CA1334852C - Chromanyl esters useful for the preparation of tocophenol - Google Patents

Abstract

Disclosed are new chromanyl ester of (a) the formula (IV) (IV) (b) the formula (IV') (IV') and (c) the formula (I''') (I''') either as a mixture of two diastereomers or as a pure diastereomer thereof, wherein the group

Description

The present application is a division of Canadian patent application serial number 449,560 filed on March 14, 1984.

In application n 449,560, a process is disclosed for the preparation of novel optically active chroman derivatives of the general formulae Ia and Ib Rl Rl HG~CH2 C~12 X 2~C~2-Cli2-X
t1 a) t1 b) where R , R , R3 and R are each hydrogen or C1-C4-alkyl and X is -OH, -O-CO-R6, -o-R6, -O-tosyl, -O-mesyl, -O-benzene-sulfonyl, Cl, Br, or I, where R6 is C1-C4-alkyl.
Also disclosed in this application n 449,560 are particularly useful members of this novel group of compounds, ie. the optically active chroman derivatives of the formulae Ia and Ib, where R1, R2, R3 and R4 are each methyl and X is -OH, Cl, Br, I, -O-CH3, -O-tert.-butyl, -O-CO-CH3 or -O-tosyl, in particular Br, Cl or O-tosyl.
The present application relates to and claims new diastereomeric chromanyl esters of (a) the formula (IV) ~' R -CH-CO-O
-Ar ~ ~ CH2 CH2--0-CO-R
R2 ~ o ~ 4 (IV) 10(b) the formula (IV') 15R'--CO--O~CH -CH -O-CO--CH--RS (IV' ) or (c) the formula (I''') Rl 2 5HO ~ 2 CH2-0-Co-CH-Rs ( I ' ' ' ) either as a mixture of two diastereomers or as a pure diastereomer thereof, wherein the group R5-CH-Co- is O-Ar optically active residue, R , R , R and R are, independently, each hydrogen or Cl-C4-alkyl, R' is Cl-C4-alkyl, RS is Cl-C4 alkyl and Ar is phenyl or naphthyl - la -unsubstituted or substituted by more than two substituents selected amongst Cl-C4-alkyl, Cl-C4-alkoxy, chlorine, bromine, cyano ana nil~o /

- lb -Particular examples of chroman derivatives of the formulae Ia and Ib are (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman, (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman, (S) -2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman, (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman, (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-chloroethyl)-chroman and (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-chloroethyl)-chroman,amongwhich the (S) derivatives having a leaving group in the side chain are particularly important for the preparation of (2R, 4'R, 8'R)- and (2R, 4'RS, 8'RS)- -tocopherol.
Examples of diastereomeric esters of the formulae IV and IV' are 2,5,7,8-tetramethyl-6-[a-(o-methyl-p-chloro-phenoxy)-propionyloxy]-2-(2-acetoxyethyl)-chroman; 2,5,7,8-tetramethyl-6-acetoxy-2-[2-(a-(naphth-1-yloxy)-propionyloxy-ethyl]-chroman and 2,5,7,8-tetramethyl-6-hydroxy-2-[2-(a-(naphth-l-yloxy)-propionyloxyethyl]-chroman.
The substituents in the optically active compounds of the formulae Ia and Ib and of the other structural formulae used in this application are denoted by the symbol where they lie in front of the plane of the molecule, and by the symbol _ where they lie behind the plane of the molecule. In the case of structural formulae where the stereochemistry of the substituents is not specially indicated, the substituents can have either an R
or an S orientation, or the substance may be a mixture of the R and S isomers.
The chroman derivatives of the formulae Ia and Ib, where Rl, R2, R3 and R4 are each methyl and X is a leaving group, are very important for the preparation of a-tocopherol (vitamin E); depending on whether they are in the 2R-, 2S- or 2RS form, they are key substances for the preparation of both natural optically active a-tocopherol (2R, 4'R, 8'R-a-tocopherol) and other optically active isomers, in particular (2R, 4'RS, 8'RS)-a-tocopherol, which is likewise very biologically active.

xi 133~852 German Laid-Open Application DOS 2,602,509 discloses that tocopherol can be synthesized by coupling a chroman derivative of the formula Alkyl-O

O~
where Y is a leaving group, with a suitable Cl4 Grignard compound, by the Schlosser-Fouquet method. An optically active chroman building block suitable for this synthesis can be prepared by one of the methods described in German Laid-Open Application DOS 2,364,165.
In this process, the chroman derivative of the 15 formula HO
~ 1' ~ O ~ CH ~ \

is resolved into the optical antipodes via a diastereomeric salt pair, with the aid of an optically active base, e.g.
phenylethylamine. The resulting optically active chromanyl-acetic acid, after esterification and protection of thephenolic hydroxyl group, can then be reduced to the corresponding optically active chromanylethanol, which can be tosylated to give a chroman derivative which is capable of coupling by the method described in German Laid-Open Application DOS 2,602,509. When the data due to Cohen et al.
in J. Org. Chem. 41 (1976), 3505 and Scott et al. in Helv.
Chim. Acta 59 (1976), 290 et seq. are also taken into account, the following overall reaction route emerges for the preparation of such a chroman derivative capable of coupling:

~, ~. ~.

