DD294479A5 - PROCESS FOR PREPARING 1- (PYRID-4-YL) -ALKAN-2-ONEN - Google Patents

Abstract

The invention relates to a process for the preparation of the formula I. These can be prepared technically simple and economically advantageous in that a 4-pyridyl-acetic acid ester with a reactive carboxylic acid derivative such as an anhydride, chloride or bromide, at temperatures between room temperature and 200C in the molar ratio of 1: 1.5 to 1: 2.5, the resulting reaction mixture anschlieszend with alkali or with an alcohol and the resulting compounds of formula I isolated. Formulas I-IV {* Intermediates for cardiotonics; milrinone; 4-pyridyl-essigsaeureester; carboxylic; acyl halides; & 1-acetyl-1H-pyrid-4-ylidene! -Acetic acid alkyl ester}

Description

R ¹ - CO - N> = CH - COOR ² _{! V}

15. Process according to claims 1 to 10, 13 and 14, characterized in that the compound of general formula III is added in two portions distributed over the two partial steps.

16. The method according to claims 1 to 10 and 13 to 16, characterized in that for the reaction of a compound of general formula II to a compound of general formula IV, a compound of general formula III is used, in which R ^{1 is} methyl and that for the subsequent implementation of a compound of the general forms obtained! IV, wherein R ^{1 is} methyl and R ^{2 has} the abovementioned meaning, to a compound of general formula I is a compound of general formula III is used, in which R ^{1 is} ethyl or propyl.

17. The method according to claims 1 to 16, characterized in that the reaction mixture obtained after heating to more than 100 ⁰ C treated with aqueous alkali, then extracted and the organic phase is fractionally distilled after removal of the solvent.

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of 1- (pyrid-4-yl) -alkan-2-ones of the general formula I, wherein R ^{1 is} methyl, ethyl or propyl, which are valuable intermediates in the pharmaceutical industry, in particular for the preparation of cardiotonics, such as milrinone.

Characteristic of the known state of the art

It is known to produce 1- (pyrid-4-yl) -alkan-2-ones of the general formula I by reacting sodium or lithium 4-methylpyridine with functional derivatives of lower aliphatic carboxylic acids in inert organic solvents. Thus, C. Osuch and R. Levine (J. Org. Chem., 22,939, [1957I] gave 1- (pyrid-4-yl) -propan-2-one in 27% yield and 1- (pyrid-4-one). yl) -butan-2-one, 1- (pyrid-4-yl) -3,3-dimethyl-propan-2-one and 1- {pyrid-4-yl) -3,3,3-trimethyl-propane -2-one by heating 4-methylpyridine with methyl-lithium in ether and adding the corresponding esters with further heating. Also prepared from 4-methylpyridine and organometallic reagents such as n-butyl-lithium or lithium diisopropylamide in an inert solvent with cyclopropane-oarbonsäureester or -carbonsäurechlorid 1-cyclopropyl-2- (pyrid-4-yl) -ethan-2-one obtained (JP-OS 60094964).

From 4-methylpyridinium-lithium and acetyl chloride, J. Cejka, M. Ferles, S. Chlddek, J. Labsky and M. Zelinka (Coll., Czech, Chem. Commun., 26, 1429 [1961]) were able to obtain in 45% iger yield 1- (pyrid-4-yl) -propan-2-one obtained. The same compound was synthesized by J.P.Wibaut and J.W.Hey (Rec. Trav. Chim. Pays-Bas 5782, [1938]) from 4-methyl-pyridinium-lithium and acetylbromide in 34% yield.

S. Raynolds and R. Levine (J. Am.Chem.Soc., 82, 472 [1960]) prepared 1- (pyrid-4-yl) -propan-2-one in a 55% yield from 4-methyl-pyridine sodium and ethyl acetate in benzene.

J P-OS 75129 571 (CA 85.32850 γ [1976]), the preparation of I (R '= methyl) by boiling 4-methyl-pyridine with sodium for 3 hours, adding acetyl chloride at 10 to 20 ° C and subsequent Isolation described in only 5% yield. '1- (Pyrid-4-yl) propan-2-one was obtained in 40% solution in hexamethylphosphoric triamide by diisopropylamine in tetrahydrofuran with an n-butyl-lithium solution in η-hexane, hexamethylphosphoric triamide, 4-methyl added pyridine and ethyl acetate in tetrahydrofuran, decomposed, extracted, concentrated, the residue was taken up with hexamethylphosphoric triamide and fractionally distilled. The yield was 40% of theory. In an analogous manner, the 1- (pyrid-4-yl) -butan-2-one as a 35% solution and the pentane-2-one as a 63% solution were obtained (GB-PS 2065642).

