DE2820861A1 - CHROME DERIVATIVES - Google Patents

Description

Patents n-.v ι'fö

O ^r . Franz ι. :: * r

DipL'inn ΐι? Κν ■. tv--. : -y3r

8000 fviün.-hsn t: u

ÜJdle-Grahn-Str. 22- Tu. (Ü3yj ·. ·· - J * '

:?. May 1978

RAN 4213/80 K-Oil

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Chroman derivatives

The present invention relates to new chroman derivatives of the general formula

CH ₃

CH ₃

where IL is hydrogen or hydroxy, as well as their production.

The compounds of the formula I can be prepared by using a compound of the general formula

Cot / April 21, 1978

809847/0872

, ..! «■" CH ₃

i _
M.

or

where R and R "can be the same or different and mean lower alkyl or R- phenyl and R _? Represent hydrogen and R., which has the above meaning,

treated with an acid.

The compounds of the above formula I are valuable intermediates in the production of vitamin E.

You can, with splitting off the hydroxyl group, if R_ is different from hydrogen, by reductive aromatization into the chroman derivative of the formula

CH ₃

, .. "'CH ₃

CH ₃

'CH ₂ OH

IV

CH ₃

be transferred.

The compound of the formula IV is known and can be converted in a known manner into the corresponding, likewise known Aldehyde of the formula

809847/0872

CH ₃

CH ₃

CH ₃

- 9 - S.

282086t

wherein R is lower alkyl, lower alkanoyl or represents benzyl,

be transferred. This aldehyde in turn can then, likewise in a known manner, for example by reaction with the Compound of formula

^{converted into natural (2R, 4 1} R, 8 ¹ R) -a-tocopherol under the conditions of the Wittig reaction and subsequent catalytic hydrogenation.

According to the invention, it is now possible to synthesize the optically active aldehyde of the formula V or the alcohol of the formula IV required for the production of natural (2R, 4 ¹ R, 8 ^{1 R) -a-tocopherol from a likewise optically active one} Starting material, while maintaining the absolute configuration at the tertiary carbon atom.

This offers considerable advantages over the previously known methods. In particular, that passed The problem with the previously known processes is that those in previous syntheses in the preparation of the above aldehyde initially obtained acid was always obtained in racemic form and only in an extremely complicated way into the optical

809847/0872

CH- (GlNAL [NSPcCTED

- 4T- k

Antipodes could be separated. Another disadvantage of this method is that the undesired antipode practically no longer racemized and can then be fed back into the process, which accordingly leads to considerable material losses. These disadvantages can now be avoided according to the invention.

In the context of the present invention, the term "lower alkyl" denotes alkyl radicals having 1 to 4 carbon atoms; atoms such as methyl, ethyl, propyl and isopropyl. The expression “Aryl” means in particular mononuclear radicals such as phenyl or lower-alkyl- or lower-alkoxy-substituted phenyl, such as ToIyI, XyIyI, mesityl, p-methoxyphenyl, and the like. from The inorganic acid anions are the chlorine, bromine and iodine ions or the hydrosulphate ion and the organic ones Acid anions, the tosyloxy ion is preferred. The term "lower alkanoyl" means carboxylic acid residues having 1 to 6 carbon; atoms such as formyl, acetyl, propionyl etc.

A compound of the formula II or III is converted into a compound of the formula I by treatment with an acid. Suitable acids that can be mentioned here are in particular mineral acids, such as dilute sulfuric acid, dilute hydrochloric acid, dilute phosphoric acid and the like as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and the same. The reaction also takes place, in particular in the case of using a mineral acid, expediently in one inert, water-miscible organic solvents such as lower alcohols, e.g. methanol, ethanol, propanol, etc., Ethers, e.g., dioxane, tetrahydrofuran, etc., diethylene glycol dimethyl ether, acetonitrile, dimethylformamide and the like at a temperature from about room temperature to about 100 ° C., preferably from about room temperature to about 70 ° C.

7/0872 ^^ _1NSPECTED

- • 5 "-

The compounds of the formulas II and III are new and likewise a subject of the present invention.

They can be prepared by taking a compound of the general formula

9 ^H 3 Fs

CH ₃

CH ₃

CH ₃

Vl

where E. is lower alkyl and IL, R «and have the above meaning
oxidized with a cerium (IV) salt or complex.