., ~

'' < 7 o ,~
Oc=i~ N

~0 O

o O O ~ ) rl 1~ ~
~ ~ ~ O

o ~e / ~ m ~ c m ~ o ~ ~
CC~

_~ ~ P~

o o :~ 4 This process is very involved and, moreover, re-quires the use of expensive hydrides, e.g.
NaAlH2(0C2H40CH3)2, in the hydrogenation stage.
It is therefore the object of application n 449,560 to provide, in a simpler and cheaper manner, chroman derivatives which are capable of coupling to give (2R, 4'R, 8'R)- or (2R, 4'RS, 8'RS)-~-tocopherol.
In practise this object is achieved, and chroman derivatives of formulas Ia and Ib as defined hereinabove are obtained by hydrolysis of the appropriate pure (R) or (S) form of a chroman ester of formula R
R -CH-C0-0 ~ "~
0-Ar ~ 2 2 R4 ~ 0 ~R4 (IV) R

5 ~L
wherein the group R -CH-C0- is an optically active 0-Ar residue, the group -C0-R' is an optically inactive residue Rl, R2, R3 and R are as defined above, R' is Cl-C4-alkyl, R5 is Cl-C4-alkyl and Ar is unsubstituted or substituted aryl.
The compound of formula (IV) can be obtained by selectively converting the racemate I':
Rl H0 ~CH -CH OH ( I ' ) R2 ~ R4 -133~852 with a carboxylic acid of formula II

R'-COOH (II) where R' is Cl-C4-alkyl, or with a lower alkyl ester of such an acid, into the ester I"

H ~ CH2-CH2--C-R' R ~ O 4 (I~) and subsequently acylating this ester I" with an optically active earboxylic acid halide of the general formula III
R -CH-CO-X (III) O-Ar where R5 is Cl-C3-alkyl, X is Cl or Br and Ar is aryl which in turn can be substituted, or with the corresponding carboxylic anhydride of the general formula V

R -fH-CO-O-CO-fH-R (V) O-Ar O-AR
The compound of formula (IV) which is so obtained and which consists of two diastereomeric esters, can be resolved by fractional crystallization. The pure diastereomers may then be hydroly~ed in a conventional manner to give the corresponding alcohols of the formulae Ia and Ib, which if desired, can be converted in a conventional manner to the other compounds of formulae Ia and Ib.
The chroman derivatives of formulas Ia and Ib as defined hereinabove can also be obtained by hydrolysis of the appropriate pure (R) or (S) form of a chroman ester of formula (I''') HO ~ CH2-CH2-o-Co-lH-R5 R2 ~ R4 O-Ar (I''') wherein the group R5-CH-Co- is an optically active residue, O-Ar R1, R , R3 and R4 are as defined above, R is Cl-C4-alkyl and Ar is unsubstituted or substituted aryl, or of the appropriate pure (R) or (S) form of a chroman ester of formula Rl R --~ CH -CH -O-CO-fH-R5 2S 5 d~-wherein the group R -ClH-CO- is an optically active residue, O-Ar the group -CO-R' is an optically inactive residue Rl, R2, R3 and R are as defined above, R' is Cl-C4-alkyl, R is C1-C4-alkyl and Ar is unsubstituted or substituted aryl.
The ester of formula I''' can be obtained by convertion of a racemate of formula I' as defined hereinabove with a carboxylic acid III' 5 ~
R -CH-COOH (III') O-Ar - 6a -13~4852 or with a lower alkyl ester of this. The ester I"' R ~ 2 CH2 O CO-bH-R (I"') then may be acylated with a carboxylic acid halide of formula R'-CO-X, where X is Cl, Br or I, or with the corresponding carboxylic anhydride, to give the ester IV' Rl R'-CO-O ~ CH2-CH2-O-CO-IH-R (IV') The esters I"' or IV' which both consist of two diastereomers can be resolved by fractional crystallization.
The pure diastereomers may be hydrolyzed in a conventional manner to give the alcohols of the formulae Ia and Ib, which, if desired, may be converted in a conventional manner to the other compounds of the formulae Ia and Ib.
In both embodiments of the novel process, the - 6b -starting material is the racemic chroman derivative I', which is disclosed in German Laid-Open Application DOS

3,010,505, and is readily obtainable by means of a Friedel-Crafts addition reaction of l-vinylpropane-1,3-diol ¦ ~ CH2-CH2-OH

~ C
with the hydroquinone HO
ll l R ~3 OH
I' has two functional hydroxyl groups, i.e. one alcoholic and one phenolic hydroxyl group, which, because of their different reactivities, can be readily esterified selectively, in accordance with general laws.
The esterification of the alcoholic hydroxyl group is carried out using a free acid or a lower alkyl ester as a mild esterification agent, whereas the subsequent esterification of the phenolic hydroxyl group requires the use of the corresponding acid halide as a stronger esterification agent.
In the novel process, the acid radical of the optically active acid III' conforming to the definition can be bonded to either the alcoholic or phenolic hydroxyl group of I', as in the embodiments a) and b). In both cases, diastereomeric bisesters are obtained, i.e. IV and IV';
contrary to expectation, these can be readily resolved into their diastereomers by fractional crystallization.
The introduction of the radical of the optically active acid III' is common to both embodiments of the ,. ,~

