DE719438C - Process for the preparation of alkylated 2-dialkyl-6-oxychromanes - Google Patents

Description

Process for the preparation of alkylated 2-dialkyl-6-oxychromanes It is known that alkylated 2-dialkyl-6-oxychromanes can be prepared by condensation of ß-dialkylallyl carbinols or halides with alkylated hydroquinones which have at least one hydrogen atom in the benzene nucleus (Helvetica Chimica Acta, Vol . 21 [19381 p. 52o; Vol. 22 [19391 pp. 337 and 61o; Nature, Vol. I: .1.2 [1938] p. 36; Journal of the Chemical Society, London [1938] p. i382). The same compounds are obtained in an analogous manner from allcylated hydroquinones and dienes (Science, Vol. 88 [1938] p. 37; Journal of Organic Chemistry, Vol. 4 [1939] p. 3i1). It is also known that 2-dialkyl-6-oxychromane with the simultaneous action of a mixture of two Grignard reagents on 5, 7, 8-trimethyl-6-oxy-2, 3-dihydrocoumarin and by action of a simple Grignard reagent on the oxidation product of 2, 5, 7, 8-tetramethyl-6-oxychroman formed (reports of the German chemical society, Volume 7 1 [1938 1 p 2637; Vol. 72 [1939] S. 1653rd).

It has been found that dialkylethinyl carbinols or their halides and alkylated hydroquinones with at least one vacant site in the core acidic condensation agents to form bicyclic condensation products, 2-dialkyl-6-oxychromenes (3, 4), to be united. These condensation products take in the presence of a suitable catalyst, such as palladium carbon, palladium calcium carbonate or platinum oxide, easily i mole of hydrogen. The hydrogenated products have the right properties with the 2-dialkyl-6-oxycfhomanen.

The implementation will likely proceed according to the following scheme: R means hydrogen or alkyl, R 'means Allcv I.

Due to the previously unknown condensation of dialkylethinyl carbinols with alkylated hydroquinones, which have at least one hydrogen atom in the benzene nucleus carry., a new body class, namely the 2-Diä.lkylci-oxychromene (3, .4) easily accessible preparatively. Surprisingly, it has been shown that these compounds are biologically active; they develop a vitamin E effect that is just as strong as that hydrogenated condensation products. Protection is claimed for the production the 2-dialkyl-6-oxychromene (3, [) according to the first part of the process described per se.

The hydrogenation of these condensation products represents a new process for the preparation of 6-oxychromanes. Trimethylhydroquinone is selected as the reaction components and 2, 6, io-trimethyl-14-äthinylpentadecanol (1.I) are obtained after hydrogenation of the condensation product d i-a-tocopherol (vitamin E).

Among the compounds which can be obtained according to the present invention, the tocols are particularly valuable because they are able to exert the effects of natural vitamin E. So far, only phytol isolated from natural substances and derivatives thereof (phytyl halides, phytadiene, i, 3-dibromophytane) or synthetic phytol or derivatives produced therefrom have been used to represent these tocols. The isolation of the phytol has to be done in a very laborious process and requires very large amounts of chlorophyll-containing plant materials and solvents. The phytol obtained in this way is antioxidant and polymerizes during storage, which makes its usability considerably more difficult: The previously known processes for the synthesis of phytol are very laborious; the last reaction stages proceed with very unsatisfactory yields (Hefvetica Chimica Acta, 13d.22 [1939] p. 61o; Annalen der Chemie, ISd. 475 [1929] p.183). These detriments are avoided by using the present method.

The dialkyl-6-oxychromane are crystallized compounds or almost colorless, viscous oils. They reduce ammoniacal silver nitrate solution immediately and neutral metal / alcoholic silver nitrate solution when heated: In potentiometric titration finite gold chloride (Helvetica Chimica Acta, 15d. 21 [1938J p. 939) the consumption of () xvdation average is the 2 H atoms equivalent amount. Example 1 3 parts of trimethylhydroquinone, 2 parts of anhydrous zinc chloride and 10 parts of decahydronaphthalene are heated to 150 ° while stirring and while passing in carbonic acid. 6 parts of 2,6-io-trimethyl-14-äthinylpentadecanol (14) (shown according to Fisc her and Löwenberg, Annalen der Chemie, Vol. 475 [1929] p. 195) are added dropwise and the mixture is then stirred at 150 ° for 2 hours . After cooling, water and petroleum ether with a boiling point of So to 70 ° are added, the petroleum ether solution is washed in sodium hydroxide solution, in hydrochloric acid and water and dried with sodium sulfate. The solution is then adsorbed on an aluminum oxide column and the chromatogram is developed with a large amount of petroleum ether. There are three zones on the column: a narrow, brown upper layer, a gray main zone and a yellow ring. Elute the gray main zone NIIT a Misghung of lIethylalkohol and ether (3: 1) and the solvent Verdam p ft. The extract is a very oxidation-sensitive, brownish 151, which reduces neutral methyl alcoholic silver nitrate solution and splits off a sublimate of durohydroquinone during thermal decomposition.