All of these methods of manufacture require a high material and equipment expense. They are due to the low yields associated with a large amount of problematic waste products. Numerous technological steps are necessary until the compounds of the general formula I are obtained, so that the preparation of these compounds from 4-methylpyridine and alkali metal organic compounds does not appear to be suitable on an industrial scale.

Another possibility for the preparation of 1 - (pyrid-4-yl) -3,3-dimethyl-butan-2-one is the reaction of N- (2,6-dimethyl-4-oxy-pyrid-1-yl ) pyridinium tetrafluoroboratmit3,3-dimethyl-but-1-en-2-olate-lithium in tetrahydrofuran at -78 ⁰ C under nitrogen atmosphere, cleavage by 16stündiges refluxing in carbon tetrachloride and added azobisisobutyronitrile (Ch. M. Lee, MP Sammes and AR Katritzky, J. ehem. Soc, Perkin Transl. 1,1980,2458). Reaction of N- (2,4-dichlorobenzyl) -pyridinium bromide with acetone in sodium hydroxide solution and subsequent potassium permanganate oxidation gives N- (2,4-dichlorobenzyl) -4-acetonylidene-dihydropyridine in 27% yield, which is heated for 1 hour with 66% hydrobromic acid in the bomb tube at 180 ° C or by standing for 15 hours in a benzenic 4-nitroso-dimethylaniline solution in 1- (pyrid-4-yl) -propan-2-one and the corresponding waste products is split (F. Kröhnke, K. Ellegast, E. Bertram, A. 600, 176 and 198 [1856]).

For both of the above-mentioned syntheses valuable substances are necessary, which are extremely hazardous because of their toxicity both occupational safety and environmental protection. The technical effort for the preparation of the compounds of general formula I in these ways is also very high, so that these synthesis variants are unsuitable for a technical application.

It is also known to boil 4-pyridyl-acetic acid hydrochloride with 165 mol% of anhydrous sodium acetate and 226 mol% acetic anhydride for 18 hours at reflux and the resulting I (R ¹ = methyl) after release in 50% yield by fine vacuum distillation to isolate (A. Burger, JR Rector and A. Ch. Schmalz, J. Am., ex. Soc., 74, 3175 [1952]). This type of production also has significant disadvantages. They consist in the instability of the 4-pyridylacetic acid hydrochloride and the even greater instability of 4-pyridyl-ossigsäure resulting intermediately from 4-pyridylacetic acid hydrochloride and sodium acetate (see Weygang-Hilgetag, Org.-Chem. Berlin, 1970, page 1041). The reaction produces large proportions of tarry products, so that this synthesis is not suitable for industrial use.

Object of the invention

It is the object of the invention to prepare 1- (pyrid-4-yl) -alkan-2-ones of the general formula I economically and in a technically simple manner in high yields.

Explanation of the essence of the invention

The present invention has the object, the compounds of general formula I, wherein R ^{1 has} the abovementioned meaning, in a technically simple manner and economically advantageous to produce.

According to the invention this is achieved by reacting a 4-pyridyl-acetic acid ester of the general formula II, wherein R ^{2 is} a straight-chain, branched or cyclic alkyl radical having 1 to 6 carbon atoms, with a reactive carboxylic acid derivative of the general formula III, wherein X is Cl, Br or the group -O-CO-R ¹ and R 'has the abovementioned meaning and wherein the meaning of the two radicals R ¹ in the general formula III is the same, at temperatures between room temperature and 200 ⁰ C in the molar ratio 1: 1.5 to 1: 2.5, the reaction mixture is then treated with alkali or with an alcohol and the resulting compounds of formula I isolated.

According to the definition of general formula III, these compounds may be carboxylic acid chlorides, bromides or carboxylic anhydrides such as acetic anhydride, propionic anhydride or butyric anhydride.

If it is also possible to use 1.5 to 2.5 mol of a compound of the general formula III per mole of a compound of the general formula II, a preferred embodiment of the invention is that per mole of a compound of the general formula II 1.8 to 2.3 moles of a compound of formula III are used.

A particular embodiment of the invention consists in that the compounds of general formula II are used in the form of salts with inorganic acids.

In the case of the use of salts of the compounds of the general formula II and / or of carboxylic acid halides of the general formula IN, it is necessary to carry out the reaction in the presence of acid acceptors, preferably of alkali metal salts of weak acids such as alkali metal acetates or alkali metal carbonates.

