CN114456156A - 一种6-取代氨基苯并呋喃化合物的纯化方法 - Google Patents
一种6-取代氨基苯并呋喃化合物的纯化方法 Download PDFInfo
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- CN114456156A CN114456156A CN202111316931.9A CN202111316931A CN114456156A CN 114456156 A CN114456156 A CN 114456156A CN 202111316931 A CN202111316931 A CN 202111316931A CN 114456156 A CN114456156 A CN 114456156A
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- formula iii
- naphthalene
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- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000000746 purification Methods 0.000 title claims abstract description 16
- -1 6-substituted aminobenzofuran compound Chemical class 0.000 title abstract description 6
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
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- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 claims description 12
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
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- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 11
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 10
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 10
- 229960004889 salicylic acid Drugs 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 229960000583 acetic acid Drugs 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 235000011054 acetic acid Nutrition 0.000 claims description 7
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 6
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 6
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 6
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 6
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 claims description 6
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 claims description 6
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- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 6
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 claims description 6
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- AEMOLEFTQBMNLQ-UHFFFAOYSA-N 3,4,5,6-tetrahydroxyoxane-2-carboxylic acid Chemical compound OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 claims description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
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- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 6
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 6
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- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 6
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本公开涉及一种6‑取代氨基苯并呋喃化合物的纯化方法。具体而言,本公开涉及一种式III所示化合物的纯化方法,经本公开提供的方法可以显著提高式III所示化合物的纯度,为工业生产提供可能。
Description
技术领域
本公开提供一种6-取代氨基苯并呋喃化合物的纯化方法,属于化学领域。
技术背景
淋巴瘤是起源于淋巴造血系统的恶性肿瘤,根据瘤细胞分为非霍奇金淋巴瘤(NHL)和霍奇金淋巴瘤(HL)两类,在亚洲,90%患者为NHL,病理上主要是分化程度不同的淋巴细胞、组织细胞或网状细胞,根据NHL的自然病程,可以归为三大临床类型,即高度侵袭性、侵袭性和惰性淋巴瘤;根据不同的淋巴细胞起源,可以分为B细胞、T细胞和自然杀伤(natural killer,NK)细胞淋巴瘤,其中B细胞的主要职能是分泌各种抗体帮助人体抵御各种外来的侵入。
EZH2基因编码的组蛋白甲基转移酶是多梳蛋白抑制性复合体2(PRC2)的催化组分。与正常组织相比,EZH2水平在癌组织异常升高,而在癌症晚期或不良预后中,EZH2的表达水平最高。在一些癌症类型中,EZH2表达过剩与EZH2基因的扩增同时发生。大量si/shRNA实验研究发现在肿瘤细胞系中减少EZH2表达,可抑制肿瘤细胞的增殖,迁移和侵袭或血管生成,并导致细胞凋亡。
目前已有进入临床开发阶段的EZH2抑制剂,以下简要列举,卫材开发的Tazemetostat(EPZ-6438)用于治疗非霍奇金B细胞淋巴瘤,目前处于临床II期阶段,Constellation公司开发的CPI-1205用于治疗B细胞淋巴瘤,目前处于临床I期阶段,葛兰素史克公司开发的GSK-2816126用于治疗弥漫大B细胞淋巴瘤、滤泡性淋巴瘤,目前处于临床I期阶段
WO2017084494A中提供了一种EZH2抑制剂,结构如下所示:
该申请中同时公开了通式化合物的制备方法,
发明内容
式III所示化合物做为合成式I所示化合物重要的中间体,其纯度的高低直接影响到式I所示化合物药用原料的质量。本公开提供一种式III所示化合物的纯化方法,通过本公开提供的方法可以显著提高式III所示化合物的纯度,
本公开提供的式III所示化合物的纯化方法,其特征在包含将式III所示化合物成盐的步骤。
本公开提供的式III所示化合物的纯化方法,其特征在于将式III所示化合物与至少一种酸成盐的步骤。基于式III所示化合物的性质,本公开中的具体的式III所示化合物的盐可以是单盐或者二盐,具体的,本公开中所述酸选自1-羟基-2-萘甲酸、2,2-二氯乙酸、2-羟基乙磺酸、2-氧代戊二酸、4-乙酰氨基苯甲酸、4-氨基水杨酸、醋酸、己二酸、抗坏血酸(L)、天冬氨酸(L)、苯磺酸、苯甲酸、樟脑酸(+)、樟脑-10-磺酸(+)、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷氨基酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、甲酸、富马酸、乳糖酸、龙胆酸、葡庚糖酸(D)、葡萄糖酸(D)、葡萄糖醛酸(D)、谷氨酸、戊二酸、甘油磷酸、乙醇酸、马尿酸、氢溴酸、盐酸、异丁酸、乳酸(DL)、乳糖酸、月桂酸、马来酸、苹果酸(-L)、丙二酸、扁桃酸(DL)、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸、烟酸、硝酸、油酸、草酸、棕榈酸、双羟萘酸、磷酸、丙酸、焦谷氨酸(-L)、水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、酒石酸(+L)、硫氰酸、甲苯磺酸(p)、十一碳烯酸。
