CN1163893A - N-[3-(3-氰基吡唑并[1，5-α]嘧啶-7-基)苯基]-N-乙基-乙酰胺合成的改进方法 - Google Patents

N-[3-(3-氰基吡唑并[1，5-α]嘧啶-7-基)苯基]-N-乙基-乙酰胺合成的改进方法 Download PDF

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CN1163893A
CN1163893A CN96118985A CN96118985A CN1163893A CN 1163893 A CN1163893 A CN 1163893A CN 96118985 A CN96118985 A CN 96118985A CN 96118985 A CN96118985 A CN 96118985A CN 1163893 A CN1163893 A CN 1163893A
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T·帕曼纳芬
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Abstract

本发明是制备用作抗焦虑、抗癫痫药、镇静安眠和骨骼肌肉松弛剂的N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺的改进方法。公开的本发明包括3-二甲基氨基-1-(3-N-乙基-N-乙酰基-氨基苯基)-2-丙烯-1-酮或其适用的盐和3-氨基吡唑-4-腈或其适用的盐在除单独使用醋酸外的含水和醋酸或其适用的盐混合物中反应。

Description

N-[3-(3-氰基吡唑并[1，5-a] 嘧啶-7-基)苯基]-N-乙基-乙酰 胺合成的改进方法
本发明涉及大规模生产N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺的改进方法。此化合物可用作抗焦虑、抗癫痫药、镇静安眠药和骨骼肌肉松弛剂。
美国专利US4626538研究了由3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮和3-氨基吡唑-4-腈在醋酸中反应制备所需化合物N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺。
现在已经发现在3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮或其适用的盐和3-氨基吡唑-4-腈或其适用的盐反应期间，由将约11％-约75％(V/V)量的水加到醋酸中减少生成N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺的反应时间，可获得高纯度产物改善了的产率。
在N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺的形成中，已意想不到地发现了将约10％-85％(V/V)的水加到醋酸中获得了极高纯度的产物和高产率。此外，反应时间从约3-3.5小时大大降低为1-3.5小时，反应温度从90℃降到约25℃-约70℃。相反，现有技术的方法在回流温度(约120℃)使用醋酸，在此温度下由于污染物使产率和纯度都很低。改进方法意想不到地除去了常常引起产物为淡黄色的污染物。因此得到基本上是白色、灰白或透明的产物(透明产物可在开始或重结晶时获得)
在N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺的形成中，已发现水和醋酸的适用的比例范围是约10％-约85％，优选11％-约75％，60％-75％(1∶2V/V醋酸∶水)是最优选的。在本发明优选的具体实例中，使用约1∶2V/V醋酸∶水的比例。当按照本发明使用醋酸水溶液时，得到的产物的产率和纯度大大高于在此以前。
水可适于在此工艺开始时加到醋酸中。此外它也可以在工艺中、步骤中或逐渐增加量的方式加到反应混合物中。本发明的一个观点包括在工艺开始将第一部份水加到反应混合物中，接着在反应基本完成时将第二部份水一次加入，例如利于产物的回收。在第二次加水期间加入的水的量优选充分使醋酸中总水量达到约10％-约85％，优选约11％-75％，最优选约60％-约75％。在本发明的一个优选的具体实施方案中达到约1∶2V/V醋酸∶水的比例。
本技术领域技术人员应清楚，使用起始化合物中的一种或两种可接受的盐也适用进行本发明。
按照本发明的改进方法可导致反时间从约3小时-3.5小时降到1小时-3.5小时，反应温度从90℃降到约25℃-约70℃和易于用最少的加工步骤从一缶工艺分离的高纯度产物的生产。优选的温度为约40℃-约60℃，更优选的温度约为50℃。优选的反应温度为约1小时-约3.5小时，更优选1小时-2.5小时或1-2小时。最优选的反应时间是约1.5小时。获得的产物的优选产率至少是80％重量，更优选至少84％重量，最优选约85％重量。
因此，本发明提供了制备所指化合物N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺的方法，其方法包括3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮和3-氨基吡咯-4-腈在醋酸水溶液中反应，直至形成所述化合物并回收纯化的产物，产率得到改善。
本发明的方法在优选温度约25℃-约70℃、优选约1小时-3.5小时内维持所述反应并分离化合物来制备所指化合物N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺是特别有效的。
图1表示了形成N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺的产物产率(HPLC面积％)对于时间、温度变化和水在醋酸中浓度的变化和现有技术比较的关系图。
下面的反应式1说明了本发明的改进方法。在反应式1中，用3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮(1)和3-氨基吡唑-4-腈(2)反应制备N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺(3)。
反应式1
根据反应式1，3-二甲基氨基-1-(3-N-乙基，N-乙酰基氨基苯基)-2-丙烯-1-酮(1)和3-氨基吡唑-4-腈(2)在约11％-约75％的水醋酸中反应。在约1小时-约1.5小时后，在约25℃-70℃下完成反应，分离无污染物的所需产物N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺(3)。过滤收集产物，水洗并干燥。使用上述改进使制备N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺(3)与使用美国专利US4626538实施例14工艺中得到的76％总产率相比，产率为85％或更高。
此外，此化合物是在温度为25℃-约70℃，反应时间1小时-3.5小时的控制条件下制备。
