WO2022262548A1 - 化合物盐酸法舒地尔的制备方法 - Google Patents

化合物盐酸法舒地尔的制备方法 Download PDF

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WO2022262548A1
WO2022262548A1 PCT/CN2022/095330 CN2022095330W WO2022262548A1 WO 2022262548 A1 WO2022262548 A1 WO 2022262548A1 CN 2022095330 W CN2022095330 W CN 2022095330W WO 2022262548 A1 WO2022262548 A1 WO 2022262548A1
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preparation
organic solvent
isoquinolinesulfonamide
fasudil hydrochloride
potassium
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PCT/CN2022/095330
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French (fr)
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赵建宏
王丁丁
杨武林
牛金铭
朱俊
吴炜婷
喻捷
孙缜
徐小丽
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华东理工大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the invention relates to the field of medicine preparation, in particular to a new preparation process of a raw material drug fasudil hydrochloride.
  • Fasudil Hydrochloride Chemical name hexahydro-1-(5-sulfonylisoquinoline)-1(H)-1,4-diazepine hydrochloride, its structural formula is as follows:
  • Fasudil hydrochloride is a new type of cardiovascular drug with a wide range of pharmacological effects.
  • MLCP myosin light chain phosphatase
  • SAH subarachnoid hemorrhage
  • the drug was developed by Japan's Asahi Kasei Co., Ltd. in the 1980s, launched in June 1995, and launched in China in 2004. It is mainly used to improve the symptoms of ischemic cerebrovascular diseases caused by cerebral vasospasm after subarachnoid hemorrhage. Its clinical application scope will continue to expand, and the market prospect is good.
  • the preparation route adopted by Japanese Asahi Kasei patent US4678783 involves the sulfonation of isoquinoline with oleum to obtain 5-isoquinolinesulfonic acid, which is obtained by reacting 5-isoquinolinesulfonic acid with thionyl chloride under the catalysis of DMF 5-isoquinolinesulfonyl chloride hydrochloride solid, the latter is freed with aqueous sodium bicarbonate (adjust the pH to about 6.0), and then extracted with dichloromethane to obtain a dichloromethane solution of 5-isoquinolinesulfonyl chloride , and react with homopiperazine for amidation condensation to obtain Fasudil (purified by silica gel column chromatography), and then form a salt with hydrochloric acid to obtain Fasudil hydrochloride.
  • the synthesis method of this process is shown in Figure 1.
  • Patent CN101863880 involves the preparation of 5-isoquinolinesulfonic acid by replacing oleum in the traditional process with chlorosulfonic acid in the sulfonation step.
  • the subsequent steps are almost the same as those of the patent US4678783, both of which are prepared under the condition of SOCl 2 /DMF to prepare 5-isoquinolinesulfonic acid
  • Acyl chloride hydrochloride use sodium bicarbonate aqueous solution to adjust the pH value to about 6, then extract with dichloromethane, and then conduct condensation reaction with excess homopiperazine in the obtained dichloromethane solution.
  • Patent CN101973782 improves the reaction of connecting the homopiperazine group in the above-mentioned patent method, and uses a protecting group to protect the N atom on the homopiperazine ring, so as to improve the selectivity of the acylation reaction and avoid the formation of dimers.
  • the process route is as follows As shown in Fig. 2, in the patent CN10212632, 4-piperidone hydrochloride hydrate is used as a raw material to synthesize a homopiperazine derivative with a protective group to improve the selectivity of the acylation reaction, which is the same as the process principle.
  • Patent CN10202536 relates to the purification method of Fasudil hydrochloride, the dichloromethane solution of Fasudil is treated with acid and alkali, that is, the 5-isoquinolinesulfonic acid is firstly treated with SOCl2 /DMF to prepare 5-isoquinolinesulfonic acid Hydrochloride, adjust the pH value to neutral with NaHCO 3 aqueous solution, then extract with dichloromethane, react the dichloromethane solution with homopiperazine to obtain the dichloromethane solution of Fasudil.
  • Chinese patents CN10200246, CN101812051, CN101962379, CN101092413 and CN101723934 all relate to how to purify and refine fasudil hydrochloride, specifically including changing column chromatography purification eluent, changing recrystallization solvent, resin adsorption and other methods.
