SI8711595A8 - Process for the production of quinoline-2-3-dicarbolic acid. - Google Patents

Description

AMERICAN CYANAMID COMPANY

PROCEDURE FOR OBTAINING QUINOLINE-2,3-DICARBONIC ACID

FIELD OF THE INVENTION

The present invention relates to the field of preparative organic heterocyclic chemistry and relates to novel processes for the preparation of quinoline-2,3-dicarboxylic acid. These acids are coke intermediates for the lambing of herbicidal poridine and quinolinimidazolinone herbicidal compounds. According to the MKP, the invention bears the following designations:

Technical problem

It is a technical problem in the present invention to provide a novel chemical process for the preparation of quinoline-2,3-dicarboxylic acid, which would overcome the disadvantages of the prior art.

The state of the art

The herbicidal pyridine and quinolinimidazoline compounds obtained from the present compounds include 2- (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) quinoline-3-carboxylic acid, esters and their salts and are disclosed in the European Patent Application 0 041 621 (incorporated herein by reference). These herbicidal imidazolyl carboxylic acids can be prepared by the procedure described in United States Patent 4,518,780 (incorporated herein by reference), cyclization under basic conditions, of the corresponding substituted 2-carbamyl-quinoline-3-carboxylic acid, obtained by the reaction of anhydride-substituted quinolin, substituted Of 3-dicarboxylic acid and the corresponding substituted aminocarboxamide or aminothiocarboxamide. Quinoline-2,3-dicarboxylic acid anhydrides are prepared from the diacid using a process well known in the art.

However, the acids themselves are not readily available. A useful process for preparing quinoline-2,3-dicarboxylic acid and its esters by reacting beta-anilino-alpha, beta-unsaturated ester with immonium salt (commonly referred to as Vilsmeier reagent) is available in the same application. Beta-anilino-alpha, beta-unsaturated esters are obtained by reacting appropriately substituted aniline with beta-esters or dialkyl-acetylene dicarboxylates. This overall reaction for the preparation of quinoline-2,3-dicarboxylate is illustrated in Scheme I.

SCHEME I

R'-CO-CH ₂ CO ₂ R ♦ or

+

Cl-CH-N- iR ') < ^V > or Cl-Cri-c * n. 4 or i

V (You ,;

wherein R ₁ is CH ₃ or CO 1 R 5 and R 5 is C 1-3 alkyl or R ₃ is CH ₃ (or C ₁ -C ₄ alkyl).

When R 'is CH _{3, the} acid is obtained by comparative oxidation and hydrolysis of the product under water-base conditions in the presence of nickel peroxide, as described in United States Patent 4,449,409.

On the other hand, the accessibility of ketoesters and dialulaethylene dicarboxylates, such as dieLyloxaloethoate and diethylethylene dicarboxylate, is limited, thereby limiting the amounts of anilino fumarate and quinoline-2,3-dicarboxylic acids, intermediates required for herbicides - (4-Isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) quinoline-3-carboxylic acid, esters and their salts.

Description of solution to a technical problem

The present invention goes beyond this limitation by providing a source of quinoline-2,3-dicarboxylic acid, esters and their salts by reaction in the first stage, dichlorgulcinate and amine to form anilinofumarate in the first stage. With the ready source of anilino fumarate in the third stage, quinoline-2,3-dicarboxylic acid is obtained which is accessible for the production of herbicides, 2- (4-isopropyl-4-methyl-S-oxo-2-imidazo) in-2-yl) in-3-carboxylic acid esters and their salts.

Process for the preparation of quinoline-2,3-dicarboxylic acid of the formula:

in which R is (C 1 -C 4) alkyl or H, is carried out by reacting the dichlorosuccinate of the formula in the first stage:

Cl - CH - CO ₂ R Cl - CH - CO ₂ R in which R is (C 1 -C ₄ ) alkyl with a minimum of 3 molar equivalents of the amine of the formula: ^v

R.R-HH

u. which and R ₂ are__swakXHHi C 1 -C 4 alkyl provided that only one of -R 1 and 1 is. H Hi when »an» · »« gA-iodine-Ri ir ₂ «a- with an ot atom for which._su_j? Richurshdeni-, r - &» τηΛτβ} ττ-ί «σ ~ 1.1Τ e ^ -members written ± ~ contains at most ~ O>ato> nMH- in an inert solvent, at a temperature of about 25 ° C to reflux, for about 1-24 hours to give a mixture of alkylaminomalate or alkylamino fumarate of the formula:

CH - CO-R

II

R R N - C - CO R I 2. 2 and hJLoraminosuccinate. tor.n ··. ! <?:

H

Cl - C - CO „R I

R RN - C - CO_R »which R, R ^ and R ^ are as defined above, which in the second stage, this mixture reacts with the mole equivalent of aniline in an inert organic solvent containing an organic acid, such as acetic acid, to temperature from about 25 ° C to 90 ° C for 1-24 hours to give anilino fumarate of the formula:

in which R is as defined above and in the third fa 2i the anilinofumarate thus obtained reacts with an equolar amount

Vilsmeier reagent in the presence of a hydrocarbon solvent or a chlorinated hydrocarbon solvent such as toluene, methylene chloride, dichloroethane, orthodichlorobenzene, chlorbenzene or mixtures thereof, at a temperature of from about 40 ° C to 110 ° C for a period sufficient to substantially complete the reaction and substantially complete the reaction dialkyl-quinoline-2,3-dicarboxyl is obtained and its hydrolysis is then carried out to give quinoline-2,3-dicarboxylic acid.

• ir?

'' V '' * '$ / ··

5The reactions described are illustrated in Schemes II Ά-C, below SCHEME II A ci-ch-co ₂ r + 3 RjRjNH

Cl-CH-COjR

II

Oi-COjR

H

Cl-C-COjR r ₁ r ₂ nc-co _? r

R R K-Č-CO.F.

i .. _H

ITIa

6-_ [lilac

Scheme II-B

Scheme II-C

To peace

co ₂ H co_k wherein R, R ^ and R2 are as previously described.

It has suddenly been found that diethylamylinofumarate or diethyloxalacetate and hence quinoline-2,3-dicarboxylic acid are obtained in high yields by the process of the present invention.

In accordance with the process of the present invention, diethyldichlorosuccinate obtainable by the method described in Japanese Patent 71.21 564, incorporated herein by reference, "reacts with 3 molar equivalents of methylamine in toluene at 80 ° C to 85 ° C for 7 hours and then at reflux for 3 hours . The reaction mixture was cooled to room temperature, washed with water and the solvent evaporated to give the products lilac and IIIb (ratio IIIa / IIIb = 7.5 / 1) with R1 being each ethyl. Solvents suitable for reacting dichlorosuccinate with aryls of formula II, which include hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons and aromatic hydrocarbons.

Diethyl anilinofumarate is obtained by adding the mole equivalent of aniline to a toluene solution (20 ml) of a mixture of compounds of the formula lil and 11b, previously obtained, which contains 5 molar equivalents of acetic acid. The reaction mixture was then stirred at 80-85 ° C for 4 hours. The product was isolated in 85-90% yields, after cooling the mixture to room temperature and washing the organic solution with water and then diluted with HCl 1 by evaporation of the solvent.

Suitable solvents for the reaction of anilines with the compounds of the formula lila and Hib include hydrocarbons, aromatic hydrocarbons and halogenated hydrocarbons and aromatic hydrocarbons. It has further been found that while the above reaction proceeds without organic acid, significantly higher yields of anilinofumarate are obtained in shorter reaction times in the presence of an organic acid such as acetic acid, propionic and the like. Thus, while the above reaction yields are 80-90% of the desired product after 4 hours at 80-85 ° C in the presence of acetic acid, only 40% of anilino fumarate remains in the reflux of the reactant in the absence of organic acid for 10 hours.

^HC i ° 2 ^C 2 ^H 5 hc-co ₂ c ₂ h ₅

Chlorine gas is

The methods of the present invention are further illustrated by the following examples, which are illustrative and not limiting.

Example 1

Preparation of dichlorosuccinate

EtOH C1-CH-CO, C_H12 2 5 * (cat) C1-CH-CO ₂ C ₂ H _{5 is} introduced by bubbling into an ethylenedichloride solution of diethyl malate, containing ethanol, (0.1 molar equivalent). After stirring the mixture for 8 hours at room temperature, it was covered with nitrogen gas for 5 minutes and the solvent removed under reduced pressure to give dichlorosuccinate in 54% yield.

