WO2016046837A1 - Procédé amélioré de préparation de composés pyrrolo[3,4-c]pyrroles et d'intermédiaires de ces composés - Google Patents

Procédé amélioré de préparation de composés pyrrolo[3,4-c]pyrroles et d'intermédiaires de ces composés Download PDF

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Publication number
WO2016046837A1
WO2016046837A1 PCT/IN2015/000368 IN2015000368W WO2016046837A1 WO 2016046837 A1 WO2016046837 A1 WO 2016046837A1 IN 2015000368 W IN2015000368 W IN 2015000368W WO 2016046837 A1 WO2016046837 A1 WO 2016046837A1
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Prior art keywords
acid
compound
formula
pharmaceutically acceptable
alkyl
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PCT/IN2015/000368
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English (en)
Inventor
Kumar Kamlesh SINGH
Suryanaresh CHUNDURU
Chintan Pramodray VAKHARIYA
Kirtipalsinh Sajjansinh Solanki
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Cadila Healthcare Limited
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Publication of WO2016046837A1 publication Critical patent/WO2016046837A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the field of the invention relates an improved process for the preparation of pyrrolo[3,4-c]pyrrole compounds and intermediates thereof.
  • the present invention relates to new pyrrolo[3,4-c]pyrrole compounds of the general Formula (1) or salts thereof.
  • n represents an integer of 1 to 3
  • n 1 or 2
  • Ri or R 2 represents hydrogen or lower alkyl and their salts.
  • U.S. Patent No. 8,003,677 B2 discloses 2- heteroaryl-pyrrolo[3,4-C]pyrrole derivatives and their use as SCD inhibitors of Formula II or their physiologically compatible salts, their pharmaceutical compositions and their uses as SCD1 inhibitors.
  • n represents an integer of 1 to 3
  • Ri and R 2 are same or different and represents hydrogen, halo, haloalkyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, S(0)n, S(0)n(C 1- )alkyl, S(0)n(C 1-6 )aryl, S(0)nNH 2 , S(0)nNH(C 1-6 )alkyl, S(0)nCONHaryl, Nitro, COO(C )alkyl, CO or CONH(C 1-6 )alkyl groups;
  • the solution prior to any solids formation, can be filtered to remove any un-dissolved solids, solid impurities and the like prior to removal of the solvent.
  • Any filtration system and filtration techniques known in the art can be used.
  • n represents an integer of 1 to 3
  • Rj and R 2 are same or different and represents hydrogen, halo, haloalkyl, amino, cyano, Ci -6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, S(0)n(Ci -6 )alkyl, S(0)n(C, -6 )aryl, S(0)nNH 2 , S(0)nNH(C 1-6 )alkyl, S(0)nCONHaryl, Nitro, COO(C 1-4 )alkyl or CONH(C 1-6 )alkyl groups.
  • the pharmaceutically acceptable salt comprises one or more of hydrochloride, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5- dinapsylate, lysinate, and arginate.
  • R 3 represents C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, aryl or cycloalkyl.
  • HX represents pharmaceutically acceptable acids
  • n represents an integer of 1 to 3
  • Ri and R 2 are same or different and represents hydrogen, halo, haloalkyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C2 -6 alkynyl, aryl, cycloalkyl, S(0)n(C 1-6 )alkyl, S(0)n(C )-6 )aryl, S(0)nNH 2 , S(0)nNH(Ci -6 )alkyl, S(0)nCONHaryl, Nitro, COO(C 1-4 )alkyl or CONH(C 1-6 )alkyl groups;
  • R 3 represents C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl or cycloalkyl; (b) reacting the compound of Formula (4) with an acid to obtain a pharmaceutically acceptable salt of compound of Formula (3 a),
  • the protecting agent in step (a) comprises one or more of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl or cycloalkyl ester groups bearing agents.
  • boc anhydride may be used.
  • the acid comprises one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, fumaric acid, malic acid, succinic acid, acetic acid, oxalic acid, tartaric acid, salicylic acid, tannic acid, citric acid, methane sulfonic acid, ethane sulfonic acid, ethane disulfonic acid, benzene sulfonic acid, toluene sulfonic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, lysine and arginine.
  • the protecting agent in step (c) comprises one or more of boc anhydride, acetyl chloride, mesyl chloride, tosyl chloride, and benzyl chloride.
  • mesyl chloride may be used.
  • the pharmaceutically acceptable salt comprises one or more of hydrochloride, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5- dinapsylate, lysinate, and arginate.
  • the reactions are performed in one or more solvents comprising methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, dimethyl form amide, dichloromethane, dimethyl acetamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, and 2-methyl tetrahydrofuran.
  • the reaction of compound (3a) with a protecting agent is performed in presence of a base.
  • the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, cesium carbonate, triethylamine, diisopropylethyl amine, diethylamine, pyridine, piperidine, and DBU.
  • triethylamine may be used.
  • the compound of formula (1), or pharmaceutically acceptable salts thereof are converted into pharmaceutically active agents or pharmaceutically acceptable salts thereof.
  • Example-1 Di-tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-di carboxylate (4)
  • Example-4 2-(methylsulfonyl)-l,2,3 ? 4,5,6-hexahydropyrrolo[3,4-c]pyrrole PTSA salt (1)
  • a 5 I- four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel Tert- butyl 5-(methylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate (95 g), methanol (1425 mL) and p-toluenesulfonic acid (125.33 g) was added and stirred.
  • the reaction mixture was heated to 55-60°C for 3 hours and cooled to 25-35°C.
  • the reaction mixture was filtered and washed with methanol (190 mL).
  • the filtrate thus obtained was distilled off under vacuum at 55-60°C to obtain the residue.
  • Isopropyl Acetate (475 mL) was added and stirred for 30 min.
  • the reaction mixture was cooled to 25-30°C and stirred for 2 hours.
  • the reaction mixture was filtered and washed with isopropyl acetate (190 mL).
  • the product thus obtained was dried and weighed to 102 g. (Yield 85.9%) and HPLC purity 98.57%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés pyrrolo[3,4-c]pyrroles de formule générale (1) ou des sels pharmaceutiquement acceptables de ces composés. La présente invention concerne également un procédé amélioré pour la préparation de composés pyrrolo[3,4-c]pyrroles et d'intermédiaires de ces composés.
PCT/IN2015/000368 2014-09-22 2015-09-22 Procédé amélioré de préparation de composés pyrrolo[3,4-c]pyrroles et d'intermédiaires de ces composés WO2016046837A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3026MU2014 2014-09-22
IN3026/MUM/2014 2014-09-22