  • homopiperazine and derivatives thereof are used as synthetic intermediates in the process route for preparing fasudil hydrochloride, resulting in extremely high raw material costs and many process shortcomings: 1) the synthesis of homopiperazine The process route is complex, the atom economy is low, and the cost is high; 2) a large amount of three wastes are produced during the synthesis process; 3) the reaction selectivity between 5-isoquinolinesulfonyl chloride and homopiperazine is not high, resulting in a large amount of homopiperazine, which further increases 4) There are many reaction steps, the production cycle is long, and the industrial production efficiency is low.
  • the object of the present invention is to overcome at least one shortcoming in the above-mentioned prior art, and provide a kind of preparation method of the compound fasudil hydrochloride that is safe, controllable, efficient and simple in process.
  • the present invention provides a preparation method of the compound Fasudil hydrochloride, and the synthetic route is shown in FIG. 4 .
  • Described method comprises the steps:
  • step (3) Deprotecting the compound (6) obtained in step (3) under acidic conditions, followed by cyclization under alkaline conditions to obtain fasudil, and salt formation with hydrochloric acid to obtain fasudil hydrochloride (1).
  • step (1) carry out acid-base treatment according to the following steps:
  • the lye is sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, preferably aqueous sodium hydroxide solution;
  • the first organic solvent is methylene dichloride, ethylene dichloride, ethylenediamine, triethylamine, diisopropylethylamine, trimethylamine, pyridine, toluene, ethyl acetate, methanol, ethanol , one or more of tetrahydrofuran or acetonitrile, preferably dichloromethane;
  • the second organic solvent is one or more of tetrahydrofuran, dioxane, acetonitrile, methanol or ethanol, preferably tetrahydrofuran;
  • the third organic solvent is dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dioxane, acetonitrile, methanol, ethanol, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, One or more of toluene, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably tetrahydrofuran.
  • the solid base is sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, preferably sodium bicarbonate or potassium bicarbonate;
  • the base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or triethylamine, preferably potassium carbonate or sodium carbonate;
  • the substituent is chlorine (Cl), bromine (Br), p-toluenesulfonate (TsO), or methanesulfonate.
  • 1-bromo-3-chloropropane is preferred;
  • the base used for cyclization under alkaline conditions is NaOH, KOH, Na 2 CO 3 , NaHCO 3 , KHCO 3 , K 2 CO 3 or triethylamine, preferably NaOH.
  • the deprotection condition is hydrochloric acid/methanol, hydrochloric acid/ethanol, or trifluoroacetic acid/dichloromethane system, preferably hydrochloric acid/methanol system, and the temperature is 50-55°C.
  • the preparation method of the compound fasudil hydrochloride of the present invention adopts cheap and easy-to-obtain ethylenediamine as the starting material and 1-bromo-3-chloropropane as the most economical cyclization reagent to synthesize the homopiperazine ring step by step,
  • the use of expensive homopiperazine and its derivatives is avoided, the reaction condition is mild, the operation is simple, the cost is low, the environment is friendly, and it is suitable for industrial production.
  • Fig. 1 is the flow chart of the process synthesis method in the Japanese Asahi Kasei patent US4678783.
  • Fig. 2 is a flowchart of the process synthesis method in the patent CN101973782.
  • Fig. 3 is the flow chart of the technological synthesis method in the document such as Wang Daolin.
  • Fig. 4 is the flowchart of the preparation method of the compound Fasudil hydrochloride of the present invention.
  • Figure 5 is the HPLC chart of Fasudil hydrochloride obtained in Example 4 of the present invention.
  • the present invention provides a kind of high-efficiency, economical new synthetic technique of Fasudil hydrochloride, and the synthetic route takes cheap and easy-to-get ethylenediamine as starting material, obtains intermediate tert-butyl-(N) through sulfonamidation and Boc protection -(2-aminoethyl)-5-isoquinolinesulfonamide) carbamate (5), and then obtain Fasudil hydrochloride through telescopic process, including nucleophilic substitution, deprotection, cyclization and formation Salt four steps.
  • the total yield of Fasudil hydrochloride (1) is 67.1%, and the purity is as high as 99.94%.
