WO2021134143A1 - 一种制备二氮嗪的方法 - Google Patents

一种制备二氮嗪的方法 Download PDF

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WO2021134143A1
WO2021134143A1 PCT/CN2019/129657 CN2019129657W WO2021134143A1 WO 2021134143 A1 WO2021134143 A1 WO 2021134143A1 CN 2019129657 W CN2019129657 W CN 2019129657W WO 2021134143 A1 WO2021134143 A1 WO 2021134143A1
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diazoxide
reaction
chlorobenzenesulfonamide
amino
preparing
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PCT/CN2019/129657
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French (fr)
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乔春华
徐义文
申贝
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苏州大学
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Priority to PCT/CN2019/129657 priority Critical patent/WO2021134143A1/zh
Priority to US17/789,474 priority patent/US11932614B2/en
Publication of WO2021134143A1 publication Critical patent/WO2021134143A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides

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  • the invention belongs to compound preparation technology, and specifically relates to a method for preparing diazoxide.
  • Diazoxide is a fast-acting antihypertensive drug, an emergency medicine for patients in hypertensive crisis, and a drug used to treat hypoglycemia symptoms caused by hyperinsulinemia, especially the drug of choice for congenital hyperinsulinemia. It is a kind of rare disease drugs for infants and young children that are not available in China and are urgently needed in clinic.
  • the reported synthetic routes of the drug mainly include the following three synthetic methods: A, B and C:
  • the reagent AlCl 3 used in the next step is also easy to absorb moisture. Therefore, the anhydrous conditions of the reaction are strictly required.
  • the last step requires the use of acetic acid.
  • the final product is processed at a high temperature of 130°C. Acetic acid has strong volatility. , Irritating and corrosive; Route B requires four steps to obtain the final product, the first two steps are the same as Route A, then the ring is opened after treatment with strong acid H 2 SO 4 , and then the product is obtained by ring-closing reaction with triethyl orthoacetate Compared with route A above, this route has one more step of reaction and uses strong corrosive sulfuric acid; route C requires acid binding agent and high temperature ring closure. Therefore, it is necessary to develop a new method for preparing diazoxide to use stable raw materials, reduce operation steps, and choose milder reagents to avoid the use of strong acids, so as to prepare azodiazine in high yield.
  • the present invention provides a new route for the synthesis of dichloroazine, which has shorter reaction steps, cheaper and more readily available reagents, milder reaction conditions and higher yield, and is a synthetic route that is more suitable for industrialization; the present invention
  • the problems of using chlorosulfonyl isocyanate, strong acid (sulfuric acid), high reaction temperature (240-250°C) in the reaction process are avoided, and the reaction steps are short; the total yield can reach 90%, and compared with the two publicly reported
  • the preparation method of nitrogen azine, the synthetic route provided by the present invention overcomes numerous shortcomings, and is more suitable for industrial production.
  • a method for preparing diazoxide includes the following steps: mixing 2-amino-5-chlorobenzenesulfonamide, imidazole salt and amide solvent and then heating and reacting to obtain diazoxide.
  • the invention discloses the application of imidazole hydrochloride as a catalyst in the preparation of diazoxide.
  • the method for preparing 2-amino-5-chlorobenzenesulfonamide disclosed in the present invention includes the following steps: reacting o-aminobenzenesulfonamide with N-chlorosuccinimide in a chlorinated solvent to obtain 2-amino-5-chlorobenzenesulfonamide Chlorobenzenesulfonamide; preferably, the reaction is refluxing for 2-6 hours.
  • the imidazole salt is imidazole hydrochloride; the amount of imidazole salt is 1-12% of the molar mass of 2-amino-5-chlorobenzenesulfonamide, preferably 3-10%, more preferably 5-7%, most Preferably 5%.
  • a preparation method of diazoxide including the following steps: o-aminobenzenesulfonamide, imidazole salt and amide solvent are mixed and then heated to react to obtain compound IV; then compound IV and N-chlorosuccinimide are mixed in chlorine In the solvent, the diazoxide is obtained.
  • the reaction in the chlorine solvent is a reflux reaction for 8-10 hours; the chlorine solvent is dichloromethane or chloroform.
  • the imidazole salt is imidazole hydrochloride; the amount of the imidazole salt is 1-12% of the molar amount of anthranilsulfonamide, preferably 3-10%, more preferably 5-7%, most preferably 5%.
  • the amide solvent is N,N-dimethylacetamide; the heating reaction temperature is 120° C. to reflux temperature, and the time is 5-50 hours; preferably, reflux reaction is 6-8 hours.
  • reaction solution is distilled and purified by column chromatography to obtain diazoxide or 3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (Compound IV).
  • the chlorine solvent is dichloromethane or chloroform; after the reaction, the pure product can be prepared by column chromatography purification or recrystallization.
  • the new synthetic route provided by the present invention uses the reagent N,N-dimethylacetamide, in the presence of a catalyst equivalent of imidazole hydrochloride, the product is prepared in high yield; wherein N,N-dimethylacetamide is The solvent commonly used in industry, compared with triethyl orthoacetate used in route C of the published synthesis of diazoxide, this reagent is more stable, non-flammable, and more than 15 times cheaper in price. The yield of this step is higher. Achieve more than 95%.
  • route D starts from the cheap and easily available raw material anthranilamide (I), reacts with N-chlorosuccinimide (NCS), and uses dichloromethane or chloroform as the solvent.
  • the yield is 85-90% to obtain compound II (2-amino-5-chlorobenzenesulfonamide), the latter with N,N-dimethylacetamide, in the presence of catalytic equivalent of imidazole hydrochloride, 90-98% high Yield Preparation of Diazoxide III.
  • Figure 1 is a mass spectrum of 2-amino-5-chlorobenzenesulfonamide prepared by the present invention
  • Figure 2 is the mass spectrum of diazoxide prepared by the present invention.
  • Figure 3 is the hydrogen nuclear magnetic spectrum of diazoxide prepared by the present invention.
  • Figure 4 is a mass spectrum of compound IV prepared by the present invention.
  • Figure 5 is the hydrogen nuclear magnetic spectrum of compound IV prepared by the present invention.
  • Figure 6 is the hydrogen nuclear magnetic spectrum of diazoxide prepared by the present invention.
  • the method for preparing diazoxide disclosed in the present invention is as follows:
  • the 2-amino-5-chlorobenzenesulfonamide, the imidazole salt and the amide solvent are mixed and heated to react to obtain diazoxide.
  • the further preparation method of 2-amino-5-chlorobenzenesulfonamide is as follows. The o-aminobenzenesulfonamide and N-chlorosuccinimide are reacted in a solvent to obtain 2-amino-5-chlorobenzenesulfonamide.
  • the o-aminobenzenesulfonamide, the imidazole salt and the amide solvent are mixed and then heated to react to obtain compound IV; then compound IV and N-chlorosuccinimide are reacted in a chlorine solvent to obtain diazoxide.
  • FIG. 5A is a partially enlarged view of FIG. 5B.
  • the structural formula is as follows:
  • Example 5 The N,N-dimethylacetamide of Example 5 was replaced with DMF, and the rest remained unchanged, and the product compound IV could not be obtained.

