CN116854582A - 一种对映纯α-甲氧基苯乙酸的制备方法 - Google Patents
一种对映纯α-甲氧基苯乙酸的制备方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
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Abstract
本发明提出一种对映纯α‑甲氧基苯乙酸的制备方法,所述方法为:以(R/S)‑扁桃酸为主原料,在碱试剂作用下与甲基化试剂完成O‑烷基化反应,随后通过有机碱进行成盐纯化、解离得到纯度高达99.0%对映纯α‑甲氧基苯乙酸。本发明在通过非质子性混合溶剂中得到最高产率88.6%,该工艺使甲基化试剂用量降低、转化率提高至99.5%,通过有机碱成盐纯化效率高、晶型好、易过滤。其中工艺流程简洁,安全性高,适合工业化规模生产。
Description
技术领域
本发明涉及一种对映纯α-甲氧基苯乙酸的制备方法,属于有机合成技术领域。
背景技术
对映纯α-甲氧基苯乙酸包括(R)-(-)-α-甲氧基苯乙酸和(S)-(+)-α-甲氧基苯乙酸。对映纯α-甲氧基苯乙酸主要用于绝对立体化学,手性磷配体合成的常用试剂,在医药、材料领域有广泛应用。其中(R)-(-)-α-甲氧基苯乙酸是抗肿瘤药物达鲁舍替(PHA-739358)重要中间体,达鲁舍替(PHA-739358)为Aurora激酶抑制剂,可抑制乳腺癌T47细胞增殖,诱导其凋亡的分子机制,也可抑制Aurora A/B/C IC50值分别为13nM/79nM/61nM,对Abl、TrkA、c-RET、FGFR1等靶点。(S)-(+)-α-甲氧基苯乙酸作为手性侧链,可作为金属阳离子价态传感器的材料等。
迄今为止,已报道合成对映纯α-甲氧基苯乙酸的方法有多种,如文献[Synthesis,1989,#1,39-40]报道采用(2S,3S)-(-)-3-苯基缩水甘油为原料,通过甲醇为溶剂在路易斯酸作用下开环,通过氧化剂氧化二醇、三氯化钌水合物裂解得到(R)-(-)-α-甲氧基苯乙酸。反应路线如下:
该路线方法原料价格高昂,经济性差,不适合工业化规模生产。
文献[Bioorganic and Medicinal Chemistry,2000,8,1957-1968]报道以R-扁桃酸为原料,先溶于6M氢氧化钠水溶液中,滴加硫酸二甲酯,50℃反应1小时,经后处理首先回收未反应R-扁桃酸,最后得到目标产物(R)-(-)-α-甲氧基苯乙酸,收率37%。该路线方法原料反应不完全,后处理分离困难反应路线如下:
文献[Tetrahedron Asymmetry,2003,14,503-510]报道以(R)-(-)-2-甲氧基-2-苯乙醇为原料,2,2,6,6-四甲基哌啶氧化物为催化剂,次氯酸钠氧化得到(R)-(-)-α-甲氧基苯乙酸,收率79%。该路线方法原料不易购,氧化有少量醛生成,不适合工业化生产,反应路线如下:
文献[Tetrahedron Asymmetry,2005,16,1897-1900]报道以(R)-(-)-2-甲氧基-2-苯乙醛为原料,亚氯酸钠在叔丁醇和磷酸二氢钠水缓冲液体系中氧化得到(R)-(-)-α-甲氧基苯乙酸,收率95%。该路线原料不易购,反应路线如下:
