DE2614400C3 - Process for the preparation of 2,6-diacyloxymethylpyridines - Google Patents

Description

CH, - O- C-R, (I)

wherein

Ri and R ,, which are identical, each represent a hydrogen atom or represent an alkyl radical having 1 to 4 carbon atoms by acylating a 2,6-disubstituted pyridine derivative. Isolating the product thus obtained from the reaction mixture and, if necessary, cleaning it the same, characterized in that a 2,6-dihalomethylpyridine of the general Formula II

X CII,

N '

CH, X

(II)

X means an halogen atom,
in the presence of an inert organic solvent and a tertiary amine with an aliphatic carboxylic acid having 1 to 4 carbon atoms, in each case in at least an equivalent amount, based on the halogen of the 2,6-dihalomethylpyridine of the general formula II, at temperatures from 0 "C to the boiling point of the reaction mixture converts.

2. The method according to claim 1, characterized in that the tertiary amine is a trialkylamine and / or a heterocyclic amine is used.

3. The method according to claim I to 2, characterized in that the reaction is carried out at Performs boiling point of the reaction mixture.

The invention relates to a process for the preparation of 2,6-Diacyloxymeihylpyridincn of the general Formula I.

R, C O CH,

C)

CH, O C R, (I)

Ri and R), which are identical, each have a hydrogen atom or denote an alkyl radical having 1 to 4 carbon atoms.

The compounds of general formula I are, with the exception of those in which Ri and R ₂ each represent a methyl radical, i.e. 2,6-diaceloxymethylpyridine, new compounds and, including the latter, valuable intermediates in the production of several active pharmaceutical ingredients that affect the bloodstream and the heart , for example from 2,6-bis (methylcarbamoyloxymethyl) pyridine.

For the production of 2,6-bis- (methylcarbamyloxymethyl) -pyridine according to the literature, only 2,6-diacetoxymethylpyridine has been used so far.

For the production of 2,6-diacetoxymethylpyridine, only one process is known from the literature. After this, the N-oxide is formed from 2,6-lutidine and this is reacted with acetic anhydride to form 2-methyl-6-acetoxymethylpyridine; 2,6-diacetoxymethylpyridine is then obtained from this by renewed N-oxide formation and renewed acetylation (cf. OH Bullitt: Am. Chem. Coc 76 [1954], p. 1370; V. Boschelheide: Am Chem. Soc, 76 [ 195- '], p. 1286; E. Ochiai: J. Org. Chem., 18 [1953], p. 535; S. G i η sbu rg: Am. Chem. Soc, 79 [1957], p . 481; VT Treynelis: Am. Chem. Soc, 80 [1958], p. 6590; Tetsuzo K a to: CA., 59 [1963], 559b; Japanese patent 14 222/43, CA, 70 [1969], 19 444c).

In this process, however, several different by-products are formed in considerable quantities in the acetylation reaction, which can only be partially removed by the 2,6-diacetoxymethylpyridine. Attempts made for the technical or industrial application of this process led to HU-PS I 67 834 ("New Process for the Production of Acetoxymethylpyridines"), which was not previously published, but even with this better process only a mixture containing 75 to 80% 2,6-diacetoxymethylpyridine can be produced can be obtained in a yield of at most 89.5% (cf. Example 2). Although the product is suitable for further processing, for example for the production of the aforementioned 2,6-bis (methylcarbamoylmethyl) pyridine, the yield is relatively low; the yield of 2,6-bis (methylcarbamoyloxymethyl) pyridine, based on the 2,6-l-butidine, is only about 15%.

In addition, there is the S> nthesis of 2,6-diacyloxymethylpyridines which proceeds via the formation of the N-oxides but not applicable in every case. For example, the 2,6-Diformyloxymethylpyridin can by this process cannot be established. Also the production of longer alkyl chains No information could be found in the literature regarding connections.

