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TWI580675B - Preparation of 4- [5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl] pyridine-2-carbonitrile and intermediates - Google Patents

Preparation of 4- [5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl] pyridine-2-carbonitrile and intermediates Download PDF

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TWI580675B
TWI580675B TW102126521A TW102126521A TWI580675B TW I580675 B TWI580675 B TW I580675B TW 102126521 A TW102126521 A TW 102126521A TW 102126521 A TW102126521 A TW 102126521A TW I580675 B TWI580675 B TW I580675B
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pyridine
triazol
pyridin
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TW201408642A (zh
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Yoshiyuki Iwabuchi
Sachiho Miyata
Junichiro Uda
Osamu Nagata
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Fujiyakuhin Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Description

4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈之製造方法及中間體
本發明係關於一種用作醫藥品之4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈之製造方法及用於其製造之新穎中間體。
4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈(1)具有黃嘌呤氧化酶阻礙作用，作為降低血清尿酸值之藥劑而為人所知(專利文獻1)。
作為上述化合物(1)之製造方法，例如已知將異菸鹼酸甲酯N-氧化物藉由Reissert Henze反應製成2-氰基異菸鹼酸甲酯，繼而將其製成醯肼，並使其與4-氰基吡啶進行縮合之方法(專利文獻1、實施例12)，及自異菸鹼酸N-氧化物獲得醯肼後，藉由Reissert Henze反應導入氰基後，與4-氰基吡啶縮合之方法(專利文獻1、實施例39)。又，亦報告有以4-氰基吡啶-N-氧化物為起始原料，與異菸鹼酸醯肼(isonicotinic acid hydrazide)縮合構築三唑環後，保護(專利文獻2)或不保護(專利文獻3)環，藉由Reissert Henze反應導入氰基獲得化合物(1)之方法。
[先前技術文獻] [專利文獻]
[專利文獻1]國際公開第2003/064410號
[專利文獻2]國際公開第2005/009991號
[專利文獻3]日本專利特開2005-41802號公報
然而，專利文獻1記載之方法係可以少量製造而達成充分目的之方法，但經取代或未經取代之2-氰基異菸鹼酸醯肼之製造煩雜，且必須根據於各步驟中生成化合物之物性選擇反應溶劑，有必須每個步驟進行單離等問題，進而，作為整體之產率未充分提高，故而於工業上生產時有問題。專利文獻2之方法由於保護三唑環而使反應步驟數增多，工業上生產時對成本亦有問題。專利文獻3之方法由於脫色或除去雜質而必需有複數個純化步驟，不適合於工業生產。
因此，本發明之課題在於提供一種用作醫藥之4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈之工業上有用的製造方法。
因此，本發明者等人對4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈之製造方法進行努力研究，結果藉由經由新穎中間體4-吡啶羧酸N'-(2-氰基吡啶-4-羧酸醯亞胺基)醯肼，發現目標化合物之工業上有用之製造方法，從而完成本發明。
即，本發明提供以下[1]~[4]。
[1]一種4-吡啶羧酸N'-(2-氰基吡啶-4-羧酸醯亞胺基)醯肼，其係下述式(4)
[化2]
所表示。
[2]一種如[1]之化合物之製造方法，其特徵在於：將下述式(2)
所表示之化合物、與異菸鹼酸醯肼於鹼金屬烷氧化物之存在下進行反應，將所獲得之下述式(3)
所表示之化合物藉由氰基化劑進行氰基化。
[3]一種下述式(1)
所表示之4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈之製造方法，其特徵在於：使下述式(2)
所表示之化合物、與異菸鹼酸醯肼於鹼金屬烷氧化物之存在下進行反應，將所獲得之下述式(3)
所表示之化合物藉由利用氰基化劑之氰基化反應獲得下述式(4)
所表示之化合物，繼而於酸觸媒下進行閉環反應。
[4]一種下述式(1)[化10]
所表示之4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈之製造方法，其特徵在於：使下述式(4)
所表示之化合物於酸觸媒下進行閉環反應。
根據本發明之製造方法，用作具有黃嘌呤氧化酶阻礙作用之醫藥之4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈藉由簡便之步驟，副生成物亦較少，可以高產率獲得。
以下，具體說明本發明。
本發明之方法係如下反應式表示。
[化11]
