CN115925588A - 一种脂肪族亚磺酸钠盐的制备方法 - Google Patents
一种脂肪族亚磺酸钠盐的制备方法 Download PDFInfo
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
本发明公开了一种脂肪族亚磺酸钠盐的制备方法,包括下述合成步骤:步骤1)将苄基‑2‑溴乙基醚(I)与2‑巯基苯并噻唑(II)在碱性下进行烷基化反应,得到式III;步骤2)直接加入氧化剂进行硫的氧化反应,得到式IV;步骤3)第三步经由硼氢化钠去除苯并噻唑,可以得到脂肪族亚磺酸钠盐(V);本发明的脂肪族亚磺酸钠盐的制备方法,具备发明整个反应过程可将溶剂整合为在醇类与水中进行反应,可以避免使用毒性较高的二甲基甲酰胺、二氯甲烷等溶剂、产品品质较高,收率较高操作简便的特点。
Description
技术领域
本发明涉及医药合成技术领域,涉及一种脂肪族亚磺酸钠盐的制备方法。
背景技术
亚磺酸钠盐是亚磺酸的基本形式,因其稳定性而构成有机合成中的关键中间体。鉴于脂肪族衍生物的商业可用性有限以及它们合成的几个缺点,烷基亚磺酸钠盐的制备仍然是一个挑战。
亚磺酸是高反应性和不稳定的化合物,通常由其相应的钠盐即亚磺酸钠原位生成。在过去的几十年里,这些后一种分子已经被广泛研究,特别是它们的稳定性。此外,亚磺酸作为亲电或亲核物质的亚磺酸盐的双重反应性使其可用作有机化学中的通用中间体。
亚磺酸可以参与砜的合成,药物化学中的关键组成部分,可以通过硫-烷基化、取代、光氧化还原催化、金属催化的烯丙基或苄基取代、炔烃的氢磺酰化、烯烃的氧磺酰化、金属催化或无金属偶联、碳氢官能化或无金属磺酰化得到。亚磺酸盐还通过其转化为磺酰氯或磺酰肼而构成磺酰胺前驱物。
文献综述如下:
2018年,Tran等以苄基-2-溴乙基醚(I)和2-巯基苯并噻唑(II)为原料,经由烷基化、氧化和还原等3步反应制备亚磺酸钠盐(V),该条路线收率为45%,且使用钠氢、间氯过氧苯甲酸等原料,极易燃爆,较为危险,不适合工业化生产。
目前现有的合成路线存在不足之处,产率较低、涉及易燃易爆等危险试剂或者生产工艺、环境污染较为严重等问题不利于大规模工业化生产。
综上所述,存在对反应简单,成本低廉,绿色环保,最终对于易于工业化生产的制备脂肪族亚磺酸钠盐的方法迫切需要。
发明内容
本发明要解决的技术问题是:
研制开发一种反应简单,成本低廉,绿色环保,品质较好,操作简便,适合工业化生产的2-烷砜基苯并噻唑合成方法;最终使得脂肪族亚磺酸钠盐也能够达到品质较高,收率较高操作简便,适合工业化生产的脂肪族亚磺酸钠盐。
为了达到上述目的,本发明采用了以下技术方案:
具体合成过程如下:
一种脂肪族亚磺酸钠盐的制备方法,
包括下述合成步骤:
步骤1)
将苄基-2-溴乙基醚(I)与2-巯基苯并噻唑(II)在碱性下进行烷基化反应,得到式III;
步骤2)
直接加入氧化剂进行硫的氧化反应,得到式IV;
步骤3)
第三步经由硼氢化钠去除苯并噻唑,可以得到脂肪族亚磺酸钠盐(V);
其中,步骤1)~3)的反应式如下:
作为本方案的进一步改进,步骤1)中,所述的碱为无机碱、有机碱的一种或多种;所述的无机碱优选为碳酸钾、氢氧化钾、氢氧化钠、氢氧化锂中的任意一种或多种;所述的有机碱为三级胺中的三乙胺。
作为本方案的进一步改进,步骤1)中,所述的无机碱为碳酸钾,所述苄基-2-溴乙基醚(I)与碳酸钾试剂摩尔比为1:0.9~1:2.0。
作为本方案的进一步改进,步骤1)中,所述的溶剂为醇类、或醇类与水的混合物;所述的醇类为甲醇、乙醇、异丙醇中的任意一种或多种。
作为本方案的进一步改进,步骤2)中,所述的氧化剂为双氧水,苄基-2-溴乙基醚(I)与双氧水试剂摩尔比为1:2~1:8。
作为本方案的进一步改进,步骤2)中,所述的助氧化剂为钨酸钠,苄基-2-溴乙基醚(I)与钨酸钠试剂摩尔比为1:0.05~1:0.2。
作为本方案的进一步改进,步骤2)中,所述的溶剂为醇类、或醇类与水的混合物,所述的醇类为甲醇、乙醇、异丙醇中的任意一种或多种。
作为本方案的进一步改进,步骤2)中,其中所述的反应温度为70~80℃。
作为本方案的进一步改进,步骤2)中,所述的氧化剂为过氧硫酸氢钾复合盐,苄基-2-溴乙基醚(I)与过氧硫酸氢钾复合盐试剂摩尔比为1:2.0~1:2.2。
