CH622257A5 - Process for the preparation of chroman aldehydes - Google Patents

Description

The present invention relates to a process for the preparation of chromanaldehydes of the formula

60

; C00H (VII Aa)

ch7

J

2S

and into the 2R enantiomers of the formula

CD

CHO

65

wherein R represents hydroxy, an ether group which can be converted into hydroxy by hydrolysis or hydrogenolysis or an ester group which can be converted into hydroxy by hydrolysis.

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622257

The chromanaldehydes of the formula I are intermediate compounds for the preparation of a-tocopherol and, depending on whether they are in the 2R, 2S or 2RS form, key substances both for the preparation of natural optically active a-tocopherol [2R, 4'R, 8'Ra-Toco-pherol] as well as for the production of a-tocopherols with the following configuration:

2R, 4'RS, 8'RS; 2S, 4'R, 8'R; 2S, 4'RS, 8'RS; 2RS, 4'RS, 8'RS and 2R, 4'R, 8'R.

The term “lower alkyl” refers to straight-chain and branched alkyl groups with 1-7 carbon atoms, for example methyl, ethyl and propyl, preferably methyl. The term “lower alkoxy” used in the further course refers to alkoxy groups with 1-7 carbon atoms, for example methoxy and ethoxy. The term “lower alkane carboxylic acids” refers to alkane carboxylic acids having 2-7 carbon atoms, for example acetic acid and propionic acid. “Halogen” means fluorine, chlorine, bromine and iodine. The term "aryl" refers to aromatic hydrocarbon groups such as phenyl, tolyl and the like, which may be unsubstituted or substituted in one or more positions with lower alkylenedioxy, halogen, nitro, lower alkyl or lower alkoxy, as well as polynuclear aryl groups such as Naphthyl, anthryl, phenanthryl, azulyl and. Like., Which may be unsubstituted or substituted with one or more of the above groups. The preferred aryl groups are the unsubstituted and substituted mononuclear aryl groups, especially phenyl. The term “aryl-lower alkyl” refers to groups in which aryl and lower alkyl have the above meaning, in particular to benzyl. The term “aryl-lower alkane carboxylic acid” refers to acids in which “aryl” and “lower alkane carboxylic acid” have the above meaning, in particular to benzoic acids. The expression “an ester group that can be converted into the hydroxyl group by hydrolysis” refers to all ester groups that can be converted into the hydroxyl group by hydrolysis. Examples of such ester groups are those in which the acid content is derived from a lower alkane carboxylic acid, an aryl-lower alkane carboxylic acid, phosphoric acid, carbonic acid or a lower alkane dicarboxylic acid. Such esters can be formed by reaction with the corresponding acid anhydrides and acid halides, preferably acid chlorides and acid bromides, for example by reaction with alkane carboxylic acid anhydrides, for example acetic acid anhydride, aryl-lower alkane carboxylic acid anhydrides, for example benzoic acid anhydride, lower alkane dicarboxylic acid and anhydride anhydrides, for example bernic anhydride, for example bernic anhydride, for example bernic anhydride, for example bernic anhydride, for example bernic anhydride, for example bernic anhydride, for example bernic anhydride, for example bernic anhydride, for example bernic anhydride, for example bernic anhydride, for example bernic anhydride, e.g. Trichloroethyl chloroformate. The expression “an ether group which can be converted into the hydroxyl group by hydrolysis or hydrogenolysis” refers to all ethers which can be converted into the corresponding hydroxyl compounds by hydrogenolysis or hydrolysis. Examples of such ether groups are benzyloxy, lower alkoxy lower alkoxy, for example methoxymethoxy, tetrahydropyranyloxy and the like.

The substituents of the structural formulas contained in this patent specification, insofar as they lie in the plane of the molecule, are identified by the following symbol ^, if they lie behind the plane of the molecule, by the symbol S. The substituents of the structural formulas not stereochemically specifically identified in this application can either be R or S oriented, or the compound can be present as a mixture of the R and S isomers.

The following can be mentioned as representative representatives of the compounds of the formula I:

(±) 6-Acetoxy-2,5,7,8-tetramethyl-chroman-2-carbon acid aldehyde.