(第一步驟)
第一步驟係使4-氰基吡啶-N-氧化物(2)、與異菸鹼酸醯肼於鹼金屬烷氧化物之存在下進行反應獲得化合物(3)之步驟。
該反應所使用之4-氰基吡啶-N-氧化物(2)及異菸鹼酸醯肼之任一者均為已知化合物，可藉由其本身公知之方法而製造。
作為使用之鹼金屬烷氧化物，較佳為鹼金屬C1-C6烷氧化物，作為具體例，可列舉：甲醇鈉、乙醇鈉等。該反應較佳為於溶劑中進行，作為溶劑，較佳為甲醇、乙醇等醇系溶劑。
該反應較佳為首先於溶劑中，利用鹼金屬烷氧化物對化合物(2)進行處理，繼而與異菸鹼酸醯肼進行反應。首先，化合物(2)與鹼金屬烷氧化物之反應的反應溫度於冷卻下至加熱回流下，較佳為於15℃至80℃，通常反應30分鐘至12小時、較佳為1~4小時左右。接著與異菸鹼酸醯肼之反應於上述溫度條件下，使用當量或過剩量之一者，通常反應30分鐘至12小時、較佳為1~5小時左右。
(第二步驟)
第二步驟係將化合物(3)藉由氰基化劑氰基化獲得化合物(4)之步驟。
作為使用之氰基化劑，可列舉：氰化鈉、氰化鉀等鹼金屬氰化物，氰化鋅、氰化三甲基矽烷等三烷基氰化物。
該氰基化反應較佳為例如藉由Reissert Henze反應(Heterocycles,Vol.22,No.5,1994)而進行。該反應例如將化合物(3)於有機溶劑中，利用烷基胺甲醯鹵進行活化後，使氰基化劑進行反應，藉此獲得化合物(4)。作為Reissert Henze反應之最初步驟即胺甲醯基化所使用之烷基胺甲醯鹵，可使用二甲基胺甲醯氯、二丙基胺甲醯氯等二C1-C6烷基胺甲醯鹵，較佳為二甲基胺甲醯氯。作為本反應所使用之溶劑，可使用N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基吡咯啶酮、四氫呋喃、乙腈等，較佳為N,N-二甲基甲醯胺。又，作為反應溫度，較佳為15~60℃，更佳為30~50℃。作為反應時間，較佳為1~24小時，更佳為1~3小時。作為接著氰基化反應所使用之氰基化劑，可使用上述氰基化劑，較佳為氰化鈉、氰化鉀、氰化鋅、三甲基矽烷基腈等，更佳為氰化鈉。反應溫度較佳為-20~60℃，更佳為-10~40℃，攪拌1~4小時。
該第二步驟中獲得之化合物(4)為新穎化合物，用作用以製造化合物(1)之中間體。化合物(4)於第二步驟中無需純化而可簡便且高產率合成，又，只要經由化合物(4)，則可工業上高效製造化合物(1)。
(第三步驟)
第三步驟係藉由使化合物(4)於酸觸媒下進行閉環反應而獲得化合物(1)之步驟。
作為酸，可使用磷酸、對甲苯磺酸、鹽酸等有機酸、無機酸，較佳為無機酸，特佳為磷酸。作為反應溶劑，可使用水、2-丁醇、2-丙醇、乙醇等醇類，或水與醇類之混合溶劑，較佳為將水與2-丁醇混合成5：1~10：1之溶劑。反應溫度及時間為60~100℃、較佳為70~90℃下攪拌2~12小時、較佳為8~10小時。
本發明方法之中間體及化合物(1)可自反應混合物中藉由洗淨、再結晶、各種層析法等通常之方法進行單離、純化。
【實施例】
以下，列舉實施例說明本發明，但本發明並不限定於該等。
實施例之縮寫之意思如下所述。
1H-NMR：質子核磁共振光譜，DMSO-d6：氘化二甲基亞碸，Hz：赫茲，J：偶合常數，s：單峰，dd：雙雙峰，d：雙峰，br：寬峰。再者，NMR表示270MHz核磁共振光譜，使用TMS(四甲基矽烷)作為內部標準物質。MS表示質量分析，使用離子化法為ESI(電噴離子化法)之測定機器。
實施例1：N"-(4-吡啶羰基)-4-吡啶醯肼醯亞胺-1-氧化物(3)之合成
使4-氰基吡啶-N-氧化物(2)5.00g懸浮於甲醇40mL中，添加甲醇鈉22.4mg，於氮氣氛圍下40℃下攪拌2小時。於相同溫度下添加異菸鹼酸醯肼5.71g於40℃攪拌4小時。將反應液冷卻至室溫之後，濾取所析出之結晶，利用甲醇15mL進行洗淨後，於80℃下乾燥15小時，獲得N"-(4-吡啶羰基)-4-吡啶醯肼醯亞胺-1-氧化物(3)9.60g。
1H-NMR(DMSO-d6)δ(ppm)：6.98(br,2H),7.81(d,2H,J=5.77Hz),7.85(d,2H,J=7.09Hz),8.29(d,2H,J=7.09Hz),8.73(d,2H,J=5.77Hz),10.37(br,1H)
MS m/z：256[M-H]-
實施例2：4-吡啶羧酸N'-(2-氰基吡啶-4-羧酸醯亞胺基)醯肼(4)之合成
使N"-(4-吡啶羰基)-4-吡啶醯肼醯亞胺-1-氧化物(3)10.0g懸浮於N,N-二甲基甲醯胺48mL中，於氮氣氛圍下，於40℃下添加二甲基胺甲醯氯9.20g並攪拌1小時。於相同溫度下添加氰化鈉2.48g，進而攪拌1小時。將反應液冷卻至5℃以下之後，依序滴加5%碳酸氫鈉水溶液100mL、水100mL。濾取析出之結晶，利用水100mL進行洗淨之 後，於80℃下減壓乾燥15小時，獲得4-吡啶羧酸N'-(2-氰基吡啶-4-羧酸醯亞胺基)醯肼(4)9.28g。
1H-NMR(DMSO-d6)δ(ppm)：7.15(br,2H),7.82(d,2H,J=5.61Hz),8.14(d,1H,J=5.11Hz),8.37(s,1H),8.75(d,2H,J=5.61Hz),8.86(d,1H,J=5.11Hz),10.47(br,1H)
MS m/z：265[M-H]-
實施例3：4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈(1)之合成
於4-吡啶羧酸N'-(2-氰基吡啶-4-羧酸醯亞胺基)醯肼(4)9.25g中添加水82mL、2-丁醇8.2mL、磷酸4.00g，於80℃下攪拌8小時。將反應液冷卻至室溫，濾取析出之結晶之後，利用水：2-丁醇=10：1之混合溶液92.5mL進行洗淨。將所獲得之結晶於80℃下減壓乾燥13小時，獲得4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈(1)7.89g。
1H-NMR(DMSO-d6)δ(ppm)：8.02(dd,2H,J=4.59,1.62Hz),8.32(dd,1H,J=5.13,1.62Hz),8.55(dd,1H,J=1.62,1.08Hz),8.80(dd,2H,J=4.59,1.62Hz),8.93(dd,1H,5.13,1.08Hz)
MS m/z：247[M-H]-