可选的实施方案中,本公开中所述酸选自盐酸、水杨酸或苹果酸(-L)。
一些实施方案中,式III所示化合物以成二盐酸盐的形式纯化。
本公开提供的方法中成盐步骤任选在溶剂存在的条件下操作,当本公开的纯化方法需要溶剂时,所述溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、水、异丙醚、异丙醇、甲醇、乙醇、丙酮、乙醚、冰醋酸、乙腈、石油醚、苯、氯仿、乙酸乙酯、二氧六环、四氢呋喃、二甲基亚砜的至少一种。
可选的实施方案中,成盐步骤在异丙醇存在条件下操作。
本公开提供的纯化方法,需要溶剂参与时,包含将式III所示化合物的盐与溶剂分离的步骤。
本公开提供的方法中成盐使式III所示化合物的纯度高于93%、94%、95%、96%、97%、98%;本公开提供的方法中成盐使未知杂质的含量小于4.0%、3.5%、3.0%、2.5%、2.0%、1.5%、1.0%。
本公开提供的纯化方法中式III所示化合物成盐后任选转化为式III所示化合物,即根据情况,式III所示化合物可以任选以盐的形式参与后续反应。
本公开还提供一种经式IIIa所示化合物发生N-乙基化从而制备式II所示的化合物的方法,
所述X选自1-羟基-2-萘甲酸、2,2-二氯乙酸、2-羟基乙磺酸、2-氧代戊二酸、4-乙酰氨基苯甲酸、4-氨基水杨酸、醋酸、己二酸、抗坏血酸(L)、天冬氨酸(L)、苯磺酸、苯甲酸、樟脑酸(+)、樟脑-10-磺酸(+)、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷氨基酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、甲酸、富马酸、乳糖酸、龙胆酸、葡庚糖酸(D)、葡萄糖酸(D)、葡萄糖醛酸(D)、谷氨酸、戊二酸、甘油磷酸、乙醇酸、马尿酸、氢溴酸、盐酸、异丁酸、乳酸(DL)、乳糖酸、月桂酸、马来酸、苹果酸(-L)、丙二酸、扁桃酸(DL)、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸、烟酸、硝酸、油酸、草酸、棕榈酸、双羟萘酸、磷酸、丙酸、焦谷氨酸(-L)、水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、酒石酸(+L)、硫氰酸、甲苯磺酸(p)、十一碳烯酸,优选盐酸、水杨酸、苹果酸(-L);
n选自1或2。
本公开提供的制备式II所示的化合物的方法,其特征在于还包含将式III所示化合物成盐得到式IIIa所示化合物的步骤。
本公开提供的制备式II所示的化合物的方法,当溶剂参与成盐步骤时,则包含将式IIIa所示化合物与溶剂分离的步骤。
本公开还提供一种式I所示的化合物的制备方法,包含式II所示化合物与3-(氨基甲基)-4,6-二甲基吡啶-2(1H)-酮盐酸盐反应制备得到式I所示的化合物的步骤,其特征在于式II所示化合物经由本公开提供的方法制备,
本公开还提供一种式IIIa所示化合物,
其中X选自1-羟基-2-萘甲酸、2,2-二氯乙酸、2-羟基乙磺酸、2-氧代戊二酸、4-乙酰氨基苯甲酸、4-氨基水杨酸、醋酸、己二酸、抗坏血酸(L)、天冬氨酸(L)、苯磺酸、苯甲酸、樟脑酸(+)、樟脑-10-磺酸(+)、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷氨基酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、甲酸、富马酸、乳糖酸、龙胆酸、葡庚糖酸(D)、葡萄糖酸(D)、葡萄糖醛酸(D)、谷氨酸、戊二酸、甘油磷酸、乙醇酸、马尿酸、氢溴酸、盐酸、异丁酸、乳酸(DL)、乳糖酸、月桂酸、马来酸、苹果酸(-L)、丙二酸、扁桃酸(DL)、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸、烟酸、硝酸、油酸、草酸、棕榈酸、双羟萘酸、磷酸、丙酸、焦谷氨酸(-L)、水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、酒石酸(+L)、硫氰酸、甲苯磺酸(p)、十一碳烯酸;
n选自1或2。
本公开还提供一种式IIIb所示的化合物
本公开提供的由式所示化合物IIIa生成式II所示的化合物的方法,具体可参考PCT申请WO2017084494A中实施例1中公开的类似物的制备方法。
本公开提供的由式II所示化合物到式I所示化合物的制备方法,具体可参考PCT申请WO2017084494A、WO2012142513、WO2013039988、WO2015-141616、WO2011140325中公开的制备酰胺的方法。