在制备N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺(3)中将水加到醋酸中的效果表明在图1中。
正如图1所示，与现有技术相比，在较低温下、在醋酸水溶液中及较短的反应时间内完成化合物N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺的制备。实施例1
N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺
将于789ml醋酸和1500ml水中的315g 3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮和138g 3-氨基吡唑-4-腈混合物加温到约50℃。约1-1.5小时后，反应混合物冷却到约5-15℃，由过滤法收集形成的结晶产物，水洗并在60℃下干燥。获得的产物产率86.2％，由HPLC测定的面积百分比纯度为99.05％。实施例2
N-[3-(3-氰基吡唑并[1，5-a ]嘧啶-7-基)苯基]-N-乙基-乙酰胺
下面的表说明了实施例1的各种反应条件的效果。
                            表1实施例  时间    温度   摩尔    溶液比      产物    产率   HPLC面积％
    小时     ℃            醋酸/H2O     克      ％       纯度1       1.5      50°  0.04m    40/80ml    10.2    83.5      99.42       1.5      50°  0.04m    30/60ml    10.6    86        99.23       1.5      50°  0.04m    25/50ml    10.3    84.5      99.064       1.5      70°  0.04m    40/80ml    10.4    85        98.865       1.5      50°  0.27m    269/538ml  67      81.7      99.16       1.5      70°  0.27m    269/538ml  68      83        98.977       1.5      50°  0.4m     263/525ml  103     84        99.18       1.5      70°  0.4m     263/525ml  102     82.9      98.779       1.5      50°  0.4m     263/500ml  106     86.7      99.210      1.5      50°  1.21m    789/1500ml 318     86.2      99.0511      1.5      50°  0.04m    40/80ml    11      90        99.2912      1.5      50°  0.064m   40/80ml    16.9    86.3      98.9实施例3
N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺
将于37.5ml醋酸和113ml水中的3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮(13.02g，0.05m)和3-氨基吡唑-4-腈(5.7g，0.0527m)混合物加热到50℃。约1.5-2小时后，反应混合物冷却到10℃-20℃，过滤收集结晶产物，水洗并在60℃下干燥。得到13.1g产物，产率85.8％，用HPLC测的面积纯度98.2％。实施例4
N-[3-(3-氰基吡唑并[1，5-a ]嘧啶-7-基)苯基]-N-乙基-乙酰胺
将于50ml醋酸和100ml水中的3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮(13.02g，0.05m)和3-氨基吡唑-4-腈(5.6g，0.052m)的混合物加热到25℃-28℃。在约4.5小时后，反应混合物冷却到7-10℃，过滤收集结晶产物，水洗并在60℃下干燥。得到12.55g产物，产率82.2％，由HPLC测得面积纯度99.1％。
上述实施例说明了本发明实践的优选方法，换句话说，用3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮和3-氨基吡唑-4-腈反应，3-氨基吡唑-4-腈在优选比例的醋酸/水中，因此可用简单的冷却反应混合物的方法回收结晶产物。
在下述的3个实施例中本发明实践的另外方法表明：换句话说，将3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮和3-氨基吡唑-4-腈反应，3-氨基吡唑-4-腈在醋酸/水初始比大于1/3-2/3(60％-75％水/醋酸)的醋酸和水中，在开始回收结晶物前加入更多的水以达到此比例。实施例5
N-[3-(3-氰基吡唑并[1，5-a ]嘧啶-7-基)苯基]-N-乙基-乙酰胺
将于12ml醋酸和1.5ml水中的3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮(2.6g，0.010m)和3-氨基吡唑-4-腈(1.14g，0.010mm)加热到70℃。在约2小时后，将30ml水加到反应混合物中并在1小时内将其冷却到室温(20℃)过滤回收产生的结晶产物，水洗并在60℃下干燥。得到的产物(2.55g)的产率为83.5％，面积纯度为97.3％。实施例6
N-[3-(3-氰基吡唑并[1，5-a ]嘧啶-7-基)苯基]-N-乙基-乙酰胺
将于85ml醋酸和50ml水中的3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮(13.02g，0.05m)和3-氨基吡唑-4-腈(5.7g，0.0527m)的混合物加热到50℃。在约2.5-3小时后，将108ml水加到反应混合物中并将此混合物冷却到10℃。得到产率为76.5％和面积纯度为99.4％的结晶产物(12.15g)。在过夜冷却到5℃后从母液收集第二批产物晶体(1.21g)，产率7.9％，96.2％面积纯度。(总产量为15.3g，总产率为87.2％)实施例7
N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺
将于60ml醋酸和18ml水中的3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮(20g，0.077m)和3-氨基吡唑-4-腈(9.3g，0.086m)混合物加热到60℃。3.5小时后，将102ml水加到反应混合物中，使其在3小时内缓慢冷却到0℃。过滤收集产生的结晶产物，水洗并在60℃下真空中干燥。得到的产物(21g)产率为88％，由HPLC测定的面积纯度为99.2％。

