DE4005115A1 - Prepn. of 2-halo-substd. pyridine derivs. - by reacting 2-amino-pyridine with gaseous methyl or ethyl nitride in presence of aprotic solvent and hydrogen halide - Google Patents

Abstract

The prepn. of 2-halo-substd. pyridine derivs. of formula (I) comprises reaching a 2-amino pyridine of formula (II) with gaseous methyl or ethyl nitrite at 0-120 deg.C in the presence of an aprotic organic solvent and in the presence of a hydrogen halide HX. In (I) X = Cl or Br; R1 and R2 = each H, opt. branched 1-4C alkyl, Cl or Br. USE/ADVANTAGE - (I) are intermediates in the prepn. of pharmaceuticals and plant protecting agents. Used in aprolic solvent which is immiscible with water and makes work-up of the reaction mixt. easier. The use of gaseous methyl or ethyl nitrite can be produced in a separate generator immediately prior to use, and led into the reactor without the need for intermediate storage.

Description

The invention relates to a method for producing in the 2-position halogen-substituted pyridines from the corresponding 2-amino-pyridines by diazotization and subsequent nitrogen elimination in the sense of a Sandmeyer reaction.

2-halogenopyridines, especially if they have further sub bear substituents, such as 2-chloro-5-methyl-pyridine important intermediates for the production of active ingredients substances in the field of pharmaceuticals and plants zenschutzmittel (DE-OS 28 12 585; EP 3 24 174).

According to EP 3 24 174 2-chloro-5-methyl-pyridine is made from 3- Methyl pyridine-1-oxide and phosphoryl chloride in the presence made from diethylamine and methylene chloride.

DE-AS 16 95 659 describes the preparation of 2-chloro pyridines, which can optionally be mono- or disubstituted by a halogen atom or a C ₁ -C ₄ alkyl group, by reacting the associated 2-amino pyridines with C ₃ - C ₅ alkyl nitrites known in the manner of a Sand Meyer reaction. The reaction is preferably carried out at 20 to 30 ° C. in methanol saturated with dry hydrogen chloride. The methanol is used in an at least 8-fold molar excess.

This is the procedure described last Reaction of the initially formed diazonium salt to 2-chloro-pyridine in the manner of a Sandmeyer reaction in essentially smooth and with yields of over 86% if a sufficiently high concentration of hydrogen chloride given is. Such a high concentration can be reach methanol in the polar reaction medium, whereby at the same time despite the high molar excess Methanol after etherification in favor of chlorination Sandmeyer is pushed back. For that another has to Side reaction between dry hydrogen chloride and Methanol, namely the formation of methyl chloride, comes into play be taken. However, methyl chloride is carcinogenic and therefore questionable in terms of occupational hygiene; his high volatility requires high expenses for ent removal from the exhaust air. Furthermore, in the last described method with liquid alkyl nitrites ge which works a separate manufacture before their on set and thus require intermediate storage. Because of the toxicity of alkyl nitrites and their tendency to Decomposition is such an interim storage conceivable and therefore represents another disadvantage of this Procedure.

It has now been found that the conversion of the 2- Amino group of pyridines in the 2-halogen group stiger can perform if instead of methanol aprotic solvent is used and for diazo tation methyl or ethyl nitrite can be used. The Use of aprotic solvents seemed to be due to the achievable low concentrations of halogen therein hydrogen is not suitable as a reaction medium; their successful use is therefore surprising.

Many aprotic solvents, especially those before are immiscible with water, which are advantages in the processing of the finished reaction mixture with brings itself. As a further advantage of the invention The procedure must be the use of methyl or ethyl nitrite, both of which are gaseous in the Reaction mixture are initiated. Both nitrites can therefore be used simultaneously in one separate generator generated in gaseous form and immediately be introduced into the reaction mixture. Thus ent any dangerous interim storage falls, since according to Be termination of the reaction of the invention, the generation be stopped immediately in the alkyl nitrite generator can.

