EP4185573A1 - Process for preparing aminofuranes - Google Patents

Process for preparing aminofuranes

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Publication number
EP4185573A1
EP4185573A1 EP21746475.9A EP21746475A EP4185573A1 EP 4185573 A1 EP4185573 A1 EP 4185573A1 EP 21746475 A EP21746475 A EP 21746475A EP 4185573 A1 EP4185573 A1 EP 4185573A1
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EP
European Patent Office
Prior art keywords
compounds
phenyl
iii
general formula
diphenyl
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EP21746475.9A
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German (de)
French (fr)
Inventor
Sergii Pazenok
Winfried Etzel
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Bayer AG
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Bayer AG
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Publication of EP4185573A1 publication Critical patent/EP4185573A1/en
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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
    • C07D307/70—Nitro radicals
    • 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 new process for preparing 4-aminofurans of the general formula (I) and their salts.
  • 4-aminofurans of the general formula (I) are important precursors of agrochemical active ingredients (cf. WO2018/228985) and pharmaceutical active ingredients (e.g. DNA binding agents: Woods, Craig R. et al. Bioorganic & Medicinal Chemistry Fetters, 12(18), 2647-2650; 2002).
  • 4-aminofurans of the general formula (I) are used as starting material for the production of tetrahydro- and dihydrofuran carboxylic acids - and esters.
  • these compounds of formula (I) have been synthesized via multistep processes including bromination, dehalogenation, coupling reaction and deprotection. (see F. Brucoli, et al. Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012).
  • the object of the present invention is to find a process for preparing the compounds mentioned which is inexpensive and can be used on an industrial scale. It is also desirable to obtain these compounds with a high yield and in high purity, so that they do not have to be subjected to any further complex purification.
  • R 1 is CF 3 , CF 2 H, C 2 F 5 , CF 2 C1, CC1 3 , COO(Ci-C 4 )alkyl, COOH
  • R 2 is H, CH 3 CO, CCI 3 CO, CF 3 CO , Phenyl-CO, CH 3 OCO, (CH 3 ) COCO, phenyl, phenyl-CH 2 , (diphenyl)CH is characterized in that in a first step compounds of the general formula (II) won
  • R 3 and R 4 independently represent H and Ci-G t -alkyl and R 1 has the meanings given above, using an amine of the general formula R 5 -NH2 (V) in compounds of the general formula (III) won
  • R 5 is H, phenyl, phenyl-CH2 , (diphenyl)CH, and these are then converted in a second reaction step in the presence of a dehydrating reagent to give compounds of the general formula (I).
  • R 1 is CF 3 , CF 2 H, CF 2 Cl, C 2 F 5 , CC 1 3 , COOCH 3 , COOC 2 H 5
  • R 2 is H, CF 3 CO, CH 3 CO, CCI 3 CO, phenyl , phenyl-QB, (diphenyl)CH CH 3 OCO, (CH 3 ) 3 COCO,
  • R 3 and R 4 independently represent H or CH 3
  • R5 represents H, phenyl, phenyl-G h , (diphenyl)CH.
  • Particularly preferred radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
  • R 1 represents CF 3 , CF 2 H, CC1 3 , COOCH 3 , COOC 2 H 5 ,
  • R 2 represents H, COCF 3 , COCH 3 , COCCl 3 , Ph-CH 2 , (diphenyl)CH CH 3 OCO, (CH 3 ) 3 COCO,
  • R 3 and R 4 are independently H or CFF R 5 is H.
  • R 1 represents CF 3 , COOCH 3 , COOC 2 H 5 ,
  • R 2 represents H, COCF 3 , (CH 3 ) 3 COCO,
  • R 3 and R 4 represent CH 3
  • R 5 represents H
  • radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
  • R 1 represents COOCH 3 , COOC 2 H 5 ,
  • R 2 is H
  • R 3 and R 4 represent CH 3
  • R 5 represents H
  • radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
  • R 1 represents COOCH 3
  • R 2 is H
  • R 3 and R 4 represent CH 3 R 5 represents H.
  • the compounds of formula (II) react in the first reaction step with ammonia or amines (compounds of general formula (V)) to form the compounds of general formula (III), which are then converted in the second reaction step into compounds of general formula (I). .
  • Some compounds of the general formulas (II) and (III) in which R 1 , R 3 , R 4 and R 5 have the meanings given above are known. These compounds can be prepared by the method known from WO 2011/073100, WO 2011/073101 and European Journal of Organic Chemistry (2016), 2018(27-28), 3853-3861.
  • the following compounds of the formula (II) may be mentioned by way of example:
  • the compounds of the formula (III) are caused to cyclize.