It is expedient to use the acid acceptors in amounts which are at least equivalent to the anions introduced or liberated by the salts of the compounds of general formula II and / or the carboxylic acid halides

This embodiment of the invention can be carried out, for example, by adding a 4-pyridylacetic acid ester of the formula II or its salt, preferably its hydrochloride, with the approximately double molar amount of acid chloride or bromide of the formula III and then adding the acid acceptor, for example sodium acetate , is slowly added. The resulting suspension is stirred while simultaneously distilling off resulting lower carboxylic acid esters until the end of the evolution of carbon dioxide.

The process of the present invention can be carried out both in the absence and in the presence of solvents such as aliphatic carboxylic acids or tertiary amines. If necessary, the tertiary amines can simultaneously act as acid acceptors.

A particular embodiment of the invention is that the reaction at temperatures above 100 ⁰ C, preferably at 130 to 17O ⁰ C, until the completion of CCyEntwicklung performed. In this case, the compounds of formula I are immediately obtained. Insofar as the reaction is to be carried out at the boiling point of the particular reaction mixture, this can be done both under reflux and with simultaneous distillation of resulting lower carboxylic acid esters.

Another Ausführunfjsform the invention is that the reaction of a compound of general formula II with a compound of general formula III, first at temperatures below 100 ⁰ C, preferably at temperatures between 30 and 8O ⁰ C, carried out and the resulting reaction mixture, which Compound of the general formula IV, wherein the radicals R 'and R ^{2 have} the abovementioned meaning, then heated to temperatures of 100 to 200 ⁰ C, preferably to 130 to 170 ° C> until the completion of the (^ -development.

In this embodiment of the invention, which is two-stage with respect to the temperature control, the compound of general formula III can be added both completely in advance or distributed in two portions in both partial steps.

In the case of a two-stage implementation of the reaction according to the invention a particular embodiment of the inventionin that for the reaction of a compound of general formula II to give a compound of the general formula IV, a compound of general formula III is used, in which R ^{1 is} methyl, and in that for the subsequent reaction of the resulting compound of the general formula IV in which R 'is methyl and R ^{2 has} the abovementioned meaning, to a compound of the general formula I a compound of the general formula III is used in which R ^{1 is} ethyl or n- Propyl means.

In this embodiment of the invention, it goes without saying that the two types of compounds of general formula III share in molar terms in about equal parts in the total amount of acylating agent.

In this particular embodiment of the stepwise reaction, it is also possible to isolate a compound of general formula IV in crude form by distilling off after completion of the reaction at 100 ° C excess III as well as resulting carboxylic acid and optionally also the solvent.

If the compounds of the formula IV are to be isolated, it is possible and sometimes advantageous to use other solvents in place of the abovementioned solvents, for example aromatic hydrocarbons in which the compounds of the formula IV are sparingly soluble and therefore extractable.

The compound of the general formula IV thus obtained can then be further reacted after addition of a compound of the formula III which is identical or different in the acyl radical, and heating to temperatures above 100 ° C.

Distillative removal of the excess acylating agent of the formula III from a compound of the formula IV obtained is then recommended in any case if a compound of the formula III is to be used for the subsequent acylation, which is different in the acyl radical from the originally used compound of the formula III ,

In pure form, the compounds of the general formula IV are obtainable if a compound of the formula II is combined with a carboxylic anhydride of the formula III in an inert organic solvent, for example toluene, and the resulting yellow substance is suctioned off after the exothermic reaction has subsided.

The final treatment of the resulting reaction mixture with alcohol or with alkali lye serves to decompose excess starting and by-products. It can be carried out both at room temperature and under heating. If this final treatment of the reaction mixture is carried out with alkali lye, the reaction mixture is then extracted, for example with chloroform, the phases are separated and the solvent is distilled off from the organic phase and the resulting residue is fractionally distilled.

If the final treatment of the reaction mixture was carried out in an alcohol, the distillative separation of the reaction mixture can then be carried out immediately.

The isolation of the pure products of formula I is conveniently carried out by fractional distillation in a fine vacuum at 50 to 100Pa. They are obtained as a function of the work-up of the reaction mixture as colorless to yellowish, viscous liquids.

With its good yields of 65 to 80% of theory, the process according to the invention surpasses all hitherto known synthesis methods for 1- (pyrid-4-yl) -propan-2-one, the yields are at most 55%, but usually below 50% derTheorie ,

The inventive method is technically easy to carry out. It contains only a few elementary procedural basic operations. The process according to the invention omits any handling of occupational safety and security and demanding environmentally harmful substances, as they include all manufacturing variants using organometallic compounds and via the N- (2,4-dichloro-benzyl) -4-acetonyliden-dihydropyridine leading way.

The by-products of the present process are only carbon dioxide, lower carboxylic acids and their esters and, in a specific embodiment, neutral salts.

