至60 °C攪拌2 h。加入14.04 g鄰胺基吡啶，加完後升溫至100 °C反應4 h。反應液用飽和碳酸鈉洗滌一次，純淨水洗滌兩次，飽和食鹽水洗滌一次，將得到的有機相濃縮至100 mL，降溫至0~5 °C後攪拌1 h，抽濾、烘乾，得到23 g白色固體，產率84%。實施例 3 將10 mL濃度為2 mol/L 的異丙基氯化鎂的四氫呋喃溶液加入反應瓶中，並加入20 mL 四氫呋喃，降溫至-20~-30 °C，滴加16.4 mL濃度為2.5 mol/L的正丁基鋰的正己烷溶液，攪拌10 min。控制內溫-20~-30 °C，滴加35 mL化合物III-a
的四氫呋喃溶液，攪拌20 min。控制內溫-20~-30 °C，滴加3.75 g硼酸三甲酯，維持-20~-30 °C反應16 h。倒入50 mL飽和氯化銨淬滅反應，用100 mL乙酸乙酯萃取三次，合併有機相，減壓蒸餾除去溶劑，用二氯甲烷/甲醇通過矽膠管柱層析純化，得2.0 g產物，產率45.8%。1
H NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 8.52-8.36 (m, 1H), 8.35-8.17 (m, 2H), 8.11-7.79 (m, 5H), 7.24-7.12 (m, 1H).實施例 4 向反應瓶中加入1.98 g化合物III-a
，加入20 mL四氫呋喃，降溫至-60~-70 °C，低溫下加入6.8 mL濃度為2.5 mol/L的正丁基鋰的正己烷溶液，加入2.72 g 硼酸三異丙酯。反應結束，反應液倒入100 mL 飽和氯化銨淬滅，用200 mL 乙酸乙酯萃取兩次，合併有機相，用飽和食鹽水洗滌，減壓蒸餾除去溶劑，用乙酸乙酯和正庚烷打漿純化，得0.92 g產物，產率53%。實施例 5 向反應瓶中加入10 mL 四氫呋喃和1.01g化合物III-a，降溫至-60~-70 °C，加入1.36 g硼酸三異丙酯。低溫下加入6 mL濃度為2.5 mol/L的正丁基鋰的正己烷溶液，中間補加1 mL硼酸三異丙酯。反應結束，將反應液倒入50 mL飽和氯化銨淬滅，用100 mL乙酸乙酯萃取兩次，合併有機相，用飽和食鹽水洗，減壓蒸餾除去溶劑，用乙酸乙酯和正庚烷打漿純化，得0.76 g產物，產率86%。實施例 6 向反應瓶中加入500 mL 四氫呋喃和50 g化合物III-a
，降溫至-60~-70 °C，加入84.9g硼酸三異丙酯。低溫下加入378 mL濃度為2.5 mol/L的正丁基鋰的正己烷溶液，反應結束，將反應液倒入500mL濃度為10%的氯化銨溶液淬滅，用500 mL乙酸乙酯萃取兩次，合併有機相，用飽和食鹽水洗，減壓蒸餾除去溶劑，用乙酸異丙酯和正庚烷打漿純化，得39 g產物，產率90%。實施例 7 向反應瓶中加入化合物IV
(17.2 g)、頻哪醇 (12.6 g) 和甲醇 (70 mL)。在40~50 °C下攪拌反應2 h。反應結束，降溫至 5 °C攪拌1 h。過濾、乾燥，得化合物XIV-b
為14.5 g，產率63%。1
H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.40-8.38 (m, 1H), 8.23-8.20 (m, 1H), 8.06-8.02 (m, 2H), 7.87-7.77 (m, 3H), 7.18-7.14 (m, 1H), 1.31 (s, 12H).實施例 8 向反應瓶中加入化合物III-b
(2.00 g)、硼酸三異丙酯 (2.90 g) 和四氫呋喃 (20 mL) ，降溫至-60~-70 °C，緩慢加入正丁基鋰正己烷溶液(8.64 mL、2.5 M)。反應結束，加入飽和NH4
Cl 溶液(50 mL) 。混合物用乙酸乙酯(2 x 100 mL) 萃取。合併有機相，用飽和食鹽水洗滌，濃縮。粗產物用乙酸乙酯和正庚烷通過矽膠管柱純化，得產物化合物IV
為0.92 g，產率62%。實施例 9 將5.0 g化合物V
、二氯甲烷（10 vol ）、N,N-二甲基甲醯胺（0.25 mL）加入到100 mL三口瓶中，攪拌溶解。加入二氯亞碸（4 eq），室溫攪拌反應。反應結束，減壓蒸餾除去溶劑，用二氯甲烷（4 vol）稀釋得化合物VI
的二氯甲烷溶液。 向另一100 mL反應瓶中加入化合物VII
（3 g），加入二氯甲烷（6 vol）和三乙胺（6 eq），攪拌降溫至0~10 °C。在0~10 °C滴加化合物VI
的二氯甲烷溶液，滴加完畢後於室溫攪拌反應。反應結束，加入二氯甲烷（10 vol）、水（20 vol）分液，水相用二氯甲烷（10 vol）萃取。合併有機相，分別用飽和氯化銨（10 vol）及飽和碳酸氫鈉（10 vol）洗滌。有機相濃縮，粗產物用乙酸異丙酯和正庚烷結晶純化得產物6.0 g，產率96%，掌性純度99.7%。 化合物VIII
核磁資料如下（樣品採用通過管柱純化得到）：1
H NMR (400 MHz, DMSO) δ 8.65-8.35 (m, 3H), 7.42-7.20 (m, 5H), 5.13-4.97 (m, 2H), 4.63-4.40 (m, 2H), 4.35-4.22 (m, 1H), 3.55-3.35 (m, 2H), 2.25-2.05 (m, 1H), 1.97-1.74 (m, 3H).實施例 10 將30 g化合物V
、二氯甲烷（10 vol ）、N,N-二甲基甲醯胺（0.5 mL）加入到1000 mL三口瓶中，攪拌溶解。加入二氯亞碸（2 eq），室溫攪拌反應。反應結束後減壓蒸餾除去溶劑，用甲苯（2 vol）真空蒸餾，用二氯甲烷（4 vol）稀釋得化合物VI
的二氯甲烷溶液。 向另一1000 mL反應瓶中加入化合物VII
（3 g），加入二氯甲烷（6 vol）和三乙胺（6 eq），攪拌降溫至0~10 °C。在0~10 °C滴加化合物VI
的二氯甲烷溶液，滴加完畢後於室溫攪拌反應。反應結束，加入二氯甲烷（10 vol）、水（20 vol）分液，水相用二氯甲烷（10 vol）萃取。合併有機相，分別用飽和氯化銨（10 vol）及飽和碳酸氫鈉（10 vol）洗滌。有機相濃縮，粗產物通過矽膠管柱純化，掌性純度90%，用乙酸異丙酯和正庚烷結晶純化得產物28.5 g，產率76%，掌性純度92.7%。實施例 11 將49.8 g化合物V
、二氯甲烷（10 vol ）、N,N-二甲基甲醯胺（0.1 vol）加入到500 mL三口瓶中，攪拌溶解。在0~10 °C加入草醯氯（1.5 eq），室溫攪拌反應。反應結束蒸除溶劑，用二氯甲烷（4 vol）稀釋得化合物VI