  • the ring closure took place in the presence of a dehydrating reagent such as SOCh, POCl 3 , PCI 3 , phosgene, diphosgene, triphosgene, C1COCOC1, (CF 3 CO) 2 , P 4 O 10 , SO 2 F 2 , trimethyl and ethyl orthoformate and HCl.
  • Preferred dehydrating reagents are SOCl 2 , POCl 3 , PCI 3 , phosgene, diphosgene, triphosgene and C1COCOC1.
  • Very particularly preferred dehydrating reagents are SOCE, POCl 3 , C1COCOC1 and phosgene.
  • the salt-free form can be obtained by treating the salt with a base, e.g. triethylamine (see Example 2).
  • the molar ratio of the compound of formula (III) to the cyclizing reagents is in the range of about 1:0.1 to 1:5, preferably 1:0.5 to 1:3.
  • Reaction step 2 is usually carried out in a temperature range from 0° C. to 40° C. and, if appropriate, in the presence of a solvent or diluent.
  • the reaction is preferably carried out at about room temperature (RT) in a solvent.
  • the solvents are preferably methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, chlorobenzene.
  • the products were characterized by means of 'H-NMR spectroscopy and/or LC/MS (Liquid Chromatography Mass Spectrometry).
  • the NMR spectra were determined with a Bruker Avance 400 equipped with a flow-through probe (60 ⁇ l volume). In individual cases, the NMR spectra were measured with a Bruker Avance II 600.
  • Methyl 4-[(2,2,2-trifluoroacetyl)amino]furan-2-carboxylate 1.59 g (0.01 mol) of methyl 4-amino-5-hydroxy-2-oxo-pent-3-enoate were dissolved in 50 ml of dichloromethane and the mixture was cooled to 0°C. 2 ml of (CFsCCfhO) were metered in at 0°C within 2 hours. The mixture was stirred at 10°C for 5 hours and 20 ml of water were added.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Furan Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a new process for preparing 4-aminofuranes of the general formula (I) and its salts.

Description

Verfahren zur Herstellung von Aminofuranen Process for the production of aminofurans
Die vorliegende Erfindung betrifft ein neues Verfahren zur Herstellung von 4-Aminofuranen der allgemeinen Formel (I) und deren Salze. The present invention relates to a new process for preparing 4-aminofurans of the general formula (I) and their salts.
4-Aminofurane der allgemeinen Formel (I) (vor allem R1=COOMe) sind wichtige Vorstufen von agrochemischen Wirkstoffen (vgl. WO2018/228985) und pharmazeutischen Wirkstoffen (z.B. DNA Binding Agents: Woods, Craig R. et al. Bioorganic & Medicinal Chemistry Fetters, 12(18), 2647-2650; 2002). 4-aminofurans of the general formula (I) (especially R 1 = COOMe) are important precursors of agrochemical active ingredients (cf. WO2018/228985) and pharmaceutical active ingredients (e.g. DNA binding agents: Woods, Craig R. et al. Bioorganic & Medicinal Chemistry Fetters, 12(18), 2647-2650; 2002).
4-Aminofurane der allgemeinen Formel (I) dienen als Ausgangsstoff für die Herstellung von Tetrahydro- und Dihydrofürancarbonsäuren - und estem. Bisher wurden diese Verbindungen der Formel (I) über mehrstufige Synthese inklusive einer Bromierung, Dehalogenierung, Kupplungsreaktion und Entschützung. (siehe F. Brucoli, et al. Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012) hergestellt. 4-aminofurans of the general formula (I) are used as starting material for the production of tetrahydro- and dihydrofuran carboxylic acids - and esters. Heretofore, these compounds of formula (I) have been synthesized via multistep processes including bromination, dehalogenation, coupling reaction and deprotection. (see F. Brucoli, et al. Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012).
Schema 1: a) Br2, A1CF: b) Zn, NH4C1; c) Cul/ (CH3NHCH2)2, Boc-NH2, K2C03 d) Entfernung Boc- Schutzgruppe Scheme 1: a) Br 2, A1CF: b) Zn, NH 4 C1; c) Cul/ (CH 3 NHCH 2 ) 2 , Boc-NH 2 , K 2 CO 3 d) Removal of Boc protecting group
Die oben genannte Synthese weist eine große Menge von Nachteilen auf, wie z.B. eine niedrige Atomökonomie (Bromierung und Dehalogenierung), Verwendung von Schwermetallen wie Zink und Verwendung von Schutzgruppen wie Boc-Amin. Darüber hinaus erfordert das in Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 beschriebene Verfahren die Verwendung von metall-haltigen (beispielsweise Kupfer(I)-iodid) Katalysatoren. The above synthesis has a large number of disadvantages such as low atom economy (bromination and dehalogenation), use of heavy metals such as zinc and use of protecting groups such as Boc-amine. In addition, as described in Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 described the use of metal-containing (e.g. copper (I) iodide) catalysts.
