CN107973724A - 一种新的沙丁胺醇药物盐-甲酸沙丁胺醇及其制备方法 - Google Patents

一种新的沙丁胺醇药物盐-甲酸沙丁胺醇及其制备方法 Download PDF

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CN107973724A
CN107973724A CN201711360911.5A CN201711360911A CN107973724A CN 107973724 A CN107973724 A CN 107973724A CN 201711360911 A CN201711360911 A CN 201711360911A CN 107973724 A CN107973724 A CN 107973724A
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salbutamol
formic acid
preparation
alcoholic solution
new
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刘文举
赵培侠
和萌林
申艳敏
赵俊廷
朱春山
刘广宇
孙晨
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Henan University of Technology
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Henan University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
    • C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/02—Formic acid
    • C07C53/06—Salts thereof

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及一种新型的沙丁胺醇药物盐‑甲酸沙丁胺醇及其制备方法。所述盐以沙丁胺醇和甲酸为原料，在比例为1:0~1:2.0的条件下，将甲酸的醇溶液滴加到含有沙丁胺醇的醇溶液中，之后搅拌3~4 h。自然挥发溶剂，结晶后过滤回收晶体，利用醇类溶剂重结晶即得到高纯度的甲酸沙丁胺醇，产率大于70%。产品的结晶性能和热稳定性能良好，在水溶液中的比沙丁胺醇有更高的溶解度。

Description

一种新的沙丁胺醇药物盐-甲酸沙丁胺醇及其制备方法
技术领域
本发明涉及药物化学领域，具体涉及到一种新的沙丁胺醇药物盐-甲酸沙丁胺醇及其制备方法。
背景技术
沙丁胺醇化学名为1-(4羟基-3羟甲基苯基)-2-(叔丁氨基)乙醇，又名咳喘宁，是一种选择性的β2受体激动剂，用于治疗喘息型支气管炎等病症。由于溶解度较小，且单一的沙丁胺醇药物会对人体健康具有一些副作用问题，多用成盐方法改善药物性能，市场上多以其硫酸盐和盐酸盐的形式存在，以改善其溶解度和药效。
目前市售的沙丁胺醇盐种类并不多，因此对沙丁胺醇做进一步的成盐探索与研究仍是很有必要的。
目前还没见有关甲酸沙丁胺醇的任何报道。
甲酸沙丁胺醇如(I)所示。
发明内容
本发明涉及用以下至少一种方法来表征甲酸沙丁胺醇：IR在3450、3170、3043、2981、2800、1593、1509、1448、1373、1349、1274、1200、1112、1080、1037、999、817、540和454cm-1处出峰；X-射线衍射在10.2、10.5、16.4、16.7、19.1、20.5、22.2、23.2、24.3和28.9°2θ处出峰；或H1-NMR(DMSO-d6,500MHz):δ8.40(s,1H),7.32(d,J＝1.9Hz,1H),7.06(dd,J＝8.2,2.1Hz,1H),6.75(d,J＝8.2Hz,1H),4.70(dd,J＝10.0,2.8Hz,1H),4.48(s,2H),2.97–2.63(m,2H),1.22(s,9H)；或DSC曲线在140℃-163℃温度范围内出现吸热峰且熔融时发生分解。
附图说明：
图1为甲酸沙丁胺醇的分子结构式
图2为甲酸沙丁胺醇的FT-IR图谱
图3为甲酸沙丁胺醇的H1-NMR图谱
图4为甲酸沙丁胺醇的XRD图谱
图5为甲酸沙丁胺醇的DSC曲线
具体实施方式
本发明的目的是提供一种新的沙丁胺醇药物盐-甲酸沙丁胺醇及其制备方法。
为了实现以上目的，主要通过以下方法实现：
以沙丁胺醇和甲酸为原料，在比例为1:1～1:1.5的条件下，将甲酸的醇溶液滴加到含有一定量的沙丁胺醇的醇类溶液中，之后搅拌3～4h,室温自然挥发溶剂，待有大量晶体后过滤，再用乙醇重结晶后，过滤即得到甲酸沙丁胺醇。产率通过直接称重计算，产率＝实际产品质量/理论产品质量。
上述方法中，所用的醇是甲醇、乙醇、正丙醇、异丙醇，所用醇类溶剂的用量为50～150mg溶质/g溶剂。
实施例
傅里叶红外光谱(FT-IR)分析在Prestige-21红外分光光度计上进行，样品以KBr做本底，在4000-400cm-1范围内扫描16次。红外图谱见附图2。
核磁共振氢谱(H1-NMR)在Bruker AVANCE 500兆核磁共振仪上进行，以DMSO-d6为溶剂，溶解5mg样品于核磁管内。其图谱见附图3。
X射线粉末衍射(XRD)在配有Cu-Ka的Rigaku MiniFlex600型的X射线粉末衍射仪上进行，在5-45°2θ范围内，扫描速率约为10°/min。粉末衍射图谱见附图4。
差示扫描量热法(DSC)在PerkinElmer DSC 8000型差示扫描量热仪上进行，样品重量约2mg，用带有1个孔的坩埚，在氮气流速20mL/min，升温速率为10℃/min的条件下在25到250℃温度范围内对样品进行扫描。DSC曲线见附图5。
实施例1：
将含有0.46g甲酸的甲醇溶液，在磁力搅拌下滴加到含有沙丁胺醇原料2.40g的甲醇溶液中，待滴加完全后，继续磁力搅拌反应4h，之后将反应液倒入100ml烧杯中，常温下自然挥发溶剂，待有大量晶体生成时，过滤回收晶体，然后再用乙醇重结晶2次,65℃真空干燥24h后计算产率，产率为70％。
实施例2：
将含有0.23g甲酸的甲醇溶液，在磁力搅拌下滴加到含有沙丁胺醇原料1.20g的甲醇溶液中，待滴加完全后，继续磁力搅拌反应3h，之后将反应液倒入100ml烧杯中，常温下自然挥发溶剂，待有大量晶体生成时，过滤回收晶体，然后再用乙醇重结晶2次，65℃真空干燥24h后计算产率，产率为68％。
实施例3：
将含有0.92g甲酸的乙醇溶液，在磁力搅拌下滴加到含有沙丁胺醇原料4.80g的乙醇溶液中，待滴加完全后，继续磁力搅拌反应4h，之后将反应液倒入100ml烧杯中，常温下自然挥发溶剂，待有大量晶体生成时，过滤回收晶体，然后再用乙醇重结晶2次，65℃真空干燥24h后计算产率，产率为64％。
实施例4：
将含有1.1g甲酸的甲醇溶液，在磁力搅拌下滴加到含有沙丁胺醇原料4.80g的乙醇溶液中，待滴加完全后，继续磁力搅拌反应3h，之后将反应液倒入100ml烧杯中，常温下自然挥发溶剂，待有大量晶体生成时，过滤回收晶体，然后再用乙醇重结晶3次，65℃真空干燥24h后计算产率，产率为60％。

