DE2726685A1 - 2-Amino-3-alkoxycarbonyl-gamma-pyrone derivs. - and isomeric hexenoate ester(s), useful e.g. as intermediates for plant-protection agents, pharmaceuticals and dyes - Google Patents

Abstract

Pyrone derivs. of formula (I) and their isomeric hexenoic acid derivs. of formula CH3CO.CH2C(OH)=C(CN)COOR (IV) are new. In the formulae, R is opt. halogenated 1-6C alkyl or 5-6C cycloalkyl, or 1-4C alkyl, NO2 or CN. Pref. cpds. have R = CH3 or C2H5. (I) are prepd. by reacting a cyanoacetate with diketene in presence of tert. base to give a salt of (IV). Acidification gives (IV) and this is rearranged to (I) by heating. (I) and (Iv) are intermediates for plant-protection a agents, pharmaceuticals and dyes; (I), esp. where R = C2H5, have antiinflammatory and diuretic activity themselves.

Description

It is already known that CH-acidic compounds are present in the presence

can be acetoacetylated from bases by diketene. Many became like that B-carbonyl compounds of the B-diketone and acetoacetic acid type reacted with diketene. This also includes many secondary products from the reaction of diketene with amines: the Acetoacetamides formed primarily can in many cases be attached to their methylene group react with further diketene; this reaction is often followed by cyclization steps which can lead to pyridone, pyrone and benzene derivatives (T. Kato, Accounts of Chemical Research 7, 265 (1974); T. Kato, Kagaku No Ryoiki Zokan (1970) 92 (pt. 2), 203; T. Kato, Heterocycles 3: 413 (1975)).

In an effort to expand the known reactions of C-acidic compounds with diketene and thus, if possible, to arrive at new, valuable compounds, it has now been found that - starting from cyanoacetic ester as CH-acidic compound and diketene - one can actually create new ones Compound classes reached. The new compounds are isomeric compounds of the formula C7H6O4NR with the structure where R is optionally halogen-substituted (C1-C6-) alkyl or (C5-C6-) cycloalkyl radicals or a phenyl or benzyl radical which is optionally substituted by halogen, (C1-C4) alkyl, nitro groups or cyano groups.

The (C1-C6) -alkyl radical for R can be straight-chain or branched; the (C5-C6) cycloalkyl radical is the cyclopentyl or cyclohexyl radical.

Both the alkyl and the cycloalkyl radical can be replaced by halogen, preferably F, Cl and / or Br, substituted, preferably up to three times be substituted.

R can also mean the phenyl or benzyl radical. Both leftovers can also be substituted (the benzyl radical only in the core). The substituents can here halogen, preferably F, Cl and / or Br, alkyl groups with 1 to 4 carbon atoms, the NO2 and / or be the CN group. Preferably the phenyl and the Benzyires-.g, when substituted, only substituted once or twice.

Preferred radicals R are the methyl and ethyl radicals. From the connections I (= 2-amino-6-methyl-4-pyrone-3-carboxylic acid ester) uld IV (= 2-cyano-3-hydroxy-4-oxo-hex-2-ene acid ester) the compounds I are preferred.

According to the invention, the compounds I are prepared by adding cyanoacetic esters of the formula NC - CH2 - COOR (11) in the presence of at least approximately equimolar amounts of a tertiary organic base NR'3 (R '= aliphatic or cycloaliphatic monovalent or divalent radical, preferably with up to 6 carbon atoms) with an approximately equimolar amount of diketene in an inert organic solvent, the ammonium salt obtained by acidification into the compound and these are rearranged by heating to temperatures between about 20 and 140.degree. C., preferably between about 80 and 130.degree. C., optionally in an inert organic solvent, into a pyrone ester of the formula I. In the formulas II, III and IV, R has the same meaning as in formula I. The special nature of the radicals R is not critical, since they can be split off or exchanged in any subsequent reactions by customary ester exchange. In principle, all cyanoacetic esters whose ester group is inert to diketene can be used for the process according to the invention.

