Synthesis of 6-hydroxychroman-2-methanol derivatives

A process for producing chroman, a compound of the formula, ##STR1## or an optically active compound thereof wherein R.sub.2, R.sub.3 and R.sub.4 are each a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group, which comprises reacting a compound of the formula, ##STR2## or an optically active compound thereof wherein A is an aryl group and R.sub.5 is a C.sub.1 -C.sub.4 alkyl group, with a compound of the formula, ##STR3## wherein R.sub.1 is a C.sub.1 -C.sub.3 alkyl group, X is a halogen atom and R.sub.2, R.sub.3 and R.sub.4 are as defined above, to obtain a compound of the formula, ##STR4## or an optically active compound thereof wherein A, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above, reacting the resulting compound with methylmagnesium halide and then hydrolyzing to obtain the corresponding 4-aryl substituted 2-hydroxy-2-methylbutanal, or an optically active compound thereof, reducing the resulting compound to obtain a diol, or an optically active compound thereof, and then oxidizing the resulting compound to obtain a compound of the formula, ##STR5## or an optically active compound thereof wherein R.sub.2, R.sub.3 and R.sub.4 are as defined above, followed by reduction. Chromans, the objective compounds of this invention, are an intermediate for the synthesis of tocopherols, particularly .alpha.-tocopherol.

The present invention relates to a method for the production of chromans. 
More particularly, it relates to a method for the production of chromans 
of the formula (7) (hereinafter, the term "chromans" means the compounds 
of this formula), 
##STR6## 
wherein R.sub.2, R.sub.3 and R.sub.4 are each a hydrogen atom or a C.sub.1 
-C.sub.4 alkyl group, which comprises reacting a compound of the formula 
(1), 
##STR7## 
wherein A is an aryl group and R.sub.5 is a C.sub.1 -C.sub.4 alkyl group, 
with a compound of the formula (2), 
##STR8## 
wherein R.sub.1 is a C.sub.1 -C.sub.3 alkyl group, X is a halogen atom and 
R.sub.2, R.sub.3 and R.sub.4 are as defined above, to obtain a compound of 
the formula (3), 
##STR9## 
wherein A, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above, 
reacting the compound of the formula (3) with methylmagnesium halide and 
then hydrolyzing to obtain a compound of the formula (4), 
##STR10## 
wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above, 
reducing the compound of the formula (4) to obtain a compound of the 
formula (5), 
##STR11## 
wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above, 
oxidizing the compound of the formula (5) to obtain a compound of the 
formula (6), 
##STR12## 
wherein R.sub.2, R.sub.3 and R.sub.4 are as defined above, followed by 
reduction. 
Chromans, the objective compounds of this invention, are an intermediate 
for the synthesis of tocopherols, particularly .alpha.-tocopherol. 
.alpha.-Tocopherol has asymmetric carbon atoms at 2-, 4'- and 8'-positions 
as shown by the following formula: 
##STR13## 
Therefore .alpha.-tocopherol has eight optical isomers and its titer of 
vitamin E activity varies with the kind of the optical isomers. For 
example, natural .alpha.-tocopherol (2R, 4'R, 8'R) has a titer of 1.49 
Iu/mg, while dl-.alpha.-tocopherol (2RS, 4'RS, 8'RS) only 1.1 Iu/mg. For 
this reason, production of .alpha.-tocopherol of the same steric 
configuration as that of the natural one is of great significance. On the 
other hand, it is well known that both of the acetic acid esters of 
.alpha.-tocopherols having different steric configurations, (2RS, 4'R, 
8'R) and (2RS, 4'RS, 8'RS), have a titer of 1 Iu/mg. This means that the 
vitamin E activity of .alpha.-tocopherol is not largely affected by the 
steric configuration of the 4'- and 8'-positions of the side chain, but 
mainly determined by the steric configuration at the 2-position. 
Consequently, a study has so far been made, taking into account the steric 
configuration at the 2-position, to produce intermediates for the 
synthesis of 2R-.alpha.-tocopherol. As methods to produce optically active 
intermediates, however, only optical resolution of various racemic 
intermediates is well known Helv. Chim, Acta, 46, 650 (1963); ibid., 59, 
290 (1976); ibid., 61, 837 (1978); ibid., 62, 2384 (1979); J. Am. Chem. 
Soc., 101, 6710 (1979)!. In such optical resolution, only 50% of the 
racemate is effectively used even by resolution of the highest efficiency, 
and the remaining 50% is useless, or, if not, additional steps are 
necessary to convert to compounds having a required steric configuration. 
