CN105949135A - Synthetic method of selexipag - Google Patents

Synthetic method of selexipag Download PDF

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CN105949135A
CN105949135A CN 201610303627 CN201610303627A CN105949135A CN 105949135 A CN105949135 A CN 105949135A CN 201610303627 CN201610303627 CN 201610303627 CN 201610303627 A CN201610303627 A CN 201610303627A CN 105949135 A CN105949135 A CN 105949135A
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isopropyl
tert
reaction
butoxycarbonyl
aminobutoxy
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CN 201610303627
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李兴民
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湖南欧亚生物有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D241/20Nitrogen atoms

Abstract

The invention discloses a synthetic method of selexipag. According to the method, 4-[(t-butyloxycarboryl)(isopropyl) amino]-1-butanol and tert-butyl bromoacetate are subjected to a condensation reaction, and obtained 4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl] tert-butyl acetate is subjected to a hydrolysis reaction under an alkaline reaction; obtained 4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl] acetic acid and methanesulfonamide are subjected to a condensation reaction; obtained 2-[4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl]-N-(methylsulfonyl) acetamide is subjected to a deprotection reaction under an acid condition, obtained 2-[4-(isopropyl) amino butoxyl]-N-(methylsulfonyl) acetamide and 5-chloro-2,3-diphenyl pyrazine are subjected to a substitution reaction, and the finished product selexipag is obtained. The method has a reasonable and concise process route and is environment-friendly and suitable for industrial production, the operation is simplified, and the cost is relatively low.

Description

一种赛乐西帕的合成方法 One method of synthesis of SIPA Zellers

技术领域 FIELD

[0001] 本发明属于药物化学合成技术领域,具体涉及一种用于治疗肺动脉高压的新药赛乐西帕的合成方法。 [0001] The present invention belongs to the field of pharmaceutical chemistry synthetic techniques, particularly directed to a method for synthesizing new drugs for the treatment of pulmonary hypertension of SIPA Seroxat.

背景技术 Background technique

[0002] 选择性非类前列腺素IP前列环素受体激动剂赛乐西帕(Selexipag)的化学名为2-[4-(5,6_二苯基吡嗪-2-基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺,其化学结构式为: [0002] IP selective non-prostanoid prostacyclin receptor agonist Seiler SIPA (Selexipag) has the chemical name 2- [4- (5,6_-diphenyl-2-yl) (iso propyl) aminobutoxy] -N- (methylsulfonyl) acetamide, its chemical structural formula:

Figure CN105949135AD00041

[0004] 赛乐西帕是瑞士Actelion生物制药公司研发的肺动脉高压(PAH)治疗新药,已于2015年底获FDA批准,正作为肺动脉高压患者开始基础治疗后的添加疗法推广,预期上市首年能够实现2亿美元的销售收入,2020销售额预测达6亿美元以上。 [0004] Zellers SIPA is a Swiss biopharmaceutical company Actelion developed pulmonary arterial hypertension (PAH) treatment drug, was approved by the FDA by the end of 2015, after the add-on therapy to promote a positive start as the basis for the treatment of pulmonary arterial hypertension, the first year can be expected on the market achieve $ 200 million in sales, 2020 sales forecast of more than $ 600 million. 肺动脉高压是一种慢性的、逐步恶化的肺部疾病,其特征是肺动脉出现异常高血压,会导致患者日常活动疲惫。 Pulmonary hypertension is a chronic, progressive deterioration of lung diseases characterized by abnormal pulmonary hypertension, can lead to fatigue in patients with daily activities. 由于心脏会更努力地将血液输送到肺部,该疾病常常会导致致命性的心力衰竭,患者可能过早死亡或需要肺移植。 Since the heart will be harder to carry blood to the lungs, the disease often leads to fatal heart failure, patients may die prematurely or need a lung transplant. 赛乐西帕作为一种选择性口服的Ip前列腺环素受体激动剂药物,与其它以环前列腺素通路为靶点、必须吸入或静脉注射给药的药物相比,在使用时更加方便, 可松弛血管壁平滑肌,扩张血管,降低肺动脉压力。 Seiler SIPA Ip as a selective oral pharmaceutical prostacyclin receptor agonist, a ring with other prostaglandin pathway as a target, as compared to the drug to be inhaled or intravenous injection, more convenient in use, It relaxes vascular smooth muscle, dilation of blood vessels, reduce pulmonary artery pressure.

[0005] 专利W02011017612、文献《Journal ofMedicinal Chemistry 2015,V〇1.58, ρ·7128-7137.》和《Bioorganic and Medicinal Chemistry 2007,Vol.15,ρ·6692-6704.》 报道了一种制备赛乐西帕的合成路线,其工艺路线如下所示: [0005] Patent W02011017612, Document "Journal ofMedicinal Chemistry 2015, V〇1.58, ρ · 7128-7137." And "Bioorganic and Medicinal Chemistry 2007, Vol.15, ρ · 6692-6704." Reported a process for preparing Seiler Scheme SIPA, the process route is as follows:

[0006] [0006]

Figure CN105949135AD00042

Figure CN105949135AD00051

[0008] 该合成路线以5_氣_2,3_二苯基P比嘆和4_(异丙基氛基)_1_丁醇为原料,通过取代、偶联、缩合等多步反应,使官能团不断叠加,制得目标产物赛乐西帕。 [0008] The synthetic route to 5_ gas _2,3_ diphenyl P ratio and sigh 4_ (isopropyl atmosphere yl) _1_ butyl alcohol, substitution by coupling, condensation multi-step reaction, continuously superimposing a functional group, to obtain the desired product Seiler SIPA. 由于4_(异丙基氨基)-1_丁醇作为原料,其结构上有-NH和-OH基团,使得第一步的取代反应产生不同位置的竞争性副反应,引入杂质,对往下的中间体和产品的质量及纯化工艺均造成不利影响,导致操作复杂繁琐,不利于放大生产和产业化推广,因此有必要探索工艺流程短、操作简单、成本低廉而藉以适合工业化生产的赛乐西帕的合成方法。 Since 4_ (isopropylamino) -1_ butanol as starting material, there is -NH and -OH groups on its structure, such that the first step substitution reaction competing side reactions at different positions, introduction of impurities, down to intermediates and product quality and purification processes are adversely affected, leading to complex and cumbersome operation is not conducive to enlarge the production and promotion of industrialization, it is necessary to explore a short process, simple operation, low cost and suitable for industrial production so as Zellers the method of synthesis of SIPA.

