CN111233685B - 一种外消旋d/l-叔亮氨酸的制备方法 - Google Patents
一种外消旋d/l-叔亮氨酸的制备方法 Download PDFInfo
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- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
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Abstract
本发明公开了一种外消旋D/L‑叔亮氨酸的制备方法,属于有机合成技术领域。以叔丁基丙酮酸为原料,经过两步反应得到外消旋D/L‑叔亮氨酸。第一步与NH2‑P缩合反应生成席夫碱。第二步对席夫碱进行还原,随后用酸脱保护,碱调节至等电点,得到外消旋D/L‑叔亮氨酸。该方法操作简便,反应收率高,得到的外消旋体纯度可达99%以上。
Description
技术领域
本发明涉及一种外消旋D/L-叔亮氨酸的制备方法,属于有机合成技术领域。
背景技术
外消旋D/L-叔亮氨酸,英文名:2-amino-3,3-dimethylbutanoic acid,CAS:33105-81-6。外消旋D/L-叔亮氨酸是非天然氨基酸,特有的位阻和疏水性,使得其在化学和生物学上得到广泛应用,叔亮氨酸的衍生物可在不对称合成中作为诱导不对称的模板,以其对多肽药物的修饰,从而使多肽药物达到提高药效的作用。因此在药物和生物应用中正迅速地发展,用与抗癌、抗艾滋病等药物和生物抑制剂H及肽等。
目前该化合物呈现出越来越多的应用价值,然而该化合物的合成文献报道不多,其中文献[US2012/245379,2012,A1]和[EP2502896,2012,A1]报道了主要采用D或L构型的叔亮氨酸为原料,与碱-氨水高温下消旋化得到外消旋D/L-叔亮氨酸,收率92%。
文献[Tetrahedron Letters,1986,vol.27,#48,p.5865-5868]报道了主要采用频哪酮为原料,经氧化后与苯基肼合成腙,再钯碳条件下高压加氢得到外消旋D/L-叔亮氨酸。该方法用到钯碳,成本较高,且需要高压设备。
因此有必要开发外消旋D/L-叔亮氨酸的合成方法,寻找合成简便、易纯化、操作安全,能够适合工业化放大的制备工艺。
发明内容
为了克服上述技术缺陷,本发明提供了一种以叔丁基丙酮酸为原料,经过两步反应得到外消旋D/L-叔亮氨酸。第一步与NH2-P缩合反应生成席夫碱。第二步对席夫碱进行还原,随后用酸脱保护,碱调节至等电点,得到外消旋D/L-叔亮氨酸。该方法操作简便,反应收率高,得到的外消旋体纯度可达99%以上。
本发明提供的外消旋D/L-叔亮氨酸的制备方法,包括如下步骤:
第一步:缩合反应
将叔丁基丙酮酸和NH2-P溶于有机溶剂中加热分水缩合生成席夫碱;
第二步:还原、脱保护
将第一步得到的席夫碱溶于有机溶剂中,加入还原剂反应,经酸解脱保护,接着加碱调节到等电点后,得到外消旋D/L-叔亮氨酸。
采用反应方程式表示如下:
进一步地,在上述技术方案中,第一步中所述NH2-P选自氨基甲酸叔丁酯或三苯基甲胺。P为Boc或Tr(三苯甲基)。
进一步地,在上述技术方案中,第一步中所述有机溶剂选自甲苯、二氧六环、二甲苯或其任意比例的混合物。
进一步地,在上述技术方案中,第一步中加入催化剂可加速缩合反应,所述催化剂选自无水硫酸酮或对甲苯磺酸。
进一步地,在上述技术方案中,第一步中,所述叔丁基丙酮酸与路易斯酸质量比为1:0.1-0.05;叔丁基丙酮酸与NH2-P摩尔比为1:1.05-1.12。
