JPS6026795B2 - Method for producing chroman derivatives - Google Patents

Description

[Detailed description of the invention] The present invention relates to chroman derivatives and methods for producing the same.

The chroman derivatives provided by the present invention include a chroman derivative having a hydroxyl group or an ether group that can be converted into a hydroxyl by hydrolysis or hydrogenolysis, or an ester group that can be converted into a hydroxyl by hydrolysis;
is lower alkyl, and m is an integer of 0 to 1], and further compounds obtained therefrom.

It is a man derivative. Chroman derivatives of formula 1 are intermediates in the production of Q tocopherol.

The compound of formula 1 exhibits the naturally occurring optically active Q-tocopherol, i.e., the following, 4'R and 81'R co-configurations, depending on whether the compound is in the S, L or S form. and Q tocopherol having the following configuration -'R,4'
It is useful as an intermediate in the production of RS, 8RS; Ru, 4'R, 8'R; $, 4'RS, 8RS: 2RS, 4'RS, 8'RS;

Accordingly, the present invention provides a simple and economical method for stereospecifically synthesizing Q-tocopherol in high yield.

As used throughout this specification, the term "lower alkyl" includes both straight-chain and branched alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl and propyl, preferably methyl. be.

As used herein, the term "lower alkoxy J" means
Included are groups having 1 to 7 carbon atoms, such as methoxy and ethoxy groups. The term "lower alkanoic acid" as used herein also includes alkanoic acids of 2 to 7 carbon atoms, such as acetic acid and propionic acid. Further, as used herein, the term "halogen" or "halo" includes fluorine, chlorine, bromine and iodine, unless otherwise specified. The term "lower alkylenedioxy" refers to lower alkylenedioxy groups containing from 2 to 6 carbon atoms, such as ethylenedioxy. The term "aryl" as used herein may also be unsubstituted or substituted at one or more positions with lower alkylenedioxy, halogen, nitro, lower alkyl, or lower alkoxy substituents. Good mononuclear aromatic hydrocarbon radicals, such as phenyl, tolyl, etc., as well as polynuclear aryl radicals, which may be unsubstituted or substituted with one or more of the above groups, such as naphthyl, anthryl, phenanthryl, Represents Azuril etc. Suitable aryl groups are substituted and unsubstituted mononuclear aryl groups, especially phenyl.
The term "aryl lower alkyl" includes groups where aryl and lower alkyl are as defined above, particularly pendyl. The term "aryl lower alkanoic acid" includes acids in which "aryl" and "lower alkanoic acid" are as defined above, particularly benzoic acid. As used herein, the term "ester group hydrolytically convertible to hydroxy" refers to any ester group that can be hydrolyzed to yield hydroxy. Examples of ester groups utilized for this purpose are those in which the acyl moiety is derived from a lower alkanoic acid, an aryl lower alkanoic acid, a phosphoric acid, a carbonic acid or a lower alkanedicarboxylic acid. Acids that can be used to generate such ester groups include acid anhydrides and acid halides, preferably chlorides or bromides, lower alkanoic anhydrides such as acetic anhydride and hydroproic anhydride, aryl lower alkanoic anhydrides. Preference is given to compounds such as benzoic anhydride, lower alkanedicarboxylic acid anhydrides such as succinic anhydride, and chloroformates such as trichlorethyl chloroformate. The term "ether group convertible to hydroxy by hydrogenolysis or hydrolysis" refers to ethers that yield hydroxy upon hydrogenolysis or hydrolysis. Suitable ether protecting groups are arylmethyl ethers such as penzyl, benzylhydryl or trityl ethers, or Q-lower alkoxy lower alkyl ethers such as methoxymethyl,
toterahydropyranyl or allylic ether. In the structural formulas described throughout this specification, substituents that are attached to the molecule above the plane of the molecule are represented by ▲, and substituents that are attached to the molecule below the plane of the molecule are represented by words.

When no configuration is represented in the structural formulas described throughout this specification, the compounds represented by those formulas can be in either the R or S configuration, or the compounds can be in the R and S configuration. It can be a mixture of isomers. Compounds of formula 1 when m is 1 have the formula: where R and R are as defined above.

A group of chroman derivatives of formula IA are compounds of formula 1 when m is 0 and have the formula: where R and R are as defined above.

Representative examples of chroman derivatives of formula 1 are: 2-methoxycarbonyl-6-acetoxy 2,5
, 7,8-tetramethyl-chroman, ±2-methoxycarbonyl-methyl-6-hydroxy-2,5,7,8-tetramethyl-chroman, 2-ethoxycarbonyl-methyl-6-hydroxy-2,5,7 , 8-tetramethyl-chroman, ±2-methoxycarbonyl-methyl-6
-benzyloxy-2,5,7,8-tetramethyl-chroman, ±2-methoxycarbonyl-6-acetoxy-2,5,7,8-tetramethyl-chroman, 2-methoxycarbonyl-6-hydroxy-2,5,7 , 8-tetramethyl-chroman.

According to the method provided by the present invention, the chroman derivative of formula 1 is a compound of the formula [wherein R is hydroxy, an ether group that can be converted to hydroxy by hydrolysis or hydrogenolysis, or an ester that can be converted to hydroxy by hydrolysis] A compound of the formula [wherein R4 is a lower alkyl group and R2, R3 and R4 are aryl] or a compound of the formula [wherein R, is as above and R5 and R
6 is aryloxy or lower alkoxy]. is as described above] or the compound of formula 0 above is treated with an alkali metal cyanide and the resulting compound of formula [wherein R is as above] is converted into a compound of formula [wherein R is as above] ．． is as described above, and R'' is hydroxy or an ether group which can be converted to hydroxy by hydrolysis or hydrogenolysis, and the hydroxy group R'' in formula IB is optionally converted into an ester group. Alternatively, it is prepared by obtaining a compound of the formula: where R and R are as defined above.

The resulting formula [wherein R and R. is as described above and m is an integer from 0 to 1], optionally a compound of the formula [wherein R and m are as described above and X is halogen] via an acid halide or an aldehyde of the formula [wherein R and m are as above], where Z is Li or MgX, x is a halogen, and n is 0 to 1 is an integer of , and the sum of m and n in Shikihada and Gen or Hata and M is 1], or through an aldehyde in which R and m are as above. , formula [wherein x is a halogen, and n is an integer from 0 to 1, and the sum of m and n in the formula plate and X is 1]
Phospho-organic condensation with a compound of
It can be converted to Q-tocopherol by ganiccondensation).

The starting compound of formula 0 can be prepared, for example, as follows: In a first step, a hydroquinone of the formula [wherein R is as above] is added to a hydroquinone of the formula [wherein R and R, is as above].

One method for producing compounds of the formula x skin is the formula x w
, with a compound of the formula: where R is as defined above.

This reaction is conveniently carried out at a temperature of 120 qo to 250 CO. Pressures from atmospheric to about 7 pressures can be used in carrying out this reaction. This reaction takes place in an inert organic solvent. Any inert organic solvent can be used in carrying out this reaction. Among the preferred inert organic solvents are aromatic hydrocarbon solvents such as toluene, xylene and benzene, with benzene being particularly preferred. Another method of producing a compound of formula x skin consists of reacting a compound of formula x with any one of the following compounds: [wherein R, is as above] The reaction between the compound and the compound of formula x plate B to x leg E is,
It is carried out in the presence of an acid catalyst.

Any conventional acid catalyst can be used in carrying out this reaction. Among the preferred acid catalysts are inorganic acids such as sulfuric acid, perchloric acid, hydrobromic acid and phosphoric acid, with sulfuric acid being particularly preferred. If necessary, this reaction can be carried out in the presence of a dehydrating agent. By using dehydrating agents,
It was found that the yield of compounds of formula × skin is increased. Any conventional dehydrating agent can be used in carrying out this reaction. Among the preferred dehydrating agents are trilower alkyl orthoformates, such as trimethyl orthoformate,
Calcium chloride, sodium sulfate, acetone dimethyl ketal and the like are included, with trimethyl orthoformate being particularly preferred. In carrying out this reaction, an organic alcohol such as a lower alkanol is used as a solvent. Preferred lower alkanols include methanol, ethanol, isopropanol and the like, with methanol being preferred. However, any conventional alcoholic solvent can be used in carrying out this reaction. Temperature and pressure are not critical in this reaction, and the reaction can be carried out at room temperature and atmospheric pressure. On the other hand, higher and lower temperatures than room temperature can be used when carrying out this reaction. Generally, a reflux temperature of -200°C or less for the reaction soot is used. If R in the compound of formula × skin is hydroxy, this free hydroxy group can be optionally protected by esterification to give an ester that can be rearranged to hydroxy by hydrolysis, or hydrogenated by etherification. Decomposition or hydrolysis can provide an ether group that can be rearranged to hydroxy. To protect the hydroxy group, any transparent ester group that can be converted to hydroxy by hydrolysis can be used. On the other hand, to protect the hydroxy group, any ether group that can be rearranged to hydroxy by hydrogenolysis can be used. Free hydroxyl groups R in compounds of formula x skin using any conventional esterification or etherification method
can be protected. Among the preferred esterification methods is the reaction of the compound of formula x with a reactive promoter of an organic acid, such as a prechloride or acid anhydride. Any conventional conditions can be used in carrying out these reactions. Preferred esters of compounds of formula x plate are lower alkanoic acid esters of compounds of formula x plate, with acetate esters being particularly preferred. In converting a hydroxy group to an ether moiety, any conventional etherification method can be used. A preferred group for use in this reaction is pendyl ether. Formula × having a free hydroxy group or the hydroxy group protected by esterification or etherification
The skin compounds are then hydrolyzed with hydric acid, in the formula:
R is as described above] A compound is prepared.