  • the route avoids the use of expensive homopiperazine and its derivatives as synthetic intermediates.
  • the advantages of the process include cheap and easy-to-obtain raw materials, simple operation, low cost, environmental friendliness, and suitability for industrial production.
  • the preparation method of a kind of compound fasudil hydrochloride provided by the invention comprises the following steps:
  • step (2) Mix N-(2-aminoethyl)-5-isoquinolinesulfonamide (4), base, organic solvent and water obtained in step (1), stir for 1 hour, and then add (Boc) 2 O solution dropwise , after the dropwise addition, react for 0.5-2h, extract and separate the reaction system after the reaction, separate and dry the organic phase and concentrate to obtain tert-butyl-(2-(5-isoquinolinesulfonamide) ethyl) carbamic acid ester(5);
  • step (3) Dissolve the tert-butyl-(2-(5-isoquinolinesulfonamide) ethyl) carbamate (5) obtained in step (2) in an organic solvent, and Reaction with 1,3-disubstituted propane (preferably 1-bromo-3-chloropropane) to obtain compound (6);
  • step (3) Deprotecting the compound (6) obtained in step (3) under acidic conditions, followed by cyclization under alkaline conditions to obtain fasudil, and salt formation with hydrochloric acid to obtain fasudil hydrochloride (1).
  • Embodiment 1 The preparation of N-(2-aminoethyl)-5-isoquinolinesulfonamide hydrochloride (4)
  • Embodiment 2 The preparation of (tert-butyl-(N-(2-aminoethyl)-5-isoquinolinesulfonamide) carbamate (5)
  • N-(2-aminoethyl)-5-isoquinolinesulfonamide (4) (107.1g) obtained in Example 1 was placed in a 1000mL three-neck flask, 450mL tetrahydrofuran and 150mL water were added, and stirred to obtain a white
  • anhydrous potassium carbonate (99%, 92.2g) was added, and after stirring for 30min, (Boc) 2 O solution in THF (99%, 72.8g, 100mL THF) was added dropwise, and the reaction progress was monitored by TLC.
  • Example 2 The solid 5 (113.7g) obtained in Example 2 was placed in a 1000mL three-necked flask, and tetrabutylammonium bromide (99%, 5.3g, 16.3mmol, 0.05eq), sodium hydroxide (96%, 27.1g) was added , add 400mL tetrahydrofuran and 30mL water, stir to obtain a colorless clear liquid; take another 1000mL three-necked flask, add 1-bromo-3-chloropropane (99%, 77.5g), 200mL tetrahydrofuran, heat up to 50-55°C, drop Add the above colorless clear liquid, react for 4-5 hours after the dropwise addition, cool down to room temperature after the conversion of raw materials is complete, add 100mL of water, 100mL of tetrahydrofuran, stir, separate liquid, discard the water layer; the organic layer is concentrated under reduced pressure to obtain compound (6) The concentrated solution was directly put into the next reaction without purification.
  • Figure 5 shows the HPLC of Fasudil hydrochloride obtained in Example 5, and its relevant information (Detector: UV; Wavelength (nm): 275nm) is as follows.