From DH-OS 22 49 770 is a process for the preparation of, optionally methyl- or ethyl-substituted, monoacetoxymethylpyridines (called pyridinmelhanolacetate there) by subjecting the isomeric acetal mixtures obtained by the action of acetic anhydride on the corresponding pyridine-N-oxides at a temperature of 0 to 60 ⁰ C by means of hydrazine, hydroxylamine, primary amines, primary Llydroxyalkylamines, primary diamines or secondary amines a partial saponification and subsequent separation of the unsaponified Monoacetoxyincthylpyridines from the acctylated saponifying agents and the much less volatile hydroxypyridines known by fractional distillation. However, this is again the above-described process via the N-oxides with all the disadvantages of the formation of several different by-products in considerable quantities, which can only be partially removed despite the implementation of a laborious fractional distillation. Another disadvantage of this known process is that it involves several stages.

For the preparation of the Monoacetoxymclhylpyridine a process is from the literature (see. Kalo and others: J. Pharm. Soc. Japan, 75 [1955], p. 1228), according to

which 2-chloromethyl pyridine is heated in a glacial acetic acid medium with anhydrous sodium acetate in a sealed tube for 8 hours at 190O ⁰ C, is known. Yield information is not given in the cited reference

Furthermore, from US-PS 25 24 838 (and CH-PS 2 58 206) a process for the preparation of 3-AcyIoxymethylpyridinen (there called pyridyl-3-carbinol ester) inter alia by reacting a 3-halomethylpyridines (there pyridyl-3 -methyl halide) known with a salt of an organic acid. Example 6 of US Pat. No. 2,524,838 relates to the relevant preparation of 3-acetoxymethylpyridine (called pyridyl-3-carbinol acetate there) by reacting 3-chloromethylpyridine hydrochloride with dehydrated potassium acetate in glacial acetic acid at 10O ⁰ Q from the use of a tertiary amine there is no talk. In the example mentioned, the yield is given as 30% of theory. So it's very bad.

In DE-AS 10 46 055 isl only the possibility the production of esters from linoleic linolenic acid mixtures with ß-pyridylcarbinol by implementing the named polyunsaturated acids inter alia with a jJ-Pyridylmethylhalogenid without further details Indications indicated. It is obviously the process of US-PS 25 24 838 in analogy Use.

The synthetic route of the last two processes is very common in preparative organic chemistry (See. Houben-Weyl: Methods of Organic Chemistry, IV. Edition, 8th p. 541). He is mainly used for that reaction-friendly halogen derivatives and is often proportionate under laboratory conditions can be carried out easily and with good yield. For example, from p-nitrobenzyl chloride, which in terms of reactivity to chloromethylpyridine closest by reacting with molten sodium acetate in boiling acetic acid p-nitrobenzyl acetate within 8 to 10 hours (p-nitrobencylacclate) in 78 to S2% strength Yield can be obtained (see Org. Synth. Coil. Vol. IM, P. 650).

From the prior art it follows that the Pyridine derivatives are abnormal in comparison with other compounds, for example p-nitrobenzyl chloride cautious, because, as stated above, they are only to be implemented under much more energetic conditions. There is none at all Reference to such reactions of dichloromethylpyridines can be found in literature.

The last-mentioned known processes are also technical because of the extreme reaction conditions or not industrially feasible, since anhydrous Alkalictate are used for the implementation have to. These salts are highly hygroscopic and can therefore only be used immediately before use be dewatered by melting. The reaction runs in one because of the presence of the alkali salts heterogeneous system, which is why the crushing of Alkuliacctatc to the necessary fineness of fundamental Meaning is. The crushing of the dehydrated melt is under absolutely dry conditions but not feasible on a technical or industrial scale.

Of the other esterification processes that are described in the ι Organic chemistry practice widely applied is still a method of making Diacyloxymethylpyridines known. After this

we drive by reacting 2,6-dihydroxymethylpyridine with 3,4,5-trimethoxybenzoyl chloride the di (trimethoxybenzoyloxymethyl) pyridine [Trimethoxybenzoate of 2,6-dihydroxymethylpyridine] produced in BE-PS 8 12 127, DE-OS 24 11 902 and FR-OS 22 21 149). This However, the method is not applicable to the present case, as the 2,6-dihydroxymethylpyridines only produced by hydrolysis of the 2,6-diacyloxymethylpyridines can be. The yields in this known process are also poor, namely only 60 up to 73% of the raw product.

