DK141167B - Intermediate for use in the preparation of 6,7-dialkoxy-4-hydroxyquinoline esters. - Google Patents

Description

(11) PUBLICATION MANUAL 141 1 67 DENMARK <«> Intel.'C 07 D 215/68 '(21) Application No 4547/74 (22) Filed on ^ 7 · SUS * 1 974 (23) Running Day ^ 7 · & Ug . 1974

(44) The application submitted and submitted to the NGO

the petition published on the 20th J & n.

DI RECTORATE FOR # ΛΛ4 _ ^ ,.

PATENT AND TRADE MARKET (30) Priority requested from it

Aug 28 1973, CI14Q3, HU

Aug 28 1973, Cl ΐ4θ4, HU

(71) CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT., To u. 1-5, Budapest, HU.

(72) Inventor: Judit Frank, 1032 Budapest, Szuloe cow 34, HU: Zolfcan

Meszaros, 1015 Budapest, Batthyany-u 34, HU: Ivan Dozsa, 1149 Budapest, Yarga Gy. Park 12, HU: Andras Kelemen, 1042 Budapest, Arpad u. 36, HU: Eva Somfai, 1014 Budapest, “Yancsies Mihaly u. 8, HU.

(74) Plenipotentiary in the proceedings:

Office of Industrial Enerent V. Svend Schønning.

(54) Intermediate for use in the preparation of 6,7-dialkoxy-4-hySi droxyquinoline acid esters.

The present invention relates to an intermediate for use in the preparation of known 6,7-dialkoxy-4-hydroxyquinolinic acid esters of the general formula

OH O

R ° ViVJ ^ | / C00R2

H

wherein R 1 is a straight or branched alkyl group having 1-4 carbon atoms, R is a saturated or unsaturated straight or branched alkyl group having up to 12 carbon atoms and R is a straight or branched alkyl group having 1-4 carbon atoms or a benzyl group.

The compounds of general formula I are known coccidiostats.

The intermediate according to the invention is peculiar in that it has the general formula 0H 0 JT L TjTj ιχ

Question '........ r1o .......

H

1 where R and R have the meanings given above, or a salt thereof.

The 6,7-dialkoxy-4-oxyquinoline-3-carboxylic acid derivatives have heretofore been prepared from 3,4-dialkoxyaniline derivatives, i.e. the dialkoxy groups concerned were already present in the benzene ring.

According to British Patent No. 1,188,364 and French Patent No. 1,531,495, e.g. 4-decyloxy-3-ethoxy-aniline with ethoxymethylene malone ester (EMNE) and by cyclization of the compound obtained, the desired 6,7-dialkoxyquinoline is obtained.

According to German Patent No. 1,954,189, 3,4-diisobutoxyaniline methylene malone ester is cyclized.

According to German patent specification 2,058,002, 3,4-dialkoxyaniline is reacted with ortho-acid ester and p-toluenesulfonic acid to give the desired 6,7-dialkoxyquinoline. 6,7-dialkoxy-4-hydroxyquinoline ester compounds can be recovered from 6,7-dialkoxy-4-chloroquinoline-3-carboxylic acid esters according to U.S. Patent No. 3,665,005.

According to the said "classic" methods, the 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylic acid derivatives are always prepared from 3,4-dialkoxyaniline derivatives.

Surprisingly, it has now been found that 6,7-dialkoxy-4-oxyquinoline-3-carboxylic acid derivatives of the general formula I, wherein R 2, R 5 and R have the above meanings, can be prepared from an intermediate of the general formula IX shown above, wherein 1 2 R and R have the meanings shown above, by alkylation with alkyl bromide of the formula R Br, wherein R has the meaning given above, in a dipolar aprotic solvent in the presence of a strong base.

3 U1167

The main disadvantage of the prior art methods for preparing coccidiostatically active 4-oxy-3-carbalkoxycinylines is that the compounds are obtained by thermal cycling at approx. 250 ° C, which makes them in contact with degradation products and is difficult to clean. The compounds are usually insoluble and their repeated crystallization results in heavy losses.

