CN115028529A - 一种4-环丙基取代的苯甲酸类似物的制备方法 - Google Patents
一种4-环丙基取代的苯甲酸类似物的制备方法 Download PDFInfo
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- 150000001558 benzoic acid derivatives Chemical class 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 28
- 239000003960 organic solvent Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 18
- -1 4-cyclopropyl-substituted benzoic acid Chemical class 0.000 claims abstract description 15
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 48
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 18
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims description 18
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- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 14
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 13
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- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000003849 aromatic solvent Substances 0.000 claims description 3
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 3
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- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
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- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
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- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000005580 one pot reaction Methods 0.000 description 4
- SEVSMVUOKAMPDO-UHFFFAOYSA-N para-Acetoxybenzaldehyde Natural products CC(=O)OC1=CC=C(C=O)C=C1 SEVSMVUOKAMPDO-UHFFFAOYSA-N 0.000 description 4
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- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical class [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 2
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- 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
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
本发明公开了一种4‑环丙基取代的苯甲酸类似物的制备方法,在有机溶剂中,一定温度下以4‑甲酰基苯甲酸酯为原料经由缩合、环合、脱氮三步反应得到产物4‑环丙基取代的苯甲酸类似物。本发明方法原料来源多且成本优势明显,制备方法更加安全、方便,总收率高且三废较少,无相关高危工艺及不需要贵金属催化剂,有利于工业化。
Description
技术领域
本发明涉及一种4-环丙基取代的苯甲酸类似物的制备方法,具体涉及一种以4-甲酰基苯甲酸酯为原料经由缩合、环合、脱氮三步反应得到产物4-环丙基取代的苯甲酸类似物的方法。
背景技术
4-环丙基取代的苯甲酸类似物是一类重要的医药中间体模块。文献中报道的合成方法主要采用4-烯基苯甲酸酯和卡宾类似物或者前体在贵金属催化剂催化下环合而成,过程涉及不稳定卡宾前体的制备及贵金属催化剂的使用,安全性、单位时间内产能不好控制;放量成本较高。
发明内容
