EP1569906A1 - Procede d'halogenation photochimique - Google Patents

Procede d'halogenation photochimique

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Publication number
EP1569906A1
EP1569906A1 EP03767641A EP03767641A EP1569906A1 EP 1569906 A1 EP1569906 A1 EP 1569906A1 EP 03767641 A EP03767641 A EP 03767641A EP 03767641 A EP03767641 A EP 03767641A EP 1569906 A1 EP1569906 A1 EP 1569906A1
Authority
EP
European Patent Office
Prior art keywords
acid
substituted
amine
starting compound
adduct
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03767641A
Other languages
German (de)
English (en)
Inventor
Max Braun
Uta Claassen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Solvay Fluor GmbH
Original Assignee
Solvay Fluor GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Solvay Fluor GmbH filed Critical Solvay Fluor GmbH
Publication of EP1569906A1 publication Critical patent/EP1569906A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals

Definitions

  • the invention relates to a process for photochemical halogenation, in particular for photochemical chlorination, and certain adducts obtained thereby.
  • the photochemical halogenation is a process with which halogenated, z. B. chlorinated target compounds that differ from the starting compounds in that they have at least 1 halogen atom, for. B. have at least 1 chlorine atom more than the starting compound.
  • the photochlorination involves a chlorine-hydrogen exchange, as a main reaction or as a side reaction, HCI is produced.
  • the HCl formed does not interact with compounds present in the reaction mixture, the photochemical irradiation is usually not adversely affected.
  • the HCI either gases out of the reaction mixture and / or remains partially dissolved in it.
  • the reaction is then adversely affected or may come to a complete standstill if the HCl formed forms adducts with one or more of the compounds in the reaction mixture which precipitate out as a solid. These solids prevent the further radiation of the photo radiation.
  • the invention aims to provide an improved method for photohalogenation, in particular for improved photochlorination, in which no hydrohalide adducts, e.g. B. hydrochloride adducts must be used, or in which starting compounds, target compounds and / or any amines with hydrohalide formed, in particular with HCl formed during photochlorination, do not form adducts which precipitate out as solids and inhibit the photoreaction.
  • no hydrohalide adducts e.g. B. hydrochloride adducts must be used, or in which starting compounds, target compounds and / or any amines with hydrohalide formed, in particular with HCl formed during photochlorination, do not form adducts which precipitate out as solids and inhibit the photoreaction.
  • the invention is based on the finding that photochemical chlorination with the exchange of hydrogen for chlorine in organic compounds which give adducts with formed HCl, which precipitate out as a solid, is possible if an acid is added which is so strong that it does so Can displace HCl from the adducts, or if the starting compounds are already used as an adduct of this acid. This finding applies to photohalogenization in general.
  • the process according to the invention for the production of target compounds substituted by at least 1 halogen atom by photochemical halogenation of starting compounds which are substituted by at least 1 halogen atom less than the target compounds, by exchanging hydrogen for halogen provides that the photohalogenation is carried out with addition and / or in In the presence of an acid which at least partially drives off the hydrogen halide which is released during the halogen-hydrogen exchange, or wherein the starting compound is used as an adduct with such an acid, so that the starting compound is at least partially prevented from the target compound and / or any amine present forms an adduct with the hydrogen halide formed, which precipitates as a solid.
  • Halogen preferably means bromine or choir, especially chlorine. The invention is further explained on the basis of the particularly preferred photochlorination.
  • the HCI formed when hydrogen is replaced by chlorine is at least partially expelled from the reaction mixture in the process.
  • photochlorination can also be carried out at even higher temperatures.
  • a preferred minimum temperature is 50 ° C.
  • the HCI formed is predominantly or essentially completely expelled.
  • the turnover is correspondingly high.
  • the upper temperature limit for the reaction mixture is variable. It is therefore expedient not to work above a temperature at which undesired by-products are formed to an undesirable extent, at which one undesirably drives off product from the mixture or at which the pressure in the reactor is undesirably high.
  • a preferred upper limit at which the reaction according to the invention is carried out is 150 ° C., particularly 140 ° C. It is therefore expedient to photochlorine in the range from 10 to 150 ° C., preferably in the range from 50 to 140 ° C.
  • the acid which is intended to drive off the HCl formed in whole or in part from the reaction mixture can be introduced into the reaction mixture in a wide variety of ways.
  • the starting compound, any amine to be added and the acid, optionally together with chlorine can be mixed in any order in a reactor.
  • the starting compound or an amine to be added if necessary can also be used, at least partially or completely, in the form of adducts with the acid.
  • Another possibility is to use the starting compound or the amine to be added as a hydrochloride adduct, but to convert it into the acid adduct by reaction with the acid before carrying out the photochemical chlorination.
