WO2022069554A1 - Procédé de production de 4-bromofuran-2-carboxylates - Google Patents

Procédé de production de 4-bromofuran-2-carboxylates Download PDF

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Publication number
WO2022069554A1
WO2022069554A1 PCT/EP2021/076814 EP2021076814W WO2022069554A1 WO 2022069554 A1 WO2022069554 A1 WO 2022069554A1 EP 2021076814 W EP2021076814 W EP 2021076814W WO 2022069554 A1 WO2022069554 A1 WO 2022069554A1
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Prior art keywords
compounds
general formula
equivalents
solvent
reaction
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PCT/EP2021/076814
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German (de)
English (en)
Inventor
Andreas REMBIAK
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Bayer Aktiengesellschaft
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Publication of WO2022069554A1 publication Critical patent/WO2022069554A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to a process for the preparation of 4-bromofuran-2-carboxylates of the general formula (I) and their use as important precursors for the synthesis of agrochemical and pharmaceutical active ingredients.
  • 4-Bromofuran-2-carboxylates of the general formula (I) are used as starting materials for the production of tetrahydro- and dihydrofurancarboxylic acids and esters (F. Brucoli, et al. Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 ).
  • methyl 4-bromofuran-2-carboxylate can be achieved by reacting methyl 4,5-dibromofuran-2-carboxylate with isopropylmagnesium chloride.
  • This reaction is described in European Journal of Medicinal Chemistry, 2016, 117, 47, CN105503832 and WO 2008/98104.
  • the disadvantages are lower yields, the necessary low reaction temperatures and the waste-intensive aqueous work-up.
  • working with isopropylmagnesium chloride on a commercial scale is difficult and expensive.
  • butyllithium can be used for the synthesis of methyl 4-bromofuran-2-carboxylate. This reaction can be found in the literature, for example in EP1489077. However, it is known that butyllithium can only be handled to a limited extent and is difficult to handle on a large scale, also due to the low temperatures.
  • the present invention has the object of finding a process for preparing the compounds mentioned, so that the compounds of general formula (I) can be obtained in higher yield, in high purity and in an environmentally friendly manner, so that important Intermediates for the production of active ingredients can be produced on an industrial scale.
  • R 1 is COO(Ci-C 4 )-alkyl, characterized in that the compounds of general formula (II) wherein
  • R 1 has the meanings given above in the presence of 1.0 to 1.8 equivalents of aluminum chloride - based on the compound of the general formula (II) - and bromine to form compounds of the general formula (III).
  • R 1 has the meanings given above and reacted further with 1.0 to 1.5 equivalents of zinc and ammonium chloride to give compounds of the formula (I).
  • R1 represents COOCH3 , COOC2 H5 .
  • radical definitions for the compounds of the general formulas (I), (II) and (HI) are the following:
  • R1 represents COOCH3 .
  • the reaction is usually carried out in a temperature range of -10 - 30°C.
  • the reaction is preferably carried out at 0-30.degree. C., very particularly preferably at 5-20.degree.
  • the reaction is usually carried out in a chlorinated solvent, preferred are dichloromethane and dichloroethane, most preferred is dichloromethane.
  • the yields of (II) achieved could be increased to >85% compared to the prior art (about a maximum of 78%).
  • the amount of secondary components formed could be reduced to 5-10% and the compounds could therefore be worked up or isolated of the general formula (II) can be significantly simplified. Isolation can be carried out by methods well known to those skilled in the art, for example extraction, distillation of the solvent and crystallization. However, in the context of the present invention, the crude product is preferably used further directly after changing to a solvent that is preferred in step 2.
  • the reaction is usually carried out in a temperature range of -10 - 60°C.
  • the reaction is preferably carried out at 10-50.degree. C., very particularly preferably at 30-50.degree.
  • the reaction is usually carried out in a solvent, preference being given to methanol.
  • the conversion into compounds of the general formula (I) can be carried out from isolated material of the compounds of the general formula (II) according to the preferred reaction conditions.
  • the compounds of the general formula (II) from step 1 are preferably used directly in step 2 without intermediate isolation after a distillative change of the solvent.
  • the solvent is preferably exchanged at temperatures from 20.degree. C. to 100.degree. C., very preferably from 30.degree. C. to 60.degree.
  • the distillation can be carried out under standard conditions or reduced pressure, particularly preferably at 50 mbar to 1000 mbar, very particularly preferably at 200 mbar to 550 mbar.
  • the suspension was cooled to ⁇ 10° C., filtered and the filter cake rinsed with 300 mL ice-cold methanol.
  • the combined filtrates were concentrated at 200 mbar and 35° C., and the residue was taken up in 1000 mL of n-heptane at 35° C.
  • the organic phase was washed twice at 40° C. with 300 ml of 10% by weight HCl each time after addition of 175 ml of /e/7-butyl methyl ether.
  • the organic phase was cooled to 30°C and the product crystallized at 25°C to 30°C. Inoculation can optionally be carried out at 30 °C. It was then cooled to 0 °C for 6 h and the product was obtained as a colorless to slightly beige solid after filtration and washing the filter cake twice with 75 mL cold n-heptane each time: Yield 248 g (83% of theory over 2 stages, > 99 wt.%).
  • reaction mixture was then added in portions to a mixture of 60 g of ice, 10 g of water and 10 mL of saturated sodium sulfite solution.
  • the phases were separated, the organic phase was diluted with 100 mL ethyl acetate and the organic phase was washed with 50 mL water. Removal of the solvent under reduced pressure at 30°C afforded the product as a dark orange solid: yield 17.4 g