Cerium sulfate in particular can be used here as cerium compounds or cerium ammonium nitrate.

The oxidation is conveniently carried out in an inert water-miscible organic solvent such as acetonitrile, tetrahydrofuran and the like at a temperature of about -10 ⁰ C to about 4O ° C. Preferably, the oxidation is carried out at a temperature between about 1O ° C and about 30 ⁰ C.

If the above-described oxidation of a compound of the formula VI is carried out in an acidic medium, can this compound of the formula VI can be converted directly into a compound of the formula I.

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A compound of the formula I is converted into a compound of the formula IV by reductive aromatization. If R _{3 is} hydrogen, the reaction is conveniently carried out by means of hydrogen in the presence of a catalyst, such as palladium or platinum, with or without a support, and by means of complex hydrides, for example lithium aluminum hydride, diisobutyl aluminum hydride, NaAlH ₃ (OCH ₂ CH ₂ OCH ₃ ) "and the like, in a suitable organic solvent or by means of zinc in acetic acid and the like. If R _{3 is} hydroxy, the reaction is expediently carried out with prior elimination of the hydroxy group. This elimination can be achieved by treatment with hydrogen in the presence of a catalyst such as palladium, with or without a support material, and in the presence of a catalytic amount of a mineral acid that does not poison the catalyst, e.g. perchloric acid, hydrochloric acid and the like, or in the presence of a strong organic acid, e.g. Toluenesulfonic acid and the like. The compound of lOrmel obtained after the hydroxyl group has been split off

I ^ ¹ I L .-- ' ^CH 3

CH ₃

spontaneously converts in the presence of oxygen into the compound of the above formula III, in which R “denotes hydrogen. The further conversion into the compound of the formula IV then takes place as indicated above.

The previously described guide for the connection of the formula I, in which R_ denotes the hydroxyl group,

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- sr - 3

in those compounds of the formula IY can also im "One-pot processes" i.e. without isolating each of the formed Intermediate products of the formulas IHa, III and I, in which R is hydrogen, are carried out.

The compounds of the above formula VI can, depending on the meaning of the substituent IU, according to scheme I or II getting produced. According to Scheme I, those compounds produced, where ß "means hydrogen.

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R ₄ O

COOR ₅

i CH ₃

^r C00H

VII

COOR ₅ 'CH ₃

CH ₃

Xl

CH ₃ R ₃

Scheme I.

CH ₃

ß 40

OOR ₅
L.

VIII

COOR ₅
L-CH ₃

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IX

- S "-
-W

In this scheme, the substituents R, R, and R is as defined above and the radicals R. benzyl, R ₅ is a lower alkyl group, X is aryl and Y is the anion of an organic or inorganic acid.

According to the following scheme II those compounds prepared, wherein R_ represents the hydroxy group.

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- OA scheme II

XIV

CH ₃

CH ₃

9 ^H 3

MgBr

Mr

XVI

CH ₃ R ₅

RO

, "In'C H ₃

VI

CH ₃

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In this scheme the substituents R, R, and R have ~ the meaning given above.

The compounds of the formula VII used as starting material in Scheme I are known. The compounds of formulas VIII, IX ₇ X, XI and XIII are novel compounds and, as such, also subject of the present invention.

The conversion of a compound of the formula ViI into a Compound of the formula VIII can be made in a manner known per se, for example by reaction with thionyl chloride in an inert organic solvent such as dimethylformamide or an ether at a temperature of about OC up to about 40 ° C. and subsequent reduction of the acid chloride obtained, for example with sodium borohydride in dimethylformamide.

The conversion of a compound of the formula VIII into a compound of the formula IX, ie the splitting off of the benzyl group: R ₄ , can likewise take place in a manner known per se. Purpose-J this splitting off is carried out by catalytic hydrogenation. An organic solvent which is inert under the reaction conditions is expediently used as the solvent, such as ethyl acetate, methanol, ethanol and the like, and a palladium / carbon catalyst is expediently used as the catalyst. '

The conversion of a compound of the formula IX into a compound of the formula X can be carried out in a manner known per se, for example by reaction with a 2,2-di-lower alkoxypropane such as 2,2-dimethoxypropane or a di-lower alkyl ketone such as acetone or with benzaldehyde, in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, phosphorus oxychloride, sulfuric acid and the like, and at a temperature of about 0 ⁰ C to about 50 ° C.

