DE2554895A1 - PROCESS FOR THE PREPARATION OF HYDRATROPASIC ACIDS AND ALKYL DERIVATIVES THEREOF - Google Patents

Description

DIPL-PHYS. WILLY LORENZ, PATENT LAWYER, 8C35 GAUTIMG, HU BEF.TUSSTRASSE 83 ¹ =

December 4, 1975 My files: a 55-j _f DT

AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO - A.C.R.A.P. Spa. Viale Amelia 70, Rome / Italy

Process for the production of hydratropic acid and alkyl deri-

fathers of this

The invention relates to a process for the production of hydratropic acid or phenylmethyl acetic acid and its alkyl derivatives.

Although hydratropic acid (Ia) has long been known (W. Wislicenus, Goldstein, 1855)> all use monosubstituted methods for their synthesis described in the literature Benzene derivatives and require the conversion of the side chain in several successive stages.

Hydratropic acid and its alkyl derivatives have the following general properties Formula:

(D

CH-COOH a ί R - H GEy, b : R = methyl C. : R = i-propyl d : R = n-butyl e : R - i-butyl f ί R ~ t-butyl

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The invention "relates to a method for the synthesis of hydratropic acid and their para-alkyl substituted analogs, where from Cyclohexanone or of 3 - ^ lkylcyclohexanonen (II) and pyruvic acid or pyruvic acid, according to the following scheme:

r <

CH-

H R - (> + CO

(II)

Pyruvic acid or pyruvic acid can be replaced by one of their Alkali or alkaline earth salts (Na, Li, K, Ca) or by a their esters (methyl, ethyl, propyl, butyl) can be replaced, or they can be produced "in situ" by pyrolysis of tartaric acid will. R can be any alkyl radical with 1 to 4 carbon atoms be e.g. B. the ethyl, ethyl, propyl, isopropyl, Butyl, isobutyl or t-butyl radical.

The reaction conditions can vary significantly from a pail to the other case may be different. Therefore it is possible to divide the reaction into two different stages, namely first in the condensation of cyclohexanone and pyruvic acid and, secondly, in carrying out the aromatization of the resultant Intermediate product. Furthermore, it is possible to carry out the reaction in a single step without isolating any intermediate perform.

If practical reasons suggest it, a two-step process apply, e.g. B. in the case of cyclohexanone, whose low boiling point otherwise the use of closed containers would require, it is possible to use various intermediates

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depending on the ftediuni (acidic, alkaline, or neutral) in which the first stage takes place. HydroxyIactone (III), which by. Cooking cyclohexanone and pyruvic acid in a solution containing acetic acid and hydrochloric acid

th, hydroxy ester (IVa; R ¹ =

that from ethyl pyruvate

and cyclohexanone is obtained without a condensing ^{agent, hydroxy acid (Va; R 1} = H) obtained from cyclohexanone and sodium pyruvate in a water-alcohol solution, and the unsaturated lactone (VIa) obtained by hydration of III are already described in the literature, see K. Irasad, Bull. Soc. Chiia. l ^p r. , (1967), B. 1579-1591.

OH

COOR

(III)

(IV) R ¹

(V) R «

G ₂ H ₅

(VI)

= H

Similar products, which are not described in the literature, are obtained under analogous conditions starting from J-alkyl-substituted cyclohexanones. The condensation takes place in the 6-position and not in the 2-position of the cyclohexanol, as is shown by the spectrophotometric properties of such intermediates and by the type of products obtained in the subsequent aromatization. By further heating between 200 and 25> O ° in the presence of acids, HCl, HBr, polyphosphoric acid etc., or of salts of organic bases with strong acids, pyridine hydrochloride, quinoline hydrochloride, isoquinoline hydrochloride, triethylamine hydrochloride, picoline hydrochloride or mixtures of hydrochlorides from commercially available pyridine bases give lactones of type III and VI as well as keto acids and keto esters

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of type IT and V the corresponding hydratropic acids in almost quantitative. yields. With the technical. Luroll guide can reaction mixtures, which derivatives of lyps III, IV, V, and VI included, also with very good authors, used v / earth. Venn the boiling point of the chosen cyclohexanone it allows the reaction to be carried out in a single step. So give J-isobutyl-cyclohexanone and Ethyl pyruvate mixed with a suitable acidic condensing agent (Hydrochloric acid, lyridine hydrochloride, Polyphosphoric acid) after several hours of heating at 230 ° p-isobutyl hydratropic acid.

