WO2023178814A1 - 一种帕西洛韦中间体的制备方法 - Google Patents

一种帕西洛韦中间体的制备方法 Download PDF

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WO2023178814A1
WO2023178814A1 PCT/CN2022/093009 CN2022093009W WO2023178814A1 WO 2023178814 A1 WO2023178814 A1 WO 2023178814A1 CN 2022093009 W CN2022093009 W CN 2022093009W WO 2023178814 A1 WO2023178814 A1 WO 2023178814A1
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reaction
preparation
cis
acid
temperature
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王鹏
胡毅方
田湘寅
刘国杰
钱刚
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杭州国瑞生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers

Definitions

  • the present invention relates to the technical field of pharmaceutical intermediate synthesis, and specifically relates to a preparation method of pasilclovir intermediate.
  • Caronic acid is an important intermediate in the production of boceprevir, a hepatitis C protease inhibitor, and is also widely used in pesticides and other organic synthesis fields. Cis-caronic acid can be used in the synthesis of Pfizer's new coronavirus drug Paxlovid and is the most critical intermediate for the drug. However, the conventional method of cis-caronic acid can only be separated by crystallization or salt formation from caronic acid, and the yield is extremely low and the effect is also very poor.
  • Patent CN104163759A discloses a synthetic route for synthesizing caronic acid. Specifically, isopentenol with protected hydroxyl groups is used as the starting material, and then the key intermediate of a three-membered ring is generated through the addition of double bonds. Next, the ethyl ester and protected Hydrolysis of the base, and then controlling the oxidation conditions to obtain carnolide and caronic acid respectively, which has the advantages of mild conditions, high production safety, easy industrial production, etc. However, this invention does not have a method for synthesizing cis-caronic acid.
  • the present invention provides a method for preparing paciclovir intermediates. This method allows the trans product to be completely converted into the cis product using a relatively cheap base, and the utilization rate is greatly improved, and the purity of the final product is Reaching more than 99%.
  • the invention provides a preparation method of pasilclovir intermediate, which includes the following steps:
  • step (3) react the pentenyl acetate obtained in step (1) with the diazo compound obtained in step (2) to obtain a three-membered ring compound;
  • R is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or benzyl.
  • formula I is isopentenol
  • formula II is pentenyl acetate
  • formula III is glycine ester hydrochloride
  • formula IV is a diazo compound
  • formula V is a three-membered ring compound
  • formula VI is 6,6-bis Methyl-3-oxazole[3.1.0]hexan-2-one
  • formula VII is cis-3-hydroxymethyl-2,2-dimethylcyclopropylcarboxylic acid
  • formula VIII is pasilol Wei intermediate cis-caronic acid.
  • step (1) is catalyzed using 4-lutidine as a catalyst.
  • step (1), (2) or (3) is synthesized using a kettle reaction.
  • the kettle type reaction in step (1) specifically includes: after isopentenol and 4-dimethylaminopyridine are mixed and stirred, acetic anhydride is added dropwise, the reaction temperature is controlled to 10-50°C, and after the reaction is completed, hydrogenation is used. Wash once with sodium aqueous solution. Preferably, the reaction temperature is 20-30°C.
  • the kettle type reaction described in step (2) specifically includes: after dissolving formula (III) with water, add sulfuric acid; cool to -10-15°C; dropwise add sodium nitrite solution to maintain the temperature; after the reaction is completed, Extract with 1,2-dichloroethane, and wash the organic layer once with sodium bicarbonate solution and water.
  • the cooling temperature is -10-0°C.
  • step (4) specifically includes: first using an inorganic weak base to remove the acetyl protection (preferably potassium carbonate), and the solvent is anhydrous ethanol; filtering to remove the solid, spin-drying and then toluene stripping; after the toluene is charged with water, use A strong organic base (most preferably sodium tert-butoxide) is used for ring closure to obtain formula (VI). If formula (V) is directly ring closed with sodium tert-butoxide, the fallen acetyl group will react with the product to generate a large number of impurities.