ORlGiHAL INSPECTED

809847/0872 - ""

2820881

-VL-

A compound of the formula X can be converted into a compound of the formula XI directly and in a manner known per se. Suitably, this is done with diisobutylaluminum hydride in an inert organic solvent such as an ether, hydrocarbon such as hexane and the like, and at a temperature of about -60 C to about -80 ⁰ C.

A compound of the formula XII can be converted into a compound of the formula XIII in a manner known per se be carried out, primarily by reaction with triphenylphosphine in toluene or benzene.

The reaction of a compound of formula XI with a compound of formula XIII to form a compound of the formula VI in known manner, to a position indicated by Wittig \ operation. The components | in the presence of a strong base, for example in the presence of a '. Alkali metal alcoholates, such as sodium methylate, or in the presence] of an optionally alkyl-substituted alkylene oxide, in particular in the presence of ethylene oxide or 1,2-butylene oxide, optionally in a solvent, for example in a chlorinated hydrocarbon such as methylene chloride, or in dimethylformamide, in one between room temperature and the temperature range lying below the boiling point of the reaction mixture reacted with one another.

The compounds of the formulas XIV and XVI used as starting material in Scheme II are known, or analogues are more known Compounds which can easily be obtained in a manner analogous to the preparation of the known compounds. The compound of the formula XV, on the other hand, is new and likewise a subject of the present invention. ;

A compound of the formula XIV can be converted into an aldehyde of the formula XV in a manner known per se. The reaction is expediently carried out by means of an oxidizing agent such as chromium trioxide in pyridine or pyridine-chloro

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chromate and the like in an inert organic solvent such as chloroform, methylene chloride, pyridine, etc. and at a temperature of about ⁰ ° C. to about 40 ^° C.

The reaction of a compound of the formula XV with a compound of the formula XVI is also carried out in a manner known per se, expediently in an organic solvent which is inert under the reaction conditions, such as an ether, for example diethyl ether, tetrahydrofuran and the like, and at a temperature between
of the reaction mixture.

a temperature between about 0 C and the reflux temperature

The temperature data contained in the following examples are in degrees Celsius.

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example 1

Production of ethyl (R) - ^ -
methyl propionate

To a solution of 34.2 g of ethyl (R) -2-benzyloxy-2-methyl-monomalonate in 60 ml of methylene chloride was added dropwise 11 g of dry dimethylformamide with stirring at 5 followed by 11 ml of freshly distilled thionyl chloride. The reaction mixture was then with exclusion of moisture left to stand for 20 hours at room temperature.

The volatile constituents were removed by distillation at 80 °, first at 12 torr and then at 0.1 torr. The remaining liquid was finally distilled at 120 ° and 0.08 torr, 33.4 g of a colorless oil being obtained. A solution of 3.05 g of sodium borohydride in 50 ml of dry dimethylformamide was added to this oil at -30 dropwise and with stirring over 45 minutes. The mixture was then stirred for a further 3 hours at room temperature. 5 ml of 1N sodium bicarbonate solution was added dropwise with stirring, followed by 10 g of solid sodium bicarbonate, and stirring was continued for 1 hour. The reaction mixture was then filtered, the residue was washed with 90% strength dimethylformamide and most of the solvent was removed from the filtrate. The remainder was taken up in 250 ml of ether and washed twice with 100 ml of distilled water each time and then with 50 ml of saturated brine. After removing the solvent, impurities were distilled off at 120 ° / 0.1 mmHg and 22 g of ethyl (R) ^ -benzyloxy-S-hydroxy ^ -methylpropionate, [a] _n = + 2.57 ° (undiluted) were obtained.

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Example 2

Production of ethyl (R) -2,3-dihydroxy-2-methylpropionate

22 g of ethyl (R) ^ -benzyloxy ^ -hydroxy ^ -methyl-propionate (prepared according to Example 1) in 150 ml of ethyl acetate were mixed with hydrogen gas in the presence of 11 g of 5% palladium / Coal catalyst hydrogenated until hydrogen uptake ceased. The catalyst was filtered off, washed with ethyl acetate (2 χ 50 ml) washed, the filtrate was concentrated in vacuo and the remaining oil was distilled at 56-57 ° / 0.1 mmHg 12.7 g of ethyl (R) -2,3-dihydroxy-2-methyl propionate in Form of a colorless viscous liquid, [cc] = + 0.339 ° (undiluted) ; = + 11.6 ° (c = 2.12 in chloroform).