发明内容 SUMMARY

[0009] 针对现有技术中存在的不足和缺陷,本发明的目的是提供一种赛乐西帕的合成方法。 [0009] For the prior art shortcomings and deficiencies exist, object of the present invention is to provide a method for the synthesis of SIPA Seroxat.

[0010] 为了实现上述发明目的,本发明采用的技术方案为: [0010] In order to achieve the above object, the technical solution adopted by the invention is:

[0011] 所述赛乐西帕的合成路线为 [0011] The synthetic routes for game music SIPA

[0012] [0012]

Figure CN105949135AD00052

[0013] 赛乐西帕的合成方法的具体步骤如下: [0013] DETAILED step method of synthesis Seiler SIPA follows:

[0014] (1)制备[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯:将4-[(叔丁氧羰基) (异丙基)氨基]-1-丁醇与溴乙酸叔丁酯在季铵盐相转移催化剂、碱试剂、溶剂、水组成的体系中进行缩合反应,得到[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯; [0014] (1) Preparation of [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate: 4 - [(tert-butoxycarbonyl) (isopropyl) amino] -1 - butanol and t-butyl bromoacetate in the phase transfer catalyst, the condensation reaction system alkaline agent, solvent, consisting of water, to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutyloxy ] acetate;

[0015] (2)制备[4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸:将[4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯投入到由碱试剂、溶剂和水组成的体系中,进行水解反应,得到[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸; [0015] (2) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate: The [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate into the system by the alkaline agent, solvent and water, the hydrolysis reaction, to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid;

[0016] (3)制备2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺:将[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸与甲基磺酰胺在缩合剂、溶剂组成的体系中进行缩合反应,得到2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺; [0016] (3) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide: [4- (tert-butoxycarbonyl) ( isopropyl) aminobutoxy] methanesulfonamide acid with a condensing agent, a condensation reaction system consisting of a solvent, to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide;

[0017] (4)制备赛乐西帕:将2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺,投入到由三氟乙酸和脱保护反应用的溶剂组成的体系中,进行脱保护反应,得到2-[4-(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺;再将2-[4-(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺与5-氯-2,3-二苯基吡嗪在缚酸剂碱和取代反应用的溶剂组成的体系中进行取代反应,得到赛乐西帕。 [0017] Preparation of (4) Seiler SIPA: 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide, trifluoroacetic into the acetic acid and deprotection solvent system consisting of the reaction, deprotection reaction, to give 2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide; then 2- [ 4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide and 5-chloro-2,3-diphenyl-pyrazine acid binder system in a substitution reaction with a base and a solvent consisting of in substitution to give Zellers SIPA.

[0018] 优选地,步骤(1)所述的季铵盐相转移催化剂为四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丁基硫酸氢铵、苄基三乙基氯化铵、苄基三乙基溴化铵、甲基三辛基氯化铵、 十二烷基三甲基氯化铵或十四烷基三甲基氯化铵;所述的碱试剂为氢氧化钾、氢氧化钠、氢氧化锂、碳酸钾、碳酸钠、碳酸铯或碳酸锂;所述的溶剂为二氯甲烷、1,2_二氯乙烷、氯仿、甲苯、甲基叔丁基醚或乙腈;其中,4-[(叔丁氧羰基)(异丙基)氨基]-1-丁醇、溴乙酸叔丁酯、 季铵盐相转移催化剂、碱试剂、溶剂、水之间的摩尔比为1.0:(1.1~1.5):(0.02~0.05): (1.4~1.8):(10.0~25.0):(5.0~10.0)。 [0018] Preferably, the step (1) said phase transfer catalyst is tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, a benzyl group triethyl ammonium chloride, benzyl triethyl ammonium bromide, trioctyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride; the alkali reagent is potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate or lithium carbonate; the solvent is methylene chloride, 1,2_ dichloroethane, chloroform, toluene, methyl t-butyl ether or acetonitrile; wherein 4 - [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol, t-butyl bromoacetate, a quaternary ammonium salt phase transfer catalyst, an alkaline agent, solvent, water molar ratio between 1.0: (1.1 to 1.5) :( 0.02 to 0.05): (1.4 to 1.8) :( 10.0 to 25.0) :( 5.0 to 10.0).

[0019] 优选地,步骤(2)所述的碱试剂为氢氧化钠、氢氧化钾、氢氧化锂或氢氧化铯;所述的溶剂为甲醇、乙醇、异丙醇、正丙醇、叔丁醇或正丁醇;其中,[4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯、碱试剂、溶剂、水之间的摩尔比为1.0: (1.1~1.4): (10.0~25.0): (5.0 ~10.0)〇 [0019] Preferably, step (2) of the alkaline agent is sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide; the solvent is methanol, ethanol, isopropanol, n-propanol, t or n-butanol; wherein the molar ratio of tert-butyl acetate, an alkaline agent, solvent, water, [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] 1.0: (1.1 to 1.4 ): (10.0 to 25.0): (5.0 to 10.0) square

