CN104031040B - 2-巯基-4-吡啶基噻唑的合成方法 - Google Patents
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 10
- CMHWFELWUFCKOF-UHFFFAOYSA-N 4-(1,3-thiazol-2-yl)-1H-pyridine-2-thione Chemical compound SC1=NC=CC(=C1)C=1SC=CN1 CMHWFELWUFCKOF-UHFFFAOYSA-N 0.000 title claims description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 9
- YNNGZCVDIREDDK-UHFFFAOYSA-N aminocarbamodithioic acid Chemical compound NNC(S)=S YNNGZCVDIREDDK-UHFFFAOYSA-N 0.000 claims abstract description 6
- -1 4 pyridyl thiazoles Chemical class 0.000 claims abstract description 4
- 239000012043 crude product Substances 0.000 claims description 12
- 238000010792 warming Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 9
- 125000001246 bromo group Chemical class Br* 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 7
- 230000006378 damage Effects 0.000 abstract description 4
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- 150000001649 bromium compounds Chemical group 0.000 abstract description 2
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical class CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WMQUKDQWMMOHSA-UHFFFAOYSA-N 1-pyridin-4-ylethanone Chemical compound CC(=O)C1=CC=NC=C1 WMQUKDQWMMOHSA-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- DCYNAHFAQKMWDW-UHFFFAOYSA-N azane;carbamodithioic acid Chemical class N.NC(S)=S DCYNAHFAQKMWDW-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 241000219095 Vitis Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000004119 disulfanediyl group Chemical group *SS* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
本发明的2‑巯基‑4‑吡啶基噻唑的合成方法技术方案为，由4‑乙酰吡啶为原料，经溴代反应后，再直接加二硫代氨基甲酸铵反应得到2‑巯基‑4‑吡啶基噻唑。该方法简洁、高效、条件温和，中间体为溴化物，不经提纯，一锅法得到目标产物，可大大减少中间体对人体的危害，而且得到的产品纯度高，产率高，非常适合工业化生产。
Description
技术领域
本发明涉及医药合成技术领域，特别是涉及2-巯基-4-吡啶基噻唑的合成方法。
背景技术
头孢洛林是一种第五代头孢菌素类抗生素。它对于包括耐甲氧西林金黄色葡萄球菌(MRSA)在内的革兰氏阳性菌具有强大的抗菌作用,同时保持了与最近几代头孢菌素相当的抗革兰氏阴性菌的活性，目前，它正在被评估用于治疗社区获得性肺炎以及复合型皮肤软组织感染。头孢洛林由Foresst Laboratories研制生产, 并由日本武田药品工业株式会社提供授权。2010年10月29日，头孢洛林获得美国FDA认证，许可用于治疗社区获得性肺炎以及急性细菌性皮肤感染。