In the method of the present invention, viz. by starting from the intermediate of the invention in the manner described above, the alkylation is carried out in a solvent which can simultaneously serve to purify the product. A favorable reaction temperature is e.g. 100 ° C, in which case you can work on a water bath.

It is of utmost importance for the product that the final step in the overall synthesis is not thermal cycling but a lower temperature alkylation reaction.

Particularly high yields are obtained by the process of this invention if sodium hydride is used as the strong base.

British Patent No. 1,042,638 discloses a process for alkylating 7-hydroxy-2-oxo-1,2-dihydroisoquinoline derivatives. This alkylation is carried out with alkyl halide in dimethylformamide in the presence of anhydrous potassium carbonate as a base.

In contrast, the present process relates to the alkylation of a 6-hydroxy group into a 6-hydroxy-7-alkoxy-4-oxo-quinoline-3-carboxylic acid ester. The reaction is carried out in a dipolar aprotic solvent in the presence of a strong base with alkyl bromide. The desired product can only be obtained under these reaction conditions. Thus, e.g. alkylation carried out in an alcohol in the presence of a sodium alcoholate or potassium carbonate is not the desired product - even though it is carried out in a dipolar aprotic solvent in the presence of potassium carbonate.

The compounds of general formulas I and IX may be present in both ketone and enol form.

In general formula IX, R 1 is a straight or branched alkyl group having 1-4 carbon atoms, particularly advantageously a methyl or ethyl group.

2 R is an alkyl group having 1-4 'carbon atoms, preferably an ethyl group, or a benzyl group.

Intermediate according to the invention, of the general formula IX can be prepared by cyclizing a compound of the formula 14 ° C

R-’o ^^ NH NH NH NH-CH = C

u

R

Wherein R and R are as defined above, R is a hydrogen atom or an alkanoyl group having 1-4 carbon atoms and R is 2 3 the group -CN or -COOR, with the proviso that R must be a hydrogen atom when R is the group -CN, to form a compound of the formula OH0

^ 1 {1 ^ ~ "I II II XI

H

wherein R ·, R₂, R3 and R ^ have the meanings set forth above, wherein if R is an alkanoyl group of 1-4 carbon atoms, the compound of formula XI selected will be subjected to selective alkanoyl cleavage or if R is the group -CN converts the compound of formula XI obtained in a manner known per se into a compound of formula II and / or if desired converts the group R of a compound of formula IX to another group R and if desired converts the compound obtained to a salt thereof or releases the compound of formula IX from a salt thereof.

The compound of the general formula X used at the ring closure can be prepared by reducing a compound of the general formula r 3 ° R 11 R 10 NO 2 3 where R and R have the above meanings to a compound of the general formula wherein R and R have the above meanings, the compound obtained is reacted with a compound of the general formula COQR

C + HcO-CH = C IV

u 2 4 where R and R have the above meanings.

3

The compounds of the general formula II wherein R is hydrogen can be prepared in the manner described in D.F. Page and 0. Clinton in Org. Chem. 27, 218, 1962. The compounds of general formula II wherein R is an alkanoyl group having 1-4 carbon atoms can be recovered from the hydroxy derivatives by acylation.

The invention is explained in more detail below by means of some examples.

A. Preparation of the Intermediate of General Formula IX. Example 1 a) 22.52 g (0.1 mole) of 4-acetoxy-4-ethoxynitrobenzene are dissolved in 225 ml of acetic acid ethyl ester and hydrogenated in the presence of 5 g of palladium / activated carbon at 5-10 at. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the reaction mixture is evaporated to dryness. On cooling, 4-acetoxy-3 <-ethoxyaniline crystallizes which is washed with cold alcohol on the suction filter. A white crystalline product is obtained in a yield of 86%, m.p. 96 ° C.

