WO2023226102A1 - 一类新颖大环内酯的设计、制备及其应用 - Google Patents

一类新颖大环内酯的设计、制备及其应用 Download PDF

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WO2023226102A1
WO2023226102A1 PCT/CN2022/098483 CN2022098483W WO2023226102A1 WO 2023226102 A1 WO2023226102 A1 WO 2023226102A1 CN 2022098483 W CN2022098483 W CN 2022098483W WO 2023226102 A1 WO2023226102 A1 WO 2023226102A1
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preparation
macrolide
prostaglandin
thp
tbs
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王方道
王猛
王东
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上海彩迩文生化科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—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
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • 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
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    • Y02P20/00—Technologies relating to chemical industry
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Definitions

  • the present invention relates to the technical field of pharmaceutical chemical preparation, and specifically relates to the design, preparation and application of novel prostaglandin macrolides.
  • Prostaglandins are a class of important endogenous products with a wide range of physiological activities. They are present in almost all mammalian tissues. They play an important role in the reproductive, digestive, respiratory and cardiovascular systems, and are involved in body temperature regulation. , inflammatory response, glaucoma, pregnancy, hypertension, ulcers, asthma and other physiological and pathological processes.
  • Org.Biomol.Chem.2017,15,6281–6301 describes the structural characteristics of PGs: it has a five-membered alicyclic ring and two side chains.
  • the upper side chain ⁇ usually has 7 carbonic acids and the lower side chain ⁇ has 8 carbons.
  • 20-carbon unsaturated fatty acids and their analogs the structural formula is as follows:
  • PGs were first discovered and named by American scholar Von Eluer in 1930. In 1962, Bergstorm extracted two pure PGs (PGFl and PGF2) and determined their chemical structures; in 1969, Willis first proposed that PGs were an inflammatory mediator in the body. Various physiological and pharmacological activities are studied in depth.
  • Prostaglandins have few natural sources, are difficult to extract, are rapidly metabolized in the body, and have poor stability. Based on the high activity, novel structure, and instability of natural prostaglandins, scientists have successively transformed and synthesized a series of prostaglandin analogs. to meet clinical needs. Nat.Chem.2021,13,692–697 reports that as of the end of 2019, more than 20 prostate analogs have entered the market, including Bimatoprost, which exceeds one billion US dollars, fully demonstrating its importance and unique value in the pharmaceutical industry.
  • the specific structural formula is as follows:
  • prostaglandin preparation methods are roughly divided into two categories:
  • Method 1 Use Corey lactone/Wittig-Horner reaction to construct the lower side chain ⁇ to obtain the corresponding intermediate 1, and then use DIBAL-H to reduce the lactone/Wittig reaction to obtain the upper side chain ⁇ .
  • the carboxyl group is changed into the corresponding acetamide, methyl ester or isopropyl ester (refer to WO02096898, EP1886992, EP2143712, JP2012246301, US6720438, US2008033176, WO2010097672 and US7582779).
  • the reaction equation is expressed as follows:
  • EP2837621 also uses Corey Lactone as the raw material, and follows the literature operation to obtain compound 7, followed by Wittig reaction to obtain intermediate 8, and then Corey-Nicolaou esterification to obtain ten-membered ring lactone 9, which is used to form a large ring and has the characteristics of easy crystallization.
  • the second recrystallization removes 3 to 8% of the 5,6-double bond trans isomer and the 15-position R isomer inevitably generated by the Wittig reaction, thereby obtaining high-purity Travoprost; the reaction equation is expressed as follows:
  • WO2011008756 uses chiral five-membered ring enone compound 15 as the starting material, uses dialkyl copper lithium to achieve side chain chiral construction to obtain intermediate 16, and then uses an intramolecular RCM reaction under a Grubbs catalyst to achieve ⁇ -ring closure of the upper side chain. , get Travoprost; the reaction equation is expressed as follows:
  • this application discloses prostaglandin macrolide intermediates A, B, C, D or E with novel structures.
  • intermediates A-E are obtained, which greatly shortens the subsequent coupling reaction steps, and at the same time avoids the 5,6-double bond trans isomer that is difficult to remove in the current process in advance.