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  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

公开了一种制备二氮嗪的方法，将邻氨基苯磺酰胺与N-氯代丁二酰亚胺在氯溶剂中反应，得到2-氨基-5-氯苯磺酰胺，将2-氨基-5-氯苯磺酰胺、咪唑盐与酰胺溶剂混合后加热反应，得到二氮嗪；或者将邻氨基苯磺酰胺、咪唑盐与酰胺溶剂混合后加热反应，得到化合物IV；再将化合物IV与N-氯代丁二酰亚胺在氯溶剂中反应，得到二氮嗪；还公开了咪唑盐酸盐作为催化剂在制备二氮嗪中的应用。避免了反应过程中使用高腐蚀性且毒性很大的氯磺酰异氰酸酯、强酸(硫酸)、反应温度温高(240-250℃)的问题，且反应步骤短；两步总收率可以达到90％以上，且相比已经公开报道的二氮嗪的制备方法，提供的合成路线克服了众多的缺点，从而更适合产业化生产。

Description

一种制备二氮嗪的方法 技术领域
本发明属于化合物制备技术，具体涉及一种制备二氮嗪的方法。
背景技术
二氮嗪是一种速效降压药，为高血压危象患者急救药，还用于治疗高胰岛素血症引起的低血糖症状的药物，特别是先天性高胰岛素血症的首选药物，该药物为国内暂无，临床急需的一类婴幼儿罕见病药物。分子式：C 8H 7ClN 2O 2S，别名：氯甲苯噻嗪；7-氯-3-甲基-2H-1，2，4-苯并噻二嗪1，1-二氧化物；降压嗪；7-氯-3-甲基-2氢-1，2，4-苯并噻二嗪1，1-二氧化物；CAS号：364-98-7；结构式如下：
Figure PCTCN2019129657-appb-000001
已报道的该药物的合成路线，主要有以下A，B和C三种合成方法：
Figure PCTCN2019129657-appb-000002
从原料对氨基苯胺出发，可以有A，B两种合成方法。这两种方法都使用了非常活泼、腐蚀性强的试剂，需要高温，无水的条件；路线C关环反应使用原乙酸三乙酯，在乙醇中回流一步关环得到产物。现有方法存在的问题：三种方法中A和B路线的步骤长，路线A需要三步反应，过程中使用sulfurisocyanatidic chloride(氯磺酰异氰酸酯)，该试剂有毒，极其活泼，水敏感，反应中放出气体，反应剧烈，下一步使用的试剂AlCl 3也易吸潮，因此反应无水条件要求严格，最后一步需要使用醋酸，在高温130℃下处理得到最终的产物，醋酸具有较强的挥发性，刺激性和腐蚀性；路线B需要四步得到最终的产物，前两步与路线A相同，然后在强酸H 2SO 4处理后开环，再用原乙酸三乙酯进行关环反应得到产物，相比上面的路线A，该路线多了一步反应，并且使用了强腐蚀性的硫酸；路线C需要缚酸剂并高温闭环。因此需要研发新的制备二氮嗪的方法，以使用稳定的原料、减少操作步骤，并且选择更温和的试剂，避免强酸的使用，从而高收率制备氮二嗪。
发明概述
技术问题
本发明提供了一条全新的合成二氯嗪的路线，该路线反应步骤更短，试剂更加便宜易得，反应条件更温和，收率更高，是一种更加适合产业化的合成路线；本发明避免了反应过程中使用氯磺酰异氰酸酯、强酸(硫酸)、反应温度温高(240-250℃)的问题，且反应步骤短；总收率可以达到90％，且相比已经公开报道的二氮嗪的制备方法，本发明提供的合成路线克服了众多的缺点，从而更适合产业化生产。
问题的解决方案
技术解决方案
本发明采用如下技术方案：
一种制备二氮嗪的方法，包括以下步骤，将2-氨基-5-氯苯磺酰胺、咪唑盐与酰胺溶剂混合后加热反应，得到二氮嗪。
本发明公开了咪唑盐酸盐作为催化剂在制备二氮嗪中的应用。
本发明公开的2-氨基-5-氯苯磺酰胺的制备方法包括如下步骤，将邻氨基苯磺酰 胺与N-氯代丁二酰亚胺在氯溶剂中反应，得到2-氨基-5-氯苯磺酰胺；优选的，反应为回流反应2～6小时。
