CN113004228A - 一种d-泛酸钙中间体d-泛内酯的合成工艺 - Google Patents
一种d-泛酸钙中间体d-泛内酯的合成工艺 Download PDFInfo
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- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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 to ring carbon atoms
- C07D307/32—Oxygen atoms
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Abstract
本发明提供一种D‑泛酸钙中间体D‑泛内酯的合成工艺,其特征在于:S1、将异丁醛、草酸二甲酯、甲醛和氢氧化钠按等摩尔质量比加入反应釜中,将温度从30度升至120度,保温4小时,蒸馏除去产物的甲醇,本发明中采用Ir(COD)Hpo3]2、配体、碱性添加物的条件下原位生成催化剂,在催化剂条件下,通入氢气对酮基泛内酯进行不对称催化氢化反应,能够得到反应活性和选择性高的手性D‑泛内脂,该种合成方法氢化反应条件温和,适用于多种酮基泛内酯衍生物,底物适用范围广,且反应过程对环境污染小。
Description
技术领域
本发明涉及有机合成领域,尤其涉及一种D-泛酸钙中间体D-泛内酯的合成工艺。
背景技术
手性D-泛内酯化合物是合成D-泛酸钙重要的有机中间体,D-泛酸钙,是人体所必需的维生素,工业上常采用异丁醛、甲醛、氢氧化钠等物料,产生氢醇中间体,通过氢醇中间体的加酸化反应可以得到DL-泛内脂,DL-泛内脂通过经酶拆分消旋得到D-泛内脂。
但是这种合成方法虽然方法简便且原料廉价,但是收率低,反应步骤长,生产过程需要大量的氰化钠对环境造成严重的污染。
发明内容
本发明的目的在于提供一种D-泛酸钙中间体D-泛内酯的合成工艺,以解决上述技术问题。
本发明为解决上述技术问题,采用以下技术方案来实现:一种D-泛酸钙中间体D-泛内酯的合成工艺,其特征在于:
S1、将异丁醛、草酸二甲酯、甲醛和氢氧化钠按等摩尔质量比加入反应釜中,将温度从30度升至120度,保温4小时,蒸馏除去产物的甲醇,得产物酮基泛内酯和甲酸钠;
S2、将酮基泛内酯和甲酸钠的混合物,按1:8兑入软化水,将酮基泛内酯和甲酸钠、软化水混合液进行用膜进行电渗析除去甲酸钠,除去甲酸钠,后得到收率为99%的酮基泛内酯,经脱水干燥后,得到淡黄色或类白色酮基泛内酯;
S3、将酮基泛内酯与无水乙醇按1:2质量比投入配料釜中,取手性催化剂投入配料釜,搅拌混合均匀;
S4、将S3的产物压入加氢釜中,进行加氢反应,反应釜采用夹套蒸气加热升温,升温至70度,开始通入氢气,压力升至2.0Mpa,釜温度升至120度,通冷却水保持温度和氢气流速,保持温度在120度,压力在2.0Mpa,,反应约4小时完成,得到产物D-泛内酯;
S5、将D-泛内酯进行脱乙醇处理,得到收率为99%D-泛内酯产品。
优选的,催化剂制备:在氮气保护下,将[Ir(COD)Hpo3]2、配体、碱性添加物溶于溶剂中,在室温下搅拌,原位生成催化剂,[Ir(COD)Hpo3]2中铱元素与配体的摩尔比为1:1~8。
优选的,所述[Ir(COD)Hpo3]2可以替换为[Rh(COD)Hpo3]2。
优选的,所述配体为差向异构酶,所述差向异构酶是一类催化单糖分子中某一个不对称碳原子发生构型变化的酶。
优选的,所述碱性添加物为氢氧化钠、氢氧化钾、叔丁醇钾和碳酸钾的其中一种。
优选的,所述溶剂为二氯甲烷、1,2-二氯乙烷、甲醇、异丙醇、甲苯、四氢呋喃和乙醇的其中一种。
优选的,所述软化水的电导率小于10μS/cm。
本发明的有益效果是:
本发明中采用Ir(COD)Hpo3]2、配体、碱性添加物的条件下原位生成催化剂,在催化剂条件下,通入氢气对酮基泛内酯进行不对称催化氢化反应,能够得到反应活性和选择性高的手性D-泛内脂,该种合成方法氢化反应条件温和,适用于多种酮基泛内酯衍生物,底物适用范围广,且反应过程对环境污染小。
附图说明
图1为本发明酮基泛内酯合成示意图;
图2为本发明的D-泛内酯合成示意图;
具体实施方式
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施例和附图,进一步阐述本发明,但下述实施例仅仅为本发明的优选实施例,并非全部。基于实施方式中的实施例,本领域技术人员在没有做出创造性劳动的前提下所获得其它实施例,都属于本发明的保护范围。
实施例1
在本实施例中,在氮气保护下,将[Ir(COD)Hpo3]20.0065mmol,0.6mol%),手性差向异构酶配体(0.0065mmol,1.2mol%)和叔丁醇钾(0.026mmol,5.4mol%)溶于乙醇(1.2mL),室温下搅拌10分钟,加入底物酮基泛内脂(0.6mmol)的乙醇(1.2mL)溶液,将其置于高压反应釜中,氢气置换3次,然后通入氢气至20个大气压,100℃下反应24小时,慢慢释放氢气,除去溶剂后用硅胶柱分离得到产物D-泛内脂。
实施例2