Examples 2-5

Preparation of diethylaminoalate and diethyl-2-chloro-3-dlethyl-aminosuccinate

Cl - CH - COC.H. j z t b

Cl - CH - CO ₂ C ₂ H ₅

HC - CO C, H,

II

(C ₂ h ₅ ) ₂ n - c - <V ₂ H ₅ (CH) N - c - CO C, H, ^ά ° H ²²⁵

- 9Diethylamine (2.41 g, 0.033 mol) was added dropwise to a stirred solution of diethyldichlorosuccinate (2.59 g. 0.01 mol) in toluene (15 ml). The resulting mixture was heated to 80 ° C to 85 ° C for 8 hours and then refluxed for 3 hours. After cooling the reaction mixture to room temperature, it was washed with water (15 ml) and the toluene layer was separated and evaporated under reduced pressure to give 2.07 g (85%) of a mixture of diethyl diethylaminolate and the title chloramine in the maleate to succinate ratio of 7.5 / 1.

Using the above procedure and replacing the corresponding amine with diethylamine, the products listed in Table I are obtained.

Table I

Example Amin % Yield (maleate x succinate) Relationship according to maleate succinate 3 0 NH 86 M: 1 M HNC ^ H _g - ⁿ MM (fumarate) - 5 v-0 52 (fumarate) -

- Td · Examples 6-9

Age of an iinoiumarate hc-co ₂ c ₂ h ₅ <W ₂ Non-CO ₂ C ₂ H ₅ ci

H-H-CO ₂ C ₂ H ₅

HOAC (c ₂ H ₅ ) ₂ N-h-e ° ₂ ^c 2 ^H 5 n

Aniline (0.93 g, 0.01 mol) was added to toluene (20 ml) acetic acid solution (3.0 g 0.05 mol) and a mixture of diethyl diethylaminolate and diethyl-2-chloro-3-diethylaminosuccinate dissolved in Example 2 above. The resulting solution was heated at 80-85 ° C for 4 hours. After cooling the reaction mixture to room temperature, it was washed with water (10 ml) and then with aqueous HCl (12% w / w, 2 ml).

Analysis of the toluene solution formed by gas-liquid chromatography and product isolation indicated that the total phase yield starting from diethyl malate was 69%.

Example 10

Preparation of dlethyloxalacetate and subsequent preparation of diethylanilinofumarate hc-co ₂ c ₂ h ₅ (C ₂ H ₅ ) jH-e-CO ₂ C ₂ H ₅

Cl

HCl toluel ^H 2 ^l f- ^CO 2 ^C 2 ^H 5

O-C-COjCjHj

HC-COjCjHj aniline < ^C 2 ^H 5> 2 ^N - ^CO 2 ^C 2 ^H 5 c ₂ h ₅ ° ₂ cc ^h ^ - ^CO 2 ^C 2 ^H 5

A toluene solution (15 ml) of a mixture of diethyl diethylaminolate and diethyl-2-chloro-3-diethylaminosuccinate (2.43 g. 0.01 mol) was obtained by the procedure of Example 2, previously, and mixed with water (5.0 g). containing 2.15 g (0.015 mol) of concentrated HCl for 2.5 hours. The toluene layer containing diethyloxalate was separated and aniline (0.93 g, 0.01 mol) was added. The resulting solution was stirred at room temperature for 30 minutes and then refluxed for 1.5 hours, collecting the water that was generated by the Dean-Stark extension. Analysis of the cooled toluene solution using gas chromatography yields 55% diethylaminofumarate.

Example 1 · 1

Preparation of quinolln-2,3-dicarboxylic acid

The Wilsmeier reagent was obtained by adding 4.61 g (0.03 mol) of POCl2, dropwise, to a solution of 2.19 g (10.03 mol) of dimethyl formamide in 12 ml of toluene, maintaining a temperature of 20-30 °. C. The two layers were stirred at 20-30 ° C for 60 minutes and then treated dropwise with a solution of 5.26 g (0.02 mol) of diethylanilinofumarate obtained by the procedure of Example 2, in 40 ml of toluene, maintaining the temperature at 20 -30 ° C. The heating solution was refluxed for 2 hours, cooled as the reflux stopped and was poured into 50 ml of water. The dark syrupy substance that precipitates dissolves when stirred at room temperature for 30 minutes. Analysis of the toluene solution using gas-liquid chromatography indicates a 72% yield. Evaporation of the dietary solution gave an oily solid mass of a low melting point, which after recrystallization from isopropyl alcohol gave 4.05 g of a dark solid, m.p. 53-56 ° C.