  • This efficient, economical and large-scale production has significantly improved the efficiency and benefits of the PGs pharmaceutical industry.
  • prostaglandin macrolides A-E of the present invention have a general structural formula expressed as follows:
  • the invention also provides a preparation method of prostaglandin macrolide A-E, which includes the following steps:
  • P 1 is selected from H, Ac, Bz, Pbz, TBS, TES, TBDPS or THP;
  • P 2 is selected from THP, TBS, TES, TBDPS, Tr or DMTr.
  • P 1 is selected from H, Ac, Bz, Pbz, TBS, TES, TBDPS or THP;
  • P 2 is selected from THP, TBS, TES, TBDPS, Tr or DMTr.
  • the present invention also provides the application of prostaglandin macrolide in the preparation of Carboprost and Travoprost products.
  • the application in the preparation of Carboprost products includes the following steps: the Wittig-Horner reaction of intermediate C with compound 37 to obtain enone 38, and then addition with methyl Grignard reagent to obtain the intermediate Form 39, after deprotection, intermediate 40 is obtained, and finally hydrolyzed to obtain Carboprost; the reaction equation is expressed as follows:
  • P 1 is preferably TBS, TES, or TBDPS.
  • the application in the preparation of Travoprost products includes the following steps: the above-mentioned terminal olefin D undergoes an intermolecular Olefin Cross Metathesis reaction with propargyl alcohol 41 in the presence of Grubbs catalyst to obtain compound 9; followed by hydrolysis and esterification to obtain the trans-double-bond-free isomer Travoprost; the reaction equation is expressed as follows:
  • P 1 is preferably TBS, TES, or TBDPS.
  • compound 34 (129.3 g, 0.77 mol) was dissolved in 600 mL of dry toluene, and cooled to below -70°C. Add 600mL 1.6M DIBAL-H dropwise to it. After the dropwise addition is completed, continue the insulation reaction until the raw materials disappear. After treatment, 130.0g of crude hemiacetal 35 was obtained, and the yield was quantitative.

Abstract