上述技术方案中，咪唑盐为咪唑盐酸盐；咪唑盐的用量为2-氨基-5-氯苯磺酰胺摩尔量的1～12％，优选3～10％，进一步优选5～7％，最优选5％。
一种二氮嗪的制备方法，包括以下步骤，将邻氨基苯磺酰胺、咪唑盐与酰胺溶剂混合后加热反应，得到化合物IV；再将化合物IV与N-氯代丁二酰亚胺在氯溶剂中反应，得到二氮嗪。优选的，氯溶剂中的反应为回流反应8～10小时；氯溶剂为二氯甲烷或者氯仿。
上述技术方案中，咪唑盐为咪唑盐酸盐；咪唑盐的用量为邻氨基苯磺酰胺摩尔量的1～12％，优选3～10％，进一步优选5～7％，最优选5％。
本发明中，酰胺溶剂为N，N-二甲基乙酰胺；加热反应的温度为120℃～回流温度，时间为5～50小时；优选回流反应6～8小时。
本发明中，加热反应结束后，反应液经过蒸馏后进行柱层析纯化，得到二氮嗪或者3-甲基-2H-1，2，4-苯并噻二嗪1，1-二氧化物(化合物IV)。
本发明中，氯溶剂为二氯甲烷或者氯仿；反应结束后可以柱层析纯化或者重结晶的方式制备纯品。
本发明提供的全新合成路线，使用了试剂N，N-二甲基乙酰胺，在催化剂当量的咪唑盐酸盐存在下，高收率制备得到产物；其中N，N-二甲基乙酰胺是工业常用的溶剂，相比已公开的合成二氮嗪的路线C使用的原乙酸三乙酯，该试剂更稳定，不易燃，价格上便宜15倍以上，这步反应的收率更高，可以达到95％以上。
具体反应如下所示合成路线D或者路线E：
路线D
Figure PCTCN2019129657-appb-000003
路线E
Figure PCTCN2019129657-appb-000004
本发明制备路线的特点是，路线D，从便宜易得的原料邻氨基苯磺酰胺(I)出发，与N-氯代丁二酰亚胺(NCS)反应，二氯甲烷或者氯仿做溶剂，收率85-90％得到化合物II(2-氨基-5-氯苯磺酰胺)，后者与N，N-二甲基乙酰胺，在催化当量咪唑盐酸盐存在时，90-98％高收率制备二氮嗪III。或者路线E，从便宜易得的原料邻氨基苯磺酰胺(I)出发，与N，N-二甲基乙酰胺，在催化当量咪唑盐酸盐存在时，90-98％高收率制备化合物IV，后者与N-氯代丁二酰亚胺(NCS)反应，二氯甲烷或者氯仿做溶剂，收率85-90％得到二氮嗪III。
发明的有益效果
对附图的简要说明
附图说明
图1为本发明制备的2-氨基-5-氯苯磺酰胺质谱图；
图2为本发明制备的二氮嗪的质谱；
图3为本发明制备的二氮嗪的核磁氢谱；
图4为本发明制备的化合物IV的质谱；
图5为本发明制备的化合物IV的核磁氢谱；
图6为本发明制备的二氮嗪的核磁氢谱。
发明实施例
本发明的实施方式
本发明公开的制备二氮嗪的方法如下：
将2-氨基-5-氯苯磺酰胺、咪唑盐与酰胺溶剂混合后加热反应，得到二氮嗪。进一步的2-氨基-5-氯苯磺酰胺的制备方法如下，将邻氨基苯磺酰胺与N-氯代丁二酰亚胺在溶剂中反应，得到2-氨基-5-氯苯磺酰胺。
Figure PCTCN2019129657-appb-000005
或者，将邻氨基苯磺酰胺、咪唑盐与酰胺溶剂混合后加热反应，得到化合物IV；再将化合物IV与N-氯代丁二酰亚胺在氯溶剂中反应，得到二氮嗪。
Figure PCTCN2019129657-appb-000006
所有实施例的柱层析纯化采用体积比为1∶1的乙酸乙酯/石油醚为洗脱剂，R f为0.3。
实施例一
将邻氨基苯磺酰胺(1.72g)与NCS(1.32g，1.0当量)混合，溶解在二氯甲烷中，在回流温度下，搅拌5小时，然后柱层析纯化，制备得到化合物II 2-氨基-5-氯苯磺酰胺，1.75g，该步收率85％，纯度大于99％。化合物质谱：计算值[M+H] +C 6H 8ClN 2O 2S，206.99；实验值：206.83。
