DE1204231B - Process for the preparation of 2-chloromethyl-pyridines or -quinolines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

C07d

German KL: 12 ρ-1/01

Number: 1204231

File number: R 29067IV d / 12 ρ

Filing date: November 12, 1960

Opening day: November 4, 1965

The production of ω-monochloromethyl pyridines has so far mainly taken place from the pyridine carbinols by reaction with thionyl chloride or Phosphorus chlorides (1). In addition, processes are known that are made from the aminomethyl compounds Reaction with nitrous acid in a strongly hydrochloric acid solution (2), from 2-picoline-N-oxide with p-toluenesulfonyl chloride (3) or from ω-di- or co-trichloromethylpyridines also lead to ω-monochloromethyl pyridines by reduction with tin (4). co-dichloromethylpyridines were previously only by reducing the ω-trichloromethylpyridines with tin in hydrochloric acid Solution accessible (4). Gradual chlorination with elemental chlorine, which is in the aromatic series for example in the case of toluene, depending on the reaction conditions, to benzyl chloride, benzal chloride or Benzotrichloride lead, do not get in the pyridine series with 2-position methyl groups. One received in these experiments, mostly in poor yields, exclusively co-trichloromethyl-pyridines (4).

The invention relates to a process for the preparation of 2- (chloromethyl) pyridines or quinolines, which is characterized in that a 2-methylpyridine or -quinoline, which is on the pyridine nucleus can still carry one or more further methyl radicals, about twice the molar amount of chlorine at temperatures from 40 ° to 80 ° C. in the presence of an inert solvent of the carbon tetrachloride type or trichlorethylene and a hydrogen chloride binding agent of the type Sodium carbonate or hydrogen carbonate can act.

The resulting (monochloromethyl) compound is expediently diluted in dilute Acid separated from the (dichloromethyl) and / or the (trichloromethyl) compound.

Thus, above all, the 2- (monochloromethyl) pyridines, which are particularly valuable for the syntheses, which could previously only be obtained by multi-stage, high-loss syntheses, in a technically feasible manner Accessible from the simplest starting materials in one reaction stage.

Experiments showed that the hydrochloric acid salts of 2-methylpyridines are very difficult in the Let the temperature range from 40 to 80 ° C chlorinate. During the chlorination, however, hydrogen chloride is formed, which immediately with the basic starting material Hydrochloride forms. As a result, the reaction comes after a short time, that is, after a low conversion to a standstill. Therefore, the hydrogen chloride formed during the chlorination has to be captured, what for example by carbonates, bicarbonates, etc.

Process for the production of
2-chloromethyl pyridines or quinolines

Applicant:

Dr. F. Raschig G. m. B. H.,

Ludwigshafen / Rhein, Mundenheimer Str. 100

Named as inventor:

Dr. Wilhelm Mathes,

Dr. Hans Schüly, Ludwigshafen / Rhine

can be done. In this way it can be achieved that all the starting material is chlorinated even at medium temperatures, for which an excess of chlorine in about twice the theoretical amount is required. This is important for the isolation of the chlorinated compounds, since the yields of monochlorine compounds drop sharply if the starting material is still present. During work-up, salts are easily formed from the monochloromethylpyridines and from non-chlorinated starting material, some of which react further to form higher molecular weight compounds. Maintaining an average temperature during the reaction is also intended to prevent salt formation which occurs easily at higher temperatures in a neutral or alkaline medium. A diluent also makes it difficult for the 2- (chloromethyl) pyridines to react with the starting material. In addition, this solvent facilitates the dissipation of the heat of reaction of the exothermic reaction and enables good mixing of the reacting substances with the additive that binds hydrogen chloride.
The substances normally used as hydrogen chloride-forming agents in reactions, such as pyridine or methylpyridines, are therefore not suitable for the present process.

The solvents used are neutral hydrocarbons such as chloroform, carbon tetrachloride, Trichlorethylene, etc., in question, which at the reaction temperature neither with nor with chlorine the 2- (chloromethyl) pyridines react.

Acidic solvents, such as acetic acid, have the effect, as numerous studies have shown (4),

5u that the reaction leads exclusively to 2-trichloromethyl) pyridines leads. In inert solvents, on the other hand, by varying the amount of

509 720/413

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conducted chlorine either preferably 2- (mono- 47 ° C 165.2 g (-65% of theory) 2- (monochlorochloromethyl) pyridines or on further introduction of methyl) pyridine (2-picolyl chloride) as a colorless distildie Obtained 2-di- or 2-trichloromethyl compounds. lat over.