- 1~34852 process, whereas the esterification with the inactive acid II is required only in embodiment a) and can be dispensed with in embodiment b).
A particularly suitable inactive lower carboxylic acid II is acetic acid, but propionic acid, butyric acid and isobutyric acid may also be used.
Particularly suitable acids III' (these correspond to the acid radicals of III) are those in which R5 is methyl. The aryl group Ar is phenyl in the simplest case, but the ~- and B-naphthyl groups and substituted phenyl and naphthyl groups are also suitable. Examples of substituents on Ar are C1-C4-alkyl, Cl-C4-alkoxy, chlorine or bromine, cyano and nitro. Preferably, the phenyl or naphthyl groups should carry no more than two of these substituents.
The optically active acids III' are known, or are obtainable by a conventional method. To our knowledge, they have not to date been employed for the resolution of racemates. The acid derivatives III are obtainable from the free acids in a conventional manner, e.g. by reaction with, for example, thionyl chloride. Other suitable optically active reagents are the corresponding anhydrides of the formula V.
Particularly preferred acids III' or acid halides III are the optically active forms of ~-phenoxypropionic acid, of ~-(2'-methyl-4'-chlorophenoxy)-propionic acid and of ~-(naphth-l-yloxy)-propionic acid.
Regarding the two embodiments of the process, the following may be stated specifically:
In embodiment a), the esterification of I' with the C2-C4-fatty acid II is carried out, as usual, preferably in an organic solvent. Examples of suitable solvents are benzene, toluene, ethyl acetate and mixtures of these.
Examples of suitable esterification catalysts are sulfuric acid and p-toluenesulfonic acid.
The same conditions also apply when the free acid is replaced with its lower alkyl ester, the methyl ester I
~ ~'7 preferably being used in this case. The transesterification has the advantage that no aqueous phase is formed when the reaction is carried out in a water-insoluble solvent.
The resulting esters I" can be isolated, but it is also possible to carry out the acylation with III directly if significant amounts of water or alcohols are not present.
The acylation of the phenolic hydroxyl group with the acid chloride III is carried out, as usual, preferably in the presence of an equimolar amount of a tertiary nitrogen base, such as pyridine, as an acid acceptor. When the acylation is complete, water is added to the reaction mixture in the usual manner, the organic phase is separated off by a conventional procedure, and, if required, the solvent is removed from this.
The residue, which consists of the diastereomers IV, is taken up in a solvent, and the solution is fractionally crystallized in a conventional manner.
Suitable solvents are those mentioned in connection with the esterification reaction, as well as C1-C4-alkanols, in particular methanol and ethanol.
Using a conventional technique, IV which crystallizes out when the extracts are evaporated down is first dissolved completely in a hot solvent, and one of the diastereomers is then obtained by crystallization when the resulting solution cools. If necessary, the crystallization should be repeated once or twice, depending on the desired purity.
The diastereomers which have been separated are finally hydrolyzed in a conventional manner, preferably using aqueous alcoholic potassium hydroxide solution. The alcohol of the formula Ia or Ib is then extracted in a conventional manner with a solvent, e.g. methylene chloride, which is not miscible with the aqueous alcoholic phase.
The alcohols of the formulae Ia and Ib are obtained by method a), i.e. via esterification, recrystallization and hydrolysis, as a rule in yields of ~,,~, .

from 25 to 30%, based on the racemate I', i.e. in yields of from 50 to 60~ of theory.
Method b) is a similar preparative procedure to method a), with the difference that in this case the alcoholic hydroxyl group of I' is first esterified with the free optically active acid III' or with a lower alkyl ester of this. The acylation of the phenolic hydroxyl group with the acid halide II' is in principle unnecessary, but is advantageous because the bisesters frequently crystallize more readily than the monoesters.
Furthermore, the novel process for the resolution of racemates has a decisive though unexpected advantage due to the special solubility relationships between monoesters and bisesters. If the racemate I' is first esterified, for example with (~ -(naphth-l-yloxy)-propionic acid, the reaction mixture is worked up in a conventional manner by shaking with water and extracting, the combined extracts are evaporated down, the resulting crude ester is dissolved in methanol or ethanol, and the solution is seeded, (R)-2,5,7,8-tetramethyl-6-hydroxychroman-2-yl-ethyl (-)-~-(naphth-1-yloxy)-propionate slowly crystallizes out. This can be converted to (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by hydrolysis (cf. Example 5). If the mother liquor which has been separated off is then evaporated down, the diastereomer mixture which then has a high concentration of the (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman ester is acetylated in the 6-position, for example with acetyl chloride or acetic anhydride, the reaction mixture is worked up in a conventional manner and the resulting crude bisester is dissolved in hot methanol or ethanol, surprisingly the bisester of the (S)-chroman derivative crystallizes out first. This can be converted to (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by hydrolysis.
All of the subsequent steps in the process for the resolution of the racemate are similar to those of X