The invention accordingly relates to a method for manufacturing position of halogen-substituted in the 2-position Pyridines of the formula  

by diazotization of amino-substituted in the 2-position Pyridines and subsequent nitrogen elimination, that there characterized in that a 2-amino-pyridine formula

at a temperature of 0 to 120 ° C in the presence of an aprotic solvent and in the presence of hydrogen halide HX is reacted with gaseous methyl or ethyl nitrite, in the formulas
X for chlorine or bromine and
R ¹ and R ^{2 are} independently hydrogen, straight-chain or branched C ₁ -C ₄ alkyl, chlorine or bromine.

As a straight-chain or branched C ₁ -C ₄ alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl or ethyl, particularly preferably methyl.

According to the invention, 2-amino are preferred pyridines of the formula  

implemented in the
R ^{1 has} the scope of meaning mentioned.

In a particularly preferred manner, according to the invention 2-aminopyridines of the formula

implemented in the
R ^{11 represents} methyl or ethyl.

In a particularly preferred manner, 2- Amino-5-methyl-pyridine implemented and very particularly preferably to 2-chloro-5-methyl-pyridine.

The necessary for the implementation of the invention For example, methyl or ethyl nitrite can be gaseous be taken from a generator, the simultaneous methanol or ethanol, highly concentrated acid z. B. hydrochloric acid or sulfuric acid and an alkali nitrite (e.g. Sodium nitrite in aqueous solution) are added. The Methyl or ethyl nitrite develops spontaneously here and escapes in gaseous form at the top of the generator  and is immediately used to implement the invention reactor provided according to the process initiated. In methyl nitrite is preferably used.

The process according to the invention is carried out in the presence of a aprotic solvent performed. As aprotic Solvents come u. a. in question: aliphatic coals Hydrogen, for example those with 5 to 12 C Atoms that are straight or branched, open chain or can be cyclic; aromatic hydrocarbons, which can have, for example, 6 to 10 carbon atoms; ali phatic halogenated hydrocarbons, for example those with 1 to 10 carbon atoms, the straight-chain or ver can be branched and 2 to 4 halogen atoms (chlorine and / or bromine), with 4 or more carbon atoms one halogen atom is sufficient; aromatic halogen hydrocarbons, for example with 6 to 10 C- Atoms; Ethers such as tetrahydrofuran or dioxane. Important Examples of the (halogen) hydrocarbons mentioned are: hexane, cyclohexane, petroleum ether, benzene, toluene, Xylene, methylene chloride, chloroform, carbon tetrachloride substance, dichloroethane, dichloropropane, chlorobenzene, bromine benzene, dichlorobenzene. Of course you can too Mixtures of several such (halogen) hydrocarbons be used. In a preferred manner, the (cyclo) aliphatic and aromatic (halo gen) hydrocarbons or a mixture of several of used them. In a particularly preferred manner as an aprotic solvent, toluene or cyclohexane used.  

The inventive method is in the presence of Hydrogen halide, such as hydrogen chloride or bromine hydrogen, carried out. In a preferred manner Worked in the presence of hydrogen chloride so that the 2-chloro-pyridines are formed.

The process according to the invention is carried out at one temperature from 0 to 120 ° C, preferably 10 to 80 ° C, especially before draws 15 to 60 ° C, carried out.

The process according to the invention can be continuous or be carried out discontinuously. In both ver three variants are required: To next, the 2-amino-pyridine becomes the hydrohalide prepared, the halide usefully from that abge later introduced in the 2-position halogen atom is leading; the methyl or ethyl nitrite reactor; and the combination of the hydrohalide and the methyl or ethyl nitrite in the implementation of the invention, the the diazotization and the subsequent nitrogen release device in the sense of the Sandmeyer reaction. In the cont These three procedures correspond to the strict procedures also three separate reactors, while in discount the hydrohalide formation process and the addition of the methyl or ethyl nitrite to the diazo tion in a reactor can run sequentially. For small reaction batches it is discontinuous Driving style typical.

The discontinuous implementation can, for example take place so that the 2-amino-pyridine in a reactor  and the aprotic solvent are presented. Like this then hydrogen halide is added, the Hydrohalide forms. Another hydrogen halide is added until saturation. Then methyl or ethyl nitrite in gaseous form, the diazo expires and immediately afterwards Nitrogen elimination the Sandmeyer reaction to the 2-halo gene pyridine expires. If the Sandmeyer If the reaction has stalled, more halogen must be used hydrogen are added. Preferably is therefore simultaneous with the introduction of gaseous Methyl or ethyl nitrite further hydrogen halide admitted.