针对在上述合成路线中,原料不易购得,成本高,分离困难能因素考虑,有必要对对映纯α-甲氧基苯乙酸的合成工艺进行深入研究并优化,提供更优、安全稳定的反应路线,符合工业化生产,以满足日益增长的市场需求。
发明内容
为了克服上述技术缺陷,本发明提出一种对映纯α-甲氧基苯乙酸的制备方法。以(R/S)-扁桃酸为主原料,在碱试剂作用下与甲基化试剂完成O-烷基化反应,随后通过有机碱进行成盐纯化、解离得到纯度高达99.0%对映纯α-甲氧基苯乙酸。
通过对甲基化试剂、亲核试剂、溶剂进行筛选,得到最优试剂和反应条件,其中甲基化试剂为碘甲烷、亲核试剂为叔丁醇钾、溶剂为四氢呋喃和环丁砜混合溶剂(9:2)。本发明在通过非质子性混合溶剂中得到最高产率88.6%,该工艺使甲基化试剂用量降低、转化率提高至99.5%,通过有机碱成盐纯化效率高、晶型好、易过滤。其中工艺流程简洁,安全性高,适合工业化规模生产。
本发明所述一种对映纯α-甲氧基苯乙酸的制备方法,反应方程式表示如下:
包括如下步骤:
A、O-烷基化:将(R/S)-扁桃酸与非质子混合溶剂混合,降温加入碱试剂,然后加入甲基化试剂得到对映纯α-甲氧基苯乙酸粗品;
B、成盐/解离:向对映纯α-甲氧基苯乙酸粗品中加入有机碱,成盐,过滤,滤饼加入氢氧化钠水溶液解离,萃取有机碱,水相调节酸性后产品析出,得到对映纯α-甲氧基苯乙酸。
进一步地,在上述技术方案中,所述非质子混合溶剂选自四氢呋喃/N,N-二甲基甲酰胺、四氢呋喃/环丁砜或四氢呋喃/二甲基亚砜混合溶剂,优选四氢呋喃/环丁砜混合溶剂。
进一步地,在上述技术方案中,所述甲基化试剂选自硫酸二甲酯、溴甲烷或碘甲烷,优选碘甲烷。
进一步地,在上述技术方案中,所述碱试剂选自氢化钠、叔丁醇钾或叔丁醇钠,优选叔丁醇钾。
进一步地,在上述技术方案中,所述(R/S)-扁桃酸、甲基化试剂和碱试剂摩尔比为1:2.3-2.6:2.3-2.6。
进一步地,在上述技术方案中,所述有机碱选自二环己基胺或二异丙基胺。
发明有益效果
1、(R/S)-扁桃酸价格相对便宜,以此为原料,可大大降低成本,工艺简洁明了,操作方便,避免用到毒性更大的硫酸二甲酯,通过有机碱成盐进行纯化,避免后处理的柱层析,适合工业化规模生产。
2、非质子性溶剂(非氢键供体)溶剂,降低了(R/S)-扁桃酸亲核性,通过加入环丁砜,使反应溶解性更好,化学选择性强,亲核试剂的碱性并不会使产物的ee值发生改变。
3、通过对溶剂、亲核试剂和甲基化试剂优化后收率高达88.6%,并通过有机碱成盐纯化效率高、晶型好、易过滤等优点。
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。
条件优化实验
1、亲核试剂筛选
以四氢呋喃为溶剂、碘甲烷为甲基化试剂的条件下选用不同碱试剂,通过转化率选出相对最优的碱试剂。如表1所示:
表1亲核试剂对产物转化率的影响
注:反应均是-10~0℃,亲核试剂与甲基化试剂摩尔比例相当,并且均大大过量。
2、反应溶剂筛选:
以叔丁醇钾为碱试剂、碘甲烷为甲基化试剂的条件下选用不同混合溶剂,通过转化率选出最优反应溶剂。如表2所示:
表2混合溶剂对产物转化率的影响
3、甲基化试剂筛选:
以叔丁醇钾为碱试剂、四氢呋喃/环丁砜(9:2)条件下选用不同甲基化试剂,通过反应液反应情况选出最优甲基化试剂。如表3所示:
表3甲基化试剂对产物纯度的影响
注:硫酸二甲酯会生成过多的副产物α-甲氧基苯乙酸甲酯,并且毒性更大;溴甲烷沸点过低,工业化不易操作。