As a result of extensive study to overcome these drawbacks, the inventors 
found a novel method for the production of chromans. According to the 
present invention, the compound of the formula (4) in high optical purity 
is obtained by asymmetric synthesis, and optically active chromans can be 
produced from it without damaging the optical purity. According to the 
present invention, compounds alone having a required absolute steric 
configuration can be obtained selectively, and besides the asymmetric 
source can be recovered and re-used repeatedly. 
The present invention, therefore, provides a method for producing optically 
active chromans in an industrially advantageous manner. Further, it is 
apparent that a method for producing racemic chromans using racemic 
compounds as material is also included in the scope of the present 
invention. 
The compound of the formula (1) can be produced from N-(aryl-substituted 
aminomethyl)pyrrolidine and alkoxyhydroxyacetic acid ester Japanese 
Patent Publication (Kokai) No. 162786/1980!. 
In the formula (1), A, an aryl group, includes unsubstituted and lower 
alkylsubstituted phenyl groups such as phenyl, p-tolyl, 2,6-xylyl groups 
etc., and of these, a phenyl group is preferable. R.sub.5, a C.sub.1 
-C.sub.4 alkyl group, includes for example methyl, ethyl, isopropyl, 
n-propyl, n-butyl groups etc. 
The compound of the formula (1) is reacted with a Grignard reagent of the 
formula (2) to obtain the compound of the formula (3). 
In the formula (2), R.sub.1, a C.sub.1 -C.sub.3 alkyl group, includes 
methyl, ethyl, n-propyl groups etc., and R.sub.2, R.sub.3 and R.sub.4 each 
includes a hydrogen atom and C.sub.1 -C.sub.4 alkyl groups such as methyl, 
ethyl, n-propyl, isopropyl, n-butyl groups etc., of which a hydrogen atom 
and a methyl group are preferred. A Grignard reagent of the formula (2) is 
obtained by reacting the corresponding halides (e.g. chlorides, bromides, 
iodides) with magnesium. As the solvent used in this reaction, those which 
are commonly used for Grignard reaction, for example tetrahydrofuran, 
ether and mixtures thereof, will do. Further, the yield of this reaction 
may be increased by adding magnesium halides (e.g. magnesium chloride, 
magnesium bromide, magnesium iodide) to the reaction system, and of these 
halides, magnesium chloride is preferred. The reaction can generally be 
effected at a temperature from the freezing point of the solvent to the 
boiling point of the solvent, but lower temperatures are desirable in 
order to decrease by-products. 
The compound of the formula (3) thus obtained is reacted with 
methylmagnesium halide and then hydrolyzed to obtain the compound of the 
formula (4). Methylmagnesium halide referred to herein means 
methylmagnesium chloride, methylmagnesium bromide and methylmagnesium 
iodide. As a solvent used in this reaction, those which are commonly used 
for Grignard reaction, for example, ether, tetrahydrofuran and mixtures 
thereof, will do. The reaction can generally be effected at a temperature 
from the freezing point of the solvent to the boiling point of the 
solvent, but lower temperatures are desirable in order to produce optical 
isomers. Hydrolysis is carried out with acids such as hydrochloric acid, 
sulfuric acid etc. The reaction temperature may be raised if necessary, 
but this reaction will proceed smoothly even at room temperature. 
The compound of the formula (4) thus obtained is reduced into the compound 
of the formula (5). As a reducing agent used in the reduction of said 
compound, common reducing agents capable of reducing a carbonyl group, for 
example metallic hydrides (e.g. lithium aluminum hydride, sodium 
borohydride, aluminum diisobutyl hydride, lithium borohydride) etc., will 
do. The solvent used in the reduction varies with the kind of reducing 
agent, but those which are commonly used will do. For example, there are 
given ether, tetrahydrofuran etc. for reduction with lithium aluminum 
hydride or lithium borohydride; ethanol, diglyme etc. for reduction with 
sodium borohydride; and benzene, toluene, ether, tetrahydrofuran etc. for 
reduction with diisobutyl aluminum hydride. The reaction can generally be 
effected at a temperature from -5.degree. C. to the boiling point of the 
solvent. 
