CN106478465B - 一种奥沙拉秦钠重要中间体氢化物的合成方法 - Google Patents
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Classifications
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
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- 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
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
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- B01J35/19—
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- 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
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/06—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of zinc, cadmium or mercury
Abstract
本发明公开了一种奥沙拉秦钠重要中间体氢化物的合成方法,它是将化合物I在催化剂(I)和催化剂(II)的协同催化下,在有机溶剂中与氢气在30‑50℃反应3‑5小时,反应完毕后,过滤,滤液降温至‑10‑0℃,加入无机酸类溶剂析晶,过滤得到氢化物。本发明的合成步骤同时采用两种催化剂协同催化化合物I与氢气进行氢化反应,可以达到提高氢化反应的选择性,降低副产物,提高产物的质量及反应收率的目的。
Description
技术领域
本发明属于药物化学合成技术领域,涉及药物重要中间体的制备方法,更具体的说是奥沙拉秦钠重要中间体:2-甲磺酰氧基-5-氨基苯甲酸甲酯盐酸盐(简称“氢化物”)的合成方法。
背景技术
奥沙拉秦钠(olsalazine sodium)化学名称为:3,3'-偶氮双(6-羟基苯甲酸钠),是由瑞士pharmaci AB 公司开发,临床治疗溃疡性结肠炎的新药。奥沙拉秦钠是通过抑制前列腺素合成,抑制炎症介质白三烯的形成,降低肠壁细胞膜的通透性,减轻肠粘膜水肿,减少炎症介质产生作用。临床用于治疗急、慢性溃疡性结肠炎,克隆氏病,节段性回肠炎及其缓解的长期维持治疗。
奥沙拉秦钠现行的生产工艺路线主要是以水杨酸为原料,经硝化、酯化,甲磺化、还原、重氮化偶合、水解反应制备(Eur.pat.appl.1981.36637)。据公开文献:《奥沙拉秦合成新路线》(赵敏,实用临床医药杂志,2009,13(11):60-61)、《奥沙拉秦的合成实验研究》(张玮,董月芬等,河北化工,2007,30(12):47-48)等文献中提供的内容在通过还原反应制备奥沙拉秦钠中间体氢化物2-甲磺酰氧基-5-氨基苯甲酸甲酯时,分别采用乙酸-铁粉、盐酸-铁粉作为催化剂将硝基还原为氨基。但在实际生产中,反应产生的铁泥对环境污染很大,后处理费用成本昂贵。并且引入重金属离子使后面奥沙拉秦钠成品的纯化变的困难。
在还原这步反应中,欧洲专利(EP 0036636)曾报道过类似方法通过10%钯碳作催化剂,甲磺化物在氢气中氢化还原生成氢化物。此方法的优势在于通过氢气将硝基还原为氨基,不引入其它杂质,副产物少产品纯度高且后处理方便,生产成本较低,适合产业化生产。然而我们在生产中发现这条工艺仍存在不足。甲磺化物(I)在单一钯碳催化下,通氢气还原过程中,发现甲磺化物中的甲磺酰基部分脱掉,生成副产物5-氨基水杨酸甲酯,使产品收率降低(70%~80%),质量变差,并且此副产物的产生会影响到终产品奥沙拉秦钠的质量。并且在试验中发现氢化反应温度越高,钯碳含量越高,副产物越多,收率越低;
发明内容
本发明的目的是克服现有技术中的缺点与不足,提供一种工艺操作简便,氢化选择性高,能够提高产品收率和质量的“氢化物”的合成方法。
为实现上述目的,本发明提供了如下的技术方案:
一种奥沙拉秦钠重要中间体氢化物的合成方法,其特征在于该方法包括如下的步骤:
化合物I(甲磺化物)在催化剂(I)和催化剂(II)的协同催化下在有机溶剂中与氢气在30-50℃反应3-5小时,反应完毕后,加入无机酸类溶剂析晶,过滤得到化合物II(氢化物盐酸盐);
本发明所述的合成方法中,所述催化剂(I)选自5%钯碳或10%钯碳。优选5%钯碳。
催化剂(II)为:优选锌粉。
本发明所述的合成方法中,其中化合物(I)与氢气反应的有机溶剂为乙酸乙酯。
无机酸性物质为:盐酸。
本发明所述的合成方法中,催化剂(I):催化剂(II)的重量份数比为;1~4:1
催化剂总量(催化剂(I)+催化剂(II)):化合物I的重量份数比为;0.02~0.06:1
化合物I与化合物II的反应时间为3-5小时,反应温度为30-50℃。
为了得到更好的效果,催化剂(I):催化剂(II)的重量份数比为;2~3:1
催化剂总量(催化剂(I)+催化剂(II)):化合物I的重量份数比为;0.03~0.05:1
化合物I与氢气的反应时间为4-5小时,反应温度为35-45℃。
更优选催化剂(I):催化剂(II)的重量份数比为;3:1;催化剂总量(催化剂(I)+催化剂(II)):化合物I的重量份数比为;0.04:1
化合物I与化合物II的反应时间为4.5小时,反应温度为40-45℃。
本发明的反应过程如下:
本发明奥沙拉秦钠中间体氢化物的合成方法与现有技术公开的内容相比所具有的优点和特点在于:
(1)本发明奥沙拉秦钠中间体氢化物的合成步骤同时采用两种催化剂对甲磺化物与氢气反应进行协同催化,提高氢化还原的选择性,在氢化还原硝基为氨基的同时,保护了甲磺酰氧基,大大提高了甲磺化物的转化率,反应完成后加入无机酸成盐析晶,就可以得到合格的氢化物(含量在98%以上)。
(2)采用本发明方法合成的中间体氢化物,收率高达90%以上,更适合奥沙拉秦钠的大规模工业化生产。
具体实施方式:
下面通过具体实施方式,对本发明的上述内容做进一步的详细说明,实施例是对本发明的进一步的解释,决不是对本发明的限制。以下结合较佳实施例,对本发明的奥沙拉秦钠中间体“氢化物”合成方法加以进一步说明。特别加以说明的是甲磺化物(化合物I)可以通过欧洲专利(EP 0036636)提供的方法制备得到或从市场上买到,催化剂(I),催化剂(II)可以从市场上买到。
实施例1
本实施例为使用单一催化剂10%钯碳的对比实施例
分别向反应瓶中加入20g甲磺化物,10%钯碳2g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时(TLC检测反应完毕),氮气置换氢气3次过滤,滤液降温,加入盐酸,析晶,过滤得“氢化物”4.6g,收率22.5%,含量为75.7%。
实施例2
本实施例为使用单一催化剂5%钯碳的对比实施例
分别向反应瓶中加入20g甲磺化物,5%钯碳2g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时,氮气置换氢气3次过滤,滤液降温,加入盐酸,析晶,过滤得“氢化物”12.8g,收率62.5%,含量为90.1%。
实施例3
本实施例为使用单一催化剂的5%钯碳对比实施例
分别向反应瓶中加入20g甲磺化物,5%钯碳0.6g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时,氮气置换氢气3次过滤,滤液降温,加入盐酸,析晶,过滤得“氢化物”16.2g,收率79.1%,含量为98.2%。
实施例4
本实施例为使用单一催化剂锌粉的对比实施例
分别向反应瓶中加入20g甲磺化物,锌粉0.4g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时,氮气置换氢气3次过滤,滤液降温,加入盐酸,未析出结晶,弃去。
上述实施例1- 4的对比实验结果说明:
(1)单一使用钯碳作为催化剂时,钯碳含量越高,副产物越多,产品收率越低。
(2)单一使用锌粉作为催化剂时,反应不发生。
实施例5
分别向反应瓶中加入20g甲磺化物,5%钯碳0.6g,铁粉0.4g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时,氮气置换氢气3次过滤,滤液降温,加入盐酸,析晶,过滤得“氢化物”16.3g,收率79.6%,含量为98.4%。
实施例6
