DE2740041A1 - 5-Hydroxy-4,4-di:methyl-1,3-dioxan and its ester(s) - prepd. e.g. from Celastrus paniculatus seed oil and having psycho-pharmaceutical esp. memory enhancing activity - Google Patents

Abstract

New 1, 3-dioxan derivs. are of formula (I): where R is H, carbamoyl, the acyl residue of an (un) satd. aliphatic monocarboxylic acid, or the acyl residue of a pharmacologically innocuous aromatic, araliphatic, cycloaliphatic or heterocyclic carboxylic acid. Specifically claimed are (I) in which R is carbamoyl or the acyl residue derive from furone-(2)-carboxylic acid, nicotinic acid, stearic acid, linolenic acid, alpha-bromoisovaleric acid. (I) may be prepd. by (a) hydrolysing cold-pressed fatty oil from seeds of Celastrus paniculatus with 0.5-N KOH or NaOH (which may be alcoholic) acidifying, extracting with Et2O, evaporting water from the aq. phase, and obtaining the required cpd. from the residue in a conventional manner by distn. and esterification, or (b) reacting 1,1-dimethylglycerine with paraformaldehyde or one of its diacetals, sepg. the resulting isomer mixt. and opt. esterifying the resulting (I, R=H).

Description

Dioxane derivatives and processes for their production.

The present invention relates to dioxane derivatives of the general formula wherein R is a hydrogen atom, the acyl radical of a saturated or unsaturated aliphatic monocarboxylic acid, in particular the acyl radical of a saturated or unsaturated fatty acid with about 16 to 22 carbon atoms or the acyl radical of a phemacologically harmless aromatic, sraliphatic, cycloaliphatic or heterocyclic carboxylic acid, especially the furoyl (2) radical, the benzyol radical, the nicotinoyl radical, the campheroyl radical, the α-bromoisoranyleriaroyl radical or the carbamoyl radical, examples of suitable saturated fatty acids are stearic acid, palmitic acid, arachidic acid, nargaric acid and behenic acid.

Examples of suitable unsaturated fatty acids are oleic acid, linoleic acid, Linolenic acid and ricinoleic acid as well as mitoleic acid, petrosilic acid and erucic acid.

The compounds of the invention are valuable as psychotropic drugs. In particular, they have memory-stimulating properties, i.e. they serve to improve memory and learning.

The compounds of the invention can be obtained from oil obtained from the seeds squeezed by Celastrus paniculatus. This oil is made in Asian Countries and in India mainly used as fuel oil, but the oil counts in folk medicine also as mild nervinum.

The compounds can be obtained by cold-pressing fatty seed oil from Celastnus paniculatus with 0.5N, alcoholic if necessary Enlil.auge or caustic soda stranded, then acidified and shaken with ether, the water evaporates from the aqueous phase containing the dioxane compounds and the mined product is obtained from the residue in a known manner, where, when R of the formula is a hydrogen atom, the compound by distillation is obtained from the residue, and when R of the formula those given above Acyl radicals means the desired compounds by distillation from the residue and subsequent esterification of the compounds or first esterification of the residue and subsequent distillation of the esterified product can be obtained.

The saponification of the oil with 0.5 N, optionally alcoholic potassium hydroxide solution or sodium hydroxide solution is usually carried out at 80 to 100 ° C, working in a water bath will.

Any suitable acid can be used for acidification.

1 N hydrochloric acid is preferably used. The transfer of the free Alcohol into the corresponding desired esters is carried out according to known methods Method, e.g. according to Schotten-Baumann using the corresponding acyl halides in the presence of dilute alkalis or a tertiary amine or other customary Esterification process.

The compounds used according to the invention can also be based on synthetic Paths are made.

The synthetic process for making the compounds is thereby characterized in that 1,1-dimethylglycerol in a known manner with paraformaldehyde or one of its diacetals is converted, the mixture of isomers obtained is separated and optionally the compound obtained in this way in a manner known per se into the corresponding Ester converted.

