CN116836108A - 一种用于合成重酒石酸间羟胺的催化剂配体的制备方法 - Google Patents
一种用于合成重酒石酸间羟胺的催化剂配体的制备方法 Download PDFInfo
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- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims abstract description 15
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 14
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims abstract description 10
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
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- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 description 1
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- VENXSELNXQXCNT-IJYXXVHRSA-N metaraminol bitartrate Chemical compound [H+].[H+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O.C[C@H](N)[C@H](O)C1=CC=CC(O)=C1 VENXSELNXQXCNT-IJYXXVHRSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen 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
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/584—Recycling of catalysts
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- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种合成重酒石酸间羟胺的催化剂配体的制备方法,属于药物合成领域。所述的催化剂配体的制备方法包括如下步骤:将化合物I、化合物II加入甲苯中,然后加入三氟化硼乙醚进行反应,得到化合物III;将化合物III溶于甲醇,然后加入氯化镍,搅拌并缓慢加入硼氢化钠,保温反应4小时,制备得到化合物IV。化合物IV可高效的不对称催化henry加成反应,应用于制备重酒石酸间羟胺。该方法操作简便,未使用特殊设备,且产品质量较好,反应生成的副产物容易去除,成本低廉,容易实现工艺化生产。
Description
技术领域
本发明涉及药物合成领域,具体涉及一种合成重酒石酸间羟胺的催化剂配体的制备方法。
背景技术
重酒石酸间羟胺(Metaraminol Bitartrate)是由FRESENIUS KABI USA LLC 开发的一种α-肾上腺素受体激动剂,于1972.04.17在美国上市,国内目前有11 家企业上市重酒石酸间羟胺注射液。重酒石酸间羟胺主要用于防治椎管内阻滞麻醉时发生的急性低血压,由于出血、药物过敏、手术并发症及脑外伤或脑肿瘤合并休克而发生的低血压,及心源性休克或败血症所致的低血压。
重酒石酸间羟胺分子结构中,含有两个手性中心,有4种光学异构体,其药用构型为(R,S),在制备过程中涉及手性合成和拆分。
关于重酒石酸间羟胺的制备方法,专利CN103739504B和CN106748818B 公开了以间羟基苯甲醛为原料,以醋酸铜和金鸡纳生物碱为催化剂进行henry加成反应,进而再氢化还原成盐进行制备。根据该专利报道的方法制备重酒石酸间羟胺,发现产品中含有较多的异构体,无法获取较高光学纯度的产品。
专利US20170210696公开了一种新的催化剂配体(化合物IV),可以催化不对称henry加成反应,定向合成光学纯的重酒石酸间羟胺,反应式如下:
同时还公开了催化剂配体(化合物IV)的制备方法,反应式如下:
但该方法制备的催化剂配体(化合物IV)收率较低,纯度较差,严重影响催化反应的活性。鉴于该催化剂配体(化合物IV)的良好效果,有必要开发出一种成本低廉、制备产品纯度高、操作简便的方法制备催化剂配体(化合物IV),以便可以高效的用于重酒石酸间羟胺的定向合成。
发明内容
为克服现有技术的不足,本发明的目的在于提供一种用于合成重酒石酸间羟胺的催化剂配体的制备方法,该方法操作简便,未使用特殊设备,且产品质量较好,反应生成的副产物容易去除,成本低廉,容易实现工艺化生产。本发明制备的催化剂配体(化合物IV)可以高收率的催化合成单一手性的重酒石酸间羟胺,具有很好的应用前景。
本发明采用的技术方案如下:
一种合成重酒石酸间羟胺的催化剂配体的制备方法,按如下步骤实现:
步骤一:将化合物I、化合物II加入甲苯中,然后加入三氟化硼乙醚进行反应,得到化合物III;
步骤二:将化合物III溶于甲醇,然后加入氯化镍,搅拌并缓慢加入硼氢化钠,保温反应4小时,制备得到化合物IV,反应式如下:
步骤一中使用三氟化硼乙醚作为缩合试剂,反应温度为20~120℃,其中优选20~30℃。
步骤二中使用硼氢化钠和氯化镍作为反应试剂,反应温度为-20~50℃,其中优选10~20℃。
化合物I、化合物II、三氟化硼乙醚的摩尔比为1:1:0.05~1:1:3.0,其中优选 1:1:1。
化合物I、硼氢化钠、氯化镍的摩尔比为1:0.5:0.1~1:10:0.1,其中优选1:3.0:0.1。
有益效果
本发明化合物III的制备中使用三氟化硼乙醚催化缩合,与现有技术使用的对甲苯磺酸相比,收率更高,纯度更好。催化剂配体(化合物IV)的制备中,使用氯化镍和硼氢化钠进行还原,与现有技术相比,增加使用氯化镍,可以有效提升反应速率,且制备获得的产物纯度和收率更高。本发明制备方法简单,操作容易,生产效率高,能够满足商业化生产的要求。
