CN114249672B - 一种利鲁唑中间体化合物 - Google Patents
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- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 229960004181 riluzole Drugs 0.000 title claims abstract description 30
- 150000001875 compounds Chemical class 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 abstract description 8
- 239000004202 carbamide Substances 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 5
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 abstract description 4
- 238000001953 recrystallisation Methods 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- XYAPVSVTNAIPQE-UHFFFAOYSA-N 2-amino-5-(trifluoromethoxy)phenol Chemical compound NC1=CC=C(OC(F)(F)F)C=C1O XYAPVSVTNAIPQE-UHFFFAOYSA-N 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 230000007794 irritation Effects 0.000 abstract description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- VPXYHAGILRLHJP-UHFFFAOYSA-N NC(NC(C=CC(OC(F)(F)F)=C1)=C1O)=O Chemical compound NC(NC(C=CC(OC(F)(F)F)=C1)=C1O)=O VPXYHAGILRLHJP-UHFFFAOYSA-N 0.000 abstract 1
- 231100000086 high toxicity Toxicity 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 239000008213 purified water Substances 0.000 description 24
- 239000012065 filter cake Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000009835 boiling Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 238000004537 pulping Methods 0.000 description 6
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- 238000005406 washing Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 238000011160 research Methods 0.000 description 3
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
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- XUJFOSLZQITUOI-UHFFFAOYSA-N 4-(trifluoromethoxy)aniline Chemical compound NC1=CC=C(OC(F)(F)F)C=C1 XUJFOSLZQITUOI-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 2
- UCOXNOVULREFCO-UHFFFAOYSA-N [4-(trifluoromethoxy)phenyl]thiourea Chemical compound NC(=S)NC1=CC=C(OC(F)(F)F)C=C1 UCOXNOVULREFCO-UHFFFAOYSA-N 0.000 description 2
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
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- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002194 freeze distillation Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