Claims (3)

  1. 一種下述式(1)所表示之4-[5-(吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-碳腈之製造方法， 其特徵在於：使下述式(2) 所表示之化合物、與異菸鹼酸醯肼，於鹼金屬烷氧化物之存在下進行反應，將所獲得之下述式(3) 之化合物，藉由利用氰基化劑之氰基化反應，獲得下述式(4) 所示之化合物，繼而於酸觸媒下，進行閉環反應。
  2. 如請求項1之製造方法，其中上述氰基化劑為鹼金屬氰化物、氰化鋅或三烷基氰化物。
  3. 如請求項1之製造方法，其中上述酸觸媒為有機酸觸媒或無機酸觸媒。
TW102126521A 2012-07-25 2013-07-24 Preparation of 4- [5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl] pyridine-2-carbonitrile and intermediates TWI580675B (zh)

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CN107531677A (zh) * 2015-02-25 2018-01-02 法尔玛赞公司 用于制备托匹司他及其中间体的方法
CN105693699B (zh) * 2015-03-30 2019-06-18 苏州晶云药物科技股份有限公司 托吡司他的晶型及其制备方法
CN104758263B (zh) * 2015-04-22 2017-08-22 青岛正大海尔制药有限公司 一种托匹司他片及其制备方法
CN105294656A (zh) * 2015-10-10 2016-02-03 大道隆达（北京）医药科技发展有限公司 一种托匹司他的制备工艺和方法
CN106008465A (zh) * 2016-03-16 2016-10-12 江苏悦兴药业有限公司 一种托匹司他杂质的合成方法
CN108101840A (zh) * 2018-01-26 2018-06-01 南京华威医药科技集团有限公司 托吡司他及其中间体制备方法
CN113666909B (zh) * 2020-05-14 2024-07-02 鲁南制药集团股份有限公司 一种托匹司他的制备方法
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IL236081A0 (en) 2015-02-01
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WO2014017516A1 (ja) 2014-01-30
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