For working up, the excess methyl or ethyl nitrite removed. This can be done by blowing out an inert gas (e.g. nitrogen) and suitable Destruction takes place in an exhaust system. For larger ones Amounts of excess methyl or ethyl nitrite could a distillative removal followed by recycling be considered; however, this is due to necessary intermediate storage is not preferred. In preferred Excess methyl or ethyl nitrite is therefore used by adding amidosulfonic acid, bisulfite, urea or others to those skilled in the art of nitrite destruction known substances removed the excess nitrite. in the This is followed by the aprotic organic solution medium separated. This can basically be done from Ab distill happen. If it is immiscible with water  Solvents spontaneously form a separate phase this water-immiscible aprotic organic solvent. This organic phase can another reaction approach can be attributed to them can also be extracted with water and the aqueous Extract can be fed for further processing. The after separating the water-immiscible aprotic organic solvent remaining aqueous phase provides a melt / solution of the reaction products that are generally with additional water is relocated and removed for removal aprotic solvent is distilled. At Be use of water-miscible aprotic solution this is averaged solely by distillation from the un indirect reaction mixture before further processing tion removed.

The remaining solvent-free residue is then with a suitable base, for example with sodium hydroxide solution, neutralized; from the neutralized aqueous mixture is then the desired 2-chlorine pyridine obtained, for example with the help of water steam distillation or after phase separation Distillation of the organic phase.

example 1

271.5 g of 2-amino-5-methyl-pyridine and 1000 g of toluene were placed in a reactor with stirrer, thermometer, gas inlet for HCl and methyl nitrite, exhaust pipe and a bottom outlet. 95 g of HCl gas were introduced within 30 minutes, the temperature rising from 20 ° to 60 ° and kept at 60 ° by cooling. After cooling to 20 ° C and maintaining this temperature by further cooling, 208 g of HCl gas and 165 g of gaseous methyl nitrite were simultaneously introduced within 2 hours. The mixture was left to stir at 20 ° for a further hour. A complete conversion of the starting material was determined using a thin layer chromatographic sample. Then dissolved methyl nitrite was blown out with N ₂ . After switching off the stirrer, two phases formed. The lower aqueous molten salt / solution was discharged into another reactor. The toluene phase remained in the first reactor for another batch.

400 g of water were added to the drained salt melt / solution added and residual toluene by azeotropic distillation tion removed. The 125 g of toluene obtained were the first reactor added and for the next batch used. The toluene-free batch was cooled to 20 ° and in the temperature range from 20 to 30 ° C with 325 g 50% aqueous sodium hydroxide solution adjusted to pH 7. Out this neutralized aqueous reaction mixture the 2-chloro-5-methyl-pyridine by steam distillation tion with a water: pyridine derivative ratio of  won about 7: 1. 258.4 g of 2-chloro-5-methyl pyridine (89%); that corresponded to a yield of 75% of the theoretical yield, based on the put aminopyridine.

Example 2

108.6 g of 2-amino-5-methyl-pyridine and 500 ml of chlorobenzene were placed in a reactor with stirrer, thermometer, gas inlet for HCl and methyl nitrite, exhaust pipe and a bottom outlet. HCl gas was introduced within 30 minutes until the solution was saturated, the temperature rising from 20 ° to 60 ° and kept at 60 ° -70 ° by cooling. After cooling to 60 ° C and maintaining this temperature by further cooling, 103 g of HCl gas and 79 g of gaseous methyl nitrite were simultaneously introduced within 1.5 hours. The mixture was left to stir at 60 ° for a further hour. A complete conversion of the starting material was determined using a thin layer chromatographic sample. Then dissolved methyl nitrite was blown out with N ₂ . After switching off the stirrer, two phases formed. The reaction mixture was evaporated to dryness on a rotary evaporator. The residue was 194 g. The residue contained 57.2% 2-chloro-5-methyl-pyridine. This corresponds to a yield of 87%.

The salt residue was taken up in 150 ml of water, neutralized with 79 g sodium hydroxide solution (50%) to pH 8 and the organic phase formed is separated off.  