  • an inorganic weak base to remove the acetyl protection
  • the solvent is anhydrous ethanol
  • filtering to remove the solid, spin-drying and then toluene stripping
  • a strong organic base most preferably sodium tert-butoxide
  • step (5) specifically includes: hydrolyzing formula (VI) with sodium hydroxide solution at 0-30°C (optimum temperature 10-20°C).
  • step (6) specifically includes: adjusting the pH to 7-13 (the optimal pH is 11-12), adding potassium permanganate in batches, and controlling the temperature below 80°C; after the reaction is completed, cool to room temperature, and add sodium sulfite. After removing the oxidation property, add acid to adjust the pH to 1-2, then add solvent to extract, spin dry, and beat to obtain cis-caronic acid (VIII).
  • the kettle type reaction in step (1) includes: mixing and stirring isopentenol and 4-dimethylaminopyridine, then adding acetic anhydride dropwise, controlling the reaction temperature to 10-50°C, and using hydrogen after the reaction is completed. Clean with sodium oxide aqueous solution.
  • step (3) is catalyzed using copper acetylacetonate as a catalyst.
  • step (4) specifically includes: using an inorganic base to remove the acetyl group from the three-membered ring compound, filtering to remove the solid, spinning to dryness, using toluene to bring water, and adding a strong organic base to ring-close to obtain 6,6-dimethyl.
  • step (5) is performed using sodium hydroxide.
  • step (6) is performed using potassium permanganate.
  • step (6) specifically includes adjusting the pH, adding potassium permanganate in batches, and controlling the temperature below 80°C. After the reaction is completed, cool down, add sodium sulfite, adjust the pH, extract, spin dry, and beat to obtain cis-caron. acid.
  • the present invention also provides the pasilclovir intermediate prepared by the above preparation method.
  • the present invention innovates the synthesis route of cis-caronic acid, the intermediate of pasilclovir, so that the trans product can be completely converted into the cis product using a relatively cheap base, the utilization rate is greatly improved, and the HPLC purity of the final product reaches more than 99%. And transcaron acid is almost non-existent.
  • Figure 1 is the HNMR spectrum of cis-caronic acid
  • Figure 2 is an enlarged schematic diagram of the spectrum with the abscissa in Figure 1 between 2.6-1.0ppm.
  • a preparation method of pasilclovir intermediate including the following steps:
  • reaction formula is specifically:
  • Example steps Add 5g isopentenol (I) and 0.355g DMAP to the reaction bottle and stir, add 6.34g acetic anhydride dropwise, control the temperature at 20-30°C during the dropwise addition, continue the reaction for 1 hour after the dropwise addition, and take samples for central control. Raw material remaining ⁇ 1%. Dissolve 2.32g NaOH in 12.5g water to prepare a solution. The reaction solution is washed once with the solution and left to separate layers to obtain formula (II). The yield is 100%, GC: 99.2%.
  • Comparative example steps Add 5g isopentenol (I) and 0.33g sulfuric acid to the reaction bottle and stir, add 6.34g acetic anhydride dropwise, control the temperature at 20-30°C during the dropwise addition, continue the reaction for 1 hour after the dropwise addition, and take samples for control. Raw material remaining ⁇ 1%. Dissolve 2.32g NaOH in 12.5g water to prepare a solution. The reaction solution is washed once with the solution and left to separate layers to obtain formula (II). The yield is 68%, GC: 83.2%.
  • Example steps Add 4g glycine ethyl ester hydrochloride (IIIa) into the reaction bottle, stir 20ml H2O and 0.05g H2SO4, cool to -10 ⁇ 0°C, prepare solution B with 2.37g NaNO2 and 20ml H2O, and add the solution dropwise B. Control the temperature at -10 ⁇ 0°C during dripping. After the dripping is completed, react for 30 minutes. Take a sample and control. The remaining raw materials are ⁇ 1%. Then extract twice with 2*12mL 1,2-dichloroethane to obtain the formula ( The 1,2-dichloroethane solution of IVa) was directly used in the next reaction, and samples were taken to measure the weight content and moisture. Yield 95%, GC: 97.8%.