Claims (4)

1.沙丁胺醇甲酸盐及其制备方法：
其特征在于在沙丁胺醇和甲酸摩尔比例为1:0~1:2.0的条件下，将甲酸的醇溶液缓慢滴加到含有一定量的沙丁胺醇的醇溶液中，之后再搅拌3~4 h, 自然挥发溶剂结晶后，利用醇类溶剂重结晶，过滤、干燥即得到甲酸沙丁胺醇。
2.根据权利1要求所述甲酸沙丁胺醇的制备方法，其特征在于反应及挥发溶液结晶后过滤得到晶体，再用水或醇类溶剂重结晶2~4次，得到甲酸沙丁胺醇。
3.根据权利1要求所述甲酸沙丁胺醇的制备方法，其特征在于所用的醇是甲醇、乙醇、正丙醇、异丙醇。
4.根据权利1或3要求所述甲酸沙丁胺醇的制备方法，其特征在于所用醇类的用量为50~150 mg溶质/g溶剂。
CN201711360911.5A 2017-12-18 2017-12-18 一种新的沙丁胺醇药物盐-甲酸沙丁胺醇及其制备方法 Pending CN107973724A (zh)

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LEITCH, DAVID C.等: "A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 *
RA˘ZVAN C. CIOC等: "One-Pot Synthesis of N-Substituted b-Amino Alcohols from", 《CHEM. EUR. J.》 *

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Application publication date: 20180501