CN112574234B - 一种海鞘素衍生物的制备方法 - Google Patents
一种海鞘素衍生物的制备方法 Download PDFInfo
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- CN112574234B CN112574234B CN202011021523.6A CN202011021523A CN112574234B CN 112574234 B CN112574234 B CN 112574234B CN 202011021523 A CN202011021523 A CN 202011021523A CN 112574234 B CN112574234 B CN 112574234B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 37
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- -1 potassium methyltrifluoroborate Chemical compound 0.000 claims abstract description 18
- 239000003446 ligand Substances 0.000 claims abstract description 10
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- 238000006243 chemical reaction Methods 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
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- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
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- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
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Abstract
本公开涉及一种海鞘素衍生物的制备方法。具体而言，提供了一种制备ET‑743、PM‑1183或其可药用盐的方法，该方法包括式(a)所示化合物在金属钯‑配体催化下甲基化以形成式(b)所示化合物的步骤，所用甲基化试剂如甲基硼酸、甲基硼酸频哪醇酯或甲基三氟硼酸钾。该工艺操作简便、收率且所样品质量，适于大规模生产。
Description
技术领域
本发明涉及一种海鞘素衍生物的制备方法。
背景技术
曲贝替定(海鞘素743，ET-743)是从海洋生物海鞘素(Ecteinascidia turbinata)中分离得到的，但包含多个手性中心，全合成难度也较大。曲贝替定是一种非常有效的海生抗肿瘤剂，2007年EMA(European Medicines Agency)已批准其在欧洲上市，用于治疗晚期软组织肉瘤，结构如下：
PM-1183(lurbinectedin)是PharmaMar公司自主研发的海鞘素衍生物，与ET-743具有相关骨架结构，正在进行治疗小细胞肺癌(SCLC)临床研究，二期临床数据显示客观缓解率(ORR)可达39.3％，患者中位总生存期(OS)11.8个月，结构如下：
然而从海鞘中提取的Trabectedin(Et-743)最高获取量为0.0001％，这使得从自然界直接获得该化合物作为药源的可能性很低。
目前已经有几条合成路线报道，主要都是从芝麻酚或其衍生物出发，如美国E.J.Corey教授报道的路线总长43步，收率0.53％(J.Am.Chem.Soc,1996,118,9202-9203)，
日本Fukuyama报道的路线总长45步，收率0.78％(J.Am.Chem.Soc,2002,124,6552-6554)，但该工艺步骤长，总产率低，部分步骤的可操作性差，
相比于Fukuyama报道的路线，Corey路线更短、总收率高，更具有可操作性，然而该路线中中间体Corey 16由中间体Corey 15在(Ph3P)2PdCl2/LiCl条件下与四甲基锡反应获得，四甲基锡属于剧毒性物质，且反应可控制差，制约了其大规模生产，
另一方面，上述合成路线被应用于生产的可行性也有限。同时，在金属Pd催化剂(如J.Am.Chem.Soc,1996,118,9202-9203中报道的(Ph3P)2PdCl2/LiCl)条件下，Corey 15转化为Corey 16过程中不可避免产生脱保护基产物杂质A，
如何避免或减少杂质A的产生直接关系到该步工艺收率以及后续产品的质量。因此，需要开发新的海鞘素衍生物的制备方法。
发明内容
本公开(The disclosure)提供了制备式(b)所示的化合物的方法，包括式(a)所示化合物在金属钯-配体催化下甲基化以形成式(b)所示化合物，
所述配体选自双齿膦-膦氧化合物(I)，
其中，R1选自H、卤素、-ORa、-NRaRb、C1-10的直链或支链烷基、C1-4烷氧基、C3-10的环烷基、或取代或未取代的C6-10芳基、含1-3个选自N、O、S的杂原子的5-8元杂环；
Ra和Rb各自独立选自氢、C1-6烷基、C1-4烷氧基、C3-10的环烷基、或取代或未取代的C6-10芳基；
R2选自卤素、C1-10的直链或支链烷基、C3-10的环烷基、或取代或未取代的C6-10芳基；
R3和R4各自独立选自卤素、C1-10的直链或支链烷基、C3-10的环烷基、或取代或未取代的C6-10芳基；
R5选自卤素(包括氯、溴、碘)或-OP3；