- 1~34852 embodiment a). Accordingly, a particularly advantageous embodiment of the novel process is carried out as follows:
the racemate I' is converted with a carboxylic acid III', or with a lower alkyl ester of this, to a mixture of diastere-omeric esters I"', this mixture is dissolved in an alcohol,the (R) form which first crystallizes out during this procedure is separated off, the monoester which remains in the isolated mother liquor and predominantly consists of the (S) form is esterified in the 6-position with a carboxylic acid halide of the formula R'-C0-X, where X is Cl, Br or I, or with the corresponding carboxylic anhydride, and the (S) form of the chroman derivative IV', which now crystallizes out preferentially, is isolated from the solution of the diastereomers IV' which predominantly contains this form.
The pure diastereomers are hydrolyzed in a conventional manner to give the alcohols of the formulae Ia and Ib, and, if desired, these are converted to the other compounds of the formulae Ia and Ib in a conventional manner.
Finally, the following may be stated regarding the novel process for the resolution of racemic 2,5,7,8-tetra-methyl-6-hydroxy-2-(2-hydroxyethyl)-chroman into its (R) and (S) form. The optically active acids III' and their derivatives have not been used to date for the resolution of racemates. It is surprising that the novel racemate resolution procedure using these optically active acids or their derivatives can be carried out so advantageously, since attempts to resolve chromanylethyl acetate with the aid of optically active acid derivatives, e.g. (-)-menthyl-oxyacetyl chloride (cf. S. Fujise et al, Chem. Ber. 69 (1936), 1893 and A.E. Knauf et al, Am. Chem. Soc. 56, (1934), 2109), which are known from the literature to be useful for resolving racemic mixtures of phenolic compounds give unsatisfactory results. Moreover, it is surprising that resolution of the racemate takes place in such an advantageous manner even when the radical of the optically active acid is bonded to the phenolic hydroxyl group of the X'' - 133485~

chroman ring and is therefore very far away from the chiral carbon atom of the chroman derivative. Furthermore, it could not be foreseen that, as a result of the special solubility relationships between the chromanylethyl monoesters and bisesters, it would be possible to isolate both diastereomeric forms of the chroman derivative in a simple manner using only one optically active form of the acid (cf.
Examples 3 and 5). This of course means that the more desirable (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxy-ethyl)-chroman can be obtained using, for example, either (-)-a-(naphth-1-yloxy)-propionic acid (cf. Example 3) or (+)-a-(naphth-l-yloxy)-propionic acid (cf. Example 6).
The chroman derivatives of the formulae Ia and Ib which are initially obtained when the racemate is resolved and in which X is OH are converted in a conventional manner to the other chroman derivatives conforming to the definition, so that detailed information in this context is unnecessary.
For example, (S)- and (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman are obtained by reacting the corresponding -2-(2-hydroxyethyl)-chroman with a solution of triphenylphosphine and bromine in anhydrous methylene chloride, and (S)- and (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-chloroethyl)-chroman are obtained by reacting the corresponding -2-(2-hydroxyethyl)-chroman with CCl4 and triphenylphosphine. Regarding further details of these processes, reference may be made to E. Schacht in "Kontakte", issue 3, page 9, 1974, and literature cited therein.
(S)- and (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-tert.-butoxyethyl)-chroman are obtained by reacting a solution of the corresponding -2-(2-hydroxyethyl)-chroman in methylene chloride with isobutene in the presence of a small amount of sulfuric acid by a method similar to that described by H.C. Beyerman et al. in Rec. Trav. Chim. 84 (1965), 203.

- 133~852 The present invention permits the preparation of optically active chroman derivatives, capable of coupling to form a-tocopherol, by a sequence of synthesis stages which, compared with the prior art, is very short and easy to carry out:

HO ~ HO ~ H ~ H

~ OH ~ O OH

HO ~ Br ( Cl, --t osyl ) The novel chroman derivatives of the formula Ia, where X is Cl, Br or O-tosyl, can be directly bonded to an appropriate C14 Grignard compound under catalysis with a di-(alkali metal) tetrahalocuprate in accordance with the Schlosser-Fouquet method to give an a-tocopherol isomer.

Preparation of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by embodiment a) a) 200 g (800 millimoles) of racemic 2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman (I') were esterified in a conventional manner with 100 g of glacial acetic acid in the presence of 4 g of p-toluene sulfonic acid and 1.5 liters of ethyl acetate in the course of 6 hours, under reflux.
Working up in a conventional manner gave the acetate of I' (2,5,7,8-tetramethyl-6-hydroxy-2-(2-acetoxy-ethyl)-chroman) in the form of a yellow oil, which was recrystallized from ethanol. Mp. = 74 C, yield = 85% of theory.
b) L-(4-chloro-2-methyl)-phenoxypropionyl chloride, obtained by heating 80 g (374 millimoles) of L-(4-'''X

