CN117534613A - 一种3-氨基吡啶-2-羧酸甲酯的制备方法 - Google Patents
一种3-氨基吡啶-2-羧酸甲酯的制备方法 Download PDFInfo
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- YQKTYFNLRUWQFV-UHFFFAOYSA-N methyl 3-aminopyridine-2-carboxylate Chemical compound COC(=O)C1=NC=CC=C1N YQKTYFNLRUWQFV-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title abstract description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000004327 boric acid Substances 0.000 claims abstract description 20
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 9
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- HOHHVJXGJVLBRW-UHFFFAOYSA-N (2-methoxycarbonylpyridin-3-yl)boronic acid Chemical compound COC(=O)C1=NC=CC=C1B(O)O HOHHVJXGJVLBRW-UHFFFAOYSA-N 0.000 description 1
- OSSIORZYXTUXBL-UHFFFAOYSA-N 2-methoxycarbonylpyridine-3-carboxylic acid Chemical compound COC(=O)C1=NC=CC=C1C(O)=O OSSIORZYXTUXBL-UHFFFAOYSA-N 0.000 description 1
- BOOMHTFCWOJWFO-UHFFFAOYSA-N 3-aminopyridine-2-carboxylic acid Chemical compound NC1=CC=CN=C1C(O)=O BOOMHTFCWOJWFO-UHFFFAOYSA-N 0.000 description 1
- PRENKBUQKMUCHQ-UHFFFAOYSA-N 3-methoxycarbonylpyridine-2-carboxylic acid Chemical compound COC(=O)C1=CC=CN=C1C(O)=O PRENKBUQKMUCHQ-UHFFFAOYSA-N 0.000 description 1
- ZYFDNIOIEFZULT-UHFFFAOYSA-N 3-sulfanylpyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1S ZYFDNIOIEFZULT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
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- 206010028980 Neoplasm Diseases 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
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- 229930029653 phosphoenolpyruvate Natural products 0.000 description 1
- DTBNBXWJWCWCIK-UHFFFAOYSA-N phosphoenolpyruvic acid Chemical compound OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种3‑氨基吡啶‑2‑羧酸甲酯的制备方法，属于精细化工技术领域。本发明以2‑羧酸吡啶为原料，与LDA和硼酸酯反应得到2‑羧酸吡啶‑3‑硼酸；随后与甲醇酯化反应得到2‑甲氧羰基吡啶‑3‑硼酸，最后在氧化亚铜作用下与氨水反应得到3‑氨基吡啶‑2‑羧酸甲酯。本发明提供的制备方法，反应步骤简单，易于控制，避免应用易制爆试剂，工艺相比更安全，同时也提高了产品市场竞争力。
Description
技术领域
本发明涉及3-氨基吡啶-2-羧酸甲酯的制备方法，属于精细化工技术领域。
背景技术
3-氨基吡啶-2-羧酸甲酯是重要的医药、农药中间体，其应用非常广泛。其中以3-氨基吡啶-2-羧酸甲酯为重要原料，可以合成3-巯基吡啶-2-甲酸，该化合物是磷酸烯醇丙酮酸羧激酶(PEPCK)抑制剂，通过糖异生途径中PEPCK特异性抑制来抑制葡萄糖合成，可以有效降低血糖。并且研究发现α位吡啶羧酸结构的化合物具有良好的抑制糖异生的作用，利用该性质可合成多种抑制剂，用来治疗包括癌症，弓形虫感染等多种疾病。3-氨基吡啶-2-羧酸甲酯中的氨基可促进亲电取代反应，利用其性质可实现氨基的官能团的转换及增加官能团。
现有文献中3-氨基吡啶-2-羧酸甲酯的制备主要有两种：