2-巯基-4-吡啶基噻唑是合成头孢洛林的重要中间体，对其合成的工艺目前研究极少。4-（溴乙酰基）吡啶氢溴酸盐（如式Ⅱ）有如下合成方法：世界专利公开号为WO2010028193、WO 2009158393、WO 2009114552和WO 2008011557，以及Journal ofMedicinal Chemistry, 53(2),787-797; 2010中等，都是利用4-乙酰吡啶（如式Ⅰ）、氢溴酸和溴素在有机溶剂乙酸下反应得到，产率在87%-97%。。有关2-巯基-4-吡啶基噻唑的合成已揭示在世界专利号WO2004060362中，利用4-（溴乙酰基）吡啶氢溴酸盐(如式Ⅱ）与二硫代基甲酸铵(如式Ⅲ）在乙醇中常温下反应18小时制得2-巯基-4-吡啶基噻唑(如式Ⅳ），收率为74%，该反应时间长，产率低。
。
现有技术方法需分步进行，两步总收率为64%-72%，中间体4-（溴乙酰基）吡啶氢溴酸盐具有强烈刺激性，对人的身心健康有较大的危害，而且现有方法反应时间较长，成本高。
发明内容
本发明的目的就是针对上述存在的缺陷而提供一种2-巯基-4-吡啶基噻唑的合成方法。该方法简洁、高效、条件温和，中间体为溴化物，不经提纯，一锅法得到目标产物，可大大减少中间体对人体的危害，得到的产品纯度在99.5%以上，产率在80%以上，成本也较低，非常适合工业化生产。
本发明的2-巯基-4-吡啶基噻唑的合成方法技术方案为，由4-乙酰吡啶为原料，经溴代反应后，再直接加二硫代氨基甲酸铵反应得到2-巯基-4-吡啶基噻唑，合成化学式如下：
。
所述的溴代反应所用试剂为溴素或三溴化吡啶鎓。
优选的，所述的溴代反应所用试剂为溴素。
所述的溴代反应溶剂为甲醇或水。
优选的，所述的溴代反应溶剂为水。
以4-乙酰吡啶为原料，在水中溴代后，降温至20℃以下直接加二硫代氨基甲酸铵反应得到2-巯基-4-吡啶基噻唑。
一种2-巯基-4-吡啶基噻唑的合成方法，具体制备过程为，在1000mL甲醇中，加入60克4-乙酰吡啶，10-15℃下，加入101克40%氢溴酸后，慢慢滴加87.9克溴素，滴加完毕后10-15℃下反应1小时后，升温至30-35℃反应4小时，HPLC检测原料反应完全后，降温至0℃，加入66克二硫代氨基甲酸铵，加完后0℃反应1小时，再升温至20-25℃反应4小时后，过滤，得到2-巯基-4-吡啶基噻唑粗品，粗品在水中回流2小时，冷却后过滤得到2-巯基-4-吡啶基噻唑精品。
一种2-巯基-4-吡啶基噻唑的合成方法，具体步骤为，在1000mL水中，加入60克4-乙酰吡啶，10-15℃下，加入101克40%氢溴酸后，慢慢滴加87.9克溴素，滴加完毕后10-15℃下反应1小时后，升温至30-35℃反应4小时，HPLC检测原料反应完全后，降温至0℃，加入66克二硫代氨基甲酸铵，加完后0℃反应1小时，再升温至20-25℃反应4小时后，过滤，得到2-巯基-4-吡啶基噻唑粗品，粗品在水中回流2小时，冷却后过滤得到2-巯基-4-吡啶基噻唑精品。
本发明的有益效果为：本发明的2-巯基-4-吡啶基噻唑的合成方法技术方案为，由4-乙酰吡啶为原料，经溴代反应后，再直接加二硫代氨基甲酸铵反应得到2-巯基-4-吡啶基噻唑。该方法简洁、高效、条件温和，中间体不用提纯，一锅法得到目标产物，得到的产品纯度高，产率高，并且避免了中间体4-（溴乙酰基）吡啶氢溴酸盐对人体的伤害，反应时间短，成本低，非常适合工业化生产。
具体实施方式：
为了更好地理解本发明，下面用具体实例来详细说明本发明的技术方案，但是本发明并不局限于此。
实施例1
在1000mL甲醇中，加入60克4-乙酰吡啶，10-15℃下，加入101克40%氢溴酸后，慢慢滴加87.9克溴素，滴加完毕后10-15℃下反应1小时后，升温至30-35℃反应4小时，HPLC检测原料反应完全后，降温至0℃，加入66克二硫代氨基甲酸铵，加完后0℃反应1小时，再升温至20-25℃反应4小时后，过滤，得到2-巯基-4-吡啶基噻唑粗品80.7克，粗品在水中回流2小时，冷却后过滤得到2-巯基-4-吡啶基噻唑精品78.2克，产率80.5%，为前黄色固体，HPLC纯度为99.7%。
实施例2
在1000mL甲醇中，加入60克4-乙酰吡啶，0℃下，加入175.9克三溴化吡啶鎓，加完后0℃下反应1小时，再升温至20-25℃反应2小时，HPLC检测原料反应完全后，降温至0℃，加入66克二硫代氨基甲酸铵（2），加完后0℃反应1小时，再升温至20-25℃反应4小时后，过滤，得到2-巯基-4-吡啶基噻唑粗品80.1克，粗品在水中回流2小时，冷却后过滤得到2-巯基-4-吡啶基噻唑精品77.6克，产率79.9 %，为前黄色固体，HPLC纯度为99.8%。