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- 238000007670 refining Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
- C07C273/1863—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety from urea
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
- C07D277/82—Nitrogen atoms
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- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02P20/00—Technologies relating to chemical industry
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Abstract
本发明属于药物合成技术领域,具体涉及一种利鲁唑中间体化合物。本发明以2‑氨基‑5‑(三氟甲氧基)苯酚为起始物料,经尿素取代后制得新化合物1‑(2‑羟基‑4‑(三氟甲氧基)苯基)脲。同时本发明提供了该新中间体化合物用于制备利鲁唑的方法:(1‑(2‑羟基‑4‑(三氟甲氧基)苯基)脲在碱的作用下与劳森试剂反应即得利鲁唑。本发明提供的新中间体合成方法简单,利用该中间体制备利鲁唑可有效避免毒性较大的溴素以及腐蚀性和刺激性较大的三氟乙酸与苯甲酰氯的使用,同时目标产品的获得只需要简单的重结晶操作,有效避免的繁琐的柱层析操作,操作简便。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种利鲁唑中间体化合物。
背景技术
利鲁唑(Riluzole),化学名为2-氨基-6-三氟甲氧基苯并噻唑,是由赛诺菲公司研发的第一个获美国FDA和欧盟EMA批准用于治疗肌萎缩性脊髓侧索硬化症(ALS,渐冻人症)的药物,该药对延长ALS患者存活期、缓解症状及改善生活质量具有非常重要的作用,并且该药具有广泛的药理学作用,包括谷氨酸、天冬氨酸抑制及钠、钙离子通道抑制作用等,其应用研究包括神经保护、镇痛、抗抑郁、抗焦虑、抗癫痫、抗心律失常等。利鲁唑于1996年获美国FDA和欧盟EMA批准上市,1999年在中国上市。其化学结构式为:
目前对其合成方法的研究较少,已公开的利鲁唑合成方法有以下几类:
方法一:文献Angew.Chem.Int.Edit.,2015,54(34):9991-9995以4-三氟甲氧基苯胺和硫氰酸盐为原料,在乙酸中经液溴氧化“一锅反应”合成:
研究发现,该方法生成的中间体未经分离纯化,导致反应液杂质较多,且液溴挥发性大、毒性强,对操作者危害较大,同时造成严重环境污染。
方法二为两步合成法,先合成中间体1-(4-(三氟甲氧基)苯基)硫脲,再环合得到目标产品:其中1-(4-(三氟甲氧基)苯基)硫脲的合成是以4-三氟甲氧基苯胺和硫氰酸盐为原料,在三氟乙酸[J.Med.Chem.,2016,59(21):9814-9824]、苯甲酰氯[Eur.J.Med.Chem.,2014,84:302-311]、苯甲酰基异硫氰酸酯/NaOH[J.Med.Chem.,1997,40(12):1901-1905]条件下反应得到,但是三氟乙酸与苯甲酰氯具有较强的腐蚀性和刺激性,文献J.Med.Chem.,2016,59(21):9814-9824同样报道了利鲁唑的制备方法,是以Br2/LiBr氧化环合得到,但该路线也同样使用到剧毒的液溴:
由上可知,目前利鲁唑的制备工艺主要存在以下问题:
1.需要应用毒性较高的溴素以及腐蚀性和刺激性较高的三氟乙酸与苯甲酰氯,使得操作安全性较低的问题;
2.需要应用价格较高的苯甲酰基异硫氰酸酯、NBS、NCS、苄基三甲基溴化铵,使得生产成本较高的问题;
3.采用“一锅反应”合成,由于中间体未经分离纯化,导致反应液杂质较多,所得粗品纯度较低需要反复精制的问题;
4.目标产品的获得需要柱层析操作进行提纯,使得操作繁琐的问题。
鉴于目前利鲁唑的制备工艺中存在上述不足。因此,研究寻找一条反应条件温和,操作过程简便,产品收率高、纯度高的适合工业化生产利鲁唑的工艺仍是目前需要解决的问题。
发明内容
针对目前现有利鲁唑制备技术存在的问题,本发明提供了一种新的利鲁唑中间体化合物及利用该中间体制备利鲁唑的方法。该方法反应条件温和,操作过程简便,所制得的目标产品具有较高的纯度、收率。
本发明第一方面提供一种利鲁唑中间体化合物,其结构式如式I-1所示:
本发明第二方面提供一种化合物I-1的制备方法,包括如下步骤:
将SM-1、SM-2加入水中,加浓盐酸,控温回流至反应结束后,经后处理制得I-1,反应路线如下:
优选地,所述的SM-1与尿素的投料摩尔比为1:1.6~5.0,其中特别优选1:2.8。
优选地,所述的SM-1与浓盐酸的投料质量体积比为1:4.0~10.0质量以g计体积以ml计,其中特别优选1:7.0。
所述的反应结束后的后处理步骤为:将反应液降温至室温析出固体后过滤,所得固体加入纯化水打浆,过滤,冰水洗涤,所得固体经沸水重结晶后即为I-1。
本发明第三方面提供一种化合物I-1用于制备利鲁唑的用途。
化合物I-1制备利鲁唑的方法,包括如下步骤:将I-1、劳森试剂、碱加入反应溶剂中,控温回流至反应结束后,经后处理制得目标产品I,其路线如下:
优选地,所述的碱选自碳酸钠、碳酸铯、氢氧化钾、三乙胺、4-二甲氨基吡啶中的一种。
优选地,所述的劳森试剂为2,4-双(4-甲氧基苯基)-1,3,2,4-二硫代二膦烷2,4-二硫化物,其化学结构式如下所示:
优选地,所述的I-1、劳森试剂、碱的投料摩尔比为1:1.5~2.0:1.0~2.0,其中特别优选1:1.8:1.5。
优选地,所述的反应溶剂为四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲基叔丁基醚中的一种或其组合,其中特别优选四氢呋喃。
优选地,所述的后处理步骤为:将反应液降温至0~5℃,搅拌析晶后过滤,所得滤饼用无水乙醇/纯化水(V乙醇:V纯化水=1:2)体系重结晶后即为目标产品I。
本发明的有益效果:
1.本发明提供了一种新的利鲁唑的中间体化合物及制备方法,该方法以2-氨基-5-(三氟甲氧基)苯酚为起始物料,经尿素取代后制得,该这备方法操作简单,所得产物纯度高。
2.同时本发明提供了利用该新中间体制备利鲁唑的方法,新中间体通过与劳森试剂反应即得利鲁唑,该方法可有效避免毒性较大的溴素以及腐蚀性和刺激性较大的三氟乙酸与苯甲酰氯的使用,同时目标产品的获得只需要简单的重结晶操作,有效避免的繁琐的柱层析操作,操作简便。
3.本发明的利鲁唑的制备工艺,相较于现有技术所得产品具有较高的收率与纯度,并且操作简便、安全,适合工业化生产。
具体实施方式
下面通过实施例来进一步说明本发明,应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属于本发明要求保护的范围。
对本发明得到的化合物结构确证:
ESI-HRMS(m/z):237.0485[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.90(br,1H),7.89(br,1H),7.58~7.35(m,2H),7.20(s,1H),5.98(br,2H);13C NMR(100MHz,DMSO-d6)δ171.94,152.17,150.06,130.12,121.88,120.08,116.17,109.63。
ESI-HRMS(m/z):235.0150[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.48(d,J=8.0Hz,2H),7.17(dd,J1=1.5Hz,J2=8.8Hz,1H),5.99(br s,2H);13C NMR(100MHz,DMSO-d6)δ167.10,150.69,143.99,132.01,120.54,119.68,119.20,114.07。
本发明采用HPLC测定利鲁唑的纯度,色谱条件如下:
色谱柱:Symmetry-C18柱(4.6mm×150mm,5μm)或效能相当的色谱柱;
流动相:乙腈-水(9:1),等度洗脱;
柱温:30℃;
检测波长:221nm;
流速:1.0ml/min;
进样量:10μl;
利鲁唑的保留时间为7.2min左右。
以下各实施例中,未详细描述的各种过程和方法是本领域中公知的常规方法。
中间体I-1的合成
实施例1
室温,将2-氨基-5-(三氟甲氧基)苯酚(SM-1,19.31g,0.10mol)、尿素(SM-2,16.82g,0.28mol)加入200ml水中,加入浓盐酸(135ml),控温回流反应,经检测反应完毕后,将反应液降温至室温,过滤,滤饼加入纯化水(250ml)中打浆,过滤,滤饼冰水(50ml×2)洗涤,所得滤饼经沸水(150ml)重结晶后即为I-1,收率85.6%,纯度99.56%。
实施例2
室温,将SM-1(19.31g,0.10mol)、尿素(9.61g,0.16mol)加入200ml水中,加入浓盐酸(100ml),控温回流反应,经检测反应完毕后,将反应液降温至室温,过滤,滤饼加入纯化水(250ml)中打浆,过滤,滤饼冰水(50ml×2)洗涤,所得滤饼经沸水(150ml)重结晶后即为I-1,收率82.3%,纯度99.28%。
实施例3
室温,将SM-1(19.31g,0.10mol)、尿素(8.41g,0.14mol)加入200ml水中,加入浓盐酸(80ml),控温回流反应,经检测反应完毕后,将反应液降温至室温,过滤,滤饼加入纯化水(250ml)中打浆,过滤,滤饼冰水(50ml×2)洗涤,所得滤饼经沸水(150ml)重结晶后即为I-1,收率78.6%,纯度98.92%。
实施例4
室温,将SM-1(19.31g,0.10mol)、尿素(30.02g,0.50mol)加入200ml水中,加入浓盐酸(150ml),控温回流反应,经检测反应完毕后,将反应液降温至室温,过滤,滤饼加入纯化水(250ml)中打浆,过滤,滤饼冰水(50ml×2)洗涤,所得滤饼经沸水(150ml)重结晶后即为I-1,收率81.8%,纯度99.12%。
实施例5
室温,将SM-1(19.31g,0.10mol)、尿素(31.23g,0.52mol)加入200ml水中,加入浓盐酸(190ml),控温回流反应,经检测反应完毕后,将反应液降温至室温,过滤,滤饼加入纯化水(250ml)中打浆,过滤,滤饼冰水(50ml×2)洗涤,所得滤饼经沸水(150ml)重结晶后即为I-1,收率77.8%,纯度98.82%。
利鲁唑的合成
实施例6