  • Comparative example steps Add 4g glycine ethyl ester hydrochloride (IIIa) into the reaction bottle, stir 20ml H2O and 0.05g H2SO4, cool to 10 ⁇ 20°C, prepare solution B with 2.37g NaNO2 and 20ml H2O, and add solution B dropwise , the temperature is controlled at -10 ⁇ 0°C when dripping, and the reaction is continued for 30 minutes after the dripping is completed, and the sampling is controlled. The remaining raw materials are ⁇ 1%, and then extracted twice with 2*12mL 1,2-dichloroethane to obtain formula (IVa ) in 1,2-dichloroethane was directly used in the next step of reaction, and samples were taken to measure the weight content and moisture. Yield 67%, GC: 90.3%.
  • Example steps Add 300g pentenyl acetate (II), 13g phenylhydrazine, 600ml 1,2-dichloroethane and 6.2g Cu(acac)2 into the reaction bottle, stir, heat up to 75 ⁇ 85°C, and add 5.34 g of 1,2-DCE solution of ethyl diazoacetate is added dropwise. During the dropwise addition, the temperature is controlled at 75 to 85°C. The dropping time is 6 to 7 hours.
  • Example steps Add Va 50g, potassium carbonate 96.5g, and absolute ethanol 250mL to the reaction bottle, stir and heat to 60°C-80°C for reaction for 3-5 hours; take samples for GC central control detection, complete the reaction, filter, and rinse with absolute ethanol. Wash; drain and then evaporate the filtrate to dryness; add 25 mL of toluene to strip at 30-35°C until dry. After rotary evaporation, add 50 mL of water and 200 mL of toluene, raise the temperature to 50°C, stir to dissolve and extract, separate the layers, reflux the organic layer with water for about 3 hours, and take a sample to detect the moisture content ⁇ 0.1%.
  • Example steps Add 11.2g of sodium hydroxide to the reaction bottle, add 150mL of water, and 30g of VI, stir at 10-20°C for 2 hours, and take samples to monitor the reaction with TLC. After the reaction is completed, add concentrated hydrochloric acid to adjust the pH to 11-12, raise the temperature to about 50°C, add 158.03g of potassium permanganate in batches, control the temperature to below 80°C, complete the addition, and keep it at 60-80°C for 1-2 hours. Take a sample of the reaction solution and add concentrated hydrochloric acid to acidify it, and add sodium sulfite to clarify the reaction solution.
  • Comparative example steps Add 11.2g of sodium hydroxide to the reaction bottle, add 150mL of water, and 30g of VI, stir at 10-20°C for 2 hours, and take samples to monitor the reaction with TLC. After the reaction is completed, the pH is above 14, directly raise the temperature to about 50°C, add 158.03g of potassium permanganate in batches, control the temperature to below 80°C, complete the addition, and keep it at 60-80°C for 1-2 hours. Take a sample of the reaction solution and add concentrated hydrochloric acid to acidify it, and add sodium sulfite to clarify the reaction solution.