本公开提供的式I所示的化合具体可由以下路线制备,
除非有相反陈述,在说明书和权利要求书中使用的英文缩写具有下述含义。
缩写 | 中文含义 |
NIS | N-碘代丁二酰亚胺 |
DMSO | 二甲基亚砜 |
DCM | 二氯甲烷 |
DIPEA | N,N-二异丙基乙胺 |
DavePhos | 2-二环己膦基-2'-(N,N-二甲胺)联苯 |
<sup>t</sup>BuONa | 叔丁醇钠 |
APTDC | 吡咯烷二硫代甲酸铵盐 |
具体实施例方式
以下将结合具体实例详细地解释本公开,使得本专业技术人员更全面地理解本公开具体实例仅用于说明本公开的技术方案,并不以任何方式限定本公开。
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用BrukerAVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS),化学位移是以10-6(ppm)作为单位给出。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号:Finnigan LCQadvantage MAX)。
HPLC的测定使用WATER e2695-2489高效液相色谱仪。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自BEPHARM等公司。
实施例1
第一步:2-乙基-6-碘苯甲酸
将VIII(100g,667mmol)溶于1000mL N,N-二甲基甲酰胺中,搅拌溶解,依次加入NIS(165g,733mmol)和Pd(OAc)2(3g,13.4mmol),氩气置换两次,升温至100℃(内温),搅拌反应4小时,薄层检测原料VIII转化完全,停止反应。
后处理:反应液倒入2L水中,乙酸乙酯萃取(1000mL×3),合并有机相,浓缩除去大部分乙酸乙酯,有机相依次用饱和硫代硫酸钠溶液洗涤(500mL),饱和氯化钠溶液洗涤(500mL),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品184g(黄色油状物),m/z[M-H]-=275.1,1H NMR(400MHz,CHLOROFORM-d)ppm:11.85(br.s.,1H),7.72(d,1H),7.28(d,1H),7.07-7.14(m,1H),2.78(q,2H),1.29(t,3H),产物不经纯化直接进行下一步反应。
第二步:3,5-二溴-2-乙基-6-碘苯甲酸
将VII(27.6g,83mmol)溶于138mL浓硫酸(5mL/g)中,降温至0-5℃,将N-溴代琥珀酰亚胺(19.6g,110mmol)溶于三氟乙酸(5mL/g),控制反应液温度0-5℃,缓慢滴加上述的N-溴代琥珀酰亚胺的三氟乙酸溶液至反应液中,加毕,自然升至室温后反应1小时,缓慢升至40℃后滴加5mL/g N-溴代琥珀酰亚胺的三氟乙酸溶液(14.2g,80mmol),检测VII<2%后停止反应。
后处理:反应液倒入4倍体积冰水中,固体析出,室温搅拌0.5小时,过滤,收集滤饼,用乙酸乙酯溶解,无水硫酸钠干燥后,旋干得粗品,乙酸乙酯重结晶,真空干燥,得到29.5g类白色固体,产率:82%;纯度95.0%。
第三步:6-溴-5-乙基-2-(哌啶-1-基甲基)苯并呋喃-4-甲酸
将VI(100g,230.4mmol)、碳酸铯(187.6g,576mmol)、碘化亚铜(13.16g,69.12mmol)、去离子水(16.6g,921.6mmol)溶于800mL DMSO中,加入V(34.04g,276.5mmol),氩气置换三次,升温至110℃,搅拌反应5小时,薄层跟踪至原料点VI消失,终止反应。
后处理:抽滤漏斗铺硅藻土,反应液趁热过滤,滤饼用少量DMSO淋洗。将滤液缓慢倒入2.4L氯化钠溶液中,冰浴条件下用2N的HCl调节pH至5.5,有固体析出,搅拌0.5小时,过滤,滤饼用水淋洗,收集滤饼,真空烘干后异丙醇重结晶,干燥后得到标题产物48.8g(类白色固体),纯度:97.3%。m/z[M,M+2]=366,368
第四步:5-乙基-2-(哌啶-1-基甲基)-6-((四氢-2H-吡喃-4-基)氨基)苯并呋喃-4-甲酸
将IV(40.8g,110mmol)、DavePhos(0.877g,2.2mmol)、Pd2(dba)3(0.255g,0.278mmol)、t-BuONa(54g,560mmol)和500mL甲苯(经除水除氧处理)加入到反应瓶中,加入四氢-2H-吡喃-4-胺(22.5g,220mmol),氩气置换三次,油浴加热至105-108℃,搅拌反应24小时,薄层跟踪至原料IV消失,停止反应。