The separation of the 2- (monochloromethyl) pyridines pj ^ at; p. 147 to 148 ° C nf 1 5365.
is achieved by using the reaction solution 5 "' ° '

with dilute acids, for example 2 normal carbon tetrachloride solution is poured

Hydrochloric acid, extracted. As a result of the various bases neutralized with soda solution, with anhydrous rate of the chlorinated compounds, the 2- (monosodium sulfate dried, the solvent abchloromethyl) -pyridines go into the hydrochloric acid phase, while the more highly chlorinated compounds are evaporated and the residue is distilled in vacuo in the organic io 22.5 g of 2- (dichloromethyl) solvent are obtained at 1.2 torr. In contrast to the pyridine (bp _{1> 2} 62 to 66 ° C, picrate m.p. 115 to 116 ° C, salts (e.g. hydrochlorides) of 2- (chloromethyl) - ηϊ? 1.5470) and 4.5g2- (trichloromethyl ) pyridine (Kp. _li8 compounds are those in the 76 to 80 ⁰ C n ² g 1.5620 according to the invention, no picrate).
Some of the free bases formed are not produced. .

durable. Thus, above all, the 2- (mono-15 i3eispieI2

chloromethyl) pyridine (C2 picolyl chloride) after only 214 g (2 mol) of 2,6-lutidine are dissolved in 800 ml of tetra few hours (red carbonate, with 400 g of sodium carbonate exercise). It is therefore necessary that these are mixed and heated to 60 ° C. Then you pass internal bonds, the work-up is done quickly and the half of 7 hours 4 moles of chlorine in the reaction distillation is carried out under good vacuum. At ao mix. The work-up is carried out as in Example 1. In industrial production, short-path or film evaporators are appropriate for the distillation of the residue of the benzene solution. The decomposable bases are at 1 Torr and a boiling temperature of 50 must either immediately for further reactions to 54 ⁰ C 162.5 g (= 57% of theory) of 6-methyl odejr Used as salts (eg. As hydrochloride) stable 2 -chloromethylpyridm obtained. Picrat: F. 159 to be lized, 25 161 ⁰ C, nf 1.5315. The compound distills colorless,

Literature ^w ^ ^rs ^ aM. ^oran S ^e · B ^e i dyed prolonged standing

they turn black-brown. It is a little more stable than

1. K. Winterfeld, K. Flick, Arch. Pharmaz. the 2- (chloromethyl) pyridine.
Ber. German pharmacy Ges., 289/61, 448 (1956).

C. 1958,3305. ₃₀ Example 3

2. J. Overhoff, J. Boeke, A. Gorter, reaction conditions: 242 g (2 mol) 2,4,6-collidine Recuiel Trav. chim. Pays-Bas, 55, 293 (1936). in 800ml carbon tetrachloride, 400g sodium

C. 1937.1, 353. reaction temperature carbonate, 55 ⁰ C, 4.5 moles of chlorine,

3. E. Matsumura, J. formerly Soc. (Japan), 74, introduction duration 8 hours. The chlorination and 363 (1953). C.A. 48, 6442b (1954). 35 Work-up is carried out in the same way as in

λ τ »τ TXo ~, * v,; ~ l · τ n% ~ ™ o""/ τ ™ a ~ w \ Example 1 described. The distillation of the back

4. DL Hammick, J. Chem. 00c. (London), K. , _ "... ,,,.,. _{φ Λ}

1923 2882 C 1924 II 1384 level of the benzene solution gives 1.4 Torr and

DL Hammick \ J. Chem. Soc. (London), ^ ₁ boiling point from 68 to 7O ⁰ C 172 g colorless iQ9fi lim ο iQ9fi TT 18S0 distillate, which is the monochlorine compound. P Dyson, D. L Hammi'ck, J. Chem. Soc. ^ Yield: 55% of theory ^ Picrate: I ^ 125 to 126 <'C ₁ (London), 1939, I. 781. C. 1939, II, 1866. ⁿ \ ¹ ^ f-? ^a $ f monochlorine compounds and the

ET McBee, MB Hass, EM Hodnett, corresponding carbmole of the 24,6-CoUidms not Ind. Eng. Chem., 39, 389 (1947). C. 1947, 588. ^h / ^ka ™ \ ^Smd '™ t? ^. Proof of the position ■ RT) !), """Η τ HamtninV" es Cl atom the chlorine compound with sulfuric acid