Any conventional acid hydrolysis method can be utilized for this conversion, such as using strong acids including sulfuric acid, hydrochloric acid, and the like. If the hydroxy group in the compound of formula 0 is etherified, this ether group can be hydrolyzed by strong acid treatment to generate the corresponding hydroxy group. According to the method of the invention, reactions of the WMing type using compounds of formula m or of the Horner type using compounds of formula W can be carried out using It has been found that compounds of formula IA can be prepared when working with -hydroxy-substituted chroman nuclei.

By using this process to prepare compounds of formula IA, the deleterious effects of ozone reactions and ozonation on chroman nuclei are avoided in the process of the present invention. The reaction between the phosphorane of formula m and the compound of formula 0 can be carried out in the presence of an organic solvent, if necessary.

Any conventional organic solvent can be used in carrying out this reaction. Among the common organic solvents obtained according to the present invention are benzene, toluene, N,N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran and dioxane. When performing this reaction,
Temperature and pressure are not critical, and the reaction can be conducted at temperatures from about 0°C to about 5°C and atmospheric pressure. The phosphorane of the above formula rainbow can be prepared from the corresponding phosphonium salt of Z by known methods. According to the invention, R
2, R3 and R4 can be aryl groups.
Aryl groups capable of forming substituents represented by R2, R3 and R4 include mononuclear aryl groups such as phenyl or directly Z-substituted phenyl such as tolyl, xylyl, mesityl, 4-methoxyphenyl, etc. .
XXXXXXXXXAryl substituents can be polynuclear aryl groups, such as naphthyl, anthryl, phenanthryl, and the like. 2 The reaction between a phosphonate of formula N and a compound of formula 0 can be carried out by first making a solution of the alkali metal base and the phosphonate of formula W in an inert organic solvent and then adding the compound of formula B to this reaction mixture. , can be done. In carrying out this reaction, the usual alkali metal bases are used; alkali metal hydrides such as sodium hydride and alkyl lithium; alkali metal lower alkoxides such as sodium methoxide and sodium ethoxide; and alkali metal bases such as sodium amide, potassium amide, etc. Alkali metal amide bases and other alkali metal lower alkylamides can be used. When performing this reaction,
Any conventional inert organic solvent can be used, such as benzene, toluene, N,N-dimethylformamide, tetrahydrofuran, dioxane, 1,2-dimethoxyethane. In carrying out this reaction, temperatures from 0° C. to the reflux temperature of the solvent can be used. Phosphonates of formula N may be substituted with alkoxy or aryloxy groups. Similar to R2, R3 and R4 in the phosphorane of formula m, the aryl group contained in R5 and R6 in the phosphonate of formula N can be a mononuclear or polynuclear aryl group, which group is substituted or It can be uncounterfeited. If the compound of formula N is substituted with an alkoxy group, it is generally preferred to use alkoxy groups containing 1 to 4 carbon atoms, such as methoxy, ethoxy and isopropoxy. Among the aryloxy groups, unsubstituted phenoxy groups are generally preferred. When R in a compound of formula D is a hydrolysable ester group, reaction via a phosphonate of formula W can prepare a compound of formula IA when R is hydroxy.

If desired, free hydroxy groups in compounds of Formula IA can be reesterified to produce hydrolysable ester groups. According to the method of the invention, formula IB
It has been found that compounds of formula 0 can be prepared from compounds of formula 0 and optionally also from compounds of formula OA: In the first step of this reaction, a compound of formula 0 or OA is reacted with an alkali metal in a medium of an inert organic solvent. cyanide and then the reaction mixture is treated with 3 to 7, preferably 4 to 6
A compound of formula 0 or OA is converted to a compound of formula V above by maintaining a pH of .

A preferred alkali metal cyanide for carrying out this reaction is cyanide. When carrying out this reaction, any conventional inert organic solvent can be used as the reaction soot. It is generally preferred to use a solvent such as dimethyl sulfoxide or dimethyl formamide. Any commonly used means can be used to maintain the pH of the reaction soot between 3 and 7.
Generally, this pH is maintained by means of adding an acid to the reaction medium containing the compound of formula 0 or OA. Any conventional acid capable of maintaining the reacting soot at a pH of 3 to 7 can be used. Among the preferred acids are sulfuric acid and hydrochloric acid. Temperatures from 0 to 40<0>C can be used when carrying out the invention. In the next step of this reaction,
Compounds of formula V can be converted into mixtures of compounds of formula where R is as defined above and R'' is hydroxy or an ether group which can be converted to hydroxy by hydrolysis or hydrogenolysis.

The reaction is carried out using anhydrous mineral acids in lower alkanols at temperatures from -20 DEG C. to 10 qo and then adding water. Any conventional mineral acid anhydride can be used to carry out this reaction. Among these, preferred key acids are hydrohalic acids, with hydrochloric acid being particularly preferred. Any conventional lower alkanol can be used in this reaction. Among the preferred lower alkanols are methanol and ethanol. The resulting compound of formula IB'' can be cyclized by reacting with a Lewis acid, in particular zinc chloride, aluminum chloride or sherachloride trifluoride.

Optionally, the hydroxy group R in the compound of formula IB
By changing ' to an ester group, compounds of formula IB can be generated. The chroman derivatives of Formula 1 can be converted to the corresponding formula acid halides and aldehydes.

The latter compound is the starting compound for producing Q-tocopherol. Conversion of compounds of formula 1 to formula skin and skin compounds is carried out via acids of formula where R and m are as defined above.

Compounds of formula 1 can be converted to acids of formula 1 via reaction step a, where R, R, and m are as described above.

Any conventional basic hydrolysis method can be used to carry out the reaction of step a.

Generally, the reaction of step a can be carried out using an alkali metal hydroxide, such as sodium hydroxide, in an aqueous soot. In carrying out this reaction, temperatures of about 5° C. to the reflux temperature of the reaction medium are used. This basic hydrolysis converts the hydrolyzable group R in the compound of formula IA to A of formula
hydroxy in the compound. When R in a compound of formula A is hydroxy, this group can be esterified by conventional methods to give a compound of formula A where R is an ester group which can be converted to hydroxy. Acids of formula W can be separated into their enantiomers if desired.

The resolution of the acid of formula A when m is 1 can be carried out according to the following reaction scheme: [wherein R
is as described above.] A compound of formula A can be separated into its enantiomers by any conventional chemical method.

Among these, a preferred chemical method is a method in which two compounds of formula WA are reacted with an optically active base. This resolution can be carried out using conventional optically active bases. Preferred optically active bases include optically active amine bases such as Q-methylbenzenamine, quinine,
These include dehydroapiethylamine and Q-methylnaphthylamine. Any technique common in the resolution of organic acids with optically active organic amine bases can be used in carrying out this reaction. In this resolution step, a compound of formula A is reacted with an optically active base in an inert organic solvent soot to form an optically active amine with both the wave and deprived isomer of the compound of formula A. Manufactures salt.

In making these salts, temperature and pressure are not critical; salt formation can occur at room temperature and atmospheric pressure. On the other hand, higher or lower temperatures can be used. When carrying out this salt formation, any conventional organic solvent can be used. The R and S salts can be separated by any conventional method, such as fractional crystallization.
After crystallization, each salt can be converted into a compound of the formula Ab and Ab by hydrolysis with an acid, respectively. Any conventional method using acids can be used to hydrolyze these salts. Among the preferred acids are
Examples include dilute aqueous mineral acids, ie, from about 0.001N to aqueous acids, such as aqueous sulfuric acid or aqueous hydrochloric acid.

The reaction of step (bl) converts the compound of formula WA into its other form (compound of formula Aa) and its fox form (compound of formula Aa).
Compound b).

If it is desired to produce natural tocopheres, a compound of formula Aa is used in the remaining synthesis disclosed below. On the other hand, if it is desired to produce other isomers of natural Q tocopherol, a compound of formula WAb or WA is used in the remaining steps of the process. On the other hand, according to the invention, the formula WA
A or a compound of formula Ab can be converted into a compound of formula A via reaction step (b2). This process method allows one to obtain an isomer of formula WA that does not give rise to natural Q tocopherol, which can also be racemized to give an isomer of formula A
can be converted back to the compound. Alternatively, the natural isomer, ie, a compound of formula Aa, can be obtained and racemized back to a compound of formula A2. Therefore, according to this method, a compound of formula Aa (
A compound that yields natural Q tocopherol) or formula A
The yield of compound b can be substantially increased.
Accordingly, the method of the present invention provides a method for producing natural Q-tocopherol and other isomers of Q-tocopherol in high yields. The reaction of compounds of formula A or of formula WAb to produce compounds of formula A can be carried out using variations of these two methods. When R in the compound of formula Aa or formula Ab is a hydroxy or ester group, the compound of formula Aa or WAb can be converted to the compound of formula A by treating with an aqueous mineral acid solution. Generally, an aqueous mineral acid solution of 1 to 1 is used. This reaction can be carried out in aqueous soot. Any conventional key acid can be used when carrying out this reaction. Among the preferred stannic acids are sulfuric acid, hydrochloric acid, hydrobromic acid, and the like. On the other hand, when R is an ether group, the reaction in step (b2) is carried out in the presence of an acid or a robber group. If the reaction is carried out in the presence of a salt, it is carried out in the same manner as described for the racemization of compounds of formula Aa or Ab when R is hydroxy. When the reaction is carried out in the presence of a strong base, it is carried out under anhydrous conditions and in the presence of an inert organic solvent. Any conventional inert organic solvent can be used to effect this racemization. Among the preferred inert organic solvents for use in carrying out this racemization are toluene, dioxane, glyme, diglyme, tetrahydrofuran, and the like. Any conventional strong alkali metal base can be used when carrying out this reaction. Among the strong bases are alkali metal hydrides such as sodium hydride and alkali metal di-lower alkylamides. Among these, preferred are alkali metal di-lower alkylamides, lithium diisopropylamide and lithium isopropylcyclohexylamide. When carrying out this racemization in the presence of an acid or base, temperature and pressure are not critical, and the reaction can be carried out at room temperature and atmospheric pressure. On the other hand, higher or lower temperatures can be used. Generally, when performing this reaction, 2
It is preferable to carry out the reaction at the reflux temperature of the reaction mixture. When R in the compounds of formulas Aa and Ab is an ester group, this group can be converted to hydroxy during the racemization process. When R forms an ether or ester group in the compounds of formulas A, Machinade, and Ab, these compounds can be converted to compounds of formula IA by hydrolysis or hydrogenolysis, and Either addition or decomposition depends on whether R is an ester group that can be converted to hydroxy by hydrolysis or an ether group that can be converted to hydroxy by hydrolysis or hydrogenolysis.