The compound of the formula (5) thus obtained is then oxidized into the 
compound of the formula (6). In this reaction step, the compound of the 
formula (6) may be obtained directly by oxidation of the compound of the 
formula (5), but it may also be obtained by another route in which the 
compound of the formula (5) is once converted to the compound of the 
formula (8), 
##STR14## 
wherein R.sub.2, R.sub.3 and R.sub.4 are as defined above, which is then 
converted to the compound of the formula (6) by ring-closure. As an 
oxidizing agent used in this reaction, there may be given those which are 
capable of oxidizing the ether form of hydroquinone into the quinone form 
thereof, for example ammonium ceric nitrate, ammonium ceric sulfate etc. 
The amount of oxidizing agent used is 1.0 to 1.3 equivalents, preferably 
1.1 equivalents based on the compound (5). As the solvent used in this 
oxidation, when ammonium ceric nitrate or ammonium ceric sulfate is for 
example used as oxidizing agent, those which are commonly used together 
with said oxidizing agents will do. For example, mixture of water and 
acetonitrile, acetic acid or methanol and the like are used. The reaction 
temperature is not particularly limited, but it is preferably from 
-10.degree. C. to 30.degree. C. Of the compounds of the formulae (6) and 
(8) thus obtained, the compound of the formula (8) can be converted to the 
compound of the formula (6) by reaction with an acid such as hydrochloric 
acid. 
The compound of the formula (6) thus obtained is then reduced into the 
objective chromans represented by the formula (7). Reduction may be 
carried out by catalytic hydrogenation. As the catalyst for catalytic 
hydrogenation, there may be given catalysts having a reducing power such 
as palladium, platinum, nickel etc. As a solvent used in this reaction, 
those which are commonly used in catalytic hydrogenation will do, and for 
example, there may be given methanol, ethanol, acetic acid etc. The 
reaction temperature is not particularly limited. It may be raised if 
necessary, but this reaction will proceed smoothly at a temperature from 
-10.degree. C. to 30.degree. C. 
The present invention will be illustrated specifically with reference to 
the following examples.

EXAMPLE 1 
(1) A benzene solution containing 541 mg (3.14 mmole) of 
(S)-2-(anilinomethyl)pyrrolidine and 425 mg (3.45 mmole) of methyl 
hydroxymethoxyacetate was heated under reflux for 30 minutes while 
removing formed water azeotropically, to form 
3-methoxycarbonyl-2-phenyl-hexahydro-1H-pyrrolo1,2-c!imidazole. After 
removing the solvent from the resulting reaction solution, the residue was 
dissolved in 20 ml of tetrahydrofuran, and 330 mg (3.48 mmole) of 
anhydrous magnesium chloride was added thereto, followed by heating under 
reflux for 1 hour. The reaction solution was cooled to -100.degree. C., 
and a solution of 2-(2,5-dimethoxy-3,4,6-trimethylphenyl)ethylmagnesium 
bromide in tetrahydrofuran was added dropwise thereto. Completion of the 
reaction was examined by thin layer chromatography. Thereafter, a 
saturated aqueous ammonium chloride solution and ether were added, and the 
organic layer was separated, dried over sodium sulfate and freed from the 
solvent by evaporation. The residue was purified on alumina column to 
obtain 730 mg (55%) of 
3-3-(2,5-dimethoxy-3,4,6-trimethylphenyl)propanoyl!-2-phenyl-hexahydro-1H 
-pyrrolo1,2-c!imidazole. 
nmr (CCl.sub.4) .delta. (ppm)=1.6-3.7 (13H, m), 2.06 (9H, s), 3.50 (6H, s), 
4.28 (1H, s), 6.25-7.16 (5H, m) 
(2) 505 mg (1.20 mmole) of 
3-3-(2,5-dimethoxy-3,4,6-trimethylphenyl)propanoyl!-2-phenyl-hexahydro-1H 
-pyrrolo1,2-c!imidazole obtained in (1) was dissolved in ether, and cooled 
to -100.degree. C. To this solution was added about three equivalents of 
methylmagnesium iodide, and after 30 minutes, a saturated aqueous ammonium 
chloride solution was added. After separating the ether layer, 13 ml of 2% 
hydrochloric acid was added to the layer which was then stirred at 
0.degree. C. for 2 hours and extracted with ethyl acetate. The organic 
extract was washed with a saturated aqueous solution of sodium chloride 
dried over sodium sulfate and freed from the solvent by evaporation. The 
residue was purified on silica gel column to obtain 181 mg (54%) of 
(S)-4-(2,5 -dimethoxy-3,4,6-trimethylphenyl)-2-hydroxy-2-methylbutanal. 