13348~2 chloro-2-methyl)-phenoxypropionic acid with 125 g of thionyl chloride at 50 C for 3 hours and distilling off the excess thionyl chloride, was added gradually, at 0 C, to a solution of 100 g of the ester prepared as described in Example la, in 250 ml of pyridine.
The reaction mixture was stirred for a further 16 hours at room temperature and then poured into ice water.
The resulting aqueous organic mixture was extracted with methylene chloride, and the organic phase obtained was washed with 5 N HCl, water and dilute sodium carbonate solution and once again with water, and was then dried and evaporated down. The oil which remained after the evaporation procedure was taken up in 500 ml of methanol, the solution was heated at the boil and then cooled slowly, and the resulting crystal slurry was filtered off. Methanol was added to the heated slurry until the crystals went into solution. The material which crystallized out on cooling the methanolic solution was filtered off, recrystallized once again from methanol and dried to give 58 g of a mixture of the diastereomeric bisesters ~, ~\ o CH2 CH2-0-CO-CH3 Cl of melting point 122 C and [~]D = -63.8 (c = 2, acetone).
The yield was 35% of theory, based on the chromanyl ester used in this stage, and the optical purity was 100%.
c) 58 g (119 millimoles) of the pure ester mixture obtained as described in Example lb) were heated at the boil with 500 ml of methanol and 132 ml of 1 N potassium hydroxide solution for 2 hours. Working up this hydrolysis mixture in a conventional manner by extraction with methylene chloride gave the desired (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman in a total yield of 26%
of theory, based on the racemic hydroxyethyl chroman used.
Mp. = 155 C; [~]2D0= -6.95 (c = 2, ethanol).

Preparation of (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman This compound was prepared by a method similar to that described in Example 1, using D-(4-chloro-2-methyl-phenoxy)-propionyl chloride as the reagent for effecting resolution. The yield was 29% of theory, based on the racemic hydroxyethyl chroman used. Mp. = 155 C;
[~] D = +7 00 (c = 2, acetone).

Preparation of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by embodiment b) with esteri-fication of the phenolic hydroxyl group 10 g (40 millimoles) of racemic 2,5,7,8-tetra-methyl-6-hydroxy-2-(2-hydroxyethyl)-chroman were esterified in the presence of 200 ml of toluene and 0.1 g of p-toluene-sulfonic acid by heating for 4 hours with 8.6 g (40 milli-moles) of (-)a-(naphth-1-yloxy)propionic acid, water being separated off. The reaction mixture obtained was cooled and then extracted by shaking with sodium bicarbonate solution and water, and the organic phase was evaporated down. The resulting crude ester was then dissolved in 40 ml of pyridine, 4 g of acetic anhydride were added to the solution, and the mixture was left to stand for 24 hours at room temperature. The crude bisester mixture (158 g) obtained by working up in a conventional manner was subjected twice to fractional crystallization from ethanol.
The yield of the S form was 29% of theory, based on the racemate, i.e. 58% of the theoretically possible amount.
Mp. = 145 C; [~]2D0= -39.0 (c = 2, chloroform).
Alkaline hydrolysis of the bisester by a method ~, similar to that described in Example lc gave the desired (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman in 26% yield, based on the racemic compound used.
[a] D = ~7-0 (c = 2, ethanol); mp. = 155 C.

Preparation of (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman The compound was prepared by a method similar to that described in Example 3, using (+)-~-(naphth-1-yloxy) propionic acid as the reagent for effecting resolution.

Preparation of (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by embodiment b), without esteri-fication of the phenolic hydroxyl group 10 g (40 millimoles) of racemic 2,5,7,8-tetra-methyl-6-hydroxy-2-(2-hydroxyethyl)-chroman were esterified in the presence of 200 ml of toluene and 0.1 g of p-toluene-sulfonic acid by heating for 4 hours with 8.6 g (40 milli-moles) of (-)-~-(naphth-1-yloxy)propionic acid, water being separated off. The crude ester (16 g) obtained by working up in a conventional manner was then dissolved in 90 ml of methanol. This solution was seeded with 20 mg of (R)-2,5,7,8-tetramethyl-6-hydroxychroman-2-ylethyl (-)-~-(naphth-l-yloxy)propionate, after which a precipitate formed in the course of two days at -20 C. This precipitate was separated off and was once again recrystallized in the same manner.
The yield was 26%, based on the racemic chroman used. Mp. = 121 C; [~] D5= -41 (c = 2, CHC13).

4 g of the ester prepared in this manner were dissolved in 140 ml of methanol, and the solution was refluxed with 9.o ml of 1 M KOH for 1.5 hours. Working up by a procedure similar to that described in Example lc gave X t 2.1 g of (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxy-ethyl)-chroman. Mp. = 155 C; [~]D = +6.95 (c = 2, ethanol).

Preparation of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman This compound was prepared by a procedure similar to that described in Example 5, using (+)-naphth-1-yloxy-propionic acid as the reagent for effecting resolution.

Preparation of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman The combined mother liquors from Example 5 were evaporated down, 3 g of acetic anhydride and 30 ml of pyridine were added, and the mixture was left to stand for 24 hours. Working up the reaction mixture by hydrolysis with ice water, extraction with methylene chloride, washing and evaporating down the organic phase, and recrystallization of the resulting precipitate twice from ethanol gave 6.6 g of (S)-2,5,7,8-tetramethyl-6-acetoxychroman-2-ylethyl (-)-a-(naphth-1-yloxy)propionate of melting point 145 C and [~]2D = -38.7 (c = 2, chloroform). The yield was 34%, based on chromanol used in Example 5.
4 g of the ester prepared in this manner were dissolved in 140 ml of methanol, and the solution was refluxed with 16.4 ml of 1 M KOH for 1.5 hours. Working up by a procedure similar to that described in Example lc gave the desired (S)-chromanyl ethanol in a yield of 31% of theory, based on racemic chromanol used.