[0020]优选地,步骤(3)所述的缩合剂为N,N'_羰基二咪唑、N,N'_二环己基碳二亚胺、N, Ν'-二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺、1-羟基苯并三氮唑、1,8_二氮杂双环[5.4.0]-^-7-烯、苯并三氮唑-N,N,N',N'_四甲基脲六氟磷酸盐、0-苯并三氮唑-N,N,N',N'_四甲基脲四氟硼酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'_四甲基脲六氟磷酸酯、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷或苯并三氮唑-1-基氧基三(二甲基氨基)磷鑰六氟磷酸盐;所述的溶剂为四氢呋喃、二氯甲烷、1,2_二氯乙烷、氯仿、氯苯、乙腈、 甲苯、N,N-二甲基甲酰胺、甲基叔丁基醚或1,4_二氧六环;其中,[4-(叔丁氧羰基)(异丙基) 氨基丁氧基]乙酸、甲基磺酰胺、缩合剂、溶剂之间的摩尔比为1.0: (1.1~1.4) :(1.1~1.6) :(10.0 ~25.0)〇 Said condensing agent [0020] Preferably, step (3) is N, N'_ carbonyldiimidazole, N, N'_ dicyclohexyl carbodiimide, N, Ν'- diisopropyl carbodiimide amine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole triazole, 1,8_-diazabicyclo [5.4.0] - ^ --7- alkenyl, benzotriazole -N, N, N ', N'_ tetramethyluronium hexafluorophosphate, 0- benzotriazole -N, N, N', N'_ tetramethylurea four fluoro borate, 2- (7-azo-benzotriazole) -N, N, N ', N'_ tetramethyluronium hexafluorophosphate, hexafluorophosphate, benzotriazol-1-yl - yloxytripyrrolidino phosphorus or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate key; said solvent is tetrahydrofuran, methylene chloride, dichloro 1,2_ ethane, chloroform, chlorobenzene, acetonitrile, toluene, N, N- dimethylformamide, methyl tert-butyl ether or dioxane 1,4_; wherein, [4- (tert-butoxycarbonyl) ( aminobutoxy molar ratio between acetic acid, methyl sulfonamide, condensing agent, solvent isopropyl)] is 1.0: (1.1 to 1.4): (1.1 to 1.6): (10.0 to 25.0) square

[0021]优选地,步骤(4)所述的脱保护反应的溶剂为甲醇、乙醇、二氯甲烷、乙酸乙酯、四氢呋喃、异丙醇或二氧六环;所述的缚酸剂碱为N,N-二异丙基乙胺、三乙胺、二乙胺、三甲胺、啦啶、哌啶、4-二甲氨基吡啶、2,6_二甲基吡啶、苯胺、N,N-二甲苯胺、N,N-二乙基苯胺、 三异丙胺、三正丁胺、四甲基胍、N-甲基吗啉或N-乙基吗啉;所述的取代反应的溶剂为甲醇、 乙醇、叔丁醇、异丙醇或四氢呋喃;其中,2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺、三氟乙酸、脱保护反应的溶剂、5-氯-2,3-二苯基吡嗪、缚酸剂碱、取代反应的溶剂之间的摩尔比为1.0: (1.1~1.4): (25.0~75.0): (1.1~1.3): (2.0~2.5): (10.0~ 25·0)〇 [0021] Preferably, the step of deprotection reaction solvent (4) are methanol, ethanol, methylene chloride, ethyl acetate, tetrahydrofuran, dioxane or isopropanol; the base is an acid binding agent N, N- diisopropylethylamine, triethylamine, diethylamine, trimethylamine, la, piperidine, 4-dimethylaminopyridine, lutidine 2,6_, aniline, N, N- dimethylaniline, N, N- diethylaniline, triisopropylamine, tri-n-butylamine, tetramethyl guanidine, N- methylmorpholine or N- ethylmorpholine; substitution reaction of the solvent is methanol , ethanol, t-butanol, isopropanol or tetrahydrofuran; wherein 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide, trifluoroacetic acid , deprotection reaction solvent, 5-chloro-2,3-diphenyl-pyrazine, the molar ratio between the acid scavenger solvent base, substitution reaction is 1.0: (1.1 to 1.4): (25.0 to 75.0): (1.1 to 1.3): (2.0 to 2.5): (10.0 to 25 · 0) 〇

[0022] 优选地,步骤(1)所述的缩合反应的温度为20~40°C,反应时间为1~5小时;步骤(2)所述的水解反应的温度为20~80°C,反应时间为1~8小时;步骤(3)所述的缩合反应的温度为70~110°C,反应时间为16~36小时;步骤(4)所述的脱保护反应的温度为50~80 °C, 脱保护反应时间为4~10小时,所述的取代反应的温度为80~120 °C,取代反应时间为6~24 小时。 [0022] Preferably, the temperature of the condensation reaction of step (1) is 20 ~ 40 ° C, the reaction time is 1 to 5 hours; the temperature of the hydrolysis reaction of step (2) is 20 ~ 80 ° C, the reaction time is 1 to 8 hours; step (3) the condensation reaction temperature is 70 ~ 110 ° C, the reaction time is 16 to 36 hours; (4) the deprotection reaction temperature is 50 to step 80 ° C, the deprotection reaction time is 4 to 10 hours, the substitution reaction temperature is 80 ~ 120 ° C, the substitution reaction for 6 to 24 hours.

[0023] 本发明所述的一种赛乐西帕的合成方法,首先以4_[(叔丁氧羰基)(异丙基)氨基]-1-丁醇和溴乙酸叔丁酯为原料,通过缩合、水解、再缩合反应,制备得到N-(甲磺酰基) 乙酰胺侧链化合物,然后脱保护并与5-氯-2,3-二苯基吡嗪进行取代反应,制备得到赛乐西帕,该路线方法即在开始避免过早引入吡嗪母核结构,有利于中间体的纯化和避免副产物产生。 [0023] Synthesis method of Seiler SIPA the present invention, firstly 4 _ [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol and tert-butyl bromoacetate as starting material, by condensing , hydrolysis and condensation reaction and then prepared to give N- (methylsulfonyl) acetamide side chain compound, followed by deprotection and substitution with 5-chloro-2,3-diphenyl-pyrazine, prepared Seiler SIPA , i.e. at the beginning of the route method to avoid premature introduction pyrazine core structure, facilitate purification of intermediates and byproducts avoided.

[0024] 本发明提供的技术方案具有以下技术效果:其一,由于各步反应完成之后只作常规性的后处理和纯化而不需要层析柱纯化,杂质较少、可控,可直接进行下一步反应,因此简化了操作,同时每一步都能获得较高的收率;其二,本发明的工艺路线起始原料和所用的试剂易得,合成反应的技术方案合理,可以大量生产来满足原料药的使用需求,适用于工业化生产;其三,由于在制备过程中不会产生污染物,因而可以体现绿色环保效果。 [0024] The present invention provides a technical solution has the following technical effects: First, since only for conventional workup and purification of each step after the completion of the reaction without the need for chromatography to purify, less impurities, controllable, direct the next step, thus simplifying the operation, while every step to obtain higher yields; Second, the present invention is the process route starting materials and reagents used in readily available and reasonable technical solution synthesis reaction can be mass-produced meet the needs of the drug substance, suitable for industrial production; Third, because the manufacturing process does not produce pollutants, it is possible to reflect the effect of green.