  • the HCl from the salt is then at least partially, preferably completely, driven off before the actual reaction.
  • the acid is present in an amount which is greater than the amount necessary to form adducts with the starting compound, target compound or any amine present. Since the starting compound is converted into the target compound and usually both are capable of forming adducts with the acid, it is sufficient to provide an excess of the acid in terms of the amount of starting compound or the sum of starting compound and any amine present.
  • acids which can prevent the precipitation of adducts of the starting or target compound and any amine present with HCl in the reaction mixture and which likewise do not form any adducts precipitating as a solid can be used as the "acid".
  • acids which are stronger than HCl and can therefore release them from its compounds for example halogenated or partially halogenated carboxylic acids, especially halogenated or partially halogenated alkane carboxylic acids or alkane dicarboxylic acids with 1 to 4 carbon atoms in the alkyl or radical.
  • a particularly preferred acid is trifluoroacetic acid.
  • Other acids that can be used are perfluoropropionic acid, chlorodifluoroacetic acid or difluoroacetic acid.
  • HCI can drive out of the reaction mixture and does not form a solid with the starting or target compound can be determined by simple manual tests.
  • the starting compound and an excess of the acid can be mixed, chlorine added and light emitted. If no solid precipitates at least during most of the reaction, the acid is suitable.
  • the starting compounds used in the preferred photochlorination are those compounds which can be substituted for chlorine by replacing hydrogen, so that at least 1 more chlorine atom is present in the target compound. It is not excluded that the addition of chlorine to unsaturated bonds can also take place, for. B. on C-C double or triple bonds. Then more chlorine must be introduced into the reaction mixture.
  • Preferred starting compounds are amines.
  • branched or unbranched aliphatic amines or cyclic aliphatic amines can be chlorinated accordingly.
  • the process for chlorinating aromatic amines which are substituted by one or more alkyl groups is very suitable.
  • the nitrogen atom can be built into the aromatic ring. However, it can also be present as a substituent on the aromatic ring. Connections can also be used that have several nitrogen atoms which are built into the aromatic ring and / or are present as a substituent.
  • one or more other substituents can be present, for example halogen atoms on the aromatic nucleus.
  • alkyl preferably denotes alkyl with 1 to 4 carbon atoms, especially methyl, ethyl, i-propyl and n-propyl.
  • Preferred classes of compounds are pyridines and quinolines which are substituted by at least one alkyl group having 1 to 4 carbon atoms.
  • Pyridines which are substituted by 1 to 5 alkyl groups each having 1 to 4 carbon atoms are very particularly preferred.
  • Pyridines which are substituted by 1, 2 or 3 alkyl groups having 1 to 3 C atoms are particularly preferred.
  • Excellent compounds are picolines (i.e. pyridine substituted by 1 methyl group), lutidines (i.e. pyridine substituted by 2 methyl groups) and collidines (i.e. pyridine substituted by 3 methyl groups). These compounds exist in several isomers, all of which can be used. 2-Picoline, 3-methylpyridine and 4-methylpyridine (i.e. the three isomeric picolines) are particularly suitable.
  • amines used as particularly preferred starting compounds can already be used as substituted compounds, for example substituted by halogen, nitro or amino groups.
  • photochlorinating amino groups it is of course not necessary to add amine.
  • Chlorine-substituted picolines are intermediates in chemical synthesis. They are useful, for example, for the preparation of herbicides, see US-A 4,577,027. They can be converted into fluoropicolines by fluorination, which in turn are intermediate products, for example in the production of active pharmaceutical ingredients, see WO 95/30670.
  • the photochemical reaction is caused by exposure to light.
  • light of any wavelength can be used, for example light of a wavelength above 200 nm.
  • Light of a wavelength of greater than 280 nm is preferably irradiated.
  • glass devices are used which absorb shorter wavelengths, e.g. B. borosilicate glass.
  • light emitters can be used which only or largely only emit light of a wavelength above 280 nm.
  • the molar ratio of acid to picoline is at least 1: 1. It can also be much larger, up to 10: 1. It can be even larger than 10: 1, preferably up to 20: 1; then the trifluoroacetic acid acts as a solvent.
  • At least 0.6 mol of chlorine is used per gram of hydrogen atom to be exchanged. It is advantageous to use at least 1 mole of chlorine per gram of hydrogen to be exchanged. A preferred range is 1 to 1.3 moles of chlorine per gram of hydrogen to be exchanged. If chlorine is also added, for example on CC double or triple bonds, a little more chlorine must be used accordingly.
  • the reaction mixture can be generated in various ways. For example, you can mix the picoline and the desired amount of trifluoroacetic acid in the reactor. Alternatively, an adduct of picoline and trifluoroacetic acid which has already been prepared beforehand can be used. It is also possible to first introduce picoline hydrochloride into the reactor and to generate the desired adduct with trifluoroacetic acid at elevated temperature while expelling the HCl formed. In all cases, free trifluoroacetic acid can be added if desired.
  • one or more hydrogen atoms can be exchanged.
  • the reaction can be stopped at the level of the monochlorinated picoline. If more chlorine is added, the chlorination continues successively.