将邻氨基苯磺酰胺(1.72g)与NCS(1.32g，1.0当量)混合，溶解在氯仿中，在回流温度下，搅拌3小时，然后柱层析纯化，制备得到化合物II2-氨基-5-氯苯磺酰胺1.96g，该步收率95％，纯度大于99％，质谱实验值：206.9，质谱图见图1。
实施例二
将2-氨基-5-氯苯磺酰胺(2.05g)溶解在8.0毫升N，N-二甲基乙酰胺中，再加入0.14g(10mol％)咪唑盐酸盐，反应温度120℃，搅拌48小时后，反应液经过蒸馏，将过量的N，N-二甲基乙酰胺蒸馏回收，剩余物进行柱层析纯化，得到产物二氮嗪(化合物III)2.07g，收率90％，纯度大于99％，质谱实验值：230.8。
实施例三
将2-氨基-5-氯苯磺酰胺(2.05g)溶解在8.0毫升N，N-二甲基乙酰胺中，再加入0.11g(7mol％)咪唑盐酸盐，反应温度150℃，搅拌16小时后，将过量的N，N-二甲基乙酰胺蒸馏回收，剩余物进行柱层析纯化，得到产物二氮嗪(III)，2.17g，收率94％，质谱实验值：230.9，纯度大于99％。
实施例四
将2-氨基-5-氯苯磺酰胺(2.05g)溶解在8.0毫升N，N-二甲基乙酰胺中，再加入0.08g(5mol％)咪唑盐酸盐，在回流温度下搅拌7小时后，将过量的N，N-二甲基乙酰胺蒸馏回收，剩余物进行柱层析纯化，得到产物二氮嗪(III)2.26g，收率98％，纯度大于99％。二氮嗪的质谱和HNMR分别如图2和图3；化合物(III)的表征：1.质谱：计算值[M+H] +C 8H 8ClN 2O 2S，230.99；实验值：230.8； 1HNMR(400MHz，CDCl 3)：12.70(br，1H，NH)，7.82(d，J＝1.6Hz1H)，7.74(dd，J＝2.0，8.8Hz，1H)，7.48(d，J＝8.8Hz，1H)，2.32(s，3H)。
将实施例四的N，N-二甲基乙酰胺更换为DMF，其余不变，得不到产物二氮嗪。
实施例五
将邻氨基苯磺酰胺(1.72g)溶解在8.0毫升N，N-二甲基乙酰胺中，再加入0.08g(5mol％)咪唑盐酸盐，在回流温度下搅拌6小时后，将过量的N，N-二甲基乙酰胺蒸馏回收，剩余物进行柱层析纯化，得到产物化合物IV1.84g，收率94％，纯度大于99％，质谱见图4，实验值196.8，计算值197.04。化合物IV氢谱：HNMR(400MHz，CDCl 3)：δ12.09(br，1H)，7.79(dd，J＝1.2Hz，8.0Hz，1H)，7.67(dt，J＝1.6Hz，7.6Hz，1H)，7.42(t，J＝7.6Hz，1H)，7.29(d，J＝8.0Hz，1H)，2.3(s，3H)，如图5所示，图5A为图5B的部分放大图。结构式如下：
Figure PCTCN2019129657-appb-000007
将上述化合物IV(1.96g)与NCS(1.32g，1.0当量)混合，溶解在氯仿中，在回流温度下，搅拌9小时，然后柱层析纯化，制备得到产物二氮嗪(III)2.06g，该步收率90％，纯度大于99％，质谱实验值：230.9；氢谱见图6。
将实施例五的N，N-二甲基乙酰胺更换为DMF，其余不变，得不到产物化合物IV。
实施例六
将邻氨基苯磺酰胺(1.72g)溶解在8.0毫升N，N-二甲基乙酰胺中，再加入0.11g(7mol％)咪唑盐酸盐，在140℃下搅拌15小时后，将过量的N，N-二甲基乙酰胺蒸馏回收，剩余物进行柱层析纯化，得到产物化合物IV1.76g，收率90％，纯度大于99％。将上述化合物IV(1.96g)与NCS(1.32g，1.0当量)混合，溶解在氯仿中，在回流温度下，搅拌10小时，然后柱层析纯化，制备得到产物二氮嗪(III)2.07g，该步收率90％，纯度大于99％，质谱实验值：231.1。