作为本方案的进一步改进,步骤2)中,所述的反应温度为40~60℃。
本发明提供的硫辛酸的合成方法具备下述优点:
1)本发明路线相对比较简单,反应简单,成本低廉,绿色环保,品质较好,操作简便,适合工业化生产的2-烷砜基苯并噻唑合成方法;最终使得脂肪族亚磺酸钠盐也能够达到品质较高,收率较高操作简便,适合工业化生产的脂肪族亚磺酸钠盐;为脂肪族亚磺酸钠盐的合成制备提供一条新的合成方案;
2)本发明整个反应过程可将溶剂整合为在醇类与水中进行反应,可以避免使用毒性较高的二甲基甲酰胺、二氯甲烷等溶剂;
3)本发明试剂也比较安全,因2-巯基苯并噻唑(I)硫醇上的氢比较酸,故使用碳酸钾替代易燃易爆的钠氢,拔除2-巯基苯并噻唑(I)硫醇上的氢,进行硫烷基化反应,得到硫醚(III);硫易氧化由亚砜变成砜,故使用双氧水/钨酸钠或过氧硫酸氢钾复合盐替代易爆的间氯过氧苯甲酸,进行硫氧化反应,得到砜(IV)。
附图
图1本发明对比例1的核磁图谱;
图2本发明对比例2的核磁图谱;
图3本发明实施例3的核磁图谱;
图4本发明实施例4的核磁图谱。
具体实施方式
为了使本发明的目的、技术方案和优点更加清楚,以下结合实施例对本发明作进一步说明:
脂肪族亚磺酸钠盐的合成路线如下:
比对例1
在反应瓶中加入10g2-巯基苯并噻唑(I)(0.060mol,1.0eq)和100mL二甲基甲酰胺,冰浴下将4.3g钠氢(0.072mol,1.2eq)分次加入反应液中,保温反应至少15分钟。将14.1g苄基-2-溴乙基醚(II)(0.066mol,1.1eq)滴加到反应液中,保温反应至少2小时。反应完毕,反应液加入甲基叔丁基醚萃取二次,合并有机层分别使用水与15%氯化钠水溶液萃取,减压旋蒸,得到18.5g化合物(III)。核磁数据如下:1HNMR(CDCl3,400MHz)δ7.85(d,J=8.1Hz,1H),7.74(dd,J=8.0,0.5Hz,1H),7.43-7.38(m,1H),7.36-7.24(m,6H),4.59(s,2H),3.87(t,J=6.3Hz,2H),3.61(t,J=6.3Hz,2H),参见图1。
比对例2
在反应瓶中加入10.4g化合物(III)(0.033mol,1.0eq),1.1g钨酸钠(3.3mmol,0.1eq)和100mL乙醇,升温至70~80℃,将18.8g双氧水(0.166mol,5.0eq)滴加到反应液中,保温反应至少2小时。反应完毕,热过滤,降温过滤,干燥得到8.6g化合物(IV)的白色固体。核磁数据如下:1HNMR(CDCl3,400MHz)δ8.23-8.16(m,1H),7.97-7.90(m,1H),7.59(dtd,J=15.2,7.3,1.2Hz,2H),7.21-7.06(m,3H),6.98(d,J=7.0Hz,2H),4.38(s,2H),3.99(t,J=5.8Hz,2H),3.85(t,J=5.8Hz,2H),参见图2。
比对例3
在反应瓶中加入10.4g化合物(III)(0.033mol,1.0eq),50g1,4-二氧六环和50g水醇,升温至25~30℃,将44.87g过氧硫酸氢钾复合盐(Oxone)(0.073mol,2.2eq)加入到反应瓶中,保温反应至少2小时。反应完毕,硫代硫酸钠萃灭,乙酸乙酯萃取,氯化钠水溶液萃取,减压旋蒸,馏余物使用乙醇再结晶,得到8.5g化合物(IV)的白色固体。
实施例1
在反应瓶中加入100g2-巯基苯并噻唑(I)(0.60mol,1.05eq),86.6g碳酸钾(0.63mol,1.1eq)和500mL乙醇,室温下将122.0g苄基-2-溴乙基醚(II)(0.57mol,1eq)滴加到反应液中,反应至少2小时。反应完毕,过滤,得到化合物(III)乙醇溶液,直接投入下一步反应。
于上步整批化合物(III)乙醇溶液的反应瓶中加入19.7g钨酸钠(0.06mol,0.1eq),升温至70~80℃,将403g双氧水(3.56mol,6.3eq)滴加到反应液中,保温反应至少2小时。反应完毕,热过滤,降温至0~10℃,过滤,干燥得到143.9g化合物(IV)的白色固体,二步反应收率76%。
实施例2
在反应瓶中加入100g2-巯基苯并噻唑(I)(0.60mol,1.05eq),86.6g碳酸钾(0.63mol,1.1eq)和500mL乙醇,将122.0g苄基-2-溴乙基醚(II)(0.57mol,1eq)滴加到反应液中,反应至少2小时。反应完毕,过滤,得到化合物(III)乙醇溶液,直接投入下一步反应。