The chromanaldehydes of the formula I are prepared according to the invention in that a compound of the formula

R

wherein R represents hydroxy, an ether group convertible by hydrolysis or hydrogenolysis to hydroxyl or an ester group convertible by hydrolysis to hydroxyl, by treatment with an alkali metal cyanide in a compound of the formula

OH

in which R has the meaning given above, converts it by treatment with an anhydrous mineral acid in a lower alkanol having 1-7 C atoms and subsequent addition of water to a compound of the formula

(IV)

COOR.

where Rj is alkyl with 1-7 C atoms and R 'hydroxyl or an ether group which can be converted into hydroxyl by hydrolysis or hydrogenolysis, cyclized, with simultaneous conversion of the cyano group into the esterified carboxy group COOR, and with simultaneous hydrolytic cleavage of an ester group R which may be present, that one optionally esterifies a hydroxy group R 'present in the compound of the formula IV, and that one obtains a compound of the formula cool?

where Rj and R have the meaning given above,

- either directly using an aluminum hydride

5

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40

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50

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60

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622257

6

reduced to the desired chromanaldehyde of the formula I if R is an ether or ester group, or by hydrolysis into the free acid of the formula

COGH (VII>

This reaction is expediently carried out at a temperature between about 150 ° C. and 250 ° C. When carrying out this reaction, pressures between normal pressure and about 70 atmospheres can be used. The 5 reaction takes place in an inert organic solvent. Preferred inert organic solvents are aromatic hydrocarbons, such as toluene, xylene and benzene, with benzene being particularly preferred

Another process for the preparation of the compounds of formula IX is to make a compound of formula VIII with one of the following compounds

O

wherein R has the meaning given above, converted this into an acid halide of the formula

15

20th

(VI)

ch2 = ch — c — ch3

O

II

ho — cho — ch2 — c — ch3 ORi

1

ch2 = ch — c — ch3

(XB),

(X C),

(XD),

wherein R has the meaning given above and X denotes a halogen atom, converts it and reduces it to the desired chromanaldehyde of the formula I.

The starting compound of formula II can e.g. manufactured in the following way:

In the first stage, a hydroquinone of the formula

25th

30th

ORi

O

R10-CH2-CH2-C-CH3

(XE),

R

wherein R has the meaning given above, converted into a compound of the formula wherein R and Rx have the meaning given above.

One method of making the compound of Formula IX is to mix a compound of Formula VIII with a compound of Formula

CH2 = CH-C = CH2

I.

OR,

in which R, which has the meaning given above, in which Rx has the meaning given above, is implemented.

The reaction of a compound of formula VIII with a compound of formulas XB to XE is carried out in the presence of an acidic catalyst. Preferred acidic catalysts are mineral acids, such as sulfuric acid, perchloric acid, hydrobromic acid and phosphoric acid, with sulfuric acid being particularly preferred. If desired, this reaction can be carried out in the presence of a Dehydration (VIII) take place, thereby increasing the yield of compound 40 of Formula IX. Preferred dehydrating agents are tri-lower alkyl orthoformates such as trimethyl orthoformate, calcium chloride, sodium sulfate, acetone dimethyl ketal and the like, with trimethyl orthoformate being particularly preferred. When this reaction is carried out, an organic alcohol, for example a lower alkanol, is used , used as a solvent. Preferred lower alkanols are methanol, ethanol, isopropanol and the like, methanol being preferred. Temperature and pressure are not critical when carrying out this reaction and the reaction can thus be carried out at room temperature and normal pressure

(IX). In general, temperatures between about -20 ° C and the reflux temperature of the reaction mixture can be used.

In the case of R in the compound of the formula IX is hydroxyl 55, this free hydroxyl group can be protected by esterification or by etherification, these ester groups being convertible to the free hydroxyl group by hydrolysis and the ether groups by hydrogenolysis or hydrolysis. Any such ester protecting groups which can be converted into the free hydroxy group by hydrolysis can be used. Any groups which can be converted into the hydroxyl group by hydrogenolysis or hydrolysis can likewise be used as ether groups.

(X) the. To manufacture the esters and ether to protect the

65 free hydroxy group R in the compounds of formula IX, the usual methods can be used. To prepare the esters, the compound of formula IX is expediently reacted with a reactive derivative of an organic

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Acid, for example reacted with an acid chloride or an acid anhydride under normal conditions. The preferred ester compounds of formula IX are the lower alkane carboxylic acid esters, with the acetic acid ester being particularly preferred. The usual etherification processes can also be used to convert the hydroxyl group into an ether group. The preferred ether group is the benzyl ether group.

The compounds of formula IX, the hydroxyl group of which is either free or protected by etherification or esterification, are next hydrolyzed with mineral acid, giving a compound of the formula

R

OH

where R has the meaning given above.

