EA027928B1 - СИНТЕЗ ПИРРОЛО[2,3-b]ПИРИДИНОВ - Google Patents

СИНТЕЗ ПИРРОЛО[2,3-b]ПИРИДИНОВ Download PDF

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EA027928B1
EA027928B1 EA201492165A EA201492165A EA027928B1 EA 027928 B1 EA027928 B1 EA 027928B1 EA 201492165 A EA201492165 A EA 201492165A EA 201492165 A EA201492165 A EA 201492165A EA 027928 B1 EA027928 B1 EA 027928B1
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pyrrolo
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EA201492165A
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EA201492165A1 (ru
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Прабха Н. Ибрахим
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Плексксикон Инк.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Steroid Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

В изобретении представлено соединение формулы

Description

Настоящая заявка в соответствии со сводом законов США, раздел 35, § 119(е), испрашивает приоритет предварительной заявки на патент США № 61/653994, поданной 31 мая 2012 года, полное содержание которой включено в настоящий документ посредством ссылки.
Область техники
Настоящее изобретение относится к конкретному гетероциклическому соединению.
Уровень техники
Н-[3-[5-(4-хлорфенил)-1Н-пирроло[2,3-Ь]пиридин-3-карбонил]-2,4-дифторфенил]пропан-1-сульфонамид или пропан-1-сульфоновой кислоты {3-[5-(4-хлорфенил)-1Н-пирроло[2,3-Ь]пиридин-3-карбонил]2,4-дифторфенил}амид (вемурафениб; 7е1ЬогаГ™) эффективен для лечения различных В-гаГ опосредованных заболеваний и состояний, включая, но не ограничиваясь ими, метастатическую меланому, рак щитовидной железы и рак толстой и прямой кишки (ЛаШте, 2010, 467, 596-599; Ие\у Епц1апс1 1оитпа1 оГ МеЙ1С1пе, 2010, 363, 80). Указанное соединение и его синтез описаны в публикациях патентов РСТ №№ АО 2007/002433 и АО 2007/002325. Сохраняется интерес к разработке других универсальных и легких способов эффективного получения этой и других биологически активных молекул, в частности, в промышленном масштабе.
В одном аспекте настоящего изобретения представлено соединение формулы
Подробное описание изобретения
Настоящее изобретение относится к новому соединению формулы
В одном аспекте настоящего изобретения представлено соединение формулы
Следующие примеры представлены для иллюстрации, но не для ограничения заявленного изобретения.
Некоторые молекулы, заявленные в настоящем патенте, могут существовать в различных энантиомерных и диастереомерных формах, и все такие варианты этих соединений являются заявленными.
Специалистам в данной области техники понятно также, что при выполнении стандартных приемов выделения в органической химии зачастую используют кислоты и основания. Иногда, если они обладают необходимой естественной кислотностью или основностью, при выполнении экспериментальных способов, описанных в настоящем патенте, образуются соли исходных соединений.
Пример 1. Получение (5-бром-1 Н-пирроло [2,3-Ь] пиридин-3 -ил)-(2,6-дифтор-3 -нитро-фенил)метанона (3).
- 1 027928
В 50 л колбу добавили 1,2-дихлорэтан (ДХЭ, 20 л), затем 5-бромазаиндол (1) (2 кг, 10,152 моль) с получением оранжевой взвеси. В колбу медленно добавили хлорид алюминия (5,421 кг, 40,608 моль). При добавлении первых 1,5 кг наблюдали выделение тепла с образованием темного раствора. Добавили остальное количество А1С13 с получением реакционной смеси. К реакционной смеси добавили 2,6дифтор-3-нитробензоилхлорид 2 (2,25 кг, 10,125 моль) через капельную воронку за период 1,5 ч. Во время добавления температуру реакционной смеси поддерживали при 45°С или ниже. После добавления реакционную смесь перемешивали при 50°С в течение ночи, охладили до комнатной температуры (~22°С) и перенесли в две отдельные 20 л колбы. В 50 л колбу добавили воду (25 л) и ацетонитрил (12 л) и охладили до 0°С. Реакционную смесь погасили добавлением раствора воды/ацетонитрила, поддерживая температуру при 40°С или ниже. Полученную смесь отфильтровали, а фильтрат промыли смесью ацетонитрила:воды (1:1, 2x4 л), водой (4 л) и ацетонитрилом (4 л), затем высушили в вакууме. Получили соединение 3 (2,948 кг, выход 73,4%). М8 (Ε8Ι): М+Н+=382,9 и 383,9. 1Н ЯМР (ДМСО-ά6, δ м.д.): 7,55 (1Н, т), 8,47 (2Н, т), 8,53 (1Н, ά, 1=2,2 Гц), 8,65 (1Н, ά, 1=2,2 Гц), 13,25 (1Н, з).