Example 3

Production of ethyl (R) -2,2,4-trimethyl-1,3-dioxolane-4-carboxylate

500 mg of p-toluenesulfonic acid were added to 10.7 g of ethyl (R) -2,3-dihydroxy-2-methylpropionate, dissolved in 35 ml of dry, freshly distilled 2,2-dimethoxypropane, and the mixture was added overnight stirred at room temperature. The excess dimethoxypropane was removed at 45 ° / 12 Torr and the residue was stirred vigorously for 30 minutes with 5 ml of 1N sodium carbonate. 150 ml of ether were then added, the aqueous phase was separated off, the ether solution was washed with saturated brine and then dried over sodium sulfate. After evaporation of the solvent, the product was distilled and 11.2 g of ethyl (R) -2,2,4-trimethyl-1,3-dioxolane-4-carboxylate were obtained in the form of a colorless liquid; Boiling point 81 ° / 15 torr. [cc] _D = -6.5 ° (c = 2 in ethanol); -9.13 ° (c = 2 in chloroform).

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Example 4
Preparation of (R) -4-formyl-2,2,4-trimethyl-1,3-dioxolane

To a solution of 5 g of ethyl (R) -2,2,4-trimethyl-1,3-dioxolane-4-carboxylate in 30 ml of anhydrous ether, cooled to -78 °, were added dropwise with stirring for approx.

30 minutes 4.55 g of diisobutyl aluminum hydride in 25 ml of anhydrous Aether added. The temperature was kept at -78 ° throughout the addition. The stirring was still during Continued for 5 hours at -70 ° to complete the reaction.

permanent. Excess reagent was then destroyed by carefully adding a mixture of 2 ml of methanol and 2 ml of water, the cooling bath removed and the reaction mixture slowly brought to room temperature. The addition of 5 ml of 1 M sodium bicarbonate while cooling with ice and stirring vigorously, followed by a total of 3 g of solid sodium carbonate in small portions led to the precipitation of aluminum hydroxide. After further vigorous stirring at 0 ° for 30 minutes, the precipitate became filtered off and washed with three times 30 ml of ether. the

The combined ether phases were dried over magnesium sulfate and the solvent was dried under normal pressure at a bath temperature of about 65 distilled off. The residue was distilled at about 80 ° bath temperature and 12 mmHg and 3.2 g were obtained in this way (R) -4-formyl-2,2,4-trimethyl-1,3-dioxolane.

A sample that was distilled and worked up again was characterized as semicarbazone and had a melting point from 201-203 °.

Example 5

Preparation of (S) -4- (2,5-dimethoxy-3,4,6-trimethylphenethyl) -2,2,4-trimethyl-1,3-dioxolane

1.84 g (R) -4-formyl-2,2,4-trimethyl-1,3-dioxolane, 11.0 g 2,5-dimethoxy-3,4,6-trimethylbenzyl triphenylphosphonium chloride

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and 3.3 g of finely ground anhydrous potassium carbonate were in 25 ml dry acetonitrile (dried over phosphorus pentoxide and distilled over potassium carbonate) heated under reflux in the presence of 55 mg crown ether for 30 hours, whereby the suspension was stirred vigorously. Then the brown suspension on 400 g of silica gel with toluene-methyl acetate-pentane (20: 3: 3) as the eluent. After bulb tube distillation at 170 ° (bath temperature) / 0.2 mmHg-obtained one 2.57 g of (S) -4- (2,5-dimethoxy-3,4,6-trimethyl-styryl) -2,2,4-

trimethyl-1,3-dioxolane as a colorless viscous oil: [cc] ²⁰ = + 17.9 ° (c = 2.1 in chloroform).

A solution of 2.51 g of (S) -4- (2,5-dimethoxy-3,5,6-trimethylstyryl) -2,2,4-trimethyl-1,3-dioxolane in 50 ml of ethyl acetate was combined with 0 , 5 g platinum / carbon catalyst (10%) shaken in a hydrogen atmosphere until the hydrogen uptake ceased (approx. 220 ml; approx. 1 hour). The catalyst was then filtered off and washed with ethyl acetate. After evaporation of the solvent, followed by a Kugelrohr distillation of the residue at 180 ° (bath temperature) / 0.6 mmHg, i 2.4 g of (S) -4- (2,5-dimethoxy-3,4,6-trimethylphenethyl) were obtained -2,2,4-trimethyl-1,3-dioxolane as a colorless, highly viscous oil. [cc] ²² = + 4.5 ° (c = 2.2 in chloroform).