的二氯甲烷溶液。 向另一1000 mL反應瓶中加入化合物V
（30 g），加入二氯甲烷（8 vol）和三乙胺（6 eq），攪拌降溫至0~10 °C。在0~10 °C滴加化合物VI
的二氯甲烷溶液，滴加完畢室溫攪拌反應。反應結束，加入水（10 vol）分液，有機相分別用1 N HCl（10 vol）、飽和碳酸氫鈉（10 vol）及水（10 vol）洗滌。有機相濃縮，粗產物用乙酸異丙酯和正庚烷結晶純化，得產物61 g，產率98%，掌性純度99.7%。實施例 12 向250 mL反應瓶中加入5 g化合物VIII
、二氯甲烷（25 vol）、N,N-二甲基甲醯胺（1 eq）並攪拌降溫至0~10 °C。在此溫度下滴加三氯氧磷（5 eq），加畢於室溫攪拌反應。反應結束加入冰水（10 vol）、飽和碳酸氫鈉（10 vol）溶液分液，有機相用飽和氯化銨（10 vol）洗滌，得化合物IX
的二氯甲烷溶液。回流分水後，加入N-溴代丁二醯亞胺（0.9 eq）。反應結束後，反應液分別用飽和氯化銨（6 vol）、飽和碳酸氫鈉（6 vol）及水（10 vol）洗滌，得化合物X
的二氯甲烷溶液。減壓蒸餾除去溶劑，加入異丙醇（8 vol）真空蒸餾後，轉至壓力反應容器中，加入異丙醇（20 vol）及氨水（10 vol），加熱120 °C反應。反應結束用減壓蒸餾除去溶劑，加入乙酸異丙酯和水分液。有機相用1 N HCl萃取兩次。水相用30% NaOH調節pH至8~9，用乙酸異丙酯萃取，乙酸異丙酯和正庚烷結晶純化得化合物XI
，總產率63.6%。 化合物XI
核磁資料如下：1
H NMR (400 MHz, DMSO) δ 7.68 (m, 1H), 7.44-7.07 (m, 4H), 6.96 (m, 1H), 6.76 (d,J
= 7.0 Hz, 1H), 6.65 (s, 2H), 5.32 (ddd,J
= 10.8, 7.5, 4.0 Hz, 1H), 5.12-4.64 (m, 2H), 3.54 (ddd,J
= 23.5, 15.8, 8.7 Hz, 2H), 2.38-2.06 (m, 2H), 2.04-1.83 (m, 2H).實施例 13 向反應瓶中加入化合物VIII
(5 g)和乙腈 (30 mL)，加熱至50~60 °C，加入PCl5
(5 g, 1.8 eq) ，在此溫度下攪拌反應20 h。反應結束時加入二氯甲烷 (25 mL) 和水 (25 mL) 。有機相用水洗並濃縮至約15 mL。加入二氯甲烷 (35 mL) 得到化合物IX
的二氯甲烷溶液。 向化合物IX
的二氯甲烷溶液中加入二溴海因(1.7 g, 0.45 eq) 於20~30 °C攪拌反應2 h。反應結束用水洗滌、濃縮，異丙醇/水結晶得到化合物X
(5.0 g)。 向壓力反應釜中加入化合物X
(3.0 g)、異丙醇 (54 mL)和氨水 (18 mL)。加熱至 120 °C反應。反應結束，濃縮，加入乙酸異丙酯和 1 N HCl水溶液進行分液，水相用30%氫氧化鈉調節pH＞10，二氯甲烷萃取。二氯甲烷相濃縮，粗產物用甲醇/水結晶得到化合物XI
為1.17 g，產率35.1%。實施例 14 向反應瓶中加入化合物XI
(4.14 g, 10 mmol)、化合物IV
(2.66 g, 11 mmol)、1,4-二氧六環 (34 mL) 和碳酸鉀水溶液 (4.14 g 碳酸鉀，15 mL水)，加入Pd(dppf)Cl2
(73 mg, 0.1 mmol)。90~100 °C攪拌反應。反應結束後分液，濃縮有機相。粗產物用正庚烷/乙酸乙酯通過矽膠管柱純化，得產物化合物 XII為4.9 g，產率92%。 反應瓶中加入化合物XII
(2.4 g)、醋酸(12 mL)和33%溴化氫醋酸溶液(12 mL)。混合物於 20~30 °C攪拌反應2 h。加入水 (300 mL)和二氯甲烷 (100 mL)分液，水相用二氯甲烷 (100 mL)洗滌。水相用30%氫氧化鈉調節pH＞10並用二氯甲烷萃取(150 mL)。濃縮二氯甲烷相，得化合物XIII
為1.64 g，產率91% 反應瓶中加入化合物XIII
(0.50 g, 1.25 mmol)、2-丁炔酸 (0.11 g, 1.31 mmol)、HATU (0.48 g, 1.25 mmol)、二氯甲烷 (10 mL)及三乙胺 (0.50 g, 5 mmol)。混合物在20~30 °C攪拌反應3 h。反應液用水 (5 mL)洗滌、濃縮。粗產物用二氯甲烷/甲醇通過矽膠管柱純化得化合物XV
為0.5 g，產率90%。 化合物XV
核磁資料如下：1
H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.42-8.39 (m, 1H), 8.26-8.15 (m, 3H), 7.90-7.73 (m, 4H), 7.21-7.11 (m, 2H), 6.25-6.05 (m, 2H), 5.75-5.40 (m, 1H), 3.90-3.55 (m, 2H), 2.47-2.20 (m, 2H), 2.20-2.10 (m, 1H), 2.07-1.90 (m, 3H), 1.63 (s, 1H).The implementation conditions adopted in the examples can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in routine experiments. Among them, the chemical reagents used in the following examples are all commercially available chemical reagents. Example 1 Add 2.0 g of p-bromobenzoic acid (compound Ia) and 1.11 g of triethylamine to the reaction flask, add 16 mL of 1,4-dioxane, add 1.25 g of methanesulfonyl chloride dropwise, and warm up to 40 °C Stir for 2 h. 1.35 g of 4-dimethylaminopyridine and 1.41 g of