5.5 g of triphenylphosphine were dissolved in 100 ml of anhydrous methylene chloride, 3.4 g of bromine were added dropwise, the reaction mixture was stirred for 30 minutes at room temperature, 5 g of (S)-2,5,7,8-tetra-.~ ' methyl-6-hydroxy-2-(2-hydroxyethyl)-chroman were added, and the mixture was refluxed for one hour and then poured onto sodium carbonate solution. The aqueous phase was extracted with methylene chloride, the combine organic phases were washed with sodium chloride solution, dried and evaporated down, and the residue was recrystallized from methanol.
5.3 gof(S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman were obtained. [a]2D = -15 (c = 2, MeOH), mp. = 120C.

(R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromo-ethyl)-chroman was prepared from (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by a procedure similar to that described in Example 8. [~]2D0 = +15.1 (c = 2, MeOH), mp. = 120C.

A mixture of 2 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman, 8 g of carbon tetra-chloride and 2.6 g of triphenylphosphine was refluxed for 3 hours, after which the reaction mixture was allowed to cool, the precipitate formed was filtered off under suction and the filtrate was chromatographed over silica gel, using a 5:1 hexane/acetone solvent mixture. 1.7 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-chloroethyl)-chroman were obtained. [~]2D0= -9.1 (c = 2, chloroform), mp. = 111 C.

(R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-chloro-ethyl)-chroman was prepared from (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by a procedure similar to that described in Example 10. [~]2Do = +9.0, (c = 2, chloro-form, mp. = 111C.

X
..

- 13348~2 5 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman were suspended in 250 ml of methylene chloride, and isobutene was passed through the suspension.
After 15 minutes, 1 ml of concentrated sulfuric acid was added, and stirring was then continued for a further 4 hours at room temperature, while a gentle stream of isobutene was passed through. The mixture was then left to stand overnight in a closed vessel. The organic phase was washed with sodium bicarbonate solution and with water, and was then dried and evaporated down. The crude product was purified over silica gel, using a 5:1 hexane/acetone solvent mixture. 4.5 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-tert.-butoxyethyl)-chroman were obtained as a colorless oil. [~]3265 = +4.23 (c = 2, ethanol).

(R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-tert.-butoxyethyl)-chroman was obtained from (R)-2,5,7,8-tetra-methyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by a procedure similar to that described in Example 12. [~]2D0= 4.2 (c = 2, ethanol).

(S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-acetoxy-ethyl)-chroman was obtained from (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by a procedure similar to that described in Example la. [~]2D0 = -0.1 (c = 2, chloro-form). Mp. = 80.5 C.

~.

Claims (20)

1. A process for the preparation of chromanyl esters of (a) the formula (IV) (IV) (b) the formula (IV') (IV') or (c) the formula (I''') (I''') either as a mixture of two diastereomers or as a pure diastereomer thereof, wherein the group is an optically active residue, the group -CO-R' is an optically inactive residue, R1, R2, R3 and R4 are, independently, each hydrogen or C1-C4-alkyl, R' is C1-C4-alkyl, R5 is C1-C4 and Ar is phenyl or naphthyl unsubstituted or substituted by no more than two substituents selected amongst C1-C4-alkyl, C1-C4-alkoxy, chlorine, bromine, cyano and nitro, characterized in that (a) to prepare chromanyl esters of the formula (IV) as defined above either as a mixture of two diastereomers or as a pure diastereromer thereof, an ester of formula (I") (I") wherein the group -COR' is as defined above and R1, R2, R3, R4 and R, are as defined above is acylated with an optically active carboxylic acid halide of formula (III) (III) wherein X is Cl or Br and R5 and Ar are as defined above, or with the corresponding carboxylic anhydride of formula (V) (V) wherein R5 and Ar are as defined above to obtain chromanyl esters of formula (IV) as defined above as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystallization, (b) to prepare chromanyl esters of formula (IV') as defined above either as a mixture of two diaster-eomers or as a pure diastereomer thereof, an ester of formula (I''') (I''') as a mixture of two diastereomers, wherein the group is as defined above and R1, R2, R3, R4 and R5 are as defined above is acylated with a carboxyic acid halide of the formula R'-CO-X wherein the group -COR' is as defined above and R' is as defined above and X is Cl, Br or I or with the corresponding carboxylic anhydride thereof, to obtain chromanyl esters of formula (IV') as defined above as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystallization, and (c) to prepare chromanyl esters of formula (I''') as defined above either as a mixture of two diaster-eomers or as a pure diastereomer thereof, a racemate of formula (I') (I') wherein R1, R2, R3 and R4 are as defined above is selectively treated with an optically active carboxylic acid of formula (III') (III') wherein R5 and Ar are as defined above or a lower alkyl ester thereof to obtain chromanyl esters of formula (I''') as defined above as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystallization.