In carrying out this process, any conventional ether or ester hydrolysis or ether hydrogenolysis process can be used. The resolution of acids of formula 1, i.e. acids of formula IB, when m is 0, can be carried out according to the following reaction scheme: where R is as above. A compound of B can be converted into its enantiomer, ie a compound of formula Bb, via a reaction step (cl).

Resolution of compounds of formula B can be carried out using separation methods similar to those described for step (bl). The preferred resolving agent for use in this reaction is an optically active organic amine base such as Q-methylbenzenamine. As in step (bl), the organic amine base has the formula W
Together with both the B wave and the A isomer, this salt is split in the usual manner, e.g. by fractional crystallization, as in step (bl) and hydrolyzed to form the respective wave and isomer forms. It can be done. Natural optically active Q-tocopherol can be prepared using enantiomers of the formula Ba. According to the invention, B of the formula
At the 2-position in the compound of a, the same configuration is maintained during the process of converting it into a vitamin E compound.
Thus, compounds of formula Ba can be used to prepare globular isomers of vitamin E compounds. On the other hand, by using the compound of formula Bb, the isomer containing Q tocopherol can be produced. If desired, a compound of formula Bb can be racemized to produce a compound of formula B. This racemization can be carried out in the same manner as described for reaction step (Q). This racemization produces the natural isomer precursor Ba or the non-natural isomer precursor WBb in high yield. On the other hand,
Compounds of formula B can be used as precursors for preparing the S isomer of vitamin E compounds. Formula 1
An acid of the formula obtained by hydrolysis of a compound of can be converted into an acid halide of the formula, where R and m are as above and X is a halogen.

Compounds of formula W can be prepared from compounds of formula W with their phenolic hydroxy groups protected by using conventional methods for converting carboxylic acids to the corresponding acid halides.

In carrying out this reaction, any method conventional in acid halogenation can be used. A preferred method for halogenating compounds of formula 1 consists of treating this compound with a halogenating agent, preferably a chlorinating agent such as oxalyl chloride, thionyl chloride, phosphorus pentachloride, and the like. Any conventional halogenating agent can be used in carrying out this reaction. An acid halide of the formula obtained by halogenation of a compound of the formula can be converted into an aldehyde of the formula where R is as defined above.

The compound on the formula side is derived from Rosenmund (R
osemm dishes d) can be produced by reduction.

When performing this reaction. Any conditions common in Senmund reductions can be used. Generally, this reaction is carried out by hydrogenation in the presence of an inactivated palladium catalyst and an acid acceptor. Any conventional deactivated palladium catalyst can be used in this reaction, such as organosulfur derivatives or quinolines commonly used in the art. Any conventional acid acceptor can be used in carrying out this reaction, such as a base. Among the preferred bases are alkali metal salts of lower alkanoic acids, such as sodium acetate, and tri-lower alkyl amines, such as triethylamine.
R is removed by hydrogenolysis and hydrogen is removed. If it is an ether group that can be converted to xy, this reaction can remove the ether group and produce a compound with the formula when R is hydroxy. However, if R is a pendyl ether group that can be converted to hydroxy by hydrogenation, this reaction surprisingly selectively reduces the acid chloride without acting on the benzyl ether moiety. Another method for preparing compounds of formula 1 consists in reducing compounds of formula 1 when R is an ether or ester group.

This reduction is performed using a compound of formula 1 with aluminum hydride or sodium dihydropis-(2) as the reducing agent.
-methoxyethoxy)-aluminum hydride. This reduction is carried out in an inert organic solvent soot. Any conventional inert organic solvent can be used when carrying out this reaction. Among the preferred inert organic solvents are bentane, dioxane, diethyl ether, hexane, toluene, benzene or xylene.

Generally, when carrying out this reaction, 112 to 130 pi
00 temperature is used. The formula aldehyde is divided into its raft form with the formula [wherein R and m are as above] and its 2R form with the formula [wherein R and m are as above] be able to.

A compound of the formula when in racemic form can be resolved into its optically active enantiomers by methods commonly used for the resolution of aldehydes. Among the methods commonly used for the resolution of aldehydes is the reaction of the aldehyde with an optically active amine such as Q-methylbenzylamine or dehydroabiethylamine to form Schiff's base. Another method for partitioning aldehydes in formulas consists of reacting the aldehyde with an optically active hydrazide to form a hydrazone. Any other conventional optically active amines, racemic amines, optically active acids, and optically active hydrazides used in the resolution of aldehydes can be used in the present method. Diastreomeric mixtures prepared by reacting an aldehyde with an optically active amine or racemic amine and then forming a salt with an optically active salt or a hydrazone made from an optically active hydrazide are commonly It can be separated by a method such as crystallization. Optically active aldehydes can be regenerated by standard methods.
If it is desired to produce natural tocopherols, the compounds of the formula Ji in the S form, ie the compounds of the formula Jiaxu and Yanagi Ba, are used in this remaining synthesis step.

On the other hand, if you want to produce natural Q-tocopherol,
The formula compound or its R form can be used in the remaining steps of the process. On the other hand, according to the present invention,
The R or S form of the formula skin compound is added to the reaction step (
The racemic form of the compound of the formula can be converted by the reaction already described under b2). According to this process method,
Formulated isomers that do not produce Q-tocopherol can be obtained and reconstituted by racemization.
Alternatively, the natural isomer, ie the S form, can be obtained and racemized back to a compound of the formula. According to this method, the yield of the S or R form of the compound of the formula can be substantially increased. According to the present invention, aldehydes of the formula and in which R is hydroxy are converted into natural optically active Q-tocopherols and derivatives thereof having the formula R is hydroxy. be able to.

Fox, 4'R and 8 configuration
In addition to producing natural optically active compounds of formula
4'RS, 8RS; raft, 4'R, 8'R; $, 4'RS, 8RS; 2RS, 4RS, 8RS, and 2RS, 4'R, 8R.

an expression with Compounds of can be produced.

Generally, an aldehyde of the formula can be converted to a wave S of the formula, an isoS isomer phosphorane, or a phosphorane of the formula [wherein R5
and R6 is as above] by reacting with a phosphonate of the formula [wherein R is as above]
Compounds of can be produced.

When the compound of formula side A is in its wave form, the reaction of the compound of formula side A with the compound of formula KXA or formula KXB results in
A compound of formula xWA is prepared in its Li, JRS, 8RS form.

On the other hand, if the compound of formula skin is in that form, Shikifu A
The reaction of the compound with a compound of formula KXA or formula ×XB produces a compound of formula XWA in the form of its waves, 4RS, 8RS. However, if the compound of formula A is a mixture of the following S isomers, this reaction results in the following S,4'RS,8'
A compound of formula xWA having the RS form is prepared. The reaction of a compound of formula side A with a compound of formula KXA or KXB is carried out in a manner analogous to that described for the reaction of a compound of formula m or N with a compound of formula 0.

If the compound of formula side A contains a hydrolyzable ester group, this reaction may result in hydrolysis to the corresponding hydroxy group. If necessary, the hydroxyl group of the compound of formula xN can be etherified or reesterified by the method described above. A compound of formula xWA can be converted into a compound of formula xV by hydrogenation.

Any conventional hydrogenation method can be used in carrying out this reaction. Generally, this reaction is preferably carried out by hydrogenating the compound of formula xWA in the presence of a noble*metal catalyst such as palladium or platinum. Any conventional noble metal catalyst can be used in carrying out this reaction, although palladium or platinum is preferred.
Any support commonly used for noble metal catalysts can be used in accordance with the present invention. Among the preferred catalyst supports for use in this reaction are supports such as carbon, barium sulfate, and the like. When carrying out this hydrogenation reaction,
Any conventional inert organic solvent can be used. When carrying out this reaction, temperature and pressure are not critical;
This reaction can be carried out at room temperature and atmospheric pressure. On the other hand, higher or lower temperatures and pressures can be used. If an ether or ester group is present, it can be converted to hydroxy. Hydroxy groups can be etherified or esterified if necessary. Compounds of formula KXA and formula KXB are prepared from the known wave S fox S isomer of compounds of formula via the following reaction scheme: Compounds of formula into a compound.

Any conventional reducing agent that can be used to convert an aldehyde to the corresponding alcohol can be used. Among the common reducing agents are metal hydride reducing agents. Any conventional metal hydride reducing agent can be used to carry out this reaction. By halogenating the compound of formula x phantom through reaction step q, it is converted into a compound of formula x yanagi. In carrying out reaction step q, any conventional method for halogenating alcohols can be used. Generally, halogenation is expressed by the formula ×
This can be done by treating the compound of XI with a halogenating agent such as hydrogen bromide gas or phosphorus tribromide.
Any conditions commonly used in the halogenation of alcohols by using halogenating agents can be used in carrying out this process. Phosphorane of formula IXXA is prepared by converting the compound of formula
2, R3 and R4 are as described above].