The hydrolysis can be carried out in a conventional manner with strong mineral acids, for example sulfuric acid, hydrochloric acid and the like. If the hydroxyl group was in etherified form, treatment with strong acid can also hydrolyze this ether group and convert it to the hydroxyl group.

The chromanes of formula I are prepared by using a compound of formula

R

(II)

or

R

(IIA)

wherein R has the meaning given above and R '"represents an ester group convertible by hydrolysis to hydroxy, by treatment with an alkali metal cyanide in an inert organic solvent and, in the case of the compounds of the formula II, while maintaining a pH of the reaction mixture of 3 to 7, preferably 4 to 6, into a compound of the formula III or, in the case of the compounds of the formula II A, while maintaining a pH of the reaction mixture of 8 in the corresponding cyanohydrin. When carrying out this reaction, potassium cyanide is preferably used as Alkali metal cyanide is used and the usual inert organic solvents can be used as solvents

Solvents are used, preferably dimethyl sulfoxide or dimethylformamide. In order to maintain a pH of 3 to 7, an acid can be added to the reaction mixture, preferably sulfuric acid or hydrochloric acid. The temperatures used here can be between 0 ° and about 40 ° C.

In the next step, the compound of formula III is converted into a mixture of compounds of the formulas

R1

COOR

(IV)

and

OH COOR

(IVA)

wherein Rt has the meaning given above and R 'denotes hydroxy or an ether group which can be converted into hydroxy by hydrolysis or hydrogenolysis. The conversion is carried out at a temperature between - 20 ° C u. 10 ° C, using an anhydrous mineral acid in a lower alkanol and then adding water. A hydrohalic acid, in particular hydrochloric acid, can preferably be used as the mineral acid. In particular, methanol or ethanol can be used as the lower alkanol.

If desired, the compound of formula IV A obtained can be crystallized and separated or cyclized by treatment with a Lewis acid, in particular with the aid of zinc chloride, aluminum chloride or boron trifluoride. However, it is also possible, after the hydrolysis of the esters, to separate the non-cyclized acid from the corresponding compound of the formula VII by crystallization. If the resulting compound of formula IV contains a hydroxyl group R, this can if desired be esterified to form a compound of formula V.

When using a concentrated mineral acid (without the addition of a lower alkanol), the cyanohydrins obtained from the compounds of the formula II A are cyclized directly to the acid of the formula VII, in which R is hydroxy, with simultaneous conversion of the cyano group into the carboxy group and with simultaneous hydrolytic cleavage the ester group R '".

The chromanes of formula V can be converted into the corresponding acid halides of formula VI and these into aldehydes of formula I.

The compounds of the formula V can be converted into the free acids of the formula VII in accordance with reaction (a).

5

io

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(a)

COOR.

COOH

(V)

(Vil)

where R has the meaning given above. Common basic hydrolysis methods can be used here. In general, the reaction of step (a) can be carried out in an aqueous medium using an alkali metal hydroxide, for example sodium hydroxide. The hydrolysis is expediently carried out at a temperature of about 5 ° C. to the reflux temperature of the reaction mixture.

The acids of formula VII obtained can, if desired, be separated into the enantiomers according to the following scheme.

15

20th

COOH

(VII)

R

4 **

COOH

2R

(VII b)

where R has the meaning given above.

The acid of the formula VII can be separated into the enantiomers VII a and VII b in a conventional manner in accordance with reaction step (cl). a-methyl-benzylamine e.g. forms salts with the acid of formula VII 2S and 2R, which can be separated by fractional crystallization and hydrolysis into the 2S acid of formula VII a and 2R acid of formula VII b. The enantiomeric 2S acid of formula VII a can be used for the synthesis of natural optically active 2R, 4'R, 8'R - a-tocopherol, while the enantiomeric 2R acid of formula VII b leads to 2S isomers of a-tocopherol. The enantiomers of the formulas VII a and VII b can be racemized to the acid VII, from which 2RS isomers of a-tocopherol are accessible.

55 The acids of the formula VII obtainable by hydrolysis from the chroman carboxylic acid esters of the formula V can be converted into acid halides of the formula

9

622257

where R has the meaning given above and X denotes a halogen atom.

This can e.g. in such a way that an acid of formula VII in which the phenolic hydroxyl group is masked, with one of the customary halogenating agents, e.g. with oxalyl chloride, thionyl chloride, phosphorus pentochloride etc. treated.