后处理:反应液冷却至室温,析出大量固体,缓慢加入250mL水和200mL饱和氯化钠溶液,搅拌溶解。硅藻土过滤除去少量黑色不溶物,滤饼用50mL水淋洗。滤液静置分层,分离有机相,水相用甲苯反萃(250mL×2),合并有机相,用水洗涤(100mL),合并水相,加入APTDC(201mg),升温至50℃搅拌1小时,趁热过滤,滤液用1N HCl溶液调pH至6左右,加入氯化钠固体至溶液饱和,二氯甲烷和甲醇混合溶剂萃取(400mL×3),合并有机相,无水硫酸钠干燥,过滤,滤液中加入2.5g活性碳,升温至回流,搅拌1小时,趁热过滤,滤液减压浓缩,得到粗品III28 g(棕色固体),m/z[M+H]+=387.4,纯度83.1%,未知杂质含量8.3%。
为降低未知杂质含量,对上述所得粗品进行纯化条件筛选,结果如下表1所示:
表1
经小试试验发现,成盐可以显著降低未知杂质的含量,而在所有显著的有益效果中,成二盐酸盐对于粗品III的纯化效果最佳。
将24.5g粗品加入到140mL异丙醇(用量为5mL/g)中,升温至50℃,搅拌15分钟,呈浑浊液,滴加12.7mL浓盐酸(2.1eq),50℃搅拌1小时,自然降至室温搅拌12小时,冰浴冷却搅拌1小时。过滤,滤饼依次用少量冰异丙醇和正己烷淋洗,收集滤饼,真空干燥,得到式III所示化合物,23.0g类白色固体,纯度为99.1%,未知杂质含量为0.55%。
第五步:5-乙基-6-(乙基(四氢-2H-吡喃-4-基)氨基)-2-(哌啶-1-基甲基)苯并呋喃-4-羧酸
将原料IIIb(22.9g,50mmol)置于500mL三颈瓶中,加入200mL DCM,冰浴下滴加入DIPEA(13.5g,105mmol),搅拌0.5小时,溶液澄清,冰浴下,加入乙醛(11g,250mmol)和乙酸(15g,250mmol),搅拌反应0.5小时,冰浴下,分三次(每次10.6g,1.0eq)加入三乙酰氧基硼氢化钠(31.8g,150mmol),升温至室温,搅拌反应反应至薄层跟踪至原料点IIIb消失,终止反应。
后处理:反应液中加入50mL饱和氯化钠溶液,搅拌0.5小时。静置分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,过滤,滤液减压浓缩,得到棕黄色固体,乙醇重结晶,干燥得到16.7g类白色固体,产率81%。m/z[M+H]+=415.5
1H NMR(400MHz,DMSO-d6)ppm 7.55(s,1H)6.76(s,1H)3.82(d,2H)3.65(s,2H)3.22(t,2H)3.05(q,4H)2.95(t,1H)2.46(br.s.,4H)1.66(br.s.,2H)1.44-1.56(m,6H)1.37(br.s.,2H)1.03-1.14(m,3H)0.81(t,3H)
第六步:N-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-5-乙基-6-(乙基(四氢-2H-吡喃-4-基)氨基)-2-(哌啶-1-基甲基)苯并呋喃-4-甲酰胺
500mL三口瓶中,将原料II(17.5g,42.2mmol),1-乙基-3(3-二甲基丙胺)碳二亚胺(12.15g,63.4mmol),1-羟基苯并三唑(8.34g,63.4mmol)和N,N-二异丙基乙基胺(27.26g,210mmol)混合,溶于180mL N,N-二甲基甲酰胺中,搅拌均匀;加入原料3-(氨基甲基)-4,6-二甲基吡啶-2(1H)-酮盐酸盐(8.76g,46.5mmol),室温搅拌反应至薄层跟踪至原料点II消失,终止反应。
将反应液缓慢倒入900mL水中,析出类白色固体,冰浴冷却,搅拌0.5小时,过滤,滤饼抽干,收集滤饼用300mL二氯甲烷溶解,滤液用100mL二氯甲烷萃取,合并有机相,依次用水(100mL×2),饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品泡沫状固体产物25g。
m/z[M+H]+=549.6
1H NMR(400MHz,DMSO-d6)ppm 11.51(s,1H)8.17(t,1H)7.39(s,1H)6.47(s,1H)5.86(s,1H)4.32(d,2H)3.83(d,2H)3.53(s,2H)3.21(t,2H)3.04(d,2H)2.94(br.s.,1H)2.79(d,2H)2.38(br.s.,4H)2.23(s,3H)2.08-2.14(m,3H)1.65(d,2H)1.44-1.56(m,6H)1.36(d,2H)1.02(t,3H)0.81(t,3H)。
Claims (13)
2.根据权利要求1所述的纯化方法,包含将式III所示化合物与至少一种酸成盐的步骤。