Accordingly, there is only a single process from the research for the production of 2,6-dihydroxymethylpyridines known, namely the acylation of 2,6-lutidine-N-oxide. However, this procedure is not generally applicable, but only known for the acetyl derivative and technically or industrially only to be realized with poor yield. In addition, there is only information about the manufacture in the literature des Monoaceloxymelhylpyridins, but the process described for it is technical or respectively industrially impracticable and no high yields can be expected.

The invention is therefore based on the object of eliminating the disadvantages of the prior art a better process for making 2,6-diacyloxymethylpyridines, which is simpler, less complex and generally applicable, and although also on a technical or industrial scale, and high yields without those that are difficult to separate By-products supplies, create.

When studying the acylation of 2,6-dihalomethylpyridines, like 2, <) - Dichlormeihylpyridin, in particular the possibilities of the implementation too 2,6-diacetoxymethylpyridine, it has now surprisingly been found that as the 2,6-dihalogeniethylpyridines, such as 2,6-dichloromethylpyridine, in the presence of at least the equivalent amount of tertiary Amine bases with lower aliphatic carboxylic acids form the corresponding 2, b-Diacy! Oxymeihy! Pyridines in practically quantitative yield can be obtained.

The invention is therefore a method for Preparation of 2,6-Diacyloxymelhylpyridinen der general formula I.

R ₁ CO CII,

~> o what

ClI. O C U,

Ri and R.), which are identical, each have a hydrogen atom or denote an alkyl radical with 1 to 4 carbon atoms,

by acylating a 2,6-disubstituted pyridine derivative, isolating the product thus obtained from the Reaction mixture and optionally cleaning the same, which is characterized in that a 2,6-dihalomethylpyridine of the general formula II

X CH,

πι. χ

(ID

wherein

X denotes a halogen atom,

in the presence of an indifferent organic solvent and a tertiary amine with an aliphatic carboxylic acid having 1 to 4 carbon atoms, each in at least equivalent amount, based on the

Halogen of 2,6-DihalogenmethyIpyridins of the general formula II, is ^{reacted at temperatures from O 0} C to the boiling point of the reaction mixture.

The invention is surprising because, based on the literature, it was not to be expected that 26-dihalomethylpyridines, such as 2,6-dichloromethylpyridine, would be more reactive than, for example, 3-halomethylpyridines or p-nitrobenzyl chloride. In contrast to this negative expectation, surprisingly, according to the invention, for example, 2,6-di-acetoxymethylpyridine is obtained under gentler reaction conditions in significantly better yield than, for example, 3-acetoxymethylpyridine from 3-chloromethylpyridine or p-nitrobenzyl acetate from p-nitrobenzyl chloride. This latter finding is particularly surprising because, when reacted with sodium acetate, 2-chloromethylpyridine is significantly less reactive than p-nitrobenzyl chloride. Also, the yield of 30% in the known process for the preparation of 3-acetoxymethylpyridine by reacting 3-chloromethylpyridine hydrochloride with dehydrated potassium acetate in glacial acetic acid at 100 ^° C. was so bad that it was suitable to inform the person skilled in the art of the application of the process mentioned to the production diverting attention from 2,6-diacyloxymethylpyridines by reacting 2,6-dihalomethylpyridines with aliphatic carboxylic acids, from which conversion, on the basis of general experience, even lower yields were to be expected.

It is also surprising that the 2,6-diacyloxymethylpyridines by the process according to the invention with practically no by-products in quantitative yield can be obtained, because based on the literature, the formation of quaternary salts from the 2,6-dihalomethylpyridines, such as 2,6-dichloromethylpyridine, and the tertiary used in excess Amines were to be expected. From I. S t u c h 1 i k (cf. Chem. Listy, 50 [1956], p. 662) was namely demonstrated that from benzyl chloride and triethylamine at 70 to 75 ° C within 5 hours corresponding quaternary salt is formed in 91% yield.