The tertiary organic bases NR 'are primarily al.iphaticc and cycloaliphatic amines and diamines in question, especially those with up to 6 carbon atoms in each of the radicals R ', for example triethylamine, tripropylamine, Tributylamine, ethyl di 1 soprepyl amine, ethyl dicyclohexylamine, N, N, N'N'-tetramethylethylenediamine, N, N, N'N'-tetramethyl-1,6-diaminohexane, 1,5-diazabicyclo (4.3.0) nor.-5-ene etc .; preferred is triethylamine.

As inert organic solvents (or dispersants) for the implementation the cyanoacetic esters (II) with diketene are preferred, those with water are not are miscible, in particular aromatic hydrocarbons such as benzene, toluene, xylene etc., aliphatic and aromatic halogenated hydrocarbons such as carbon tetrachloride, Chloroform, methylene chloride, chlorobenzene etc., and aliphatic ethers such as diethyl ether, Diisopropyl ether, dioxane etc.

Also water-miscible ethers such as dimethoxyethane, diethylene glycol dimethyl ether and diethylene glycol diethyl ether are useful.

The process according to the invention is generally carried out in such a way that the cyanoacetic ester (II) with the tertiary organic base NR'3 in the inert Introduce solvent (or dispersant) and slowly add diketene. One can also choose a different order, as long as you make sure that there are always free ones Base is present in the reaction mixture.

Since the base NR'3 is consumed by the salt formation to form the ammonium salt III it is necessary to use at least one of the amounts of cyanoacetic ester (II) used about equimolar amount of base NR'3 to be used. An excess of up to is advantageous to about 25 mol%, preferably up to about 10 mol%. Higher amounts of base are available possible, but without advantage.

Diketene is in approximately equimolar amounts, based on the cyanoacetic ester (II), or in a slight excess up to about 5 mol% applied. It is usually used undiluted or diluted with a solvent admitted.

Since the implementation of the cyanoacetic ester with diketene in the presence of tertiary organic base NR '3 is exothermic, the reaction temperature must be maintained by cooling. It is expedient to choose it in the range of approximately -10 to + 50.degree. C., preferably about 0 to 300.degree. C. and in particular from about +10 to +20.degree. C. Here, higher temperatures cause an increased formation of colored by-products, while at lower temperatures the reaction rate is naturally lower is.

After adding the entire amount of diketene it is usually about 1 hour stirred at 150 to 25 ° C to complete after the exothermic reaction has subsided Implementation of the diketen to achieve safely. The end of the reaction is easy IR spectroscopy on the disappearance of the characteristic diketene bands at 5.3 and 5.4> recognize.

The product of the formula III obtained in this way is generally in solution Form before and can in a manner known per se, in particular by distilling off the solvent and optionally the excess amine can be isolated. In most cases, it is more expedient to pass the salt obtained through without isolation Treating with an acid, preferably a strong inorganic acid, into one To convert compound of formula IV. This can be done a) by exposure to anhydrous Acid, preferably HCl, and the amine salt formed is filtered off.

However, it is preferred for purer products and when used of water-immiscible solvents b) first the reaction mixture stir in water and the aqueous phase, which now contains the compound III, separated from the organic solvent. Wash the solvent with more Water, combines the aqueous phases and acidifies. The unusual product of the Formula IV is suctioned off and can in the usual way, e.g. by recrystallization (Cyclohexane) can be further purified.

The compounds of the formula thus obtainable in various ways IV are well-defined substances whose analytical data! Z tC, H, N analysis, IR, NMR and street spectra) are in full inclusion, with the specified structure.

However, these open-chain compounds are thermally unstable and transform into the pyrons of the formula even after prolonged storage at room temperature I around. This ring closure reaction can be accelerated by increasing the temperature.

For example, if a melt of a compound IV is heated above approx. 1000 C, this quickly crystallizes again into the pyrone of formula I.

The rearrangement of the product IV obtained according to the invention can depending be carried out according to the work-up method in various ways. Lie by procedure (a) the product IV in the solvents of 1.

Stage before, this can be brought to the rearrangement temperature as such heat. This is preferably in the range from 600 to 1400 ° C., in particular from 800 to 1300C. The pyrone I can then in the usual way, e.g. by suction or by distilling off the solvent.