o-aminopyridine were added, and after the addition, the temperature was raised to 60 °C for 3 h. The reaction was quenched by adding 20 mL of water, extracted twice with 20 mL of ethyl acetate, the organic phases were combined, the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography with n-heptane/ethyl acetate to obtain the product. The rate is 69%. The compound III-a NMR data are as follows: 1 H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.40 (dd, J = 4.8, 1.1 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H) , 8.03-7.93 (m, 2H), 7.91-7.81 (m, 1H), 7.77-7.67 (m, 2H), 7.26-7.11 (m, 1H). Example 2 20.0 g of p-bromobenzoic acid (compound Ia) and 19.34 g of N,N-carbonyldiimidazole were added to the reaction flask, 200 mL of toluene was added, and the temperature was raised to 60 °C and stirred for 2 h. 14.04 g o-aminopyridine was added, and the temperature was raised to 100 °C for 4 h after the addition. The reaction solution was washed once with saturated sodium carbonate, twice with purified water, and once with saturated brine. The obtained organic phase was concentrated to 100 mL, cooled to 0~5 °C, stirred for 1 h, filtered and dried by suction to obtain 23 g white solid, yield 84%. Example 3 Add 10 mL of a 2 mol/L isopropylmagnesium chloride solution in tetrahydrofuran to the reaction flask, and add 20 mL of tetrahydrofuran, cool to -20~-30 °C, and drop 16.4 mL of a 2.5 mol/L positive solution The n-hexane solution of butyl lithium was stirred for 10 min. Control the internal temperature from -20 to -30 °C, add 35 mL of compound III-a in tetrahydrofuran dropwise, and stir for 20 min. Control the internal temperature -20~-30 °C, add 3.75 g trimethyl borate dropwise, maintain -20~-30 °C for 16 h. Pour into 50 mL of saturated ammonium chloride to quench the reaction, extract three times with 100 mL of ethyl acetate, combine the organic phases, distill off the solvent under reduced pressure, and purify by silica gel column chromatography with dichloromethane/methanol to obtain 2.0 g of product. The yield is 45.8%. 1 H NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 8.52-8.36 (m, 1H), 8.35-8.17 (m, 2H), 8.11-7.79 (m, 5H), 7.24-7.12 (m, 1H). Example 4 1.98 g of compound III-a was added to the reaction flask, 20 mL of tetrahydrofuran was added, and the temperature was lowered to -60~-70 °C. At a low temperature, 6.8 mL of a 2.5 mol/L n-butyl lithium n-hexane solution was added, and 2.72 was added. g Triisopropyl borate. At the end of the reaction, the reaction solution was poured into 100 mL of saturated ammonium chloride and quenched, and extracted twice with 200 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, the solvent was distilled off under reduced pressure, and slurried with