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WO2018234962A1 - Procédé de o-sulfonation de composés 1,6-diazabicyclo[3.2.1]octane - Google Patents

Procédé de o-sulfonation de composés 1,6-diazabicyclo[3.2.1]octane Download PDF

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Publication number
WO2018234962A1
WO2018234962A1 PCT/IB2018/054420 IB2018054420W WO2018234962A1 WO 2018234962 A1 WO2018234962 A1 WO 2018234962A1 IB 2018054420 W IB2018054420 W IB 2018054420W WO 2018234962 A1 WO2018234962 A1 WO 2018234962A1
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WIPO (PCT)
Prior art keywords
formula
compound
tetra
process according
butyl ammonium
Prior art date
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Ceased
Application number
PCT/IB2018/054420
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English (en)
Inventor
Shivaji Sampatrao Pawar
Bharat Daulatrao DOND
Satish Bhavsar
Ashok Sukadev JADHAV
Vinod Kashinath AHIRRAO
Kiran Ramchandra PATIL
Ravindra Dattatraya Yeole
Prasad Keshav Deshpande
Mahesh Vithalbhai Patel
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Wockhardt Ltd
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Wockhardt Ltd
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Publication date
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Publication of WO2018234962A1 publication Critical patent/WO2018234962A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07D471/08—Bridged systems