If the work-up to IV according to (b) is carried out by an aqueous route, the product IV obtained is thus taken in a suitable solvent or suspension medium on and reached by heating to the above temperatures - if necessary in a closed vessel - the cyclization.

As such - inert - solvents are particularly suitable, that boil in the specified temperature range such as toluene, xylene, octane, chlorobenzene, 2,2, 3-trimethylpentane, ethylcyclohexane etc.

inert solvents but also other such as o-dichlorobenzene, dimethoxyethane, Diethylene glycol dimethyl ether, white spirit, isopropylbenzene, anisole, dioxane, and more also alcohols such as 1-propanol, 2-butanol, glycol monomethyl ether and methanol, ethanol, can be used with good success if the rearrangement temperature is in the range mentioned is held.

A rearrangement process is preferred, according to which the according to (b) obtained suction filter product IV in one with water not mixable Absorbs solvent that boils in the temperature range 60C to 1400C and / or with Water boils azeotropically, so that the water residues contained in the suction filter are distilled can be removed. In this way, drying and rearrangement can be done in one Achieve process step. If anhydrous product IV is used, then in particular Toluene and carboxylic acid esters preferred, such as butyl acetate, which dissolve IV well while the I formed precipitates in crystalline form.

The rearrangement takes place in just a few in the upper temperature range Minutes. The end of the reaction can easily be seen to disappear by TR spectroscopy follow the nitrile band of IV at 4.5 ß.

The method according to the invention can be represented by the following equation: In this reaction sequence shown schematically, the slight rearrangement of the compound IV into the pyrone derivative I was particularly surprising.

Both compound groups I and IV are useful as intermediates for the production of pesticides, pharmaceutical preparations and dyes applicable. The pyrone derivatives I also have certain anthlogistic and diuretic ones Properties, especially when R = C2H5.

B E I S P I E L E A. Preparation of the hexenoic acid esters of the formula III Example 1: 2-cyano-3-hydroxy-4-oxo-hex-2-en-acid methyl ester 2 mol (198 g) cyanoacetic acid methyl ester were placed in 200 ml of CH3Cl2 with 2 mol (202 g) of triethylamine in a stirred flask. With external cooling, 2 mol (168 g) of diketene were added dropwise at 10 "-200C. After one hour The oily reaction mixture was subsequently stirred at room temperature in 1 liter of water stirred in, the CH2Cl2 phase separated and washed with water. The United aqueous phases were added dropwise with cooling in 200 ml of conc.

HC1, sucked off the light yellow product formed, which at 500C im Drying cabinet.

Yield 311 g = 85% of theory. Th .; M.p .: 85 ° -86 ° C C8H9NO4 MW 183.17 MW (masssp.) 183 Analysis: calc .: C 52.5%; H 5.0%; N 7.6%; Found: C 52.7%; H 5.1 ojos; N 7.5 The ethyl ester (R = C2H5) was prepared analogously 0.11 mol (14.2 g) of diisopropylethylamine and 0.1 mol (8.4 g) of diketene were added simultaneously from two dropping funnels at 20 ° to a solution of 0.1 mol (9.9 g) of methyl cyanoacetate in 50 ml of CH3Cl2 -32 ° C was added dropwise. After stirring for one hour, the CH2Cl2 phase was extracted with 100 ml of water and the aqueous phase was stirred into 32 ml of 18% HCl. Fine yellowish crystals of III (R = CH3) precipitated out and were filtered off with suction and dried. The yield was 13 g (17% of theory).

The identity with the compound obtained according to Example (1) was secured by m.p., TLC and IR spectrum.

Example 3: 2-cyano-3-hydroxy-4-oxo-hex-2-en-acid ethyl ester Solution of 0.1 mol (11.3 g) ethyl cyanoacetate and 0.055 mol (9.5 g) N, N, N ', N'-Z-tetramethylhexanediamine 0.1 mol (8.4 g) of diketene were added dropwise to 50 ml of CH3Cl2 at 30 ° -40 ° C. After an hour After stirring, the reaction solution was extracted with 100 ml of water and the aqueous solution Phase stirred into 30 ml of 18% hydrochloric acid, an oily substance precipitated out which is obtained by column chromatography on SiO2 6.4 g (35% of theory) of 2-cyano-3-hydroxy-4-oxo-hex-2-ene-acid ethyl ester let isolate pure. The crude product contained, in addition to other, non-determined regulating substances Dehydroacetic acid identified by thin-layer chromatographic and IR spectroscopic Comparison with authentic material was characterized.