Two phases formed from 4.1 g (0.015 mol) of the diester in 25 ml of toluene and 16 ml of 15% NaOH were refluxed with good stirring for 8 hours. The two phases were cooled to 50-55 ° C and diluted with 20 ml of water. The aqueous layer was separated and added dropwise in 11 ml of 35% H 2 SO 4, maintaining the temperature below 40 ° C, and the resulting thick mixture was filtered, and the solid was collected and dried overnight at 60 ° C / 30- 50 mm Hg to give 3.19 g of quinoline-2,3-dicarboxylic acid.

Claims (3)

A process for the preparation of quinoline-2,3-dicarboxylic acid of the formula: in which R is (C 1 -C 4) alkyl or H, denoted by t and m e, which reacts in the first stage with dichlorosuccinate of the formula: Cl - CH - CO R I Cl - CH - CO ₂ R in which R is (C 1 -C 6 alkyl) with a minimum of 3 molar equivalents of the amine of the formula: ^R , ^R 2 ^NH in which R and R represent an ethyl group, in an inert solvent, at a temperature of from about 25 C to a reflux temperature for about 1-24 hours to give a mixture of alkylaminolate or alkylamino fumarate of the formula: CH - CO ₂ R ^R 1 ^R 2 ^N - C - CO ₂ and chlorinosuccinate of the formula: H Cl-C - co ₂ r ^R , ^R 2 ^N '' ^C - ^CO 2 ^R in which R, and R ₃ are as previously defined, which in the second stage this mixture reacts with the mole equivalent of aniline in an inert organic solvent containing an organic acid, such as acetic acid, at a temperature of from about 25 ° C to 90 ° C for 1-24 hours to give anilino fumarate of the formula: ROjC-GH 'NH-N-CO in which R is as previously defined and in the third stage the anilino fumarate thus obtained reacts with an equolar amount of Vilsmeier reagent in the presence of a hydrocarbon solvent or a chlorinated hydrocarbon solvent such as toluene, methylene chloride. dichloroethane, orthodichlorobenzene, chlorobenzene, or mixtures thereof, at a temperature of from about 40 ° C to 110 ° C for a period sufficient to substantially complete the reaction and obtain dialkyl-quinoline-2,3-dicarboxyl and subsequently hydrolyze it to obtained quinoline-2,3-dicarboxylic acid. 2. The process of claim 1 wherein the inert organic solvent is a chlorinated solvent, a chlorinated aromatic solvent, an aromatic hydrocarbon or mixtures thereof, such as ethylenedichloride, monochlorobenzene, toluene or mixtures thereof. 3. The process according to claim 112, wherein the second stage reaction is carried out at a temperature of about 75-85 [deg.] C. for 2-9 hours. AMERICAN CYANAMID COMPANY Authorized Agent, ABSTRACT A process for the preparation of quinoline-2,3-dicarboxylic acid of the formula is described: wherein R is (C 1 -C 4) alkyl or H, which is effected by reacting the dichlorosuccinate of the formula in the first stage: Cl - CH - C0 ₉ RI ² Cl - CH - CO ₂ R in which R is (C 1 -C 4) alkyl with a minimum of 3 molar equivalents of an amine of the formula: R ^ NH in which R ^ and R ₂ are each H or C ^-C ^ alkyl provided that only one of R ₁ and R ^ is H or when taken together and R ₂ with the nitrogen atom to which they are attached form A 5 or 6-0 membered ring containing at most 2 hetero atoms; in an inert solvent, at a temperature of about 25 ° C to reflux, for about 1-24 hours to give a mixture of alkylaminomalate or alkylamino fumarate of the formula: CH - CO_R H ² R ₁ R ₂ N - C - CO ₂ R and chloraminosuccinate of the formula: H Cl - C - CO R t R RN - θ '- CO R' ² H