This extract of the gray main zone is dissolved in ten times the amount of ethyl acetate and shaken with hydrogen in the presence of a palladium-carbon catalyst at room temperature without the use of pressure, with 11o1 of hydrogen being taken up. The catalyst is then filtered off, the ethyl acetate is evaporated, the hydrogenated condensation product is dissolved in petroleum ether from boiling point So to 70 ° and filtered through a small magnesium sulfate column for purification. The filtrate is now adsorbed on an aluminum oxide column and the chromatogram is developed with a lot of petroleum ether boiling from 50 to 70 °. The almost colorless main zone in the uppermost part of the column is eluted with a mixture of methyl alcohol and ether (3: i) and the solvent is evaporated. The extract, which is obtained in a yield of 1.5 to 2 parts, is a yellowish 01 n 'v -: t, 5 (; 6, which is identical to d, 1-a-Tocoph, erol (lielvetica Chimica Acta , Vol. 21 [1938J p. S20). 5 mg of the compound are biologically active on rats fed vitamin E-free nutrition.

Example e 4 parts of 2,6-Diinetliyl-io-Etliinylundecanol (io) (prepared according to Fischer and Löwenberg, Annalen der Chemie, Vol. 47 [1929] p. 189), 3 parts of trimethylhydroquinone, 2 parts of anhydrous citric chloride and 10 parts of decahydronaphthalene are heated to 150 ° for 3 hours while stirring and passing in carbonic acid. After cooling, water and petroleum ether with a boiling point of 50 to 70 ° are added, the petroleum ether solution is washed with sodium hydroxide solution, hydrochloric acid and water, dried with sodium sulfate and the solution is concentrated. The residue is taken up in methyl alcohol and shaken with hydrogen in the presence of a palladium-carbon catalyst at room temperature without pressure. The catalyst is then frozen off and the methyl alcohol evaporated. The hydrogenation product is dissolved in petroleum ether with a boiling point of 50 to 70 °, it is adsorbed on an aluminum oxide column and developed - the chromatogram with a large amount of petroleum ether. The gray main zone is eluted with a mixture of methyl alcohol and ether (3: i). After driving off the solvent, the extract is rectified by molecular distillation. The middle fraction is a yellow oil, n 2D `1,515, which is identical to 2, 5, 7, 8-tetramethyl-2 (q .'- 8'-dimethylnonyl) -6-oxychroman (Helvetica Chimica Acta, Vol. 21 [ 1938] p. 1623). Yield: 1.5 parts. Example 3 3 parts of trimethylhydroquinone, 2 parts of anhydrous zinc chloride and 10 parts of decahydronaphthalene are heated to 150 ° with stirring and while passing in carbonic acid. 2 parts of methylbutynol are added dropwise (represented by the condensation of sodium acetone and acetylene) and then stirred for 3 hours at 150 '. The condensation product is taken up with a lot of Pctrolether from the boiling point 50 to 70 °. - Wash with sodium hydroxide solution, hydrochloric acid and water, dry with sodium sulfate and adsorb on an aluminum oxide column. The gray main zone is eluted with a mixture of methyl alcohol and ether (3: 1), the solvent is evaporated and the residue is hydrogenated in a methyl alcohol solution in the presence of a palladium-calcium carbonate catalyst. After the catalyst and the solvent have been removed, the hydrogenation product is taken up in a large amount of petroleum ether and filtered through a layer of dry magnesium sulphate. When the filtrate is concentrated, 0.5 parts of 2, 2, 5, 7, 8-pentamethyl-6-oxychroman crystallize in beautiful crystal flakes with a melting point of 93 °. Example 4 ro parts 2, 6, io-trimethyl-i4-äthinylpentadecanol (14) are dissolved in 20 parts of dry petroleum ether, the liquid is cooled to -15 ° and a solution of 10 parts of phosphorus tribromide in 10 parts of absolute petroleum ether is added dropwise with stirring. At the same time, a dry stream of CO 2 is passed through the reaction vessel. The temperature of the solution is kept below -5 °. The reaction mixture is then left to stand at room temperature for 12 hours, then poured onto ice and etherified. The ether extract is washed successively with n-soda solution, n-hydrochloric acid and with water; Any emulsions that occur can be destroyed by adding a little ethyl alcohol. After drying the ether extract with sodium sulfate, the solvent is evaporated and the bromide in the form of an almost colorless oil. 7.5 parts of this bromide are heated with 1.7 parts of trimethylhydroquinone and 2 parts of anhydrous zinc chloride in 5o parts of dry petroleum ether from the boiling point 6o to 80 ° for 1 hour on a water bath on a reflux condenser. After one hour, when the intensive evolution of hydrogen bromide has subsided, the reaction mass is poured onto ice, ether is extracted, the ether solution is dried and the solvent is evaporated.