[0025]总之,该方法工艺路线合理、操作简洁、试剂易得和总收率高而得以满足工业化放大生产要求并能体现优异的绿色环保效果。 [0025] In summary, the method and reasonable process route, simple operation, readily available reagents and overall yield is satisfied and industrial production requirements and to reflect the enlarged green excellent effect.

具体实施方式 detailed description

[0026] 实施例1 [0026] Example 1

[0027] A)制备[4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯: [0027] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0028] 4-[(叔丁氧羰基)(异丙基)氨基]-1_丁醇(20.(^,0.09111 〇1)和溴乙酸叔丁酯(21 · lg,0. llmol)溶于二氯甲烧(90mL),加入四丁基氯化铵(0.72g,2.6mmol)、氢氧化钾(7.3g,0.13mol)和水(12.0g),反应混合物25°C搅拌反应2小时,反应液减压旋蒸浓缩至干, 加入乙酸乙酯萃取,硫酸镁干燥,旋蒸浓缩至干,乙醇和异丙醇混合溶剂重结晶,得[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯,浅黄色油状物(26.6g),收率89.0%,本步骤的反应式如下: [0028] 4 - [(tert-butoxycarbonyl) (isopropyl) amino] butanol -1_ (20 (^, 0.09111 〇1) and tert-butyl bromoacetate (21 · lg, 0 llmol) solution. The reaction was stirred for 2 hours to burn dichloromethane (90mL), was added tetrabutylammonium chloride (0.72g, 2.6mmol), potassium hydroxide (7.3g, 0.13mol) and water (12.0g), the reaction mixture was 25 ° C The reaction solution was concentrated under reduced pressure and rotary evaporated to dryness and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl yl) aminobutoxy] acetate, as a pale yellow oil (26.6 g of), a yield of 89.0%, the reaction formula of this step is as follows:

[0029] [0029]

Figure CN105949135AD00071

[0030] B)制备[4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸: [0030] B) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0031] [4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯(26.(^,0.075!11〇1)溶于甲醇(50mL),加入氢氧化钠溶液(NaOH=3 · 3g,0 · 08mol;水9 · 0g),加热至80°C反应6小时,降至室温,经过后处理和纯化,得到[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸(20.7g),收率95.0%,本步骤的反应式如下: [0031] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (26. (^, 0.075! 11〇1) was dissolved in methanol (50 mL), was added sodium hydroxide solution (NaOH = 3 · 3g, 0 · 08mol; water 9 · 0g), was heated to 80 ° C for 6 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid (20.7 g of), a yield of 95.0%, the reaction formula of this step is as follows:

Figure CN105949135AD00081

[0033] C)制备2-[4_(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺: [0033] C) Preparation of 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0034] [4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸(20.(^,0.07!11〇1)和叱『-羰基二咪P坐(14.0g,0.09mo 1)溶于四氢咲喃(70mL),搅拌,加入甲基磺酰胺(7.9g,0.08mol),反应混合物90 °C搅拌反应18小时,反应液旋蒸浓缩至干,加入乙酸乙酯萃取,硫酸镁干燥,旋蒸浓缩至干,甲醇重结晶,得2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺, 类白色固体(21.2g),收率83.7%,本步骤的反应式如下: [0034] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (20 (^, 0.07 11〇1) and a hoot "-.! P sitting carbonyldiimidazole (14.0g, 0.09mo 1 ) was dissolved in tetrahydro-thiopyran Misaki (70 mL), with stirring, was added methyl sulfonamide (7.9g, 0.08mol), the reaction mixture was 90 ° C the reaction stirred for 18 hours, the reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (21.2 g), yield 83.7%, the reaction formula of this step is as follows:

Figure CN105949135AD00082

[0036] D)制备赛乐西帕:2-[4_(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺(20.(^,0.055111〇1)和溶于甲醇(1101^),加入三氟乙酸(6.88,0.06111〇1),65°(:搅拌反应6 小时至反应完全,反应液滴加到搅拌的水(200mL),冷却至0°C析晶3小时,过滤,得中间体化合物(2-[4-(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺),然后溶于甲醇(40mL),加入5-氯-2,3-二苯基吡嗪(16 · 0g,0 · 06mol)、N,N-二异丙基乙胺(15 · 5g,0 · 12mol),反应混合物100°C搅拌反应8小时,反应液降至室温,加入水(40mL),冷却至-10°C析晶3小时,过滤,得赛乐西帕,白色固体(25.0g),收率92.3%,本步骤的反应式如下: [0036] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (20 (^, 0.055111〇1. ) and dissolved in methanol (1101 ^), trifluoroacetic acid (6.88,0.06111〇1), 65 ° (: the reaction stirred for 6 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (200 mL), cooled to 0 ° C crystallization for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in methanol (40 mL), was added 5 - chloro-2,3-diphenyl-pyrazine (16 · 0g, 0 · 06mol), N, N- diisopropylethylamine (15 · 5g, 0 · 12mol), the reaction mixture was stirred reactor 8 100 ° C hours, the reaction was cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (25.0 g of), a yield of 92.3%, the reaction step formula as follows:

[0037] [0037]