The most significant surprising advantages of the method according to the invention are that with a very simple process technology obtained such a pure product in practically quantitative yield it can be done without any purification further implementations, turn the example of the not prepublished HU-PS 1 67 834 described hydrolysis to 2,6-dihydroxymethylpyridine, can be subjected. The method according to the invention is also related to the technical or industrial implementation advantageous because the 2,6-diacyloxymethylpyridines are not made from pure 2,6-dihalomethylpyridines must be assumed. This can also be done, for example, by chlorinating 2,6-lutidine obtained crude product, which contains 85% 2,6-dichloromethylpyridine, can be used. From this crude product can use the pure 2,6-diacetoxymethylpyridine in a yield of 90 to 99%, based on the 2,6-dichloromethylpyridine content of the crude product mentioned. Another advantage of the invention Process is that by it also 2,6-diacyloxymethylpyridines, their synthesis on others Way has not yet succeeded in producing, for example, 2,6-diformyloxymethylpyridine is therefore to be found that the inventive method for the production of 2,6-Diacyloxymethylpyridinen a generally applicable, good yields with simple process engineering resulting synthesis, the application of which in technology or industry is very economical.

A solvent that is indifferent to the reactants can be used as the organic solvent,

ίο that means any solvent which is among the Conditions of reaction with the reactants not responding may be used. examples for suitable solvents are ethyl acetate and n-butyl acetate. Benzene, toluene, xylene, cyclohexane, diisopropyl ether and tetrahydrofuran. Also the use of Mixtures of solvents can be useful.

The process according to the invention can expediently be carried out as follows: 2,6-Dihalomethylpyridine is made in an organic

2 (i dissolved and then in the presence of a at least equivalent amount of a tertiary amine with an aliphatic carboxylic acid with 1 to 4 Carbon atoms, each based on the halogen of the 2,6-dihalomethylpyridines, for the implementation

r> brought. The reaction proceeds practically quantitatively within a few hours. In most cases (depending on the Type of solvent used) the salt of the tertiary amine separates out during the reaction. This is removed by filtration. The Fillrat contains

Practically only 2,6-diacyloxymethylpyridine in solution. The solvent is removed from the filtrate under atmospheric pressure or under vacuum. That The crude product obtained is a practically pure, 95 to 100% strength 2,6-diacyloxymethylpyridine. The yield

j j is about 95 to 99% of theory.

In a preferred embodiment of the process according to the invention, an excess of one is Reactant or both reactants used as a solvent. In this case it will

j (i in other words the tertiary amine and / or the aliphatic carboxylic acid used in excess. In this embodiment of the method according to the invention the reaction time is shorter and the isolation of the product is simplified. The latter

4 ") can namely be carried out in such a way that the reaction mixture after the reaction has ended on ice or poured into water, the product from the aqueous solution with a solvent, for example a chlorinated hydrocarbon, preferably

■> o Chloroform, extracted and the solvent evaporated will. So the product is in a yield of about 95 to 99% and a purity of 96 to 100% obtain.

Advantageously, a trialkylamine, in particular triethylamine, and / or a tertiary amine is used as the tertiary amine heterocyclic amine, especially N-methylpiperidine, used.

Particularly advantageous cases in which the method according to the invention can be used are those in

wi which as 2,6-dihalomethylpyridine 2,6-dichloromethylpyridine and formic acid or n-propionic acid is used as the carboxylic acid, and so are the new compounds 2,6-diformyloxymethylpyridine or 2,6-di-n-propionyloxymethylpyridine are obtained,

ti3 mentioned.

In the case of appropriately chosen reactants, the reaction already runs at relatively low levels Temperatures almost quantitatively, with only

the reaction time is correspondingly longer. It is therefore more advantageous at elevated, preferably close The temperatures below the boiling point work because the reaction then occurs within a few hours is going.

The structure of the compounds prepared according to the invention, even if they are new, was carried out by '' Ultrared spectroscopy, elemental analysis and comparison with those produced by other methods Vergieichssubstanzen proven. The purity of the manufactured substances was determined by UV spectroscopy, Gas chromatography and titrimetric methods controlled.

The invention is explained in more detail with reference to the following examples, which are not to be interpreted as limiting.

The gas chromatograms given in the examples were recorded in a 2.4 m long silanized glass column with an internal diameter of 3 mm at 100 to 200 ^° C., the carrier or entrainment gas containing 1% OV-17 distribution liquid and the column being filled with the chromium Q carrier was.

The thin-layer chromatographic investigations were carried out with silica gel on 0.25 mm thick layers carried out using a mixture of chloroform and ethyl acetate in a ratio of 50:50 as the eluent and iodine vapor was used as a developer.