2. Chromanyl esters of (a) the formula (IV) (IV) (b) the formula (IV') (IV') or (c) the formula (I''') (I'') either as a mixture of two diastereomers or as a pure diastereomer thereof, wherein the group is optically active residue, R1, R2, R3 and R4 are, independently, each hydrogen or C1-C4-alkyl, R' is C1-C4-alkyl, R5 is C1-C4 alkyl and Ar is phenyl or naphthyl unsubstituted or substituted by more than two substituents selected amongst C1-C4-alkyl, C1-C4-alkoxy, chlorine, bromine, cyano and nitro.

3. A process for the preparation of chromanyl esters of the formula (IV) (IV) either as a mixture of two diastereomers or as a pure diastereomer thereof, wherein the group is an optically active residue, the group -CO-R' is an optically inactive residue R1, R2, R3 and R4 are, independently, each hydrogen or C1-C4-alkyl R' is C1-C4-alkyl, R5 is C1-C4-alkyl and Ar is phenyl or naphthyl unsubstituted or substituted by no more than two substituents selected amongst C1-C4-alkyl, C1-C4-alkoxy, chlorine, bromine, cyano and nitro, characterized in that an ester of formula (I") (I") as racemate wherein the group -COR' is as defined above and R1, R2, R3, R4 and R' are as defined above is acylated with an optically active carboxylic acid halide of formula (III) (III) wherein R5 and Ar are as defined above and X is Br or Cl, or with the corresponding carboxylic anhydride of formula (V) (V) wherein R5 and Ar are as defined above to obtain chromanyl esters of formula (IV) as defined above as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystalli-zation.

4. Chromanyl esters of the formula (IV) (IV) either as a mixture of two diastereomers or as a pure diastereomer thereof, wherein the group is an optically active residue, the group -CO-R' is an optically inactive residue R1, R2, R3 and R4 are, independently, each hydrogen or C1-C4-alkyl, R' is C1-C4-alkyl, R5 is C1-C4-alkyl and Ar is phenyl or naphthyl unsubstituted or substituted by no more than two substituents selected amongst C1-C4-alkyl, C1-C4-alkoxy, chlorine, bromine, cyano and nitro.

5. A process for the preparation of chromanyl esters of formula (IV') (IV') either as a mixture of two diastereomers or as a pure diastereomer thereof, wherein the group is an optically active residue, the group -CO-R' is an optically inactive residue R1, R2, R3 and R4 are, independently, each hydrogen or C1-C4-alkyl, R' is C1-C4 alkyl, R5 is C1-C4 alkyl and Ar is phenyl or naphthyl unsubstituted or substituted by no more than two substituents selected amongst C1-C4-alkyl, C1-C4-alkoxy, chlorine, bromine, cyano and nitro, characterized in that an ester of formula (I''') (I''') as a mixture of two diastereomers, wherein the group is as defined above and R1, R2, R3, R4 and R5 are as defined above is acylated with an optically inactive carboxylic acid halide of the formula R'-CO-X wherein the group -COR' is as defined above and R, is as defined above and X is Cl, Br or I or with the corresponding carboxylic anhydride thereof, to obtain chromanyl esters of formula (IV') as defined above as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystallization.

6. Chromanyl esters of formula (IV') (IV') either as a mixture of two diastereomers or as a pure diastereomer thereof, wherein the group is an optically active residue, the group -CO-R' is an optically inactive residue R1, R2, R3 and R4 are, independently, each hydrogen or C1-C4-alkyl, R' is C1-C4 alkyl, R5 is C1-C4 alkyl and Ar is phenyl or naphthyl unsubstituted or substituted by no more than two substituents selected amongst C1-C4-alkyl, C1-C4-alkoxy, chlorine, bromine, cyano and nitro.

7. A process for the preparation of chromanyl esters of formula (I''') (I''') either as a mixture of two diastereomers or as a pure diastereomer thereof, wherein the group is an optically active residue, R , R2, R3 and R4 are, indepen-dently, each hydrogen or C1-C4-alkyl, R5 is C1-C4-alkyl and Ar is phenyl or naphthyl unsubstituted or substituted by no more than two substituents selected amongst C1-C4-alkyl, C1-C4-alkoxy, chloride, bromine, cyano and nitro, characterized in that a racemate of formula (I') (I') wherein R1, R2, R3 and R4 are as defined above is selectively treated with an optically active carboxylic acid of formula (III') (III') wherein R5 and Ar are as defined above or a lower alkyl ester thereof to obtain chromanyl esters of formula (I''') as defined above as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystallization.

8. Chromanyl esters of formula (I''') (I''') either as a mixture of two diastereomers or as a pure diastereomer thereof, wherein the group is an optically active residue, R1, R2, R3 and R4 are, indepen-dently, each hydrogen or C1-C4-alkyl, R5 is C1-C4-alkyl and Ar is phenyl or naphthyl unsubstituted or substituted by no more than two substituents selected amongst C1-C4-alkyl, C1-C4-alkoxy, chloride, bromine, cyano and nitro.

9. A process for the preparation of (-)-2,5,7,8-tetramethyl-6-[.alpha.-(2-methyl-4-chlorophenoxy)-propionyloxy]-2-(2-acetoxyethyl)-chroman as a mixture of two diastereomers or as a pure diastereomer thereof characterized in that 2,5,7,8-tetramethyl-6-hydroxy-2-(2-acetoxyethyl)-chroman as a racemate is acylated with (-)-.alpha.-(4-chloro-2-methyl-phenoxy)propionyl chloride to obtain (-)-2,5,7,8-tetramethyl-6-[.alpha.-(2-methyl-4-chlorophenoxy)-propionyloxy]-2-(2-acetoxyethyl)-chroman as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystallization.