In a preferred embodiment of the process according to the invention, the lower carboxylic acid esters formed as by-products can be obtained in pure form.

Fin essential technological advantage of the method according to the invention is that the reaction temperature can vary over a wide temperature interval and the process can be aligned to a technically manageable carbon dioxide emissions.

The 4-pyridyl-acetic acid esters of the general formula II used as starting materials are in some cases known or can be prepared in an analogous manner as the known compounds.

The similarity of the process according to the invention with the synthesis of 1 - (pyrid-4-yl) -propan-2-one proceeding from 4-pyridylacetic acid hydrochloride (cf A. Burger, JR Rector, A. Ch. Schmalz, J Am. Former Soc., 74,3175 [1952J] is only of a formal nature. It is useful for both the acetylation of these and other aryl or hetaryl acetic acids such as 3-pyridylacetic acid (A. Burger and CR

Walther Jr., J. Am. former Soc. 72, 1988 [1950]), 3-indolyl-acetic acid (J. B. Brown, H. B. Henbest and E. R. H. Jones, J., ex.

1952, 312) or phenylacetic acid (JAKing and LH, McMillan, J. Am., Soc., 73, 4911, 1951)), the mechanism of "decarboxylative acylation" (see Weygang-Hilgetag, Org.-Chem. Berlin, 1970, pages 1943-1944)

does not explain the mechanism of the reaction according to the invention. .

embodiments

Bolsplol 1

193.2 g of 4-pyridylacetic acid n-butyl & ster (1 mol), 184 g of acetic anhydride (1.8 mol) and 30 g of acetic acid are placed for 5 hours in a 500 ml three-necked flask with distillation head, Lieblgkühler, vacuum and a 100 ml Stirred template at 145 to 1O ⁰ C. It is cooled, added to 85 ml of butanol (1), boiled for 30 minutes at reflux and distilled under reduced pressure of 4kPaein.

The resulting residue of about 165 g is fractionally distilled in a fine vacuum at 80Pa. The main run is at a head temperature of 77 to 82 ⁰ C over. There are obtained 117g 1- (pyrid-4-yl) -propan-2-one with a content of 93% (by gas chromatographic and ¹ H NMR spectroscopic determination). That's 80.5% of theory.

Example 2

In a 2-liter three-necked flask equipped with stirrer, internal thermometer, distillation attachment with Liebig cooling and 500 ml template 661 g of 4-pyridyl-acetic acid ethyl ester (4mol) with 840g technical acetic anhydride (about 8mol) are combined. The mixture is stirred for 15 hours at 13O ⁰ C, cooled, added to 340 ml of 96% ethanol and boiled for 1 hour at reflux. The steam bath is distilled under reduced pressure. The residue is fractionated under fine vacuum at 65 Pa. Approximately 30g up to a head temperature of 74 ⁰ C overflow consists mainly of acetic acid, some 4-methylpyridine and 1- (pyrid-4-yl) -propan-2-one.

The main fraction is cut from 74 to 78 ° C. It consists of 420g of 1- (pyrid-4-yl) -propan-2-one as a yellowish oil with a content of 95%.

Yield: 73.8% of theory.

Example 3

a) 41.3 g of 4-pyridyl-acetic acid ethyl ester (0.25 mol) in 40 ml toluene are mixed with 28.1 g of acetic anhydride (0.275 mol). It is stirred for 1 hour at 50 ° C and cooled. It is suctioned off, washed with toluene and after drying 30g [1-acetyl-1 H-pyrid-4-ylidene] acetic acid ethyl ester as a bright yellow crystalline substance of melting point 121-125 ⁰ C, corresponding to 58% of theory.

C ₁₁ H ₁₃ NO ₃ Mm 207.2

Elemental analysis:

Calculated: C 63.76% H 6.32% N 6.76 found: C64.16% H6.29% N7.26%

IR (fixed in KBr): Ό «1710 and 1680cm" ¹

V ₀ . c 1640 cm " ¹

b) 41.4 g of [1-acetyl-1H-pyrid-4-ylidene] -acetic acid ethyl ester (0.2 mol) are mixed with 32.5 g of propionic anhydride (0.25 mmol)

Cooked for 6 hours at reflux. It is cooled. Then 60 ml of water are added, while cooling with about 15 ml of concentrated sodium hydroxide solution to a pH of about 10 and stirred for a further 2 hours, extracted 3 more times with 50 ml of chloroform, the extracts combined and dried with sodium sulfate. The chloroform is driven off in vacuo and the residue is fractionated at a temperature of 75 to 8O ⁰ C and a pressure of 65Pa

 Yield: 12.0 g of 1- (pyrid-4-yl) -butan-2-one, corresponding to 44.5% of theory.