Claims (9)

1.制备N-[3-(3-氰基吡唑并[1，5-a]嘧啶-7-基)苯基]-N-乙基-乙酰胺的方法，其包括在含水和醋酸或其适用的盐的混合物中将3-二甲基氨基-1-(3-N-乙基-N-乙酰基氨基苯基)-2-丙烯-1-酮或其适用的盐和3-氨基吡唑-4-腈或其适用的盐反应。
2.根据权利要求1的方法，其中反应是在含水∶醋酸约为10％-85％(V/V)的混合物中进行。
3.根据权利要求1的方法，其中反应是在含水∶醋酸为约11％-约75％的混合物中进行。
4.根据权利要求1的方法，其中反应是在含水∶醋酸为约60％-约75％(V/V)的混合物中进行。
5.根据权利要求1-4中任一权利要求的方法，其中反应温度为约25℃-约70℃。
6.根据权利要求1-4中任一权利要求的方法，其中反应温度为约40℃-60℃。
7.根据权利要求1-6中任一权利要求的方法，其中完成反应的时间为约1小时-3.5小时。
8.根据权利要求1-6中任一权利要求的方法，其中完成反应的时间为约1小时-2.5小时。
9.根据权利要求1-6中任一权利要求的方法，其中完成反应的时间为约1小时-2小时。
CN96118985A 1995-12-01 1996-11-30 N－[3－(3－氰基吡唑并[1,5－a]嘧啶－7－基)苯基]－N－乙基－乙酰胺合成的改进方法 Expired - Fee Related CN1057525C (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102816163A (zh) * 2012-08-20 2012-12-12 四川禾邦阳光制药股份有限公司 扎来普隆的新晶型及制备方法