一类新颖大环内酯的设计、制备及其应用，属于医药中间体技术领域。从Corey lactone出发，通过5-7步转化，得到前列腺素大环内酯中间体A-E，从共同中间体A-E出发，还成功地运用到Carboprost和Travoprost产品的制备中，同时也推广至Bimatoprost、Tafluprost、Latanprost和Dinoprostone等PGF2a的制备。提供了共同中间体A-E大大缩短了后续偶联反应步骤，同时将目前工艺中难以去除5,6-双键反式异构体提前规避，经过这种高效节约化和规模化的生产，给PGs制药工业带来了效率和效益的明显提升。

Description

一类新颖大环内酯的设计、制备及其应用 技术领域
本发明涉及药物化学制备技术领域，具体涉及前列腺素新颖大环内酯的设计、制备及其应用。
背景技术
前列腺素(prostaglandins，简称PGs)是一类具有广泛生理活性的重要内源性产物，存在于几乎所有哺乳动物组织中，在生殖、消化、呼吸和心血管系统中发挥着重要作用，参与体温调节、炎症反应、青光眼、妊娠、高血压、溃疡及哮喘等生理病理过程。
Org.Biomol.Chem.2017,15,6281–6301描述了PGs结构特征：具有一个五元脂环及两个侧链，上侧链α通常有7个碳酸、下侧链ω有8个碳组成20碳不饱和脂肪酸及其类似物，结构式表示如下：
Figure PCTCN2022098483-appb-000001
PGs最早由美国学者Von Eluer在1930年发现并命名，1962年Bergstorm提取出两种PG纯品(PGFl和PGF2)并确定其化学结构；1969年Willis首次提出PGs是体内一种炎症介质后，相关各种生理和药理活性得以深入研究。
前列腺素天然来源少，提取困难，体内代谢迅速，稳定性差等缺点，科学家基于天然前列腺素的高活性，结构新颖性以及其不稳定性等特点，相继改造并合成了一系列前列腺素类似物，以满足临床需求。Nat.Chem.2021,13,692–697报道截止2019末为止，超过20种前列 腺类似物进入市场，其中不乏超过十亿美元的比马前列素Bimatoprost，充分显示其在制药工业的重要性和独特价值，具体结构式如下：
Figure PCTCN2022098483-appb-000002
目前，基于现有已发表文献或公开专利，前列腺素的制备方法大致分为两大类：
方法一：利用Corey lactone/通过Wittig-Horner反应，构建下侧链ω，得到相应中间体1，接着DIBAL-H还原内酯/Wittig反应，得到上侧链α。根据不同目标分子，将羧基变成相应乙酰胺、甲酯或异丙酯等(参考WO02096898、EP1886992、EP2143712、JP2012246301、US6720438、US2008033176、WO2010097672和US7582779)，采用反应方程式表示如下：
Figure PCTCN2022098483-appb-000003
J.Org.Chem.2008,73,7213-7218报道了采用化合物4和手性烯丙醇5，在Grubbs催化剂存在下分子间RCM，得到了前列腺素15(R)-Me-PGD2；反应方程式表示如下：
Figure PCTCN2022098483-appb-000004
EP2837621同样以Corey Lactone为原料，按照文献操作得到化合物7，接着Wittig反应得到中间体8，然后Corey-Nicolaou酯化得到十元环内酯9，利用其形成大环而具有易结晶的特点，多次重结晶除去Wittig反应而不可避免生成的3～8％5,6-双键反式异构体以及15位R异构体，从而得到高纯度Travoprost；反应方程式表示如下：
Figure PCTCN2022098483-appb-000005
方法二：基于不对称合成构建四个手性中心五元环，该方式极具挑战性。WO0209034和US2009259058报道了以下合成策略：
Figure PCTCN2022098483-appb-000006
WO2011008756以手性五元环烯酮化合物15为起始原料，采用二烷基铜锂实现侧链手性构建得到中间体16，接着在Grubbs催化剂下分子内RCM反应实现了上侧链α关环，得到Travoprost；反应方程式表示如下：
Figure PCTCN2022098483-appb-000007
Nature,2012,489,278–281报道了前列素的制备路线：以二醛19为原料，利用手性脯氨酸诱导得到中间体20，接着醚化与二烷基铜锂22偶联反应，接着氧化/还原后得到中间体24，从而实现多前列腺素25制备；反应方程式表示如下：
Figure PCTCN2022098483-appb-000008
Nat.Chem.2021,13,692–697报道了不对称氢化方式构建五元环的方法。从烯酮26开始，不对称还原得到中间体27，接着采用原创 性方法得到前列腺素内酯30，然后利用分子间Olefin Cross Metathesis反应，构建下侧链ω，最后经过Wittig反应上侧链α，从而实现了前列腺素33等类似物的制备；反应方程式表示如下：
Figure PCTCN2022098483-appb-000009