Diese Nachteile machen das Verfahren zur Herstellung der Verbindungen der allgemeinen Formel (I) unwirtschaftlich und damit sehr teuer. F.Wolter et al in (Organic Letters, 11(13), 2804-2807; 2009) beschreibt eine andere Methode für die Herstellung von Aminofüranen der allgemeinen Formel (I), und zwar über eine Curtius Umlagerung von Furan-2,4-dicarbonsäure-2-methylester unter Verwendung von (Ph03)2P(0)N3. Diese Methode ist wegen der hochexplosiven Eigenschaften der organischen Azide für großtechnische Anwendungen nicht geeignet. These disadvantages make the process for preparing the compounds of the general formula (I) uneconomical and therefore very expensive. F.Wolter et al in (Organic Letters, 11(13), 2804-2807; 2009) describes another method for the preparation of aminofurans of general formula (I), namely via a Curtius rearrangement of furan-2,4- dicarboxylic acid 2-methyl ester using (Ph03)2P(0)N3. This method is not suitable for large-scale technical applications because of the highly explosive properties of the organic azides.
Einige Verbindungen der allgemeinen Formel (I), z.B. mit R1= CF3 und R2 = NHAryl, wurden in European Journal of Organic Chemistry 2018, 3853-3861 beschrieben. Allerding wurde diese Verbindung im Gemisch von mehreren Komponenten nachgewiesen. Some compounds of the general formula (I), for example with R 1 = CF 3 and R 2 = NHAryl, have been described in European Journal of Organic Chemistry 2018, 3853-3861. However, this compound was detected in a mixture of several components.
Im Lichte des zuvor beschriebenen Standes der Technik liegt der vorliegenden Erfindung die Aufgabe zugrunde, ein Verfahren zur Herstellung der genannten Verbindungen zu finden, das kostengünstig ist und großtechnisch eingesetzt werden kann. Auch ist es erstrebenswert, diese Verbindungen mit hoher Ausbeute und in hoher Reinheit zu erhalten, so dass sie keiner weiteren komplexen Aufreinigung unterzogen werden müssen. In the light of the prior art described above, the object of the present invention is to find a process for preparing the compounds mentioned which is inexpensive and can be used on an industrial scale. It is also desirable to obtain these compounds with a high yield and in high purity, so that they do not have to be subjected to any further complex purification.
Die zuvor beschriebene Aufgabe - einfache, kostengünstige und großtechnische Herstellung - wird gelöst durch ein Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (I) und deren Salze The problem described above--simple, inexpensive and large-scale production--is achieved by a process for the production of compounds of the general formula (I) and their salts
(I), worin (I), wherein
R1 für CF3, CF2H, C2F5, CF2C1, CC13, COO(Ci-C4)Alkyl, COOH steht, R2 für H, CH3CO, CCI3CO, CF3CO, Phenyl-CO, CH3OCO, (CH3) COCO, Phenyl, Phenyl-CH2 , (Diphenyl)CH steht dadurch gekennzeichnet, dass in einem ersten Schritt Verbindungen der allgemeinen Formel (II) wonn R 1 is CF 3 , CF 2 H, C 2 F 5 , CF 2 C1, CC1 3 , COO(Ci-C 4 )alkyl, COOH, R 2 is H, CH 3 CO, CCI 3 CO, CF 3 CO , Phenyl-CO, CH 3 OCO, (CH 3 ) COCO, phenyl, phenyl-CH 2 , (diphenyl)CH is characterized in that in a first step compounds of the general formula (II) won
R3 und R4 unabhängig voneinander für H und Ci-Gt-Alkyl stehen und R1 die oben genannten Bedeutungen hat, mit Hilfe eines Amins der allgemeinen Formel R5-NH2 (V) in Verbindungen der allgemeinen Formel (III) wonn R 3 and R 4 independently represent H and Ci-G t -alkyl and R 1 has the meanings given above, using an amine of the general formula R 5 -NH2 (V) in compounds of the general formula (III) won
R5 für H, Phenyl, Phenyl-CH2, (Diphenyl)CH steht, überführt werden und diese anschließend in einem zweiten Reaktionsschritt in Gegenwart eines wasserentziehenden Reagenzes zu Verbindungen der allgemeinen Formel (I) umgesetzt werden. R 5 is H, phenyl, phenyl-CH2 , (diphenyl)CH, and these are then converted in a second reaction step in the presence of a dehydrating reagent to give compounds of the general formula (I).