本发明所要解决的技术问题是针对现有技术中存在的不足,而提供一种4-环丙基取代的苯甲酸类似物的制备方法,在有机溶剂中,一定温度下以4-甲酰基苯甲酸酯为原料经由缩合、环合、脱氮三步反应得到产物4-环丙基取代的苯甲酸类似物。
为了实现上述目的,本发明采用如下技术方案:一种4-环丙基取代的苯甲酸类似物的制备方法,包括以下步骤:
(1)在有机溶剂中,一定温度下加入4-甲酰基苯甲酸酯和甲基酮、催化剂A进行缩合反应得到产物烯酮中间体I;
(2)在有机溶剂中,一定温度下加入烯酮中间体I和水合肼进行环合反应得到产物吡唑中间体II;
(3)在有机溶剂中,一定温度下加入吡唑中间体II和催化剂B进行脱氮反应得到产物4-环丙基取代的苯甲酸类似物;
反应式为:
其中,R1、R2为烷基、环烷基、芳基、酯基、硝基、烯基等;其中的烷基为甲基、乙基、丙基等饱和取代基。
上述技术方案中,制备方法具体为:
(1)在氮气保护下向反应容器中依次加入有机溶剂、4-甲酰基苯甲酸酯、甲基酮、催化剂A,搅拌均匀后升至设定温度;在此温度下保温至总物料中4-甲酰基苯甲酸酯液相色谱归一含量<1%;脱溶后降温、结晶烘干得到烯酮中间体I;
(2)在氮气保护下向反应容器中依次加入有机溶剂、烯酮中间体I、水合肼,搅拌均匀后升至设定温度;在此温度下保温至总物料中烯酮中间体I液相色谱归一含量<1%;脱溶后降温、结晶烘干得到吡唑中间体II;
(3)在氮气保护下向反应容器中依次加入有机溶剂、吡唑中间体II、催化剂B,搅拌均匀后升至设定温度;在此温度下保温至总物料中吡唑中间体II液相色谱归一含量<1%;脱溶后降温、结晶烘干得到4-环丙基取代的苯甲酸类似物;
上述技术方案中,步骤(1)中,所述的4-甲酰基苯甲酸酯、甲基酮的摩尔比为1:1-5,所述的有机溶剂的用量和4-甲酰基苯甲酸酯的摩尔比为1-10:1,所述的4-甲酰基苯甲酸酯、催化剂A的摩尔比为1-20:1;步骤(2)中,所述的烯酮中间体I、水合肼的摩尔比为1:1-5,所述的有机溶剂的用量和烯酮中间体I的摩尔比为1-10:1;步骤(3)中,所述的吡唑中间体II、催化剂B的摩尔比为1-20:1,所述的有机溶剂的用量和吡唑中间体II的摩尔比为1-10:1。
上述技术方案中,步骤(1)(2)中所述的反应温度为0—100℃;步骤(3)中所述的反应温度为100—220℃。
上述技术方案中,步骤(1)、(2)、(3)中所述的有机溶剂为卤代烃类溶剂、芳香族类溶剂、醚类溶剂、酯类溶剂或醇类溶剂、含杂原子的强极性溶剂中的任意一种。
上述技术方案中,步骤(1)中所述的催化剂A为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、氢化钠、甲醇钠、叔丁醇钠、叔丁醇钾中的任意一种或者两种混合物。
步骤(3)中所述的催化剂B为碱和金属盐的复合物,碱包括氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、氢化钠、甲醇钠、叔丁醇钠、叔丁醇钾中的任意一种或者两种混合物;金属盐包括氯化亚铜、碘化亚铜、氯化亚铁、氯化铝、硫酸铜等非贵金属。
优选的,所述的卤代烃类溶剂为二氯甲烷、二氯乙烷等,所述的芳香族类溶剂为甲苯、二甲苯等,所述的醚类溶剂为四氢呋喃等,所述的酯类溶剂为乙酸甲酯、乙酸乙酯等,所述的醇类溶剂为甲醇、乙醇、乙二醇等,所述的含杂原子的强极性溶剂DMF、DMA、DMSO、NMP、环丁砜、DMI等。
上述技术方案中,步骤(1)、(2)中,所述的反应温度优选为50-80℃;步骤(3)中,所述的反应温度优选为150-180℃
本发明方法原料来源多且成本优势明显,制备方法更加安全、方便,总收率高且三废较少,无相关高危工艺及不需要贵金属催化剂,有利于工业化。
具体实施方式
以下对本发明技术方案的具体实施方式详细描述,但本发明并不限于以下描述内容:
实施例1:4-甲基环丙基苯甲酸
小试制备目标产物:
(1)500mL反应釜中投入4-甲酰基苯甲酸甲酯16.4g(0.10mol)、甲醇30mL、丙酮10.6g(0.2mol)、催化剂A固体2g,加热至50度搅拌反应12h,减压回收甲醇和丙酮混合液(直接套用至下一批反应),回收率90%,加入50mL水,调pH=7,乙酸乙酯萃取、脱溶得>98%的烯酮中间体16.3g,收率80%;
(2)500mL反应釜中投入烯酮中间体20.4g(0.10mol)、乙醇30mL、80%水合肼6.25g(0.1mol),加热至50度搅拌反应4h,减压回收乙醇(直接套用至下一批反应),回收率90%,加入50mL水,调pH=7,乙酸乙酯萃取、脱溶得>95%的吡唑中间体19g,收率93%;
(3)500mL反应釜中投入吡唑中间体20.4g(0.10mol)、NMP 50mL、催化剂B1g,加热至160度搅拌反应8h,减压回收NMP(直接套用至下一批反应),回收率90%,加入50mL水,调pH=7,乙酸乙酯萃取、脱溶得>99%的目标产物4-甲基环丙基苯甲酸15g,收率85%。
实施例2:4-甲基异丁基环丙基苯甲酸
小试制备目标产物:
(1)500mL反应釜中投入4-甲酰基苯甲酸甲酯16.4g(0.10mol)、甲醇30mL、甲基异丁基酮20g(0.2mol)、催化剂A固体2g,加热至50度搅拌反应12h,减压回收甲醇和甲基异丁基酮混合液(直接套用至下一批反应),回收率92%,加入50mL水,调pH=7,乙酸乙酯萃取、脱溶得>96%的烯酮中间体20g,收率81.3%;