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6399621B1 (en) 1999-08-10 2002-06-04 American Cyanamid Company N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1, 5-α]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto
US20030091632A1 (en) * 1999-08-26 2003-05-15 Neurocrine Biosciences, Inc. Controlled-release sedative-hypnotic compositions and methods related thereto
US6485746B1 (en) 2000-08-25 2002-11-26 Neurocrine Biosciences, Inc. Controlled-release sedative-hypnotic compositions and methods related thereto
US6384221B1 (en) 1999-09-02 2002-05-07 Neurocrine Biosciences, Inc. Polymorphs of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto
CN1610682A (zh) * 2000-08-03 2005-04-27 Wyeth公司 扎来普隆多晶型物及其制备方法
EP1526136A1 (en) * 2000-08-03 2005-04-27 Wyeth Polymorphs of zaleplon and methods for the preparation thereof
AR029780A1 (es) 2000-12-13 2003-07-16 Gador Sa Procedimiento mejorado para la obtencion de n-[3(3-ciano-pirazolo[1,5-a]pirimidin-7-il)fenil]-n-etil-acetamida
US20050032818A1 (en) * 2001-06-12 2005-02-10 Entire Interest N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide and crystalline forms of zaleplon
IL159281A0 (en) * 2001-06-12 2004-06-01 Biogal Pharmaceutical Co Ltd Process for the production of n-[3-(3-cyanopyrazolo{1,5-a} pyrimidin-7-yl) phenyl]-n-ethylacetamide (zaleplon)
HUP0402253A3 (en) * 2001-08-01 2005-12-28 Teva Gyogyszergyar Zartkoeruee Process for the purification of n-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-n-ethylacetamide(zaleplon) and the preparation of its novel crystalline forms and pharmaceutical compositions containing the latters
ATE368667T1 (de) * 2002-02-14 2007-08-15 Cilag Ag Verfahren zur herstellung von n-ethyl-n-(3-(3- cyanopyrazolo-(1,5-a)-pyrimidin-7-yl)phenyl)- acetamid
EP1490068A1 (en) * 2002-02-15 2004-12-29 Biogal Gyogyszergyar Rt. Powder composition comprising zaleplon of defined particle size distribution and pharmaceutical products made therefrom
PL207322B1 (pl) * 2002-05-14 2010-11-30 Adamed Społka Z Ograniczoną Odpowiedzialnością Sposób wytwarzania zaleplonu
DE112004001615T5 (de) * 2003-09-04 2006-06-14 Cipla Ltd. Zaleplon-Synthese
US20050176680A1 (en) 2003-12-11 2005-08-11 Sepracor, Inc. Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
CA2553465A1 (en) * 2004-01-14 2005-08-04 Mallinckrodt Inc. Two-phase method for the synthesis of selected pyrazolopyrimidines
HUP0400325A3 (en) * 2004-02-02 2005-11-28 Richter Gedeon Vegyeszet Pure n-[3-(-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-n-ethyl-acetamide, process for its preparation and intermediates
AU2005215376B2 (en) 2004-02-18 2011-01-20 Sunovion Pharmaceuticals Inc. Dopamine-agonist combination therapy with sedatives for improving sleep quality
WO2006070244A2 (en) * 2004-11-22 2006-07-06 Bakulesh Mafatlal Khamar A process for the preparation of zaleplon
TW200815428A (en) * 2006-08-15 2008-04-01 Wyeth Corp Oxazolidone derivatives as PR modulators
US7538107B2 (en) 2006-08-15 2009-05-26 Wyeth Oxazinan-2-one derivatives useful as PR modulators
US7652018B2 (en) * 2006-08-15 2010-01-26 Wyeth Llc Imidazolidin-2-one derivatives useful as PR modulators
US7649007B2 (en) * 2006-08-15 2010-01-19 Wyeth Llc Oxazolidine derivatives as PR modulators
WO2008068600A2 (en) * 2006-12-06 2008-06-12 Orchid Chemicals & Pharmaceuticals Limited An improved process for the preparation of zaleplo
CZ301145B6 (cs) 2008-07-31 2009-11-18 Farmak, A. S. Zpusob prípravy N-(1-benzo[b]thien-2-ylethyl)-N-hydroxymocoviny
CN112694336B (zh) * 2020-12-29 2021-11-16 哈尔滨工业大学 一种高纯α相氮化硅纤维毡的制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4281000A (en) * 1979-07-09 1981-07-28 American Cyanamid Company Substituted pyrazolo (1,5-a)pyrimidines and their use as anxiolytic agents
US4626538A (en) * 1983-06-23 1986-12-02 American Cyanamid Company [7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines
US4521422A (en) * 1983-06-23 1985-06-04 American Cyanamid Company Aryl and heteroaryl[7-(aryl and heteroaryl)pyrazolo[1,5-a]pyrimidin-3-yl]methanones
NZ208554A (en) * 1983-06-23 1987-06-30 American Cyanamid Co (aryl and heteroaryl)-(7-(aryl and heteroaryl)-pyrazolo (1,5-a) pyrimidin-3-yl)-methanone derivatives and pharmaceutical compositions
JPS62270584A (ja) * 1986-04-28 1987-11-24 Yoshitomi Pharmaceut Ind Ltd ４，７−ジヒドロピラゾロ〔１，５−ａ〕ピリミジン誘導体
GB9321162D0 (en) * 1993-10-13 1993-12-01 Boots Co Plc Therapeutic agents

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102816163A (zh) * 2012-08-20 2012-12-12 四川禾邦阳光制药股份有限公司 扎来普隆的新晶型及制备方法

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