进一步地,在上述技术方案中,第二步中还原剂选自硼氢化钠或硼氢化锂。
进一步地,在上述技术方案中,第二步中还原剂加入摩尔量为叔丁基丙酮酸的1.0-2.0。
进一步地,在上述技术方案中,第二步所述有机溶剂选自2-甲基四氢呋喃或四氢呋喃。
进一步地,在上述技术方案中,第二步脱保护酸选自盐酸或氢溴酸;
进一步地,在上述技术方案中,第二步碱选自氢氧化钾、碳酸钾、氢氧化钠或碳酸钠;等电点为pH=5.9-6.2。
发明有益效果
本发明以叔丁基丙酮酸为原料,经过两步步反应完成。第一步与保护的氨基缩合反应生产席夫碱。第二步对席夫碱还原,再在酸性条件下脱除氨基的保护基团,最后用碱调节pH到等电点得到外消旋D/L-叔亮氨酸。该方法操作简便,反应收率高,得到的纯度及含量大于99%,单一杂质小于0.2%,外消旋D/L-叔亮氨酸为0-1.5%ee,具备潜在的工艺放大前景。
具体实施例
下面通过具体实例对本发明进行进一步说明。
这些实施例应理解为仅用于说明本发明而不用于限制本发明的保护范围。在阅读了本发明记载的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等效变化和修改同样落入本发明权利要求所限定的范围。
本发明以下实施例中未注明具体条件的实验方法,通常按照常规条件进行。
本发明以下实施例中所用的原料或试剂除特别说明之外,均市售可得。
本发明以下实施例中所述的室温均值20-25℃。除非特别指出,所述的试剂不特别说明均为不经纯化直接使用。所有溶剂均购自商业化供应商,并且不经处理就可使用。反应通过TLC、HPLC分析,通过起始材料的消耗来判断反应的终止。
第一步:2-P-亚氨基-3,3-二甲基丁酸的合成
实施例1
在氮气保护下,向反应瓶内投入叔丁基丙酮酸130.2g(1.0mol)、对甲苯磺酸6.5g和甲苯500mL。搅拌下升温至50-55℃,缓慢滴加含氨基甲酸叔丁酯140g(1.2mol,1.2eq)的甲苯溶液。滴加结束后,内温40-55℃条件下真空回流分水3小时,TLC检测原料消失(HPLC检测原料<0.4%)。反应结束后浓缩除去甲苯,替换成乙醇,加入正庚烷打浆,过滤得到席夫碱2-叔丁氧羰基亚氨基-3,3-二甲基丁酸204g,收率89%,HPLC纯度98.8%。1HNMR(400MHz,CDCl3):11.3(s,1H),1.4(s,9H),1.1(s,9H).
实施例2
向反应瓶内投入叔丁基丙酮酸130.2g(1mol)、对甲苯磺酸6.5g和二氧六环450mL。搅拌下升温至50-55℃,缓慢滴加含氨基甲酸叔丁酯140g(1.2mol,1.2eq)的二氧六环溶液,滴加结束后,升温至回流,蒸出约110mL溶剂,HPLC检测原料<0.4%。反应结束后浓缩除去二氧六环,替换成乙醇,加入正庚烷打浆,过滤得到席夫碱2-叔丁氧羰基亚氨基-3,3-二甲基丁酸202.7g,收率88.4%,HPLC纯度99.3%。
实施例3
在氮气保护下,向反应瓶内投入三甲基丙酮酸130.2g(1mol)、无水硫酸酮13g和二甲苯500mL。搅拌下升温至50-55℃,缓慢滴加含三苯基甲胺273g(1.05eq)的二甲苯溶液,滴加结束后,内温60-55℃条件下真空回流分水3小时,HPLC检测原料<0.5%。反应结束后过滤,滤液浓缩除去二甲苯和N-甲基四氢吡咯,替换成甲醇,降温至15-20℃,打浆1小时后过滤得到席夫碱2-三苯基甲基亚氨基-3,3-二甲基丁酸339.2g,收率91.3%,HPLC纯度99.1%。1HNMR(400MHz,CDCl3):12.4(s,1H),7.30-7.18(m,15H),0.98(s,9H).
