CN113549060A - 一种3-氨基-1-(四氢呋喃-2-基氧基)-1h-吡唑-4-甲腈的合成方法 - Google Patents
一种3-氨基-1-(四氢呋喃-2-基氧基)-1h-吡唑-4-甲腈的合成方法 Download PDFInfo
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- CN113549060A CN113549060A CN202110854247.XA CN202110854247A CN113549060A CN 113549060 A CN113549060 A CN 113549060A CN 202110854247 A CN202110854247 A CN 202110854247A CN 113549060 A CN113549060 A CN 113549060A
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- WSRLPLSXYHFHCP-UHFFFAOYSA-N 3-amino-1-(oxolan-2-yloxy)pyrazole-4-carbonitrile Chemical compound NC(C(C#N)=C1)=NN1OC1OCCC1 WSRLPLSXYHFHCP-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000010189 synthetic method Methods 0.000 title claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- FFNKBQRKZRMYCL-UHFFFAOYSA-N 5-amino-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC=C1C#N FFNKBQRKZRMYCL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940126062 Compound A Drugs 0.000 claims abstract description 8
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims abstract description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 150000003217 pyrazoles Chemical class 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940127108 compound 5g Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D307/20—Oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明属于医药中间体技术领域，具体涉及一种3‑氨基‑1‑(四氢呋喃‑2‑基氧基)‑1H‑吡唑‑4‑甲腈的合成方法。本发明将化合物A、甲磺酰氯等进行酯化反应，合成化合物B，将化合物B、3‑氨基‑4‑氰基吡唑等进行亲核取代反应，得到3‑氨基‑1‑(四氢呋喃‑2‑基氧基)‑1H‑吡唑‑4‑甲腈，该路线简短，易于操作。
Description
技术领域
本发明属于医药中间体技术领域，具体涉及一种3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈的合成方法。
背景技术
大量研究和实践表明吡唑类化合物具有广泛的生物活性，无论在医药领域还是在农药领域吡唑类化合物都得到了广泛的应用，而且吡唑环上取代位点和取代基的多样性变化使市场化的吡唑类化合物日益丰富。
3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈是吡唑类化合物中的一种，目前尚未有对其进行合成的报道。
发明内容
本发明所要解决的技术问题：针对上述所述的问题，提供一种3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈的合成方法。
为解决上述技术问题，本发明采用如下所述的技术方案是：
一种3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈的合成方法，该制备方法包括如下步骤：
（1）将化合物A、三乙胺溶解于四氢呋喃，加入甲磺酰氯，升温，搅拌反应，即得化合物B
（2）将3-氨基-4-氰基吡唑、化合物B及碳酸铯加入到N,N-二甲基甲酰胺，氮气保护，加热，反应，即得3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈
优选地，所述步骤（1）中化合物A、三乙胺及甲磺酰氯的质量比为2:3～5:4。
优选地，所述步骤（2）中3-氨基-4-氰基吡唑、化合物B及碳酸铯的质量比为2:4:10～13。
本发明与其他方法相比，有益技术效果是：
（1）本发明供了一种3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈的合成路线，且该路线合成的3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈的产率高、纯度高；
（2）本发明将化合物A、甲磺酰氯等进行酯化反应，合成化合物B，将化合物B、3-氨基-4-氰基吡唑等进行亲核取代反应，得到3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈，改路线简短，易于操作。
具体实施方式
实施例1
一种3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈的合成方法，该制备方法包括如下步骤：
（1）将2g化合物A和3g三乙胺溶于60mL四氢呋喃中，冰水浴下向该溶液中滴加4g甲磺酰氯，升至室温反应3h，TLC检测原料反应完全，将溶剂旋蒸除去，剩余物加入碳酸氢钠溶液（20ml）和乙酸乙酯（50ml*2），萃取分离合并有机相，将有机溶剂旋蒸除去得5.3g淡黄色液体，纯度为98.6％；
（2）将2g3-氨基-4-氰基吡唑、4g化合物B及10g碳酸铯加入到50mL，氮气保护，加热到80℃反应4h，TLC检测原料反应完全，冷却至室温后，加入100ml水和100ml乙酸乙酯萃取分离，合并有机相，加入硅胶粉，经硅胶柱分离（正己烷：乙酸乙酯=3:1）得3.2g白色固体，纯度为99.6％，即为3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈。
核磁数据：
1H NM（d6-DMSO）: 8.17(s, 1H), 5.63(s, 2H), 4.76(m, 1H),3.95-3.75(m,4H),2.34-2.16(m, 2H)。
实施例2
一种3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈的合成方法，该制备方法包括如下步骤：
（1）将2g化合物A和5g三乙胺溶于60mL四氢呋喃中，冰水浴下向该溶液中滴加4g甲磺酰氯，升至室温反应3h，TLC检测原料反应完全，将溶剂旋蒸除去，剩余物加入碳酸氢钠溶液（20ml）和乙酸乙酯（50ml*2），萃取分离合并有机相，将有机溶剂旋蒸除去得5.4g淡黄色液体，纯度为99.1％；
（2）将2g3-氨基-4-氰基吡唑、4g化合物B及13g碳酸铯加入到50mL，氮气保护，加热到80℃反应4h，TLC检测原料反应完全，冷却至室温后，加入100ml水和100ml乙酸乙酯萃取分离，合并有机相，加入硅胶粉，经硅胶柱分离（正己烷：乙酸乙酯=3:1）得3.4g白色固体，纯度为99.7％，即为3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈。
核磁数据：
1H NM（d6-DMSO）: 8.17(s, 1H), 5.63(s, 2H), 4.76(m, 1H),3.95-3.75(m,4H),2.34-2.16(m, 2H)。
Claims (3)
1.一种3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈的合成方法，其特征在于，该制备方法包括如下步骤：
（1）将化合物A、三乙胺溶解于四氢呋喃，加入甲磺酰氯，升温，搅拌反应，即得化合物B
（2）将3-氨基-4-氰基吡唑、化合物B及碳酸铯加入到N,N-二甲基甲酰胺，氮气保护，加热，反应，即得3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈
2.根据权利要求1所述的3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈的合成方法，其特征在于，所述步骤（1）中化合物A、三乙胺及甲磺酰氯的质量比为2:3～5:4。
3.根据权利要求1所述的3-氨基-1-(四氢呋喃-2-基氧基)-1H-吡唑-4-甲腈的合成方法，其特征在于，所述步骤（2）中3-氨基-4-氰基吡唑、化合物B及碳酸铯的质量比为2:4:10～13。
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| CN112105385A (zh) * | 2017-12-26 | 2020-12-18 | 凯麦拉医疗公司 | Irak降解剂和其用途 |
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| CN112105385A (zh) * | 2017-12-26 | 2020-12-18 | 凯麦拉医疗公司 | Irak降解剂和其用途 |
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| 温娜: "《材料有机化学学习指导》", 30 June 2017 * |
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Application publication date: 20211026 |