ethyl acetate and n-heptane After purification, 0.92 g of product was obtained with a yield of 53%. Example 5 Add 10 mL of tetrahydrofuran and 1.01 g of compound III-a to the reaction flask, cool to -60~-70 °C, and add 1.36 g of triisopropyl borate. At a low temperature, 6 mL of a 2.5 mol/L n-butyl lithium solution in n-hexane was added, and 1 mL of triisopropyl borate was added in the middle. At the end of the reaction, the reaction solution was poured into 50 mL of saturated ammonium chloride and quenched, and extracted twice with 100 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, the solvent was distilled off under reduced pressure, and slurried with ethyl acetate and n-heptane Purification gave 0.76 g of product with a yield of 86%. Example 6 Add 500 mL of tetrahydrofuran and 50 g of compound III-a to the reaction flask, cool to -60~-70 °C, and add 84.9 g of triisopropyl borate. At a low temperature, 378 mL of a 2.5 mol/L n-butyllithium solution in n-hexane was added. After the reaction was completed, the reaction solution was poured into 500 mL of a 10% ammonium chloride solution to quench, and extracted with 500 mL of ethyl acetate. Next, the organic phases were combined, washed with saturated brine, the solvent was distilled off under reduced pressure, and purified by slurrying with isopropyl acetate and n-heptane to obtain 39 g of product with a 90% yield. Example 7 Add compound IV (17.2 g), pinacol (12.6 g), and methanol (70 mL) to the reaction flask. The reaction was stirred at 40~50 °C for 2 h. After the reaction was completed, the temperature was lowered to 5 °C and stirred for 1 h. Filtration and drying gave compound XIV-b 14.5 g, yield 63%. 1 H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.40-8.38 (m, 1H), 8.23-8.20 (m, 1H), 8.06-8.02 (m, 2H), 7.87-7.77 (m, 3H), 7.18-7.14 (m, 1H), 1.31 (s, 12H). Example 8 Add compound III-b (2.00 g), triisopropyl borate (2.90 g) and tetrahydrofuran (20 mL) to the reaction flask, cool to -60~-70 °C, and slowly add n-butyl lithium n-hexane solution ( 8.64 mL, 2.5 M). After the reaction was completed, saturated NH 4 Cl solution (50 mL) was added. The mixture was extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, washed with saturated brine, and concentrated. The crude product was purified through a silica gel column with ethyl acetate and n-heptane to obtain the product compound IV was 0.92 g, and the yield was 62%. Example 9 Add 5.0 g of compound V , dichloromethane (10 vol), N,N-dimethylformamide (0.25 mL) to a 100 mL three-necked flask, and stir to dissolve. Add dichloromethane (4 eq) and stir the reaction at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure and diluted with dichloromethane (4 vol) to obtain a dichloromethane solution