Calculated: C 61.53 H 6.71 N 7.17 Found: C 61.30 H 6.40 N 6.81% b) 25.4 g (0.13 mole) of 4-acetoxy-3-ethoxyaniline are dissolved in 250 ml of ethyl acetate and 32.4 g (0.15 mol) of ethoxymethylene malonic acid diethyl ester are added to the solution. The reaction mixture is boiled for three hours and then evaporated to dryness. The residue is crystallized by cooling. The crystals are washed with cold alcohol on the suction filter.

The white 4-acetoxy-3-ethoxyaniline-methylene malonic acid ester melting at 102 ° C is obtained in a 91% yield.

Calculated: C 59.17 H 6.34 N 3.83 found: C 59.3 H 6.50 N 3.91% c) 35.45 g (0.1 mole) of 4-acetoxy-3-ethoxyaniline methylene malonic acid ester Boil for 60 minutes in 365 ml of diphyl. The product is slowly separated from the solution. The suspension is cooled, diluted with 350 ml of gasoline and then filtered. The product is put on the suction filter under gasoline. The melting sand-colored 6-acetoxy-7-ethoxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester is obtained at 300 ° C with decomposition in 95% yield. After recrystallization from dimethyl sulfoxide, the melting point is 310 ° C.

Calculated: C 60.18 H 5.36 N 4.38 Found: C 60.20 H 5.16 N 4.32% d) A mixture of 25.52 g (0.08 mol) of 6-acetoxy-7- Ethoxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester, 2000 ml of alcohol, 200 ml of water and 240.28 g (2.4 moles) of potassium hydrogen carbonate are boiled for one hour. Then the alcohol is distilled off in vacuo and the remaining thick suspension is mixed with 2000 ml of water. The undissolved substance is filtered off and suspended in 200 ml of water in the suction filter moist state. The pH of the suspension is adjusted to 3 with 5% hydrochloric acid. The undissolved substance is filtered off, washed with water and put under alcohol.

16.87 g of sand colored 6-hydroxy-7-ethoxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester are obtained, melting at 268-270 ° C. The yield is 76.0%. The melting point of the dimethylformamide recrystallized product is at 272 ° C.

Example 2 a) 18.31 g (0.1 mole) of 2-ethoxy-4-nitrophenol are reduced in a mixture of 180 ml of water, 10 ml of concentrated hydrochloric acid and 50 ml of acetic acid in the presence of a palladium carbon catalyst. After filtering off the catalyst, the pH of the reaction mixture is adjusted to 6 with 10% s sodium carbonate solution. The separated substance is suctioned off, washed with water and then put under acetone. 13.6 g (89%) of sand colored 2-ethoxy-4-aminophenol are obtained.

Calculated C 63.73 H 7.23 N 9.14 found: c 62.22 H 7.18 N 9.08% b) 15.31 g (0.1 mole) of 2-ethoxy-4-aminophenol and 26 0 g (0.12 mole) of ethoxymethylene malonic acid ester are heated for two hours on a water bath. To the cool reaction mass is then added 30 ml of gasoline and the mixture is refluxed for two hours. From the biphasic mixture, upon cooling, a solid is filtered off and filtered under gasoline. 27.78 g of sand colored 4-hydroxy-3-ethoxyaniline malonic acid ester are obtained, melting at 80 ° C. The yield is 86%.

Calculated: C 59.43 H 6.54 N 4.33 Found: C 59.57 H 6.61 N 4.30% c) 19.35 g (0.06 mole) of 4-hydroxy-3-ethoxyaniline methylene malonic acid diethyl ester is kept in 190 ml of difyl for 30 minutes at 250 ° C. The reaction mixture is cooled and the product formed at the cyclization precipitates by the addition of 190 ml of gasoline. The product is washed on the filter with gasoline. 14.8 g of sand colored 6-hydroxy-7-ethoxy-4-oxoquinoline-3-carboxylic acid ethyl ester are obtained, melting at 26 ° C.

