(19)
(11)EP 3 743 407 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
03.08.2022 Bulletin 2022/31

(21)Application number: 19700502.8

(22)Date of filing:  14.01.2019
(51)International Patent Classification (IPC): 
C07D 217/26(2006.01)
C07D 213/61(2006.01)
C07D 401/04(2006.01)
(52)Cooperative Patent Classification (CPC):
C07D 217/26; C07D 401/04; C07D 213/61
(86)International application number:
PCT/EP2019/050794
(87)International publication number:
WO 2019/145177 (01.08.2019 Gazette  2019/31)

(54)

BROMINATION OF PYRIDINE DERIVATIVES

BROMIERUNG DER DERIVATE DES PYRIDINS

BROMATION DES DÉRIVÉS DE PYRIDINE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 23.01.2018 EP 18152984

(43)Date of publication of application:
02.12.2020 Bulletin 2020/49

(73)Proprietor: BASF SE
67056 Ludwigshafen am Rhein (DE)

(72)Inventors:
  • RACK, Michael
    67056 Ludwigshafen (DE)
  • MUELLER, Bernd
    67056 Ludwigshafen (DE)

(74)Representative: BASF IP Association 
BASF SE GBI-C006
67056 Ludwigshafen
67056 Ludwigshafen (DE)


(56)References cited: : 
WO-A1-2016/007731
WO-A2-2006/025979
  
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  • DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 29 November 2011 (2011-11-29), "Pyridine, 5-bromo-3-(fluoromethyl)-2-methyl-", XP002779435, Database accession no. 1346531-70-1
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  • DUNN ALLAN D ET AL: "The Bromination of lutidines", ZEITSCHRIFT FUER CHEMIE, DT. VERL. FÜR GRUNDSTOFFINDUSTRIE, DE, vol. 28, no. 2, 1 February 1988 (1988-02-01), pages 59-60, XP009504239, ISSN: 0044-2402, DOI: 10.1002/ZFCH.19880280205
  • PRASENJIT MAL ET AL: "Conformational Control and Photoenolization of Pyridine-3-carboxaldehydes in the Solid State: Stabilization of Photoenols via Hydrogen Bonding and Electronic Control", JOURNAL OF ORGANIC CHEMISTRY , 28, 1105-7 CODEN: JOCEAH; ISSN: 0022-3263, vol. 68, no. 9, 1 May 2003 (2003-05-01), pages 3446-3453, XP055460703, ISSN: 0022-3263, DOI: 10.1021/jo026621n
  • DUNN A D ET AL: "Bromination of Pyridines. II. Bromination of Aminopyridines", JOURNAL FÜR PRAKTISCHE CHEMIE : PRACTICAL APPLICATIONS AND APPLIED CHEMISTRY : COVERING ALL ASPECTS OF APPLIED CHEMISTRY, WILEY, DE, vol. 331, no. 3, 1 January 1989 (1989-01-01), pages 369-374, XP009504241, ISSN: 0021-8383
  • THALHAMMER A ET AL: "Inhibition of the histone demethylase JMJD2E by 3-substituted pyridine 2,4-dicarboxylates", ORGANIC & BIOMOLECULAR CHEMISTRY,, vol. 9, no. 1, 1 January 2011 (2011-01-01) , pages 127-135, XP002756355, ISSN: 1477-0520, DOI: 10.1039/C0OB00592D [retrieved on 2010-11-15]
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description


[0001] The present invention relates to a process for the preparation pyridine derivatives of the formula I



[0002] Bromination of similar pyridine derivatives is known from US 20140194386 and WO 2008/070740. One of the disadvantages of the reactions described in the above mentioned documents lies in the use of bromine in the presence of fuming sulfuric acid.

[0003] From Z. Chem 1988 28 2 50 a bromination is known using 65% oleum and Br2. From Dunn et al., Zeitschrift für Chemie, vol. 28, no. 2, pages 59-60 discloses a bromination of 2-methylpyridines with 65% oleum and Br2.