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Abstract

本发明提供了一种帕西洛韦中间体的制备方法，涉及药物中间体合成技术领域，包括以下步骤：(1)将异戊烯醇与乙酸酐反应得到乙酸戊烯酯；(2)将甘氨酸酯盐酸盐与亚硝酸钠反应得到重氮化合物；(3)将步骤(1)得到的乙酸戊烯酯与步骤(2)得到的重氮化合物反应得到三元环化合物；(4)将三元环化合物关环得到6,6-二甲基-3-恶唑环[3.1.0]己烷-2-酮；(5)将步骤(4)得到的6,6-二甲基-3-恶唑环[3.1.0]己烷-2-酮进行水解得到顺式-3-羟甲基-2,2-二甲基环丙基甲酸；(6)将步骤(5)得到的顺式-3-羟甲基-2,2-二甲基环丙基甲酸进行氧化得到帕西洛韦中间体顺式卡龙酸。该方法使反式产物利用比较廉价的碱完全转变为顺式产物，利用率大幅提高，最后产物纯度达99％以上。

Description

一种帕西洛韦中间体的制备方法 技术领域
本发明涉及药物中间体合成技术领域，具体涉及一种帕西洛韦中间体的制备方法。
背景技术
卡龙酸是生产丙肝蛋白酶抑制剂博赛泼维(boceprevir)的重要中间体，同时也广泛应用于农药和其他有机合成领域内。而顺式卡龙酸则可用于辉瑞新冠药物帕西洛韦(Paxlovid)的合成，是该药物最关键的中间体。而常规方法顺式卡龙酸只能由卡龙酸进行结晶或成盐分离，收率极低，效果也很差。
专利CN104163759A公开了合成卡龙酸的合成路线，具体采用羟基被保护的异戊烯醇为起始物料，然后通过对双键的加成生成三元环关键中间体，接下来对乙酯和保护基水解，再通过控制氧化条件分别得到蒈醛酸内酯及卡龙酸，具有条件温和，生产安全性高，易于工业化生产等优势，但该发明并没有合成得到顺式卡龙酸的方法。
针对现有技术中顺式卡龙酸存在的收率低、效果差等问题，寻找一种价格低廉、利用率高、纯度高的顺式卡龙酸的制备方法十分必要。
发明内容
本发明针对现有技术存在的问题，提供了一种帕西洛韦中间体的制备方法，该方法使反式产物利用比较廉价的碱完全转变为顺式产物，利用率大幅提高，最后产物纯度达到99％以上。
为实现上述目的，本发明采用的技术方案如下：
本发明提供了一种帕西洛韦中间体的制备方法，包括以下步骤：
(1)将异戊烯醇与乙酸酐反应得到乙酸戊烯酯；
(2)将甘氨酸酯盐酸盐与亚硝酸钠反应得到重氮化合物；
(3)将步骤(1)得到的乙酸戊烯酯与步骤(2)得到的重氮化合物反应得到三元环化合物；
(4)将三元环化合物关环得到6,6-二甲基-3-恶唑环[3.1.0]己烷-2-酮；
(5)将步骤(4)得到的6,6-二甲基-3-恶唑环[3.1.0]己烷-2-酮进行水解得到顺式-3-羟甲基-2,2-二甲基环丙基甲酸；
(6)将步骤(5)得到的顺式-3-羟甲基-2,2-二甲基环丙基甲酸进行氧化得到帕西洛韦中间体顺式卡龙酸；
反应路线具体如下式所示：
Figure PCTCN2022093009-appb-000001
其中，R为甲基、乙基、正丙基、异丙基、正丁基、叔丁基或苄基。
其中，式I为异戊烯醇，式II为乙酸戊烯酯，式III为甘氨酸酯盐酸盐，式IV为重氮化合物，式V为三元环化合物，式VI为6,6-二甲基-3-恶唑环[3.1.0]己烷-2-酮，式VII为顺式-3-羟甲基-2,2-二甲基环丙基甲酸，式VIII为帕西洛韦中间体顺式卡龙酸。
进一步地，步骤(1)中所述反应使用4-二甲基吡啶作为催化剂进行催化。
进一步地，步骤(1)、(2)或(3)中所述反应采用釜式反应进行合成。
进一步地，步骤(1)中所述釜式反具体包括：异戊烯醇和4-二甲氨基吡啶混合搅拌后，滴加乙酸酐，控制反应温度为10-50℃，反应结束后用氢氧化钠水溶液洗一次。优选地，所述反应温度为20-30℃。
进一步地，步骤(2)中所述釜式反具体包括：用水溶解式(III)后，加入硫酸；降温至-10-15℃；滴加亚硝酸钠溶液，保持该温度；反应结束后，用1,2-二氯乙烷萃取，有机层分别用碳酸氢钠溶液和水各洗一次。优选地，所述降温的温度为-10-0℃。