  • the chlorinated amine produced in the photochemical chlorination for example chloropicolin
  • the isolation can be done in different ways. For example, a base can be added and the free amine formed can be extracted from the reaction mixture with water. After the water has been separated off by customary methods, the free amine is present. Another method is to precipitate the amine, e.g. B. as salt.
  • the chlorinated amine can be used after the photochlorination z. B. precipitated as an HCI adduct by introducing gaseous HCI.
  • Yet another method provides for the chlorinated amine and trifluoroacetic acid adduct to be distilled out of the reaction mixture.
  • the isolated adduct of chlorinated amine, for example 2-chloropicolin (2-chloromethyl-pyridine) and trifluoroacetic acid can then be mixed with a base in order to obtain the free chlorinated amine, for example the free 2-chloropicolin, or alternatively one can also do this Continue reacting the adduct of chloropicolin and trifluoroacetic acid without isolating the free base.
  • Another object of the invention are adducts of trifluoroacetic acid, perfluoropropionic acid, difluoroacetic acid and chlorodifluoroacetic acid with pyridines and Quinolines which are substituted by one or more C1-C4-alkyl groups with the proviso that at least one alkyl group is substituted by at least 1 chlorine atom.
  • Adducts of trifluoroacetic acid and pyridine which are substituted by at least one C1-C4-alkyl group, preferably by 1, 2 or 3 alkyl groups, wherein at least one alkyl group is substituted by at least 1 chlorine atom are particularly preferred.
  • Adducts of trifluoroacetic acid and chloromethylpicolin, in particular 2-chloromethylpicolin, are particularly preferred. Such adducts can be used, for example, as intermediates in the production of fluorine-substituted amines with chlorine-fluorine exchange.
  • the invention further relates to adducts of trifluoroacetic acid, perfluoropropionic acid, difluoroacetic acid and chlorodifluoroacetic acid with pyridines and quinolines which are substituted by one or more C1-C4-alkyl groups.
  • Adducts of trifluoroacetic acid and pyridine which are substituted by at least one C1-C4-alkyl group, preferably by 1, 2 or 3 alkyl groups, are particularly preferred.
  • Adducts of trifluoroacetic acid and methylpicolin, in particular with 2-methylpicolin are particularly preferred.
  • Such adducts can be used, for example, as intermediates in the process according to the invention.
  • the invention has the advantage that the photochemical chlorination of amines in particular is possible.
  • Picolin x 3 TFA was placed in the photoreactor with a cooling water jacket and a 500 watt UV lamp was ignited. After 10 min. was chlorine in there. 25 ° C warm reaction solution initiated. After adding about 30 g of chlorine there was a slight evolution of gas observable (Kl solution turned brown). After the addition of 87.4 mol% chlorine, a sample was taken, only 51 mol% chlorinated. Chlorine was passed in further, after adding 119.6 mol% of chlorine, the mixture became cloudy, the introduction of chlorine was stopped, and the chlorination was now 66%. Part of the batch was distilled over a packed column.
  • the 2-chloromethylpyridine was about 66% pure. Vacuum was applied and slowly reduced to 1 mbar, since there was a strong gas evolution. Then it was heated. The approach turned black. The distillation gave brown colored fractions.
  • Example 1 shows that even at 25 ° C, photochlorination is already possible. However, sales are not complete because too little HCI has been driven out.
  • the amine was placed in a 250 ml three-necked flask and the TFA was added dropwise at room temperature. It was cooled with a dry ice cooler and ice bath. The temperature of 38 ° C was not exceeded during the dropping. After the reaction, the mixture was colored slightly yellow, but clear.
  • the example shows that an almost quantitative, selective conversion to 2-chloromethylpyridine (2-chloropicolin) is possible at a sufficiently high temperature.
  • 3-Picolin x 3 TFA was placed in a double jacket in the photoreactor and heated to 60 ° C. by means of a thermostat, then the 150 watt UV lamp (with compressed air cooling) was ignited and chlorine was introduced after a further 10 min. The batch turned yellow, gaseous HCl escaped from the photoreactor. No precipitate (HCI adducts) was visible in the reactor. The selectivity to 3-trichloromethylpyridine was 98% (purity determination by NMR). Repetition with high lamp power and higher chlorine introduction rate
  • Experiment 3 shows that the photochemical chlorination according to the invention can also be carried out with other isomers of methylpyridine. It also shows that, depending on the amount of chlorine used, the chlorination can be stopped in the monochlorinated adduct or can be chlorinated through to the trichloromethyl compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Selon l'invention, l'addition d'un acide qui expulse un halogénure d'hydrogène, notamment, HCl, contenu dans le mélange réactionnel, permet l'halogénation photochimique, notamment la chloration de composés organiques, par substitution chlore-hydrogène, même si les composés de départ, les composés cibles ou les amines éventuellement présentes, forment avec l'halogénure d'hydrogène libéré, par exemple HCl, des produits d'addition qui, sans l'addition d'acide, formeraient un précipité.
EP03767641A 2002-12-06 2003-11-25 Procede d'halogenation photochimique Withdrawn EP1569906A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10156999 2002-12-06
DE2002156999 DE10256999A1 (de) 2002-12-06 2002-12-06 Photochemisches Halogenierungsverfahren
PCT/EP2003/013223 WO2004052860A1 (fr) 2002-12-06 2003-11-25 Procede d'halogenation photochimique

