CN1215040C - 4－羧甲基－2－乙氧基苯甲酸乙酯的合成方法 - Google Patents
4－羧甲基－2－乙氧基苯甲酸乙酯的合成方法 Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims description 8
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- -1 malonate-2-ethoxy benzonitrile Chemical compound 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- WMNIMNHDKXPJPF-UHFFFAOYSA-N 2-(4-cyano-3-ethoxyphenyl)acetic acid Chemical compound CCOC1=CC(CC(O)=O)=CC=C1C#N WMNIMNHDKXPJPF-UHFFFAOYSA-N 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 6
- AJOOJWNBCFXLFS-UHFFFAOYSA-N CCOc1cc(I)ccc1C#N Chemical compound CCOc1cc(I)ccc1C#N AJOOJWNBCFXLFS-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 3
- 238000010931 ester hydrolysis Methods 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
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- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 235000010755 mineral Nutrition 0.000 claims description 3
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- 150000002148 esters Chemical class 0.000 claims description 2
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- DXTLCLWOCYLDHL-UHFFFAOYSA-N 2-ethoxybenzonitrile Chemical compound CCOC1=CC=CC=C1C#N DXTLCLWOCYLDHL-UHFFFAOYSA-N 0.000 claims 2
- AJBAIEIZLKPREH-UHFFFAOYSA-N CCOC1(C#N)CC=CC=C1 Chemical compound CCOC1(C#N)CC=CC=C1 AJBAIEIZLKPREH-UHFFFAOYSA-N 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract 2
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- 229960004909 aminosalicylic acid Drugs 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 9
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- 239000012043 crude product Substances 0.000 description 2
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- JDVUCGQRDDFTJL-UHFFFAOYSA-N 3-carbamoyl-2-methylbenzoic acid Chemical class CC1=C(C(N)=O)C=CC=C1C(O)=O JDVUCGQRDDFTJL-UHFFFAOYSA-N 0.000 description 1
- HCEQQASHRRPQFE-UHFFFAOYSA-N 5-chloro-n-[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]-2-methoxybenzamide;3-(diaminomethylidene)-1,1-dimethylguanidine;hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N.COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 HCEQQASHRRPQFE-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