进一步地，步骤(4)具体包括：先用无机弱碱脱去乙酰基保护(优选为碳酸钾)，溶剂为无水乙醇；过滤除去固体，旋干后甲苯脱带；甲苯带水后，用有机强碱(最优选为叔丁醇钠)进行关环得到式(VI)。若式(V)直接用叔丁醇钠直接进行关环，则掉落的乙酰基会与产物进行反应生成大量杂质。
进一步地，步骤(5)具体包括：0-30℃(最佳温度10-20℃)下用氢氧化钠溶液水解式(VI)。
进一步地，步骤(6)具体包括：调pH为7-13(最佳pH为11-12)，分批加入高锰酸钾，温度控制80℃以下；反应完毕后，降温至室温，加入亚硫酸钠去除氧化性后，加酸调pH为1-2，后加入溶剂萃取后旋干，打浆得到顺式卡龙酸(VIII)。
进一步地，步骤(1)中所述釜式反具体包括：将异戊烯醇和4-二甲氨基吡啶混合搅拌后，滴加乙酸酐，控制反应温度为10-50℃，反应结束后用氢氧化钠水溶液清洗。
进一步地，步骤(3)中所述反应过程使用乙酰丙酮铜作为催化剂进行催化。
进一步地，步骤(4)具体包括：使用无机碱将三元环化合物脱去乙酰基，过滤除去固体后，旋干，使用甲苯带水后，加入有机强碱关环得到6,6-二甲基-3-恶唑环[3.1.0]己烷-2-酮。
进一步地，步骤(5)中所述水解使用氢氧化钠进行。
进一步地，步骤(6)中所述氧化使用高锰酸钾进行。
进一步地，步骤(6)具体包括调节pH后分批次加入高锰酸钾，温度控制80℃以下，反应完毕后，降温，加入亚硫酸钠，调节pH，萃取旋干、打浆，得到顺式卡龙酸。
本发明还提供了上述的制备方法制备得到的帕西洛韦中间体。
本发明所取得的技术效果是：
本发明创新了帕西洛韦中间体顺式卡龙酸的合成路线，使反式产物利用比较廉价的碱完全转变为顺式产物，利用率大幅提高，并且最后产物HPLC纯度达到99％以上，并且几乎不存在反式卡龙酸。
附图说明
图1为顺式卡龙酸的HNMR谱图；
图2为图1横坐标在2.6-1.0ppm之间谱图的放大示意图。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式，本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用，本说明书中的各项细节也可以基于不同观点与应用，在没有背离本发明的精神下进行各种修饰或改变。
在进一步描述本发明具体实施方式之前，应理解，本发明的保护范围不局限于下述特定的具体实施方案；还应当理解，本发明实施例中使用的术语是为了描述特定的具体实施方案，而不是为了限制本发明的保护范围。
当实施例给出数值范围时，应理解，除非本发明另有说明，每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义，本文中使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同意义。
值得说明的是，本发明中使用的原料均为普通市售产品，因此对其来源不做具体限定。
实施例1
一种帕西洛韦中间体的制备方法，包括以下步骤：
(1)反应式具体为：
Figure PCTCN2022093009-appb-000002
实施例步骤：反应瓶中加入5g异戊烯醇(I)和0.355g DMAP搅拌，滴加6.34g乙酸酐，滴加时控温20～30℃，滴完后继续反应1h，取样中控，原料剩余≤1％。将2.32g NaOH溶于12.5g水，配成溶液，反应液用该溶液洗一次，静置分层，得到式(II)，收率100％，GC：99.2％。
对比例步骤：反应瓶中加入5g异戊烯醇(I)和0.33g硫酸搅拌，滴加6.34g乙酸酐，滴加时控温20～30℃，滴完后继续反应1h，取样中控，原料剩余≤1％。将2.32g NaOH溶于12.5g水，配成溶液，反应液用该溶液洗一次，静置分层，得到式(II)，收率68％，GC：83.2％。
(2)反应式具体为：
Figure PCTCN2022093009-appb-000003