在本实施例中,在氮气保护下,将Ir(COD)Hpo3]2(0.0025mmol,0.5mol%),手性差向异构酶配体(0.0050mmol,1.0mol%)和氢氧化钾(0.025mmol,5.0mol%)溶于乙醇(1.0mL),室温下搅拌10分钟,加入底物酮基泛内脂(0.5mmol)的乙醇(1.0mL)溶液,将其置于高压反应釜中,氢气置换3次,然后通入氢气至100个大气压,100℃下反应48小时,慢慢释放氢气,除去溶剂后用硅胶柱分离得到产物D-泛内脂。
实施例3
在本实施例中,在氮气保护下,将Ir(COD)Hpo3]2(0.0025mmol,0.5mol%),手性差向异构酶配体(0.0050mmol,1.0mol%)和叔丁醇钾(0.025mmolIr(COD)Hpo3]25.0mol%)溶于二氯乙烷(1.0mL),室温下搅拌10分钟,加入底物苯乙酰乙酸乙酯(0.5mmol)的二氯乙烷(1.0mL)溶液,将其置于高压反应釜中,氢气置换3次,然后通入氢气至60个大气压,100℃下反应36小时,慢慢释放氢气,除去溶剂后用电渗析分离得到产物D-泛内脂。
手性高效液相色谱的条件与实施例1相同。
实施例4
在氮气保护下,将Ir(COD)Hpo3]2(0.00025mmol,0.05mol%),手性差向异构酶配体(0.00055mmol,0.11mol%)和碳酸钾(0.025mmol,0.50mol%)溶于DMF(1.0mL),室温下搅拌10分钟,加入底物酮基泛内脂(0.5mmol)的DMF(1.0mL)溶液,将其置于高压反应釜中,氢气置换3次,然后通入氢气至20个大气压,100℃下反应24小时,慢慢释放氢气,除去溶剂后用硅胶柱分离得到产物D-泛内脂。
实施例5
在本实施例中,在氮气保护下,将Ir(COD)Hpo3]2((0.0025mmol,0.5mol%),手性差向异构酶配体(0.0055mmol,1.1mol%)和氢氧化钠(0.025mmol,5.0mol%)溶于四氢呋喃(1.0mL),室温下搅拌10分钟,加入底物酮基泛内脂(0.5mmol)的四氢呋喃(1.0mL)溶液,将其置于高压反应釜中,氢气置换3次,然后通入氢气至60个大气压,100℃下反应24小时,慢慢释放氢气,除去溶剂后用硅胶柱分离得到产物D-泛内脂。
在本发明中,除非另有明确的规定和限定,第一特征在第二特征之“上”或之“下”可以包括第一和第二特征直接接触,也可以包括第一和第二特征不是直接接触而是通过它们之间的另外的特征接触。而且,第一特征在第二特征“之上”、“上方”和“上面”包括第一特征在第二特征正上方和斜上方,或仅仅表示第一特征水平高度高于第二特征。第一特征在第二特征“之下”、“下方”和“下面”包括第一特征在第二特征正下方和斜下方,或仅仅表示第一特征水平高度小于第二特征。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的仅为本发明的优选例,并不用来限制本发明,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (7)
1.一种D-泛酸钙中间体D-泛内酯的合成工艺,其特征在于:
S1、将异丁醛、草酸二甲酯、甲醛和氢氧化钠按等摩尔质量比加入反应釜中,将温度从30度升至120度,保温4小时,蒸馏除去产物的甲醇,得产物酮基泛内酯和甲酸钠;
S2、将酮基泛内酯和甲酸钠的混合物,按1:8兑入软化水,将酮基泛内酯和甲酸钠、软化水混合液进行用膜进行电渗析除去甲酸钠,除去甲酸钠,后得到收率为99%的酮基泛内酯,经脱水干燥后,得到淡黄色或类白色酮基泛内酯;
S3、将酮基泛内酯与无水乙醇按1:2质量比投入配料釜中,取手性催化剂投入配料釜,搅拌混合均匀;
S4、将S3的产物压入加氢釜中,进行加氢反应,反应釜采用夹套蒸气加热升温,升温至70度,开始通入氢气,压力升至2.0Mpa,釜温度升至120度,通冷却水保持温度和氢气流速,保持温度在120度,压力在2.0Mpa,,反应约4小时完成,得到产物D-泛内酯;
S5、将D-泛内酯进行脱乙醇处理,得到收率为99%D-泛内酯产品。
2.根据权利要求1所述的一种D-泛酸钙中间体D-泛内酯的合成工艺,其特征在于:催化剂制备:在氮气保护下,将[Ir(COD)Hpo3]2、配体、碱性添加物溶于溶剂中,在室温下搅拌,原位生成催化剂,[Ir(COD)Hpo3]2中铱元素与配体的摩尔比为1:1~8。
3.根据权利要求2所述的一种D-泛酸钙中间体D-泛内酯的合成工艺,其特征在于:所述[Ir(COD)Hpo3]2可以替换为[Rh(COD)Hpo3]2。
4.根据权利要求2所述的一种D-泛酸钙中间体D-泛内酯的合成工艺,其特征在于:所述配体为差向异构酶,所述差向异构酶是一类催化单糖分子中某一个不对称碳原子发生构型变化的酶。
5.根据权利要求2所述的一种D-泛酸钙中间体D-泛内酯的合成工艺,其特征在于:所述碱性添加物为氢氧化钠、氢氧化钾、叔丁醇钾和碳酸钾的其中一种。
6.根据权利要求2所述的一种D-泛酸钙中间体D-泛内酯的合成工艺,其特征在于:所述溶剂为二氯甲烷、1,2-二氯乙烷、甲醇、异丙醇、甲苯、四氢呋喃和乙醇的其中一种。
7.根据权利要求1所述的一种D-泛酸钙中间体D-泛内酯的合成工艺,其特征在于:所述软化水的电导率小于10μS/cm。
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