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Abstract

本发明涉及一种高效、经济的盐酸法舒地尔的合成新工艺，制备方法包括以下步骤：合成路线以廉价易得的乙二胺为起始原料，通过磺酰胺化，Boc保护获得中间叔丁基-(N-(2-氨乙基)-5-异喹啉磺酰胺)氨基甲酸酯(5)，进而经过叠缩工艺获得盐酸法舒地尔，其中包括亲核取代、脱保护、环化和成盐四个步骤。盐酸法舒地尔(1)的总收率为67.1％，纯度高达99.94％。与传统工艺相比，路线中避免使用价格昂贵的高哌嗪及其衍生物作为合成中间体，工艺的优势包括原料廉价易得、操作简单、成本低、环境友好、适合工业化生产。

Description

化合物盐酸法舒地尔的制备方法
相关申请的交叉引用
本申请主张2021年6月15日提交的申请号为202110661695.8的中国发明专利申请的优先权，其内容通过引用的方式并入本申请中。
技术领域
本发明涉及药物制备领域，特别地，涉及原料药盐酸法舒地尔的制备新工艺。
背景技术
盐酸法舒地尔(Fasudil Hydrochloride)，化学名称六氢-1-(5-磺酰基异喹啉)-1(H)-1,4-二氮杂卓盐酸盐，其结构式如下：
Figure PCTCN2022095330-appb-000001
盐酸法舒地尔是一种新型心血管药物，具有广泛的药理作用。作为一种RHO激酶抑制剂和细胞内新型Ca 2+拮抗剂，具有良好的血管扩张作用，通过增加肌球蛋白轻链磷酸酶(MLCP)的活性扩张血管，降低内皮细胞的张力，从而改善脑组织微循环，改善蛛网膜下隙出血(SAH)患者的预后，不产生和加重脑的盗血，同时可拮抗炎性因子，保护神经抗凋亡，促进神经再生。该药由日本旭化成株式会社于上世纪80年代开发，1995年6月上市，2004年在中国上市，主要用于蛛网膜下腔出血后脑血管痉挛等引起的缺血性脑血管疾病症状的改善，其临床应用范围还将不断扩展，市场前景良好。
目前国内外报道的制备方法不多，现有公开的制备工艺如下：
日本Asahi Kasei专利US4678783(原研专利)采用的制备路线涉及异喹啉经过发烟硫酸磺化得到5-异喹啉磺酸，5-异喹啉磺酸在DMF催化下和氯化亚砜反应得到5-异喹啉磺酰氯盐酸盐固体，后者用碳酸氢钠水溶液进行游离(调pH值到6.0左右)，然后再用二氯甲烷萃取得到5-异喹啉磺酰氯的二氯甲烷溶液，再与高哌嗪反应酰胺化缩合得到法舒地尔(硅胶柱层析纯化)，然后与盐酸成盐得到盐酸法舒地尔。该工艺的合成方法如图1所示。
专利CN101863880涉及磺化步骤用氯磺酸替代传统工艺中的发烟硫酸制备5-异喹啉磺酸， 后续步骤与专利US4678783几乎相同，均为通过SOCl 2/DMF条件制备5-异喹啉磺酰氯盐酸盐，用碳酸氢钠水溶液调pH值到6左右后用二氯甲烷萃取，所得二氯甲烷溶液再与过量的高哌嗪进行缩合反应。
专利CN101973782改进上述专利方法中设计连接高哌嗪基团的反应，利用保护基对高哌嗪环上的N原子进行保护，提高酰化反应的选择性，避免二聚体的生成，工艺路线如图2所示，专利CN10212632中以4-哌啶酮盐酸盐水合物为原料合成保护基的高哌嗪衍生物，提高酰化反应的选择性，与此工艺原理相同。
专利CN10202536涉及盐酸法舒地尔的提纯方法，通过酸碱处理法舒地尔的二氯甲烷溶液，即先通过SOCl 2/DMF条件处理5-异喹啉磺酸制备5-异喹啉磺酸盐酸盐，用NaHCO 3水溶液调节pH值到中性后用二氯甲烷萃取，二氯甲烷溶液和高哌嗪反应得到法舒地尔的二氯甲烷溶液。该溶液用酸液调pH值至4.5～5.5，然后用二氯甲烷萃取水相，弃去溶有二聚物杂质的有机相，所得水相用碱液调节pH至9.5～10.5，然后用二氯甲烷萃取水相，弃去溶有高哌嗪杂质的水相，然后溶液通过硅胶柱层析提纯后，与盐酸成盐后得到盐酸法舒地尔。通过调酸碱处理法舒地尔的二氯甲烷溶液纯化的方法在专利US5942505中的实施案例中同样使用过。