This reaction is carried out using methods well known and conventional in the art for preparing phospholanes from phosphines.

Generally, this reaction is carried out at a temperature of 80<0>C to 250 qo in the presence or absence of an inert organic solvent having a boiling point above 80<0>C. By heating the phosphine with a compound of formula
A phosphonium salt of compound XA is prepared. By treating this phosphonium salt with a base, formula IXXAA
Switch to phosphorane. Any base commonly used in the preparation of phosphoranes can be used in this reaction. Among the preferred bases are alkali metal hydrides, alkali metal lower alkoxides or alkali metal hydroxides. When carrying out this reaction, any conditions commonly used when producing the corresponding phosphorane from a phosphonium salt can be used. The compound of formula IXXB is obtained by converting the compound of formula
5 and R6 are as above and R7 is lower alkoxy or aryloxy.

When carrying out the reaction of step s, any method commonly used for the production of phosphonates can be used. Formula IXX
Among the methods for preparing the phosphonate of B is to heat the phosphite and a compound of formula XO in an inert organic solvent to a temperature of 8000 to 150 oo. Any conventional inert organic solvent having a boiling point of at least 8000 can be used in carrying out this reaction. Generally, it is preferred to carry out the reaction at the reflux temperature of the reaction medium. By a method similar to the above, an aldehyde of the formula [wherein R is as above] is prepared from an aldehyde of the formula [wherein R2, R3 and R4 are as above]*
The plaque S, 7RS isomer phosphorane, and the formula [wherein R
5 and R6 are as defined above], a compound of the formula [wherein R is as defined above] can be prepared.

The reaction of compounds of formulas IXXAA and IXXBB with compounds of formula side B to produce compounds of formula It is done.

The compound of formula ×IVB is converted from the compound of formula ×IVA to the compound of formula ×V
in a manner similar to that described for the conversion to compounds of formula
It can be *changed into a compound of V. Compounds of formula xV having the following isomeric forms: 2RS,4'R,8'R; can be manufactured.

First of all, a compound of the above formula WA can be prepared in the above method using a phosphorane of the formula [wherein R2, R3 and R4 are as above] or a phosphorane of the formula [wherein R5 and R6 are as above] ] to produce a compound of the formula: [wherein R is as defined above].

According to this method, a compound of formula B and a compound of formula [wherein R2
, R3 and R4 are as defined above] or phosphonates of the formula, in which R2 and R6 are as defined above, in the manner described above. , R is as described above].

Compounds of formula XIV Pine or XIVBa can be prepared using 4'R
, 8R isomer Q-tocopherol can be hydrogenated.

If R in the compound of formula XIV or XIV is an ether group that can be converted to hydroxy by hydrogenolysis, the hydrogenation step cleaves this ether group to yield hydroxy. This free hydroxy group in the compound of formula xV can be etherified or esterified. If the compound of formula A or WB is in wave form, the compound of formula xV prepared therefrom will be in wave form. On the other hand, if the compound of formula A or WB is in the form of Q-
Tocopherol will be in wave form. On the other hand, Shikifu A
or the compound of formula B is a mixture of fox S isomers, the compound of formula
It will be a mixture of isomers. Formula IXX side, IXXBa
, IXXA meal and IXXBBa can be produced from a compound of the formula [wherein n is an integer of 0 to 1] via an intermediate of the formula [wherein X and n are as described above]. I can do it.

A compound of formula xA is converted to a compound of formula XA using the conditions described in reaction step q.

A compound of formula xA can be converted to a compound of formula IXXAa or formula IXXAAa using the conditions described for the reaction in step r. When n is 0, this reaction produces compounds of formula IXXAa. On the other hand, when n is 1, this reaction produces a compound of formula IX×AAa. Compounds of formula xA are converted to compounds of formula IXX or formula IXXB using the conditions described for reaction step s.

When n is 0, this reaction produces compounds of formula IXXBa. On the other hand, when n is 1, formula IX
A compound of XBBa is produced. A compound of formula IXA is
It consists of the 7R isomer, which has the formula, and the 7R isomer, which has the formula.

Compounds of formula IX pine and MAb are prepared from 7R,11R-phytol. These compounds are produced from phytol by dehydrating the phytol, then treating the resulting product with ozone gas to produce various ozonides, and finally reducing these ozonides with rust metal hydrates. . When an ozonide is treated with a tsuba metal hydrate reducing agent, a mixture containing a compound of formula xAa and a compound of formula xAb is produced. In the first step of this method,
The phytol is treated with a dehydrating agent in the presence of an inert organic solvent.

Any method commonly used in the dehydration of phytol can be used in this reaction step. Any conventional dehydrating agent may be used, such as phthalic anhydride, p-toluenesulfonic acid, phosphorus oxychloride and key acids such as sulfuric acid. Any conventional inert organic solvent or water can be used as a solvent. However, when phosphorus oxychloride is used as a dehydrating agent, no water is present in the reaction soot. By using these common dehydrating agents to dehydrate phytol, a mixture of phytagene isomers of the formula is produced.

This mixture of isomers is treated with ozone gas in an inert organic solvent to convert isomers of various structures into their corresponding ozonides. This conversion is carried out by bubbling ozone gas into the reaction medium containing the mixture of isomers, preferably at a temperature of -50 to 700 mm.
Any conventional inert organic solvent can be used when carrying out this step. Among the preferred inert organic solvents are hydrocarbon solvents such as pentane, benzene, toluene, etc., and ethereal solvents such as tetrahydrofuran. The ozonide is then treated with a complex metal hydrate reducing agent to produce a mixture containing compounds of formulas KAa and KAb. Thus, according to the invention, these isomeric compounds prepared from phytol can be directly converted into mixtures containing compounds of formula Aa and compounds of formula KAb. This mixture can be separated by fractional distillation. According to the present invention, it has been found that the difference in boiling points between compounds of formula KAa and formula KAb is such that these compounds can be easily separated by any conventional fractional distillation method. Any conventional fractional distillation method can be used in carrying out this reaction.
**Next, class form [n=0] or double, 7R
A compound of the formula [wherein , R and X are as above, and Z
is MgX or Li, and m and n are 0 to 1
is an integer, where the sum of m and n is 1] Formula ×
is converted into a compound of formula x by preparing its Grignard salt or its alkyllithium salt.

When carrying out the reaction of step t, any conventional method for producing Grignard salts or alkyllithium salts can be used. Additionally, a compound of the formula: where R, X and m are as defined above, can be converted to Q-tocopherol.

If a compound of formula xV is used as an intermediate in preparing a compound of formula xV, and the compound of formula xV has a $ configuration, then the compound of formula xV will have a spherical configuration.

On the other hand, if the formula skin compound has a fox configuration, the formula x V
The compound would have much more orientation. The compound of formula × is reacted with the compound of formula skin through a normal coupling reaction,
A compound of formula xm is prepared.

This step reaction is carried out using standard Grignard conditions. Any conventional standard Grignard conditions can be used to carry out this coupling reaction. On the other hand, a compound of formula M can be reacted with a compound of formula fox through reaction step u to produce a compound of formula fox. The reaction of step u is a standard Grignard reaction, and any conditions commonly used in Grignard reactions can be used to carry out the reaction of step u. When carrying out the reaction of step u, the substituents m in the compound of formula H and the substituents n in the compound of formula x must be chosen such that their sum is equal to 1. This also applies to the substituents m and n in the compound of formula and K in the step reaction. The compound of formula yanagi can be converted into the compound of formula xm by oxidation through a reaction step (matsu).

In this oxidation, it is necessary to protect free phenolic hydroxy groups in compounds of formula FOX when R is hydroxy. The formula fox compound is silver carbonate (
A2C03), chromium trioxide-pyridine reagent (Collins reagent); chromium trioxide dispersed in a support such as graphite (LalaM
ette) reagent]; and sulfur trioxide in pyridine. Mu [
It can be converted into a compound of formula xm by oxidation with Saett's reagent]. When silver carbonate is used as an oxidizing agent, it is generally used in conjunction with a carrier.
Although any conventional carrier can be used, diatomaceous earth is preferred. When carrying out this oxidation, any conditions commonly used in oxidation with silver carbonate can be used. When Collins's reagent is used as the oxidizing agent, it may be used under conditions commonly used when using Collins's reagent, such as in a halogenated hydrocarbon solvent, preferably methylene chloride, at room temperature, i.e., at a temperature of from about 1 to about 3 degrees centigrade. Perform oxidation. When using the Lallancet reagent, the oxidation is carried out under conditions commonly used when using this reagent as an oxidizing agent. Generally, when using Lallancet reagents, oxidation is carried out in aromatic hydrocarbon solvents such as benzene and toluene under reflux. When using Surrett's reagent,
The oxidation is carried out under conditions commonly used when using such reagents. By using these oxidizing agents in the oxidation of the compound of formula xm to the compound of formula xm, this reaction can be carried out without decomposition of the chroman ring.
This is quite surprising since Miss Croman is known to be extremely sensitive to oxidation. On the other hand, by reducing the compound of formula xm with a mirror metal hydride reducing agent through step (x,), it can be converted into a compound of formula xm.