10. (-)-2,5,7,8-tetramethyl-6-[.alpha.-(2-methyl-4-chlorophenoxy)-propionyloxy]-2-(2-acetoxyethyl)-chroman as a mixture of two diastereomers or as a pure diastereomer thereof.

11. A process for the preparation of (+)-2,5,7,8-tetramethyl-6-[.alpha.-(2-methyl-4-chlorophenoxy)-propionyloxy]-2-(2-acetoxymethyl)-chroman as a mixture of two diastereomers or as a pure diastereomer thereof characterized in that 2,5,7,8-tetramethyl-6-hydroxy-2-(2-acetoxyethyl)-chroman as a racemate is acylated with (+)-.alpha.-(4-chloro-2-methyl-phenoxy) propionyl chloride to obtain (+)-2,5,7,8-tetramethyl-6-[.alpha.-(2-methyI-4-chlorophenoxy)-propionyloxy]-2-(2-acetoxyethyl)-chroman as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystallization.

12. (+)-2,5,7,8-tetramethyl-6-[.alpha.-(2-methyl-4-chlorophenoxy)-propionyloxy]-2-(2-acetoxyethyl)-chroman as a mixture of two diastereomers or as a pure diastereomer thereof.

13. A process for the preparation of (-)-2,5,7,8-tetramethyl-6-acetoxy-2-r2-[.alpha.-(naphth-l-yloxy)-propionyloxy) ethyl]-chroman as a mixture of two diastereomers or as a pure diastereomer thereof characterized in that (-)-2,5,7,8-tetramethyl-6-hydroxy-2-[2-(.alpha.-(naphth-l-yloxy)-propionyloxy) ethyl]-chroman as a mixture of two diastereomers is acylated with acetic anhydride to obtain (-)-2,5,7,8-tetramethyl-6-acetoxy-2-[2-(.alpha.-(naphth-l-yloxy)-propionyloxy)ethyl]-chroman as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystallization.

14. (-)-2,5,7,8-tetramethyl-6-acetoxy-2-[2-(.alpha.-(naphth-l-yloxy)-propionyloxy)ethyl]-chroman as a mixture of two diastereomers or as a pure diastereomer thereof.

15. A process for the preparation of (+)-2,5,7,8-tetramethyl-6-acetoxy-2-[2-(.alpha.-(naphth-1-yloxy)-propionyloxy) ethyl]-chroman as a mixture of two diastereomers or as a pure diastereomer thereof characterized in that (+)-2,5,7,8-tetramethyl-6-hydroxy-2-[2-(.alpha.-(naphth-1-yloxy)-propionyl-oxy)ethyl]-chroman as a mixture of two diastereomers is acylated with acetic anhydride to obtain (+)-2,5,7,8-tetramethyl-6-acetoxy-2-[2-(.alpha.-(naphth-1-yloxy)-propionyl-oxy)ethyl]-chroman as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resoLved by fractional crystallization.

16. (+)-2,5,7,8-tetramethyl-6-acetoxy-2-[2-(.alpha.-(naphth-l-yloxy)-propionyloxy)ethyl]-chroman as a mixture of two diastereomers or as a pure diastereomer thereof.

17. A process for the preparation of (-)-2,5,7,8-tetramethyl-6-hydroxy-2-[2-(.alpha.-(naphth-1-yloxy)-propionyl-oxy)ethyl]-chroman as a mixture of two diastereomers or as a pure diastereomer thereof characterized in that the racemate of 2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl 0-chroman is selectively treated with (-)-.alpha.-(naphth-l-yloxy)-propionic acid to obtain (-)2,5,7,8-tetramethyl-6-hydroxy-2-[2-(.alpha.-(naphth-l-yloxy-propionyloxy)ethyl]-chroman as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystalli-zation.

18. (-)-2,5,7,8-tetramethyl-6-hydroxy-2-[2-(.alpha.-(naphth-l-yloxy)-propionyloxy)ethyl]-chroman as a mixture of two diastereomers or as a pure diastereomer thereof.

19. A process for the preparation of (+)-2,5,7,8-tetramethyl-6-hydroxy-2-[2-(.alpha.-(naphth-1-yloxy)-propionyl-oxy)ethyl]-chroman as a mixture of two diastereomers or as a pure diastereomer thereof characterized in that the racemate of 2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman is selectively treated with (+)-.alpha.-(naphth-l-yloxy)-propionic acid to obtain (+)-2,5,7,8-tetramethyl-6-hydroxy-2-[2-.alpha.-(naphth-l-yloxy-propionyloxy)ethyl]-chroman as a mixture of two diastereomers and, if a pure diastereomer thereof is desired, said mixture is resolved by fractional crystalli-zation.

20. (+)-2,5,7,8-tetramethyl-6-hydroxy-2-[2-.alpha.-(naphth-l-yloxy)-propionyloxy)ethyl]-chroman as a mixture of two diastereomers or as a pure diastereomer thereof.