Publications (1)

Publication Number Publication Date
EP1569906A1 true EP1569906A1 (fr) 2005-09-07

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EP03767641A Withdrawn EP1569906A1 (fr) 2002-12-06 2003-11-25 Procede d'halogenation photochimique

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EP (1) EP1569906A1 (fr)
JP (1) JP2006512331A (fr)
CN (1) CN1720229A (fr)
AU (1) AU2003292101A1 (fr)
DE (1) DE10256999A1 (fr)
WO (1) WO2004052860A1 (fr)

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CN101337924B (zh) * 2008-08-28 2011-04-20 山东省分析测试中心 一种用于甲基吡啶类侧链氯化反应的方法
CN105503703A (zh) * 2014-10-09 2016-04-20 江苏笃诚医药科技股份有限公司 卢帕他定中间体3-氯甲基-5-甲基吡啶的合成方法
CN104610137A (zh) * 2015-01-30 2015-05-13 大连世慕化学有限公司 2-氯-5-三氯甲基吡啶及2-氯-5-三氟甲基吡啶合成方法
CN114763368B (zh) * 2021-01-14 2024-03-12 中国科学院大连化学物理研究所 一种芳香族氨基酸卤化修饰的直接光化学方法

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Publication number Priority date Publication date Assignee Title
DE1204231B (de) * 1960-11-12 1965-11-04 Raschig Gmbh Dr F Verfahren zur Herstellung von 2-Chlormethyl-pyridinen oder -chinolinen
JPS6236358A (ja) * 1985-08-12 1987-02-17 Daicel Chem Ind Ltd クロルメチルピリジンの製造方法

Non-Patent Citations (1)

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Title
See references of WO2004052860A1 *

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Publication number Publication date
CN1720229A (zh) 2006-01-11
WO2004052860A1 (fr) 2004-06-24
DE10256999A1 (de) 2004-06-24
JP2006512331A (ja) 2006-04-13
AU2003292101A1 (en) 2004-06-30

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