The acid halides of formula VI obtained from the acids of formula VII are converted as follows into the aldehydes of the formula and into the enantiomeric 2R form of the formula

CHO

(i)

10th

15

(Ib)

II MCHO

where R has the meaning given above.

A suitable method is the Rosenmund reduction, i.e. hydrogenation using a deactivated palladium catalyst in the presence of an acid-binding agent. Furthermore, the usual palladium catalysts which are partially deactivated by an organic sulfur compound but by quinoline can be used. Suitable acid-binding agents are e.g. Bases such as alkali metal salts of lower alkane carboxylic acids e.g. Sodium acetate or also tertiary lower alkylamines, such as triethylamine and others. If R represents an ether group which can be converted into hydroxy by hydrogenolysis, this is generally converted to hydroxy during the reduction, with the exception of the benzyl ether group, which is unexpectedly retained when the acid halide is reduced.

However, the chromanaldehydes of formula I can also be obtained directly by reducing the chromancarboxylic acid esters of formula V, in which R represents an ether or ester group, e.g. with the help of diisobutylaluminium hydride or dihydro-bis- (2-methoxy-ethoxy) sodium aluminum hydride. The reduction is carried out in a conventional inert organic solvent e.g. in pentane, dioxane, diethyl ether, hexane, toluene, benzene or xylene. The range between - 120 ° C and - 30 ° C can be specified as the temperature interval.

The chromanaldehydes of the formula I can also be separated into the enantiomeric 2S form of the formula in which R has the meaning given above.

The aldehydes of the formula I present as racemates can be separated into the optically active antipodes using any of the means customary for the cleavage of aldehyde-20. The aldehydes are e.g. converted into a Schiff base using an optically active amine, such as a-methyl-benzylamine or de-hydroabiethylamine. The aldehydes of the formula I can also first be reacted with a racemic amine and then converted into optically active salts using an optically active acid. Another method for separating the aldehydes of the formula I into the enantiomers is to react the aldehydes with an optically active hydrazide 30 to give the corresponding hydrazones.

The customarily used optically active amines, racemic amines, optically active acids and optically active hydrazides can be used for the processes mentioned.

The resulting mixture of diastereomers can be obtained in a conventional manner, e.g. separated by fractional crystallization. The optically active aldehydes can also be racemized in a known manner.

A 2S aldehyde of the formula I a is used for the synthesis of natural optically active a-40 tocopherol, the racemate of an aldehyde of the formula I or a 2R aldehyde of the formula I b is used for the preparation of a-tocopherol isomers.

As mentioned above, both the 2S and 45R 2R aldehydes can be racemized as previously described. In this way, the 2R aldehydes of the formula I b which do not lead to the natural a-tocopherol can be racemized and new 2S aldehydes of the formula I a can be obtained from the racemate.

so the chromanaldehydes of the formula cho

(I a) 55

60

aa)

where R has the meaning given above, are starting compounds for the synthesis of natural optically active a-tocopherol of the formula

622257

10th

R

o ^ ch2- ch2'ch2

CH3 2r ch,

r 3

* "c chr A

h h1R

ch2-ch2 "

where R denotes hydroxy [cf. Helv. Chim. Acta 46 (1963) 650].

In addition to this natural a-tocopherol of the formula IX, starting from the racemate of the aldehydes of the formula I and the 2R-aldehydes of the formula I, b a-tocopherol 15 isomers of the formula ch,

▼ 3

• c "* ch2'ch2'ch2 h

8'r ch3

'ch'

ch-

(XI)

r

0-

ïh-

gh2 * ch2'ch2'6h'ch2'ch2 'cîy ch-ch2'ch2- ch, / ch'ch-

çh,

* ch:

ch_ I 3

(XII)

where R has the meaning given above, with the following configuration 2R, 4'RS, 8'RS; 2S, 4'R, 8'R; 2S, 4'RS, 8'RS; 2RS, 4'RS, 8'RS; 2RS, 4'R, 8'R can be produced.

example 1

A solution of 26.4 g (= t) -6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman in 200 ml of dimethyl sulfoxide is stirred vigorously and 32.5 g of granular KCN are added by sieving that a uniform suspension is obtained. The mixture obtained is cooled to 15 ° C. and 47 ml of 12N aqueous H2SO4 are added over 1.25 h, the internal temperature being kept at 20 ° C. Thin layer chromatography at this point gives a strong slower progressing stain in addition to traces of starting material. The material is poured into diethyl ether and water. The ether solutions are washed with water and brine and dried over NaS04.