中国专利CN10200246、CN101812051、CN101962379、CN101092413及CN101723934都涉及如何纯化精制盐酸法舒地尔，具体包括改变柱层析纯化洗脱剂、改变重结晶溶剂、树脂吸附等方法。
以上所报道合成路线中均涉及到以价格昂贵的高哌嗪或其衍生物为合成中间体，文献王道林,钱建华，等.高哌嗪的新合成法[J].化学试剂,205.(05):311-312.中报道了高哌嗪的合成方法，以乙二胺为原料经磺酰化、环化、脱磺酰化3步反应合成高哌嗪，收率78％，合成路线如图3所示。
综上所述，制备盐酸法舒地尔的工艺路线中均用到价格昂贵的高哌嗪及其衍生物作为合成中间体，导致原料成本极高，工艺缺点多：1)高哌嗪的合成工艺路线复杂，原子经济性低，成本高；2)合成过程中产生大量的三废；3)5-异喹啉磺酰氯与高哌嗪反应选择性不高，导致高哌嗪用量大，进一步增加了原料成本；4)反应步骤多，生产周期长，工业化生产效率低。
发明内容
本发明的目的是为了克服上述现有技术中的至少一个缺点，提供一种安全可控、高效、工艺简单的化合物盐酸法舒地尔的制备方法。
本发明提供了一种化合物盐酸法舒地尔的制备方法，合成路线如图4所示。
所述的方法包括如下步骤：
(1)将5-异喹啉磺酰氯置于第一有机溶剂中，滴加到乙二胺、固体碱和第一有机溶剂的混合溶剂中，于20～25℃下反应2～5h，通过酸碱处理，得到N-(2-氨乙基)-5-异喹啉磺酰胺(4)；
(2)将步骤(1)得到的N-(2-氨乙基)-5-异喹啉磺酰胺(4)、碱、第二有机溶剂与水混合，搅拌后滴加(Boc) 2O溶液，滴加完毕后反应0.5～2h，对反应后的反应体系进行萃取分离，将有机相分离干燥后浓缩得到叔丁基-(2-(5-异喹啉磺酰胺)乙基)氨基甲酸酯(5)；
(3)将步骤(2)中得到的叔丁基-(2-(5-异喹啉磺酰胺)乙基)氨基甲酸酯(5)溶于第三有机溶剂中，在50～55℃条件下与1，3-二取代丙烷发生亲核取代反应，得到化合物(6)；
(4)将步骤(3)中所得的化合物(6)在酸性条件下脱保护，之后碱性条件下环合得到法舒地尔，与盐酸成盐得到盐酸法舒地尔(1)。
较佳地，在所述的步骤(1)中，按以下步骤进行酸碱处理：
向反应液中滴加盐酸溶液，调pH值至2～3，分液，弃去有机层；
水层滴加碱液调pH值至7～8，所述的碱液为碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、碳酸钠或碳酸钾，优选为氢氧化钠水溶液；
搅拌，析出白色固体，加饱和食盐水促进固体析出，抽滤，滤饼经干燥，得到N-(2-氨乙基)-5-异喹啉磺酰胺。
较佳地，所述的第一有机溶剂为二氯甲烷、二氯乙烷、乙二胺、三乙胺、二异丙基乙胺、三甲胺、吡啶、甲苯、乙酸乙酯、甲醇、乙醇、四氢呋喃或乙腈中的一种或多种，优选为二氯甲烷；
所述的第二有机溶剂为四氢呋喃、二氧六环、乙腈、甲醇或乙醇中的一种或多种，优选为四氢呋喃；
所述的第三有机溶剂为二氯甲烷、1,2-二氯乙烷、四氢呋喃、二氧六环、乙腈、甲醇、乙醇、乙酸乙酯、乙酸异丙酯、甲基异丁基酮、甲苯、醋酸异丙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲基亚砜中的一种或多种，优选为四氢呋喃。
较佳地，在所述的步骤(1)中，固体碱为碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、碳酸钠或碳酸钾，优选为碳酸氢钠或碳酸氢钾；
在所述的步骤(2)中，碱为碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾或三乙胺，优选为碳酸钾或碳酸钠；
在所述的步骤(3)中，取代基为氯(Cl)、溴(Br)、对甲苯磺酸酯(TsO)、或甲烷磺酸 酯。优选为1-溴-3-氯丙烷；
在所述的步骤(4)中，碱性条件下环合所用的碱为NaOH、KOH、Na 2CO 3、NaHCO 3、KHCO 3、K 2CO 3或三乙胺，优选为NaOH。