实施例步骤：反应瓶中加入4g甘氨酸乙酯盐酸盐(IIIa)，20ml H2O和0.05g H2SO4搅拌，降温至-10～0℃，将2.37g NaNO2和20ml H2O配成溶液B，滴加溶液B，滴加时控温-10～0℃，滴完后再反应30min，取样中控，原料剩余≤1％，然后用2*12mL 1,2-二氯乙烷萃取两次，得到式(IVa)的1,2-二氯乙烷溶液直接用于下一步反应，取样测重量含量和水分。收率95％，GC：97.8％。
对比例步骤：反应瓶中加入4g甘氨酸乙酯盐酸盐(IIIa)，20ml H2O和0.05g H2SO4搅拌，降温至10～20℃，将2.37g NaNO2和20ml H2O配成溶液B，滴加溶液B，滴加时控温-10～0℃，滴完后再反应30min，取样中控，原料剩余≤1％，然后用2*12mL 1,2-二氯乙烷萃取两次，得到式(IVa)的1,2-二氯乙烷溶液直接用于下一步反应，取样测重量含量和水分。收率67％，GC：90.3％。
(3)反应式具体为：
Figure PCTCN2022093009-appb-000004
实施例步骤：反应瓶中加入300g乙酸戊烯酯(II)，13g苯肼，600ml 1,2-二氯乙烷和6.2g Cu(acac)2搅拌，升温至75～85℃，将含5.34g重氮乙酸乙酯的1,2-DCE溶液滴入，滴加时控温75～85℃，滴加时间6～7h，取样检测：式(Va)顺式+反式应该在80％左右，降温至30～40℃，旋干溶剂。用油泵精馏，收集馏出温度90℃以上产物；得到产物Va(GC纯度顺式：48.07％；反式：43.06％)；收率75％。
对比例步骤：反应瓶中加入300g乙酸戊烯酯(II)，13g苯肼，600ml 1,2-二氯乙烷和2.35g CuCl搅拌，升温至75～85℃，将含5.34g重氮乙酸乙酯的1,2-DCE溶液滴入，滴加时控温75～85℃，滴加时间6～7h，取样检测：原料乙酸戊烯酯(II)残留52.3％，继续增加搅拌时间原料几乎不下降。降温至30～40℃，旋干溶剂。用油泵精馏，收集馏出温度90℃以上产物；得到产物Va(GC纯度顺式：43.22％；反式：48.39％)；收率35％。
(4)反应式具体为：
Figure PCTCN2022093009-appb-000005
实施例步骤：向反应瓶中加入Va 50g，碳酸钾96.5g，无水乙醇250mL，搅拌升温至60℃-80℃反应3-5h；取样GC中控检测，反应毕，过滤，无水乙醇淋洗；抽干后滤液旋蒸至干；加入25mL甲苯30-35℃脱带至干。旋蒸毕，加入水50mL，甲苯200mL，升温至50℃搅拌溶清萃取，分层，有机层回流带水3h左右，取样检测水分<0.1％。带水毕，降温至80℃左右；加入叔丁醇钠(0.5eq)，80℃左右反应2-3h(取样反应液倒入盐酸水溶液中酸化后，有机层送GC直至反式酯<3％；反应完毕后，降温至室温，将反应液倒入盐酸水溶液中(保证一直是酸性)，搅拌15min；加碳酸钠调pH至8-9左右。升温至50℃搅拌15min分层，水层用甲苯50℃搅拌再萃取一次，分层毕，合并有机层。洗毕，旋干得到VI产物HPLC：92.8％；反式残留2.46％；收率 83％。
对比例步骤：向反应瓶中加入Va 10g，加入乙醇100mL，乙醇钠(0.5eq)，搅拌升温至回流3h，取样GC：产物VI 33.32％；还有一个大杂质(结构式：
Figure PCTCN2022093009-appb-000006
)55.33％；原料Va 8.21％。
(5)反应式具体为：
Figure PCTCN2022093009-appb-000007