Figure CN105949135AD00083

[0038] 实施例2 [0038] Example 2

[0039] A)制备[4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯: [0039] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0040] 4-[(叔丁氧羰基)(异丙基)氨基]-1-丁醇(23.(^,0.10111 〇1)和溴乙酸叔丁酯(25 · 2g,0 · 13mol)溶于1,2-二氯乙烧(110mL),加入四丁基溴化铵(1 · lg,3 · 5mmol)、氢氧化钠(6.4g,0.16mol)和水(14.0g),反应混合物30°C搅拌反应3小时,反应液减压旋蒸浓缩至干,加入乙酸乙酯萃取,硫酸镁干燥,旋蒸浓缩至干,乙醇和异丙醇混合溶剂重结晶,得[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯,浅黄色油状物(30.3g),收率88.2%,本步骤的反应式同实施例1; [0040] 4 - [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (23 (^, 0.10111 〇1) and tert-butyl bromoacetate (25 · 2g, 0 · 13mol) was dissolved. burning in 1,2-dichloroethane (110mL), was added tetrabutylammonium bromide (1 · lg, 3 · 5mmol), sodium hydroxide (6.4g, 0.16mol) and water (14.0g), the reaction mixture was 30 ° C The reaction was stirred for 3 hours, the reaction solution was concentrated by rotary evaporation to dryness under reduced pressure and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxy butoxycarbonyl) (isopropyl) aminobutoxy] acetate, as a pale yellow oil (30.3 g of), a yield of 88.2%, the reaction of the present step is the same formula as in Example 1;

[0041] B)制备[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸: [0041] B) Preparation of [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0042] [4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯(30.(^,0.09!11〇1)溶于乙醇(85mL),加入氢氧化钾溶液(1(0!1 = 5.78,0.10111〇1;水128),加热至75°(:反应7小时,降至室温,经过后处理和纯化,得到[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸,类白色固体(23.5g),收率93.7%,本步骤的反应式同实施例1; [0042] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (30. (^, 0.09! 11〇1) was dissolved in ethanol (85 mL), was added potassium hydroxide solution ( 1 (! = 5.78,0.10111〇1 01; 128 water), heated to 75 ° (: 7 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid, an off-white solid (23.5 g of), a yield of 93.7%, the reaction of the present step is the same formula as in Example 1;

[0043] C)制备2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺: [0043] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0044] [4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸(23.(^,0.08!11〇1)和叱^-二环己基碳二亚胺(22. lg,0. llmol)溶于氯仿(120mL),搅拌,加入甲基磺酰胺(9.8g,0. lOmol),反应混合物80 °C搅拌反应19小时,反应液旋蒸浓缩至干,加入乙酸乙酯萃取,硫酸镁干燥,旋蒸浓缩至干,甲醇重结晶,得2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺,类白色固体(24.8g),收率85.0%,本步骤的反应式同实施例1; [0044] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (23 (^, 0.08 11〇1) and Chi ^ -! Dicyclohexyl carbodiimide (22. lg, 0. llmol) was dissolved in chloroform (120 mL), with stirring, was added methyl sulfonamide (9.8g, 0. lOmol), the reaction mixture was 80 ° C the reaction stirred for 19 hours, the reaction solution was concentrated by rotary evaporation to dryness, ethyl acetate was added and extracted dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide, off-white the solid (24.8 g of), a yield of 85.0%, the reaction of the present step is the same formula as in Example 1;

[0045] D)制备赛乐西帕:2-[4_(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺(24.(^,0.065111〇1)和溶于乙醇(1601^),加入三氟乙酸(9.(^,0.08111〇1),70°(:搅拌反应7 小时至反应完全,反应液滴加到搅拌的水(260mL),冷却至0°C析晶3小时,过滤,得中间体化合物(2-[4-(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺),然后溶于乙醇(90mL),加入5-氯-2,3-二苯基吡嗪(21.8 8,0.08!11〇1)、三乙胺(14.98,0.15111〇1),反应混合物100°(:搅拌反应18小时,反应液降至室温,加入水(40mL),冷却至-10 °C析晶3小时,过滤,得赛乐西帕,白色固体(29.6g),收率91.0%,本步骤的反应式同实施例1。 [0045] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (24 (^, 0.065111〇1. ) and dissolved in ethanol (1601 ^), trifluoroacetic acid (9 (^, 0.08111〇1.), 70 ° (: the reaction was stirred for 7 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (260 mL of), cooled crystallization to 0 ° C for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in ethanol (90 mL) , 5-chloro-2,3-diphenyl-pyrazine (! 11〇1 21.8 8,0.08), triethylamine (14.98,0.15111〇1), the reaction mixture was 100 ° (: The reaction was stirred for 18 hours, the reaction solution cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (29.6 g of), a yield of 91.0%, the reaction of the present step is the same formula as in Example 1 .

[0046] 实施例3 [0046] Example 3

[0047] A)制备[4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯: [0047] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0048] 4-[(叔丁氧羰基)(异丙基)氨基]-1-丁醇(12g,0.05mol)和溴乙酸叔丁酯(12.1g, 0.06mol)溶于氯仿(70mL),加入四丁基碘化铵(0 · 5g, 1 · 3mmol)、氢氧化锂(1 · 7g,0 · 07mol) 和水(6.5g),反应混合物20°C搅拌反应4小时,反应液减压旋蒸浓缩至干,加入乙酸乙酯萃取,硫酸镁干燥,旋蒸浓缩至干,乙醇和异丙醇混合溶剂重结晶,得[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯,浅黄色油状物(15.6g),收率86.8%,本步骤的反应式同实施例1; [0048] 4 - [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (12g, 0.05mol) and t-butyl bromoacetate (12.1g, 0.06mol) was dissolved in chloroform (70mL), was added tetrabutylammonium iodide (0 · 5g, 1 · 3mmol), lithium hydroxide (1 · 7g, 0 · 07mol) and water (6.5 g of), the reaction mixture was stirred 20 ° C for 4 hours, the reaction solution under reduced pressure concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutyrate oxygen yl] acetate, as a pale yellow oil (15.6 g of), a yield of 86.8%, the reaction of the present step is the same formula as in Example 1;

[0049] B)制备[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸: [0049] B) Preparation of [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0050] [4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯(15.0g,0.04mol)溶于异丙醇(40mL),加入氢氧化锂溶液(LiOH= 1 · 3g,0 · 05mol;水6 · 0g),加热至70°C反应8小时,降至室温,经过后处理和纯化,得到[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸,类白色固体(11.7g),收率93.0%,本步骤的反应式同实施例1; [0050] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (15.0g, 0.04mol) was dissolved in isopropanol (40mL), was added a solution of lithium hydroxide (LiOH = 1 · 3g, 0 · 05mol; water 6 · 0g), was heated to 70 ° C for 8 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutyrate oxy] acetic acid as an off-white solid (11.7 g), 93.0% yield, this step is the same reaction scheme of Example 1;