Hydratropic acid and its p-alkyl analogs can be used in medicine in human or in the field of veterinary medicine, as agrochemicals or used as intermediates in the synthesis of organic substances.

The invention is illustrated in more detail by means of the following examples.

Example 1 - Hydratropic Acid

A mixture containing 5 g of ethyl cc- (2-cyclohexanone) lactate (see Iv. W. Roseinund et al .; Arch. Hiarm. _2§7 (195 ² O-, S- W) and ■ Ί> € Pyridine hydrochloride was heated for 4 to 5 hours to 220 ° C. It was then poured into 100 ml v / ater, and the oil which separated out was extracted with ether. The residue obtained after removal of the solvent was distilled ; K .. = 150-2 ° (18 mm Hg). The HFiR, IR and UV spectra were identical to those obtained on an authentic sample.

In an analogous manner, hydratropic acid is produced under the same conditions obtained from α- (2-cyclohexanone) lactic acid (see M. Prasad (1967)).

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255A895

In an analogous way, hydratropic acid is obtained by heating a Mixture consisting of 3 parts by weight of pyridine hydrochloride and 1 weight ΙΊ 3-ethyl-2,4, ;;, 6-tetrahydro ~ benzoLbJ-iuran-2-one (see LI.

if-r · "}} is formed, received at the same time.

In an analogous manner, hydratropic acid is produced by heating a Mixture consisting of 3 parts by weight of conc. HCl and 4-hydroxy-2-methyl-3,4-tetramethylene-butenolide (see M .. Prasad (1967)) is obtained at the same time.

Example 2

p-Isobutylhydratropic acid can be obtained from ethyl pyruvate and 3-isobutylcyclohexanone can be obtained without separating the intermediates.

A mixture, the equimolar! Narrow of ethyl pyruvate and 3-1sobutyl-cyclohexanone contains, is heated to 1 ^ 0 ° for 14 hours. 5 parts by weight of lyridine hydrochloride add to the viscous oil that is added and the mixture is allowed to last 4 to 5 hours heated under reflux (external bath at 230 °). The mixture is cooled, treated with water / water, filtered and the resultant Solid is recrystallized from petroleum ether. K. = 73-7 ^ also mixed with an authentic Frobe (GB-FS 971 90C-. The yield was 63%.

Example 3

This example describes the preparation of ethyl α- [2- (5-isobutyl) cyclohexanone] lactate.

The viscous oil obtained in Example 2 before treatment with pyridine hydrochloride was distilled. After a small portion is obtained as the top product, formed from a mixture of 3-1sobutyl-cyclohexanone and ethylpyruvate, a colorless oil is obtained; K. = 142-4 ° (0.4 mm Hg). The yield was 72 %.

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-G-

Analysis on C _x ,.-H ^ G ,,:

found: C = 66.39 % H = 9.36 ^c / o calculated: C = 66.63 % H = 9.69 %

IR (5% in CCl ₄ ): IT ^ ₁ = 3540 cm "¹; f _{Q = Q (ester)} - 1730 cm"¹;

f C = O (ketone) ^{= 1} ? ^10cm ~ ¹

Example 4

This example describes the preparation of p-isobutyl hydratropic acid from ethyl a- [2- (5-isobutyl ^ cyclohexanone] lactate.

One part of ethyl a- [2- (5 ~ isobutyl) ~ cyclohexanone] lactate and 5 parts Iyridine hydrochloride are refluxed (external bath at 230 °) cooked for 4 to 5 hours. The solution is cooled with water treated, filtered and recrystallized from petroleum ether; F. = 72-73 °, also mixed with an authentic sample. The yield was> 85%

Example 5

This example describes the preparation of 6-isobutyl-3-methyl-2,4,5,6-tetrahydro-benzoCb] -furan-2-one.

