Novel optically active chroman derivatives, their preparation and novel intermediates

Novel optically active chroman derivatives of the general formulae Ia and Ib ##STR1## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each hydrogen or alkyl and X is --OH, --O--CO-alkyl, --O-alkyl, --O-tosyl, --O-mesyl, --O-benzenesulfonyl, Cl, Br or I, are prepared by a process in which PA0 (a) the racemate of the formula I' ##STR2## is esterified in the side chain with a carboxylic acid and then acylated with an optically active carboxylic acid halide of the general formula III ##STR3## or with the corresponding carboxylic anhydride, to give a chroman derivative IV ##STR4## or (b) the racemate I' is esterified in the side chain with the carboxylic acid from which III is derived, and, if required, the resulting ester is acylated with a carboxylic acid halide to give IV' ##STR5## the resulting mixture IV or IV', which consists of two diastereomers, is resolved by fractional crystallization, the diastereomers are hydrolyzed to the alcohols Ia and Ib and, if desired, these are converted to the other compounds Ia and Ib in a conventional manner. Useful optically active chroman derivatives Ia and Ib and diastereomeric chromanyl esters IV and IV' are also claimed.

The present invention relates to a process for the preparation of novel 
optically active chroman derivatives of the general formulae Ia and Ib 
##STR6## 
where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each hydrogen or C.sub.1 
-C.sub.4 --alkyl and X is --OH, --O--CO--R.sup.6, --O--R.sup.6, 
--O--tosyl, --O--mesyl, --O--benzenesulfonyl, Cl, Br or I, where R.sup.6 
is C.sub.1 -C.sub.4 --alkyl. 
The present invention furthermore relates to the particularly useful 
members of this novel group of compounds, ie. the optically active chroman 
derivatives of the formulae Ia and Ib, where R.sup.1, R.sup.2, R.sup.3 and 
R.sup.4 are each methyl and X is --OH, Cl, Br, I, --O--CH.sub.3, 
--O--tert.-butyl, --O--CO--CH.sub.3 or --O--tosyl, in particular Br, Cl or 
O-tosyl. 
The present invention furthermore relates to diastereomeric esters of the 
general formulae IV and IV' 
##STR7## 
where R.sup.5 is a C.sub.1 -C.sub.3 --alkyl, R' is C.sub.1 -C.sub.4 
--alkyl and Ar is aryl which in turn can be substituted, these esters 
being novel intermediates in the preparation process. 
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, among which 
the (S) derivatives having a leaving group in the side chains 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-[2'-(o-methyl-p-chlorophenoxy)-propionyl]-2-(2-acetox 
yethyl)-chroman; 
2,5,7,8-tetramethyl-6-acetoxy-2-[2-(.alpha.-naphth-2'-yloxy)-propionylethyl 
]-chroman and 
2,5,7,8-tetramethyl-6-hydroxy-2-[2-(.alpha.-naphth-2'-yloxy)-propionylethyl 
]-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 R.sup.1, R.sup.2, 
R.sup.3 and R.sup.4 are each methyl and X is a leaving group, are very 
important for the preparation of .alpha.-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 .alpha.-tocopherol 
(2R, 4'R, 8'R-.alpha.-tocopherol) and other optically active isomers, in 
particular (2R, 4'RS, 8'RS)-.alpha.-tocopherol, which is likewise very 
biologically active. 
German Laid-Open Application DOS No. 2,602,509 discloses that tocopherol 
can be synthesized by coupling a chroman derivative of the formula 
##STR8## 
where Y is a leaving group, with a suitable C.sub.14 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 No. 2,364,165. 
In this process, the chroman derivative of the formula 
##STR9## 
is resolved into the optical antipodes via a diastereomeric salt pair, 
with the aid of an optically active base, eg. phenylethylamine. The 
resulting optically active chromanylacetic acid, after esterification and 
protection of the phenolic 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 No. 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: 
##STR10## 
This process is very involved and, moreover, requires the use of expensive 
hydrides, eg. NaAlH.sub.2 (OC.sub.2 H.sub.4 OCH.sub.3).sub.2, in the 
hydrogenation stage. 
It is therefore an object of the present invention 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)-.alpha.-tocopherol. 