The yield is 89.3%. The dimethylformamide recrystallized product melts at 270-272 ° C.

Calculated: C 60.64 H 5.45 N 5.05 Found: C 60.24 H 5.55 N 5.04%

Example 3 4.59 g (0.03 mole) of 2-ethoxy-4-aminophenol and 10.52 g (0.031 mole) of ethoxymethylene malonic acid dibenzyl ester are kept in a water bath for four hours at 100 ° C. Then, 50 ml of difyl is added to the reaction mixture and boiled for 60 minutes at 250 ° C. The mixture is cooled, 50 ml of gasoline is added, the precipitated product is filtered off and washed with alcohol. 3.4 g of brown 6-hydroxy-7-ethoxy-4-oxoquinoline-3-carboxylic acid benzyl ester are obtained, melting at 256 ° C. The yield is 50.2%. Calculated: C 67.25 H 5.05 N 4.13 found: C 66.76 H 4.88 N 4.37% B. Preparation of compounds of general formula I from the intermediate of formula IX.

Example 4 1.38 g (0.005 mol) of 6-hydroxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid ethyl ester are suspended in 60 ml of hot dimethylformamide. To the suspension is added 0.5 g (0.01 mole) of oily sodium hydride suspension at 50 ° C and rinsed with 10 ml of dimethylformamide.

After the addition of 1.32 g (0.06 mol) of n-decyl bromide, the water bath is heated to 100 ° C and the reaction mixture is stirred for 20 hours at this temperature. The mixture is then evaporated in vacuo, the residue is taken up in 40 ml of water and the pH of the suspension is adjusted to a neutral value with dilute hydrochloric acid. The precipitated precipitate is filtered off and washed with water. 1.47 g of sand colored 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester are obtained, melting at 230-232 ° C, Yield 71%. The dimethylformamide recrystallized product melts at 242-244 ° C.

Example 5 6-Decyloxy-7-ethoxyquinoline-3-carboxylic acid benzyl ester is prepared in the manner described in Example 1. The crude product melts at 198 ° C, upon recrystallization the melting point rises to 202-203 ° C. Calculated: C 72.62 H 7.78 N 2.92 Found: C 72.78 H 7.93 N 3.04%

Example 6 6.76 g (0.1 mole) of 6-hydroxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid ethyl ester are hot mixed in 120 ml of dimethylformamide and the mixture is mixed at 50 ° C with 1.0 g ( 0.02 mole) oily sodium hydride suspension. Rinse with 20 ml of dimethylformamide. After the addition of 1.64 g (0.012 mol) of n-butyl bromide, the water bath is slowly heated to 100 ° C and the reaction mixture is stirred for 30 hours at this temperature. The reaction mixture is then evaporated to dryness under vacuum and the residue taken up in water and the pH adjusted to neutral with dilute hydrochloric acid. The separated solid product is filtered off and tear off with water. 3.1 g of 6-n-butoxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid ethyl ester are obtained, melting at 220 ° C. Yield 93.2%. The recrystallized product melts at 257 ° C.

Example 7

Work is done in the manner described but allylated with allyl bromide. The reaction time in this case is 50 hours.

The 6-allyloxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid ethyl ester melting at 220 ° C is obtained in 91.5% yield. After recrystallization from dimethylformamide, the product melts at 233 ° C.

Example 8 1.38 g (0.005 mol) of 6-hydroxy-7-ethoxy-4-oxyquinoline-3-carboxylic acid ethyl ester are hot mixed in 60 ml of dimethylformamide. At 50 ° C, 0.8 g (0.01 mole) of sodium amide suspended in the same amount of xylene is added to the mixture. After the addition of 1.32 g (0.006 mol) of decyl bromide, the water bath is slowly heated to 100 ° C. The reaction mixture is stirred at this temperature for 20 hours and then evaporated under vacuum to dryness. The residue is taken up in water and the pH is adjusted to a neutral value with dilute hydrochloric acid. The precipitated solid pro-