The specific absorbance of 2,6-diacetoxymethylpyridine is E | ^ = 383 (at 269 m μ).

example 1

5.28 g (0.03 mol) of 2,6-dichloromethylpyridine were dissolved in 50 cm ^{3 of} ethyl acetate and 3.43 cm ³ (0.06 mol) of glacial acetic acid and 832 cm ³ (0, 06 mol) triethylamine added. The reaction mixture was heated and refluxed for 12 hours. The triethylamine hydrochloride began to precipitate approximately 15 to 20 minutes after the start of boiling. After the stated reaction time had elapsed, the mixture was cooled to about 20 ° C. and the precipitated salt was filtered off. The filtrate was evaporated to dryness

635 g of 2,6-diacetoxymethylpyridine were obtained in the form of a pale yellow oil. The spectrometric determined content of pure substance was 94.2%. This corresponds to a yield of 92.3% of theory. The product could be further processed immediately.

By fractionating the crude product under a pressure of 5 torr, at 166 to 168 ° C at a Cleaning loss of 10% of a colorless oil, its pure substance content determined by UV spectrophotometry was 98.8% and which had a π ^ value of 1.4966.

Example 2

332 g (0.02 mol) of 2,6-dichloromethylpyridine were dissolved in 35 cm ^{3 of} glacial acetic acid, and 5.06 cm ³ (0.044 mol) of N-methylpiperidine were added. The reaction mixture was ^{boiled at 116 to 118 °} C. for 12 hours It was then concentrated to 13 to 15 cm ³ and diluted with 30 cm ^{3 of} water. The pH of the solution was adjusted to 8 with solid potassium carbonate. Then it was ^{extracted with 3 × 10 cm 3 of} chloroform. The chloroform phases were combined with 0.20 g Activated charcoal clarified and evaporated to dryness after filtration. Thus, 4.40 g of a pale yellow oil whose 2,6-diacetoxymethylpyridine content was 96.9%, which corresponds to a yield of 95.5% of theory, was obtained. The product was suitable for processing.

Example 3

17.61 g (0.1 mol) of 2,6-dichloromebylpyridine were dissolved in 88 cm ^{1 of} glacial acetic acid, and 41.5 cm ¹ (0.3 mol) of triethylamine were added. The reaction mixture was heated to the boil for 5 hours and then concentrated to about 60 tons of 7C. After diluting with 200 cm ^J V'iuser, the pH of the solution was adjusted to 8 to 9 with solid potassium carbonate. The solution was extracted with 4 × 50 cm ^{3 of} chloroform, and the! 3 chloroform phases were combined, clarified with 2 g of activated carbon and then evaporated.

So were 22.10 g of a light yellow oil which contained 98.2% 2,6-diacetoxymethylpyridine, which is a yield of 97.4% of theory is obtained. The 2u product was suitable for further processing.

Example 4

There were 5.28 g (0.03 mol) of 2,6-dichloromethylpyridine in a mixture of 3.43 cm ³ (0.06 mol) of glacial acetic acid and

2-, 53 cm ^{3 of} triethylamine dissolved. The reaction mixture was heated to boiling for 5 hours. The crystals began to precipitate as soon as they were heated. After the specified time, the reaction mixture was evaporated to dryness. That so

The oily crystalline mixture obtained was dissolved in 50 cm ^{3 of} chloroform, and the solution was ^{washed with 3 × 25 cm 3 of} water and then dried over anhydrous sodium sulfate. After filtering. Clarifying and evaporating the solvent gave 6.27 g of a

r, yellow oil, which contained 96.1% 2,6-diacetoxymethylpyridine, which corresponds to a yield of 93.8% of theory corresponds to received. The product was suitable for further processing,

_{4 ()} Example 5

5.30 g (0.02 mol) of 2,6-dibromomethyl ^{pyridine were dissolved in 53 cm 3 of} glacial acetic acid, and 8.30 cm ³ (0.06 mol) of triethylamine were added. The reaction mixture was heated to boiling for 7 hours, then to about 15 cm ³

a; concentrated and diluted with 30 cm ^{3 of} water. The pH of the solution was adjusted to 8 with solid potassium carbonate and then the solution was ^{extracted with 3 × 20 cm 3 of} chloroform. The combined chloroform phases were washed with water until

, Ci chung the neutral reaction washed over anhydrous Sodium sulfate dried and clarified with 0.2 g activated charcoal Solvent removed So 4.20 g of a pale yellow oil which contained 97.4% 2,6-diacetoxymethylpyridine, which corresponds to a yield of 94.2% of theory.