Publications (1)

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WO2016046837A1 true WO2016046837A1 (fr) 2016-03-31

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10208052B1 (en) 2017-03-20 2019-02-19 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
CN109755580A (zh) * 2018-12-29 2019-05-14 桑德集团有限公司 一种锂硫电池粘结剂及其制备方法、正极材料
WO2020061255A1 (fr) * 2018-09-19 2020-03-26 Forma Therapeutics, Inc. Activation de la pyruvate kinase r
WO2020061378A1 (fr) * 2018-09-19 2020-03-26 Forma Therapeutics, Inc. Traitement de la drépanocytose avec un composé activant la pyruvate kinase r
WO2021055863A1 (fr) * 2019-09-19 2021-03-25 Forma Therapeutics, Inc. Compositions d'activation de la pyruvate kinase r (pkr)

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EP0424852A1 (fr) * 1989-10-23 1991-05-02 Korea Research Institute Of Chemical Technology Composés de diazabicycloamine et leur procédé de préparation
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EP0424850A1 (fr) * 1989-10-23 1991-05-02 Korea Research Institute Of Chemical Technology Composés de quinolone et procédé pour leur préparation
EP0424852A1 (fr) * 1989-10-23 1991-05-02 Korea Research Institute Of Chemical Technology Composés de diazabicycloamine et leur procédé de préparation
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WO2010108268A1 (fr) * 2009-03-23 2010-09-30 Merck Frosst Canada Ltd. Composés hétérocycliques inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase

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KEUN-SOO NAM ET AL: "Synthesis of quinolone antimicrobial agents and their antibacterial activities", KOREAN JOURNAL OF MEDICINAL CHEMISTRY, KOREAN CHEMICAL SOCIETY, SEOUL, KR, vol. 5, no. 1, 1 January 1995 (1995-01-01), pages 2 - 5, XP009188016, ISSN: 1225-0058 *

Cited By (21)

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US11014927B2 (en) 2017-03-20 2021-05-25 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US11649242B2 (en) 2017-03-20 2023-05-16 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
JP2019521090A (ja) * 2017-03-20 2019-07-25 フォーマ セラピューティクス，インコーポレイテッド ピルビン酸キナーゼ（ｐｋｒ）活性化剤としてのピロロピロール組成物
US10472371B2 (en) 2017-03-20 2019-11-12 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
JP2019206587A (ja) * 2017-03-20 2019-12-05 フォーマ セラピューティクス，インコーポレイテッド ピルビン酸キナーゼ（ｐｋｒ）活性化剤としてのピロロピロール組成物
US10208052B1 (en) 2017-03-20 2019-02-19 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
JP7213775B2 (ja) 2017-03-20 2023-01-27 フォーマ セラピューティクス，インコーポレイテッド ピルビン酸キナーゼ（ｐｋｒ）活性化剤としてのピロロピロール組成物
US11396513B2 (en) 2017-03-20 2022-07-26 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US10836771B2 (en) 2017-03-20 2020-11-17 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
WO2020061255A1 (fr) * 2018-09-19 2020-03-26 Forma Therapeutics, Inc. Activation de la pyruvate kinase r
US11001588B2 (en) 2018-09-19 2021-05-11 Forma Therapeutics, Inc. Activating pyruvate kinase R and mutants thereof
CN113166060A (zh) * 2018-09-19 2021-07-23 福马治疗股份有限公司 用丙酮酸激酶激活化合物治疗镰状细胞病
US11071725B2 (en) 2018-09-19 2021-07-27 Forma Therapeutics, Inc. Activating pyruvate kinase R
CN113226356A (zh) * 2018-09-19 2021-08-06 福马治疗股份有限公司 活化丙酮酸激酶r
US10675274B2 (en) 2018-09-19 2020-06-09 Forma Therapeutics, Inc. Activating pyruvate kinase R
WO2020061378A1 (fr) * 2018-09-19 2020-03-26 Forma Therapeutics, Inc. Traitement de la drépanocytose avec un composé activant la pyruvate kinase r
US11844787B2 (en) 2018-09-19 2023-12-19 Novo Nordisk Health Care Ag Activating pyruvate kinase R
CN113166060B (zh) * 2018-09-19 2024-01-09 诺沃挪第克健康护理股份公司 用丙酮酸激酶激活化合物治疗镰状细胞病
US11980611B2 (en) 2018-09-19 2024-05-14 Novo Nordisk Health Care Ag Treating sickle cell disease with a pyruvate kinase R activating compound
CN109755580A (zh) * 2018-12-29 2019-05-14 桑德集团有限公司 一种锂硫电池粘结剂及其制备方法、正极材料
WO2021055863A1 (fr) * 2019-09-19 2021-03-25 Forma Therapeutics, Inc. Compositions d'activation de la pyruvate kinase r (pkr)

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