Definitions

  • the invention relates to a process for O-sulfonation of l,6-diazabicyclo[3.2.1]octane compounds.
  • the compound of Formula (I) may be obtained by O-sulfonation of a compound of Formula (II) using various sulfonation agents such as, for example, pyridine- sulfur trioxide complex.
  • the present invention provides an improved process for O-sulfonation of compounds of general Formula (II) to obtain the corresponding compounds of general Formula (I).
  • Rl and R2 are independently selected from hydrogen or an amine protecting groups; the process comprising steps of:
  • step (c) removing triethyl amine hydrochloride from the reaction mixture obtained in step (b), by addition of anti-solvent; (d) adding aqueous buffer solution having a pH between about 4 to 8, to the reaction mass obtained in step (c) to obtain organic and aqueous layers;
  • step (f) extracting the reaction mass obtained in step (e) above with an organic solvent to obtain tetra-butyl ammonium salt of Formula (III);
  • Rl and R2 are independently selected from hydrogen or an amine protecting groups; the process comprising steps of:
  • step (c) removing triethyl amine hydrochloride from the reaction mixture obtained in step (b), by addition of anti-solvent;
  • step (d) adding aqueous buffer solution having a pH between about 4 to 8, to the reaction mass obtained in step (c) to obtain organic and aqueous layers;
  • step (e) adding tetra-butyl ammonium hydrogen sulfate to the aqueous layer; (f) extracting the reaction mass obtained in step (e) above with an organic solvent to obtain tetra-butyl ammonium salt of Formula (III);
  • amine protecting groups refers to the protecting groups that are used in the synthetic chemistry procedures to prevent the amine group for reacting with one or more of the reagents. Typical non-limiting example of such groups include ie/t-Butyloxycarbonyl (BOC) group.
  • the process according to the invention involves preparation of an O- sulfonation reagent by reacting chlorosulfonic acid with triethyl amine in presence of an organic solvent.
  • solvents can be used for this step. Typical, non-limiting examples of such solvents include chlorinated solvents such as dichloromethane, ethylene dichloride, chloroform and so on. In some embodiment, the solvent used is dichloromethane.
  • the O-sulfonation reagent is prepared by reacting one equivalent of chlorosulfonic acid with two equivalents of triethyl amine. The O-sulfonation reagent may be used as such in further steps. Alternatively, the O-sulfonation reagent may be isolated and then used in the solid form in the further reactions.
  • the compound of Formula (II) is reacted with the O-sulfonation reagent in presence of a base and organic solvent.
  • solvents can be used for this step. Typical, non-limiting examples of such solvents include chlorinated solvents such as dichloromethane, ethylene dichloride, chloroform and so on. In some embodiment, the solvent used is dichloromethane.
  • the reaction of the compound of Formula (II) with the O-sulfonation reagent is carried in presence of a base.
  • bases can be used in this step. In some embodiments, the based used in this step is an organic base. In some other embodiments, the base used in this step is triethyl amine.
  • the reaction of the compound of Formula (II) with the O-sulfonation reagents results in the formation of triethyl amine hydrochloride, which can be removed by addition of an anti-solvent into the reaction mixture obtained in step (b).
  • an anti-solvent A wide variety of solvents that result in removal of triethyl amine hydrochloride can be used as anti-solvents.
  • the triethyl amine hydrochloride is removed by addition of ethyl acetate.
  • triethyl amine hydrochloride separates as solid and can removed by a simple filtration.
  • an aqueous buffer solution having a pH in the range within about 4 to 8 is added to the reaction mixture obtained in step (c), which results in the separation of organic and aqueous layers.
  • aqueous buffer solutions can be used to obtain separation of organic and aqueous layers.
  • the organic and aqueous layers are obtained by addition of aqueous potassium hydrogen phosphate solution. The aqueous layer is used as such in further reactions.
  • step (c) tetra-butyl ammonium hydrogen sulfate is added to the aqueous layer obtained in step (d) to obtain the tetra-butyl ammonium salt of Formula (III).
  • organic solvent is added to the aqueous layer obtained in the step (e) above to extract the tetra-butyl ammonium salt of Formula (III). Addition of the organic solvent results in the separation of organic and aqueous layers.
  • the tetra-butyl ammonium salt of Formula (III) is present in the organic solvent.
  • a wide variety of organic solvents can be used in this step.
  • the organic solvent used in this step is dichloro methane.
  • the tetra-butyl ammonium salt of Formula (III) may be isolated or used such in the further reactions.
  • the tetra-butyl ammonium salt of Formula (III) obtained in step (f) above is converted into corresponding compound of Formula (I) or a salt thereof.
  • a wide variety of reagents can be used to convert the tetra-butyl ammonium salt of Formula (III) into the corresponding compound of Formula (I) or a salt thereof.
  • the compound of Formula (I) is obtained by treating the tetra-butyl ammonium salt of Formula (III) with trifluoro acetic acid.
  • the corresponding compound of Formula (I) may or may not contain the amine protecting group depending on the reagents used in the conversion of the tetra- butyl ammonium salt of Formula (III) into the corresponding compound of Formula (I).
  • the compound of Formula (I) obtained can be converted into the corresponding salt by procedures known in the art.
  • tetra-butyl ammonium salt of Formula (III) can be treated with a suitable reagent to obtain the compound of Formula (I) in a salt form.
  • the tetra-butyl ammonium salt of Formula (III) is converted into a sodium salt of the compound of Formula (I) by treating the tetra-butyl ammonium salt of Formula (III) with sodium-2- ethyl hexanoate or a suitable ion-exchange resin.
  • the O-sulfonation reagent was prepared as follows. A solution of triethyl amine (20.2 gm, 0.1996 mol) in dichloro methane (125 ml) was cooled to about 0 - 5°C under stirring. To the clear solution so obtained, chlorosulfonic acid (11.68 gm, 0.0998 mol) was added via addition funnel by maintaining temperature between within the range of about 0 - 5°C. The reaction contents were stirred for 1 hour at room temperature. The reagent suspension so obtained is used as it is in the further steps.
  • the compound of Formula (Il-a) (20.5 gm, 0.0499 mol) was dissolved in dichloromethane (125 ml) and triethyl amine (15.12 gm, 0.1497 mol) was added to this solution to obtain a clear solution.
  • the solution was cooled to about 0 - 5°C.
  • the O-sulfonation reagent (in the form of a suspension) obtained above was added to this solution using addition funnel while maintaining the temperature in the range within about 0 - 5°C.
  • the reaction contents were stirred for about 1.5 hours at room temperature and the reaction progress was monitored with the help of TLC.
  • ethyl acetate 500 ml was added to the reaction contents to precipitate out triethyl amine hydrochloride as a solid.
  • the suspension thus obtained was cooled to about 0 - 5°C and the solids were removed by filtration.
  • 0.5 N aqueous potassium hydrogen phosphate solution 500 ml was added and the contents were stirred for about 15 minutes at room temperature to obtain organic and aqueous layers, which were separated.
  • Tetra-butyl ammonium hydrogen sulfate (15.24 gm, 0.0449 mol) was added to the aqueous layer and the contents were stirred overnight at room temperature before adding dichloromethane (375 ml) to separate aqueous and dichloromethane layers. The dichloromethane layer was evaporated under vacuum to provide the tetra-butyl ammonium salt of Formula (Ill-a) as a solid (33.5 gm, 92% yield), which was analyzed.
  • Example 2 The compounds according to Examples 2 - 5 were prepared following the general procedure given in Example 1.
  • Example 2 The compounds according to Examples 2 - 5 were prepared following the general procedure given in Example 1.
  • the O-sulfonation reagent suspension was prepared according to the procedure in Example 1.
  • Compound of Formula (Il-b) (2.37 gm, 0.0069 mol) was reacted with the O-sulfonation reagent in the form of a suspension prepared above in presence of triethyl amine (2.09 gm, 0.020 mol) and dichloromethane, to obtain 3.3 gm of tetra-butyl ammonium salt of Formula (Ill-b).
  • the O-sulfonation reagent was prepared according to the procedure given in Example 1 using triethyl amine (3.08 gm, 0.030 mol) and chlorosulfonic acid (1.77 gm, 0.015 mol).
  • the O-sulfonation reagent was prepared according to the procedure given in Example 1 using triethyl amine (2.46 gm, 0.0244 mol) and chloro sulfonic acid (1.43 gm, 0.0123 mol).
  • the O-sulfonation reagent was prepared according to the procedure given in Example g triethylamine (4.41 gm, 0.0436 mol) and chloro sulfonic acid (2.55 gm, 0.0218 mol).
  • Example 2 the procedure in Example 1 was followed except for a change that the O- sulfonation reagent was isolated as a solid and then used in the further reactions.
  • a solution of triethyl amine (26 gm, 0.2564 mol) in dichloromethane (100 ml) was cooled to 0° to 5°C under stirring.
  • chloro sulfonic acid (10 gm, 0.0854 mol) was added via addition funnel by maintaining temperature between 0°C - 5°C. Precipitation was observed in the reaction mixture. The mixture was stirred for additional 1 hour at room temperature.
  • the O-sulfonation reagent in the form of a solid obtained earlier was added to this cooled solution maintaining the temperature in the range of about 0 - 5°C. Following completing of addition, the reaction mixture was stirred for further 1.5 hours at room temperature and the reaction progress was monitored using TLC. After completion of the reaction, ethyl acetate (20 ml) was added to the reaction mixture followed by addition of 0.5N aqueous potassium hydrogen phosphate solution (20 ml) and the biphasic mixture thus obtained was stirred for about 15 minutes at room temperature. Aqueous layer was separated.
  • Tetra-butyl ammonium hydrogen sulfate (0.74 gm, 0.0022 mol) was added into the aqueous layer under stirring and the reaction mixture was stirred overnight at room temperature.
  • Dichloromethane (15 ml) was added to the reaction mixture and the contents were stirred for 15 minutes.
  • Organic layer was separated, and evaporated under vacuum on rotatory evaporator to provide the tetra-butyl ammonium salt of Formula (Ill-a) as a solid (1.39 gm), which further converted into the compound of Formula (I-a) following the procedure given in Example 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un composé de formule (I), ou d'un sel pharmaceutiquement acceptable ce celui-ci.
PCT/IB2018/054420 2017-06-20 2018-06-15 Procédé de o-sulfonation de composés 1,6-diazabicyclo[3.2.1]octane Ceased WO2018234962A1 (fr)