[0051] C)制备2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺: [0051] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0052] [4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸(11.(^,0.04!11〇1)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺(8.38,0.05111〇1)溶于乙腈(4〇1111^),搅拌,加入甲基磺酰胺(5.]^, 0.05mol ),反应混合物95 °C搅拌反应22小时,反应液旋蒸浓缩至干,加入乙酸乙酯萃取,硫酸镁干燥,旋蒸浓缩至干,甲醇重结晶,得2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺,类白色固体(11.7g),收率84.2%,本步骤的反应式同实施例1; [0052] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (11 (^, 0.04! 11〇1) and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide (8.38,0.05111〇1) was dissolved in acetonitrile (4〇1111 ^), with stirring, was added methyl sulfonamide (5.] ^, 0.05mol), the reaction mixture was 95 ° C the reaction stirred for 22 hours, The reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (11.7 g), yield 84.2%, the reaction of the present step is the same formula as in Example 1;

[0053] D)制备赛乐西帕:2-[4_(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺(11.(^,0.03111〇1)和溶于二氯甲烷(601^),加入三氟乙酸(4.48,0.04111〇1),50°(:搅拌反应10小时至反应完全,反应液滴加到搅拌的水(120mL ),冷却至0 °C析晶3小时,过滤,得中间体化合物(2-[4-(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺),然后溶于叔丁醇(40mL),加入5-氯-2,3-二苯基吡嗪(9.68,0.036!11〇1)、4-二甲氨基吡啶(8.18,0.07111〇1),反应混合物110 °(:搅拌反应14小时,反应液降至室温,加入水(15mL),冷却至-10°C析晶3小时,过滤,得赛乐西帕,白色固体(13.5g),收率90.5%,本步骤的反应式同实施例1。 [0053] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (11 (^, 0.03111〇1. ) and dissolved in dichloromethane (601 ^), trifluoroacetic acid (4.48,0.04111〇1), 50 ° (: the reaction was stirred for 10 hours to water (120 mL completion of the reaction, the reaction liquid was added to a stirred), cooled to crystallization 0 ° C for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in tert-butanol (40 mL ), 5-chloro-2,3-diphenyl-pyrazine (9.68,0.036 11〇1), 4-dimethylaminopyridine (8.18,0.07111〇1), the reaction mixture was 110 ° (:! reaction was stirred for 14 hours the reaction was cooled to room temperature, water (15 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (13.5 g of), a yield of 90.5%, the reaction in this step is the same formula Example 1.

[0054] 实施例4 [0054] Example 4

[0055] A)制备[4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯: [0055] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0056] 4-[(叔丁氧羰基)(异丙基)氨基]-1-丁醇(15.(^,0.065111〇1)和溴乙酸叔丁酯(17.78,0.09111〇1)溶于甲苯(701]11^),加入四丁基硫酸氢铵(0.888,2.61]11]1〇1)、碳酸钾(15.2区, 0.1 lmol)和水(9.5g),反应混合物40°C搅拌反应1.5小时,反应液减压旋蒸浓缩至干,加入乙酸乙酯萃取,硫酸镁干燥,旋蒸浓缩至干,乙醇和异丙醇混合溶剂重结晶,得[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯,浅黄色油状物(19.6g),收率87.5%,本步骤的反应式同实施例1; [0056] 4 - [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (15 (^, 0.065111〇1) and t-butyl bromoacetate (17.78,0.09111〇1) was dissolved in toluene (701] 11 ^), was added tetrabutylammonium hydrogen sulfate (0.888,2.61] 11] 1〇1), potassium carbonate (15.2 area, 0.1 lmol) and water (9.5 g of), the reaction mixture was stirred 40 ° C for 1.5 hours, the reaction solution was concentrated under reduced pressure and rotary evaporated to dryness and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl propyl) aminobutoxy] acetate, as a pale yellow oil (19.6 g of), in the same reaction formula in this step a yield of 87.5% in Example 1;

[0057] B)制备[4_(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸: [0057] B) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0058] [4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯(19.(^,0.055!11〇1)溶于叔丁醇(60mL),加入氢氧化铯溶液(CsOH= 11. lg,0.07mol;水8.0g),加热至75°C反应6.5小时, 降至室温,经过后处理和纯化,得到[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸,类白色固体(15.0g),收率94.2%,本步骤的反应式同实施例1; [0058] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (19 (^, 0.055! 11〇1) was dissolved in tert-butanol (60 mL), hydroxide solution of cesium (CsOH = 11. lg, 0.07mol; water, 8.0 g), the reaction was heated to 75 ° C for 6.5 hours cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid, an off-white solid (15.0 g of), a yield of 94.2%, the reaction of the present step is the same formula as in Example 1;

[0059] C)制备2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺: [0059] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0060] [4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸(15.0g,0.05mol)和1,8_二氮杂双环 [0060] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (15.0g, 0.05mol) and diazabicyclo 1,8_

[5.4.0]--| -7-稀(9.5区,0.06111〇1)溶于甲苯(8〇1111^),搅拌,加入甲基磺酰胺(5.7区, 0.06mo 1 ),反应混合物105 °C搅拌反应16小时,反应液旋蒸浓缩至干,加入乙酸乙酯萃取,硫酸镁干燥,旋蒸浓缩至干,甲醇重结晶,得2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺,类白色固体(16.6g),收率87.3%,本步骤的反应式同实施例1; [5.4.0] - | -7- dilute (9.5 region, 0.06111〇1) was dissolved in toluene (8〇1111 ^), with stirring, was added methyl sulfonamide (5.7 region, 0.06mo 1), the reaction mixture was 105 ° C for 16 hours, the reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (16.6 g of), 87.3% yield, this step is the same reaction scheme of Example 1;