The 2,5-dimethoxy-3,4,6-trimethylbenzyl-triphenylphosphonium chloride used as the starting material was made as follows:

25.7 g of 2,5-dimethoxy-3,4,6-trimethylbenzyl chloride in 100 ml of toluene were refluxed with 30 g of triphenylphosphine for 16 hours while stirring, a white suspension being formed was formed. The precipitate was filtered off, washed three times with 50 ml of toluene each time and in a high vacuum until dried to constant weight. This gave 53.1 g of the desired product as a white powder with a melting point from 23O-231 ° C.

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Example 6

Preparation of (S) - (+) - 2,3,6-trimethyl-5- (2,2,4-trimethyl-1,3-dioxolane-4-ethyl) -p-benzoquinone and of (S) - (+) - 5- (3,4-dihydroxy-3-methyl-1-butyl) -2,3,6-trimethyl-p-benzoquinone

To a solution of 550 mg of (S) -4- (3,5-dimethoxy-3,4,6-trimethyl-phenylethyl) -2,2,4-trimethyl-1,3-dioxolane in 7.5 ml of acetonitrile were added dropwise with stirring over 2 minutes at room temperature 2.01 g of cerium ammonium nitrate in 7.5 ml of water admitted. After stirring an additional 2 minutes, the reaction mixture became extracted three times with 20 ml of chloroform each time. The combined organic extracts were dried over sodium sulfate, whereupon the solvent was removed. After chromatography of the residue obtained on silica gel with Benzene / ethyl acetate (2: 1) and ethyl acetate were obtained 266 mg

(S) - (+) - 2,3,6-Trimethyl-5- (2,2,4-trimethyl-1,3-dioxolane-3-ethyl) -p-benzoquinone and 177 mg (S) - (+ ) -5- (3,4-Dihydroxy-3-methyl-1-butyl) -2,3,6-trimethyl-p-benzoquinone in the form of yellow needles with a melting point of 111-112. [σ] ρ ² = + 6.1 ° (c = 1.5 in chloroform). '

Example 7

Production of (3S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-

3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one

A mixture of the quinones obtained according to Example 6 was in a mixture of 12.7 ml of methanol and 3.8 ml of 1N aqueous hydrochloric acid for 16 hours at room] temperature left to stand. The acid was then neutralized by adding solid sodium bicarbonate, the reaction mixture was poured into 50 ml of saturated brine and the product was mixed with it extracted three times 50 ml of ether. The combined ether extracts were dried over sodium sulfate and then evaporated. By Chromatography of the residue on 40 g of silica gel with toluene / ethyl acetate (9: 1 and 2: 1) as the eluent gave 315 mg

809847/0872

, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one. After recrystallization from hexane, the product had a melting point of 99-100 °; [a] ^ ² = -58.4 ° (c = 2.7 in chloroform).

In a manner analogous to the preceding, it was also possible to use the individual quinones prepared according to Example 6 the (3S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one getting produced.

Example 8

Preparation of (S) - (+) - 6-hydroxy-2,5,7,8-tetramethylchr oman-2-methanol

250 mg (3S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one in 50 ml of ethanol were in the presence of 200 mg 5 $ palladium / carbon with hydrogen gas hydrogenated for 10 minutes. The catalyst was then filtered off, the solvent evaporated and the Chromatograph residue on silica gel with benzene / ethyl acetate (2: 1). Pure (S) - (+) - 6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol was obtained in this way as colorless crystals with a melting point of 127-128 °.

Example 9

Preparation of (3S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one

160 mg (S) -4- (2,5-dimethoxy-3,4,6-trimethylphenethyl) -2,2,4-trimethyl-1,3-dioxolane in 20 ml of methanol and 4 ml of 0.8 N sulfuric acid were suspended overnight stirred by 400 mg of cerium sulfate at room temperature. Sodium bicarbonate was then added and the reaction mixture

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extracted with methylene chloride. After drying the united Extracts from magnesium sulfate and removal of the solvent gave 134 mg of a viscous yellow oil. Chromatography of this oil on silica gel with benzene / ethyl acetate (2: 1) gave 17 mg (3S, 9aR) - (-) - 2,3,4,5, 7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one, which after recrystallization from hexane had a melting point of 99-100 °.