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IN201721021620 2017-06-20
IN201721021620 2017-06-20

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7112592B2 (en) 2000-08-01 2006-09-26 Aventis Pharma S.A. Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents
US7612087B2 (en) 2002-01-28 2009-11-03 Novexel Heterocyclic compounds as inhibitors of beta-lactamases
EP2657234A1 (fr) * 2010-12-22 2013-10-30 Meiji Seika Pharma Co., Ltd. Dérivé de diazabicyclooctane optiquement actif, et procédé de fabrication de celui-ci
US8822450B2 (en) 2011-08-27 2014-09-02 Wockhardt Ltd. 1,6-diazabicyclo [3,2,1] octan-7-one derivatives and their use in the treatment of bacterial infections
US9127004B2 (en) 2011-08-30 2015-09-08 Wockhardt Ltd. Nitrogen containing heterocyclic compounds
US9505761B2 (en) 2011-12-02 2016-11-29 Fedora Pharmaceuticals Inc. Bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
WO2017045510A1 (fr) * 2015-09-16 2017-03-23 山东轩竹医药科技有限公司 Inhibiteur de ss-lactamase et son application
CN106699756A (zh) * 2016-12-30 2017-05-24 淄博鑫泉医药技术服务有限公司 β内酰胺酶抑制剂阿维巴坦的合成方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7112592B2 (en) 2000-08-01 2006-09-26 Aventis Pharma S.A. Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents
US7612087B2 (en) 2002-01-28 2009-11-03 Novexel Heterocyclic compounds as inhibitors of beta-lactamases
EP2657234A1 (fr) * 2010-12-22 2013-10-30 Meiji Seika Pharma Co., Ltd. Dérivé de diazabicyclooctane optiquement actif, et procédé de fabrication de celui-ci
US8822450B2 (en) 2011-08-27 2014-09-02 Wockhardt Ltd. 1,6-diazabicyclo [3,2,1] octan-7-one derivatives and their use in the treatment of bacterial infections
US9127004B2 (en) 2011-08-30 2015-09-08 Wockhardt Ltd. Nitrogen containing heterocyclic compounds
US9505761B2 (en) 2011-12-02 2016-11-29 Fedora Pharmaceuticals Inc. Bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
WO2017045510A1 (fr) * 2015-09-16 2017-03-23 山东轩竹医药科技有限公司 Inhibiteur de ss-lactamase et son application
EP3281942A1 (fr) * 2015-09-16 2018-02-14 Xuanzhu Pharma Co., Ltd. Inhibiteur de ss-lactamase et son application
CN106699756A (zh) * 2016-12-30 2017-05-24 淄博鑫泉医药技术服务有限公司 β内酰胺酶抑制剂阿维巴坦的合成方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AL-HORANI R A ET AL: "Chemical sulfation of small moleculesadvances and challenges", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 66, no. 16, 17 April 2010 (2010-04-17), pages 2907 - 2918, XP026983361, ISSN: 0040-4020, [retrieved on 20100210] *
VIJAY NAIR ET AL: "A CONVENIENT PROCEDURE FOR THE PREPARATION OF TRIETHYLAMINE-SULFUR TRIOXIDE", ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL: THE NEW JOURNAL FOR ORGANIC SYNTHESIS, vol. 19, no. 6, 1 December 1987 (1987-12-01), US, pages 466 - 467, XP055503796, ISSN: 0030-4948, DOI: 10.1080/00304948709356213 *

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