实施例4
在氮气保护下,向反应瓶内投入叔丁基丙酮酸130.2g(1mol)和二甲苯1200mL。搅拌下升温至50-55℃,缓慢滴加含三苯基甲胺280g(1.08eq)的二氧六环溶液,滴加结束后,控制内温100-108℃条件下微真空回流分水22小时,HPLC检测原料<0.8%。反应结束后过滤,滤液浓缩除去二甲苯和二氧六环,替换成甲醇,降温至15-20℃,打浆1小时后过滤得到席夫碱2-三苯基甲基亚氨基-3,3-二甲基丁酸324.3g,收率87.3%,HPLC纯度99.7%。
第二步:外消旋D/L-叔亮氨酸的合成
实施例5
在氮气保护下,向反应瓶内投入2-叔丁氧羰基亚氨基-3,3-二甲基丁酸115g(0.5mol,1eq)和600mL乙醇,降温至0-5℃,2小时内分批加入硼氢化钠30.3g(0.8mol,1.6eq),控制温度0-5℃下反应2小时,缓慢升温至室温反应2小时,取样TLC检测无原料剩余,减压浓缩除去乙醇。加入1000mL 2-甲基四氢呋喃和300mL水,加入氢溴酸调节pH=6-7,静置分出水相并收集有机相,萃取后的有机相加入100mL水,升温至25-35℃,加入氢溴酸溶液调pH=1-2,搅拌反应2小时,TLC检测保护脱掉,有机相降温至5-10℃,加入2M氢氧化钠调pH=12-12.5,静置分出有机相并收集水相,水相加入氢溴酸溶液调pH=5.9-6.2,室温搅拌,有大量固体析出,过滤,少量去离子水进行漂洗,烘干得到外消旋D/L-叔亮氨酸54.9g,收率83.7%,HPLC纯度99.5%,外标含量98.7%,溶清度合格。
实施例6
在氮气保护下,向反应瓶内投入2-三苯基甲基亚氨基-3,3-二甲基丁酸185.8g(0.5mol,1eq)和900mL异丙醇。降温至0-5℃,2小时内分批加入硼氢化锂12g(0.55mol,1.1eq),控制温度0-5℃下反应2小时,缓慢升温至室温反应0.5小时,取样TLC检测无原料剩余,加入氢溴酸溶液调pH=6-7,减压浓缩除去异丙醇。加入1000mL四氢呋喃和200mL水,过滤,滤液静置分出水相并收集有机相,萃取后的有机相加入100mL水,升温至25-35℃,加入氢溴酸溶液调节pH=1-2反应2小时,TLC检测保护脱掉,有机相降温至5-10℃,加入2M氢氧化钠调pH>12,静置分出有机相并收集水相,水相用氢溴酸调pH=5.9-6.2,室温搅拌,有大量固体析出,过滤,少量去离子水和正庚烷进行漂洗,烘干得到外消旋D/L-叔亮氨酸58.4g,收率89.1%,HPLC纯度99.3%,外标含量98.6%,溶清度合格。
实施例7
在氮气保护下,向反应瓶内投入2-三苯基甲基亚氨基-3,3-二甲基丁酸185.8g(0.5mol,1eq)和800mL乙醇,降温至0-5℃,2小时内分批加入硼氢化钠34.1g(0.9mol,1.8eq),控制温度0-5℃下反应2小时,缓慢升温至室温反应0.5小时,取样TLC检测无原料剩余,加入4M盐酸调pH=6-7,减压浓缩除去乙醇。加入1000mL 2-甲基四氢呋喃和200mL水,过滤,滤液静置分出水相并收集有机相,萃取后的有机相加入100mL水,升温至25-35℃,加入4M盐酸调pH=1-2,搅拌反应2小时,TLC检测保护脱掉,有机相降温至5-10℃,加入2M氢氧化钾调pH=11-12,静置分出有机相并收集水相,水相用4M盐酸调pH=5.9-6.2,室温搅拌,有大量固体析出,加入2-甲基四氢呋喃萃取500mL萃取,共萃取两次,合并有机相浓缩至不流液,加入少量去离子水和200mL正庚烷打浆,过滤,烘干得到外消旋D/L-叔亮氨酸60.2g,收率91.8%,HPLC纯度99.6%,外标含量99.0%,溶清度合格。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明披露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (6)
2.根据权利要求1所述外消旋D/L-叔亮氨酸的制备方法,其特征在于:第一步中,所述三甲基丙酮酸与催化剂质量比为1:0.1-0.05;三甲基丙酮酸与NH2-P摩尔比为1:1.05-1.12。
3.根据权利要求1所述外消旋D/L-叔亮氨酸的制备方法,其特征在于:第二步中,还原剂选自硼氢化钠或硼氢化锂。
4.根据权利要求1所述外消旋D/L-叔亮氨酸的制备方法,其特征在于:第二步中,还原剂加入摩尔量为三甲基丙酮酸的1.0-2.0。
5.根据权利要求1所述外消旋D/L-叔亮氨酸的制备方法,其特征在于:第二步中,有机溶剂选自四氢呋喃或2-甲基四氢呋喃。
6.根据权利要求1所述外消旋D/L-叔亮氨酸的制备方法,其特征在于:第二步中,碱选自氢氧化钾、碳酸钾、氢氧化钠或碳酸钠;等电点为pH=5.9-6.2。
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