第一种：文献[Bioorganic and Medicinal Chemistry,2001,vol.9,#8,p.2061-2071]以2,3-吡啶二甲酸为原料，与乙酸酐在120℃反应脱水成酐，接着与乙酰胺反应得到2,3-吡啶二酰亚胺；随后与次溴酸钠和氢氧化钠发生重排反应得到3-氨基吡啶-2-羧酸，最后与重氮甲烷反应得到3-氨基吡啶-2-羧酸甲酯。存在如下缺陷：
A、总收率为3％，收率较低；
B、用到重氮甲烷这样易制爆物试剂，成本高昂，不利于扩大化生产。
反应路线表示如下：
第二种：文献[Journal of Medicinal Chemistry,2009,vol.52,#9,p.2754-2761]以2,3-吡啶二甲酸为原料，与乙酸酐120℃反应脱水，接着与甲醇反应得到2-甲氧羰基-3-吡啶羧酸；随后与叠氮磷酸二苯酯和三乙胺在叔丁醇中反应得到N-BOC-3-氨基吡啶-2-羧酸甲酯，最后三氟乙酸脱保护，调节碱性得到3-氨基吡啶-2-羧酸甲酯。存在如下缺陷：
A、2,3-吡啶二甲酸与乙酸酐脱水后，再与甲醇反应会有异构体3-甲氧羰基-2-吡啶羧酸，异构体不易除去，收率较低；
B、用到叠氮磷酸二苯酯这样易制爆试剂，成本高昂，不利于扩大化生产。
反应路线表示如下：
为了弥补现有合成方法的不足，有必要对3-氨基吡啶-2-羧酸甲酯的制备方法进行改进，开发出一种收率较高、无异构体、更适合工业化生产的合成路线。
发明内容
为了更好的解决上述问题，本发现公开了一种3-氨基吡啶-2-羧酸甲酯的制备方法。本发明以2-羧酸吡啶为原料，与LDA和硼酸酯反应得到3-硼酸吡啶-2-羧酸；随后与甲醇酯化反应得到2-甲氧羰基吡啶-3-硼酸，最后在氧化亚铜作用下与氨水反应得到3-氨基吡啶-2-羧酸甲酯。本发明提供的制备方法，反应步骤简单，易于控制，避免应用易制爆试剂，工艺相比更安全，同时也提高产品市场竞争力。
为实现上述目的，本发明所述3-氨基吡啶-2-羧酸甲酯的制备工艺，包括以下步骤：以2-羧酸吡啶为原料，与LDA和硼酸酯反应得到2-羧酸吡啶-3-硼酸；随后与甲醇酯化反应得到2-甲氧羰基吡啶-3-硼酸；最后在氧化亚铜作用下与氨水反应得到3-氨基吡啶-2-羧酸甲酯。
进一步地，在上述技术方案中，其制备方法采用反应方程式表示如下：
具体操作步骤如下：
1)将2-羧酸吡啶和四氢呋喃混合，降温至超低温状态，依次加入LDA和硼酸酯，加入冰醋酸淬灭，二氯甲烷萃取，有机相纯化得到2-羧酸吡啶-3-硼酸；
2)将2-羧酸吡啶-3-硼酸和甲醇混合，加入氯化亚砜，升温反应，减压浓缩，降温加入水析出，过滤得到2-甲氧羰基吡啶-3-硼酸；
3)将2-甲氧羰基吡啶-3-硼酸、氧化亚铜和甲醇混合，加入氨水室温反应得到3-氨基吡啶-2-羧酸甲酯。
进一步地，所述步骤1)中，硼酸酯选自硼酸三甲酯或硼酸三异丙酯；所述超低温为-80℃～-60℃。
进一步地，所述步骤1)中，2-羧酸吡啶、LDA与硼酸酯摩尔比为1:2.1-2.2:1.3-1.4。
进一步地，所述步骤2)中，2-羧酸吡啶-3-硼酸与氯化亚砜摩尔比为1:1.2-1.8；所述升温反应为55-65℃。
进一步地，所述步骤3)中，2-甲氧羰基吡啶-3-硼酸、氧化亚铜与氨水摩尔比为1:0.1-0.2:5-6。
发明有益效果
本发明提供的3-氨基吡啶-2-羧酸甲酯的制备方法相比于现有技术，本发明的有益效果为：反应无异构体生成，收率和纯度得到很大的提升，同时避免了易制爆物试剂的应用。
具体实施方式
下面详细描述本发明的实施例。下面描述实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
实施例1合成3-硼酸吡啶-2-羧酸
室温下反应瓶中加入2-羧酸吡啶61.6g和四氢呋喃600mL，降温至-85℃，滴加550mL LDA(2.0M)，然后滴加硼酸三异丙酯122.2g，-75～-70℃反应2小时，缓慢升温至10℃，再降温至-5℃加入冰醋酸和水淬灭，静置分层，上层有机相减压浓缩掉四氢呋喃，下层水相用二氯甲烷萃取，合并有机相，用食盐水洗涤，减压浓缩掉二氯甲烷，加入75％甲醇重结晶纯化得到3-硼酸吡啶-2-羧酸61g，收率73.1％，HPLC 99.3％。1H-NMR(400MHz,DMSO-d6)δ:12.72(s,1H),8.20-8.18(m,1H),7.89-7.87(m,1H),6.97-6.95(m,1H),5.68(s,2H)。
实施例2
室温下反应瓶中加入2-羧酸吡啶61.6g和四氢呋喃600mL，降温至-85℃，滴加550mL LDA(2.0M)，然后滴加硼酸三甲酯72.7g，-75～-70℃反应2小时，缓慢升温至10℃，再降温至-5℃加入冰醋酸和水淬灭，静置分层，上层有机相减压浓缩掉四氢呋喃，下层水相二氯甲烷萃取，合并有机相，用食盐水洗涤，减压浓缩二氯甲烷，加入75％甲醇重结晶纯化得到3-硼酸吡啶-2-羧酸54.8g，收率65.7％，HPLC 98.7％。
实施例3合成2-甲氧羰基吡啶-3-硼酸
室温下反应瓶中加入3-硼酸吡啶-2-羧酸50.1g和甲醇750mL，降温至35℃，滴加氯化亚砜46.4g，60℃反应6小时，HPLC无原料剩余，减压浓缩掉甲醇，降温至10-15℃，加入水350g，打浆过滤，烘干得到2-甲氧羰基吡啶-3-硼酸51.2g，收率94.3％，HPLC 99.4％。1H-NMR(400MHz,DMSO-d6)δ:8.19-8.17(m,1H),7.83-7.81(m,1H),6.99-6.97(m,1H),5.06(s,2H),3.81(s,3H).