Claims (10)

  1. 一种制备二氮嗪的方法，其特征在于，包括以下步骤，将2-氨基-5-氯苯磺酰胺、咪唑盐与酰胺溶剂混合后加热反应，得到二氮嗪。
  2. 根据权利要求1所述制备二氮嗪的方法，其特征在于，将邻氨基苯磺酰胺与N-氯代丁二酰亚胺在氯溶剂中反应，得到2-氨基-5-氯苯磺酰胺。
  3. 根据权利要求2所述制备二氮嗪的方法，其特征在于，反应为回流反应2～6小时；氯溶剂为二氯甲烷或者氯仿。
  4. 根据权利要求1所述制备二氮嗪的方法，其特征在于，咪唑盐为咪唑盐酸盐；咪唑盐的用量为2-氨基-5-氯苯磺酰胺摩尔量的1～12％；酰胺溶剂为N，N-二甲基乙酰胺；加热反应的温度为120℃～回流温度，时间为5～50小时。
  5. 根据权利要求4所述制备二氮嗪的方法，其特征在于，咪唑盐的用量为2-氨基-5-氯苯磺酰胺摩尔量的3～10％；加热反应为回流反应6～8小时。
  6. 一种二氮嗪的制备方法，其特征在于，包括以下步骤，将邻氨基苯磺酰胺、咪唑盐与酰胺溶剂混合后加热反应，得到化合物IV；再将化合物IV与N-氯代丁二酰亚胺在氯溶剂中反应，得到二氮嗪。
  7. 根据权利要求6所述制备二氮嗪的方法，其特征在于，咪唑盐为咪唑盐酸盐；咪唑盐的用量为2-氨基-5-氯苯磺酰胺摩尔量的1～12％；酰胺溶剂为N，N-二甲基乙酰胺；加热反应的温度为120℃～回流温度，时间为5～50小时。
  8. 根据权利要求7所述制备二氮嗪的方法，其特征在于，咪唑盐的用量为2-氨基-5-氯苯磺酰胺摩尔量的3～10％；加热反应为回流反应6～8小时。
  9. 根据权利要求6所述制备二氮嗪的方法，其特征在于，氯溶剂中的反应为回流反应8～10小时；氯溶剂为二氯甲烷或者氯仿。
  10. 咪唑盐酸盐作为催化剂在制备二氮嗪中的应用。
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