较佳地，在所述的步骤(4)中，脱保护条件为盐酸/甲醇、盐酸/乙醇、或三氟乙酸/二氯甲烷体系，优选为盐酸/甲醇体系，温度为50～55℃。
本发明的化合物盐酸法舒地尔的制备方法，采用价廉易得的乙二胺为起始原料、1-溴-3-氯丙烷作为最经济环合试剂，分步合成高哌嗪环，避免了价格昂贵的高哌嗪及其衍生物的使用，反应条件温和、操作简单、成本低、环境友好、适合工业化生产。
附图说明
图1为日本Asahi Kasei专利US4678783中的工艺合成方法流程图。
图2为专利CN101973782中的工艺合成方法流程图。
图3为王道林等的文献中的工艺合成方法流程图。
图4为本发明的化合物盐酸法舒地尔的制备方法的流程图。
图5为本发明的实施例4获得的盐酸法舒地尔HPLC图。
具体实施方式
为了能够更清楚地理解本发明的技术内容，特举以下实施例详细说明。应理解，实施例仅是用于说明本发明，而不是对本发明的限制。
本发明提供了一种高效、经济的盐酸法舒地尔的合成新工艺，合成路线以廉价易得的乙二胺为起始原料，通过磺酰胺化，Boc保护获得中间叔丁基-(N-(2-氨乙基)-5-异喹啉磺酰胺)氨基甲酸酯(5)，进而经过叠缩工艺获得盐酸法舒地尔，其中包括亲核取代、脱保护、环化和成盐四个步骤。盐酸法舒地尔(1)的总收率为67.1％，纯度高达99.94％。与传统工艺相比，路线中避免使用价格昂贵的高哌嗪及其衍生物作为合成中间体，工艺的优势包括原料廉价易得、操作简单、成本低、环境友好、适合工业化生产。
具体地，本发明提供的一种化合物盐酸法舒地尔的制备方法，包括如下步骤：
(1)将5-异喹啉磺酰氯置于第一有机溶剂中，滴加到乙二胺、固体碱和第一有机溶剂的混合溶剂中，于20～25℃下反应2～5h，通过酸碱处理，得到N-(2-氨乙基)-5-异喹啉磺酰胺(4)，按下述方法处理反应液：
(a)向反应液中滴加盐酸溶液，调pH值至2～3，分液，弃去有机层；
(b)水层滴加碱液调pH值至7～8；
(c)搅拌，析出白色固体，加饱和食盐水促进固体析出，抽滤，滤饼经干燥得到N-(2-氨乙基)-5-异喹啉磺酰胺(4)。
(2)将步骤(1)得到的N-(2-氨乙基)-5-异喹啉磺酰胺(4)、碱、有机溶剂与水混合，搅拌1h后滴加(Boc) 2O溶液，滴加完毕后反应0.5～2h，对反应后的反应体系进行萃取分离，将有机相分离干燥后浓缩得到叔丁基-(2-(5-异喹啉磺酰胺)乙基)氨基甲酸酯(5)；
(3)将步骤(2)中得到的叔丁基-(2-(5-异喹啉磺酰胺)乙基)氨基甲酸酯(5)溶于有机溶剂中，在50～55℃条件下与1，3-二取代丙烷(优选1-溴-3-氯丙烷)反应，得到化合物(6)；
(4)将步骤(3)中所得的化合物(6)在酸性条件下脱保护，之后碱性条件下环合得到法舒地尔，与盐酸成盐得到盐酸法舒地尔(1)。
实施例1 N-(2-氨乙基)-5-异喹啉磺酰胺盐酸盐(4)的制备
将5-异喹啉磺酰氯(86.5g)用500mL二氯甲烷溶解后，慢慢滴入乙二胺(2)(99％，68.6g)、固体NaHCO 3(99％,63.68g)和100mL二氯甲烷的混合物中，滴毕后反应2h；向反应液中逐滴滴加浓HCl，调节pH至溶液pH≈2，得到透明清液，分液，弃去有机层；向水层中滴加40％的NaOH溶液调pH至pH≈8，置于0～5℃下搅拌沉淀2h，抽滤，滤饼以乙醇淋洗(200mL*2)，置于45℃下干燥2h，得到白色粉末状固体(化合物4)107.1g。mp:249.9～250.8℃。文献(253～254℃)。MS-ESI:m/z 252.1,[M+H] +(100％)； 1H NMR(400MHz,D2O)δ(ppm):9.04(s,1H),8.41(d,J＝6.2Hz,1H),8.27(d,J＝6.2Hz,1H),8.20(dd,J1＝7.4,J2＝1.2Hz,1H),8.04(d,J＝8.3,1H),7.59(t,J＝7.8Hz,1H,),2.92(t,J＝5.8Hz,2H),2.68(t,J＝6.2,2H).