of compound VI . To another 100 mL reaction flask, add compound VII (3 g), add dichloromethane (6 vol) and triethylamine (6 eq), and stir to cool to 0~10 °C. The methylene chloride solution of compound VI was added dropwise at 0~10 °C. After the addition, the reaction was stirred at room temperature. At the end of the reaction, dichloromethane (10 vol) and water (20 vol) were added for liquid separation, and the aqueous phase was extracted with dichloromethane (10 vol). The organic phases were combined and washed with saturated ammonium chloride (10 vol) and saturated sodium bicarbonate (10 vol), respectively. The organic phase was concentrated, and the crude product was crystallized with isopropyl acetate and n-heptane to obtain 6.0 g of the product, with a yield of 96% and a palm purity of 99.7%. The nuclear magnetic data of Compound VIII are as follows (the sample was obtained by column purification): 1 H NMR (400 MHz, DMSO) δ 8.65-8.35 (m, 3H), 7.42-7.20 (m, 5H), 5.13-4.97 (m, 2H ), 4.63-4.40 (m, 2H), 4.35-4.22 (m, 1H), 3.55-3.35 (m, 2H), 2.25-2.05 (m, 1H), 1.97-1.74 (m, 3H). Example 10 30 g of compound V , dichloromethane (10 vol), and N,N-dimethylformamide (0.5 mL) were added to a 1000 mL three-necked flask, and stirred to dissolve. Dichloromethane (2 eq) was added and the reaction was stirred at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure, vacuum distillation with toluene (2 vol) and dilution with dichloromethane (4 vol) to obtain a dichloromethane solution of compound VI . To another 1000 mL reaction flask, add compound VII (3 g), add dichloromethane (6 vol) and triethylamine (6 eq), and stir to cool to 0~10 °C. The methylene chloride solution of compound VI was added dropwise at 0~10 °C. After the addition, the reaction was stirred at room temperature. At the end of the reaction, dichloromethane (10 vol) and water (20 vol) were added for liquid separation, and the aqueous phase was extracted with dichloromethane (10 vol). The organic phases were combined and washed with saturated ammonium chloride (10 vol) and saturated sodium bicarbonate (10 vol), respectively. The organic phase was concentrated, and the crude product was purified through a silica gel column with a palm purity of 90%. The product was purified by crystallization with isopropyl acetate and n-heptane to give 28.5 g of the product, with a yield of 76% and a palm purity of 92.7%. Example 11 49.8 g of compound V , dichloromethane (10 vol), and N,N-dimethylformamide (0.1 vol) were added to a 500 mL three-necked flask and stirred to dissolve. Add oxalyl chloride (1.5 eq) at 0~10 °C and stir the reaction at room temperature. At the end of the reaction, the solvent was distilled off and diluted with dichloromethane (4 vol) to