The residue is chromatographed on aluminum oxide from petroleum ether solution. The eluates of the middle layers result in saturation when processed for allophanate the benzene solution with cyanic acid) about 0.5 parts d, 1-3, 4-dehydro-a-tocopherol allophanate, which can be recrystallized from alcohol and from acetone. Melting point 163o.

By saponifying the allophanate for one hour with n-alcoholic Potassium hydroxide solution gives the free d, 1-3, 4-dehydro-a-tocopherol as a viscous oil. This is obtained from the hydrogenation in the presence of a palladium-carbon catalyst d, 1-a-tocopherol.

Example s 3 parts of 3,5-dimethyl-2-ethylhydroquinone are in 10 parts Decahydronaphthalene with i part of anhydrous zinc chloride with stirring and. heated to 170 ° while passing in carbonic acid. One drips in the course of a Hour 6 parts of 2, 6, io-trimethyl-14-äthinylpentadecanol (14) and stirred thereupon another hour at 170 °. After cooling, the condensation products are absorbed in petroleum ether from the boiling point 5o to 70 °, with dilute sodium hydroxide solution, Washed hydrochloric acid and water, dried with atrium sulfate and attached to an aluminum oxide column adsorbed. When developing the chromatogram with a lot of petroleum ether, a brown, upper zone, a wide, build main layer and a small, lower, yellow one Zone. By eluting the middle main zone, the 5, 7-dimethyl-8-ethyl-3, a-dehydrotocol in a yield of 2.5 parts as a brownish, viscous C51.

In the catalytic hydrogenation with a palladium-carbon catalyst in alcoholic solution, the compound takes up 1 mol of hydrogen. Working up the reducing solution yields the well-known 5, 7-dimethyl-8-iithyltocol (Helvetica Chimica Acta, vol. 22 [1939] p.656), which is characterized by the allophanate from 170 to 171 °. 15 mg of 5, 7-dimethyl-8-ätliyl- (3, 4) -dehydrotocols are fully biologically effective in the vitamin E-free fed rat.

'Example 6. 2 parts of 3, 5-Dimetliy lhydroquinone are heated to 170 ° in 10 parts of decahydronaphthalene with iTeil, anhydrous zinc chloride. With stirring and introduction of carbonic acid, 3 parts of 2,6-io-trimethyl-i4-ethinylpentadecanol (14) are added dropwise and the reaction mixture is stirred at 170 ° for a further 1/2 hour. After cooling, the reaction products are taken up in petroleum ether as in Example s, washed and purified by chromatographic adsorption on aluminum oxide. The extract of the eluate of the middle gray main zone is hydrogenated in a methyl alcoholic solution with palladium carbon and then acetylated for purification with acetic anhydride and fractionated in a high vacuum. A small forerun, which passes below 200 ° at 0.1 mm, is discarded. The main amount, acetyl-5, 7-dimethyltocöl, distills at 0.1 mm and 225 ' as a yellowish, viscous C51. Yield 0.5 parts: The well-known 5, 7-dimethyltocol is obtained therefrom by saponification with 5% alcoholic sulfuric acid (Helvetica Chimica Acta, Vol. 21 [19381 S-1239). Allophanate of the F. i5o °.

Claims (1)

PATENT CLAIM: Process for the preparation of alkylated 2-dialkyl-6-oxychromanes, characterized in that alkylated hydroquinones with at least one vacant position in the core are converted to dialkylethinyl carbinols of the general formula in the presence of acidic condensing agents in which R and R 'are alkyl radicals, or their halides can act and the resulting alkylated 2-dialkylcliromenes are hydrogenated.