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- ZLWLTDZLUVBSRJ-UHFFFAOYSA-K chembl2360149 Chemical compound [Na+].[Na+].[Na+].O=C1C(N=NC=2C=CC(=CC=2)S([O-])(=O)=O)=C(C(=O)[O-])NN1C1=CC=C(S([O-])(=O)=O)C=C1 ZLWLTDZLUVBSRJ-UHFFFAOYSA-K 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
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- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及4-羧甲基-2-乙氧基苯甲酸乙酯的合成方法。本发明以4-氨基水杨酸为起始原料，提供了一种新型的高产物收率、高纯度的4-羧甲基-2-乙氧基苯甲酸乙酯合成方法。
Description
技术领域
本发明涉及化学合成领域。具体涉及4-羧甲基-2-乙氧基苯甲酸乙酯的合成方法。
背景技术
4-羧甲基-2-乙氧基苯甲酸乙酯(I)是糖尿病新药Repaglinide的重要侧链。
Repaglinide(瑞格列奈)，化学名称(S)(+)-2-乙基-4-{[3-甲基-1-[2-(1-六氢吡啶)苯基]-丁基]-2-氧代乙基}苯甲酸(VI)，系新一类非胰岛素依赖性抗糖尿病药[Drugs of the Future 1996；21(7)：694-599]。
其结构系氨基甲酰甲基苯甲酸衍生物，是一种剂量小(0.5～4mg/d)起效快、作用时间短的，胰岛素分泌的餐时血糖调节剂。化合物I是制备Repaglinide必需的中间体，有关制备方法的报道很少。一般制备方法通过化合物VII水解得到(EP.0147850)，但VII化合物
的制备较困难，且要用到NaCN之类毒性大的化合物，不利于成品质量的控制和环保要求。
发明内容
本发明所要解决的技术问题是提供一种高收率、高纯度地合成4-羧甲基-2-乙氧基苯甲酸乙酯的方法。
本发明公开的化合物I的合成方法包括下列步骤：
以4-氨基水杨酸(VIII)为原料，通过卤化反应制得4-碘代水杨酸(II)，经酯化得4-碘-2-乙氧基苯甲酸乙酯(III)，在氯化亚铜存在下III与丙二酸二甲酯反应得4-丙二酸二甲酯-2-乙氧基苯甲酸乙酯(IV)，IV在二甲基亚砜存在下脱1份羧基得4-甲氧羰基甲基-2-乙氧基苯甲酸乙酯(V)，V在强碱醇溶液存在下选择性酯水解得产物(I)。合成路线如下：
本发明所述的化合物V选择性酯水解所用的强碱为无机碱，选自碳酸钾、氢氧化钾或氢氧化钠。强碱在醇溶液中的浓度为0.1～10％w/w，优选浓度为1～5％w/w。
本发明通过调节无机碱在醇溶液中的浓度，解决了双酯化合物V选择性水解问题，制得的产物4-羧甲基-2-乙氧基苯甲酸乙酯的纯度以HPLC测定大于98％，五步反应的总收率达25～30％。
具体实施方式
实施例1 4-碘代水杨酸制备(II)
23g的无水硫酸铜和11g铜粉110g碘化钾被加入到220ml水中搅拌，室温下加入20％的硫酸溶液200ml，反应1hr，冷却至5℃即得CuI。
在另一反应瓶中加入22g 4-氨基水杨酸和50％的硫酸溶液400ml搅拌成浆状，冷却至0℃，慢慢滴加11g亚硝酸钠与72ml水配成的溶液，温度控制在0～5℃加完，反应10min，将此反应液倾入到上述制备好的CuI中，反应1hr，过滤得黄色固体物。
将固体物用150ml乙醇加热溶解，过滤，滤液减压浓缩至100ml左右体积加入100ml水，自然冷却结晶，10℃左右过滤，水洗，真空干燥得棕黄色固体(II)30g。mp：225～230℃(分解)
实施例2 4-碘-2-乙氧基苯甲酸乙酯制备(III)
在反应瓶中投入36g 4-碘代水杨酸(II)和94g碳酸钾和400ml水的溶液，搅拌加入10g四丁基碘化铵和100g碘乙烷，30℃反应6hrs分出有机相、水相用乙酸乙酯提取合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩至溶剂尽，加入20ml乙醇，结晶，0℃过滤，得淡黄色结晶(III)30g。HPLC≥95％.
实施例3 4-丙二酸二甲酯-2-乙氧基苯甲酸乙酯制备(IV)
在反应瓶中投入18g氯化亚铜和21g 4-碘-2-乙氧基苯甲酸乙酯(III)和25g丙二酸二甲酯和50ml二甲基甲酰胺搅拌冷却至0℃加入60％氢化钠5g，在室温反应1hr，加入100ml二氯甲烷，滤去固体物，滤液用稀盐酸洗，再用水洗有机层，无水硫酸钠干燥，过滤，减压浓缩至溶剂尽，加入30ml石油醚结晶，过滤得白色结晶(IV)19g。HPLC≥96％
NMR(CDCl3)δ：1.36～1.45(6H m CH2CH3×2).3.75(6H s OCH3×2).4.13(2H dd OCH2CH3).4.35(2H dd COOCH2CH3).4.64[H sCH(COOCH3)2].6.97～7.05(2H m苯环).7.75(H d苯环).
实施例4 4-甲氧羰基甲基-2-乙氧基苯甲酸乙酯制备(V)
在反应瓶中投入19g(准备实例3产物)70ml二甲基亚砜加热至150℃反应2hrs，冷却加入200ml水用乙酸乙酯提取，有机相用水洗，无水硫酸钠干燥，过滤，减压浓缩至溶剂尽得理论量产物(V)。
NMR(CDCl3)δ：1.3～1.5(6H m CH2CH3×2).3.3(2H s CH2COOH)3.6(3H s OCH3).4.1(2H dd OCH2CH3).4.3(2H dd COOCH2CH3).6.9～7.1(2H m苯环).7.6(H d苯环).