The dried organic phase let through Distillation on a 100 cm packed column Chloromethylpyridine at a head temperature of Win 142 ° / 10 mbar in 99% purity.

Example 3

108.6 g of 2-amino-5-methyl-pyridine and 500 ml of carbon tetrachloride were placed in a reactor with stirrer, thermometer, gas inlet for HCl and methyl nitrite, exhaust pipe and a bottom outlet. 34 g of HCl gas were introduced within 30 minutes, the temperature rising from 20 ° to 60 ° and kept at 60 ° -70 ° by cooling. After cooling to 60 ° C. and maintaining this temperature by further cooling, 163 g of HCl gas and 109 g of gaseous methyl nitrite were introduced simultaneously within 1.5 hours. The mixture was left to stir at 60 ° for a further hour. A complete conversion of the starting material was determined using a thin layer chromatographic sample. Then dissolved methyl nitrite was blown out with N ₂ . After switching off the stirrer, two phases formed. The reaction mixture was evaporated to dryness on a rotary evaporator. The residue was 196 g. The residue contained 46.5% 2-chloro-5-methyl-pyridine. This corresponds to a yield of 72%.

Example 4

108.6 g of 2-amino-5-methyl-pyridine and 600 ml of dioxane were placed in a reactor with stirrer, thermometer, gas inlet for HCl and methyl nitrite, exhaust pipe and a bottom outlet. 39 g of HCl gas were introduced within 30 minutes, the temperature rising from 20 ° to 60 ° and being kept at 60 ° -70 ° by cooling. After cooling to 60 ° C and maintaining this temperature by further cooling, 47 g of HCl gas and 79 g of gaseous methyl nitrite were simultaneously introduced within 1.5 hours. The mixture was left to stir at 60 ° for two hours. A complete conversion of the starting material was determined using a thin layer chromatographic sample. Then dissolved methyl nitrite was blown out with N ₂ . The reaction mixture was neutralized with 95 g sodium hydroxide solution (50%) (pH 8) and freed from the salt residue. The distillable solution for cleaning (809 g) contains 8.1% 2-chloro-5-methylpyride corresponding to 51% of the theoretical yield.

Claims (9)

1. Process for the preparation of 2-substituted halogen-substituted pyridines of the formula by diazotization of pyridines substituted in the 2-position and subsequent nitrogen cleavage, characterized in that a 2-amino pyridine of the formula at a temperature of 0 to 120 ° C in the presence of an aprotic organic solvent and in the presence of hydrogen halide HX with gaseous methyl or ethyl nitrite, in the formulas
X for chlorine or bromine and
R ¹ and R ² independently of one another represent hydrogen, straight-chain or branched C ₁ -C ₄ -alkyl, chlorine or bromine. 2. The method according to claim 1, characterized in that a 2-amino-pyridine of the formula is implemented in the
R ^{1 has} the scope of meaning mentioned in claim 1. 3. The method according to claim 2, characterized in that a 2-amino-pyridine of the formula is implemented in the
R ^{11 represents} methyl or ethyl. 4. The method according to claim 3, characterized in that 2-amino-5-methyl-pyridine is reacted. 5. The method according to claim 1, characterized in that working with methyl nitrite.   6. The method according to claim 1, characterized in that the 2-halogen substituted pyridine is a 2-chlorine is pyridine and for this purpose for diazotization in counter Was working with hydrogen chloride. 7. The method according to claim 1, characterized in that as an aprotic solvent a straight chain or branched, open chain or cyclic aliphatic hydrocarbon with 5 to 12 C- Atoms, an aromatic hydrocarbon with 6 up to 10 carbon atoms, one straight-chain or branched aliphatic halogenated hydrocarbon with 1 to 10 carbon atoms, an aromatic halogenated hydrocarbon substance with 6 to 10 carbon atoms or a mixture several of them are used. 8. The method according to claim 7, characterized in that that as aprotic solvent toluene or Cyclohexane is used. 9. The method according to claim 1, characterized in that the aprotic solvent first with halo hydrogen is added and then others Hydrogen halide simultaneously with the methyl or Ethyl nitrite is added.