Bevorzugte Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) sind die folgenden: Preferred radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für CF3, CF2H, CF2C1, C2F5, CC13, COOCH3, COOC2H5, R2 steht für H, CF3CO, CH3CO, CCI3CO, Phenyl, Phenyl-QB, (Diphenyl)CH CH3OCO, (CH3)3COCO, R 1 is CF 3 , CF 2 H, CF 2 Cl, C 2 F 5 , CC 1 3 , COOCH 3 , COOC 2 H 5 , R 2 is H, CF 3 CO, CH 3 CO, CCI 3 CO, phenyl , phenyl-QB, (diphenyl)CH CH 3 OCO, (CH 3 ) 3 COCO,
R3 und R4 stehen unabhängig voneinander für H oder CH3, R 3 and R 4 independently represent H or CH 3,
R5 steht für H, Phenyl, Phenyl-G h, (Diphenyl)CH. Besonders bevorzugte Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) sind die folgenden: R5 represents H, phenyl, phenyl-G h , (diphenyl)CH. Particularly preferred radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für CF3, CF2H, CC13, COOCH3, COOC2H5, R 1 represents CF 3 , CF 2 H, CC1 3 , COOCH 3 , COOC 2 H 5 ,
R2 steht für H, COCF3, COCH3, COCCl3, Ph-CH2, (Diphenyl)CH CH3OCO, (CH3)3COCO,R 2 represents H, COCF 3 , COCH 3 , COCCl 3 , Ph-CH 2 , (diphenyl)CH CH 3 OCO, (CH 3 ) 3 COCO,
R3 und R4 stehen unabhängig voneinander für H oder CFF R5 steht für H. R 3 and R 4 are independently H or CFF R 5 is H.
Ganz besonders bevorzugte Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) sind die folgenden: Very particularly preferred definitions of radicals for the compounds of the general formulas (I), (II), (III), (IV) and (V) are as follows:
R1 steht für CF3, COOCH3, COOC2H5, R 1 represents CF 3 , COOCH 3 , COOC 2 H 5 ,
R2 steht für H, COCF3, (CH3)3COCO, R 2 represents H, COCF 3 , (CH 3 ) 3 COCO,
R3 und R4 stehen für CH3 R 3 and R 4 represent CH 3
R5 steht für H. R 5 represents H
Weiterhin ganz besonders bevorzugte Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) sind die folgenden: Furthermore, very particularly preferred radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für COOCH3, COOC2H5, R 1 represents COOCH 3 , COOC 2 H 5 ,
R2 steht für H, R 2 is H,
R3 und R4 stehen für CH3 R 3 and R 4 represent CH 3
R5 steht für H. R 5 represents H
Weiterhin ganz besonders bevorzugte Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) sind die folgenden: Furthermore, very particularly preferred radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für COOCH3, R 1 represents COOCH 3 ,
R2 steht für H, R 2 is H,
R3 und R4 stehen für CH3 R5 steht für H. R 3 and R 4 represent CH 3 R 5 represents H.
Die Reaktionsfolge zur Herstellung von Verbindungen der Formel (I) ist im Schema 2 dargestellt. Schema 2 The reaction sequence for preparing compounds of formula (I) is shown in Scheme 2. Scheme 2
Die Verbindungen der Formel (II) reagieren im ersten Reaktionsschritt mit Ammoniak oder Aminen (Verbindungen der allgemeinen Formel (V)) unter Bildung der Verbindungen der allgemeinen Formel (III), die dann im zweiten Reaktionsschritt in Verbindungen der allgemeinen Formel (I) umgewandelt werden. Einige Verbindungen der allgemeinen Formel (II) und (III), in denen R1, R3, R4 und R5 die oben genannten Bedeutungen haben, sind bekannt. Die Herstellung dieser Verbindungen kann nach dem aus WO 2011/073100, WO 2011/073101 und European Journal of Organic Chemistry (2018), 2018(27-28), 3853-3861 bekannten Verfahren erfolgen. Beispielhaft seien folgende Verbindungen der Formel (II) genannt: The compounds of formula (II) react in the first reaction step with ammonia or amines (compounds of general formula (V)) to form the compounds of general formula (III), which are then converted in the second reaction step into compounds of general formula (I). . Some compounds of the general formulas (II) and (III) in which R 1 , R 3 , R 4 and R 5 have the meanings given above are known. These compounds can be prepared by the method known from WO 2011/073100, WO 2011/073101 and European Journal of Organic Chemistry (2018), 2018(27-28), 3853-3861. The following compounds of the formula (II) may be mentioned by way of example:
3 -(2,2-Dimethyl- 1 ,3 -dioxolan-4-ylidene)- 1,1,1 -trifluor-propan-2-one 3 -( 1 ,3 -Dioxolan-4-ylidene)- 1,1,1 -trifluor-propan-2-one Methyl-3-(2,2-dimethyl-l,3-dioxolan-4-ylidene)-2-oxo-propanoate Ethyl-3-(2,2-dimethyl-l,3-dioxolan-4-ylidene)-2-oxo-propanoate Beispielhaft seien folgende Verbindungen der Formel (III) genannt: 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-1,1,1-trifluoro-propan-2-one 3-(1,3-dioxolan-4-ylidene)-1,1,1-trifluoro-propan-2-one methyl-3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2 -oxo-propanoate Ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxo-propanoate The following compounds of the formula (III) may be mentioned by way of example:
4-Amino- 1,1,1 -trifluoro— 5 -hydroxy-pent-3 -en-2-one 4-Amino- 1 , 1 -difluoro— 5 -hydroxy-pent-3 -en-2-one 4-Amino- 1,1,1 -trichloro— 5 -hydroxy-pent-3 -en-2-one Methyl-4-amino-5 -hydroxy-2-oxo-pent-3 -enoate Ethyl-4-amino-5 -hydroxy-2-oxo-pent-3 -enoate Methyl-4-benzylamino-5 -hydroxy-2-oxo-pent-3 -enoate . 4-amino- 1,1,1 -trifluoro— 5 -hydroxy-pent-3 -en-2-one 4-amino- 1 ,1 -difluoro— 5 -hydroxy-pent-3 -en-2-one 4- Amino- 1,1,1 -trichloro— 5 -hydroxy-pent-3 -en-2-one Methyl-4-amino-5 -hydroxy-2-oxo-pent-3 -enoate Ethyl-4-amino-5 - hydroxy-2-oxo-pent-3-enoate Methyl 4-benzylamino-5-hydroxy-2-oxo-pent-3-enoate .
In zweiten Reaktionsschritt werden die Verbindungen der Formel (III) zum Zyklisieren gebracht. Der Ringschluss erfolgte in Gegenwart eines wasserentziehenden Reagenzes wie SOCh, POCI3, PCI3, Phosgen, Diphosgen, Triphosgen, C1COCOC1, (CF3CO)2, P4O10, SO2F2, Orthoameisensäuretrimethyl- und -ethylester und HCl. Bevorzugte wasserentziehenden Reagenzien sind SOCI2, POCI3, PCI3, Phosgen, Diphosgen, Triphosgen und C1COCOC1. Ganz besonders bevorzugte wasserentziehenden Reagenzien sind SOCE, POCI3, C1COCOC1 und Phosgen. In the second reaction step, the compounds of the formula (III) are caused to cyclize. The ring closure took place in the presence of a dehydrating reagent such as SOCh, POCl 3 , PCI 3 , phosgene, diphosgene, triphosgene, C1COCOC1, (CF 3 CO) 2 , P 4 O 10 , SO 2 F 2 , trimethyl and ethyl orthoformate and HCl. Preferred dehydrating reagents are SOCl 2 , POCl 3 , PCI 3 , phosgene, diphosgene, triphosgene and C1COCOC1. Very particularly preferred dehydrating reagents are SOCE, POCl 3 , C1COCOC1 and phosgene.
Mit Reagenzien wie SOCE, POCI3, PCI3, Phosgen, Diphosgen, Triphosgen und C1COCOC1, erhält man die Verbindungen der Formel (I) mit R2= H, CH3, Phenyl, Phenyl-CH2.(Diphenyl)CH. Sie entstehen in Form ihrer HCl-Salze. With reagents such as SOCE, POCI 3 , PCI 3 , phosgene, diphosgene, triphosgene and C1COCOC1, the compounds of the formula (I) with R 2 = H, CH 3 , phenyl, phenyl-CH 2 .(diphenyl)CH are obtained. They arise in the form of their HCl salts.
Fallen die Verbindungen der allgemeinen Formel (I) in Form ihrer Salze an, z.B. als Hydrochlorid, kann die salzfreie Form gewonnen werden, indem das Salz mit einer Base, z.B. Triethylamin, behandelt wird (s. Beispiel 2). If the compounds of general formula (I) are obtained in the form of their salts, e.g. as the hydrochloride, the salt-free form can be obtained by treating the salt with a base, e.g. triethylamine (see Example 2).
Mit Reagenzien wie (CF3C0)20 erhält man die Verbindungen der Formel (I) mit R2 = CF3CO. Das molare Verhältnis der Verbindung der Formel (III) zur den Zyklisierungsreagenzien liegt im Bereich von etwa 1:0,1 bis 1:5, bevorzugt 1:0,5 bis 1:3. With reagents such as (CF 3 CO) 2 0, the compounds of the formula (I) with R 2 = CF 3 CO are obtained. The molar ratio of the compound of formula (III) to the cyclizing reagents is in the range of about 1:0.1 to 1:5, preferably 1:0.5 to 1:3.