Пример 2. Получение (3-амино-2,6-дифторфенил)-(5-бром-1Н-пирроло[2,3-Ь]пиридин-3ил)метанона (4)
В 50 л колбу добавили 2-метил-тетрагидрофуран (2-метил-ТГФ) (36 л), соединение 3 (2,85 кг, 7,455 моль) и хлорид олова (ΙΙ) (5,03 кг, 22,365 моль). Смесь нагревали до 60°С. После завершения реакции смесь погасили водным раствором карбоната калия (20%). Полученную смесь отфильтровали через целит, а твердый остаток промыли 2-метил-ТГФ и тетрагидрофураном (ТГФ). Фильтрат промыли водным раствором \аС’1 (15 л, 10%), и отделили органический слой. Органический слой дополнительно промыли водным раствором \аС’1 (15 л, 20%) и концентрировали на ротационном испарителе с получением соединения 4 (2,536 кг, выход 96,65%). М8 (Ε8Ι): М+Н+=353 и 354. 1Н ЯМР (ДМСО- ά6, δ м.д.): 5,22 (2Н, з), 6,93 (2Н, т), 8,12 (1Н, з), 8,47 (1Н, ά 1=2,3 Гц), 8,54 (1Н, ά 1=1,6 Гц), 13,2 (1Н, з).
Пример 3. Получение (3-амино-2,6-дифторфенил)-[5-бром-1-(2,6-дихлорбензоил)пирроло[2,3Ь]пиридин-3-ил]метанона (5)
Соединение 4 (2,5 кг, 7,114 моль), полученное в примере 2, добавили в 50 л колбу и охладили до 9,3°С. К соединению 4 в 50 л колбе добавили триэтиламин (0,864 мг, 8,537 моль), затем 4диметиламинопиридин (ΏΜΑΡ) (0,087 кг, 0,7114 моль) и 2,6-дихлорбензоилхлорид (1,34 кг, 6,40 моль) в 2-метил-ТГФ (25 л) за период времени 2 ч. Реакцию погасили метанолом (0,30 л) при комнатной температуре и добавили водный раствор \аС’1 (12,5 л, 15%) и целит (0,5 кг). Смесь перемешали и отфильтровали через целит. Фильтрат концентрировали и добавили 5 объемов гептана. Полученный раствор перемешивали в течение около 1 ч, высушили при помощи сульфата натрия (1 кг) и отфильтровали. Соединение 5 выделили удалением растворителей под вакуумом (3,47 кг, выход 92,93%). М8 (Ε8Ι): М+Н+=524, 525,8, 527,8. 1Н ЯМР (ДМСО-ά6, δ м.д.): 5,36 (2Н, з), 7,01 (2Н, т), 7,68 (3Н, з), 8,34 (1Н, Ьгз), 8,61 (1Н, Ьгз), 8,72 (1Н, ά 1=2,3 Гц).
Специалистам в данной области техники понятно, что настоящее изобретение хорошо подходит для достижения упомянутых, а также присущих ему целей и преимуществ. Способы, варианты и композиции, описанные в настоящем документе, представлены в качестве иллюстрации предпочтительных вариантов реализации, и они являются лишь примерными и не предназначены для ограничения рамок на- 2 027928 стоящего изобретения. Специалистам в данной области техники понятны изменения в них и в других применениях, которые охвачены общей идеей изобретения и определены в рамках формулы изобретения.
Хотя настоящее изобретение было описано со ссылкой на конкретные варианты реализации, понятно, что другие варианты реализации и альтернативы настоящего изобретения могут быть разработаны специалистами в данной области техники без отклонения от реальной идеи и рамок настоящего изобретения.

Claims (1)

  1. ФОРМУЛА ИЗОБРЕТЕНИЯ
    Соединение формулы
EA201492165A 2012-05-31 2013-05-30 СИНТЕЗ ПИРРОЛО[2,3-b]ПИРИДИНОВ EA027928B1 (ru)

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US201261653994P 2012-05-31 2012-05-31
US13/793,917 US9150570B2 (en) 2012-05-31 2013-03-11 Synthesis of heterocyclic compounds
PCT/US2013/043400 WO2013181415A1 (en) 2012-05-31 2013-05-30 Synthesis of pyrrolo [2, 3 - b] pyridines

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