obtain a dichloromethane solution of compound VI . To another 1000 mL reaction flask, add compound V (30 g), add dichloromethane (8 vol) and triethylamine (6 eq), and stir to cool to 0-10 °C. The methylene chloride solution of compound VI was added dropwise at 0~10 °C, and the reaction was stirred at room temperature after the addition. After the reaction was completed, water (10 vol) was added for liquid separation, and the organic phase was washed with 1 N HCl (10 vol), saturated sodium bicarbonate (10 vol), and water (10 vol), respectively. The organic phase was concentrated, and the crude product was purified by crystallization with isopropyl acetate and n-heptane to obtain 61 g of the product, with a yield of 98% and a palm purity of 99.7%. Example 12 Add 5 g of compound VIII , dichloromethane (25 vol), N,N-dimethylformamide (1 eq) to a 250 mL reaction flask and stir to cool to 0~10 °C. Phosphorus oxychloride (5 eq) was added dropwise at this temperature, and the reaction was stirred at room temperature after the addition. At the end of the reaction, ice-water (10 vol) and saturated sodium bicarbonate (10 vol) solutions were added for liquid separation, and the organic phase was washed with saturated ammonium chloride (10 vol) to obtain a dichloromethane solution of compound IX . After refluxing water, add N-bromobutanediimide (0.9 eq). After the reaction, the reaction solution was washed with saturated ammonium chloride (6 vol), saturated sodium bicarbonate (6 vol), and water (10 vol), respectively, to obtain a dichloromethane solution of compound X. The solvent was distilled off under reduced pressure, isopropyl alcohol (8 vol) was added for vacuum distillation, then transferred to a pressure reaction vessel, isopropyl alcohol (20 vol) and ammonia water (10 vol) were added, and the reaction was heated at 120 °C. At the end of the reaction, the solvent was distilled off under reduced pressure, and isopropyl acetate and water were added. The organic phase was extracted twice with 1 N HCl. The aqueous phase was adjusted to pH 8-9 with 30% NaOH, extracted with isopropyl acetate, and purified by isopropyl acetate and n-heptane crystallization to obtain compound XI with a total yield of 63.6%. The NMR data of Compound XI are as follows: 1 H NMR (400 MHz, DMSO) δ 7.68 (m, 1H), 7.44-7.07 (m, 4H), 6.96 (m, 1H), 6.76 (d, J = 7.0 Hz, 1H) , 6.65 (s, 2H), 5.32 (ddd, J = 10.8, 7.5, 4.0 Hz, 1H), 5.12-4.64 (m, 2H), 3.54 (ddd, J = 23.5, 15.8, 8.7 Hz, 2H), 2.38 -2.06 (m, 2H), 2.04-1.83 (m, 2H). Example 13 Add compound VIII (5 g) and acetonitrile (30 mL) to the reaction flask, heat to 50~60 °C, add PCl 5 (5 g, 1.8 eq), and stir the reaction at this temperature for 20 h. At the end of the reaction, dichloromethane (25 