附图说明
图1实施例1化合物III MS图谱,
图2实施例2化合物IV HPLC图谱,
图3实施例2化合物IV MS图谱,
图4实施例3加成物MS图谱,
图5实施例3重酒石酸间羟胺HPLC图谱,
图6实施例3重酒石酸间羟胺MS图谱,
图7对比实施例重酒石酸间羟胺HPLC图谱。
具体实施方式
下面结合具体实施方式,对本发明做进一步描述:
实施例1
化合物III的制备(步骤一)
20~30℃下,将化合物I(10.00g,66mmol)、化合物II(7.14g,66mmol) 和三氟化硼乙醚(9.32g,66mmol)投入甲苯(100mL)中,然后维持温度搅拌反应5h。待反应完毕,向反应液中加入饱和碳酸氢钠溶液(100mL),搅拌10min,静置分液,取有机相,然后加入5%盐酸溶液调节pH1~2,静置分液,取水相。然后再加入乙酸乙酯(100mL),并用5%氢氧化钠溶液调节pH7~8,静置分液,取有机相,然后使用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,并于40℃下减压蒸馏除去溶剂,即可得到化合物III,ESI-MS[M+1]+m/z 243。
实施例2
化合物IV的制备(步骤二)
将步骤一制备得到的化合物III溶于甲醇(100mL)中,然后加入氯化镍(0.76g,6.6mmol),然后降温至10~20℃,缓慢加入硼氢化钠(7.49g,198mmol),加完后,维持温度反应4h。待反应完毕,加入水(100mL)和乙酸乙酯(100mL),搅拌10min后,静置分液,取有机相。然后向有机相中加入5%盐酸溶液调节 pH1~2,静置分液,取水相。然后向水相中加入乙酸乙酯,并用5%氢氧化钠溶液调节pH7~8,静置分液,取有机相,然后加入饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,并于40℃下减压蒸馏除去溶剂。向残余物中加入异丙醚(50mL),搅拌降温至0~5℃,析晶1h,过滤,将得到的产品于30℃下真空干燥即可得到类白色固体,即为化合物IV(13.95g,86.5%),HPLC%=95.48%,ESI-MS[M+1]+ m/z 245。
实施例3
重酒石酸间羟胺的制备
化合物IV用于催化合成重酒石酸间羟胺,反应式如下:
制备方法如下:
将一水合醋酸铜(0.65g,3.26mmol)和化合物IV(0.80g,3.27mmol)投入甲醇(40mL)中,氮气保护下于室温搅拌10min,然后加入间羟基苯甲醛(4.00g, 32.7mmol)和DIPEA(8.47g,65.54mmol),然后降温至-10~0℃,缓慢滴加硝基乙烷(12.27g,163.5mmol),待加完后,维持温度反应10h。待反应完毕,向反应体系中,加入40mL乙酸乙酯和2M盐酸(20mL),搅拌10min,静置分液取有机相,然后用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤蒸馏,得到加成物。 ESI-MS[M-1]-m/z 196。
向加成物中加入甲醇(40mL),然后加入10%钯碳(0.2g),于氢化反应釜中反应5h。待反应完毕,过滤除去钯碳,然后于室温下,向反应体系中滴加L- 酒石酸(4.91g,32.7mmol)的甲醇溶液(20mL),滴加完毕后,降温至0~5℃析晶1h,过滤,将得到的产品于30℃下真空干燥即可得到白色固体,即为重酒石酸间羟胺(6.48g,62.4%),HPLC%=92.47%(间羟胺),HPLC%=7.46%(酒石酸),ESI-MS[M+1]+m/z 168。
对比实施例
依据专利US20170210696公开的方法制备催化剂配体(化合物L)
将化合物I(10.00g,66mmol)、化合物II(7.14g,66mmol)投入甲苯(100mL) 中,然后加入对甲苯磺酸(1.13g,6.6mmol),然后加热回流分水反应4h。待反应完毕,向反应体系中加入饱和碳酸氢钠溶液(100mL),分液取有机相,然后用水洗涤,无水硫酸钠干燥,过滤蒸馏,即可得到化合物III。
将化合物III溶于甲醇中,然后于0℃下滴加硼氢化钠(39.95g,1056mmol) 的THF溶液(200mL),加完后维持温度反应24h。反应完毕后,加入5%盐酸溶液(50mL),分液取有机相,减压蒸馏除去溶剂,然后加入5%氢氧化钠溶液至pH=12,然后加入二氯甲烷(100mL)萃取,分液取有机相,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂,即可得到油状物化合物IV(9.84g,61.5%), HPLC%=73.95%。
Claims (5)
1.一种合成重酒石酸间羟胺的催化剂配体的制备方法,其特征在于,所述方法按如下步骤实现:
步骤一:将化合物I、化合物II加入甲苯中,然后加入三氟化硼乙醚进行反应,得到化合物III;
步骤二:将化合物III溶于甲醇,然后加入氯化镍,搅拌并缓慢加入硼氢化钠,保温反应4小时,制备得到化合物IV,反应式如下:
2.如权利要求1所述的一种合成重酒石酸间羟胺的催化剂配体的制备方法,其特征在于,步骤一中使用三氟化硼乙醚作为缩合试剂,反应温度为20~120℃,其中优选20~30℃。
3.如权利要求1所述的一种合成重酒石酸间羟胺的催化剂配体的制备方法,其特征在于,步骤二中使用硼氢化钠和氯化镍作为反应试剂,反应温度为-20~50℃,其中优选10~20℃。
4.如权利要求1所述的一种合成重酒石酸间羟胺的催化剂配体的制备方法,其特征在于,化合物I、化合物II、三氟化硼乙醚的摩尔比为1:1:0.05~1:1:3.0,其中优选1:1:1。
5.如权利要求1所述的一种合成重酒石酸间羟胺的催化剂配体的制备方法,其特征在于,化合物I、硼氢化钠、氯化镍的摩尔比为1:0.5:0.1~1:10:0.1,其中优选1:3.0:0.1。
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