Xi. Jx. J5 Γ Ο WH, XJ. xji XX dm III IUK, ^ ₁ -. _Λ .λ ti · ·, η ι

BH Thhewlis, J. Chem. Soc. _(Lond o _{n) 5} 'to Carbmol saponified IMD ^ this oxidized with nitric acid 1951 1145 1952 845 C ^to monocarboxylic acid. The acid obtained

Ch. H. B re tt, EM H ο dη e tt, USA.- Pa- ™ * ^sioh : ^as identical to 4,6-Dim? ThylpyridintpntcfViWft ο Λ7Ο AW ο 1QS * Aduo 2-carboxylic acid. This proves that the

Monochlorine compound the 4,6-dimethyl-2-chloromethane

For example ⁵ ° t ^ yl-pyridine. The substance is more permanent than that

corresponding compounds of 2-picoline and des

186.2 g (2 mol) of pure 2-picoline are in 1000 ml of 2,6-lutidine. It turns yellow on standing, can be dissolved in anhydrous carbon tetrachloride and stored with but without significant decomposition.
300 g of anhydrous sodium carbonate are added. Under . · ■> _A

Stir the mixture in a three-necked flask 55 Example 4

with reflux condenser to 6O ⁰ C internal temperature - 286 g (2MoI) of pure 2-methylquinoline (quinaldine)

heats; then 4MoI are dissolved in 1000ml carbon tetrachloride within 6 hours and introduced with chlorine. The temperature is added during this 300 g of anhydrous sodium carbonate and chlorinated in the manner described by slight cooling between 60 and 65 ° C. Maintained temperature 50 ⁰ C. After cooling down, the thick orange becomes. 60 Amount of chlorine: 4MoI. Duration of introduction: 6 hours, yellow colored pulp with stirring with 1000 ml of 2η salt. After extraction with 2η hydrochloric acid, this acid is added. Then it is neutralized with solid sodium carbonate in a separating funnel. The carbon tetrachloride phase is separated off and a somewhat gray-colored precipitate separates out, which is extracted twice with 200 ml of 2η hydrochloric acid each time. The HCl solutions combined with suction for one hour and washed with water are neutralized with soda. After drying, the precipitate is concentrated and extracted with benzene. After drying petroleum ether (bp. 80 to 100 ⁰ C) with the addition of concentrated by evaporation, the benzene solutions and recrystallized distilled activated carbon. 214 g of 2-chlorodene residue are obtained. At 1.5 torr, between 45 and methylquinoline go as colorless needles. Yield: 60%

of theory, m.p. 56.5 to 57.5 ° C. Picrat: F. 171 to 172 ^° C. The compound is very stable and can be stored in brown bottles without significant changes. 42 g of 2- (dichloromethyl) -quinone can still be obtained from the residue of the evaporated carbon tetrachloride solution by recrystallization from petroleum ether. M.p. 82 to 83 ° C. Picrat: E. 118 'to 119 ⁰ C.

Example 5

ΪΟ

107 g (1 mol) of 2,3-lutidine are chlorinated in 800 ml of carbon tetrachloride with the addition of 200 g of anhydrous sodium carbonate at 60 to 65 ° C. as described. Amount of chlorine: 2MoI, initiation time: 3 hours. When working up, make sure that the benzene solution is gently evaporated (with a weak vacuum) and the residue is immediately distilled with a good vacuum. The 3-methyl-2-chloromethylpyridine distilled colorless at 1,4TnTn Hg, between 59 and 6I ⁰ C, but is already bright red in the cooler. Yield: 90.5 g = 64% of theory.

!. κ "1.5407 picrate: mp 146 to 146.5 ° C Hydrochloride:. F. 157 ⁰ C.

Claims (2)

Patent claims: 1. A process for the preparation of 2- (chloromethyl) -pyridines or -quinolines, characterized in that about twice the molar amount of chlorine is added to a 2-methylpyridine or -quinoline, which can also carry one or more further methyl groups on the pyridine nucleus at temperatures of 40 to 80 ⁰ C in the presence of an inert solvent of the type of carbon tetrachloride or trichlorethylene and a hydrogen chloride-binding agent of the type of sodium carbonate or hydrogen carbonate. 2. The method according to claim 1, characterized in that the resulting (monochloromethyl) Connection by dissolving in dilute acid of the (dichloromethyl) and / or the (trichloromethyl) Connection is disconnected. 509 720/413 10.65 © Bundesdruckerei Bed »