nmr (CCl.sub.4) .delta. (ppm)=1.20 (3H, s), 1.56-1.85 (2H, m), 2.05 (9H, 
s), 2.16-2.80 (2H, m), 3.40 (1H, s), 3.46 (3H, s), 3.51 (3H, s), 9.25 (1H, 
s) 
.alpha.!.sub.D +39.6.degree. (C. 0.53, benzene) 
(3) 180 mg (0.643 mmole) of 
(S)-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-hydroxy-2-methylbutanal was 
dissolved in 5 ml of ethanol, and 30 mg (0.79 mmole) of sodium borohydride 
was added, followed by stirring at room temperature for 30 minutes. Water 
was added to the reaction solution which was then extracted with methylene 
chloride. The organic extract was washed with a saturated aqueous solution 
of sodium chloride dried over sodium sulfate and freed from the solvent 
under reduced pressure. The residue was purified on silica gel column to 
obtain 156 mg (86%) of 
(S)-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-methyl-1,2-butanediol. 
nmr (CCl.sub.4) .delta. (ppm)=1.17 (3H, s), 1.50 (2H, m), 2.08 (6H, s), 
2.13 (3H, s), 2.67 (4H, m), 3.37 (2H, s), 3.55 (3H, s), 3.62 (3H, s), 
mp=83.degree.-84.degree. C. 
.alpha.!.sub.D +3.1.degree. (c 1.14, methylene chloride) 
(4) 278 mg (0.986 mmole) of 
(S)-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-methyl-1,2-butanediol was 
dissolved in 4 ml of acetonitrile, and an aqueous solution (4 ml) 
containing 1.16 g (2.07 mmole) of ammonium ceric nitrate was added 
dropwise at room temperature for 2 minutes. After stirring for 5 minutes, 
the reaction solution was extracted with chloroform, and the chloroform 
extract was washed with a saturated aqueous solution of sodium chloride, 
dried over sodium sulfate and freed from the solvent under reduced 
pressure. The residue was purified on silica gel column to obtain 150 mg 
(65%) of (3S, 
9aR)-3,6,8,9-tetramethyl-3,9a-epoxy-2,3,4,5,7,9a-hexahydro-1-benzoxepin-7- 
one and 50 mg (20%) of 
(S)-2-(3,4-dihydroxy-3-methylbutyl)-3,5,6-trimethyl-1,4-benzoquinone. 
Physical properties of (3S, 
9aR)-3,6,8,9-tetramethyl-3,9a-epoxy-2,3,4,5,7,9a-hexahydro-1-benzoxepin-7- 
one 
nmr (CCl.sub.4) .delta. (ppm)=1.35 (3H, s), 1.72 (3H, s), 1.80 (6H, s), 
1.7-2.7 (4H, m), 3.48 (1H, d), 4.02 (1H, d) 
mp=98.degree. -99.degree. C. 
.alpha.!.sub.D -66.1.degree. (c 0.039, benzene) 
physical properties of 
(S)-2-(3,4-dihydroxy-3-methylbutyl)-3,5,6-trimethyl-1,4-benzoquinone 
nmr (CCl.sub.4) .delta. (ppm)=1.23 (3H, s), 1.36-1.60 (2H, m), 2.00 (6H, 
s), 2.03 (3H, s), 2.40-2.73 (4H, s), 3.50 (2H, s) 
(5) 
##STR15## 
81 mg (0.35 mmole) of (3S, 
9aR)-3,6,8,9-tetramethyl-3,9a-epoxy-2,3,4,5,7,9a-hexahydro-1-benzoxepin-7- 
one was dissolved in 8 ml of ethanol, and then catalytic hydrogenation was 
carried out at room temperature under atmospheric pressure with addition 
of 60 mg of 5% palladium/carbon. After removing the catalyst by 
filtration, the reaction solution was concentrated. The residue was 
purified on silica gel column to obtain 62 mg (76%) of 
S-6-hydroxy-2,5,7,8-tetramethyl-2-chromanmethanol. 
nmr (CCl.sub.4) .delta. (ppm)= 1.36 (3H, s), 2.17 (6H, s), 2.20 (3H, s), 
1.5-2.8 (5H, m), 3.63 (2H, brs), 4.43 (1H, s) 
mp 127.degree.-128.degree. C. 
.alpha.!.sub.D -2.8.degree. (c 0.50, methylene chloride)