Example 10

Preparation of (S) -2,2,4-trimethyl-1,3-dioxolane-4-acetaldehyde

4.33 g of (S) -2,2,4-trimethyl-1,3-dioxolane-4-ethanol dissolved in 7 ml of abs. Methylene chloride were made into a suspension of 7.59 g of pyridine chlorochromate in 30 ml of abs. Methylene chloride was added dropwise. The reaction mixture was stirred for 3 hours at room temperature. By adding 75 ml of ether were the chromium salts precipitated and separated off by filtration through 120 g of silica gel. After removal of the solvent on Rotary evaporator and distillation of the residue at 90-100 ° / 10 Torr gave 3.00 g of (S) -2,2,4-trimethyl-

1,3-dioxolane-4-acetaldehyde. [cc] q ° = -35.5 ° (c = 1.50; η-hexane)

Example 11

Production of cc- (2, 5-dimethoxy-3, 4, 6-trimethylphenyl) 2,2,4- (S) -trimethyl-1,3-dioxolane-4-ethanol

To 0.8 g of magnesium shavings activated with methyl iodide became a solution of 7.77 g of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene in 20 ml abs. Tetrahydrofuran is added dropwise at such a rate that the solvent is just about Simmering was brought. The mixture was then refluxed for a further 1 hour. To the Grignard solution cooled to 0 °

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were 5.0 g of (S) -2,2,4-trimethyl-1,3-dioxolane-4-acetaldehyde added dropwise. The reaction mixture was then refluxed for a further 4 hours at room temperature and 15 minutes touched. For work-up, the reaction mixture was cooled to 0, and 10 ml of saturated ammonium chloride solution were added followed by 10 ml of 2N sulfuric acid and extracted with a total of 0.5 l of ether. The organic phase was washed with water washed neutral and dried over magnesium sulfate. After removing the solvent on a rotary evaporator and Drying the residue in a high vacuum gave 10.4 g of a highly viscous oil, which was used on 450 g for purification Silica gel with ether / hexane / ethyl acetate (4: 4: 1) chromato- ' was graphed. The yield of α- (2,5-dimethoxy-3,4,6-trimethylphenyl) -2,2,4- (S) -trimethyl-1,3-dioxolane-4-ethanol

was 8.83 g; [a] J ⁰ = -5.5 ° (c = 1.20; CHCl ₃ ).

Example 12

Production of 2,3,6-trimethyl-5- (2,2,4- (S) -trimethyl-1,3-dioxolane-4-ß-hydroxyethyl) -p-benzoquinone

A solution of 3.38 g of cc- (2,5-dimethoxy-3, 4, 6-trimethylphenyl) -2,2,4- (S) -trimethyl-1,3-dioxolane-4-ethanol in 40 ml of acetonitrile was poured into a solution of 11.2 g of Ce (NH ₄ ) "(NO-.) _ß in 40 ml of water and stirred for 3.5 minutes at room temperature. The yellow solution was then extracted with a total of 0.5 l of methylene chloride. The combined organic phases were first washed with sat. Sodium bicarbonate solution, then with sat. Washed sodium chloride solution until neutral and dried over magnesium sulfate. After removal of the solvent on a rotary evaporator at 50 °, 3.30 g of 2,3,6-trimethyl-5- (2,2,4- (S) -trimethyl-1,3-dioxolane-4-, which was uniform in the thin-chromatogram) were obtained. β-hydroxyethyl) -p-benzoquinone, which could be separated into the two epimers by chromatography on silica gel with toluene / pentane / methyl acetate (20/3/3), which had the following rotation values: [ct] J ° = -60 , 2 ° (c = 1.6; CHCl ₃ ) or ta] p ° = + 17.3 ° (c = 2.0; CHCl ₃ ).

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extracted. The combined organic phases were dried over magnesium sulfate. After distilling off the solvent in a rotary evaporator, 0.62 g of brown crystals were obtained, which were chromatographed on silica gel for purification with ethyl acetate / toluene (1/1). The thus obtained. (S) - (+) - 6-Hydroxy-2,5,7,8-tetramethylchroman-2-methanol crystallized from methylene chloride / hexane in a yield of 487 mg. M.p. 126.5-128.5 °. [a] £ ° = -2.7 ° (c = 1.38, CH ₂ Cl ₂ ).