P1、P2、P3和P4不同时为氢且各自独立地分别为氢或羟基保护基，优选P1为-SiR5R6R7，其中R5、R6和R7各自分别为C1-10的直链或支链烷基、C3-10的环烷基、或取代或未取代的C6-10芳基，P2、P4各自独立地为氢或取代或未取代的C1-10烷基，P3为烷基或芳基磷酸酯基、三氟甲磺酰基、甲磺酰基或对甲苯磺酰基。
在一些实施方案中，式(I)化合物中R2、R3和R4各自独立选自叔丁基。
在金属Pd催化剂(如J.Am.Chem.Soc,1996,118,9202-9203中报道的(Ph3P)2PdCl2/LiCl)条件下，Corey 15转化为Corey 16过程中不可避免产生脱保护基产物杂质A，杂质A与Corey16的理化性质相近，后续的纯化不能够有效降低该杂质的含量，影响corey 16的质量和收率。
相比而言，本公开所选用的催化体系可以避免或减少杂质A的产生，从而提高该步工艺收率甚至后续产品的质量。
另一方面，在一些所述方案中，本公开所选用的催化体系催化活性高，能快速、高效地甲基化，抑制了其他副反应的发生量，譬如，在PdCl2(dppf)/K3PO4条件下，脱-TBS副产物(如下所示)生成量(含量)不低于10％，一般12-15％，相应地，脱-TBS副产物生成量(含量)不高于5％，一般1.2～4.3％(粗品中)，
在另一些实施方案中，所述配体选自：
其中，R1-R4如式(I)化合物中所定义。
在另一些实施方案中，所述配体选自：
进一步地，在另一些实施方案中，所示配体选自：
在一些实施方案中，本公开中所述甲基化试剂选自甲基硼酸、甲基硼酸频哪醇酯或甲基三氟硼酸钾，优选甲基硼酸。
另一方面，一些实施方案中所述金属钯为二价钯。在一些实施方案中，二价钯来自Pd(OAc)2、Pd(tfa)2、Pd(Piv)2、Pd(OTf)2、PdCl2、Pd(PPh3)2Cl2、Pd(dppf)Cl2中的一种或多种。
本公开所述反应还含有碱性试剂，额外添加的碱更有利于促进反应的进行，所述碱性试剂选自但不限于碳酸钾、碳酸钠、磷酸钾或磷酸钠。
在一些实施方案中，所述反应溶剂选自二甲基甲酰胺、二甲基乙酰胺、1-甲基-2-吡咯烷酮、四氢呋喃、甲基四氢呋喃、二氧六环、甲苯、二甲苯、二甲亚砜、乙醚、异丙醚、甲基叔丁基醚、乙腈、丙腈、异丙醇、丙醇、乙醇、甲醇中的一种或多种，优选二氧六环。
另一方面，本公开所述甲基化反应需要在无水、无氧条件下进行。所用溶剂的处理方式可参见《溶剂手册》(第四版)-程能林编著。
在一些实施方案中，所述反应温度选自60～150℃，可以为60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃、100℃、110℃、120℃、130℃、140℃、150℃或任意两数值之间任意数值，优选80～120℃。
在一些实施方案中，所述二价钯的用量为式(a)化合物摩尔量0.01～0.5(当量)，可以为0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5或任意两数值之间任意数值。
在一些实施方案中，所述配体的用量为式(a)化合物摩尔量0.01～0.5(当量)，可以为0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5或任意两数值之间任意数值。
在一些实施方案中，所述碱的用量为式(a)化合物摩尔量1～10(当量)，可以为1、2、3、、4、5、6、7、8、9、10或任意两数值之间任意数值。
本公开另一方面还提供了一种制备ET-743或其可药用盐的方法，包括前述制备式(b)所示化合物的方法步骤，以及式(b)所示化合物转化为式ET-743或其可药用盐的步骤，
一些实施方案提供制备ET-743或其可药用盐的方法，包括前述制备式(b)所示化合物的方法步骤，以及式(b)所示化合物转化为式ET-743或其可药用盐的步骤，
其中，P1、P2为羟基保护基，优选P1为TBS，P2为MOM；P4为氢。
一些实施方案提供制备ET-743或其可药用盐的方法包括：
在一些实施方案中，制备ET-743或其可药用盐的方法包括以下步骤：
其中，P1选自叔丁基二甲基硅基(TBS)，具体反应条件或操作可参照期刊文献J.Am.Chem.Soc,1996,118,9202-9203中所述。
本公开还提供制备PM-1183或其可药用盐的方法，包括前述制备式(b)所示化合物所述的方法步骤，以及式(b)所示化合物转化为式PM-1183或其可药用盐的步骤，
一些实施方案提供制备PM-1183或其可药用盐的方法，包括前述制备式(b)所示化合物的方法步骤，以及式(b)所示化合物转化为式ET-743或其可药用盐的步骤，
其中，P1、P2为羟基保护基，P4为氢。
一些实施方案提供制备PM-1183或其可药用盐的方法包括：
在一些实施方案中，制备PM-1183或其可药用盐的方法包括以下步骤：
其中，P1选自叔丁基二甲基硅基(TBS)，具体反应条件或操作可参照期刊文献J.Am.Chem.Soc,1996,118,9202-9203或ZL02819651.1中所述。
本公开所述方法还包括后处理操作，如过滤、萃取、浓缩或柱层析的步骤，以获得纯的目标产物。
本公开可药用盐为ET-743或PM-1183与酸成盐的产物，所述酸选自但不限于盐酸、硫酸、磷酸、甲磺酸、苹果酸或草酸等。
本公开还提供了一种药物组合物，其含有有效治疗量的由前述方法制备获得ET-743或其可药用盐或由前述方法制备获得PM-1183或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开还提供一种药物组合物的制备方法，该方法包括将由前述方法制备获得ET-743或其可药用盐或由前述方法制备获得PM-1183或其可药用盐，和一种或多种药学上可接受的载体、稀释剂或赋形剂相互混合的步骤。
本公开还提供了前述方法制备获得ET-743或其可药用盐或由前述方法制备获得PM-1183或其可药用盐在制备治疗肿瘤疾病的药物中用途，所述肿瘤疾病优选软组织肉瘤、非细胞肺癌、乳腺癌、黑色素瘤。