实施例5 4-羧甲基-2-乙氧基苯甲酸乙酯得制备(I)
在反应瓶中投入14g 4-甲氧羰基甲基-2-乙氧基苯甲酸乙酯(V)和40ml 5％的碳酸钾的乙醇溶液，在20℃搅拌反应20hrs，冷却至0℃，用10％盐酸酸化至PH1.5减压浓缩至溶剂尽，得盐和油状物，加入150ml水，溶去盐，过滤，得淡黄色结晶粗品，粗品用2％～3％碳酸氢钠溶解，用乙酸乙酯提取水相，活性炭脱色后，用10％盐酸酸化至PH1～1.5结晶，过滤，水洗，得白色结晶，真空干燥得成品(I)8g。HPLC≥98％
NMR(CDCl3)δ：1.34～1.46(6H m CH3×2).3.64(2H sCH2COOH).4.1(2H dd OCH2CH3).4.35(2H ddCOOCH2CH3).6.88(2H m苯环).7.74(1H d苯环)10(1H COOH).
实施例6 4-羧甲基-2-乙氧基苯甲酸乙酯的制备(I)
在反应瓶中投入14g 4-甲氧羰基甲基-2-乙氧基苯甲酸乙酯(V)和280ml 1％的氢氧化钾的甲醇溶液，在10℃反应10hrs补加1％氢氧化钾的甲醇溶液150ml，再反应10hrs，后处理同实例1，得(I)7.5g成品。HPLC≥98％。
Claims (4)
1、4-羧甲基-2-乙氧基苯甲酸乙酯的合成方法，其特征在于该化合物以4-氨基水杨酸(VIII)为原料，通过与CuI反应制得4-碘代水杨酸(II)，经与碘乙烷反应得4-碘-2-乙氧基苯甲酸乙酯(III)，在氯化亚铜存在下III与丙二酸二甲酯反应得4-丙二酸二甲酯-2-乙氧基苯甲酸乙酯(IV)，IV在二甲基亚砜存在下脱1份羧基得4-甲氧羰基甲基-2-乙氧基苯甲酸乙酯(V)，V在强碱醇溶液存在下选择性酯水解，其中强碱在醇溶液中的浓度为0.1-10％w/w，从而获得产物。
2、如权利要求1所述的4-羧甲基-2-乙氧基苯甲酸乙酯的合成方法，其特征在于其中所述的化合物4-甲氧羰基甲基-2-乙氧基苯甲酸乙酯(V)选择性酯水解所用的强碱为无机碱。
3、如权利要求1或2所述的4-羧甲基-2-乙氧基苯甲酸乙酯的合成方法，其特征在于其中所述的强碱选自碳酸钾、氢氧化钾或氢氧化钠。
4、如权利要求1所述的4-羧甲基-2-乙氧基苯甲酸乙酯的合成方法，其特征在于其中所述强碱在醇溶液中的浓度为1～5％w/w。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US11999670B2 (en) | 2019-11-13 | 2024-06-04 | Profile Products Llc | Delivery of bioactive molecules in coatings or surface layers of organically enhanced inorganic fertilizers |
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| DE102008046995B4 (de) * | 2008-09-12 | 2010-08-26 | Stada Arzneimittel Ag | 2-Ethoxy-benzoesäurederivat |
| CN103880679B (zh) * | 2014-03-13 | 2015-02-11 | 河北科技大学 | 3-乙氧基-4-乙氧羰基苯乙酸的合成方法 |
| CN107868005A (zh) * | 2016-09-28 | 2018-04-03 | 齐鲁工业大学 | 一种羧酸化合物的晶体结构及荧光性能 |
| CN112079712B (zh) * | 2020-09-18 | 2022-12-13 | 江苏美迪克化学品有限公司 | 一种对乙烯基水杨酸的制备方法 |
| CN115420826B (zh) * | 2022-08-30 | 2023-05-30 | 北京悦康科创医药科技股份有限公司 | 一种枸橼酸爱地那非原料药中起始物料邻乙氧基苯甲酸中杂质的分离检测方法 |
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| US11999670B2 (en) | 2019-11-13 | 2024-06-04 | Profile Products Llc | Delivery of bioactive molecules in coatings or surface layers of organically enhanced inorganic fertilizers |
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