mL) and water (25 mL) were added. The organic phase was washed with water and concentrated to about 15 mL. Dichloromethane (35 mL) was added to obtain a dichloromethane solution of compound IX . Add dibromohydantoin (1.7 g, 0.45 eq) to the dichloromethane solution of compound IX and stir at 20~30 °C for 2 h. At the end of the reaction, it was washed with water, concentrated, and crystallized from isopropanol/water to obtain compound X (5.0 g). To the pressure reactor was added compound X (3.0 g), isopropanol (54 mL) and ammonia water (18 mL). Heat to 120 °C to react. After the reaction, the solution was concentrated, isopropyl acetate and 1 N HCl aqueous solution were added for liquid separation. The aqueous phase was adjusted to pH>10 with 30% sodium hydroxide, and extracted with dichloromethane. The dichloromethane phase was concentrated, and the crude product was crystallized from methanol/water to obtain compound XI 1.17 g, yield 35.1%. Example 14 Add compound XI (4.14 g, 10 mmol), compound IV (2.66 g, 11 mmol), 1,4-dioxane (34 mL) and aqueous potassium carbonate solution (4.14 g potassium carbonate, 15 mL water) to the reaction flask ), Pd(dppf)Cl 2 (73 mg, 0.1 mmol) was added. Stir the reaction at 90~100 °C. After the reaction, the layers were separated and the organic phase was concentrated. The crude product was purified through a silica gel column with n-heptane/ethyl acetate to obtain the product compound XII was 4.9 g, and the yield was 92%. The compound XII (2.4 g), acetic acid (12 mL) and 33% hydrogen bromide acetic acid solution (12 mL) were added to the reaction flask. The mixture was stirred at 20~30 °C for 2 h. Water (300 mL) and dichloromethane (100 mL) were added for liquid separation, and the aqueous phase was washed with dichloromethane (100 mL). The aqueous phase was adjusted to pH>10 with 30% sodium hydroxide and extracted with dichloromethane (150 mL). Concentrate the dichloromethane phase to obtain compound XIII is 1.64 g, yield 91% The reaction flask was added compound XIII (0.50 g, 1.25 mmol), 2-butynoic acid (0.11 g, 1.31 mmol), HATU (0.48 g, 1.25 mmol), dichloromethane (10 mL) and triethylamine (0.50 g, 5 mmol). The mixture was stirred at 20~30 °C for 3 h. The reaction solution was washed with water (5 mL) and concentrated. The crude product was purified through a silica gel column with dichloromethane/methanol to obtain compound XV of 0.5 g, and the yield was 90%. The XV nuclear magnetic data of the compound are as follows: 1 H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.42-8.39 (m, 1H), 8.26-8.15 (m, 3H), 7.90-7.73 (m, 4H), 7.21-7.11 (m, 2H), 6.25-6.05 (m, 2H), 5.75-5.40 (m, 1H), 3.90-3.55 (m, 2H), 2.47-2.20 (m, 2H), 2.20-2.10 (m , 1H), 2.07-1.90 (m, 3H), 1.63 (s, 1H).
