CN101058581B - 右佐匹克隆中间体6-(5-氯-2-吡啶基)-5,7-二氧代-6,7-二氢-5H-吡咯并[3,4-b]吡嗪的制备方法 - Google Patents
右佐匹克隆中间体6-(5-氯-2-吡啶基)-5,7-二氧代-6,7-二氢-5H-吡咯并[3,4-b]吡嗪的制备方法 Download PDFInfo
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- GBBSUAFBMRNDJC-INIZCTEOSA-N eszopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-INIZCTEOSA-N 0.000 title claims description 8
- 229960001578 eszopiclone Drugs 0.000 title description 2
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- -1 aminomethyl phenyl Chemical group 0.000 claims description 12
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
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- 239000012190 activator Substances 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
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- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 4
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 4
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical group COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
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Abstract
本发明提供一种制备右佐匹克隆的中间体6-(5-氯-2-吡啶基)-5，7-二氧代-6，7-二氢-5H-吡咯并[3，4-b]吡嗪(I)的方法。本发明通过下述方法实施：3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸(II)溶解有机溶剂/胺混合液中，然后向反应液中加入氯甲酸酯，得到目的物I。
Description
技术领域
本发明涉及一种制备抗失眠药右佐匹克隆的中间体的方法，特别是涉及一种制备化合物6-(5-氯-2-吡啶基)-5，7-二氧代-6，7-二氢-5H-吡咯并[3，4-b]吡嗪(I)的方法。
背景技术
临床用于失眠症治疗的药物主要包括巴比妥类(第一代)、苯二氮类(第二代)及非苯二氮类(第三代)和中药类。由于副作用大及易产生依赖性和耐受性等原因，第一代和第二代抗失眠药的市场呈明显下降趋势。第三代非苯二氮类催眠药能选择性地作用于BZ1受体，产生的遗留效应相对较小，次晨极少产生″宿睡″现象，不影响次晨的精神活动和动作的机敏度，而且剂量较小，重复应用也极少积聚，因此较为安全。由于非苯二氮类药诱发停药反应的倾向不明显，可以采用全新的″按需″用药方案，目前已成为治疗失眠症的标准药物。当前，在国内临床应用的非苯二氮类镇静催眠药物主要有唑吡坦、佐匹克隆和扎来普隆。
消旋佐匹克隆为第三代镇静催眠药，由法国罗纳普朗克乐安(Rhone-Poulenc Rorer)公司于80年代中期在欧洲等80多个国家上市，用于治疗睡眠紊乱。2004年12月，FDA批准右旋佐匹克隆(eszopiclone，Lunesta)上市，它是佐匹克隆(zopiclone)的单一异构体。Lunesta的优势是其为第一个获准用于长期使用的失眠症治疗药物，是首个可长期用于改善起始睡眠(难以入睡)和维持睡眠质量(夜间觉醒或早间觉醒过早)的药物。6-(5-氯-2-吡啶基)-5，7-二氧代-6，7-二氢-5H-吡格并[3，4-b]吡嗪(I)为制备佐匹克隆的中间体，US3862149采用的方法是将3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸(II)在二氯亚砜中回流，收率为77％。左黛珠等(中国药物化学杂志1996，6，25～3)采用的方法是将3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸(II)在3倍体积的醋酸酐中加热至120～130℃的环合方法，收率为77％。上述方法均只能得到中等收率的目标产物，且US3862149中使用大量强腐蚀性的的二氯亚砜做溶剂，在反应过程中放出氯化氢气体，存在较严重的劳动防护和环保问题，同时对设备的腐蚀性较大。醋酸酐属于易制毒品，其购买和使用均收到很大的限制。