于上步整批化合物(III)乙醇溶液的反应瓶中加入750mL水,升温至45~55℃,将716g过氧硫酸氢钾复合盐(Oxone)(1.16mol,2.05eq)分批加入到反应瓶中,保温反应至少4小时。反应完毕,降温至0~10℃过滤。滤饼使用乙酸乙酯溶解,10%硫代硫酸钠萃取,减压旋蒸,加入乙醇打浆,过滤,干燥得到156.1g化合物(IV)的白色固体,纯度99.4%,二步反应产率82%。
实施例3
在反应瓶中加入100g化合物(IV)(0.3mol,1eq)和800mL乙醇,室温下将22.7g硼氢化钠(0.6mol,2eq)加入反应液中,反应至少1小时。反应完毕,减压旋蒸,加入甲基叔丁基醚打浆,过滤,干燥得到77.7g化合物(V)的白色固体,纯度99.3%,产率97%,总产率80%。核磁数据如下:1HNMR(CD3OD,400MHz)δ7.37-7.21(m,5H),4.51(s,2H),3.77(t,J=6.4Hz,2H),2.53(t,J=6.4Hz,2H),参见图3。
比对例4
在反应瓶中加入30g化合物(V)(0.135mol,1eq)和150g水,室温下将19g39.5%氯化钙水溶液(67.5mmol,0.5eq)加入反应瓶中,降温过滤,水淋洗,干燥得到13.7g化合物(VII)的白色固体产品,产率46%。
实施例4
在反应瓶中加入70g化合物(V)(0.315mol,1eq)、350mL水和350mL甲基叔丁基醚,室温下将31.9g浓盐酸(0.315mol,1eq)加入反应瓶中,酸化萃取分层。有机层加入11.2g氢氧化钙(0.15mol,0.48eq),过滤,粗产物加入90%乙醇打浆,过滤,干燥得到57.0g化合物(VII)的白色固体产品,纯度99.9%,产率79%,总产率63%。核磁数据如下:1HNMR(D2O,400MHz)δ7.54-7.30(m,5H),4.80(s,4H),4.54(s,2H),3.81(t,J=6.1Hz,2H),2.59(t,J=6.1Hz,2H);13CNMR(D2O,100MHz)δ137.1,128.7,128.5,128.3,72.9,64.8,61.1,参见图4;质谱[C18H23CaO6S2]+计算值439.06,实验值439.06。
Claims (10)
2.根据权利要求1所述的脂肪族亚磺酸钠盐的制备方法,其特征在于,步骤1)中,所述的碱为无机碱、有机碱的一种或多种;所述的无机碱优选为碳酸钾、氢氧化钾、氢氧化钠、氢氧化锂中的任意一种或多种;所述的有机碱为三级胺中的三乙胺。
3.根据权利要求1所述的脂肪族亚磺酸钠盐的制备方法,其特征在于,步骤1)中,所述的无机碱为碳酸钾,所述苄基-2-溴乙基醚(I)与碳酸钾试剂摩尔比为1:0.9~1:2.0。
4.根据权利要求1所述的脂肪族亚磺酸钠盐的制备方法,其特征在于,步骤1)中,所述的溶剂为醇类、或醇类与水的混合物;所述的醇类为甲醇、乙醇、异丙醇中的任意一种或多种。
5.根据权利要求1所述的脂肪族亚磺酸钠盐的制备方法,其特征在于,步骤2)中,所述的氧化剂为双氧水,苄基-2-溴乙基醚(I)与双氧水试剂摩尔比为1:2~1:8。
6.根据权利要求5所述的脂肪族亚磺酸钠盐的制备方法,其特征在于,步骤2)中,所述的助氧化剂为钨酸钠,苄基-2-溴乙基醚(I)与钨酸钠试剂摩尔比为1:0.05~1:0.2。
7.根据权利要求1所述的脂肪族亚磺酸钠盐的制备方法,其特征在于,步骤2)中,所述的溶剂为醇类、或醇类与水的混合物,所述的醇类为甲醇、乙醇、异丙醇中的任意一种或多种。
8.根据权利要求5所述的脂肪族亚磺酸钠盐的制备方法,其特征在于,步骤2)中,其中所述的反应温度为70~80℃。
9.根据权利要求1所述的脂肪族亚磺酸钠盐的制备方法,其特征在于,步骤2)中,所述的氧化剂为过氧硫酸氢钾复合盐,苄基-2-溴乙基醚(I)与过氧硫酸氢钾复合盐试剂摩尔比为1:2.0~1:2.2。
10.根据权利要求9所述的脂肪族亚磺酸钠盐的制备方法,其特征在于,步骤2)中,所述的反应温度为40~60℃。
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