Die Reaktionsschritt 2 wird gewöhnlich in einem Temperaturbereich von 0 °C bis 40 °C und gegebenenfalls in Gegenwart eines Lösungs- oder Verdünnungsmittel durchgeführt. Vorzugsweise wird die Umsetzung bei etwa Raumtemperatur (RT) in einem Lösemittel vorgenommen. Reaction step 2 is usually carried out in a temperature range from 0° C. to 40° C. and, if appropriate, in the presence of a solvent or diluent. The reaction is preferably carried out at about room temperature (RT) in a solvent.
Bevorzugt sind die Lösemitteln Methanol, Ethanol, Isopropanol, Butanol, Acetonitril, N,N- Dimethylacetamid, Toluol, Chlorbenzol. The solvents are preferably methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, chlorobenzene.
Erläuterung der Verfahren und Zwischenprodukte Explanation of the processes and intermediates
Beispiele examples
Die vorliegende Erfindung wird anhand der nachfolgenden Beispiele näher erläutert, ohne die Erfindung dabei auf diese einzuschränken. The present invention is explained in more detail using the following examples, without restricting the invention to these.
Messverfahren measurement method
Die Produkte wurden mittels 'H-NMR Spektroskopie und/oder LC/MS (Liquid Chromatography Mass Spectrometry) charakterisiert. The products were characterized by means of 'H-NMR spectroscopy and/or LC/MS (Liquid Chromatography Mass Spectrometry).
Die NMR-Spektren wurden mit einem Bruker Avance 400, ausgestattet mit einem Durchflussprobenkopf (60 pl Volumen), bestimmt. In Einzelfällen wurden die NMR Spektren mit einem Bruker Avance II 600 gemessen. The NMR spectra were determined with a Bruker Avance 400 equipped with a flow-through probe (60 μl volume). In individual cases, the NMR spectra were measured with a Bruker Avance II 600.
Beispiel 1 example 1
Methyl 4-aminofuran-2-carboxylathydrochlorid (Salz der Formel (I) Methyl 4-aminofuran-2-carboxylate hydrochloride (salt of formula (I)
15,9 g (0.1 mol) Methyl 4-amino-5-hydroxy-2-oxo-pent-3-enoat wurden in 50 ml Methanol suspendiert und das Gemisch auf 0°C gekühlt. 17,7 g (0,15 mol) von SOCE wurden bei 0°C binnen 2 Stunden (Std.) dazu dosiert. Das Gemisch wurde 5 Std. bei 10°C nachgerührt und der Niederschlag wurde abfiltriert, mit 5 ml Methanol gewaschen und getrocknet. Man erhielt 16,8 g, 95 % von hell beigen Kristallen. 15.9 g (0.1 mol) of methyl 4-amino-5-hydroxy-2-oxo-pent-3-enoate were suspended in 50 ml of methanol and the mixture was cooled to 0°C. 17.7 g (0.15 mol) of SOCE were dosed at 0°C within 2 hours (h). The mixture was stirred at 10° C. for 5 hours and the precipitate was filtered off, washed with 5 ml of methanol and dried. 16.8 g, 95% of light beige crystals were obtained.
^-NMR (400MHz, CDCI3): d 10.07 (3H, s, br.); 8.10 (1H, d); 7.32 (1H, d); 3,83 (3H, s) ppm. ^-NMR (400MHz, CDCl 3 ): d 10.07 (3H, s, br.); 8.10(1H,d); 7.32 (1H,d); 3.83(3H,s)ppm.
13C-NMR 158,0 (s); 143,6 (s); 140,2 (d); 121,8 (s); 114,5 (d); 52,3 (q) ppm. 13 C NMR 158.0 (s); 143.6(s); 140.2 (d); 121.8(s); 114.5(d); 52.3 (q)ppm.
Beispiel 2 Überführung von Methyl 4-aminofuran-2-carboxylathydrochlorid (Salz der Formel (I)) in Methyl 4- aminofüran-2-carboxylat (salzfreies Produkt der Formel (I)) example 2 Conversion of methyl 4-aminofuran-2-carboxylate hydrochloride (salt of formula (I)) to methyl 4-aminofuran-2-carboxylate (salt free product of formula (I))
9,2 g von Methyl 4-aminofüran-2-carboxylathydrochlorid wurden in 50 ml Ethylacetate suspendiert und 15,7 g von Et3N wurden zugegeben. Das Gemisch wurde 3 Std bei RT gerührt, der Niederschlag wurde abfiltriert und Ethylacetat komplett im Vakuum eingeengt. Man erhielt 6,96 g, 95 % von beigen Kristallen, mit Schmp.79-81°C. 9.2 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 50 mL of ethyl acetate and 15.7 g of Et3N was added. The mixture was stirred at RT for 3 h, the precipitate was filtered off and ethyl acetate was completely concentrated in vacuo. 6.96 g, 95% of beige crystals with mp 79-81°C were obtained.