发明内容
本发明的目的是提供一种新的制备右佐匹克隆中间体6-(5-氯-2-吡啶基)-5，7-二氧代-6，7-二氢-5H-吡咯并[3，4-b]吡嗪(I)的方法，该方法具有后处理简便、生产安全可靠、反应收率高、产品质量好的特点。
本发明的目的是通过以下技术方案实现的：以3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸(II)为原料，在无水有机溶剂中以有机碱为缚酸剂，以氯甲酸酯为羧基活化剂，通过活泼中间体混酐(III)制得6-(5-氯-2-吡啶基)-5，7-二氧代-6，7-二氢-5H-吡咯并[3，4-b]吡嗪(I)。
其中，R为C1～C8直链或支链烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基等；C7～C15芳烷基，如苄基、苯乙基、苯丙基、萘甲基等；C3～C8环烷基，如环丙基、环戊基、环己基等；或芳香基，如苯基、甲基苯基、氯苯基、萘基等。优选甲基、乙基、正丙基和异丙基。
本发明所用的有机溶剂可以是本领域常用的或者常规的有机溶剂，选自但不限于下述溶剂中的一种或者多种：酮类溶剂，如丙酮、丁酮、环己酮等脂肪族酮类和苯乙酮等芳香族酮类；醚类溶剂，如乙醚、异丙醚、丁醚、四氢呋喃、二氧六环等脂肪族醚类和苯甲醚等芳香族醚类；酯类溶剂，如乙酸乙酯、乙酸异丙酯等脂肪族酯类和苯甲酯等芳香族酯类；醇类溶剂，如甲醇、乙醇等脂肪族醇类和苯甲醇等芳香族醇类；烃类溶剂，如正己烷、环己烷等脂肪烃类和苯、甲苯等芳香烃类以及二氯甲烷、三氯甲烷、氯苯、二氯苯、硝基苯等卤代烃类；腈类如乙腈。这些溶剂可以相互交替或改变，也可以合并使用，其比例无限制；有机溶剂优选苯、甲苯、氯苯、二氯苯、硝基苯；二氯甲烷、氯仿；正己烷或环己烷；乙腈；四氢呋喃；二氧六环等。用量优选3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸(II)的3～50倍，更优选10～25倍。
有机碱可以是本领域常用的或者常规的有机碱，选自但不限于胺类和吡啶类，胺类如甲胺；二乙胺，三乙胺；二丙胺，二异丙胺；二异丙基乙基胺；环丙胺，环己胺；苯胺，甲基苯胺，N，N-二甲基苯胺；吡啶类如吡啶，4-二甲胺基吡啶等。这些有机碱可以单独使用或者合并使用，合并使用时其比例无限制，用量为本领域常规用量。
氯甲酸酯可以是本领域常用的或者常规的氯甲酸酯，选自但不限于氯甲酸甲酯、氯甲酸乙酯、氯甲酸正丙酯、氯甲酸异丙酯、氯甲酸正丁酯、氯甲酸异丁酯、氯甲酸叔丁酯、氯甲酸辛酯等；氯甲酸环戊酯、氯甲酸环己酯；氯甲酸苄酯、对硝基氯甲酸苄酯、对甲氧基氯甲酸苄酯等；氯甲酸苯酯、氯甲酸甲苯酯等。优选氯甲酸甲酯、氯甲酸乙酯、氯甲酸正丙酯、氯甲酸异丙酯。这些氯甲酸酯可以单独使用，也可以合并使用，合并使用时其比例无限制，用量为本领域常规用量。
反应温度为-50℃至溶剂体系的沸点，优选-25～10℃。
该方法具反应收率高达85％以上、产品纯度达95％以上的特征。
附图说明
6-(5-氯-2-吡啶基)-5，7-二氧代-6，7-二氢-5H-吡咯并[3，4-b]吡嗪的核磁共振氢谱(CDCl3，300MHz)
具体实施方式
下述实施例是为了进一步说明本发明专利，并不构成对本发明的任何限制。
实施例1
在干燥氮气保护下，向反应瓶中依次加入氯仿(560mL)、3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸(II，55.7g，0.2mol)、二异丙胺(23.3g，0.23mol)，搅拌溶解。降至-20℃，滴加氯甲酸甲酯(23.87g，0.22mol)，每隔半小时取样HPLC监测，至原料含量＜1％，终止反应。
用盐酸(10％150mL×2)，水(200mL×3)洗涤反应液。分取有机相，用无水硫酸钠(4g)干燥4h，活性炭(5g)室温脱色2h。抽滤，减压浓缩除去全部溶剂，得到近白色固体50.5g，收率96.9％，，HPLC含量98.5％。mp239～241℃。1H NMR(CDCl3，300MHz)，δ：9.06(s，2H，ArH)，8.67(d，1H，PyH，J＝2.58Hz)，7.93(dd，1H，J＝8.46Hz & 2.52Hz，PyH)，7.49(d，1H，8.52Hz，PyH).(见附图)