实施例步骤：向反应瓶中加入氢氧化钠11.2g，加入水150mL，VI 30g，10-20℃搅拌2h，取样TLC监控反应。反应毕，加入浓盐酸调pH至11-12，升温至50℃左右，分批加入高锰酸钾158.03g，控温至80℃以下，加毕，60-80℃保温1-2h。取样反应液加浓盐酸酸化并加亚硫酸钠使反应液澄清以后HPLC检测是否还有VI(VII在强酸性条件下会重新关环变为VI)；未反应完则继续补加高锰酸钾。反应毕，加入亚硫酸钠去除氧化性(淀粉碘化钾试纸监测)，调毕，滴加浓盐酸调pH1-2。调毕，加入240mL醋酸异丙酯升温至50℃萃取分液；水层再用120mL醋酸异丙酯50℃再萃取一次。合并有机层，减压蒸馏至剩余约50mL溶剂左右，降温至0-10℃打浆2h后抽滤淋洗烘干得到顺式卡龙酸VIII，HPLC：99.33％；收率90％，HNMR图如图1-2所示。
对比例步骤：向反应瓶中加入氢氧化钠11.2g，加入水150mL，VI 30g，10-20℃搅拌2h，取样TLC监控反应。反应毕，pH为14以上，直接升温至50℃左右，分批加入高锰酸钾158.03g，控温至80℃以下，加毕，60-80℃保温1-2h。取样反应液加浓盐酸酸化并加亚硫酸钠使反应液澄清以后HPLC检测是否还有VI(VII在强酸性条件下会重新关环变为VI)；未反应完则继续补加高锰酸钾。反应毕，加入亚硫酸钠去除氧化性(淀粉碘化钾试纸监测)，调毕，滴加浓盐酸调pH1-2。调毕，加入240mL醋酸异丙酯升温至50℃萃取分液；水层再用120mL醋酸异丙酯50℃再萃取一次。合并有机层，减压蒸馏至剩余约50mL溶剂左右，降温至0-10℃打浆2h后抽滤淋洗烘干得到顺式卡龙酸VIII，HPLC：顺式77.35％；反式21.88％；收率85％，
最后应当说明的是，以上内容仅用以说明本发明的技术方案，而非对本发明保护范围的限制，本领域的普通技术人员对本发明的技术方案进行的简单修改或者等同替换，均不脱离本发明技术方案的实质和范围。

Claims (10)

  1. 一种帕西洛韦中间体的制备方法，其特征在于：包括以下步骤：
    (1)将异戊烯醇与乙酸酐反应得到乙酸戊烯酯；
    (2)将甘氨酸酯盐酸盐与亚硝酸钠反应得到重氮化合物；
    (3)将步骤(1)得到的乙酸戊烯酯与步骤(2)得到的重氮化合物反应得到三元环化合物；
    (4)将三元环化合物关环得到6,6-二甲基-3-恶唑环[3.1.0]己烷-2-酮；
    (5)将步骤(4)得到的6,6-二甲基-3-恶唑环[3.1.0]己烷-2-酮进行水解得到顺式-3-羟甲基-2,2-二甲基环丙基甲酸；
    (6)将步骤(5)得到的顺式-3-羟甲基-2,2-二甲基环丙基甲酸进行氧化得到帕西洛韦中间体顺式卡龙酸；
    反应路线具体如下式所示：
    Figure PCTCN2022093009-appb-100001
    其中，R为甲基、乙基、正丙基、异丙基、正丁基、叔丁基或苄基。
  2. 根据权利要求1所述的制备方法，其特征在于：步骤(1)中所述反应使用4-二甲基吡啶作为催化剂进行催化。
  3. 根据权利要求1所述的制备方法，其特征在于：步骤(1)、(2)或(3)中所述反应采用 釜式反应进行合成。
  4. 根据权利要求3所述的制备方法，其特征在于：步骤(1)中所述釜式反应具体包括：将异戊烯醇和4-二甲氨基吡啶混合搅拌后，滴加乙酸酐，控制反应温度为10-50℃，反应结束后用氢氧化钠水溶液清洗。
  5. 根据权利要求1所述的制备方法，其特征在于：步骤(3)中所述反应过程使用乙酰丙酮铜作为催化剂进行催化。
  6. 根据权利要求1所述的制备方法，其特征在于：步骤(4)具体包括：使用无机碱将三元环化合物脱去乙酰基，过滤除去固体后，旋干，使用甲苯带水后，加入有机强碱关环得到6,6-二甲基-3-恶唑环[3.1.0]己烷-2-酮。
  7. 根据权利要求1所述的制备方法，其特征在于：步骤(5)中所述水解使用氢氧化钠进行。
  8. 根据权利要求1所述的制备方法，其特征在于：步骤(6)中所述氧化使用高锰酸钾进行。
  9. 根据权利要求1所述的制备方法，其特征在于：步骤(6)具体包括调节pH后分批次加入高锰酸钾，温度控制80℃以下，反应完毕后，降温，加入亚硫酸钠，调节pH，萃取旋干、打浆，得到顺式卡龙酸。
  10. 如权利要求1-9任一项所述的制备方法制备得到的帕西洛韦中间体。