We have found that this object is achieved, and that the chroman 
derivatives Ia and Ib defined at the outset are obtained, if 
(a) the racemate I' 
##STR11## 
is selectively converted with a carboxylic acid of the formula II 
EQU R'--COOH (II) 
where R' is C.sub.1 -C.sub.4 --alkyl, or with a lower alkyl ester of such 
an acid, to the ester I" 
##STR12## 
this is acylated with an optically active carboxylic acid halide of the 
general formula III 
##STR13## 
where R.sup.5 is C.sub.1 -C.sub.3 --alkyl, Y 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 
##STR14## 
to give the chroman derivative IV 
##STR15## 
which consists of two diastereomeric esters, this is resolved by 
fractional crystallization, pure diastereomers are hydrolyzed in a 
conventional manner to give the alcohols of the formulae Ia and Ib, and, 
if desired, these are converted in a conventional manner to the other 
compounds of the formulae Ia and Ib, or if 
(b) the racemate I' is converted with a carboxylic acid III' 
##STR16## 
or with a lower alkyl ester of this, to an ester I'" 
##STR17## 
this is, if desired, acylated with a carboxylic acid halide of the formula 
R'--CO--X.sup.1, where X.sup.1 is Cl, Br or I, or with the corresponding 
carboxylic anhydride, to give IV' 
##STR18## 
I"'or IV', which consists of two diastereomers, is resolved by fractional 
crystallization, 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 in a conventional manner to the other compounds of the 
formulae Ia and Ib. 
In both embodiments of the novel process, the starting material is the 
racemic chroman derivative I', which is disclosed in German Laid-Open 
Application DOS No. 3,010,505, and is readily obtainable by means of a 
Friedel-Crafts addition reaction of 1-vinylpropane-1,3-diol 
##STR19## 
with the hydroquinone 
##STR20## 
I' has two functional hydroxyl groups, ie. 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, ie. 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 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 R.sup.5 is methyl. The aryl group Ar is phenyl in 
the simplest case, but the .alpha.- and .beta.-naphthyl groups and 
substituted phenyl and naphthyl groups are also suitable. Examples of 
substituents on Ar are C.sub.1 -C.sub.4 --alkyl, C.sub.1 -C.sub.4 
--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, eg. 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 1-phenoxypropionic acid, of 
2-(2'-methyl-4'-chlorophenoxy)-propionic acid and of 
1-(naphth-1-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 C.sub.2 
-C.sub.4 -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 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 C.sub.1 -C.sub.4 --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, eg. methylene chloride, which is 
not miscible with the aqueous alcoholic phase. 
The alcohols of the formulae Ia and Ib are obtained by method (a), ie. via 
esterification, recrystallization and hydrolysis, as a rule in yields of 
from 25 to 30%, based on the racemate I', ie. 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 groups of I' is first 
esterified with the free optically active acid IIl' 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 (-)-1-(naphth-1-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 
(-)-1-(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 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 diastereomeric 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'--CO--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-tetramethyl-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, eg. (-)-menthyloxyacetyl 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 gave unsatisfactory results. 
Moveover, 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 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-hydroxyethyl)-chroman can be 
obtained using, for example, either (-)-1-(naphth-1-yloxy)-propionic acid 
(cf. Example 3) or (+)-1-(naphth-1-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 
CCl.sub.4 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. 
The present invention permits the preparation of optically active chroman 
derivatives, capable of coupling to form .alpha.-tocopherol, by a sequence 
of synthesis stages which, compared with the prior art, is very short and 
easy to carry out: 
##STR21## 
The novel chroman derivatives of the formula Ia, where X is Cl, Br or 
O--tosyl, can be directly bonded to an appropriate C.sub.14 Grignard 
compound under catalysis with a di-(alkali metal) tetrahalocuprate in 
accordance with the Schlosser-Fouquet method to give an .alpha.-tocopherol 
isomer, the reaction being carried out very advantageously by the process 
described in a patent application filed on the same date.

EXAMPLE 1 
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-acetoxyethyl)-chroman) in the form of 
a yellow oil, which was recrystallized from ethanol. Mp.=74.degree. C., 
yield=85% of theory. 
(b) L-(4-chloro-2-methyl)-phenoxypropionyl chloride, obtained by heating 80 
g (374 millimoles) of L-(4-chloro-2-methyl)-phenoxypropionic acid with 125 
g of thionyl chloride at 50.degree. C. for 3 hours and distilling off the 
excess thionyl chloride, was added gradually, at 0.degree. C., to a 
solution of 100 g of the ester prepared as described in Example 1a, 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 5N 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 cyrstals 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 mixtue 
of the diastereomeric bisesters 
##STR22## 
of melting point 122.degree. C. and [.alpha.].sub.D.sup.20 =-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 (1b) were heated at the boil with 500 ml of methanol and 132 ml 
of 1N 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.degree. C.; [.alpha.].sub.D.sup.20 =-6.95.degree. (c=2, ethanol). 