The implementation is usually carried out without a solvent at temperatures of 150 up to 1600 C or in boiling absolute benzene. Preferably be per mole of 1,1-dimethylglycerol, 1.2 moles of paraformaldehyde or one of the diacetals, preferably the di-t-butyl diacetal is used.

The reaction can optionally be carried out in the presence of catalytic amounts p-Toluenesulfonic acid can be carried out.

The isomers are separated by customary methods, for example by fractional crystallization or distillation or by reaction with optical active partners.

The desired esters are obtained from the alcohol in accordance with known methods Procedure received.

The following examples serve to illustrate the present Invention.

Example 1 100 g of oil can be obtained from the seeds of Celastrus paniculatus saponified for 4 hours with 500 ml of 1 N alcoholic sodium hydroxide solution and then freed from alcohol by distillation in vacuo. The residue is dissolved in 400 ml of water added and extracted 4 times with ether. The saponification liquor is treated with 1 N hydrochloric acid exactly neutralized and then concentrated in vacuo. The residue (34.8 g) is digested with 80 m absolute methanol, the insoluble NaCl is suctioned off and twice washed with absolute methanol. The collected methanol extracts are concentrated, leaving 3m, 4 g of a slightly brown oil.

The oil is determined by means of preparative thin layer chromatography (SiO2 PF 254 (Merck): benzene / acetone 1: 1) separated.

The zone with an RF value of o.34 - o.38 is isolated.

1.5 g of the substance isolated from this clay (obtained from further Saponification reactions) is treated with 3.5 g of nitrobenzoyl chloride in pyridine. The reaction product (2.o g) is determined by means of preparative thin layer chromatography (SiO2 PF 254; benzene / ethyl acetate 9: 1) separated into three zones.

The second zone, the main fraction, (RF: o.5) is again using Separate dry column chromatography. The residue (after elution of the SiO2 with Ethyl acetate) gave, after recrystallization, 31 g of white crystals (melting point 79 ° -40 ° C.).

The analysis showed: found C: 47.85 io H: 4.36% N: 8.46X calc. for C13H14N2O4: C: 48.59%, H: 4.29%, N: 8.59% On the basis of NMR and mass spectrometry Data of the synthetic 1,3 dioxolane and 1,3 dioxane alcohols was made the Structure of the alcohol obtained from Colastrus oil as 414-dimethyl-1,3-dioxan-5-ol established.

Example 2 A) 300 parts of the oil obtained from the seeds of Celastrus paniculatus was pressed out in a known manner with 600 parts of 5N sodium hydroxide solution and t ooo parts of water saponified. Then it is boiled with about 1,000 parts Salt out the table salt and lift off the soap cake, which has solidified after cooling.

B) 300 parts of the oil obtained from the seeds of Celastrus paniculatus was squeezed, are in a known manner with 4,000 parts o, 5 N alcoholic Saponified caustic soda or caustic soda and then distilled off the alcohol in vacuo freed.

The saponification liquor obtained according to A or B is precise with hydrochloric acid neutralized, the excreted organic acids are filtered off and / or odorized To remove these acids, the lye is extracted with a maximum of 250 parts of ether. The aqueous alkali treated in this way is then evaporated in vacuo. The during the resulting precipitate is filtered off with suction, washed with a little alcohol, and the filtrate is freed from water as far as possible. The residue is 150 parts an alcohol / ether mixture digested and sucked off from the insoluble.

The filtrate is concentrated as much as possible and the residue in Vacuum fractionated. The fraction between Kp10 75 to 90 ° C mainly contains the 4,4-dimethyl-1,3 dioxan-5-ol, which by repeated distillation or by Recrystallize its ester is purified.

The pure 4,4-dimethyl] -1,3-dioxan-5-ol obtained in this way (yield approx. 20%) is characterized by Kp10 75 to 800 C.