After removal of the solvent, (dt) -2 - cyano-4- (5-acetoxy-2-hydroxv-3,4,6-trimethylphenyl) butane - 2-0I is obtained.

The (ie) -6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman used as the starting compound can e.g. can be produced as follows:

A solution of 304.4 g of trimethylhydroquinone in 1.21 methanol and 300 ml of trimethyl orthoformate is degassed, placed under nitrogen and cooled to 3 ° C. in an ice bath. 5 ml of concentrated aqueous sulfuric acid are added and then 340 ml of methyl vinyl ketone are added dropwise over a period of 3 hours. The suspension is stirred without cooling for 44 h. The mixture is then worked up by extraction with diethyl ether, washing with water and saturated aqueous sodium bicarbonate solution and drying over sodium sulfate. The solvent is removed in a rotary evaporator at 30-35 ° C. and (= t) -6-hydroxy-2-methoxy-2,5,7,8-tetramethylchroman is obtained. 900 ml of acetic anhydride are added to a solution of (±) -6-hydroxy-2-methoxy-2,5,7,8-tetramethylchroman in 600 ml of pyridine. The orange-colored solution is degassed, placed under nitrogen and stirred at 23 ° C. for 18 h. The mixture is then poured into 8000 ml of ice water and the suspension obtained is stirred vigorously at 23 ° C. for 3 h. After about 1 h, inoculate with (±) -6-acet-

oxy-2-methoxy-2,5,7,8-tetramethylchroman brought the suspended oil to crystallize. The solid is filtered off, washed again with water, 2N aqueous hydrochloric acid and with saturated aqueous sodium bicarbonate solution and dried over sodium sulfate. After removing the solvent, 570 g of a red-brown oil are obtained, which slowly crystallizes on standing. A similarly prepared sample is distilled at 175-180 ° C / 0.015 mmHg and analytically pure (±) -6-acetoxy-2-methoxy-35 -2,5,7,8-tetramethylchroman is obtained in the form of a colorless oil, which soon crystallized: melting point 71-72.5 ° C.

2000 ml of water and 16.6 ml of concentrated aqueous HCl are added to a solution of (±) -6-acetoxy-2-methoxy-2,5,7,8-tetramethylchroman in 2500 ml of acetone. 40 The solvent is evaporated from the stirred mixture until the temperature has reached 90 ° C. The suspension is cooled to 50 ° C in a water bath. At 70 ° C 2000 ml of acetone are added, whereupon a clear solution is obtained. The solution is inoculated occasionally until crystallization begins. After 3J / £ h, 1500 ml of water are added and the suspension is cooled in an ice bath. The solid is filtered off, washed with water and dried at 50 ° C / 0.1 mmHg. This gives (±) -6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman in the form of a yellow-50 brown solid which sinters from 114 ° C.: melting point 127-132 ° C.

The cyanohydrin produced according to Example 1, paragraph 1 is immediately taken up in 250 ml of methanol. This solution is cooled in an ice bath, saturated with anhydrous hydrochloric acid and allowed to stand at -2 ° C for 18 hours. The solvent is removed in a rotary evaporator (bath temperature below 30 ° C). The remaining mass is taken up in 250 ml of water, degassed, placed under nitrogen and heated at 40 ° C. for 2 h, forming an aqueous suspension. The aqueous suspension is worked up using a solvent mixture of ethyl acetate and diethyl ether and dried. One obtains from (±) -2-carbomethoxy-4- (2,5-dihydroxy-3,4,6-trimethylphenyl) butan-2-ol and (±) -2-carbo-65 methoxy-6-hydroxy -2,5,7,8-tetramethylchroman existing mixture.

The brown solid is treated with diethyl ether and crystallized from diethyl ether. (±) -2-carbo-

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methoxy-4- (2,5-dihydroxy-3,4,6-trimethylphenyl) butan-2-ol as white prisms with a melting point of 135-136.5 ° C.

