CN100567277C - 一种含n五元芳香杂环甲脒及其盐的制备方法 - Google Patents
一种含n五元芳香杂环甲脒及其盐的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000003839 salts Chemical class 0.000 title claims abstract description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 10
- 150000002825 nitriles Chemical class 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 4
- SYNHCENRCUAUNM-UHFFFAOYSA-N Nitrogen mustard N-oxide hydrochloride Chemical compound Cl.ClCC[N+]([O-])(C)CCCl SYNHCENRCUAUNM-UHFFFAOYSA-N 0.000 claims abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 35
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 22
- -1 hydroxyl amidoxime Chemical compound 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000005984 hydrogenation reaction Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 10
- 238000001291 vacuum drying Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 150000001409 amidines Chemical class 0.000 claims description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 229930013930 alkaloid Natural products 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 239000003205 fragrance Substances 0.000 claims 1
- 230000001988 toxicity Effects 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 238000010438 heat treatment Methods 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000007812 deficiency Effects 0.000 description 4
- 150000002923 oximes Chemical class 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- AZFSRJWWAXEWED-UHFFFAOYSA-N 1,3-oxazol-2-yl acetate Chemical compound CC(=O)OC1=NC=CO1 AZFSRJWWAXEWED-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- BYHXLDZDSZVDJH-UHFFFAOYSA-N acetic acid;1,3-thiazole Chemical compound CC(O)=O.C1=CSC=N1 BYHXLDZDSZVDJH-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- ZIRGWUZHKJDYKT-UHFFFAOYSA-N 1,3-thiazole-2-carbonitrile Chemical compound N#CC1=NC=CS1 ZIRGWUZHKJDYKT-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 238000003482 Pinner synthesis reaction Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010644 ester aminolysis reaction Methods 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical compound NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
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- 239000011593 sulfur Substances 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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Abstract
本发明涉及制药领域，特别涉及一种含N五元芳香杂环甲脒及其盐的制备方法，它包括使相应的腈与羟基胺无需加热或回流在室温下反应，以及用Pd/C还原成甲脒及其盐的方法，本发明工艺简单，毒性小，产物收率高，操作容易控制。
Description
技术领域：
本发明属于制药领域，特别涉及合成血拴抑制剂等的关键中间体含脒基化合物。
背景技术：
已报导的脒的制备途径有很多，列举如下：
(1)强碱存在下与铵盐直接加成，WO9,954,329，CN 1,134,434C此方法存在的不足是：需要用到较危险的化学品金属钠，且反应时间较长，产物收率不太理想等。
(2)加压将氨直接加入杂环芳基或芳基腈中，P.C.Srivastava，J.Med.Chem.27，(1984)266，此方法存在的不足是：反应时间长(16h)，且用取代腈进行的研究表明，即使在加压下转化率也有限，且由此造成脒收率相应较低。
(3)pinner反应后再将亚氨基羧酸酯氨解(Ber.18(1885)2845).此方法存在的不足是：两步反应，需要使用大量的氯化氢，最终产生大量的盐副产物，有时导致后续分离困难，且此反应同样存在反应时间长，转化率偏低从而只能获得中等收率。