综合上述现有技术方法，既有基于经典Corey Lactone路线，也有充满创造性不对称合成路线，更进一步丰富了前列腺素合成方法。前述开创性策略可制备各种前列腺素，然而从制药工业角度而言，一般都是从Corey lactone为起始物料基于两点：Corey lactone工业制备工艺经过多年的优化、改进和提高，其生产成本大大降低，市售价格可接受度得到了市场接受；另一方面，复杂五元环中的四个相邻手性中心已经完美构建并确立，给后续相应前列腺素的质量提供了充分保证。
通过对比全球销量比较好PGs类似物文献调研，发现大部分都是具有上侧链α为7个碳的羧酸或羧酸酯，同时在5/6位具有一个顺式双键烯烃。然而对于具有上侧链顺式双键结构和Corey环手性特征，且能更好匹配前列系列化合物的更高级中间体(十元环内酯)仍需进一步开发。
发明内容
为了解决上述技术问题，本申请公开了具有新颖结构前列腺素大环内酯中间体A、B、C、D或E。从Corey lactone出发，通过5-7步转化，得到中间体A-E，从大大缩短了后续偶联反应步骤，同时将目前工艺中难以去除5,6-双键反式异构体提前规避，经过这种高效节约化和规模化的生产，给PGs制药工业效率和效益带来了明显提升。
从共同中间体A-E出发，还成功地运用到Carboprost和Travoprost产品的制备中，同时也推广至Bimatoprost、Tafluprost、Latanprost和–Dinoprostone等PGF2a的制备。从该类型新颖大环内酯出发，大大缩短了规模生产路线，提高了制备效率，从而增强了产品的竞争力。
本发明所述前列腺素大环内酯A-E，结构通式表示如下：
Figure PCTCN2022098483-appb-000010
本发明还提供了前列腺素大环内酯A-E的制备方法，包括如下步骤：
1、前列腺素大环内酯A的制备方法：以Corey lactone为起始物料，伯醇保护后，得到中间体34；接着DIBAL-H还原得到半缩醛35，然后与磷盐CBPBr反应得到中间体36；通过大环内酯关环得到双保护关键中间体A；采用反应方程式表示如下：
Figure PCTCN2022098483-appb-000011
P 1选自H、Ac、Bz、Pbz、TBS、TES、TBDPS或THP；P 2选自THP、TBS、TES、TBDPS、Tr或DMTr。
2、前列腺素大环内酯B-E的制备方法：大环内酯A选择性脱伯醇保护得到中间体B，接着氧化反应得到中间体醛C；中间体醛C再与三苯基磷溴甲烷盐Wittig反应得到末端烯烃D；中间体B氢化双键还原，得到饱和十元环E；采用反应方程式表示如下：
Figure PCTCN2022098483-appb-000012
P 1选自H、Ac、Bz、Pbz、TBS、TES、TBDPS或THP；P 2选自THP、TBS、TES、TBDPS、Tr或DMTr。
本发明还提供了前列腺素大环内酯在Carboprost和Travoprost产品制备中的应用。
进一步地，在上述技术方案中，在Carboprost产品制备中的应用，包括如下步骤：所述中间体C与化合物37发生Wittig-Horner反应得 到烯酮38，接着与甲基格氏试剂加成得到中间体39，脱保护基后得到中间体40，最后水解得到Carboprost；采用反应方程式表示如下：
Figure PCTCN2022098483-appb-000013
进一步地，在上述技术方案中，P 1优选TBS、TES、TBDPS。
进一步地，在上述技术方案中，在Travoprost产品制备中的应用，包括如下步骤：上述端烯D在Grubbs催化剂存在下，与炔丙醇41发生分子间Olefin Cross Metathesis反应，得到化合物9；接着水解和酯化，得到无反式双键异构体Travoprost；采用反应方程式表示如下：
Figure PCTCN2022098483-appb-000014
进一步地，在上述技术方案中，P 1优选TBS、TES、TBDPS。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。以下实施例子 按照P1 P2为＝TBS、THP为例进行的。本发明所用试剂和原料均市售可得。
实施例1：中间体34的制备【P1＝THP；P2＝TBS】【US2013/217879】
将Corey Lactone Diol(77.8g,452.3mmol)和咪唑(43.1g,633.8mmol)溶解于450mL干燥DMF，分批加入TBSCl(68.5g,454.5mmol)。加毕搅拌过夜，反应完毕，常规处理得到100.0g单保护中间体；接着将其用400mL二氯甲烷溶解，接着加入二氢吡喃(100.0g,1.2mol)和0.5g对甲苯磺酸，室温搅拌过夜，浓缩至干，得到129.3g双保护中间体34，油状液体，收率77％。从其他Corey Lactone不同取代基原料开始，制备得到相应双保护的中间体34，结果如下：
Corey Lactone P1＝ 中间体34 P2＝ 收率
Bz THP 95％
Pbz THP 92％
TBS THP 98％
TBS TBS 95％