实施例2 (叔丁基-(N-(2-氨乙基)-5-异喹啉磺酰胺)氨基甲酸酯(5)的制备
室温下，将实施例1中所得N-(2-氨乙基)-5-异喹啉磺酰胺(4)(107.1g)置于1000mL三口瓶中，加入450mL四氢呋喃和150mL水，搅拌得到白色浑液，加入无水碳酸钾(99％，92.2g)，搅拌30min后，滴加(Boc) 2O的四氢呋喃溶液(99％，72.8g，100mL四氢呋喃)，TLC监测反应进程，原料完全转化后搅拌30min，加入100mL水，200mL甲叔醚搅拌萃取，有机层中加入无水硫酸镁搅拌干燥2h，抽滤，滤液减压浓缩除去溶剂得到白色固体物，加入乙酸乙酯打浆得到113.7g白色固体(5)，mp：146.8～147.9℃。MS-ESI:m/z 352.1,[M+H] +； 1H NMR(400MHz,CDCl3)δ(ppm):9.33(s,1H),8.61(d,J＝5.9Hz,1H,),8.41-8.39(m,2H),8.18(d,J＝8.2Hz),7.67(t,J＝7.9Hz,1H),6.39(t,J＝5.8Hz,1H),5.02(s,1H),3.19(q,J＝5.8Hz,2H),3.04(q,J＝5.7Hz,2H),1.35(s,9H).
实施例3 叔丁基-(2-(N-(3-氯丙烷)5-异喹啉磺酰胺)乙基)氨基甲酸酯(6)的制备
将实施例2中所得固体5(113.7g)置于1000mL三口瓶中，加入四丁基溴化铵(99％，5.3g，16.3mmol，0.05eq)，氢氧化钠(96％，27.1g)，加入400mL四氢呋喃和30mL水，搅拌得到无色清液；另取一个1000mL三口瓶，加入1-溴-3-氯丙烷(99％，77.5g)，200mL四氢呋喃，升温至50～55℃，滴加上述无色清液，滴加完毕后反应4～5h，原料转化完全后降至室温，加入100mL水，100mL四氢呋喃搅拌，分液，弃去水层；有机层减压浓缩得到化合物(6)的浓缩液，不经纯化，直接投入下一步反应。
实施例4 盐酸法舒地尔(1)的制备
向实施例3中所得化合物(6)的浓缩液中加入400mL甲醇溶解后，滴加浓HCl(36％，135.5mL)，滴毕后升温至50～55℃下搅拌1～2h，TLC检测完全脱保护后，降温，反应液减压浓缩除去甲醇，加入200mL水稀释所得浓缩液，调pH≈8，DCM萃取(200mL*3)，合并DCM萃取液，减压浓缩除去DCM得到油状物；加入400mL甲醇溶解油状物，加入NaOH(96％，27.1g)，四丁基溴化铵(99％，5.3g)，碘化钾(99％，2.7g)，回流4h，降温后加入200mL水，DCM萃取(300mL*2)，分液，弃去水层，保留DCM层，加入40g无水硫酸镁搅拌干燥后减压浓缩得到黄色油状物；加入200mL乙醇溶解，降温至0～5℃，以浓盐酸调节溶液pH至5.5～6.0，搅拌2h后减压浓缩得到粗品盐酸法舒地尔，在甲醇和异丙醚的混合溶剂中重结晶得到白色固体盐酸法舒地尔(1)83.2g，HPLC纯度达99.94％，总收率67.1％(以5-异喹啉磺酰氯为原料计)。mp:247.4-248.2℃(文献值：213-215℃)；MS-ESI:292.1,[M+H] +； 1H NMR(400MHz,CDCl3)δ(ppm):9.31(s,1H),8.65(d,J＝6.1Hz,1H),8.41(d,J＝6.1Hz,1H),8.31(dd,J1＝7.4Hz,J2＝1.2Hz,1H),8.16(d,J＝8.2Hz,1H),7.66(t,J＝7.7Hz,1H),3.47(t,J＝6.1Hz,2H),3.42(t,J＝5.2Hz,2H),2.95(t,J＝5.4Hz,2H),2.92(t,J＝5.8Hz,2H),1.85-1.78(m,2H).