The experiment proceeds analogously with 0.55 mol (6.4 g) of N, N, N ', N'-tetramethylethylenediamine.

Example 4: 2-cyano-3-hydroxy-4-oxo-hex-2-one-acid ethyl ester Solution of 0.1 mol (11.3 g) of ethyl cyanoacetate in 50 ml of CH2Cl2 were simultaneously from two dropping funnels 0.11 mol 813.7 g) 1,5-diazabicyclo (4.3.0) non-5-en and 0.1 Mol (8.4 g) of diketene were added dropwise at 10 ° -20 ° C. After stirring for one more time the CH2Cl2 phase extracted with 100 ml of water, and the aqueous phase in 30 ml of 18 Stir in% hydrochloric acid.

The yield was 10.5 g (= 57.4% do Th)) of 2-cyano-3-hydroxy-4-oxo-hex-2-one-acid ethyl ester.

B. Preparation of the pyrones of the formula I Example 5 a: 2-Amino-3-methoxycarbonyl-6-methyl-4-pyrone 1 mol (183 g) of the ester prepared according to Example (1) were violently Riillren added a little at a time to butyl acetate at 900C and then slowly increased Heated to reflux.

From 110 ° C, the pyron began to precipitate after boiling for one hour suctioned off under reflux, washed with ethyl acetate and dried.

Yield: 166 g (> 90% of theory) Example 5b: Was the stirrer apparatus provided with a water separator, the pipe product, which is moist with suction, could already be used can be used according to example (1) without prior drying. The yields are related on cyanoacetic ester were 137 - 146 g (75 - 80 0 d.

Th.).

C8H9NO4 MW 183.17 Mp. 191 ° C (decomp.) MW (mass sp.) 183 Analysis: calc .: C 52.5%; H 5.0%; N 7.6% Found: C 52.4%; H 5.0%; N 7.6% The ethyl ester dre Formula I (R = C2H5) was prepared analogously.

C9H11NO4 MW 197.19 Mp. 161 ° -162 ° C MW (mass sp.) 197 Analysis: calc .: C 54.8%; H 5.6; N 7.1% Found: C 54.8%; H 5.6%; N 7.0% Example 6: 10 g des according to example (1) obtained ester were at 150 to 300C (room temperature) for 6 weeks stored dry for a long time.

After this time the complete rearrangement into the pyrone was the Formula I (R = CH3) occurred.

The corresponding ethyl ester behaved analogously.

Example 7: 5 g of the ester obtained according to example (1) (R = CH3) were heated above the melting point of 85 ° C up to 1100C.

At this temperature the melt crystallized again.

The pyrone of formula I (R = CH3) was formed.

The corresponding ethyl ester behaved analogously.

Example 8: 17.0 g of the moist filter obtained according to Example (1) Esters III (R = CH3), corresponding to 13.1 g of dried III, were dissolved in 200 ml of toluene Refluxed for 1 hour, c ,.

4 g of water were distilled off azeotropically and 12 g (91.6% of theory)

Th.) Of the pyron of the formula I (R = OH3) failed.

Example 9: 17.0 g of the moist filter obtained according to Example (1) Esters III (R = CH3), corresponding to 13.1 g of dried III, were dissolved in 200 ml of white spirit Suspended (bp 150 ° -180 ° C) and heated at 12000 for 1 hour, with 2.7 ml of H20 distilled off.

The yield was 12.3 g (93.9% of theory) of the pyron of the formula I (R = CH3).

Example 10: 17.0 g of the moist filter obtained according to Example (1) Esters III (R = CH3), corresponding to 13.1 g of dried III, were dissolved in 50 ml of chlorobenzene Heated for 1 hour at 120 ° C, 3.0 ml of H20 distilled off and 12.1 g (92.4 d0 d. Th.) Of the pyron of the formula I (R = OH3) failed.