The brown solid is suspended in 100 ml of methanol and 100 ml of 2N aqueous NaOH are added to the mixture over 10 minutes. The solution obtained is stirred under nitrogen for 24 h, treated with 57 ml of 2N aqueous HCl and with 10 ml of saturated aqueous NaHC03 solution, and a solution with a pH of 7.5-8.0 is obtained. The solution is extracted with diethyl ether, acidified with 2N aqueous HCl and extracted again with diethyl ether. The latter extracts are washed with brine and dried over Na2S04. Then the solvent is evaporated. The product obtained (24.3 g), which partially crystallizes, consists, according to thin layer chromatography, of an approximately equimolar mixture of cyclized and non-cyclized acids. Pure, non-cyclized acid, (±) -2-carboxy-4- (2,5-dihydroxy-3,4,6-trimethyl) -butan-2-ol is obtained from this mixture by filtration of the aqueous suspension obtained after acidification , Extraction with diethyl ether and crystallization from diethyl ether in the form of a white solid, easily oxidizable in air, isolated: melting point 177-178 ° C.

The crude mixture of acids and 0.57 g of p-toluenesulfonic acid monohydrate obtained in 300 ml of benzene is heated under nitrogen for 1.25 h, with azeotropic removal of HaO. The cooled solution is washed with 150 ml of saturated aqueous NaHC03 and with 150 ml of brine. The aqueous solutions are treated with activated carbon, acidified with 2N aqueous HCl and filtered. (±) -6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid is obtained in the form of a powder with a melting point of 189-190 ° C.

A mixture of 25.0 g (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, 100 ml 1,2-dichloroethane, 17.5 ml ethanol and 1.0 ml concentrated Sulfuric acid is heated to boiling under nitrogen for 20 h. The reaction mixture is washed successively with water, with a saturated aqueous sodium hydrogen carbonate solution and with a saline solution, dried over sodium sulfate and evaporated. The remaining (±) -6-hydroxy-2,5,7,8-tetra-methylchroman-2-carboxylic acid ethyl ester melts at 124 to 126 ° C.

Example 2

A solution of crude 4- (2,5-diacetoxy-3,4,6-trimethylphenyl) butan-2-one in 963 ml of dimethylformamide is cooled in an ice bath under nitrogen. A solution of 69.4 g of potassium cyanide in 150 ml of H20 is added over 20 minutes. The mixture is stirred for a further 10 min and then 161 ml of 6N H2S04 are added dropwise over the course of 20 min, the internal temperature being kept between + 10 ° C. and + 13 ° C. The viscous suspension (pH 8) is stirred for a further 30 min, brought to a pH of 4 by adding 16.5 ml of 6N H2S04, then poured onto ice water and extracted with ether. The ether solutions are washed with brine and dried over Na2S04.

After removal of the solvent, (±) -2 - cyano-4- (2,5-diacetoxy-3,4,6-trimethylphenyl) butan-2-ol is obtained as an orange-brown foam.

(rfc) -2-cyano-4- (2,5-diacetoxy-3,4,6-trimethylphenyl) -bu-tan-2-ol (made from 0.1 mole of 4- (2,5-diacetoxy-3 , 4,6-tri-methylphenyl) butan-2-one) is dissolved in 250 ml of concentrated HCl under nitrogen. The mixture is held at 25 ° C for 1.5 hours and then at 60 ° C for 44 hours. The suspension is then cooled and filtered. The solid is washed with water, air-dried and stirred for 1 h with 180 ml of saturated NaHC03 solution and 50 ml of ether. The aqueous phase is washed with additional ether, acidified with 6N HCl, then cooled and filtered. The solid is washed with H20 and then dried. This gives 20.64 g (83%) (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid as a white powder with a melting point of 190-192 ° C (decomposition).

As described in Example 1, (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid is converted into the (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2 -carboxylic acid methyl ester, mp. 158.5-161.5 ° C, converted.

The 4- (2,5-diacetoxy-3,4,6-trimethylphenyl) butan-2-one used as the starting compound in Example 2 can e.g. can be produced as follows:

A solution of (±) -6-hydroxy-2-methoxy-2,5,7,8-tetra-methylchroman (prepared according to Example 1 from 1 mol of tri-methylhydroquinone) in 1250 ml of acetone, 1000 ml of H20 and 8.30 ml of concentrated HCl is heated under reflux under nitrogen. The solvent is removed by distillation up to a temperature of 95 ° C. The suspension is cooled to 70 ° C, then diluted with 800 ml acetone and further cooled to 15 ° C. The solvent is then evaporated under reduced pressure at 30 ° C to about 1000 ml. The suspension obtained is cooled, filtered and dried and (±) -2,6-dihydroxy-2,5,7,8-tetramethylchroman is obtained as a gray-brown powder with a melting point of 105-107 ° C.