[0004] WO 2006/025979 A2, Prasentjit Mal et al. J. of Org. Chem. vol. 68, pages 3446-345 and Dunn et al., Journal für praktische Chemie, vol. 331, no. 3, pages 369-374 disclose bromination of compounds which are not structurally similar with the compound of the formula I.

[0005] One of the disadvantages of the use of Br2 as brominating agent is that the reaction is very slow and requires high temperatures. Furthermore, the use of Br2 as brominating agent leads to a mixture of mono and dibromo isomers which are usually very difficult to purify.

[0006] Thus, it was an object of the present invention to overcome the disadvantages of the known processes and to provide an improved, selective and more economical and production plant friendly process.It was now found a process for preparing compounds of formula I,

in which

R1 is in each case independently selected from hydrogen, halogen, C1-C6-alkyl and C1-C6-halogenalkyl;

R2 is in each case independently selected from hydrogen and halogen;

R10 is in each case independently selected from H, halogen, O(R95), C1-C6-alkyl and C1-C6-halogenalkyl; wherein

R95 is C1-C6-alkyl, C1-C6-halogenalkyl;

comprising the following steps:

  1. (i) reacting a compound of the formula II

    wherein R1, R2 and R10 are as defined above with a brominating agent which is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in the presence of oleum 65%.



[0007] The process of this invention is very selective because it leads to the desired pyridines with a low content of side products which is desirable from the economical point of view and such process is suitable for the production on a large scale.

[0008] Preferably the brominating agent in the process according to the invention is selected from the group consisting of such as N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) or a system consisting of HBr/H2O2. The preferred brominating agents are NBS und DBDMH. The most preferred brominating agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

[0009] Typical reaction times are in the range of from 1 to 20 hours, preferably from 2 to 15 hours and more preferably from 3 to 10 hours, most preferably 3 to 5 hours.

[0010] Typical the product will be extracted using an inert organic solvent.

[0011] By "inert organic solvent" is meant an organic solvent which, under the reaction conditions of the process of this invention, does not enter into any appreciable reaction with either the reactants or the products.

[0012] In one embodiment, the inert organic solvent is selected from non-halogenated inert organic solvents; preferably from non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, , ethers, esters, ketones, and any combination thereof.

[0013] Examples of suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, heptane, and the like. Preference is given to saturated aliphatic hydrocarbons having from 5 to 10 carbon atoms.

[0014] Examples of suitable non-halogenated cycloaliphatic hydrocarbons include cyclopentane, cyclohexane, cycloheptane, and the like. Preference is given to non-halogenated saturated cycloaliphatic hydrocarbons having from 5 to 10 carbon atoms. Cyclohexane is particularly preferred.

[0015] Examples of suitable a non-halogenated aromatic hydrocarbons include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymol), 3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol), 1,3,5-trimethylbenzene (mesitylene), and the like. Preference is given to toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesitylene), and any combination thereof. Especially preferred among the non-halogenated aromatic hydrocarbons are toluene, o-xylene, m-xylene, p-xylene, and any combination thereof, with toluene being the most preferred.

[0016] Examples of suitable halogenated aliphatic hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, and the like. Preference is given to dichloromethane and 1,2-dichloroethane and any combination thereof.

[0017] Examples of suitable halogenated aromatic hydrocarbons include chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, α,α,α-trifluorotoluene (benzotrifluoride) and the like and any combination thereof.

[0018] Examples of suitable ethers include cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, methyl-tetrahydrofuran, tetrahydrofuran, 1,4-dioxane, and the like and any combination thereof.

[0019] Examples of suitable esters include ethyl acetate, n-propylacetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, and the like and any combination thereof.

[0020] Examples of suitable ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone and the like, and any combination thereof..

[0021] After the extraction the inert solvent will be evaporated and the crude product will be purified by distillation.

[0022] The molar ratio of the brominating agent DBDMH to the pyridine derivative of the formula I where R1 = H and R2 = H can vary widely and depends on the reaction conditions used, but is generally from 0.40 : 1.1 to 1.5 : 1, preferably from 0.40 : 1 to 1.2 : 1, more preferably from 0.40 : 1 to 1.1 : 1 and even more preferably from 0.50 : 1 to 1.0 : 1. It is preferably to use the brominating agent less then 1 eq compared to the pyridine in order to avoid sideproducts. Therefore, the molar ratio of the brominating agent DBDMH to the pyridine derivative of the formula I where R1 = H and R2 = H is preferably 0.4 to 1.1, more preferably 0.4 to 0.9.

