CN103601688A - 一种甲氧苄啶杂质的合成方法 - Google Patents
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- CN103601688A CN103601688A CN201310599182.4A CN201310599182A CN103601688A CN 103601688 A CN103601688 A CN 103601688A CN 201310599182 A CN201310599182 A CN 201310599182A CN 103601688 A CN103601688 A CN 103601688A
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- tmp
- bromo
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- trimethoprim
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- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960001082 trimethoprim Drugs 0.000 title claims abstract description 19
- 239000012535 impurity Substances 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title claims description 9
- XJSNBPJINGRLAM-UHFFFAOYSA-N 5-[(3-bromo-4,5-dimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound BrC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 XJSNBPJINGRLAM-UHFFFAOYSA-N 0.000 claims abstract description 4
- -1 sodium alkoxide Chemical class 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- STIAPHVBRDNOAJ-UHFFFAOYSA-N carbamimidoylazanium;carbonate Chemical compound NC(N)=N.NC(N)=N.OC(O)=O STIAPHVBRDNOAJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- ICVODPFGWCUVJC-UHFFFAOYSA-N 3-bromo-4,5-dimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(Br)=C1OC ICVODPFGWCUVJC-UHFFFAOYSA-N 0.000 claims 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- 230000035484 reaction time Effects 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 claims 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- 108700007696 Tetrahydrofolate Dehydrogenase Proteins 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 108020001096 dihydrofolate reductase Proteins 0.000 description 1
- 239000002019 doping agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000012747 synergistic agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及甲氧苄啶一个杂质5-（3-溴-4,5-二甲氧基苄基）嘧啶-2,4-二胺（TMP-F）的合成方法。本发明首次定向设计并合成甲氧苄啶杂质TMP-F，合成路线合理，原料便宜易得，操作简单易行，收率较高，纯度符合要求。
Description
技术领域
本发明属于化学制药技术领域，涉及甲氧苄啶一个杂质的合成方法。
背景技术
甲氧苄啶（Trimethoprim，TMP），化学名称为5-[(3,4,5-三甲氧基苯基)-甲基]-2,4-嘧啶二胺(TMP-F)，是嘧啶类的二氢叶酸还原酶（DHFR）抑制剂，通过影响微生物的DNA、RNA和蛋白质的合成，常用作杀菌剂或杀菌增效剂，目前上市的剂型有片剂和注射液，主要用于肾病内科,尿路感染。TMP目前的世界年销量近万吨，我国年销量近千吨，且一半用作外贸出口。我国一度成为TMP的主要消费国和供应商。面对国内外市场的严峻挑战，提高国产TMP质量是提高其竞争力的一个重要手段。而提高药品质量的一个重要标准就是提高纯度，按照欧洲药典、英国药典对TMP杂质种类及含量的要求，本发明设计并合成出TMP有关的一个杂质TMP-F，可获得用于质量检测的杂质对照品，以控制国产TMP的质量，促进其外贸进口。
British Pharmacopoeia在Page1554-1556中提及甲氧苄啶的杂质5-（3-溴-4,5-二甲氧基苄基）嘧啶-2,4-二胺（TMP-F）的化学结构。但目前尚未有文献报道TMP-F的合成方法。
本发明首次定向的设计并合成甲氧苄啶（TMP）的杂质TMP-F，合成路线合理，原料便宜易得，操作简单易行，收率较高，纯度符合要求。
发明内容
在本发明的目的在于，提供甲氧苄啶（TMP）的杂质TMP-F的合成方法其特征如下：
TMP-F的合成包括以下几个步骤：
a. 将3-溴-4，5-二甲氧基苯甲醛(1)与丙烯腈，醇钠混合，在醇类溶液中反应得到3-(3-溴-4,5-二甲氧基苯基）-2-（甲氧基甲基）丙烯腈 (2)。
b. 将3-(3-溴-4,5-二甲氧基苯基）-2-（甲氧基甲基）丙烯腈(2)与醇钠，碳酸胍混合，在醇类溶剂中反应得到目标化合物5-（3-溴-4,5-二甲氧基苄基）嘧啶-2,4-二胺（TMP-F）。
经过上述操作，能够合成纯度达到要求的杂质TMP-F。
具体实施方式
本说明书中公开的所有特征，或公开的所有方法或过程中的步骤，除了互相排斥的特征和/或步骤以外，均可以以任何方式组合。
实施例1. 3-(3-溴-4,5-二甲氧基苯基)-2-(甲氧基甲基)丙烯腈（2）的合成