A suspension of (±) -2,6-dihydroxy-2,5,7,8-tetramethylchroman in 600 ml pyridine is placed under nitrogen. 900 ml of acetic anhydride are then added over a period of 1 h. The orange-colored solution obtained is stirred at 23 ° C. overnight, poured into ice water, stirred for a further 2 h and then extracted with benzene and ether. The organic extracts are washed with 2N HCl, brine, saturated NaHC03 solution and brine and dried over Na2S04. After removal of the solvent, 4- (2,5-diacetoxy - 3,4,6-trimethylphenyl) butan-2-one is obtained as a very hard solid with a melting point of 85-87.5 ° C.

Example 3

40 2.94 g (±) -6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid is added to a mixture of 1.34 g dimethylchlorofoimiminium chloride and 12 ml chlorobenzene. The reaction mixture is heated to 110 ° C. under nitrogen for 40 min and then evaporated. 4 mmol of the remaining-45 den (±) -6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid chloride are dissolved in 4 ml of acetone and after adding 0.43 ml of triethylamine using 90 mg Palladium-carbon 10% by weight: 90% by weight hydrogenated under normal conditions. The hydrogenation comes to a standstill after about 1 h. The catalyst is filtered off. The filtrate is evaporated. The residue is taken up in ether and worked up. The (±) -6-acetoxy-2,5,7,8-tetrame-thylchroman-2-carboxylic acid aldehyde obtained melts after recrystallization from petroleum ether [boiling range 30-60 ° C.] at 92.5 55 to 96 ° C.

The S-6-acetoxy-2,5,7,8-tetramethylchroman-carboxylic acid chloride and the S-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid can be prepared in an analogous manner. 6-acetoxy-2,5,7,8-tetramethylchroman-carbon-60 acid aldehyde, - the R-6-acetoxy-2 from R-6-acetoxy-2,5,7,8-tetramethylchro-man-2-carboxylic acid , 5,7,8-tetramethyl-chroman-carboxylic acid chloride and the R-6-acetoxy-2,5,7,8-tetramethyl-chroman-carboxylic acid aldehyde.

65 Example 4

The compound (±) - (6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl) -carboxylic acid is mixed with S-a-methyl-benzylamine. The mixture obtained is at 25 ° C for 1 h

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622 2S7

12

Stirred nitrogen and then filtered. After removal of the solvent, a brownish resin is obtained. After two recrystallizations of this material from methanol ether, S- (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) -carboxylic acid is obtained. S-a-methyl-benzylamine salt with a melting point of 153.5-154 ° C, after crystallization from a mixture of ethanol-diethyl ether.

The mother liquors of this crystallization are treated with R - «- methylbenzylamine and R- (6-hydroxy-

-2,5,7,8-tetramethylchroman-2-yl) carboxylic acid. R-a-methyl - benzylamine salt with a melting point of 153.5-155 ° C, after crystallization from a mixture of ethanol-diethyl ether.

5 The S-acid-S-salt and the R-acid-R-salt are treated with 2N aqueous hydrochloric acid and S- (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) -carbon is obtained Acid and R- (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) carboxylic acid.

v

Claims (8)