实施例2
反应溶剂为苯，其余同实施例1。
收率95％，含量99％。
实施例3
反应溶剂为甲苯，羧基活化剂是氯甲酸乙酯，其余同实施例1。
收率93％，含量98％。
实施例4
反应溶剂为二氯甲烷，碱为三乙胺，羧基活化剂是氯甲酸正丙酯，其余同实施例1。
收率91％，含量98％。
实施例5
反应溶剂为四氢呋喃，其余同实施例1。
收率88％，含量99％。
实施例6
反应溶剂四氢呋喃，碱为三乙胺，溶剂用量为3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸(II)的25倍，羧基活化剂是氯甲酸异丙酯，其余同实施例1。
收率86％，含量98％。
实施例7
反应溶剂为四氢呋喃，碱为二异丙基乙基胺，溶剂用量为3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸(II)的25倍，降至-10℃，其余同实施例1。
收率90％，含量98％。
实施例8
反应溶剂为四氢呋喃，碱为吡啶，溶剂用量为3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸(II)的25倍，其余同实施例1。
收率90％，含量98.3％。
实施例9
反应溶剂为二氯甲烷，碱为N，N-二甲基苯胺，溶剂用量为3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸(II)的3倍，降至-5℃，其余同实施例1。
收率90％，含量98.3％。
实施例10
反应温度为0℃，其余同实施例9。
收率85％，含量98％。
实施例11
反应温度为5℃，其余同实施例9。
收率88％，含量98％。
实施例12
反应温度为10℃，其余同实施例9。
收率90％，含量98％。
Claims (8)
1.一种制备右佐匹克隆中间体6-(5-氯-2-吡啶基)-5，7-二氧代-6，7-二氢-5H-吡咯并[3，4-b]吡嗪I的方法，其特征在于是以3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸II为原料，在无水有机溶剂中以有机碱为缚酸剂，以氯甲酸酯为羧基活化剂，通过活性中间体混酐III制得。
其中，R为C1～C8直链或支链烷基；C7～C15芳烷基；C3～C8环烷基；或苯基、甲基苯基、氯苯基或萘基。
2.如权利要求1所述的方法，其特征在于所述的活性中间体混酐III中R为甲基、乙基、正丙基和异丙基。
3.如权利要求1所述的方法，其特征在于所述的无水有机溶剂是苯、甲苯、氯苯、二氯苯、硝基苯；二氯甲烷、氯仿；正己烷或环己烷；乙腈；四氢呋喃；或者二氧六环，可以单独使用或者合并使用，用量为3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸II的3～50倍。
4.如权利要求3所述的方法，其特征在于所述的无水有机溶剂的用量是3-(5-氯吡啶-2-氨基)甲酰基吡嗪-2-羧酸II的10～25倍。
5.如权利要求1所述的方法，其特征在于所述的有机碱为甲胺；二乙胺，三乙胺；二丙胺，二异丙胺；二异丙基乙基胺；环丙胺，环己胺；苯胺，甲基苯胺，N，N-二甲基苯胺；吡啶或者4-二甲胺基吡啶，可以单独使用或者合并使用。
6.如权利要求1所述的方法，其特征在于所述的氯甲酸酯选自氯甲酸甲酯、氯甲酸乙酯、氯甲酸正丙酯、氯甲酸异丙酯，可以单独使用或者合并使用。
7.如权利要求1所述的方法，其特征在于反应温度为-50℃至溶剂体系的沸点。
8.如权利要求7所述的方法，其特征是反应温度为-25～10℃。
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| US3862149A (en) * | 1972-01-07 | 1975-01-21 | Rhone Poulenc Sa | Pyrrolo (3,4-b) pyrazine derivatives |
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| US3862149A (en) * | 1972-01-07 | 1975-01-21 | Rhone Poulenc Sa | Pyrrolo (3,4-b) pyrazine derivatives |
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| 左代姝.新型催眠镇静药佐匹克隆类似物的合成.中国药物化学杂志.1996,6(1),26-30. * |
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