The reduction in step (x,) for producing compounds of formula KAa and formula xAb and the reduction of ozonide from phytol is carried out using a conventional tsuba metal reducing agent. Among the preferred reducing agents are rust metal hydrides. Any conventional complex metal hydride reducing agent can be used when carrying out this reaction. Rust metal hydrides that can be used include alkali metal borohydrides, such as sodium or lithium shelchloride hydride, alkali metal aluminum hydrides, such as lithium aluminum hydride, diisobutylaluminum hydride, diisopropylaluminum hydride, and Includes sodium dihydro-pis(2-methoxyshethoxy)-aluminum hydride. This reduction is carried out in an inert organic solvent. Any conventional inert organic solvent can be used when carrying out this reaction. Among the preferred inert organic solvents are tetrahydrofuran, dioxane, diethyl ether, hexane, toluene, benzene or xylene. This reaction can be carried out at room temperature, ie 20-30°C and atmospheric pressure. However, lower temperatures are preferred. Generally, this reaction is carried out at a temperature of -80q0 to about 45°C. The compound of formula xm can be prepared in reaction step (y2) by using any method to completely reduce the ketone.
can be directly converted into a compound of formula xV via

Among the methods commonly used to accomplish this reduction are:
These include the CIemmensen or WoIH-Kish reaction or the alkali metal boro/hydride reduction of the derivative of formula xm, in which the ketone group is converted to a hydrazone. When carrying out the Clemensen reaction, a compound of formula xm is treated with zinc in acetic acid. Any conditions commonly used in carrying out the Clemensen reaction can be used in carrying out the reduction step. If it is desired to convert a compound of formula xm directly into a compound of formula xV using a Wolff-Kitsschner reaction, the compound of formula xm can be converted to a compound of formula xm by
In the presence of a strong base such as sodium hydroxide, 100 qo
Treat with hydrazone in the presence of a high boiling solvent at a temperature of ~250 qo. Any conditions commonly used in carrying out the Wolff-Kishner reaction can be used to carry out the reaction of step (y2). −
However, by first converting the free ketone group contained in the compound of formula xm into hydrazone, and then treating the compound of formula xm with an alkali metal por/hydride reducing agent,
A compound of formula xm can be changed to a compound of formula xV. The ketone hydrothylazone of formula Xm is prepared in a conventional manner. Any conventional method for making hydrazones can be used, such as treating a compound of formula xm with tosylhydrazone. The tosyl hydrazone of formula xm is then treated with an alkali metal borohydride reducing agent such as sodium shelchloride hydride to form a compound of formula xV.
Any conditions commonly used in reduction with alkali metal borohydrides can be used to carry out this reaction.

When the free hydroxy group contained on the side chain of the compound of the formula Kitsune is changed into a leaving group using an anchor metal hydride, the derivative of the compound of the formula Yanagi is given by the formula ×
A compound of formula V can be directly converted to a compound of formula xV by treatment in the manner described for the reduction of a compound of m to a compound of formula xV. The free hydroxy group on the side key of the formula fox compound can be converted into a leaving group by conventional methods. Any conventional leaving group can be used in this method. Among the preferred leaving groups formed are lower alkylsulfonyloxy such as methanesulfonyloxy and arylsulfonyloxy such as p-toluenesulfonyloxy. Any conventional method used for converting a hydroxy group to a leaving group can be used in this method of preparation. The compound of Shikiyanagi can also be converted to the compound of Formula XIV by treating the compound of Shikali with an alcohol dehydrating agent.

Any conventional alcohol dehydrating agent can be used.
Among the preferred alcohol dehydrating agents are thionyl chloride, phosphorus oxychloride, inorganic acids such as sulfuric acid, hydrogen bromide, hydrogen chloride, etc.; strong organic acids such as p-toluenesulfonic acid, alkylsulfonic acids such as methanesulfonic acid. . Generally, this reaction is carried out in an inert organic solvent. Any conventional inert organic solvent can be used in carrying out this reaction. Among the preferred inert organic solvents when using thionyl chloride and phosphorus oxychloride is pyridine. On the other hand, when hydrogen bromide is used, methylene chloride or chloroform are preferred solvents. Temperature and pressure are not critical when carrying out this reaction, and the reaction is carried out at room temperature and atmospheric pressure. Higher or lower temperatures can be used as desired. On the other hand, by first esterifying the hydroxyl group on the side chain of the compound of Shikisara to convert it into a derivative of the compound of Formula Fox, and then subjecting this derivative to thermal decomposition, the compound of Shikiyanagi is converted to the compound of Formula ×IV. It can be changed.

Esterification of the Shikiyanagi derivative can be carried out using conventional esterification methods. Among the preferred esters are lower alkanoic acid esters and benzoic acid esters. The ester derivative of the Shikiyanagi compound can be thermally decomposed simply by heating the Shikiyanagi compound at a temperature of 150 to 300 qo. This heating step can be performed with or without an inert organic solvent. If desired, the pyrolysis can be carried out in customary high-boiling solvents such as decalin. The compound of formula ×IV is the compound of formula
By hydrogenation in a manner similar to that described for the hydrogenation of compounds of IVA to compounds of formula
It can be changed to a compound of V.

Z In the above reaction R or 8'
When is an ether group that can be converted to hydroxy by hydrogenolysis, these groups can be made by any conventional method for making ethers. These groups can be converted to hydroxy by conventional hydrogenolysis methods. According to a preferred embodiment, the hydrogenolysis is carried out by catalytic hydrogenation. When carrying out this hydrogenation step, any conventional catalytic hydrogenation method can be used. Among the preferred hydrogenation methods are palladium catalysts,
A method of hydrogenation in a solvent consisting of an alcohol, such as methanol, preferably in the presence of palladium on carbon is included. However, according to the present invention, any conventional hydrogenation catalyst such as palladium oxide, palladium chloride, etc. can be used. Any conventional inert organic solvent can be used in carrying out this reaction, such as those mentioned above. Preferred solvents for use in this reaction include tetrahydrofuran, ethyl acetate, dioxane, diethyl ether, and the like. in general,
This reaction is carried out at room temperature. However, higher or lower temperatures can be used. Next, the present invention will be further explained by examples.

EXAMPLE In a dry flask under 1N2, a suspension of 47.2 moles (1.10 moles) of 5 wt. 4 evenings (1.15 moles)
I worshiped the candle while adding it for 2.2 hours. The white paste was soaked for 0.2 hours, and then diluted with 1000 g of tetrahydrofuran (132 g of di-6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman).
．． A solution of 2 mL (0.50 mol) was added over 0.5 q hours. The pale yellow suspension was stirred at 23° C. for 18 hours and then refluxed for 4. Heated for q hours. The cooled solutions from the two reactions were stripped of solvent, worked up and dried. Residual (±)-methyl-
(6-acetoxy 2,5,7,8-tetramethylchroman-2-yl)acetate is 145 to 14
It has a boiling point of 8°C/lmorr. Starting compound of Example 1, namely 6-acetoxy-2-hydroxy-2,5,7
, 8-tetramethylchroman can be produced as follows.

Methanol 1.2 and trimethyl orthoformate 3
Trimethyl hydride in 00.

A solution of K/N 304.4 (2.0 mol) was degassed and replaced with N
2 and cooled to 3° C. in an ice bath. Add 5.0 g of concentrated aqueous sulfuric acid to the flask, then 3. Methyl vinyl ketone (approximately 4.0 moles) was added dropwise over the feeding period. This suspension was poured for 4 hours without cooling.
The mixture was extracted with diethyl ether, washed and worked up with water and saturated aqueous sodium carbonate solution, and dried over sodium sulfate. The solvent was evaporated by a rotary evaporator to 30 to 500
The residue was removed with ◯ to obtain (±)-6-hydroxy-2-methoxy-2,5,7,80-tetramethylchroman as a pale yellowish brown solid. 600 pieces of pyridine and the ketal inside (
-6-hydroxy-2-methoxy-2,5,7,8
- Acetic anhydride 900 skin was added to a solution of tetramethylchroman.

The clear solution was degassed, placed in N2F, and heated for 1 hour at 2°C in the evening. Next, this is Kazuya Hyou08
000 to make a suspension, and heat it at 23°C. Feeding time came quickly. Approximately 1. After a special pause, (
±) -6-acetoxy 2-methoxy 2,5,7,8
The suspended oil was crystallized by seeding with 1-tetramethylchroman. The solids were filtered off, washed with 20 days, extracted with methylene chloride, washed with water, aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, dried over sodium sulfate, and stripped of the solvent, giving a reddish-brown color. 570 g of oil was obtained which gradually crystallized on standing. Samples produced in the same manner were 175 to 18
Evaporative distillation at 0° C./0.015° C. gives analytically pure 16-acetoxy-2-methoxy-2,5,7,8-tetramethylchroman as a colorless oil, which is Crystallized immediately: melting point 71-72.
P0. A solution of 6-acetoxy-2-methoxy-2,5,7,8-tetramethylchroman in 2,500 ml of acetone was added with 0.02000 ml of concentrated aqueous HCI (16.0 ml of concentrated aqueous HCI).
6' was added.

The solvent was distilled from the crushed mixture until the head temperature reached 90q0. 50 qo of this suspension was added to QO Yuchu.
It was cooled to At 70°C, acetone 2000 was added to obtain a clear solution.

Seeds were added to this solution from time to time until crystals started. 3
．． After 5 hours, a ratio of 01500' was added and the suspension was cooled in an ice bath.

The solid was filtered off, washed with QO, and dried in an oven at 50°C/0.1 leg as a granular yellow-brown solid with a melting point of 127-13 or ○, semi-melting from 11400 (soil). )-6-acetoxy-2-hydroxy-2,5,
7,8-tetramethylchroman was obtained. Example 2 By the method of Example 1, (Sat)-6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman 2
6.43 mol (0.10 mol) of trimethylphosphonoacetate, then 80 mol of pyridine [and 12 mol of acetic anhydride]
I made it react by shouting 0 and bowing under N2 overnight.