^-NMR (400MHz, CDC13): d: 7,24 (1H, d); 6,8 (1H, d) ; 4,3 (2H,s ) 3,75 (3H, s) ppm. ^-NMR (400MHz, CDC1 3 ): d: 7.24 (1H, d); 6.8(1H,d) ; 4.3(2H,s) 3.75(3H,s)ppm.
Beispiel 3 Example 3
Methyl-4-[(2,2,2-trifluoracetyl)amino]furan-2-carboxylat 1,59 g (0.01 mol) Methyl 4-amino-5-hydroxy-2-oxo-pent-3-enoat wurden in 50 ml Dichlormethan suspendiert und das Gemisch auf 0°C gekühlt. 2 ml von (CFsCCfhO wurde bei 0°C binnen 2 Std. dazu dosiert. Das Gemisch wurde 5 Std. bei 10°C nachgerührt und mit 20 ml Wasser versetzt. Das Gemisch wurde 5 Std bei Raumtemperatur (RT) verrührt und die Phasen anschließend getrennt. Die organische Phase wurde eingeengt. Der Niederschlag wurde mit 5 ml Diisopropylether verrührt und abfiltriert. Man erhielt 1 g des Produktes als beige Feststoff. Methyl 4-[(2,2,2-trifluoroacetyl)amino]furan-2-carboxylate 1.59 g (0.01 mol) of methyl 4-amino-5-hydroxy-2-oxo-pent-3-enoate were dissolved in 50 ml of dichloromethane and the mixture was cooled to 0°C. 2 ml of (CFsCCfhO) were metered in at 0°C within 2 hours. The mixture was stirred at 10°C for 5 hours and 20 ml of water were added. The mixture was stirred at room temperature (RT) for 5 hours and the phases then stirred The organic phase was evaporated down.The precipitate was stirred with 5 ml of diisopropyl ether and filtered off.1 g of the product was obtained as a beige solid.
^-NMR (400MHz, CDC13): d 11.76 (1H, s, br.); 8.26 (1H, d); 7.24 (1H, d); 3,76 (3H, s) ppm. ^-NMR (400MHz, CDC1 3 ): d 11.76 (1H, s, br.); 8.26 (1H,d); 7.24 (1H,d); 3.76(3H,s)ppm.
13C-NMR 158,2 (s); 154,1 (s, q); 142,5 (s); 137,4 (d); 124,7 (s); 115,8 (s); 112,1 (d); 52,3 (q) ppm. 13 C NMR 158.2(s); 154.1 (s, q); 142.5(s); 137.4(d); 124.7(s); 115.8(s); 112.1(d); 52.3 (q)ppm.

Claims

Patentansprüche: Patent Claims:
1. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (I) und deren Salze worin 1. Process for the preparation of compounds of the general formula (I) and their salts wherein
R1 für CF3, CF2H, C2F5, CF2CI, CC13, COO(Ci-C4)Alkyl, COOH steht, R 1 is CF 3 , CF 2 H, C 2 F 5 , CF2Cl, CC1 3 , COO(Ci-C 4 )alkyl, COOH,
R2 für H, CH3CO, CCI3CO, CF3CO, Phenyl-CO, CH3OCO, (CH3) COCO, Phenyl, Phenyl-CH2 , (Diphenyl)CH steht, dadurch gekennzeichnet, dass in einem ersten Schritt Verbindungen der allgemeinen Formel (II) worin R 2 represents H, CH 3 CO, CCI 3 CO, CF 3 CO, phenyl-CO, CH 3 OCO, (CH 3 )COCO, phenyl, phenyl-CH 2 , (diphenyl)CH, characterized in that in one first step compounds of general formula (II) wherein
R3 und R4 unabhängig voneinander für H und Ci-Ci-Alkyl stehen und R1 die oben genannten Bedeutungen hat, mit Hilfe eines Amins der allgemeinen Formel R5-NH2 (V) in Verbindungen der allgemeinen Formel (III) worin R 3 and R 4 independently represent H and Ci-Ci-alkyl and R 1 has the meanings given above, using an amine of the general formula R 5 -NH 2 (V) in compounds of the general formula (III) wherein
R5 für H, Phenyl, Phenyl-CPh, (Diphenyl)CH steht, überführt werden und diese anschließend in einem zweiten Reaktionsschritt in Gegenwart eines wasserentziehenden Reagenzes zu Verbindungen der allgemeinen Formel (I) umgesetzt werden. R 5 stands for H, phenyl, phenyl-CPh , (diphenyl)CH, and these are then converted in a second reaction step in the presence of a dehydrating reagent to give compounds of the general formula (I).