Example 3 120 parts of formaldehyde diisobutyl acetal and 81 parts of dimethyl glycerin is used in the presence of catalytic amounts of p-toluenesulfonic acid for 25 hours heated to reflux.

The flask contents, which initially consist of two phases, are at the end of the Reaction homogeneous. At a vacuum of about 35 mm Hg will be at a boiling point from 40 - 70 ° C 110 parts isobutyl alcohol and unused formaldehyde diisobutyl acetal distilled off. The fraction Kp10 mm = 40 to 95 ° C contains 70 parts of a mixture from the desired 4,4-dimethyl-1,3-dioxan-5-ol and its two isomers.

The distillation residue (approx. 10-20 parts) contains higher molecular weight Shares and is discarded.

The 4,4-dimethyl-1,3-dioxan-5-ol is produced by distillation on a (spinning band) column obtained in pure form; Bp10 75 to 800 ° C, n2D50 = 1.4355, yield: approx. 35% of the Theory.

Example 4 The preparation of the esters as described above 4,4-dimethyl-1,3-dioxan-5-ols produced is carried out, unless otherwise stated, by reacting the acid chlorides in the presence of an auxiliary base in benzene or a other water-immiscible aprotic solvent at room temperature. After washing with water, the esters are in pure form. That way using the appropriate starting materials, the following esters were obtained manufactured: furan (2) carboxylic acid ester: Kp12 loo to 1o50 C nicotinic acid ester: M.p. 130 to 1350 ° C. stearic acid ester: M.p. 70 to 750 ° C. linolenic acid ester: solidified at -2o0 C α-bromoisovaleic acid ester: bp17 1o5 - 1070 C. example 5 The D-camphoric acid a (or o) -ester (1,2,2-trimethyl-cyclopentanedicarboxylic acid- (1,3) -1-ester) is made by treating the sodium salt of 4,4-dimethyl-1,3-dioxan-5-ol with camphoric anhydride manufactured in benzene and has a melting point of 175 to 176 ° C.

Example 6 4,4-Dimethyl-1,3-dioxan-5-ol is known per se Way implemented with NH3 and phosgene. The carbaminate has a melting point of 12o 1230 C.

Claims (9)

Patent claims 1.) Dioxane derivatives of the general formula in which R is a hydrogen atom, the aryl radical is a saturated or unsaturated aliphatic monocarboxylic acid or the acyl radical of a pharmacologically acceptable aromatic, araliphatic, cycloaliphatic or heterocyclic carboxylic acid or the carbamoyl radical. 2.) dioxane derivatives according to claim 1), characterized in that R the acyl radical of a saturated or unsaturated fatty acid with about 16 to 22 carbon atoms means. 3.) Furon (2) carboxylic acid (4,4-dimethyl-1 5-ol) ester. 4.) Nicotinic acid (4,4-dimethyl-1,3-dioxan-5-ol) ester. 5.) Stearic acid (4,4-dimethyl-1,3-dioxan-5-ol) ester. 6.) Linolenic acid (4,4-dimethyl-1,3-dioxan-5-ol) ester. 7.) α-Carbamic acid (4,4-dimethyl-1,3-dioxan-5-ol) ester. 8.) Carbamic acid (4,4-dimethyl-1,3-dioxan-5-ol) ester. 9.) Process for the preparation of the compound according to claim 1) to 8), characterized in that either a) cold-pressed fatty oil from the Seeds of strain paniculatus with 0.5 N, possibly alcoholic, potassium hydroxide solution or caustic soda saponified, then acidified and shaken out with ether, from the watery phase Water evaporates and from the residue in a known manner the desired pre-binding is obtained by distillation and esterification, or b) 1,1-dimethylglycerol in a manner known per se with driving formaldehyde or one of its diacetyls, the isomer mixture obtained separates and, if appropriate, the compound obtained in the process invested in a manner known per se. 1 a) Medicinal product characterized by a preservation of compound according to claim 1) to 8).