[0023] Preferably, a bromination of the compounds of the formula I where R1 = H and R2 = H will be performed. The preferred brominating agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). In that case, preference is given to performing the bromination withouth an additional solvent.

[0024] In this case, the the reaction temperature is preferably in the range from 0 to 150°C and especially 80 to 125°C temperature and the reaction times are in the range of from 2 to 10 hours, more preferred 2 to 5 hours.

[0025] Preferably the purification is a distillation under reduced pressure (50-55°C; 1.6-2.0 mbar).

[0026] The terms "compounds I", "compounds II", "compounds IIa" and "compounds III" refer to compounds of formulae I, II, IIa and III, respectively. In the definitions of the variables given above, collective terms are used which are generally representative for the substituents in question.

[0027] In the definitions of the variables given herein, collective terms are used which are generally representative for the substituents in question. The term "Cn-Cm" indicates the number of carbon atoms possible in each case in the substituent or substituent moiety in question.

[0028] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0029] The term "C1-C6-alkyl" refers to a straight-chained or branched saturated hydrocarbon group having 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Likewise, the term "C2-C4-alkyl" refers to a straight-chained or branched alkyl group having 2 to 4 carbon atoms, such as ethyl, propyl (n-propyl), 1-methylethyl (iso-propoyl), butyl, 1-methylpropyl (sec.-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert.-butyl).

[0030] The term "C1-C6-halogenalkyl" refers to an alkyl group having 1 or 6 carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above. Examples are "C1-C2-haloalkyl" groups such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl.

[0031] The term "C2-C6-alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and a double bond in any position. Examples are "C2-C4-alkenyl" groups, such as ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl.

[0032] The term " C2-C6-halogenalkenyl" refers to an alkyl group having 2 or 6 carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above.

[0033] The term "C2-C6-alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and containing at least one triple bond. Examples are "C2-C4-alkynyl" groups, such as ethynyl, prop-1-ynyl, prop-2-ynyl (propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl.

[0034] The term " C2-C6-halogenalkynyl" refers to an alkyl group having 2 or 6 carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above.

[0035] The term "C1-C6-alkoxy" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms which is bonded via an oxygen, at any position in the alkyl group. Examples are "C1-C4-alkoxy" groups, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methyhpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

[0036] The term "C1-C6-halogenalkoxy" refers to a C1-C6-alkoxy radical as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above. Examples are "C1-C4-haloalkoxy" groups, such as OCH2F, OCHF2, OCF3, OCH2Cl, OCHCl2, OCCl3, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-tri-fluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloro¬ethoxy, OC2F5, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoro¬propoxy, 2 chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromo¬propoxy, 3 bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, OCH2-C2F5, OCF2-C2F5, 1-fluoromethyl-2-fluoroethoxy, 1-chloromethyl-2-chloroethoxy, 1-bromomethyl-2-bromo¬ethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.

[0037] The term "phenyl-C1-C6-alkyl" refers to alkyl having 1 to 6 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a phenyl radical. Likewise, the terms "phenyl-C2-C6-alkenyl" and "phenyl-C2-C6-alkynyl" refer to alkenyl and alkynyl, respectively, wherein one hydrogen atom of the aforementioned radicals is replaced by a phenyl radical.

[0038] The invention is illustrated by the following examples:

Example 1 - Bromination of 2,3-dimethylpyridine with DBDMH



[0039] To a stirred solution of 2,3-dimethylpyridine (10g, 0.09mol) in oleum 65% (30mL) at 10°C DBDMH (14.5g, 0,05mol) was added. There after the exothermic reactions started. The reaction mixture was then heated at 105°C for 2h. After cooling to room temperature, the mixture was poured onto ice (150g) and the ph adjusted to 12 with aqueous sodium hydroxide solution. The product was extracted into MTBE (3x100mL), the organic phases were dried with MgSO4 and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine as yellow oil (. Purity acc. to GC 87.3%; yield: 83.3%.