本发明所使用的术语，除有相反的表述外，具有如下的含义：
“烷基”指饱和的脂族烃基团，包括1至10个碳原子的直链和支链基团，优选包括1至6个碳原子。非限制性实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，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、氧代。
“环烷基”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10个碳原子，优选C3-8环烷基，更优选C3-6环烷基，最优选5元或6元环烷基。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。多环环烷基包括螺环、稠环和桥环的环烷基。环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，独立地选自烷基、烷氧基、卤素、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基。
“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，更优选苯基和萘基。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、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。
“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”，5Th 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(C1-10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C1-10烷基或取代烷基，例如：甲基，叔丁基，烯丙基，苄基，甲氧基甲基，乙氧基乙基，2-四氢吡喃基(THP)等；可以是(C1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基等；可以是(C1-6烷基或C6-10芳基)磺酰基；也可以是(C1-6烷氧基或C6-10芳基氧基)羰基，可以是乙酰基(Ac)、2-甲氧基乙氧甲基醚(MEM)、甲氧甲基醚(MOM)、对甲氧基苄基醚(PMB)、甲硫甲基醚(MTM).。
本披露中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
具体实施方式
以下将结合具体实施例详细地说明本公开，以使得本专业技术人员更全面地理解本公开内容，具体实施例仅用于说明本公开的技术方案，并不以任何方式限定本发明。
实施例1：
向1L反应瓶中依次加入1.4-二氧六环(540mL)，化合物a-1(27g)，甲基硼酸(10.47g)，无水磷酸钾(44.56g)，用氮气置换，然后继续加入1,1'-双二苯基膦二茂铁二氯化钯(2.56g)，将反应体系加热90～110℃搅拌反应。将反应体系降至室温，加入水(100ml)淬灭反应，用乙酸乙酯(60ml)×2)萃取，用食盐水(100ml×2)，干燥，浓缩得粗品，经HPLC检测，杂质A含量为7.1％。该粗品经柱层析分离纯化得产品，收率51％。
实施例2
向250mL反应瓶中依次加入1.4-二氧六环(100mL)，化合物a-1(5g)，甲基硼酸(1.94g)，无水磷酸钾(8.26g)，用氮气置，继续加入1,1'-双二苯基膦二茂铁二氯化钯(45mg)和L-磷配体(46mg)，加热至内温90～110℃搅拌反应。
将反应体系降至室温，加入水(100ml)淬灭反应，用乙酸乙酯(60ml)×2)萃取，用食盐水(100ml×2)，干燥，浓缩得粗品，再经柱层析分离纯化得产品3.3g，收率：79.9％，杂质A含量为低于0.5％以下。
Claims (10)
1.制备式(b)所示的化合物的方法，包括在反应溶剂中，式(a)所示化合物在金属钯-配体催化下甲基化以形成式(b)所示化合物，
所述配体选自
其中，
R5选自-OP3，P3为C1-6烷基或芳基磷酸酯基、三氟甲磺酰基、甲磺酰基或对甲苯磺酰基；
P1为-SiR5R6R7，其中R5、R6和R7各自分别为C1-10的直链或支链烷基，P2为MOM，P4为氢，
其中所述甲基化试剂选自甲基硼酸、甲基硼酸频哪醇酯或甲基三氟硼酸钾。
2.根据权利要求1所述的方法，其中所述甲基化试剂选自甲基硼酸。
3.根据权利要求1所述的方法，其中所述金属钯为二价钯。
4.根据权利要求1所述的方法，其中所述反应还含有碱性试剂，所述碱性试剂选自碳酸钾、磷酸钾或磷酸钠。
5.根据权利要求1所述的方法，其中反应溶剂选自二甲基甲酰胺、二甲基乙酰胺、1-甲基-2-吡咯烷酮、四氢呋喃、甲基四氢呋喃、二氧六环、甲苯、二甲苯、二甲亚砜、乙醚、异丙醚、甲基叔丁基醚、乙腈、丙腈、异丙醇、丙醇、乙醇、甲醇中的一种或多种。
6.根据权利要求1所述的方法，其中反应溶剂为二氧六环。
7.制备ET-743或其可药用盐的方法，包括如权利要求1-6任一项所述的方法步骤，以及式(b)所示化合物转化为式ET-743或其可药用盐的步骤，
其中，P1、P2和P4如权利要求1所述定义。
8.根据权利要求7所述的方法，其包括如下步骤：
其中，P1、P2和P4如权利要求1所述定义。
9.制备PM-1183或其可药用盐的方法，包括如权利要求1-6任一项所述的方法步骤，以及式(b)所示化合物转化为式PM-1183或其可药用盐的步骤，
其中，P1，P2和P4如权利要求1所述定义。
10.根据权利要求9所述的方法，其包括如下步骤：
其中，P1，P2和P4如权利要求1所述定义。
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