The solution was poured into ice-star ○ and processed and dried as in Example 1. The crude product was filtered with 95:5 parts by volume of benzene ether through 0.05-0.2 side silica gel 750 and then distilled.
(±)-Methyl-(6-acetoxy2,5,7,8-
Tetramethylc. Man-2-yl) acetate was obtained as a colorless resin. Boiling point 147o~149qC/1 warehouse day and night. Example 3 By the method described in Example 1, (±)
-6-benzyloxy-2-hydroxy-2,5,7,
8-tetramethylchroman (Sat)-methyl-6-benzyloxy-2,5,7,8-tetramethylchroman-
It was converted to 2-acetate.

It was obtained after crystallization from ether-30-60qo petroleum ether as a white solid with a melting point of 47.5-48.5qo. Example 4 A solution of 200 dimethyl sulfoxide (0.1 mol) in 2,5,7,8-tetramethylchroman was rapidly added to the solution. 32.5 moles (0.5 mol) of granulated KCN were added through a sieve to obtain a homogeneously dispersed suspension.

The resulting mixture was cooled to 15°C, with one state of H
47.0 qo of Bu04 aqueous solution was added for 1.2 hours while maintaining the internal temperature at 20 qo. At this point, thin layer chromatography revealed that, in addition to traces of starting material, most of the throwing spots (
slower-r side nlngspot) was observed.
This material was poured into ethyl ether and filtrate.
The ethereal solution was washed with water and brine, dried over NaSQ, and the solvent was stripped from (S)12-cyano-4-(5-acetoxy-2-hydroxy-3,4,6-trimethylphenyl)-butane. -2-ol was obtained as a rubber.

The cyanohydrin produced in Example 4 was immediately taken out into 250 methanol vessels.

The solution was cooled in an ice bath, saturated with anhydrous hydrochloric acid, stored at 1 hr - 20 qo, and heated on a rotary evaporator (3
The solvent was stripped at a temperature below 0 qo. The resulting rubber was taken out in 250 ml of water, degassed and soaked with N.
2 and heated at 40 oo for 2.0 hours to make an aqueous suspension. This aqueous suspension was treated and dried in the manner of Example 1 using a solvent mixture of ethyl acetate and diethyl ether, and dried. -Trimethylphenyl)butan-2-ol and (earth)-2-carbomethoxy-6-hydroxy-2,5,7,8-tetramethylchroman were prepared. This mixture was a tan solid. This tan solid was triturated with diethyl ether and then crystallized from diethyl ether as white prismatic crystals (±)-
2-carpomethoxy-4-(2,5-dihydroxy-3
,4,6-trimethylphenyl)butan-2-ol was obtained: melting point 135-136.5°C.

The light tan solid was suspended in 100 g of methanol to which was added 100 g of aqueous NaOH solution over a 10 minute period.

The resulting solution was kept under N2 for 24 hours and treated with 57 g of an aqueous solution of HCI followed by 10 g of a saturated aqueous NaHC03 solution to obtain a solution with a pH of 7.5-80. The solution was extracted with diethyl ether, acidified with aqueous HCI, and extracted again with diethyl ether. This latter extract was washed with brine, dried (Na2S04) and stripped of solvent. The resulting partially crystallized rubber 24.3 was found by thin layer chromatography to be an approximately equimolar mixture of cyclized and non-cyclized acids. By filtering the aqueous suspension obtained by acidification, extraction with diethyl ether and crystallization from diethyl ether, the pure cyclized acid,
(Sat)-2-carboxy-4-(2,5-dihydroxy-3,4,6-trimethyl)butan-2-ol was isolated from this mixture as a white solid that is highly susceptible to air oxidation: mp 177 ~17 Pa○. A crude mixture of the resulting acid and 0.57 g of P-toluenesulfonic acid hydrate in 300 g of benzene was heated under reflux for 1.25 hours with azeotropic removal of the ratio 0 under N2.

Cool this solution and add a total of 300' of 1/2 saturated N
Washed with aHC03 aqueous solution and brine. The aqueous solution was treated with charcoal, acidified with an aqueous solution of Su's HCL and filtered as a light tan powder with a melting point of 189-19,000. Obtained acid. (Sat) 16-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid 25.0%, 1,2-dichloroethane 100% Z, ethanol 17.5% [and concentrated Hb 041.0%] The mixture was heated at reflux under N2 for two hours.

The dark mixture was washed with 100 ml, saturated sodium carbonate solution, and brine, dried over sodium sulfate, and stripped of solvent to give a pale yellow solid. When crystallized from phenol, the melting point was 124-12
(±)-ethyl-6-hydroxy-2,5,7,
8-tetramethylchroman-2-carboxylate was obtained. By the method of Example 4, (±)-6-hydroxy-2,5,7,8-tetramethylchromaso-2-carboxylic acid was prepared from acetone with a melting point of 158.5 to 161.5.
(±)-Methyl-6-hydroxy-2,5,7,8-tetramethylchroman-2- as white prismatic crystals at °C.
Converted to carboxylate.

Example 5 A solution of crude 4-(2,5-diacetoxy-3,4,6-trimethylphenyl)butan-2-one in 963M dimethylformamide was cooled in an ice bath under N2.

A solution of 69.4 ml of potassium cyanide in 20150' was added over 20 minutes. The mixture was allowed to stand for an additional 10 minutes, then State's WS04161' was added dropwise over a 20 minute period while maintaining the internal temperature at 110-110. This viscous suspension (pH 8) was heated for another 3 minutes, and the pH was adjusted by adding Funohibiyo 0416.5.
4, poured into ice 20 ml and extracted with ether. The ether solution was washed with brine, dried over Na2S04, stripped of solvent and extracted with (2)-2-cyano-4-(2,5-diacetoxy-3,4,6-trimethylphenyl)butane as a light brown foam. 12-ol obtained o4-(2,5-diacetoxy 3,4,6
(±)-2-cyano-4-(2,5-diacetoxy-3,4,6-trimethylphenyl)-2-ol prepared from 0.1 mol of -trimethylphenyl)butan-2-one was concentrated under N2. It was dissolved in HC1250 solution.

This mixture was heated at 25°C for 1.5 hours, then at 60°C.
Maintained 4 hours in qo. The suspension was cooled and filtered. The solid was washed with water, air dried, and
1. with 60 Z of 1/2 saturated NaHC03 solution and 50 volumes of ether. I worshiped the light during feeding time. The aqueous layer was washed with additional ether, acidified with carp HCI, cooled and filtered. The solid was washed and dried for 20 days as a white powder with a melting point of 190-19C with decomposition. .64 evening (83%
) was obtained. The starting compound of Example 5 can be prepared, for example, as follows. :0 (±)-6-hydroxy-2 prepared from 1.0 mol of trimethylhydroquinone
-Methoxy 2,5,7,8-tetramethylchroman in acetone 1250', ratio 01000 I and concentrated HC18
．． A solution of 30 mL was heated under N2 at reflux.

The solvent was removed by distillation until the distillation overhead temperature reached 95 qo. The suspension was cooled to 70:00 and diluted with acetone 8:00.
00', cooled to about 15q0 and stripped of solvent under reduced pressure and at 30°C to about 1000
It was. The resulting suspension is cooled, filtered and dried to give (di)-2,6-dihydroxy-2,5,7,8 as a grayish-yellow powder with a melting point of 105-107q0.
One tetramethylchroman was obtained. A suspension of (di)-2,6-dihydroxy-2,5,7,8-tetramethylchroman prepared as described above in pyridine 600 was placed under N2.

Acetic anhydride (900 ships) 1. Added over field time.
The resulting light-colored solution was incubated at 23° C. overnight, poured into ice for 20 days, and 2. It was washed for a while and extracted with benzene and ether. The organic extract was washed with HCl, brine, saturated NaHC03 solution and brine, and N
Dry on a2S04. Remove solvent, melting point 85~
4-(2,
5-diacetoxy3,4,6-trimethylphenyl)
-Butan-2-one was obtained. Example 6 A solution of 100 g of (±)-methyl-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetate in 2000 g of ethanol was added with Q02000 on the table and 240 g of NaOH (6.0 mol). ) was added.

This solution was incubated at 23 qo for 4 hours, washed with petroleum ether (boiling point 30-60 qo), diluted with ice at 20,600 qo, and incubated with concentrated HCI aqueous solution at 60 qo for 0.50 h.
The mixture was acidified by adding 0.0 ml of the solution dropwise. Filter out the solids,
(±)-(6-hydroxy-2,5
,7,8-tetramethylchroman-2-yl)acetic acid was obtained: mp 1-171°C. Example 7 By the method described in Example 6, (±)-ethyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-acetate was saponified to give (di)-6-hydroxy-2,5, 7
, 8-tetramethylchroman-2-monoacetic acid was obtained.

After crystallization from ethanol, it has a melting point of 172
Obtained as a milky white powder with a temperature of ~175°C. Example 8 In a dry flask, 100% of benzene (±)15.32% (50 mmol) of (6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid The solution was heated to 50.degree. C. under N.sub.2 upon addition of 21.15 oxalyl chloride (0.25 mol) over 20 minutes.

The solution was incubated for an additional 20 minutes at 50:00 am, cooled, and the solvent was stripped from (±)-(6-acetoxy2,5,7,8-tetramethylchroman-2).
-yl) acetyl chloride was produced. To a solution of this acid chloride in 200' of dry toluene was added 15' of sodium acetate, and 1.5' of 9 wt% palladium on carbon, and 0.30' of quinoline. Ta.
This mixture was hydrogenated in a Pan apparatus.
After 1 hour, day 2 absorption (approximately 55 mmol) had virtually ceased.

The catalyst was removed by filtration and the filtrate was stripped of solvent. The residue was taken up in ether and purified with HCI
Washing with aqueous solution, saturated aqueous sodium carbonate solution and saturated brine, drying over sodium sulfate and stripping the solvent gave a pale yellow solid 15.4%, which was
．． Chromatographed on 063-0.2 silica gel lk9. Elution with 95:5 parts by volume benzene-ethyl acetate gave 11.0 parts of a pale yellow resin.