Example 11: 17.0 g of the moist filter obtained according to Example (1) Esters III (R = CH3), corresponding to 13.1 g of dried III, were dissolved in 50 ml of dimethoxyethane Heated to reflux for 2 hours, 9.8 g of the pyron of the formula I (R = CH3) precipitating out. A further 2.5 g could be isolated by concentrating the solvent, so that the Yield 93.9% of theory Th. Fraud.

Example 12: 17.0 g of the moist filter obtained according to Example (1) Esters III (R = CH3), corresponding to 13.1 g of dried III, were dissolved in 50 ml of glycol monomethyl ether Heated to reflux for 1 hour, with 5.8 g of the pyron of the formula I (R = CH3) precipitated. A further 6.6 g could be isolated from the middle liquor by concentration, so that the yield ° 4.7% d. Th. Fraud.

Example 13; 17, C g of the suction filter obtained according to Example (1) Esters III (R = OH3), corresponding to 13.1 g of dried III, were in 200 ml of toluene at 500 - 60 ° C; dissolved and the water separated.

The toluene phase was then heated to 80 ° C. for 3 hours, with 9.8 g (74.8% of theory) of the pyron of the formula I (R = CH3) were obtained.

Example 14: 17.0 g of the moist suction filter obtained according to Example (1) Esters III (R = CH3), corresponding to 13.1 g of dried III, were dissolved in 200 ml of benzene Dissolved at 500-60 ° C., the water was separated off and the benzene phase was refluxed for 3 hours heated, whereby 11.9 g (90.8 g0 d. Th.) Of the pyron of the formula I (R = CH3)) were obtained.

Example 15: 10.0 g of the moist filter obtained according to Example (1) Esters III (R = CH3), corresponding to 7.7 g of dried III, were dissolved in 150 ml of methanol dissolved, dried over sodium sulfate and after separating off the drying agent 3 Heated to reflux for hours.

When the methanol was evaporated, 7.1 g (92.1% of theory) of the pyron were obtained of the formula I isolated.

Claims (7)

New # -Pyronic and hexenoic acid derivatives as well as processes for their production PATINT CLAIMS: 1. Isomeric compounds of the empirical formula C7H6O4NR with the structure wherein R denotes an optionally halogen-substituted (C1-C6-) alkyl or (C5-C6-) cycloalkyl radical or a phenyl or benzyl radical optionally substituted by halogen, (C1-C4) alkyl, nitro groups or CN groups. 2. Isomeric compounds according to claim 1 with R = CH3 or C2H 3. Process for the preparation of # pyrone derivatives of the formula in which R has the same meaning as in claim 1, characterized in that cyanoacetic esters of the form 1 NC - C112 - COOR (11) in which R also has the meaning b given in claim 1 in the presence of at least approximately equimolar amounts of a tertiary aliphatic organic base NR ' 3 (R '= aliphatic: or cycloaliphatic 1- or 2-valent radical, delayed with up to 6 carbon atoms) with an approximately equimolar amount of diketene in an inert organic solvent, the ammonium salt obtained wherein R and R 'have the meanings given above, by acidification into the compound in which R likewise has the above meaning, and the compound IV is then converted into a # -pyrone derivative of the formula I by heating to temperatures of about 20-140 ° C., preferably about 80-130 ° C., optionally in an inert organic solvent surrounded. 4. The method according to claim 3, characterized in that as Cyanoacetic ester (II) uses the methyl or ethyl ester. 5. Process according to Claims 3 to 4, characterized in that triethylamine is used as the tertiary organic base. 6. Process according to Claims 3 to 5, characterized in that man as an inert organic solvent for the reaction of the cyanoacetic ester (II) with Diketene aromatic hydrocarbons, aliphatic or aromatic halogenated hydrocarbons, aliphatic ether used. 7. The method according to claims 3 to 6, characterized in that daf to wipe the implementation of the cyanoacetic ester (II) mot diketene at temperatures about -10 and + 50 ° C, preferably between about 0 and 30 ° C and especially between about 10 and 20 ° C.