Example 15

Preparation of (S) -6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol

108 mg (3S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy-l-benzoxepine- 7-on were together with 100 mg palladium on carbon (5%) and 20 mg p-toluenesulfonic acid hydrogenated in 20 ml of methanol at normal pressure. The uptake of hydrogen was 22 ml and the reaction time was 1 hour. After filtering off the catalyst and removal the solvent in the rotary evaporator was the; Residue on a PSC silica gel plate (Merck) with Toluene / ethyl acetate (1/1), the oxidation to (S) - (+) - 5- (3,4-dihydroxy-3-methyl-l-butyl) -2,3,6-trimethyl-p- benzoquinone entered. 70 mg of this product with a melting point of 112-113 were obtained. [«] _, = +6.28 (c = 2 in Chloroform).

The further conversion of this compound into (3S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9aepoxy-1-benzoxepin-7 -on and its conversion into the (S) - (+) - 6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol took place in a manner analogous to Examples 7 and 8, respectively.

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Example 13

Preparation of (3S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy-l-benzoxepine 7-on

A mixture of 2.33 g of 2,3,6-trimethyl-5- (2,2,4- (S) trimethyl-1,3-dioxolane-4-j3-hydroxyethyl) -p-benzoquinone, 80 ml of dioxane and 16 ml of 2N sulfuric acid were stirred at 70 ° for 2 hours. The cooled solution was neutralized by adding solid sodium hydrogen carbonate and then extracting with methylene chloride. The United organic phases were first washed with sat. Washed brine, then dried with magnesium sulfate. After removal the solvent on a rotary evaporator at 50 ° gave 2.16 g of (3S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8, which is uniform in the thin-layer chromatogram , 9-tetramethyl-3,9aepoxy-1-benzoxepin-7-one.

To determine the optical rotation of a part of the product with toluene / Essigester (1/1) was graphiert on silica gel chromato- '■: [a] ^ ° = + 178 ° (c = 3.8; CHCl _3). '

Example 14

Production of (S) -e-Hydroxy ^^^ jS-tetramethylchroman- • 2-methanol

A mixture of 0.59 g (3S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy -l-benzoxepin-7-one, 0.7 g palladium on barium sulfate (5%) and 3 drops of conc. Perchloric acid in 20 ml of methanol was mixed with about 120 ml of hydrogen hydrogenated under normal pressure. Then 2 ml of 2N sulfuric acid were added and air was let into the for 15 hours Mixture initiated. The reaction mixture obtained was hydrogenated again with about 25 ml of hydrogen. After removal of the catalyst by filtration through Hyflo, the filtrate was mixed with dilute sodium bicarbonate solution and with ether

809847/0872

Claims (7)

Claims 'I ^ Chrcxnanderivate of the general formula "CH ₃ CH ₃ CH ₃ wherein R denotes hydrogen or the hydroxyl group. 2. (3 S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9- € 3. (3 S, 9aR) - (-) - 2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,3,9-tetramethyl-3,9a-epoxy-1-benzoxepine -7-on. 4 · Process for the production of chroman derivatives according to Claim 1, characterized in that a compound of the general formula CH ₃ R, CH ₃ Vl CH ₃ 809847/0872 where R is lower alkyl, R-, and Rp are equal to or can be different and are lower alkyl or R, phenyl and Rp are hydrogen represent and R_ denotes hydrogen or the hydroxyl group, oxidized with a cerium (IV) salt or complex and a quinone obtained in this way of the formula 9 ^H 3 CH ₃ 9 ^H 3 or ".." • C Hq CH ₃ CH ₃ III where R,,]
treated with an acid. and R_ have the above meaning 5. The method according to claim 4, characterized in that the oxidation of a compound of formula VI with Cerium sulfate or cerium ammonium nitrate. 6. The method according to claim 4 or 5, characterized in that the oxidation is carried out at a temperature between about -10 ⁰ C and about 40 ⁰ C, preferably at a temperature between about 10 ⁰ C and about 3O ⁰ C. 7. The method according to any one of claims 4-6, characterized in that the oxidation in the presence of a Acid performs. 809847/0872