US2007813A - x--- x x x x - Google Patents

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ffflrhoenss'ron PATENT OFF-ICE PRODUCTION OF I LACTONES 1 Georg Scheuing and Bruno Walach, Nieder- Hngelheim-on-the-Rhine, Germany, assignors to C. H. Boehringer Schn Aktiengesellschaft, Nieder-llngelheim-on-the-Rhine, Germany, a.

corporation of Germany its Drawing. Application May 11, 1931, Serial No. 536,652. In Germany May 17, 1931) 10 Claims. (01. 260-423 This invention relates to a process for the production 1 of hydro-aromatic gamma-lactones.

Gamma-lactcnes are of importance,"because.

many of them occur in nature as physiologically active substances, thus for example, santonin contains the gamma-lactone group. Thus, for example, also the action of santonin on intestinal parasites has been ascribed to its lactone group. 7 'ainmalactoneysuch as, for example,

Simple yereindeedelso examined for their amhelrmntic actionj They have, however, been iound to he of n o tl erapeutic importance.

i I u'nd faccordfing to this invention that gammaones possessing a-santonin-like action and he ingthe generaltformula r R3o1i o\ cof R2;-oH-.-o A

"(wherein represents hydrogen 'or alkyl, R2 and "R c'arbon radicalswhich-areclosed up into hy-' droaromatic-ring systems) can be produced'by heating beta-hydroxyracid esters of the type cooRi (wherein Rig-R 'and'Rs'have the same meaning as "inF rmula -I, R4 is analliyl group) with mineral a-cids such for 'example, sulphuric acid or 'hydrobr'om-icaoid "The"'hetahydroiiy-acid esters of the type II serving as the initia-l'material, may be obtained in knownf manner according to the Reformatsky synth e s fromhalogen fatty acid esters, ketones "such for example'those with hydro-aromatic ,I By 'an lexhaustic investigation it has now been gen fattyacid esters and zinc and which possess the structure The gamma-lactones of decahydronaphthalene so obtained are particularly close to santonin in their constitution.

In the conversion of the said beta hydroxy-acid esters into the gamma-lactones according to this invention, the esters are probably first converted by a splitting out of water into the unsaturated esters and thereafter thesefare saponified into {the beta-gamma-unsaturated' acids, which by again adding on water are converted into the gamma-hydroxy-acids which can then undergo lactone formation. Quite possibly the" individual reaction stages are passed through in other sequences'or also take place side by side.

instead 01" conv'erting the betaehydro'xy-acid ester into the lactone direct by treatment with 3 mineral acid in the warm, the reaction can be effected in stages for example. so that the'betahydroXy-acid ester is converted by water splitting-out agents into the unsaturated ester which, by saponification, is converted into the free acid and ultimately by treatment with mineral acid'in the warm, into the lactone. 1

The concentration of the acid employed for the lactonization depends upon the solubility of the beta-hydroxy acid ester employed, and in particular upon thereaction temperature. At the boiling temperature, iorexample, a moderately concentrated sulphuric acid of about -60%, suffiCGS for complete lactonizatiom whereas at,50 50 C. it is necessary to employ an -85% sulphuric 1 acid. In like manner also if other acids, for example, hydrobromic acid, are employed, higher treatment temperatures are necessitated by lower concentrations of acid. ;55

simply isolated.

The lactones obtained according to the invention are insoluble in soda and ammonia, are split up by lyes and then yield on acidification the corresponding gamma-hydroxy-acid. The gammalactones can be regenerated therefrom, whereby these compounds are recognized as analogues of the already known gamma-lactones.

The conversions according to the present invention are illustrated by way'of example by the grams alpha-octahydronaphthyl-2-proplonic acid are mixed with 200 cos. of 70% sulphuric acid and the clear solution warmed gently for some time, whereby lactonization takes place under slight self-warming. The solution thereby becomes turbid and after dilution with ice the lactone which has separated is shaken out with ether or benzene and the ether or benzene solution removed from the almost non-lactonlzing following structural formulae:- acid by washing with diulte soda solution. '17

I?! Iii:

Saponiiication H; H: Splitting out of water H:-

\ u H C Cor-R4 H2\ C-CO2-R4 08) R1 H 1 11 1 H1 H2 alpha(1hydroxycyclohexyl1)fatty acid ester.