(2)500mL反应釜中投入烯酮中间体24.6g(0.10mol)、异丙醇30mL、80%水合肼12.5g(0.2mol),加热至50度搅拌反应4h,减压回收异丙醇和水合肼(直接套用至下一批反应),回收率93%,加入50mL水,调pH=7,乙酸乙酯萃取、脱溶得>97%的吡唑中间体19.8g,收率80.5%;
(3)500mL反应釜中投入吡唑中间体24.6g(0.10mol)、DMSO 50mL、催化剂B1g,加热至180度搅拌反应8h,减压回收DMSO(直接套用至下一批反应),回收率94%,加入50mL水,调pH=7,乙酸乙酯萃取、脱溶得>97%的目标产物4-甲基异丁基环丙基苯甲酸16g,收率73.4%。
实施例3:一锅法制备4-甲基环丙基苯甲酸
小试一锅法制备目标产物过程:
(1)500mL反应釜中投入4-甲酰基苯甲酸甲酯16.4g(0.10mol)、甲醇30mL、丙酮10.6g(0.2mol)、催化剂A固体2g,加热至50度搅拌反应12h,直接进入下一步;
(2)上述反应瓶滴加80%水合肼6.25g(0.1mol),加热至50度搅拌反应4h,减压回收甲醇和水合肼(直接套用至下一批反应),回收率90%,直接进入下一步;
(3)上述反应瓶中投入NMP 50mL、催化剂B1g,加热至190度搅拌反应4h,减压回收NMP(直接套用至下一批反应),加入50mL水,调pH=3,降温抽滤得>99%的目标产物4-甲基环丙基苯甲酸10g,三步总收率56.8%。
实施例4:一锅法中试制备4-甲基环丙基苯甲酸
中试一锅法制备目标产物过程:
(1)1000L不锈钢反应釜中投入4-甲酰基苯甲酸甲酯164kg(1kmol)、甲醇300kg、控制40度滴加丙酮106kg(2kmol)、催化剂A固体2kg,滴加完搅拌反应12h,直接进入下一步;
(2)上述反应瓶40度滴加80%水合肼62.5kg(1kmol),滴加完保温搅拌反应4h,减压回收甲醇和水合肼(直接套用至下一批反应),回收率90%,直接进入下一步;
(3)上述反应瓶中投入NMP 500kg、催化剂B1kg,加热至190度搅拌反应12h,减压回收NMP(直接套用至下一批反应),加入500L水,调pH=3,降温抽滤得>99%的目标产物4-甲基环丙基苯甲酸93kg,三步总收率52.8%。
上述实例只是为说明本发明的技术构思以及技术特点,并不能以此限制本发明的保护范围。凡根据本发明的实质所做的等效变换或修饰,都应该涵盖在本发明的保护范围之内。
Claims (8)
2.根据权利要求1所述的4-环丙基取代的苯甲酸类似物的制备方法,其特征在于,包括以下步骤:
(1)在氮气保护下向反应容器中依次加入有机溶剂、4-甲酰基苯甲酸酯、甲基酮、催化剂A,搅拌均匀后升至设定温度;在此温度下保温至总物料中4-甲酰基苯甲酸酯液相色谱归一含量<1%;脱溶后降温、结晶烘干得到烯酮中间体I;
(2)在氮气保护下向反应容器中依次加入有机溶剂、烯酮中间体I、水合肼,搅拌均匀后升至设定温度;在此温度下保温至总物料中烯酮中间体I液相色谱归一含量<1%;脱溶后降温、结晶烘干得到吡唑中间体II;
(3)在氮气保护下向反应容器中依次加入有机溶剂、吡唑中间体II、催化剂B,搅拌均匀后升至设定温度;在此温度下保温至总物料中吡唑中间体II液相色谱归一含量<1%;脱溶后降温、结晶烘干得到4-环丙基取代的苯甲酸类似物。
3.根据权利要求2所述的4-环丙基取代的苯甲酸类似物的制备方法,其特征在于,步骤(1)中所述的4-甲酰基苯甲酸酯、甲基酮的摩尔比为1:1-5,所述的有机溶剂的用量和4-甲酰基苯甲酸酯的摩尔比为1-10:1,所述的4-甲酰基苯甲酸酯、催化剂A的摩尔比为1-20:1;步骤(2)中,所述的烯酮中间体I、水合肼的摩尔比为1:1-5,所述的有机溶剂的用量和烯酮中间体I的摩尔比为1-10:1;步骤(3)中,所述的吡唑中间体II、催化剂B的摩尔比为1-20:1,所述的有机溶剂的用量和吡唑中间体II的摩尔比为1-10:1。
4.根据权利要求2所述的4-环丙基取代的苯甲酸类似物的制备方法,其特征在于,步骤(1)和步骤(2)中所述的反应温度为0—100℃;(3)中所述的反应温度为100—220℃。
5.根据权利要求2所述的4-环丙基取代的苯甲酸类似物的制备方法,其特征在于,步骤(1)、步骤(2)、步骤(3)中所述的有机溶剂为卤代烃类溶剂、芳香族类溶剂、醚类溶剂、酯类溶剂或醇类溶剂、含杂原子的强极性溶剂中的任意一种。
6.根据权利要求2所述的4-环丙基取代的苯甲酸类似物的制备方法,其特征在于,步骤(1)中所述的催化剂A为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、氢化钠、甲醇钠、叔丁醇钠、叔丁醇钾中的任意一种或者两种混合物。
7.根据权利要求2所述的4-环丙基取代的苯甲酸类似物的制备方法,其特征在于,步骤(3)中所述的催化剂B为碱和金属盐的复合物。
8.根据权利要求7所述的4-环丙基取代的苯甲酸类似物的制备方法,其特征在于,所述碱包括氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、氢化钠、甲醇钠、叔丁醇钠、叔丁醇钾中的任意一种或者两种混合物;所述金属盐包括氯化亚铜、碘化亚铜、氯化亚铁、氯化铝、硫酸铜的任意一种或者两种混合物。
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