Example 2 - Bromination of 2,3-dimethylpyridine with DBDMH



[0040] To a stirred solution of 2,3-dimethylpyridine (20g, 0.185mol) in oleum 65% (60mL) at 10°C DBDMH (31.7g, 0,11mol) was added. There after the exothermic reactions started. The reaction mixture was then heated at 105°C for 2h. After cooling to room temperature, the mixture was poured onto ice (250g) and the ph adjusted to 12 with aqueous sodium hydroxide solution. The product was extracted into MTBE (3x100mL), the organic phases were dried with MgSO4 and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine as yellow oil (34.3g). Purity acc. to GC 87.0%; yield: 86.7%.


Claims

1. A process for preparing compounds of formula I,

in which

R1 is in each case independently selected from hydrogen, halogen, C1-C6-alkyl and C1-C6-halogenalkyl;

R2 is in each case independently selected from hydrogen and halogen;

R10 is in each case independently selected from H, halogen, O(R95), C1-C6-alkyl and C1-C6-halogenalkyl; wherein

R95 is C1-C6-alkyl, C1-C6-halogenalkyl;

comprising the following steps:

(i) reacting a compound of the formula II

wherein R1, R2 and R10 are as defined above with a brominating agent which is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in the presence of oleum 65%.


 
2. The process according to any one of claims 1 to 2, wherein R1 and R2 are hydrogen, and R10 is C1-C6-alkyl.
 
3. The process according to any one of claims 1 to 3, wherein R1 and R2 are hydrogen and R10 is CH3.
 


Ansprüche

1. Verfahren zur Herstellung von Verbindungen der Formel I,

in der

R1 jeweils unabhängig aus Wasserstoff, Halogen, C1-C6-Alkyl und C1-C6-Halogenalkyl ausgewählt ist;

R2 jeweils unabhängig aus Wasserstoff und Halogen ausgewählt ist;

R10 jeweils unabhängig aus H, Halogen, O(R95), C1-C6-Alkyl und C1-C6-Halogenalkyl ausgewählt ist; wobei R95 für C1-C6-Alkyl, C1-C6-Halogenalkyl steht; umfassend die folgenden Schritte:

(i) Umsetzen einer Verbindung der Formel II

wobei R1, R2 und R10 wie oben definiert sind, mit einem Bromierungsmittel, bei dem es sich um 1,3-Dibrom-5,5-dimethylhydantoin (DBDMH) handelt, in Gegenwart von 65%igem Oleum.


 
2. Verfahren nach Anspruch 1, wobei R1 und R2 für Wasserstoff stehen und R10 für C1-C6-Alkyl steht.
 
3. Verfahren nach einem der Ansprüche 1 bis 2, wobei R1 und R2 für Wasserstoff stehen und R10 für CH3 steht.
 


Revendications

1. Procédé pour la préparation de composés de formule I,

dans laquelle

R1 est en chaque cas indépendamment choisi parmi hydrogène, halogène, C1-6 alkyle et C1-6 halogénoalkyle ;

R2 est en chaque cas indépendamment choisi parmi hydrogène et halogène ;

R10 est en chaque cas indépendamment choisi parmi H, halogène, O(R95), C1-6 alkyle et C1-6 halogénoalkyle ; R95 étant C1-6 alkyle, C1-6 halogénoalkyle ; comprenant les étapes suivantes :

(i) mise en réaction d'un composé de la formule II

R1, R2 et R10 étant tels que définis ci-dessus avec un agent de bromation qui est la 1,3-dibromo-5,5-diméthylhydantoine (DBDMH) en la présence d'oléum à 65 %.


 
2. Procédé selon la revendication 1, dans lequel R1 et R2 étant hydrogène, et R10 étant C1-6 alkyle.
 
3. Procédé selon l'une quelconque des revendications 1 à 2, R1 et R2 étant hydrogène, et R10 étant CH3.
 






Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description