$2 I IIz /OH a H:- H H:-

Addition of water H Ring closure (B) (a) H COO1H Hz 0-0011?! \H R; H R, H H: H:

alpha-(2-hydroxycyclohexyll)-fatty acid.

grams of the theoretical) of the gammalactone of alpha-(I-hydroxy-decahydronaphthy1-2) -a1pha-methy1-acetic acid of boilin! point 145 C./0.6 mm. are obtained. If the above-mentioned hydroxy acid ester or 3 R1 11 unsaturated ester are treated under like conditions with 70% sulphuric acid, there is likewise Lactone. R1=H or Alkyl- R4= y obtained the gamma-lactone described. The

The gamma-lactones obtained according to the process of the present invention may be employed as agents against animal parasites, for example as anthelmintics; and as agents for destroying noxious pests and the like.

Compounds possessing a constitution like santonin have indeed already been produced, but according to the known processes, for example by .double decomposition of alpha-halogen ketones contrast to these troublesome processes, the process according to the present invention provides the gamma-lactones of the kind hereinbefore described easily and in a formin which they can be Examples 1. '76 .grams of 2-keto-decahydronaphthalene /z mol.) are decomposed with about 50 grams of zinc borings and 84 grams of alpha-brompropionic acid methyl ester (:Vg mol.) in a benzene-ether solution according to Reformatsky. There are obtained grams (92% of the theoretical) of alpha-(2-hydroxydecahydronaphthyl- 2)-propionic acid methyl ester of boiling point 128 C./0.6 mm. By treatment with water splitting out agents there are obtained from 110 grams of this hydroxy-ester by a lengthy distillation with about 70 grams of potassium bisulphate, 95 grams (93% of the theoretical) of alpha-(octahydronaphthyl-Z) -propionic acid methyl ester of boiling point C./ 13 mm. By saponification with aqueous-alcoholic alkali there are obtained 85 grams (95% of theory) of alpha-octahydronaphthyl-2-propionic acid of boiling point 143 C./0.9 mm.

gamma-lactone is sparingly soluble in water, whereas it is easily soluble in almost all organic solvents. The barium salt of the corresponding hydroxyacid alpha (1-hydroxy-2-deca-hydronaphthyl) alpha-methyl acetic acid of boiling point 153 C./0.9 mm. can be obtained from the gamma-lactone by saponification with barium hydroxide. By treatment with acid the original gamma-lactone can be regenerated. The structural formula may be expressed as follows:

2. '75 grams of alpha-(l-hydroxycyclohexyl- 1) -butyric acid methyl ester (of. Wallach, Annalen vol. 360, pages 44-81) are dissolved in 300 cos. of 70% sulphuric acid under gentle warming. After some time the solution becomes turbid with a slight darkening of the colour. After an hour it is entered into ice. The oil which separates out is taken up in benzene, the benzene solution is washed with soda and dried. The residue from the benzene solution distils at 15 mms. between 141-145-147 C. There are obtained 53 grams of the gamma lactone of alpha-(Z-hydroxycyclohexyl-l) -,butyric acid. 7

The product has the following formula:

7 a The lact'one is insoluble insodasandfiammo'nia but in the presenceof some alcohol easily-converted' bybarium hydroxide into thesaltof alpha (cyclohexanol-Z) -butyric acid. This boilsiunder 0.6 mm, pressure at 108C. and is easily further converted by mineral acids back into the lactone.

Under like conditions" the walplna-(AA-cyclohexenyl-l) -butyric acid methyl ester is converted into the lactonei ester is obtained by intro- I" Y C2115 3. '70 grams of alpha-(lshydroxycyclohexyl- 1)-acetic acid methylester (0.4 mol.) is allowed to flow into 250 cos. of gently boiling-% hydrobromic acid. Splitting out of water, saponification of the ester and lactonization take place with evolution of methyl bromide. By employing concentratedhydrobromic acid (50-60%) a temp'eratureQbffiQfBDHC... sufiices for effecting the reaction. When the ev'olutionof methyl bromide subsides the lactonization is complete. There is obtained 42 grams of an oil of boiling point 130 C./ 12 mm. which is insoluble in sodium car-1 bonate. The yield is 75% of the theoretical. The