实施例1
氮气保护下,向反应瓶内加入R-扁桃酸15.2g(0.1mol)、四氢呋喃135mL和环丁砜30mL,降温至-5℃,加入叔丁醇钾11.2g(0.1mol),加入碘甲烷34.1g(0.24mol),控制温度-5~0℃分批加入叔丁醇钾15.7g(0.14mol),反应2小时,降温至-15℃,加入醋酸水溶液调节pH=6.8,静置分层,分去下层水层,有机层减压浓缩至不流液,加入二氯甲烷50mL,水洗有机相,有机相加入二环已胺18.1g(0.1mol),降温至-5~0℃,加入甲基叔丁基醚,白色固体析出,过滤,滤饼重新投入釜内,加入甲基叔丁基醚70mL,加入5%氢氧化钠调节pH=12-13,静置分层,保留水层,水相缓慢加入5%盐酸调节pH=2-3,白色固体析出,过滤得到(R)-(-)-α-甲氧基苯乙酸14.6g,收率87.9%,HPLC 99.3%。1H-NMR(400MHz,CDCl3):8.89(s,1H),7.54-7.41(m,2H),7.39-7.28(m,3H),4.53(s,1H),3.47(s,3H).
实施例2
氮气保护下,向反应瓶内加入S-扁桃酸15.2g(0.1mol)、四氢呋喃135mL和环丁砜30mL,降温至-5℃,加入叔丁醇钾11.2g(0.1mol),加入碘甲烷34.1g(0.24mol),控制温度-5~0℃分批加入叔丁醇钾15.7g(0.14mol),反应2小时,降温至-15℃,加入醋酸水溶液调节pH=6.8,静置分层,分去下层水层,有机层减压浓缩至不流液,加入二氯甲烷50mL,水洗有机相,有机相加入二异丙基胺10.1g(0.1mol),降温至-5~0℃,加入甲基叔丁基醚,白色固体析出,过滤,滤饼重新投入釜内,加入甲基叔丁基醚70mL,加入5%氢氧化钠调节pH=12-13,静置分层,保留水层,水相缓慢加入5%盐酸调节pH=2-3,白色固体析出,过滤得到(S)-(-)-α-甲氧基苯乙酸14.1g,收率84.9%,HPLC 99.1%。1H-NMR(400MHz,CDCl3):8.86(s,1H),7.51-7.42(m,2H),7.40-7.28(m,3H),4.57(s,1H),3.42(s,3H).
实施例3
氮气保护下,向反应瓶内加入R-扁桃酸15.2g(0.1mol)、四氢呋喃120mL和二甲基亚砜15mL,降温至-5℃,加入叔丁醇钾11.2g(0.1mol),加入碘甲烷34.1g(0.24mol),控制温度-5~0℃分批加入叔丁醇钾15.7g(0.14mol),反应2小时,降温至-15℃,加入醋酸水溶液调节pH=6.8,静置分层,分去下层水层,有机层减压浓缩至不流液,加入二氯甲烷50mL,水洗有机相,有机相加入二异丙基胺10.1g(0.1mol),降温至-5~0℃,加入甲基叔丁基醚,白色固体析出,过滤,滤饼重新投入釜内,加入甲基叔丁基醚70mL,加入5%氢氧化钠调节pH=12-13,静置分层,保留水层,水相缓慢加入5%盐酸调节pH=2-3,白色固体析出,过滤得到(R)-(-)-α-甲氧基苯乙酸13.3g,收率80.3%,HPLC 99.6%。
实施例4