实施例4合成3-氨基吡啶-2-羧酸甲酯
室温下反应瓶中加入2-甲氧羰基吡啶-3-硼酸45.2g、氧化亚铜8.6g和甲醇260mL，降温至15℃，滴加25％氨水102g，室温反应16小时，HPLC无原料剩余，过滤，滤液减压浓缩掉甲醇，加入甲基叔丁基醚300mL，用2N盐酸调节pH＝1.5-2.0，产品在水相，静置分层，保留下层水相，水相加入碳酸钾水溶液调节pH＝9.0-9.5，二氯甲烷萃取，有机相用水和食盐水洗涤，加入1g活性炭，升温搅拌3小时，过滤，滤液减压浓缩掉二氯甲烷，加入醋酸正丁酯和正庚烷热打浆，降温过滤，烘干得到3-氨基吡啶-2-羧酸甲酯32.2g，收率84.7％，HPLC99.6％。1H NMR(400MHz,CDCl3)δ:8.08-8.06(m,1H),7.24-7.20(m,1H),7.06-7.01(m,1H),5.75(s,1H),3.97(s,3H)。
以上所述结合实施例对本发明的实施方式作了详细说明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为属于本发明的保护范围。
Claims (6)
1.一种3-氨基吡啶-2-羧酸甲酯的制备方法，其特征在于，包括如下步骤：以2-羧酸吡啶为原料，与LDA和硼酸酯反应得到2-羧酸吡啶-3-硼酸；随后与甲醇酯化反应得到2-甲氧羰基吡啶-3-硼酸；最后在氧化亚铜作用下与氨水反应得到3-氨基吡啶-2-羧酸甲酯。
2.根据权利要求1所述3-氨基吡啶-2-羧酸甲酯的制备方法，其特征在于，具体步骤如下：
1)将2-羧酸吡啶和四氢呋喃混合，降温至超低温状态，依次加入LDA和硼酸酯，加入冰醋酸淬灭，二氯甲烷萃取，有机相纯化得到2-羧酸吡啶-3-硼酸；
2)将2-羧酸吡啶-3-硼酸和甲醇混合，加入氯化亚砜，升温反应，减压浓缩，降温加入水析出，过滤得到2-甲氧羰基吡啶-3-硼酸；
3)将2-甲氧羰基吡啶-3-硼酸、氧化亚铜和甲醇混合，加入氨水室温反应得到3-氨基吡啶-2-羧酸甲酯。
3.根据权利要求2所述3-氨基吡啶-2-羧酸甲酯的制备方法，其特征在于：所述步骤1)中，硼酸酯选自硼酸三甲酯或硼酸三异丙酯。
4.根据权利要求2所述3-氨基吡啶-2-羧酸甲酯的制备方法，其特征在于：所述步骤1)中，2-羧酸吡啶、LDA与硼酸酯摩尔比为1:2.1-2.2:1.3-1.4。
5.根据权利要求2所述3-氨基吡啶-2-羧酸甲酯的制备方法，其特征在于：所述步骤2)中，2-羧酸吡啶-3-硼酸与氯化亚砜摩尔比为1:1.2-1.8。
6.根据权利要求2所述3-氨基吡啶-2-羧酸甲酯的制备方法，其特征在于：所述步骤3)中，2-甲氧羰基吡啶-3-硼酸、氧化亚铜与氨水摩尔比为1:0.1-0.2:5-6。
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