3.根据权利要求2所述的纯化方法,所述酸选自1-羟基-2-萘甲酸、2,2-二氯乙酸、2-羟基乙磺酸、2-氧代戊二酸、4-乙酰氨基苯甲酸、4-氨基水杨酸、醋酸、己二酸、抗坏血酸(L)、天冬氨酸(L)、苯磺酸、苯甲酸、樟脑酸(+)、樟脑-10-磺酸(+)、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷氨基酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、甲酸、富马酸、乳糖酸、龙胆酸、葡庚糖酸(D)、葡萄糖酸(D)、葡萄糖醛酸(D)、谷氨酸、戊二酸、甘油磷酸、乙醇酸、马尿酸、氢溴酸、盐酸、异丁酸、乳酸(DL)、乳糖酸、月桂酸、马来酸、苹果酸(-L)、丙二酸、扁桃酸(DL)、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸、烟酸、硝酸、油酸、草酸、棕榈酸、双羟萘酸、磷酸、丙酸、焦谷氨酸(-L)、水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、酒石酸(+L)、硫氰酸、甲苯磺酸(p)、十一碳烯酸,优选盐酸、水杨酸、苹果酸(-L),最优选盐酸。
4.根据权利要求1-3任一项所述的纯化方法,所述成盐步骤任选在溶剂存在的条件下操作。
5.根据权利要求4所述的纯化方法,所述溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、水、异丙醚、异丙醇、甲醇、乙醇、丙酮、乙醚、冰醋酸、乙腈、石油醚、苯、氯仿、乙酸乙酯、二氧六环、四氢呋喃、二甲基亚砜的至少一种,优选异丙醇。
6.根据权利要求5所述的纯化方法,包含将式III所示化合物的盐与溶剂分离的步骤。
7.根据权利要求1-6任一项所述的纯化方法,所述式III所示化合物成盐后任选包含游离为式III所示化合物的步骤。
8.一种式II所示的化合物的制备方法,包含由式IIIa所示化合物发生N-乙基化的步骤,
其中X选自1-羟基-2-萘甲酸、2,2-二氯乙酸、2-羟基乙磺酸、2-氧代戊二酸、4-乙酰氨基苯甲酸、4-氨基水杨酸、醋酸、己二酸、抗坏血酸(L)、天冬氨酸(L)、苯磺酸、苯甲酸、樟脑酸(+)、樟脑-10-磺酸(+)、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷氨基酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、甲酸、富马酸、乳糖酸、龙胆酸、葡庚糖酸(D)、葡萄糖酸(D)、葡萄糖醛酸(D)、谷氨酸、戊二酸、甘油磷酸、乙醇酸、马尿酸、氢溴酸、盐酸、异丁酸、乳酸(DL)、乳糖酸、月桂酸、马来酸、苹果酸(-L)、丙二酸、扁桃酸(DL)、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸、烟酸、硝酸、油酸、草酸、棕榈酸、双羟萘酸、磷酸、丙酸、焦谷氨酸(-L)、水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、酒石酸(+L)、硫氰酸、甲苯磺酸(p)、十一碳烯酸,优选盐酸、水杨酸、苹果酸(-L),最优选盐酸;
n选自1或2。
9.根据权利要求8所述的制备方法,包含将式III所示化合物成盐得到式IIIa所示化合物的步骤。
10.根据权利要求9所述的制备方法,其特征在于溶剂参与成盐步骤且包括将式IIIa所示化合物与溶剂分离的步骤。
12.一种式IIIa所示化合物
其中X选自1-羟基-2-萘甲酸、2,2-二氯乙酸、2-羟基乙磺酸、2-氧代戊二酸、4-乙酰氨基苯甲酸、4-氨基水杨酸、醋酸、己二酸、抗坏血酸(L)、天冬氨酸(L)、苯磺酸、苯甲酸、樟脑酸(+)、樟脑-10-磺酸(+)、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷氨基酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、甲酸、富马酸、乳糖酸、龙胆酸、葡庚糖酸(D)、葡萄糖酸(D)、葡萄糖醛酸(D)、谷氨酸、戊二酸、甘油磷酸、乙醇酸、马尿酸、氢溴酸、盐酸、异丁酸、乳酸(DL)、乳糖酸、月桂酸、马来酸、苹果酸(-L)、丙二酸、扁桃酸(DL)、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸、烟酸、硝酸、油酸、草酸、棕榈酸、双羟萘酸、磷酸、丙酸、焦谷氨酸(-L)、水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、酒石酸(+L)、硫氰酸、甲苯磺酸(p)、十一碳烯酸;
n选自1或2。
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