将甲醇钠（240g，4.44mol)冷却至10℃，缓慢滴加丙烯腈(39.18g,0.734mol)的甲醇(300mL)溶液，再加入1(60g，0.245mol)，室温搅拌70h后，将反应液冷却至-5℃，析出大量固体，过滤，用水、甲醇依次洗涤滤饼，得白色固体37.2g，收率48.7%，mp: 73-77℃。
实施例2. 5-(3-溴-4,5-二甲氧基苄基)嘧啶-2,4-二胺（TMP-F）的合成
将甲醇钠(26g,0.48mol)、甲醇20mL和乙酸乙酯1mL加入三颈瓶内，50℃搅拌30min后加入2（10g，32.05mmol），回流搅拌5h后加入碳酸胍(6.92g，38.46mmol)，继续回流搅拌3h后，向反应液中加入水120mL，回流搅拌30min。冷却，析出褐色固体，柱层析得白色固体3.71g，收率34.1%。mp: 205-206℃。HPLC检测含量98.78%。1H-NMR ( 400MHz, DMSO-d6 ): δ 3.55(2H, s, CH2), 3.79(3H, s,OCH3), 3.81(3H, s, OCH3), 5.78(2H,s,NH2), 6.19（2H, s, NH2），6.96(1H, d, J=2Hz, ArH), 6.99(1H, d, J=2Hz, ArH), 7.57(1H, s, PyH)。MS(m/z): 338.9[M] +, 337.0[M+H]+。13C-NMR(200MHz, DMSO)：δ32.29, 56.29, 80.32(OCH3), 123.70, 138.20, 113.20, 153.43, 144.12, 116.85, 162.62, 105.57, 162.52, 156.32。IR (KBr, cm-1): ν3471, 3366, 3182, 2995, 2938, 1598, 1491, 1264, 1232, 1132, 825, 813, 770。
Claims (4)
1.一种甲氧苄啶杂质5-（3-溴-4,5-二甲氧基苄基）嘧啶-2,4-二胺（TMP-F）的合成方法，其特征于：分以下几个步骤合成：
a. 将3-溴-4，5-二甲氧基苯甲醛（1）与丙烯腈，醇钠混合，在醇类溶液中反应得到3-(3-溴-4,5-二甲氧基苯基）-2-（甲氧基甲基）丙烯腈（2）；
b. 将3-(3-溴-4,5-二甲氧基苯基）-2-（甲氧基甲基）丙烯腈（2）与醇钠，碳酸胍混合，在醇类溶剂中反应得到目标化合物5-（3-溴-4,5-二甲氧基苄基）嘧啶-2,4-二胺TMP-F；
。
2.据权利要求1所述的一种甲氧苄啶的杂质TMP-F的合成方法，其特征在于：所述步骤a中的反应温度为-5-40℃,反应时间为1-80小时，3-溴-4，5-二甲氧基苯甲醛（1）与丙烯腈的摩尔投料比为1：1-5，与醇钠的摩尔投料比为1：1-30。
3.据权利要求1所述的一种甲氧苄啶的杂质TMP-F的合成方法，其特征在于：所述步骤b中使用的醇钠选自：甲醇钠、乙醇钠，优选甲醇钠；使用的醇类溶剂选自：甲醇、乙醇、正丙醇、异丙醇，优选甲醇。
4.据权利要求1所述的一种甲氧苄啶的杂质TMP-F的合成方法，其特征在于：所述步骤b中的反应温度为0-100℃，反应时间为0.5-6 h，3-(3-溴-4,5-二甲氧基苯基）-2-（甲氧基甲基）丙烯腈（2）与醇钠的摩尔投料比为1：1-20，与碳酸胍的摩尔投料比为1：0.5-20。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928151A (zh) * | 2017-03-21 | 2017-07-07 | 山东新华制药股份有限公司 | 甲氧苄啶环合工序回收品的精制方法 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3513185A (en) * | 1965-10-28 | 1970-05-19 | Burroughs Wellcome Co | Preparation of benzyl cyano-acetals |
| US3852276A (en) * | 1969-03-06 | 1974-12-03 | Burroughs Wellcome Co | 5-benzyl pyrimidines intermediate therefore, and method |
| CN101575303A (zh) * | 2008-05-05 | 2009-11-11 | 华东理工大学 | 一种3-苯胺基-2-(3,4,5-三甲氧基苄基)丙烯腈的制备方法 |
| CN102180839A (zh) * | 2011-03-25 | 2011-09-14 | 济南大学 | 一种水溶的三甲氧苄氨嘧啶衍生物及其制备方法 |
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2013
- 2013-11-25 CN CN201310599182.4A patent/CN103601688A/zh active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3513185A (en) * | 1965-10-28 | 1970-05-19 | Burroughs Wellcome Co | Preparation of benzyl cyano-acetals |
| US3852276A (en) * | 1969-03-06 | 1974-12-03 | Burroughs Wellcome Co | 5-benzyl pyrimidines intermediate therefore, and method |
| CN101575303A (zh) * | 2008-05-05 | 2009-11-11 | 华东理工大学 | 一种3-苯胺基-2-(3,4,5-三甲氧基苄基)丙烯腈的制备方法 |
| CN102180839A (zh) * | 2011-03-25 | 2011-09-14 | 济南大学 | 一种水溶的三甲氧苄氨嘧啶衍生物及其制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| PERCY S. MANCHAND，等: "Syntheses of Antibacterial 2,4-Diamino-5-benzylpyrimidines. Ormetoprim and Trimethoprim", 《J.ORG.CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928151A (zh) * | 2017-03-21 | 2017-07-07 | 山东新华制药股份有限公司 | 甲氧苄啶环合工序回收品的精制方法 |
| CN106928151B (zh) * | 2017-03-21 | 2019-05-21 | 山东新华制药股份有限公司 | 甲氧苄啶环合工序回收品的精制方法 |
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Application publication date: 20140226 |