The materials obtained from such two reactions were combined and crystallized from acetone-petroleum ether (boiling point 30-60°C) as a white powder with a half melting point of 66.5°C and a melting point of 68-70°C (±). -(6-acetoxy-2
, 5,7,8-tetramethylchroman-2-yl)-acetaldehyde was obtained. Example 9 S-acetoxy acid, S-(6-acetoxy-2,5,7
, 8-tetramethylchroman-2-yl)acetic acid to form the acid chloride, S-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl), as described in Example 8. It was converted to the desired aldehyde via acetyl chloride.

The crude product was crystallized from acetone-hexane to give S-(6-acetoxy-2,5,
7,8-Tetramethylchroman-2-yl)acetaldehyde was obtained: melting point 87.5-9000. Example 10
By the method of Example 8, compound R-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)
Treatment with acetic acid produces R-(6-acetoxy 2,5,7,8
-Tetramethylchroman-2-yl)acetyl chloride to produce R-(6-acetoxy2,5,7,8-tetramethylchroman-2-yl)acetaldehyde.

Example 11 By the method of Example 8, (±)-6-penzyloxy-2,5,7,8-tetramethylchroman-
2-monoacetic acid (±)-6-benzyloxy-2,5,7,
(±)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetaldehyde was converted via 8-tetramethylchroman-2-acetyl chloride.

It is obtained as an oil and crystallizes with a melting point of 65-67
．． It became a solid of 5 qo. Example 12 To a mixture of 1.34 g of dimethylchloroforminium chloride and 12 g of chlorobenzene was added 2.92 g of (±)-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. .

The resulting solution was heated under N2 at 110 oo for 40 minutes and the solvent was stripped to give (±)-6-acetoxy-2,5,
7,8-tetramethylchroman-2-tricarboxylic acid chloride was obtained. To a mixture of 2.98 mmol of this material in 4M acetone was added 0.43 parts of triethylamine and 9 parts of 10% palladium on carbon catalyst. This mixture was hydrogenated at atmospheric pressure and room temperature. Absorption is about 1.
It stopped after 0 hours. The suspension was filtered and the filtrate was stripped of the solvent, taken up in ether, washed with saturated aqueous sodium carbonate, aqueous HCI, and brine, dried over sodium sulfate, and the solvent was stripped. Ripped. The residue was chromatographed on silica gel with 8:2 parts by volume of benzene-ethyl acetate and then crystallized from petroleum ether with a boiling point of 30-60 oo as a white solid with a melting point of 92.5-96 qo. )-6-acetoxy-2,5,7,8-tetramethylchroman-2-hydroxyaldehyde was obtained. Using the method described above, S-(6-acetoxy-2,5
,7,8-tetramethylchroman-2-yl)carboxylic acid to S-(6-acetoxy2,5,7,8-tetramethylchroman-2-yl)carboxylic acid chloride to S-(6-acetoxy2,5,7 , 8-tetramethylchroman-2yl)carboxaldehyde.

Using the method described above, R-(6-acetoxy-2,5,7
, 8-tetramethylchroman-2-yl)carboxylic acid via R-(6-acetoxy2,5,7,8-tetramethylchroman-2-yl)carboxylic acid chloride.
(6-acetoxy-2,5,7,8-tetramethylchroman-2yl)carboxaldehyde was converted.
Example 13 Tetrahydrofuran 500% (±)-
(6-Hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid (about 1
5 mmol) was added.

The resulting mixture was heated at 25 qo under N2 for 1.0 h, filtered, and the solvent was stripped to give a brownish resin. This material was crystallized twice from methanol-ether as shiny, opalescent prismatic crystals of S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid S-Q. -Methylbenzylamine salt was obtained. Half melting point 16 o ○, melting point 164 o ~ 16
600. S-(6-hydroxy-2,5,7,
A suspension of 8-tetramethylchroman-2-yl)acetic acid S-Q methylbenzylamine salt was prepared at 23 qo for 1. I watched it during feeding time.

The ether solution was washed with water and saturated brine, dried over sodium sulfate, and the solvent was stripped to produce a milky white mass. This sample was crystallized from ethanol-ratio ○ as a white granular solid with a melting point of 145.5° to 148.5°.
-tetramethylchroman-2-yl)acetic acid was obtained. S-
The mother liquor from the first crystallization of the acid S-salt was treated with 2N aqueous HCI to give R-epimer, R-(6-hydroxy-2
, 8.80 g of an acid rich in acetic acid (5,7,8-tetramethylchroman-2-yl) were obtained.

Treatment of this material with R-Q-methylbenzylamine followed by two crystallizations from methanol-ether yields analytically pure R-(6-hydroxy-2,5 , 7,8-tetramethylchroman-2-yl)acetic acid R-Q-methylbenzylamine salt was obtained: half-melting point 1 °C, melting point 164.5-166.
P○. A sample of this R-acid R-salt was treated with an aqueous solution of HCI in ethanol and after crystallization from 20 to 2 times a day, R-(6-hydroxy-2,5,7, 8-tetramethylchroman-2-yl)acetic acid was obtained: melting point 124-127.50〇. Example 14 (Sat) in methanol 30' and ether 170'
-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid 13.22 hours (50 mmol)
A suspension of S-Q-methylbenzylamine 7.5 [(
62.5 mmol) was added at 2000 ml.

Immediately, S-acid S-salt and S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid S-Q-methylbenzylamine salt were added to the resulting solution as crystal seeds. The mixture was evaporated and finally cooled to -20q0, yielding 7.80 kg of white powder. This material was crystallized from 25% methanol and 175% ether as a white powder with a melting point of 162.50-165%.
- 6.78 g of salt was obtained. Conversion and crystallization of this salt to S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid was performed as described in Example 13. The mother liquor obtained by preparing and crystallizing the S-acid S-salt was stripped of the solvent, yielding a light brown resin, 19.3%. This material was converted to the free acid as described in Example 13, yielding 8.70 g of a tan solid.

R-epimer, R-(6-hydroxy-2,5,7,8
This acid, which is rich in (tetramethylchroman-2-yl)acetic acid, is suspended in 1 state day o 4480, degassed and N
2 and heated under reflux for 30 hours.
The resulting light red suspension was treated by the method of Example 15 using ethyl acetate as solvent, yielding a brown solid 8.4
I got 0 nights. Shred this material together with heat ether scream,
Cooled to -20 qo and filtered. The resulting tan powder (7.1) was crystallized from ether and 25% each of strings to form a pale tan powder (±)-acid (earth)-(6
-Hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid was obtained at 6.88%, melting point 173.50.
~175qo. Thus, the S-acid S-(6-hydroxy-2,5,7,8
The effective yield of -tetramethylchroman-2-yl)acetic acid was 71% based on 48% conversion. Example 1
5 Compound (±)-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-carboxylic acid was resolved using S-alphamethylbenzylamine according to the method of Example 13, and S -(6-hydro.

xy-2,5,7,8-tetramethylchroman-2-yl)-carboxylic acid S-Q-methylbenzylamine salt was prepared: melting point after crystallization from a mixture of ethanol-dimethyl ether. 153.5-154.000. The mother liquor from this crystallization was treated with R-Q as in Example 13.
-Methylbenzylamine and R-(6-hydroxy-2,5,7,8-tetramethylchroman-2
-yl)carboxylic acid R-Q-methylbenzylamine salt was prepared: mp 153.5-155 qo after crystallization from a mixture of ethanol-jethyl ether.

Both the obtained S-acid S-salt and R-acid R-salt were treated with aqueous hydrochloric acid solution of S-(6-hydroxy-2,5,7
, 8-tetramethylchroman-2yl)carboxylic acid and R-(6-hydroxy-2,5,7,8-tetramethylchroman-2yl)carboxylic acid were obtained.

Example 16 To a solution of 3.54 g of (6)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetic acid in 35 g of warm ethyl acetate was added 3.24 g of quinine followed by 25 g of ether. ' was added.

The solution was cooled to 0°C and allowed to stand. The solid was filtered off and crystallized twice from ethyl acetate as white needles with a melting point of 163-164°C.
6-benzyloxy-2,5,7,8-tetramethylchroman-2-monoacetic acid quinine salt was obtained. S-6-penzyloxy-2,5,7,8-tetramethylchroman-2-monoacetic acid was decomposed by the method described in Example 13 and extracted from hexane as a white solid with a melting point of 95.5-96.5q0. S-6-benzyloxy-2,5,7,8-tetramethylchroman-2-monoacetic acid was obtained. Example 17 By the method of Example 16 but using only ethyl acetate as solvent, (±)-6-penzyloxy-2,5,7
, 8-tetramethylchroman-2-monoacetic acid with R- and S-
Reacted with Q-(1-naphthyl)ethylamine, melting point 1
S-6-benzyloxy-2,5,7,8-tetramethylchroman-2-monoacetic acid S-Q-(1 naphthyl)ethylamine salt with a temperature of 61.5-162.5°C and a melting point of 16
R-6-benzyloxy-2 having 1.5-1620
,5,7,8-tetramethylchroman-2-monoacetic acid R-Q
-(1-naphthyl)ethylamine salt was obtained.

The resulting Q-(1 naphthyl)ethylamine salt was hydrolyzed by the method described in Example 15 to give a melting point of 95-9.
S-6-penzyloxy-2,5,7, with 6qo
8-Tetramethylchroman-2-acetic acid and melting point 94-9
R-6-penzyloxy-2,5,7, with 5qo
8-tetramethylchroman-2-acetic acid.

Example 18 (Sat)-6-benzyloxy-2,5,7,8-tetramethyl-chroman-2-acetaldehyde 3.389,
A mixture of 5 parts of benzylamine, 10 parts of p-toluenesulfonic acid, and 50 parts of benzene was heated under reflux for 2 hours under N2 with azeotropic removal of the 0%.