实施例3
在1000mL水中，加入60克4-乙酰吡啶，10-15℃下，加入101克40%氢溴酸后，慢慢滴加87.9克溴素，滴加完毕后10-15℃下反应1小时后，升温至30-35℃反应4小时，HPLC检测原料反应完全后，降温至0℃，加入66克二硫代氨基甲酸铵，加完后0℃反应1小时，再升温至20-25℃反应4小时后，过滤，得到2-巯基-4-吡啶基噻唑粗品81.7克，粗品在水中回流2小时，冷却后过滤得到2-巯基-4-吡啶基噻唑精品80.2克，产率82.6%，为浅黄色固体， HPLC纯度为99.7%。
Claims (1)
1.一种2-巯基-4-吡啶基噻唑的合成方法，其特征在于，在1000mL水中，加入60克4-乙酰吡啶，10-15℃下，加入101克40%氢溴酸后，慢慢滴加87.9克溴素，滴加完毕后10-15℃下反应1小时后，升温至30-35℃反应4小时，HPLC检测原料反应完全后，降温至0℃，加入66克二硫代氨基甲酸铵，加完后0℃反应1小时，再升温至20-25℃反应4小时后，过滤，得到2-巯基-4-吡啶基噻唑粗品，粗品在水中回流2小时，冷却后过滤得到2-巯基-4-吡啶基噻唑精品。
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| CN105566313A (zh) * | 2016-03-22 | 2016-05-11 | 陕西思尔生物科技有限公司 | 头孢洛林酯中间体4-(4’-吡啶)-1,3-噻唑-2-硫醇的合成方法 |
| CN106632001A (zh) * | 2016-12-28 | 2017-05-10 | 山东诚汇双达药业有限公司 | 一种4‑（溴乙酰基）吡啶氢溴酸盐的制备方法 |
| CN107602503A (zh) * | 2017-09-22 | 2018-01-19 | 山东金城医药化工有限公司 | 2‑巯基‑4‑甲基‑5‑噻唑乙酸的合成方法 |
Citations (4)
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| WO2004060362A2 (en) * | 2003-01-02 | 2004-07-22 | Millennium Pharmaceuticals, Inc. | COMPOSITIONS AND METHODS FOR INHIBITING TGF-β |
| US20050176776A1 (en) * | 2004-02-06 | 2005-08-11 | Coleman Paul J. | Mitotic kinesin inhibitors |
| CN102558094A (zh) * | 2011-11-30 | 2012-07-11 | 浙江工业大学 | 一种头孢洛林侧链酸的制备方法 |
| WO2013084171A1 (en) * | 2011-12-07 | 2013-06-13 | Ranbaxy Laboratories Limited | Process for preparing ceftaroline salts or hydrates thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004060362A2 (en) * | 2003-01-02 | 2004-07-22 | Millennium Pharmaceuticals, Inc. | COMPOSITIONS AND METHODS FOR INHIBITING TGF-β |
| US20050176776A1 (en) * | 2004-02-06 | 2005-08-11 | Coleman Paul J. | Mitotic kinesin inhibitors |
| CN102558094A (zh) * | 2011-11-30 | 2012-07-11 | 浙江工业大学 | 一种头孢洛林侧链酸的制备方法 |
| WO2013084171A1 (en) * | 2011-12-07 | 2013-06-13 | Ranbaxy Laboratories Limited | Process for preparing ceftaroline salts or hydrates thereof |
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