PCT/CN2022/093009 2022-03-25 2022-05-16 一种帕西洛韦中间体的制备方法 WO2023178814A1 (zh)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1459285A (en) * 1974-12-03 1976-12-22 Ici Ltd Process for the preparation of cyclopropane carboxylic acid esters
CN1062345A (zh) * 1990-12-13 1992-07-01 中国科学院大连化学物理研究所 2，2，3，3-四甲基环丙烷羧酸的制备
CN101300245A (zh) * 2005-11-01 2008-11-05 住友化学株式会社 6，6-二甲基-3-氧杂二环[3.1.0]己烷-2-酮的制造方法
CN102952011A (zh) * 2011-08-24 2013-03-06 上海北卡医药技术有限公司 蒈醛酸内酯、卡龙酸、卡龙酸酐及其关键中间体的新合成方法
CN114105859A (zh) * 2022-01-27 2022-03-01 南京桦冠生物技术有限公司 一种6,6-二甲基-3-氮杂双环[3.1.0]己烷的合成方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104163759B (zh) * 2011-08-24 2016-05-04 南通雅本化学有限公司 卡龙酸、卡龙酸酐的新合成方法
CN105175261A (zh) * 2015-09-22 2015-12-23 山东新和成药业有限公司 一种利用醋酐进行乙酰化的方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1459285A (en) * 1974-12-03 1976-12-22 Ici Ltd Process for the preparation of cyclopropane carboxylic acid esters
CN1062345A (zh) * 1990-12-13 1992-07-01 中国科学院大连化学物理研究所 2，2，3，3-四甲基环丙烷羧酸的制备
CN101300245A (zh) * 2005-11-01 2008-11-05 住友化学株式会社 6，6-二甲基-3-氧杂二环[3.1.0]己烷-2-酮的制造方法
CN102952011A (zh) * 2011-08-24 2013-03-06 上海北卡医药技术有限公司 蒈醛酸内酯、卡龙酸、卡龙酸酐及其关键中间体的新合成方法
CN114105859A (zh) * 2022-01-27 2022-03-01 南京桦冠生物技术有限公司 一种6,6-二甲基-3-氮杂双环[3.1.0]己烷的合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HITOSHI TAMIAKI ET AL.: "Preparation of regio- and stereoisomeric di- and tetrahydrogeranylgeraniols and identification of esterifying roups in natural (bacterio)chlorophylls", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 25, no. 24, 6 October 2017 (2017-10-06), XP085254678, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2017.10.002 *

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