氮气保护下,向反应瓶内加入S-扁桃酸15.2g(0.1mol)、四氢呋喃150mL和二甲基亚砜15mL,降温至-5℃,加入叔丁醇钾11.2g(0.1mol),加入碘甲烷34.1g(0.24mol),控制温度-5~0℃分批加入叔丁醇钾15.7g(0.14mol),反应2小时,降温至-15℃,加入醋酸水溶液调节pH=6.8,静置分层,分去下层水层,有机层减压浓缩至不流液,加入二氯甲烷50mL,水洗有机相,有机相加入二环已胺18.1g(0.1mol),降温至-5~0℃,加入甲基叔丁基醚,白色固体析出,过滤,滤饼重新投入釜内,加入甲基叔丁基醚70mL,加入5%氢氧化钠调节pH=12-13,静置分层,保留水层,水相缓慢加入5%盐酸调节pH=2-3,白色固体析出,过滤得到(S)-(-)-α-甲氧基苯乙酸13.5g,收率81.1%,HPLC 99.6%。
实施例5
公斤级实验
氮气保护下,向不锈钢釜内加入R-扁桃酸2.0Kg、四氢呋喃8L和环丁砜4L,降温至-8℃,分批加入叔丁醇钾1.606Kg,加入碘甲烷34.1g(0.24mol),控制温度-5~0℃缓慢滴加叔丁醇钾2.065Kg溶于四氢呋喃10L溶液,滴加结束后反应2小时,随后降温至-20℃,快速加入醋酸水溶液调节pH=6.8,静置分层,分去下层水层,有机层减压浓缩至不流液,加入二氯甲烷7L,水洗有机相,通过减压浓缩二氯甲烷替换使有机相水份<0.1%,加入二环已胺2.383Kg,降温至-5~0℃,加入甲基叔丁基醚,白色固体析出,过滤,滤饼重新投入釜内,加入甲基叔丁基醚10L,加入5%氢氧化钠调节pH=12-13,静置分层,保留水层,水相缓慢加入5%盐酸调节pH=2-3,白色固体析出,过滤得到(R)-(-)-α-甲氧基苯乙酸1.935Kg,收率88.6%,HPLC 99.5%。
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 (9)
1.一种对映纯α-甲氧基苯乙酸的制备方法,其特征在于,所述方法为:O-烷基化:将(R/S)-扁桃酸与非质子混合溶剂混合,降温加入碱试剂,然后加入甲基化试剂得到对映纯α-甲氧基苯乙酸粗品;成盐/解离:向对映纯α-甲氧基苯乙酸粗品中加入有机碱,成盐,过滤,滤饼加入氢氧化钠水溶液解离,萃取有机碱,水相调节酸性后产品析出,得到对映纯α-甲氧基苯乙酸。
2.根据权利要求1所述对映纯α-甲氧基苯乙酸的制备方法,其特征在于:所述非质子混合溶剂选自四氢呋喃/N,N-二甲基甲酰胺、四氢呋喃/环丁砜或四氢呋喃/二甲基亚砜混合溶剂。
3.根据权利要求2所述对映纯α-甲氧基苯乙酸的制备方法,其特征在于:所述非质子混合溶剂选自四氢呋喃/环丁砜混合溶剂。
4.根据权利要求1所述对映纯α-甲氧基苯乙酸的制备方法,其特征在于:所述甲基化试剂选自硫酸二甲酯、溴甲烷或碘甲烷。
5.根据权利要求4所述对映纯α-甲氧基苯乙酸的制备方法,其特征在于:所述甲基化试剂选自碘甲烷。
6.根据权利要求1所述对映纯α-甲氧基苯乙酸的制备方法,其特征在于:所述碱试剂选自氢化钠、叔丁醇钾或叔丁醇钠。
7.根据权利要求6所述对映纯α-甲氧基苯乙酸的制备方法,其特征在于:所述碱试剂选自叔丁醇钾。
8.根据权利要求1所述对映纯α-甲氧基苯乙酸的制备方法,其特征在于:(R/S)-扁桃酸、甲基化试剂和碱试剂摩尔比为1:2.3-2.6:2.3-2.6。
9.根据权利要求1所述对映纯α-甲氧基苯乙酸的制备方法,其特征在于:所述有机碱选自二环己基胺或二异丙基胺。
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