图5显示实施例5所得盐酸法舒地尔的HPLC，其相关信息(Detector:UV；Wavelength(nm):275nm)如下。
Figure PCTCN2022095330-appb-000002
本发明并不局限于上述实施例，而是覆盖在不脱离本发明的精神和范围的情况下所进行的所有改变和修改。这些改变和修改不应被认为是脱离了本发明的精神和范围，并且所有诸如对于本领域技术人员来说显而易见的修改均应被包括在所附权利要求的范围内。

Claims (5)

  1. 一种化合物盐酸法舒地尔的制备方法，其特征在于：所述的方法包括如下步骤：
    (1)将5-异喹啉磺酰氯置于第一有机溶剂中，滴加到乙二胺、固体碱和第一有机溶剂的混合溶剂中，于20～25℃下反应2～5h，通过酸碱处理，得到N-(2-氨乙基)-5-异喹啉磺酰胺；
    (2)将步骤(1)得到的N-(2-氨乙基)-5-异喹啉磺酰胺、碱、第二有机溶剂与水混合，搅拌后滴加(Boc) 2O溶液，滴加完毕后反应0.5～2h，对反应后的反应体系进行萃取分离，将有机相分离干燥后浓缩得到叔丁基-(2-(5-异喹啉磺酰胺)乙基)氨基甲酸酯；
    (3)将步骤(2)中得到的叔丁基-(2-(5-异喹啉磺酰胺)乙基)氨基甲酸酯溶于第三有机溶剂中，在50～55℃条件下与1，3-二取代丙烷发生亲核取代反应，得到化合物(6)；
    (4)将步骤(3)中所得的化合物(6)在酸性条件下脱保护，之后碱性条件下环合得到法舒地尔，与盐酸成盐得到盐酸法舒地尔。
  2. 根据权利要求1所述的制备方法，其特征在于，在所述的步骤(1)中，按以下步骤进行酸碱处理：
    向反应液中滴加盐酸溶液，调pH值至2～3，分液，弃去有机层；
    水层滴加碱液调pH值至7～8，所述的碱液为碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、碳酸钠或碳酸钾；
    搅拌，析出白色固体，加饱和食盐水促进固体析出，抽滤，滤饼经干燥，得到N-(2-氨乙基)-5-异喹啉磺酰胺。
  3. 根据权利要求1所述的制备方法，其特征在于，所述的第一有机溶剂为二氯甲烷、二氯乙烷、乙二胺、三乙胺、二异丙基乙胺、三甲胺、吡啶、甲苯、乙酸乙酯、甲醇、乙醇、四氢呋喃或乙腈中的一种或多种；
    所述的第二有机溶剂为四氢呋喃、二氧六环、乙腈、甲醇或乙醇中的一种或多种；
    所述的第三有机溶剂为二氯甲烷、1,2-二氯乙烷、四氢呋喃、二氧六环、乙腈、甲醇、乙醇、乙酸乙酯、乙酸异丙酯、甲基异丁基酮、甲苯、醋酸异丙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲基亚砜中的一种或多种。
  4. 根据权利要求1所述的制备方法，其特征在于，在所述的步骤(1)中，固体碱为碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、碳酸钠或碳酸钾；
    在所述的步骤(2)中，碱为碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾或三乙胺；
    在所述的步骤(3)中，取代基为氯、溴、对甲苯磺酸酯、或甲烷磺酸酯；
    在所述的步骤(4)中，碱性条件下环合所用的碱为NaOH、KOH、Na 2CO 3、NaHCO 3、KHCO 3、K 2CO 3或三乙胺。
  5. 根据权利要求1所述的制备方法，其特征在于，在所述的步骤(4)中，脱保护条件为盐酸/甲醇、盐酸/乙醇、或三氟乙酸/二氯甲烷体系，温度为50～55℃。
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