A mixture containing 31 g of 3-isobutyl-cyclohexanone, 1756 g of pyruvic acid, 90 ml of glacial acetic acid and 90 ml of conc. HCl was refluxed for 4 hours with stirring. The solution was cooled, diluted with 100 ml of water and extracted with ether. The essential extracts were washed with a saturated solution of sodium bicarbonate and then with 21T NaOH and then with water. After drying over sodium sulfate and removing the solvent, the residue (3 "N 3 g) was distilled. A first fraction, which was ^{collected at K. = 80-83 (0.3 mm} Hg), consisted of 3-isobutyl-cyclohexanone , and a second fraction was obtained at K. = 164-168 ° (0.3 mm Hg), which from 6-isobutyl-3-methyl-2,4,5,6-tetrahydro-benzo-Cb] -furan- 2-one was formed, the yield was 52% and the end product was in the form of a viscous oil.

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Analysis on C., H. _q O _? :

found: C = 74.90 yo H = 6.91 ^c , ö

calculated: C = 75.69 ^c / o H = 6.30 %

LTilt-bpektruui. (CCl ₄ , TKS): 6 = 5.5; Doublet J = 4 cps (IH), (-CH = C <); i = 1.73; Singlet, 3K (CH, -).

-1

IR spectrum (CCl ₄ ) V "q _{= 0} = 1775 cm

Example 6

This example "describes the preparation of p-isobutyl hydratropic acid from 6-isobutyl-5-niethyl-2,4,5,6-tetralihydro likewise- [bJ-fura.n-2-one.

10 g of the product obtained in Example 5 and 50 g of one Mixture of hydrochloride obtained from a commercial Mixture of pyridine bases were refluxed for 4 to 5 hours boiled (outer bath at 230). The solution was cooled, treated with water, filtered and recrystallized from petroleum ether. The axis loot was> 80%. F. = 73-74 °, also mixed with an authentic sample.

Example 7

This example describes the preparation of p-isobutylhydratropic acid, which consist of a mixture of heat. of 3-isobutyl cyclohexanone and sodium pyruvate were obtained.

71.5 E liatrium pyruvate, 50 g 3-isobutyl-cyclohexanone, 200 ml Glacial acetic acid and 300 ml conc. Hydrochloric acid were stirred for 8 hours refluxed. The solution was cooled, diluted with 200 ml v / water and the upper oily phase extracted with benzene. After removal of the solvent, there was obtained 330 g of pyridine hydrochloride added to the residue.

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-B-

The mixture was refluxed with stirring for 4 to 5 hours held (outer bath at 230 °). The solution was cooled, diluted with 1.2 l of water and extracted with 2 × 300 ml of chloroform.

The chloroform extracts were combined and concentrated to dryness. The residue was in a water bath, in 60 ml of 20% NaOH dissolved. After cooling, the sodium salt of p-isobutylhydratropic acid solidified. It was triturated with 600 ml of acetone. After brief storage in a refrigerator, the solution was filtered and washed with acetone and dried at 50 °. The yield of the product was 67%. The sodium salt thus obtained was dissolved in 10 parts of water and extracted with HCl 1 ·; 1 strongly acidified. p-isobutyl hydratropic acid precipitated in the form of small particles and was separated off by filtration, washed several quays with water and dried at 50 to constant weight. F. = 72-74- °? also mixed with an authentic sample.

Example 8

This example describes the preparation of p-isopropyl, hydratropic acid from 3-isopropyl-cyclohexanone and tartaric acid.

A mixture which 1 part 3-isopropyl-cyclohexanone, 3 parts Tartaric acid and 15 parts of a-picoline hydrochloride Boiled under reflux for 5 hours. It was then cooled, poured into water and extracted with ether. The essential Solution was back extracted with 1N NaOH. The aqueous solution was acidified and the precipitated oil was back-extracted with ether. The residue obtained after removal of the solvent was converted into the sodium salt according to the procedure purified from example 7. After recrystallization from petroleum ether, a substance with a mp = 67-68 ° was obtained.

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Examples 9 to 11

The following compounds were prepared in accordance with the procedures described in the preceding examples: p-Ilethylhydratropic acid - K. = 165-8 ° (18 min Eg) pn-butylhydratropic acid - K. = 14-5 ° (0.3 mm Hg ) pt-butyl hydratropic acid - E '. = 100-2 °.