室温,将I-1(11.81g,0.05mol)、2,4-双(4-甲氧基苯基)-1,3,2,4-二硫代二膦烷2,4-二硫化物(36.40g,0.09mol)、碳酸钠(7.95g,0.075mol)加入四氢呋喃(100ml)中,控温回流反应,经检测反应完毕后,将反应液降温至0~5℃,搅拌析晶后过滤,所得滤饼用无水乙醇/纯化水(V乙醇:V纯化水=1:2,50ml)体系重结晶后即为目标产品I,收率97.5%,纯度99.92%。
实施例7
室温,将I-1(11.81g,0.05mol)、2,4-双(4-甲氧基苯基)-1,3,2,4-二硫代二膦烷2,4-二硫化物(30.33g,0.075mol)、碳酸铯(24.44g,0.075mol)加入四氢呋喃(100ml)中,控温回流反应,经检测反应完毕后,将反应液降温至0~5℃,搅拌析晶后过滤,所得滤饼用无水乙醇/纯化水(V乙醇:V纯化水=1:2,50ml)体系重结晶后即为目标产品I,收率94.1%,纯度99.71%。
实施例8
室温,将I-1(11.8 1g,0.05mol)、2,4-双(4-甲氧基苯基)-1,3,2,4-二硫代二膦烷2,4-二硫化物(24.27g,0.06mol)、碳酸氢钠(6.30g,0.075mol)加入四氢呋喃(100ml)中,控温回流反应,经检测反应完毕后,将反应液降温至0~5℃,搅拌析晶后过滤,所得滤饼用无水乙醇/纯化水(V乙醇:V纯化水=1:2,50ml)体系重结晶后即为目标产品I,收率89.5%,纯度99.42%。
实施例9
室温,将I-1(11.81g,0.05mol)、2,4-双(4-甲氧基苯基)-1,3,2,4-二硫代二膦烷2,4-二硫化物(40.44g,0.10mol)、三乙胺(7.59g,0.075mol)加入四氢呋喃(100ml)中,控温回流反应,经检测反应完毕后,将反应液降温至0~5℃,搅拌析晶后过滤,所得滤饼用无水乙醇/纯化水(V乙醇:V纯化水=1:2,50ml)体系重结晶后即为目标产品I,收率93.6%,纯度99.68%。
实施例10
室温,将I-1(11.81g,0.05mol)、2,4-双(4-甲氧基苯基)-1,3,2,4-二硫代二膦烷2,4-二硫化物(44.50g,0.11mol)、4-二甲氨基吡啶(9.16g,0.075mol)加入四氢呋喃(100ml)中,控温回流反应,经检测反应完毕后,将反应液降温至0~5℃,搅拌析晶后过滤,所得滤饼用无水乙醇/纯化水(V乙醇:V纯化水=1:2,50ml)体系重结晶后即为目标产品I,收率88.9%,纯度99.20%。
实施例11
室温,将I-1(11.81g,0.05mol)、2,4-双(4-甲氧基苯基)-1,3,2,4-二硫代二膦烷2,4-二硫化物(36.40g,0.09mol)、碳酸钠(5.30g,0.05mol)加入2-甲基四氢呋喃(100ml)中,控温回流反应,经检测反应完毕后,将反应液降温至0~5℃,搅拌析晶后过滤,所得滤饼用无水乙醇/纯化水(V乙醇:V纯化水=1:2,50ml)体系重结晶后即为目标产品I,收率93.3%,纯度99.80%。
实施例12
室温,将I-1(11.81g,0.05mol)、2,4-双(4-甲氧基苯基)-1,3,2,4-二硫代二膦烷2,4-二硫化物(36.40g,0.09mol)、碳酸钠(10.60g,0.1mol)加入1,4-二氧六环(100ml)中,控温回流反应,经检测反应完毕后,将反应液降温至0~5℃,搅拌析晶后过滤,所得滤饼用无水乙醇/纯化水(V乙醇:V纯化水=1:2,50ml)体系重结晶后即为目标产品I,收率90.7%,纯度99.68%。
实施例13
室温,将I-1(11.81g,0.05mol)、2,4-双(4-甲氧基苯基)-1,3,2,4-二硫代二膦烷2,4-二硫化物(36.40g,0.09mol)、碳酸钠(11.66g,0.11mol)加入甲基叔丁基醚(100ml)中,控温回流反应,经检测反应完毕后,将反应液降温至0~5℃,搅拌析晶后过滤,所得滤饼用无水乙醇/纯化水(V乙醇:V纯化水=1:2,50ml)体系重结晶后即为目标产品I,收率86.8%,纯度98.89%。
Claims (8)
1.一种利鲁唑中间体化合物,其特征在于,其结构如式I-1所示:
。
2.一种权利要求1所述的利鲁唑中间体化合物I-1的制备方法,其特征在于,包括如下步骤:将化合物SM-1、SM-2加入水中,加入浓盐酸,控温回流至反应结束后,经后处理制得I-1,反应路线如下:
。
3.根据权利要求2所述的制备方法,其特征在于,所述的SM-1与SM-2的投料摩尔比为1:1.6~5.0。
4.根据权利要求2所述的制备方法,其特征在于,所述的SM-1与浓盐酸的投料质量体积比为1:4.0~10.0,其中,质量以g计,体积以ml计。
5.一种权利要求1所述的化合物I-1用于制备利鲁唑的用途,其特征在于,制备方法包括如下步骤:将化合物I-1、劳森试剂、碱加入反应溶剂中,控温回流至反应结束后,经后处理制得目标产品I;其路线如下:
。
6.根据权利要求5所述的用途,其特征在于,所述碱选自碳酸钠、碳酸铯、氢氧化钾、三乙胺、4-二甲氨基吡啶中的一种。
7.根据权利要求5所述的用途,其特征在于,所述的I-1、劳森试剂、碱的投料摩尔比为1:1.5~2.0:1.0~2.0。
8.根据权利要求5所述的用途,其特征在于,所述的反应溶剂为四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲基叔丁基醚中的一种或其组合。
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