Example 6

1036 g (0.06 mol) of 2,6-dichloromethylpyridine were dissolved in 53 cm ^{3 of} formic acid, and 25.0 cm ³ (0.18 mol) of triethylamine were added. The mixture was heated to the boil for 6 hours, then to about 40 cm ³ concentrated and poured into 120 cm ^{3 of} water. The pH of the solution was adjusted to 8 with solid potassium carbonate, and the solution was ^{extracted with 4 × 50 cm 3 of} chloroform. After the chloroform phases had been combined and cleared, the solvent was removed

ίο

97.1% of 2,6-difo-myloxymethylpyridine, which corresponds to a yield of 95.5% of theory, was obtained.

The crude product was fractionated in a vacuum. Boiling point: 130 to 132 ^o C / 3 torr; ηϊ, '- value = 1.5145. The fractionated product had a degree of purity of 99.7% and it was practically pure on the basis of the gas chromatographic and thin-layer chromatographic investigations.

Analysis for C ₄ H ₉ NO ₄ (molecular weight = 195.18):

Calculated:

C 55.38, H 4.65, N 7.18, 0 32.79%;
found (2 parallel determinations):
C 55.28, H 4.59, N 7.20. 0 32.70%;
C 55.34, H 4.65, N 7.27, O 32.68%.

2,6-Diformyloxymethylpyridine is a new one Link.

Example 7

10.56 g (0.06 mol) of 2,6-dichloromethylpyridine were dissolved in 106 cm ^{3 of} toluene, and 9.85 cm ³ (0.132 mol) of n-propionic acid and 18.3 cm ³ (0.132 mol) of triethylamine were added to the solution admitted. The solution was heated to boiling for 11 hours. The salt which separated out during the boiling process was filtered off and the filtrate was washed with water, then with a 5% strength sodium bicarbonate solution and finally again with water until a neutral reaction was achieved. The solution was dried over anhydrous sodium sulfate, then clarified and then filtered. Evaporation under reduced pressure gave 14.70 g of crude product which contained 95.5% of 2,6-di-n-propionyloxymethylpyridine, which corresponds to a yield of 93.1% of theory.

The crude product was fractionated under a pressure of 5 torr. The one passed over at 167 to 169 ° C

Main fraction had a purity of 99.8%; n? value = 1.4889. The product was due to the Gas-chromatographic and thin-layer chromatographic investigations practically pure.

Analysis for CuHi ₇ NO ₄ (molecular weight = 251.28):

Calculated:

C 62.14%, H 6.82%, N 5.57%, O 25.47%;

Found (2 parallel determinations):

C 62.07%, H 6.90%, N 5.50%, 0 25.50%;

C 62.11%, H 6.81%, N 5.54%, O 25.59%.

2,6-Di-n-propionyloxymethyl pyridine is a new one Link.

Example 8

88 g of crude 2,6-dichloromethylpyridine (product obtained by chlorinating 2,6-lutidine with 85% pure substance) were dissolved in 440 cm ^{3 of} concentrated acetic acid, and 207 cm ^{3 of} triethylamine were added. The reaction mixture was heated to boiling for 6 hours, then concentrated to half its volume under reduced pressure and ^{poured into 1000 cm 3 of} water. The aqueous solution was extracted with 4 × 100 cm ^{3 of} chloroform. The chloroform phases were combined and washed first with a 5% sodium bicarbonate solution and then with water. The solution was dried over anhydrous sodium sulfate and clarified with activated charcoal, and then the solvent was removed. Thus, 105 to HOg of an oil which contained 85 to 90% 2,6-diacetoxymethylpyridine, which corresponds to a bulge of more than 95% of theory, was obtained.

The crude 2,6-diacetoxymethylpyridine obtained in this way could be further processed immediately, for example to 2,6-dihydroxymethyl pyridine.

Claims (1)

Patent claims: I. Process for the preparation of 2,6-diacyloxymethylpyridines of the general formula I. C) R -C- O CH, C)