(4)使用硫醇作为辅剂制备脒(R.C.Schnur，J.Org.Chem.44，(1979)3726)或者向腈中加入硫化氢得到硫代羧酰胺，然后将硫烷基化并氨解(H.Rappoport，J.Org.Chem.46，(1981)2455；M.Ohno，Tetrahedeon lett.(1979)2517)此方法存在的不足是：上述工艺需要用到极臭而且毒性极高的化合物，而且烷基化，一般使用碘甲烷或硫酸二甲酯等强致癌物。
发明内容：
本发明的目的在于提供一种操作简便，原料易得，毒性小，反应时间短，收率高且产品纯度高的含N五元芳香杂环甲脒及其盐的制备方法。
本发明的制备方法可以用如下反应式表示：
其中：D代表O或S，或NH
本发明具体包括以下步骤：
1、将水和乙醇或甲醇或异丙醇的混合溶剂投入反应器中，再按mol比为1∶1∶1～1∶4∶4投入腈、盐酸羟胺和碱类物质，常温搅拌，抽滤得到相应的羟酰胺肟，真空干燥。
2、在氢化反应釜中加入体积比为(25～40)∶1的醋酸与醋酐的混合溶剂，再把羟酰胺肟投入反应釜中，搅拌形成澄清溶液。
3、按Pd/C∶羟酰胺肟为(5～30)g∶1mol投入Pd/C后加氢。
4、抽滤除掉Pd/C，蒸馏除掉醋酸，得到相应的产物脒，真空干燥得到产物。
本发明采用上述工艺，可以在常温下很简便的制备获得高纯度(＞98％)的中间体产物羟酰胺肟，通过在醋酸与醋酐的混合液中氢化还原，可以获得高收率(＞95％)高纯度(＞98％)的脒，与WO9,954,329，CN 1,134,434C工艺相比，操作简便，节约了制备成本，并且对环境不会造成污染。
具体实施方式：
实施例1
制备2-甲脒噻唑醋酸盐的方法
具体包括以下步骤：
(1)在反应器中加入200ml水和30ml乙醇，10g(0.09mol)2-氰基噻唑。
(2)在反应器中加入12.5g(0.18mol)盐酸羟胺和7.2g(0.18mol)氢氧化钠。
(3)搅拌2h，抽滤，60℃真空干燥，得到10.36g羟肟噻唑，HPLC纯度为99％。
(4)在氢化反应釜中加入150ml醋酸，5ml醋酐，5g上述的羟肟噻唑，搅拌10min，往反应釜中加入0.5gPd/C，1bar下加氢，2h后停止。
(5)过滤除Pd/C，60℃减压蒸馏除掉醋酸，近干时用30ml丙酮结晶，抽滤得到2-甲脒噻唑醋酸盐，60℃真空干燥，得到4.6g 2-甲脒噻唑醋酸盐，HPLC纯度＞99％。
实施例2
制备2-甲脒恶唑醋酸盐的方法
具体包括以下步骤：
(1)在反应器中加入100ml水和10ml乙醇，5g(0.05mol)2-氰基-恶唑。
(2)在反应器中加入5.21g(0.075mol)盐酸羟胺和10.6g(0.1mol)碳酸钠。
(3)搅拌2h，抽滤，60℃真空干燥，得到6.3g羟肟恶唑，HPLC纯度为98.3％。
(4)在氢化反应釜中加入125ml醋酸，5ml醋酐，5g(0.045mol)上述的2-羟肟恶唑，搅拌，往反应釜中加入0.5gPd/C，1bar下加氢，2h后停止。
(5)过滤除Pd/C，60℃减压蒸馏除掉醋酸，近干时用20ml丙酮结晶，抽滤得到2-甲脒恶唑醋酸盐，60℃真空干燥，得到4.2g 2-甲脒恶唑醋酸盐，HPLC纯度＞98％。
实施例3
制备2-甲脒咪唑醋酸盐的方法
具体包括以下步骤：
(1)在反应器中加入100ml水和15ml乙醇，5g(0.054mol)2-氰基咪唑。
(2)在反应器中加入7.5g(0.11mol)盐酸羟胺和11.66g(0.11mol)碳酸钠。
(3)搅拌2h，抽滤，60℃真空干燥，得到5.5g 2-羟肟咪唑，HPLC纯度为98％。
(4)在氢化反应釜中加入100ml醋酸，5ml醋酐，5g(0.045mol)上述的2-羟肟咪唑，搅拌10min，往反应釜中加入0.5gPd/C，1bar下加氢，2h后停止。
(5)过滤除Pd/C，60℃减压蒸馏除掉醋酸，近干时用20ml丙酮结晶，抽滤得到2-甲脒咪唑醋酸盐，60℃真空干燥，得到4.8g 2-甲脒咪唑醋酸盐，HPLC纯度＞99％。
Claims (2)
1、一种含N五元芳香杂环甲脒及其盐的制备方法，通式为：
其中：D代表O或S，或NH，其特征在于：制备上述化合物的方法，可以用如下反应式表示：
在常温下，在碱存在条件下使上述含N芳香腈与羟基胺反应成相应的羟酰胺肟，后用醋酸、醋酐混合溶剂在Pd/C催化下氢化成上述甲脒的方法。
2、根据权利要求1所述的一种含N五元芳香杂环甲脒及其盐的制备方法，其特征在于：制备上述化合物包括以下步骤：
a.将水和乙醇或甲醇或异丙醇的混合溶剂投入反应器中，再按mol比为1∶1∶1～1∶4∶4投入腈、盐酸羟胺和碱类物质，常温搅拌，抽滤得到相应的羟酰胺肟，真空干燥；
b.在氢化反应釜中加入体积比为(25～40)∶1的醋酸与醋酐的混合溶剂，再把羟酰胺肟投入反应釜中，搅拌形成澄清溶液；
c.按Pd/C∶羟酰胺肟为(5～30)g∶1mol投入Pd/C后加氢；
d.抽滤除掉Pd/C，蒸馏除掉醋酸，得到相应的产物脒及其盐，真空干燥得到产物。
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Non-Patent Citations (2)
| Title |
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| 化学化工大辞典. 贺国强等，1763-1764，化学工业出版社. 2003 |
| 化学化工大辞典. 贺国强等，1763-1764，化学工业出版社. 2003 * |
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Denomination of invention: Production of N-contained pentabasic heteroaromatic dimethyl ether Effective date of registration: 20161207 Granted publication date: 20091209 Pledgee: China Development Bank Co. Pledgor: SUNSHINE LAKE PHARMA Co.,Ltd. Registration number: 2016990001089 |
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Date of cancellation: 20230606 Granted publication date: 20091209 Pledgee: China Development Bank Co. Pledgor: SUNSHINE LAKE PHARMA Co.,Ltd. Registration number: 2016990001089 |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |
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