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de production de 4-bromofuran-2-carboxylates de formule générale (I) et l'utilisation de ces composés comme précurseurs importants pour la synthèse de substances actives agrochimiques et pharmaceutiques. (I).
PCT/EP2021/076814 2020-10-01 2021-09-29 Procédé de production de 4-bromofuran-2-carboxylates WO2022069554A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20199676.6 2020-10-01
EP20199676 2020-10-01

Publications (1)

Publication Number Publication Date
WO2022069554A1 true WO2022069554A1 (fr) 2022-04-07

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TW (1) TW202222790A (fr)
WO (1) WO2022069554A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1489077A1 (fr) 2002-02-01 2004-12-22 Dainippon Pharmaceutical Co., Ltd. Hydrazides d'acide 2-furancarboxylique et compositions pharmaceutiques les contenant
WO2008098104A1 (fr) 2007-02-07 2008-08-14 Smithkline Beecham Corporation Inhibiteurs de l'activité de akt
CN105503832A (zh) 2015-12-18 2016-04-20 浙江大学 取代吡唑环类衍生物及其用途
US20160264544A1 (en) 2015-03-09 2016-09-15 Northwestern University Tetrahydrothiophene-based GABA Aminotransferase Inactivators
WO2018228985A1 (fr) 2017-06-13 2018-12-20 Bayer Aktiengesellschaft 3-phénylisoxazoline-5-carboxamides d'acides carboxyliques et d'esters de tétrahydro- et dihydrofurane à effet herbicide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1489077A1 (fr) 2002-02-01 2004-12-22 Dainippon Pharmaceutical Co., Ltd. Hydrazides d'acide 2-furancarboxylique et compositions pharmaceutiques les contenant
WO2008098104A1 (fr) 2007-02-07 2008-08-14 Smithkline Beecham Corporation Inhibiteurs de l'activité de akt
US20160264544A1 (en) 2015-03-09 2016-09-15 Northwestern University Tetrahydrothiophene-based GABA Aminotransferase Inactivators
CN105503832A (zh) 2015-12-18 2016-04-20 浙江大学 取代吡唑环类衍生物及其用途
WO2018228985A1 (fr) 2017-06-13 2018-12-20 Bayer Aktiengesellschaft 3-phénylisoxazoline-5-carboxamides d'acides carboxyliques et d'esters de tétrahydro- et dihydrofurane à effet herbicide

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CRAIG ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 12, no. 18, 2002, pages 2647 - 2650
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 117, 2016, pages 47
F. BRUCOLI ET AL., BIOORGANIC & MEDICINAL CHEMISTRY, vol. 20, no. 6, 2012, pages 2019 - 2024
FEDERICO BRUCOLI ET AL: "Efficient synthesis and biological evaluation of proximicins A, B and C", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, NL, vol. 20, no. 6, 26 January 2012 (2012-01-26), pages 2019 - 2024, XP028465313, ISSN: 0968-0896, [retrieved on 20120204], DOI: 10.1016/J.BMC.2012.01.043 *
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 65, 2017, pages 5397
YAO TING-TING ET AL: "Design, Synthesis, and Fungicidal Evaluation of Novel Pyrazole-furan and Pyrazole-pyrrole Carboxamide as Succinate Dehydrogenase Inhibitors", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 65, no. 26, 5 July 2017 (2017-07-05), US, pages 5397 - 5403, XP055777130, ISSN: 0021-8561, DOI: 10.1021/acs.jafc.7b01251 *
ZHAN WENHU ET AL: "Design, synthesis and biological evaluation of pyrazol-furan carboxamide analogues as novel Akt kinase inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 117, 5 April 2016 (2016-04-05), pages 47 - 58, XP029532800, ISSN: 0223-5234, DOI: 10.1016/J.EJMECH.2016.03.074 *

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