实施例2：中间体35的制备【P1＝THP；P2＝TBS】【US2013/217879】
氮气保护下，将化合物34(129.3g,0.77mol)溶解于600mL干燥甲苯中，冷却到-70℃以下。向其中滴加600mL 1.6M DIBAL-H，滴加完毕，继续保温反应直至原料消失。经处理后得到130.0g半缩醛35粗品，收率定量。
实施例3：中间体36的制备【P1＝THP；P2＝TBS】
氮气保护下，在带有机械搅拌3L反应瓶中，加入4-羧丁基三苯基溴化磷(359.0g,810.4mmol)和1000mL四氢呋喃，降温到-10℃， 加入叔丁醇钾(181.5g,1.62mol)，升至室温。接着控温-25℃至-20℃，向反应液中滴加中间体35(130.0g,0.77mol)/四氢呋喃600mL溶液。滴毕保温反应直至原料完全消失。经后处理，得到浓缩液，柱层析纯化，得到120g浅黄色油状液体有机羧酸36，收率80％。 1H-NMR(400MHz,CDCl 3):5.45(m,1H),5.35(m,1H),4.65(m,0.8H),4.57(m,0.2H),4.18(m,1H),4.10(m,1H),3.80(m,1H),3.60-3.30(m,3H),2.30(m,3H),2.00-1.40(m,15H),0.90(s,9H),0.00(s,6H).LC-MS:(m/z):479.3[M+Na] +。
实施例4：化合物A的制备【P1＝THP；P2＝TBS】
氮气保护下，在10L三口瓶中，加入上述中间体36(120.0g,262.7mmol)和4.0L甲苯，搅拌下完全溶解后，接着加入三苯基磷(183.5g,700.4mmol)和2,2-二硫二吡啶(135.0g,613.6mmol)，室温搅拌过夜；然后再加入4L甲苯升温回流反应15小时。停止加热，降温。浓缩后处理，柱层析纯化得到90.0g浅黄色油状液体A，收率78％。 1H-NMR(400MHz,CDCl 3):5.50(m,1H),5.12(s,1H),4.57(m,1H),4.11-3.91(m,1H),3.90-3.56(m,3H),3.42(m,1H),2.40-2.37(m,4H),2.26(m,1H),2.18-1.47(m,13H),0.84(s,9H),0.00(s,6H).
实施例5：化合物B【P1＝THP】的制备
在1L反应瓶中加入化合物A(90.0g,205.2mmol)和500mL四氢呋喃，搅拌下完全溶解，得到浅黄色透明体系，氮气保护下，冰水降温。控温15℃以下分批加入TBAF(88.8g,3339.6mmol)，室温搅拌过夜。经过后处理，柱层析得到65.6g浅黄色油状液体B，收率98％。 1H-NMR(400MHz,CDCl 3):5.34(m,2H),5.15(m,1H),4.72(m,0.7H),4.55(m,0.3H),3.81-4.13(m,3H),3.64(m,1H),3.52(m,1H),3.12(brs,1H),2.34-2.52(m,4H),2.26(m,1H),2.11-1.53(m,11H),1.26(m,2H).LC-MS:(m/z):347.2[M+Na] +。
实施例6：化合物B【P1＝H】的制备
在反应瓶中，加入化合物B(5.0g,15.4mmol)和50mL甲醇，搅拌下完全溶解后加入0.1g PPTS，室温搅拌过夜，浓缩至干，乙酸乙酯溶解，洗涤干燥，浓缩，重结晶，得到3.2g白色固体，收率86％。 1H-NMR(400MHz,CD 3OD):5.19(dd,J＝4.4,8.0Hz,2H),5.03(dd,J＝4.0,4.8Hz,1H),3.94(m,1H),3.65(dd,J＝4.4,11.2Hz,1H),3.57(dd,J＝4.4,11.2Hz,1H),2.42-2.17(m,3H),1.99(m,2H),1.73(m,2H),1.70(m,1H),1.47(m,2H).LC-MS:(m/z):263.2[M+Na] +。
实施例7：化合物C制备【P1＝THP】
氮气保护下，将化合物A(5.0g,15.4mmol)溶解于50mL二氯甲烷中，冷却到0～10℃，接着加入戴斯-马丁高碘烷DMP(10.0g,23.6mmol)，然后慢慢升至室温，直至原料完全消失为止。过滤，浓缩，得到5.0g中间体C粗品，收率定量。
实施例8：化合物D制备【P1＝THP】
将三苯基溴甲烷(10.0g,31.0mmol)悬浮于100mL四氢呋喃溶液中，冷却到0℃以下，向其中滴加30mL 1.0M LHMDS溶液，加毕继续搅拌反应1小时，向其中滴加化合物C粗品(5.0g,15.4mmol)/四氢呋喃溶液。加毕继续反应，直至原料完全消失。经过后处理，处理后得到 3.0g端烯D，无色油状液体，收率60％。 1H-NMR(400MHz,CDCl 3):5.75(m,1H),5.05-5.40(m,5H),4.6(m,1H),4.10-3.81(m,2H),4.20(m,1H),2.60-2.30(m,5H),2.30-2.05(m,2H),1.95-1.42(m,12H),1.12(m,1H).