EXAMPLE 2 
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-methylphenoxy)-propionyl chloride as the reagent 
for effecting resolution. The yield was 29% of theory, based on the 
racemic hydroxyethyl chroman used. Mp.=155.degree. C.; 
[.alpha.].sub.D.sup.20 =+7.00.degree. (c=2, acetone). 
EXAMPLE 3 
Preparation of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman 
by embodiment (b) with esterification of the phenolic hydroxyl group 
10 g (40 millimoles) of racemic 
2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman were esterified 
in the presence of 200 ml of toluene and 0.1 g of p-toluenesulfonic acid 
by heating for 4 hours with 8.6 g (40 millimoles) of 
(-)-naphth-1-yloxypropionic 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, ie. 58% of the theoretically possible 
amount. Mp.=145.degree. C.; [.alpha.].sub.D.sup.20 =-39.0.degree. (c=2 , 
chloroform). 
Alkaline hydrolysis of the bisester by a method similar to that described 
in Example 1c gave the desired 
(S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman in 26% yield, 
based on the racemic compound used. [.alpha.].sub.D.sup.20 =-7.0 (c=2, 
ethanol); mp.=155.degree. C. 
EXAMPLE 4 
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-yloxypropionic acid as the reagent for effecting 
resolution. 
EXAMPLE 5 
Preparation of (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman 
by embodiment (b), without esterification of the phenolic hydroxyl group. 
10 g (40 millimoles) of racemic 
2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman were esterified 
in the presence of 200 ml of toluene and 0.1 g of p-toluenesulfonic acid 
by heating for 4 hours with 8.6 g (40 millimoles) of 
(-)-naphth-1-yloxypropionic 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-1-yloxypropionate, after which a precipitate formed in the 
course of two days at -20.degree. 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.degree. C.; 
[.alpha.].sub.D.sup.25 =-41.degree. (c=2, CHCl.sub.3). 
4 g of the ester prepared in this manner were dissolved in 140 ml of 
methanol, and the solution was refluxed with 9.0 ml of 1M KOH for 1.5 
hours. Working up by a procedure similar to that described in Example 1c 
gave 2.1 g of 
(R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman. 
Mp.=155.degree. C.; [.alpha.].sub.D.sup.20 =+6.95 (c=2, ethanol). 
EXAMPLE 6 
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-yloxypropionic acid as the reagent for 
effecting resolution. 
EXAMPLE 7 
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 
(-)-naphth-1-yloxypropionate of melting point 145.degree. C. and 
[.alpha.].sub.D.sup.20 =-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 1M KOH for 1.5 
hours. Working up by a procedure similar to that described in Example 1c 
gave the desired (S)-chromanyl ethanol in a yield of 31% of theory, based 
on racemic chromanol used. 
EXAMPLE 8 
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-tetramethyl-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 combined organic phases were washed with sodium chloride 
solution, dried and evaporated down, and the residue was recrystallized 
from methanol. 5.3 g of 
(S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman were obtained. 
[.alpha.].sub.D.sup.20 =-15 (c=2, MeOH), mp.=120.degree. C. 
EXAMPLE 9 
(R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-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. [.alpha.].sub.D.sup.20 
=+15.1 (c=2, MeOH), mp.=120.degree. C. 
EXAMPLE 10 
A mixture of 2 g of 
(S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman, 8 g of 
carbon tetrachloride 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. 
[.alpha.].sub.D.sup.20 =-9.1.degree. (c=2, chloroform), mp.=111.degree. C. 
EXAMPLE 11 
(R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-chloroethyl)-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. [.alpha.].sub.D.sup.20 
=+9.0, (c=2, chloroform), mp.=111.degree. C. 
EXAMPLE 12 
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. [.alpha.].sub.365.sup.20 =+4.23.degree. (c=2, 
ethanol). 
EXAMPLE 13 
(R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-tert.-butoxyethyl)-chroman was 
obtained from (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman 
by a procedure similar to that described in Example 12. 
[.alpha.].sub.D.sup.20 =4.2 (c=2, ethanol). 
EXAMPLE 14 
(S)-2,5,7,8-Tetramethyl-6-hydroxy-2-(2-acetoxyethyl)-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 1a. [.alpha.].sub.D.sup.20 
=-0.1 (c=2, chloroform). Mp.=80.5.degree. C.