622257 1 60 in which Rj represents alkyl having 1-7 C atoms and R 'hydroxyl or an ether group which can be converted into hydroxyl by hydrolysis or hydrogenolysis, cyclized, with simultaneous conversion of the cyano group into the esterified carboxy group COORj and simultaneous hydrolytic cleavage of any ester group R present, that an existing hydroxy group R 'is esterified and that a compound of the formula obtained is obtained 622257 1 wherein Rj and R '"have the meaning given above, by hydrolysis to the free acid of the formula wherein R is hydroxyl, an ether group which can be converted to hydroxy by hydrolysis or hydrogenolysis or an ester group which can be converted to hydroxy by hydrolysis, by treatment with an alkali metal cyanide at pH 3 to 7 into a compound of the formula R ' 35 COOH (VII B) 40 (III) wherein R '"has the meaning given above, converted this into an acid halide of the formula R ' where R has the meaning given above, 45 converts this by treatment with an anhydrous mineral acid in a lower alkanol with 1-7 C atoms and subsequent addition of water to a compound of the formula oox (VIB) 50 55 where R '"has the meaning given above and X denotes a halogen atom, converted and this reduced to the desired chromanaldehyde of the formula IB. 1 (IVB) CHO (IC) 10th wherein Rj is alkyl with 1-7 carbon atoms and Rv is hydroxy, cyclized, with simultaneous conversion of the cyano group into the esterified carboxy group COORj ^ and with simultaneous hydrolytic cleavage of an ester group RIV, if any, that the existing in the compound of formula IV B Hydroxyl group Rv is esterified and that a compound of the formula wherein R "is an ether group which can be converted to hydroxy by hydrolysis or hydrogenolysis or an ester group which can be converted to hydroxy by hydrolysis 15 characterized in that a compound of the formula 20th R ' (II) 25th COOK (VB) 2. A process for the preparation of chromanaldehydes of the formula wherein R is hydroxyl, an ether group which can be converted to hydroxyl by hydrolysis or hydrogenolysis or an ester group which can be converted to hydroxyl by hydrolysis, by treatment with an alkali metal cyanide at a pH of 3 to 7 in a compound of formula 30th 35 R ' CIIO (IB) (III) 40 in which R '"represents an ester group which can be converted into hydroxy by hydrolysis, characterized in that a compound of the formula in which R has the meaning given above is converted, this by treatment with an anhydrous mineral acid in a lower alkanol having 1-7 C atoms and subsequent addition of water to a compound of the formula 45 50 R IV (HB) COOR ^ in which RIV is hydroxy or an ester group which can be converted into hydroxy (IV) 55 by hydrolysis, cyclized by treatment with an alkali metal cyanide at a pH of 3 to 7 into a compound of the formula in which Rj is alkyl having 1-7 C atoms and R 'is hydroxy or an ether group which can be converted into hydroxy by hydrolysis or hydrogenolysis, with simultaneous conversion of the cyano group into the esterified carboxy group COORj and with simultaneous hydrolytic cleavage of an ester group R which may be present, and that the ester obtained is hydrolysed into the free acid of the formula 60 65 (III A) where RIV has the meaning given above, 2nd PATENT CLAIMS 1. Process for the preparation of chromanaldehydes of the formula CHO (IA) -COOH (VII A) 10th in which R 'has the meaning given above, converts it into an acid halide of the formula in which R' is hydroxyl, or an ether group which can be converted into hydroxyl by hydrolysis or hydrogenolysis, characterized in that a compound of the formula 15 20th (VIA) (II) 25 wherein R 'has the meaning given above and X denotes a halogen atom, converts it and reduces it to the desired chromanaldehyde of the formula IA. 3. Process for the preparation of chromanaldehydes of the formula (IV) COOR 3rd 622257 converts this by treatment with an anhydrous mineral acid in a lower alkanol with 1-7 C atoms and subsequent addition of water to a compound of the formula COOK 4. The method according to claim 3, characterized in that one uses for the direct reduction of the ester of the formula V A diisobutyl aluminum hydride or dihydro - bis (2-methoxy-ethoxy) sodium aluminum hydride. 4th O COOR, (VA) where Ri and R "have the meaning given above, reduced with the aid of an aluminum hydride to the desired chrommanaldehyde of the formula IC 5. The method according to claim 1, characterized in that one carries out the reduction of the acid halide obtained of the formula VI A with the aid of a deactivated palladium catalyst in the presence of an acid-binding agent. 6. The method according to claim 1, characterized in that obtained racemic aldehydes of the formula IA with the aid of an optically active base in the 2S en-antiomers of the formula JIUICOOH (VII Ab) 10th separates. 9. The method according to claim 8, characterized in that the separation into the enantiomers using op- 15 table-active a-methyl-benzylamine in an organic solvent. 10. The method according to claim 8, characterized in that the enantiomeric 2S and 2R acids of the formulas VII Aa and VII Ab by halogenation in the enantiomers 20 acid halides of the formula 25th (I Aa) 30th (VI Aa) and in the enantiomeric acid halides of the formula and in the 2R enantiomers of the formula 35 40 i / MCHO (I Ab) 45 jCOX (VI Ab) separates. 7. The method according to claim 6, characterized in that one carries out the separation into the enantiomers with the aid of optically active a-methyl-benzylamine in an organic solvent. 8. The method according to claim 1, characterized in that the intermediate obtained racemic acids of the formula VII A are converted with the aid of an optically active base into the 2S enantiomers of the formula, and that the enantiomeric 2S and 2R acid halides of the formulas VI Aa and VI Ab by reduction into the corresponding enantiomeric 2S and 2R so aldehydes of the formulas I Aa and I Ab are converted.