Example 4

To 40.3 g of 4-pyridyl-acetic acid ethyl ester hydrochloride (0.2 mol) in a 250 ml three-necked flask, dropping funnel and distillation head with Liebig condenser and 20 ml of template 31.7 g of acetyl chloride and then 49g anhydrous sodium acetate are added within 20 minutes. The mixture is heated slowly and stirred for 4 hours at a bath temperature of 170 ° C. To the dark brown suspension 60 ml of water are added and then added dropwise to a pH of 10 about 28 ml of concentrated sodium hydroxide solution. The mixture is stirred for 1 hour, extracted 3 times with 60 ml of chloroform, the extracts combined and dried with sodium sulfate. The chloroform is driven off and the residue is distilled in a fine vacuum at 85 Pa. The fraction from 75 to 77 ⁰ C is taken as the main run. This gives 18.0 g of 1- (pyrid-4-yl) -propan-2-one corresponding to 66.7% of theory.

Elemental analysis for C ₈ H ₉ NO Mm 135.2

Calculated: C71.09% H6.71% N10.36% Found: C70.33% H6.68% N10.27%

ο-

N V-CHo-CO-R

ο-

N \) - CHo - COOR ² II

R ¹ - CO - X IH

R ¹ - CO - N \ = CH - COOR ² IV

Claims (14)

1. A process for the preparation of 1- (pyrid-4-yl) -alkan-2-ones of the general formula I, wherein R ^{1 is} methyl, ethyl or propyl, characterized in that a 4-pyridylacetic acid ester of the general formula II, wherein R ^{2 is} a straight-chain, branched or cyclic alkyl radical having 1 to 6 C atoms, with a reactive carboxylic acid derivative of the general formula III, wherein X is Cl, Br or the group -O-CO-R ¹ and R ^{1 is} the abovementioned Meaning and wherein the meaning of the two radicals R ¹ in the general formula III is the same, at temperatures between room temperature and 200 ⁰ C in a molar ratio of 1: 1.5 to 1: 2.5, the resulting reaction mixture then with alkali or with an alcohol treated and isolated the resulting compound of formula I. - CH ₉ - CO - R ¹ - CH ₉ - COOR R ¹ -CO-X IM 2. The method according to claim 1, characterized in that are used as compounds of the general formula ill carboxylic anhydrides. 3. Process according to claims 1 and 2, characterized in that are used as the carboxylic acid anhydrides acetic anhydride, propionic anhydride or butyric anhydride. 4. The method according to claim 1, characterized in that are used as compounds of general formula III carboxylic acid chlorides or bromides. 5. Process according to claims 1 to 4, characterized in that per mole of a compound of general formula II 1.8 to 2.3 moles of a compound of general formula III are used. 6. Process according to claims 1 to 5, characterized in that the compounds of general formula II are used in the form of salts with inorganic acids. 7. Process according to claims 1 to 6, characterized in that in the case of the use of salts of the compounds of the general formula II and / or of carboxylic acid halides of the general formula III, the reaction is carried out in the presence of acid acceptors. 8. Process according to claims 1 to 7, characterized in that the alkali metal salts of weak acids, for example alkali metal acetates or alkali metal carbonates, are used as acid acceptors. 9. Process according to claims 1 to 8, characterized in that the acid acceptors are used in amounts which are at least equivalent to the anions introduced or liberated by the salts of the compounds of the general formula II and / or the carboxylic acid halides. 10. The method according to claims 1 to 9, characterized in that the reaction of the compound of general formula II with compounds of general formula III in the presence of a solvent selected from aliphatic carboxylic acids or tertiary amines is performed. 11. The method according to claims 1 to 10, characterized in that the reaction of a compound of general formula II with a compound of general formula III is carried out at temperatures above 100 ° C. 12. The method according to claims 1 to 11, characterized in that the reaction of a compound of general formula II with a compound of general formula III is carried out at temperatures of 130 to 170 ⁰ C. 13. Process according to claims 1 to 10, characterized in that the reaction is carried out in two stages. 14. The method according to claims 1 to 10 and 13, characterized in that the reaction of a compound of general formula II with a compound of general formula III first at temperatures below 100 ⁰ C, preferably at temperatures between 30 and 80 ⁰ C, is reacted and the resulting reaction mixture containing a compound of general formula IV ₁ wherein the radicals R ¹ and R ^{2 have} the abovementioned meaning, then to temperatures of 100 to 200 ⁰ C, preferably heated to 130 to 170 ° C.