实施例9：化合物E制备【P1＝THP】
将化合物B(1.0g,3.1mmol)溶解于10mL乙酸乙酯溶液中，加入0.1g Pd/C，氢气气球氛下室温搅拌过夜，过滤，浓缩至干，得到1.0g油状液体E，收率定量。 1H-NMR(400MHz,CDCl 3):5.26(m,1H),4.77(m,0.7H),4.58(m,0.3H),3.75-4.13(m,3H),3.62-3.45(m,2H),3.52(m,1H),3.10(brs,1H),2.55(m,1H),2.36-2.20(m,2H),2.05(m,1H),1.95-1.40(m,15H),1.26(m,2H).LC-MS:(m/z):349.2[M+Na] +。
实施例10：化合物38制备【P1＝TBS】
氮气保护下，在100mL四氢呋喃溶液中，加入60％NaH(1.8g,45.0mmol)，冷却到0～5℃滴加化合物37(10.0g,45.0mmol)，加毕搅拌反应30分钟，向其中滴加中间体醛C(10.0g,28.4mmol)。加毕继续反应，直至原料C消失。常规后处理，柱层析得到9.8g烯酮中间体38，无色油状液体，收率77％。 1H-NMR(400MHz,CDCl 3):6.61(dd,J＝9.2,15.6Hz,1H),6.24(d,J＝9.2Hz,1H),5.34(m,1H),5.23(m,2H),3.91(dd,J＝8.0,16.8Hz,1H),2.60-2.37(m,7H),2.24(m,1H),2.10(m,2H),1.90-1.80(m,3H),1.39-1.21(m,4H),0.90(t,J＝6.8Hz,3H),0.85(s,9H),0.00(s,6H).
实施例11：化合物39制备【P1＝TBS】
氮气保护下，将化合物38(9.0g,20.1mmol)溶解于200mL甲苯溶液中，冷却到-70℃滴加3.0M MeMgCl(30mL,90.0mmol)。加毕保温搅拌30分钟，检测原料反应完毕。常规后处理，得到中间体39粗品10.0g，不经纯化直接进入下一步反应。
实施例12：化合物40制备
将实施例11得到化合物39(10.0g,20.1mmol)溶解于100mL四氢呋喃中，向其中加入TBAF(10.0g,38.2mmol)，室温搅拌过夜，检测原料消失。常规后处理，柱层析得到3.5g所需构型中间体40。 1H-NMR(400MHz,CDCl 3):5.72(d,J＝15.6Hz,1H),5.43(m,1H),5.35(m,1H),5.30(m,2H),2.60(m,1H),2.56-2.17(m,6H),1.95-1.50(m,8H),1.29(m,11H),0.88(t,J＝6.8Hz,3H).LC-MS:(m/z):373.3[M+Na] +。
实施例13：化合物9制备
先按照文献Nat.Chem.2021,13,692–697报道，制备得到中间体41待用。烯醇中间体41表征数据为： 1H-NMR(400MHz,CDCl 3):7.40(t,J＝8.0Hz,1H),7.24(t,J＝8.0Hz,1H),7.15(s,1H),7.08(dd,J＝8.0,2.4Hz,1H),6.00-5.92(m,1H),5.49(dt，J＝17.2,1.2Hz,1H),5.30(dt,J＝11.8,1.2Hz,1H),4.57(m,1H),4.06(dd,J＝11.2,3.6Hz,1H),3.93(dd,J＝9.2,7.2Hz,1H),2.36(brs,1H).