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) die folgenden sind: 2. The method according to claim 1, characterized in that the radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für CF3, CF2H, CF2C1, C2F5, CC13, COOCH3, COOC2H5, R 1 represents CF 3 , CF 2 H, CF 2 C1 , C 2 F 5 , CC1 3 , COOCH 3 , COOC 2 H 5 ,
R2 steht für H, CF3CO, CH3CO, CCl3CO, Phenyl, Phenyl-CH2, (Diphenyl)CH CH3OCO, (CH3)3COCO, R 2 represents H, CF 3 CO, CH 3 CO, CCl 3 CO, phenyl, phenyl-CH 2 , (diphenyl)CH CH 3 OCO, (CH 3 ) 3 COCO,
R3 und R4 stehen unabhängig voneinander für H oder CFF R5 steht für H, Phenyl, Phenyl-CH2 (Diphenyl)CH. R 3 and R 4 are independently H or CFF R5 is H, phenyl, phenyl-CH 2 (diphenyl)CH.
3. Verfahren nach Anspmch 1, dadurch gekennzeichnet, dass die Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) die folgenden sind: 3. The method according to claim 1, characterized in that the radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für CF3, CF2H, CC13, COOCH3, COOC2H5, R 1 represents CF 3 , CF 2 H, CC1 3 , COOCH 3 , COOC 2 H 5 ,
R2 steht für H, COCF3, COCH3, COCCl3, Phenyl-CH2, (Diphenyl)CH CH3OCO, (CH3)3COCO,R 2 represents H, COCF 3 , COCH 3 , COCCl 3 , phenyl-CH 2 , (diphenyl)CH CH 3 OCO, (CH 3 ) 3 COCO,
R3 und R4 stehen unabhängig voneinander für H oder CFF R5 steht für H. R 3 and R 4 are independently H or CFF R 5 is H.
4. Verfahren nach Anspmch 1, dadurch gekennzeichnet, dass die Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) die folgenden sind: 4. The method according to claim 1, characterized in that the radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für CF3, COOCH3, COOC2H5, R 1 represents CF 3 , COOCH 3 , COOC 2 H 5 ,
R2 steht für H, COCF3, (CH3)3COCO, R 2 represents H, COCF 3 , (CH 3 ) 3 COCO,
R3 und R4 stehen für CH3 R 3 and R 4 represent CH 3
R5 steht für H. R 5 represents H
5. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Restedefinitionen für die5. The method according to claim 1, characterized in that the radical definitions for the
Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) die folgenden sind: Compounds of general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für COOCH3, COOC2H5, R 1 represents COOCH 3 , COOC 2 H 5 ,
R2 steht für H, R 2 is H,
R3 und R4 stehen für CH3 R5 steht für H. R 3 and R 4 represent CH 3 R 5 represents H.
6. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Restedefinitionen für die6. The method according to claim 1, characterized in that the radical definitions for the
Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) die folgenden sind: Compounds of general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für COOCH3, R 1 represents COOCH 3 ,
R2 steht für H, R 2 is H,
R3 und R4 stehen für CH3 R5 steht für H. R 3 and R 4 represent CH 3 R 5 represents H.
7. Verfahren nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass die Reaktion bei Raumtemperatur durchgeführt wird. 7. The method according to any one of claims 1 to 6, characterized in that the reaction is carried out at room temperature.
8. Verfahren nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass das Lösungsmittel Methanol, Ethanol, Isopropanol, Butanol, Acetonitril, N,N-Dimethylacetamid, Toluol oder Chlorbenzol ist. 8. The method according to any one of claims 1 to 7, characterized in that the solvent is methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene or chlorobenzene.
9. Verfahren nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass das wasserentziehende Reagenz SOCL, POCI3, PCL, Phosgen, Diphosgen, Triphosgen, C1COCOC1, (CF3CO)2, P4O10, SO2F2, Orthoameisensäuretrimethyl- und -ethylester oder HCl ist. 9. The method according to any one of claims 1 to 8, characterized in that the dehydrating reagent SOCL, POCl3, PCL, phosgene, diphosgene, triphosgene, C1COCOC1, (CF 3 CO) 2 , P4O10, SO2F2, trimethyl and ethyl orthoformate or HCl is.
10. Verfahren nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass das wasserentziehende Reagenz SOCL, POCI3, PCL, Phosgen, Diphosgen, Triphosgen oder C1COCOC1 ist. 10. The method according to any one of claims 1 to 8, characterized in that the dehydrating reagent is SOCL, POCl3, PCL, phosgene, diphosgene, triphosgene or C1COCOC1.
11. Verfahren nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass das wasserentziehende Reagenz SOCk, POCI3, C1C0C0C1 oder Phosgen ist. 11. The method according to any one of claims 1 to 8, characterized in that the dehydrating reagent is SOCk, POCl3, C1C0C0C1 or phosgene.
EP21746475.9A 2020-07-23 2021-07-20 Process for preparing aminofuranes Pending EP4185573A1 (en)

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