[0061] D)制备赛乐西帕:2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺(16.(^,0.04111〇1)和溶于乙酸乙酯(1301111^),加入三氟乙酸(5.78,0.051]1〇1),80 <€搅拌反应5小时至反应完全,反应液滴加到搅拌的水(150mL),冷却至0°C析晶3小时,过滤,得中间体化合物(2-[4-(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺),然后溶于异丙醇(50mL),加入5-氯-2,3-二苯基吡嗪(13.58,0.05!11〇1)、叱1二甲苯胺(12.28,0.10111〇1),反应混合物95 °(:搅拌反应12小时,反应液降至室温,加入水(40mL),冷却至-10°C析晶3小时,过滤,得赛乐西帕,白色固体(19.7g),收率91.0%,本步骤的反应式同实施例1。 [0061] D) Preparation of SIPA Seiler: 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (16 (^, 0.04111〇. 1) and dissolved in ethyl acetate (^ 1,301,111), trifluoroacetic acid (5.78,0.051] 1〇1), 80 <€ the reaction was stirred for 5 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (150 mL), was cooled to 0 ° C crystallization for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), then dissolved in isopropanol (50 mL), was added 5-chloro-2,3-diphenyl-pyrazine (13.58,0.05 11〇1!), a hoot dimethylaniline (12.28,0.10111〇1), the reaction mixture was 95 ° (: The reaction was stirred 12 hours, the reaction was cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (19.7 g of), a yield of 91.0%, the reaction step formula in Example 1.

Claims (9)