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Claims (1)

-AO- Claims M. w "learn about the production of hydropaic acid, thereby g e k e η η ζ e i c h η e t that cyclohexanone in the presence a suitable acid or a salt of an organic base with pyruvic acid or a simple derivative in l'oroi of an ester or a salt thereof "treated will. ...-._ ■ 2. A process for the preparation of hydratropic acid, characterized in that ethyl oc- (2-cyclohexanone) lactate is heated to 22C-23O ⁰ for 4 to 5 hours with an acid or with a salt of an organic base. ■ ο 3- Process for the preparation of hydratropic acid, characterized that 4-hydroxy-2-methyl-3,4-tetramethylene butenolide is heated to 220-230 ° with a suitable acid or with a salt of an organic base. 3-- Process for the production of hydropaic acid, characterized in that that 3-ftethyl-2,4-, 5,6-tetrahydro- [b] -furaii-2-one with a suitable acid or a salt · an organic base is heated. 5- Process for the preparation of ρ-alkyl-hydratropic acid, thereby characterized that J-alkylcycloliexanone with pyruvic acid or with a simple derivative of pyruvic acid in the form of the salt or ester in the presence of one acidic catalyst is heated. 6. Process for the preparation of ρ-alkyl-hydratropic acid, thereby characterized that J-Alkji-cyc-loliexanone with pyruvic acid or tr. with one of their simple derivatives in alkaline or acidic hedium. or without condensation agent 609830/0867 is reacted with the formation of a condensation product or a .Geniisches of rondensation products. 7 · Process for the production of p-alkylhydratropic acid, thereby ker.r-zericlcnet. that the condensation product or a mixture of zondensation products according to claim 6 is heated to 220 to 250 ° in the presence of acids. 8. Process for the preparation of ethyl-a- [2- (5-isobutyl) -cyclohexanonJ-lactate, characterized in that Iüotutylcyclohexaiion and ethylpynavate without solvent with each other heated v / ground. 9 process for the preparation of p-isobutylhydratropic acid, thereby pekennseiclmet that J-isobutyl-cyclohexanone and Ethyl pyruvate can be heated without a solvent to form a mixture of condensation products. 10. Process for the preparation of p-isobutylhydratropic acid ', characterized in that ethyl a- [2- (5-isobutyl) cyclohexanone] ethyl lactate with fyridine hydrochloride or with a hydrochloride -of other organic bases to 220 "to 230 is heated. 11. Process for the production of p-isobutylhydfatropic acid, characterized in that the mixture of condensation products according to claim 9 to 220 to 2J0 ° with fyridine hydrochloride or heated with the hydrochloride of other organic bases. 12. Process for the preparation of 6-isocutyl-5-methyl-2,4,5,6-tetrahydro-benso- [b] -furan-2-one, characterized in that 609830/0867 COPY ΛΖ - 3-isobutyl-cyclohexanone and pyruvic acid or sodium pyruvate or iithylpyruvate in a solution of HCl and acetic acid be heated. 13 Process for the production of ρ-isobutylhydratropic acid, characterized in that 3-isobutyl-cyclohexanone and Pyruvic acid or ratriutupyruvate or iithylpyruvate in a solution of HCl and acetic acid to form a mixture of condensation products. 14-. Process for the production of p-isobutylhydratropic acid, characterized in that 6-isobutyl ~ 3-methyl-2,4-, 5,6-tetrahydro-benzo- [b] -furan-2-one 4 to 5 hours at -230 ° with pyridine hydrochloride or with a mixture of Ilydrochloriden is heated by organic bases. 15 process for the preparation of p-ioobutylhydratropic acid, characterized in that the mixture of I condensation products according to claim 13 4 to 5 hours with i-yridine hydrochloride or heated with mixtures of hydrochlorides of pyridine bases. 16. Process for the preparation of p-alkylhydratropa acids, characterized in that 5-alkyl-cyclohexanone to 220 up to 23Ο ° with tartaric acid in the presence of a suitable, acidic condensing agent is heated. 6098 30/0867