氮气保护下，将化合物D/P1＝H(0.5g,2.1mmol)和烯醇中间体41(0.5g,2.0mmol)溶解于5mL二氯甲烷，接着加入Hoveyda-Grubbs催化剂(0.5g,0.8mmol)。室温搅拌过夜，常规处理后得到粗品9。接着将粗品进行常规后处理，柱层析得到320mg化合物9纯品，白色 固体，收率47％。 1H-NMR(400MHz,CDCl 3):7.39(t,J＝8.0Hz,1H),7.24(d,J＝7.6Hz,1H),7.15(s,1H),7.08(dd,J＝8.0,2.0Hz,1H),5.76(dd,J＝15.6,7.2Hz,1H),5.65(dd,J＝15.2,8.4Hz,1H),5.34(m,1H),5.21(m,2H),4.53(m,1H),4.00(m,2H),3.86(m,1H),3.57(d,J＝2.8Hz,1H),3.76(d,J＝4.4Hz,1H),2.60(m,1H),2.37(m,4H),2.23(m,3H),1.90-1.50(m,4H).LC-MS:(m/z):463.2[M+Na] +。
工业实用性
将现有技术中以Corey Lactone为起始物料来制备相应PGs，推进到以A、B、C、D和E为起始物料，通过节约化和规模化生产降低了生产成本。特别是对PGF2a类似物而言，从源头革除了一直以来Wittig反应而不可避免产生上侧链5,6-反式双键异构体的难题；以该新颖大环内酯为中间体作为起始物料，成功地运用到Travoprost和Carboprost的制备，同时推广到Bimatoprost、Tafluprost、Latanprost和Dinoprostone等制备中，反应路线缩短提高了产品的竞争力。
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (7)

  1. 前列腺素大环内酯A-E，结构通式表示如下：
    Figure PCTCN2022098483-appb-100001
    P 1选自H、Ac、Bz、Pbz、TBS、TES、TBDPS或THP；P 2选自THP、TBS、TES、TBDPS、Tr或DMTr。
  2. 如权利要求1所述前列腺素大环内酯A的制备方法，其特征在于，包括如下步骤：以Corey lactone为起始物料，伯醇保护后，得到中间体34；接着DIBAL-H还原得到半缩醛35，然后与磷盐CBPBr反应得到中间体36；通过大环内酯关环得到双保护关键中间体A；采用反应方程式表示如下：
    Figure PCTCN2022098483-appb-100002
    P 1选自H、Ac、Bz、Pbz、TBS、TES、TBDPS或THP；P 2选自THP、TBS、TES、TBDPS、Tr或DMTr。
  3. 如权利要求1所述前列腺素大环内酯B-E的制备方法，其特征在于，包括如下步骤：采用权利要求2所述方法制备得到大环内酯A；接着大环内酯A选择性脱伯醇保护得到中间体B，接着氧化反应得到中间体醛C；中间体醛C再与三苯基磷溴甲烷盐Wittig反应得到末端烯烃D；中间体B氢化双键还原，得到饱和十元环E；采用反应方程式表示如下：
    Figure PCTCN2022098483-appb-100003
    P 1选自H、Ac、Bz、Pbz、TBS、TES、TBDPS或THP；P 2选自THP、TBS、TES、TBDPS、Tr或DMTr。
  4. 如权利要求1所述前列腺素大环内酯在Carboprost产品制备中的应用。
  5. 根据权利要求4所述前列腺素大环内酯在Carboprost产品制备中的应用，其特征在于，包括如下步骤：
    Figure PCTCN2022098483-appb-100004
    中间体C与化合物37发生Wittig-Horner反应得到烯酮38，接着与甲基格氏试剂加成得到中间体39，脱保护基后得到中间体40，最后水解得到Carboprost。
  6. 如权利要求1所述前列腺素大环内酯在Travoprost产品制备中的 应用。
  7. 根据权利要求6所述前列腺素大环内酯在Travoprost产品制备中的应用，其特征在于，包括如下步骤：
    Figure PCTCN2022098483-appb-100005
    端烯D在Grubbs催化剂存在下，与炔丙醇41发生分子间Olefin Cross Metathesis反应，得到化合物9；接着水解和酯化，得到无反式双键异构体Travoprost。
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