purity of the product is demonstrated by treating it with barium hydroxide and splitting out water from the gamma-hydroXy-acid by warming with dilute sulphuric acid and thus converting itback again into the lactone. The yield is, 40 grams (=95% of I the theoretical) and the boiling point 130 C./ 12 mm. The lactone of the alpha- (2-hydroXycycloheXyl-1-)acetic acid (=gammalactone of o-hydroxyhexahydrophenyl acetic acid) is very easily soluble in organic solvents, is appreciably soluble in water and possesses the characteristic lactone odour. The corresponding gamma-hydroXy-acid is almost insoluble in benzene. The product has the following formula:-

4. 93 grams of alpha-(l-hydroxycyclohexyl-l) propionic acid methyl ester mol.) is introduced into 300 ccs. of gently boilng 50% sulphuric acid under stirring. After a short period of warming the solution is diluted and the lactone taken up in benzene. The yield of the lactone which is insoluble in sodium1carbonate amounts to 53 grams (32% oithe theoretical) of boiling point 130 C./1lmm. After conversion with baryta to the gamma-hydroxy acid and again lactonizing 61 grams of gamma-lactone of the alpha- (Z-hydroxycyclohexyl-l) -propionic 'acid are obtained (=97% of the theoretical).

1 The boiling: point is-130 has the following formula:

5. 93 grams of alpha-(Lhydroxycyclohexyl-l) propionic acid methyl ester mol.) are dissolved at 60-70 C. in 200 cos. of 85% sulphuric acid, after a short time the solution is diluted and worked up as in Example 4. The yield is 71 grams (92%=ofthe theoretical) of gamma-lactone of the alpha-(Z-hydroxycyclohexyl-l)-propionic acid. The boiling point is 130 C./ 10 mm. The product has the following formula:

What we claim is: 1. A process 'forthe direct production of gamma-lactones of the general formula, Type 1,:

Ra-C H-0 wherein R1 represents a member of the group consisting of hydrogen and alkyl, and R2 and R3 represent carbon radicals which are closed up jointly into hydroaromatic ring systems of not more than two rings which comprises heating in the presence of a non-oxidizing, strong mineral acid, beta-hydroxy acid esters of the general formula, Type II,

wherein R1 to R3 have the same meaning as in Formula I and R4 is an alkyl group to effect their conversion into gamma-lactones of the aforesaid type.

2. A process as claimed in claim 1, wherein the beta-hydroxy acid esters of the Type II are converted by stages into the desired lactones by first converting them into the corresponding betagamma unsaturated acid esters by means of water removing agents, saponifying these and converting the acidsobtained into gamma-lactones by heating with non-oxidizing, strong mineral acids.

3. A process as claimed in claim 1, wherein the higher the treatment temperature the lower. is the concentration of acid employed.

4. A process as claimed in claim 1, wherein the lactonization is effected with sulphiu'ic acid.

5. A process as claimed in claim 1, wherein the substituents R2 and R3 of the general Formula II are closed up into a hexahydro-benzene ring so that alpha-(l-hydroxycyclohexyl-l) lower fatty acid ester is converted into the gamma lactone of alpha-(Z-hydroxycyclohexyl-l) lower fatty acid.

6. 'A process as claimed in claim 1, wherein the substituents R2 and R5 of the general Formula II are closed up into a decahydronaphthalene ring so that gamma-hydroxy acid esters of the type III E: H:

. OH H are converted-into -lactones of the type by heating with non-oxidizing, strong mineral acids. I

'7. As a. new compound, gamma-lactone having the general formula:

wherein R1 represents an alkyl, R2 and R3 represent carbon radicals which are closed up jointly into hydroaromatic ring systems of. not more than two rings.

9. As a new compound the gamma-lactone of the alpha. -(2 hydroxycyclohexyl 1) propionic acid having the following formula.

10. As a new compound gamma-lactone of the alpha (2 hydroxycyclohexyl- 1) butyric acid having the following formula:

GEORG SCHEUING. BRUNO WALACH.