  1. 1. 一种赛乐西帕的合成方法,其特征在于,所述方法包括如下步骤: (1) 制备[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯:将4-[(叔丁氧羰基)(异丙基)氨基]-1-丁醇与溴乙酸叔丁酯在季铵盐相转移催化剂、碱试剂、溶剂、水组成的体系中进行缩合反应,得到[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯; (2) 制备[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸:将[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯投入到由碱试剂、溶剂和水组成的体系中,进行水解反应,得到[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸; (3) 制备2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺:将[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸与甲基磺酰胺在缩合剂、溶剂组成的体系中进行缩合反应,得到2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺 1. A method of synthesis of SIPA game music, wherein, said method comprising the steps of: [aminobutoxy 4- (tert-butoxycarbonyl) (isopropyl)] acetate (1) Preparation of : 4 - [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol and t-butyl bromoacetate in the phase transfer catalyst, the condensation reaction system alkaline agent, solvent, consisting of water, to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate; (2) preparation of [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid : [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate into the system by the alkaline agent, solvent and water, the hydrolysis reaction, to give [4- (tert-butoxy butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid; (3) preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide : [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid with methyl sulfonamide system of a condensing agent, a solvent consisting of a condensation reaction, to give 2- [4- (tert carbonyl) (isopropyl) aminobutoxy] -N- (methanesulfonamide 基)乙酰胺; (4) 制备赛乐西帕:将2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺,投入到由三氟乙酸和脱保护反应用的溶剂组成的体系中,进行脱保护反应,得到2-[4_ (异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺;再将2-[4-(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺与5-氯-2,3-二苯基吡嗪在缚酸剂碱和取代反应用的溶剂组成的体系中进行取代反应,得到赛乐西帕。 Yl) acetamide; (4) Preparation Seiler SIPA: 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide, into the trifluoroacetic acid and deprotection solvent system consisting of the reaction, deprotection reaction, to give 2- [4_ (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide; 2- then [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide and 5-chloro-2,3-diphenyl-pyrazine acid scavenger in a solvent and substitution reaction with a base consisting of system substitution reaction to obtain Zellers SIPA.
  2. 2. 根据权利要求1所述的一种赛乐西帕的合成方法,其特征在于,步骤(1)所述的季铵盐相转移催化剂为四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丁基硫酸氢铵、苄基三乙基氯化铵、苄基三乙基溴化铵、甲基三辛基氯化铵、十二烷基三甲基氯化铵或十四烷基三甲基氯化铵;所述的碱试剂为氢氧化钾、氢氧化钠、氢氧化锂、碳酸钾、碳酸钠、碳酸铯或碳酸锂;所述的溶剂为二氯甲烷、1,2_二氯乙烷、氯仿、甲苯、甲基叔丁基醚或乙腈;其中,4-[(叔丁氧羰基)(异丙基)氨基]-1-丁醇、溴乙酸叔丁酯、季铵盐相转移催化剂、碱试剂、溶剂、水之间的摩尔比为1.0: (1.1~1.5) :(0.02~0.05) :(1.4~1.8) :(10.0~25.0):(5.0~ 10.0)〇 The method of synthesis according to game music SIPA claimed in claim 1, wherein the quaternary ammonium salt in step (1) the phase transfer catalyst is tetrabutylammonium chloride, tetrabutylammonium bromide , tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, benzyl triethyl ammonium bromide, methyltrioctylammonium chloride, dodecyltrimethylammonium chloride ammonium or myristyl trimethyl ammonium chloride; the alkaline agent is potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate or lithium carbonate; the solvent is two chloride, 1,2_ dichloroethane, chloroform, toluene, acetonitrile, or methyl tert-butyl ether; wherein 4 - [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol, bromo acid tert-butyl ester, quaternary ammonium salt phase transfer catalyst, the molar ratio between the alkaline agent, the solvent, water is 1.0: (1.1 to 1.5): (0.02 to 0.05): (1.4 to 1.8): (10.0 to 25.0): (5.0 to 10.0) square
  3. 3. 根据权利要求1所述的一种赛乐西帕的合成方法,其特征在于,步骤(2)所述的碱试剂为氢氧化钠、氢氧化钾、氢氧化锂或氢氧化铯;所述的溶剂为甲醇、乙醇、异丙醇、正丙醇、 叔丁醇或正丁醇;其中,[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸叔丁酯、碱试剂、溶剂、 水之间的摩尔比为1.0: (1.1~1.4) :(10.0~25.0) :(5.0~10.0)。 The method of synthesis according to game music SIPA claimed in claim 1, characterized in that the alkaline agent in step (2) is sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide; the said solvents are methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; wherein, [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate, the molar ratio between the alkaline agent, the solvent, water is 1.0: (1.1 to 1.4): (10.0 to 25.0): (5.0 to 10.0).
  4. 4. 根据权利要求1所述的一种赛乐西帕的合成方法,其特征在于,步骤(3)所述的缩合剂为N,N'_羰基二咪唑、N,N'_二环己基碳二亚胺、N,N'_二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺、1-羟基苯并三氮唑、1,8_二氮杂双环[5.4.0]-^-7-烯、苯并三氮唑- N,N,N',N'-四甲基脲六氟磷酸盐、〇-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、 2-(7-偶氮苯并三氮唑)-N,N,N',N'_四甲基脲六氟磷酸酯、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷或苯并三氮唑-1-基氧基三(二甲基氨基)磷鑰六氟磷酸盐;所述的溶剂为四氢呋喃、二氯甲烷、1,2_二氯乙烷、氯仿、氯苯、乙腈、甲苯、N,N-二甲基甲酰胺、甲基叔丁基醚或1,4-二氧六环;其中,[4-(叔丁氧羰基)(异丙基)氨基丁氧基]乙酸、甲基磺酰胺、缩合剂、溶剂之间的摩尔比为1.0: (1.1~1.4) :(1.1~1.6) :(10.0~25.0)。 The method of synthesis according to game music SIPA claimed in claim 1, wherein the condensing agent in step (3) is N, N'_ carbonyldiimidazole, N, N'_ dicyclohexyl carbodiimide, N, N'_ diisopropyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole triazole, 1 , 8_ diazabicyclo [5.4.0] - ^ --7- ene, benzotriazole - N, N, N ', N'- tetramethyluronium hexafluorophosphate, benzotriazol 〇- yl -N, N, N ', N'- tetramethyluronium tetrafluoroborate, 2- (7-azo-benzotriazole) -N, N, N', N'_ tetramethylurea hexafluorophosphate, hexafluorophosphate, benzotriazol-1-yl - yloxy tripyrrolidinophosphonium or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate key; said solvent is tetrahydrofuran, methylene chloride, 1,2_ dichloroethane, chloroform, chlorobenzene, acetonitrile, toluene, N, N- dimethylformamide, methyl tert-butyl ether or 1,4 dioxane; wherein, [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] molar ratio between the acid, methyl sulfonamide, condensing agent, solvent 1.0: (1.1 to 1.4) : (1.1 to 1.6): (10.0 to 25.0).
  5. 5. 根据权利要求1所述的一种赛乐西帕的合成方法,其特征在于,步骤(4)所述的脱保护反应的溶剂为甲醇、乙醇、二氯甲烷、乙酸乙酯、四氢呋喃、异丙醇或二氧六环;所述的缚酸剂碱为N,N-二异丙基乙胺、三乙胺、二乙胺、三甲胺、啦啶、哌啶、4-二甲氨基吡啶、2,6_二甲基吡啶、苯胺、N,N-二甲苯胺、N,N-二乙基苯胺、三异丙胺、三正丁胺、四甲基胍、N-甲基吗啉或N-乙基吗啉;所述的取代反应的溶剂为甲醇、乙醇、叔丁醇、异丙醇或四氢呋喃;其中, 2-[4-(叔丁氧羰基)(异丙基)氨基丁氧基]-N-(甲磺酰基)乙酰胺、三氟乙酸、脱保护反应的溶剂、5-氯-2,3-二苯基吡嗪、缚酸剂碱、取代反应的溶剂之间的摩尔比为1.0: (1.1~1.4): (25.0~75.0) :(1.1~1.3) :(2.0~2.5):(10.0~25.0)。 The synthesis method of claim 1. A method as claimed in claim SIPA game music, wherein the step (4) the desolvation protection reaction are methanol, ethanol, methylene chloride, ethyl acetate, tetrahydrofuran, isopropanol or dioxane; said acid scavenger base is N, N- diisopropylethylamine, triethylamine, diethylamine, trimethylamine, la, piperidine, 4-dimethylaminopyridine pyridine, lutidine 2,6_, aniline, N, N- dimethylaniline, N, N- diethylaniline, triisopropylamine, tri-n-butylamine, tetramethyl guanidine, N- methylmorpholine or N- ethylmorpholine; substitution reaction of the solvent is methanol, ethanol, t-butanol, isopropanol or tetrahydrofuran; wherein 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutyrate between oxy] -N- (methylsulfonyl) acetamide, trifluoroacetic acid, the reaction solvent removal protection, 5-chloro-2,3-diphenyl-pyrazine acid binding agent a base, a solvent substitution reaction molar ratio of 1.0: (1.1 to 1.4): (25.0 to 75.0): (1.1 to 1.3): (2.0 to 2.5) :( 10.0 to 25.0).
  6. 6. 根据权利要求1所述的一种赛乐西帕的合成方法,其特征在于,步骤(1)所述的缩合反应的温度为20~40°C,反应时间为1~5小时。 The method of synthesis according to game music SIPA claimed in claim 1, wherein the step (1) the condensation reaction temperature is 20 ~ 40 ° C, the reaction time is 1 to 5 hours.
  7. 7. 根据权利要求1所述的一种赛乐西帕的合成方法,其特征在于,步骤(2)所述的水解反应的温度为20~80°C,反应时间为1~8小时。 The method of synthesis according to game music SIPA claimed in claim 1, wherein the step (2) the temperature of the hydrolysis reaction is 20 ~ 80 ° C, the reaction time is 1 to 8 hours.
  8. 8. 根据权利要求1所述的一种赛乐西帕的合成方法,其特征在于,步骤(3)所述的缩合反应的温度为70~110°C,反应时间为16~36小时。 8. A method of synthesis according to game music SIPA according to claim 1, wherein the step (3) the condensation reaction temperature is 70 ~ 110 ° C, the reaction time is 16 to 36 hours.
  9. 9. 根据权利要求1所述的一种赛乐西帕的合成方法,其特征在于,步骤(4)所述的脱保护反应的温度为50~80°C,脱保护反应时间为4~10小时,所述的取代反应的温度为80~ 120 °C,取代反应时间为6~24小时。 9. A method of synthesis according to game music SIPA according to claim 1, wherein (4) said deprotection reaction temperature in step is 50 ~ 80 ° C, the deprotection reaction time is 4 to 10 hours, the substitution reaction temperature is 80 ~ 120 ° C, the substitution reaction for 6 to 24 hours.
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CN1516690A (en) * 2001-04-26 2004-07-28 日本新药株式会社 Heterocyclic derivatives and medicines
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