分别向反应瓶中加入20g甲磺化物,5%钯碳0.6g,镁粉0.4g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时,氮气置换氢气3次过滤,滤液降温,加入盐酸,析晶,过滤得“氢化物”15.8g,收率77.2%,含量为97.9%。
实施例7
分别向反应瓶中加入20g甲磺化物,5%钯碳0.8g,锌粉0.4g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时,氮气置换氢气3次过滤,滤液降温,加入盐酸,析晶,过滤得“氢化物”18.4g,收率89.9%,含量为98.9%。
实施例8
分别向反应瓶中加入20g甲磺化物,5%钯碳0.6g,锌粉0.2g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时,氮气置换氢气3次过滤,滤液降温,加入盐酸,析晶,过滤得“氢化物”18.6g,收率90.9%,含量为99.2%。
实施例9
分别向反应瓶中加入20g甲磺化物,5%钯碳0.4g,锌粉0.2g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时,氮气置换氢气3次过滤,滤液降温,加入盐酸,析晶,过滤得“氢化物”17.8g,收率86.9%,含量为98.6%。
实施例10
分别向反应瓶中加入20g甲磺化物,10%钯碳0.4g,锌粉0.2g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时,氮气置换氢气3次过滤,滤液降温,加入盐酸,析晶,过滤得“氢化物”14.4g,收率70.3%,含量为97.5%。
实施例11
分别向反应瓶中加入20g甲磺化物,10%钯碳0.6g,锌粉0.2g,乙酸乙酯120ml,通氮气置换空气3次,再通氢气置换氮气3次,搅拌升温至40-45℃,通氢气开始吸氢4.5小时,氮气置换氢气3次过滤,滤液降温,加入盐酸,析晶,过滤得“氢化物”13.7g,收率66.9%,含量为96.8%。
实施例12
制备奥沙拉秦钠
加入15g氢化物至反应瓶,加入45ml盐酸水溶液,搅拌降温至0℃以下,滴加25g亚硝酸钠水溶液,滴毕,-2~0℃反应30分钟,将13g氢氧化钾水溶液和15g冬青油降温至0℃以下,搅拌下加入氢化物反应瓶中进行偶合反应,完毕滴加盐酸水溶液调节PH=3。二氯乙烷提取,降温析晶,过滤得偶合物17.4g。
将15g偶合物,10g氢氧化钠和80g水投入反应瓶,加热升温至回流,反应1小时,滴加冰乙酸至PH=6,再回流反应1小时,冷却析晶,过滤得奥沙拉秦钠粗品,在水中重结晶得奥沙拉秦钠精品9.2g。
本发明所制备的终产品奥沙拉秦钠测定数据如下:
IR(KBr)(cm-1):3434cm-1(υOH),1657 cm-1(υN=N),1605cm-1,1486cm-1,1587 cm-1(υas coo),1451 cm-1(υs coo),970 cm-1(δAr-H),830 cm-1(δAr-H)
1H-NMRδ:6.94(J=8Hz),δ:7.74(J=8Hz,J=2Hz),δ:8.12(J=2Hz)
结果表明:以上光谱数据证明实施例12所制得化合物为奥沙拉秦钠。
在详细说明的较佳实施例之后,熟悉该项技术人士可清楚地了解,在不脱离上述申请专利范围与精神下可进行各种变化与修改,凡依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均属于本发明技术方案的范围。且本发明亦不受说明书中所举实例实施方式的限制。
Claims (4)
1.一种奥沙拉秦钠重要中间体氢化物的合成方法,其特征在于:将钯金属元素催化剂I、锌金属元素催化剂II按一定比例加入溶剂中,协同催化化合物I与氢气进行氢化反应,反应结束后加入无机酸析晶,最终得到化合物II:
催化剂I:催化剂II的重量份数比为: 1~4:1;
其中催化剂I+II总量:化合物I的重量份数比为: 0.02~0.06:1;
所述钯金属元素催化剂I为5%钯碳;所述锌金属元素催化剂II为锌粉。
2.权利要求1所述的合成方法,其特征在于所述催化剂(I):催化剂(II)的重量份数比为:2~3:1。
3.权利要求1所述的合成方法,其特征在于所述溶剂为有机溶剂乙酸乙酯。
4.权利要求1所述的合成方法,其特征在于所述化合物I与化合物II的反应时间为3-5小时,反应温度为30-50℃。
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