The resulting solution was cooled and 2.25 g of d-camphorsulfonic acid was added. 1. After field time, the resulting salt is filtered off and purified from ethanol-ether under N2.
It was crystallized twice below.

The separated salts were mixed with a mixture of 50 parts ether, 10 parts acetic acid and 40 parts water under N2 for 1 hour. I admired the leg time. The ether layer is 20 days, HC1 is 20 days, saturated NaHC0 is
3 solution and brine and dried (Na2S
04). The solvent was removed to yield optically pure 6-penzyloxy-2,5,7,8-tetramethyl-chroman-2-acetaldehyde with a melting point of 85°C to 85°C. Example 1
9 to a solution of 7% by weight bis(2-methoxyethoxy) sodium aluminum hydride 70 M (0.25 mol) in toluene in anhydrous diethyl ether 500'. 69.2 mol (0.326 mol) of 2,6,10-trimethylundecanal were added dropwise over a period of time.

The solution was allowed to stand for 1.0 hour, poured onto ice and aqueous NaOH, and treated with ether and dried as described in Example 1. The crude product was distilled to give (2)-2,6,10-trimethylundecan-1-ol as a colorless oil; boiling point 96-98°C/0.2%. (Sat)-12,6,10-trimethylundecane
A 21.44 mol (0.10 mol) portion of 1-ol was heated to 140 pm for 4 hours while heating and bubbling HBr gas into the liquid. The two-phase mixture is cooled, diluted with petroleum ether (boiling point 30-60 o○), and string ○,
Washed with saturated aqueous NaHC02 and brine.

This solution was prepared using Woelm neutral alumina.
Filter through 0.00 mL, strip the solvent, and distill as a colorless liquid.
Obtained trimethylundecane: boiling point 97-99 pm
/0. Plate day. In a dry flask, (±)-1-from 2,6,10-trimethylundecane (20 mmol) and triphenylphosphine 6.56
The mixture (25 mmol) was heated at 200°C under N2 for 6.0 hours.

The cooled rubber, triphenyl-2,6,10-trimethylundecanylphosphonium furomide, is dissolved in 100 glyme (freshly distilled from ○aH2) and dissolved in a 2.3 M phenyllithium solution in benzene. 11.0 birds were worshiped while being introduced from a syringe. 2
, 6,10-trimethylundecylidenetriphenylphosphorane was passed through four streams at 25°C.

Grime 25 underground (±)-6-acetoxy 2,5,
A solution of 2.90 g (10 mmol) of 7,8-tetramethylchroman-2-yl)-acetaldehyde was added over 5 minutes and the resulting mixture was heated at 60 qo for 3.
It was heated for a while. The mixture was diluted with ether and Example 1
processed and dried to obtain a clear colored oil,
It is combined with 25 parts of pyridine and 25 parts of acetic anhydride.
We worshiped with candlelight at Hiroshita Yu for 8 hours. The resulting mixture was treated in the manner of Example 1 and dried, combined with benzene at 0.0
2RS,4'RS,8RS-2',3'-dehydro-a after chromatography on silica gel lk9 on the 63-0.2 side yielding a colorless resin by evaporative distillation.
10 tocopheryl acetate was obtained. A solution of the chromatographed 2RS,4'RS,8RS-2,3'-dehydro-Q-tocopheryl acetate in 60 ml of ethyl acetate was hydrogenated over 90 ml of prereduced Pt024000. 7. After hours G, day 2 absorption (213 skin) virtually ceased.

The catalyst was filtered off and washed with fresh ethyl acetate. Remove the solvent and then perform evaporative distillation to obtain a boiling point of 210-215 qo
2R as a slightly yellowish resin with /10 Buddha
S,4RS,8RS-Q-tocopheryl acetate was obtained. Example 20 “Helv.ChimAc” by Mayer et al.
Phytol was dehydrated to a mixture of Δ2,4- and Δ35-phytagenes by the method disclosed in J. E. 46.650 (1963).

The boiling point of pentane 150 is 131-14000/0.
A solution of this phytagene mixture with 5 ml of water was cooled to -50 qo in a dry ice bath. Ozone (0.8
0-0.88 mmol/min) was bubbled through this solution for 3 hours at -50 to -7000 (total 03 = approx.
75 mmol). Nitrogen was then bubbled through the solution for 20 minutes to remove excess ozone. The ozonated solution was transferred into a chilled (170 qo) addition funnel and 7 wt. Added dropwise onto sodium aluminum hydride 107 (internal temperature during addition
~8°C). The solution is 2000, and at this temperature 1. Wait for an hour and pour on ice and a plate of aqueous NaOH solution. Treatment with ether and drying according to the method of Example 1 gave a pale yellow oil. It takes 4
The product from the reaction of the seeds is made into 20 Vigreau (Vimochie).
blood) distilled through a column, wave, vein-2,6,10-trimethylundecane-1-ol and plaque, 7R-3,7
, 11-trimethyldecane-1-ol was obtained. Desired C-14 alcohol, 2R,QR-2,6
, 10-trimethylundecane-1-ol has a spinning band or 3
It could be separated from this mixture by distillation through a Goodloe column at 0 arc and was obtained as a colorless liquid: boiling point 76-78 qo/0.
．． The residue remaining after separating the H&C-14 alcohol was further distilled to obtain Chi,7R-3,7,11-trimethyldodecane-1-ol. 2R,QR-alcohol, 2R, mother R-2,6,10-trimethylundecane-1-ol was treated with HBr at 140°C by the method of Example 19 to give a colorless oil.
0 mu 2,6,10-trimethylundecane was obtained: boiling point 80-820/〇.

5th side Japan.

By the method described in Example 19, Nami, Kenichi 1-from 2,6,10-trimethylundecane was reacted with triphenylphosphine to form triphenyl-2R,8R-2.
, 6,10-trimethylundecanylphosphonium bromide was prepared, which was then reacted with phenyllithium to produce 2,6,10-trimethylundecylidenetriphenylphosphorane.

By the method of Example 19, this phosphorane was converted to S1(6-acetoxy-2,5,7,8-tetramethylchroman-
Wave, 4R, 8 by reacting with 2-yl) acetaldehyde
R-2,3'-dehydro-tocopheryl acetate was produced. This dehydro-Q-tocopheryl acetate was hydrogenated by the method of Example 13, and the t-wave and 4'R
, 8R-o-tocopheryl acetate was prepared. Example 21 By the method of Example 19, triphenyl-wave S,8RS
4′RS, 8RS-2 ,3-dehydro Q
- Tocopheryl acetate was prepared and used in Example 19.
By hydrogenation method, fox, 4RS, 8'RS-o-
Tocopheryl acetate was produced.

Example 22 By the method of Example 19, triphenyl-koi, mother R-2
,6,10-trimethylundecanylphosphonium bromide (S)-(6-acetoxy-2,5,7,8-
Example 1
9 to produce fox S,4R,8R-o-tocopheryl acetate.

Example 23 By the method of Example 19, triphenyl one, mother R12
, 6,10-trimethylundecanylphosphonium bromide is reacted with S-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetaldehyde to form 4R,8R-2,3'- Dohydro-Q tocopheryl acetate was prepared, which was hydrogenated by the method of Example 19, and then 4'R,8R-o-tocopheryl acetate was prepared.

Example 24 A solution of 25% of anhydrous diethyl ether and 2.8% of 70% bis(methoxyethoxy)sodium aluminum hydride in toluene was added to 1% of diethyl ether.
Next, a solution of 2.36 mmol (5.0 mmol) of 4'R,8R-Q-tocopheryl acetate was added to the top of the ZI tube for 1 minute.

This solution was further sailed for 1.0 hour, and the ice and ice ratio S04 was
Pour onto aqueous solution, treat with ether and dry according to the method described in Example 1. Next, 4R,8R-Q-TOKOFUZRIL was obtained as a yellowish resin by evaporative distillation. Example 25 By the method of Example 19, triphenyl-2'6,10
-trimethylundecanylphosphonium bromide and (S)-6-benzyloxy-2,5,7
, 8-tetramethylchroman-2-acetaldehyde to obtain wave S, 4'RS, 8RS, 2',3'-dehyde o-Q tocopheryl benzyl ether as a resin.

Ethanol 10 underground next S, 4'RS, 8RS-2,3
-Dehydro Q Tocopheryl Benzyl Enal 0.3
10% palladium catalyst on carbon in solution for 4 nights 9 in 100
added.

The mixture was hydrogenated at atmospheric pressure, filtered and the solvent was stripped to yield S,4'RS,8RS-o-tocopherol. This material was acetylated as in Example 19 to yield 2RS, 4'RS, 8RS 1Q tocopheryl acetate as a very pale yellow resin with a boiling point of 195 °C/0.02 willow. Example 26 Magnesium powder 486 to 9 in a dry flask under N2, Fox S, Spot S-2,6 in tetrahydrofuran 25
, 10-trimethylundecanylfuromide 4.70 ml of solution was added.

The mixture was heated to reflux when the reaction started. The remaining bromide was added over three eaves and heating continued for an additional 30 minutes. Tetrahydrofuran 25% (
A solution of 3.38 ml of -6-penzyloxy-2,5,7,8-tetramethylchromaso-2-acetaldehyde was added over 1 minute and heating was continued for an additional 2 hours.
The mixture was cooled, poured onto ice and cold HCI, and extracted with ether. The ether solution was washed with Suzu's HCl, Day 20 and brine, dried over sodium sulfate and stripped of solvent. The residue was chromatographed on silica gel with 97.5:2.5 benzene-ethyl acetate as a pale yellow oil.
S,8RS-2'-hydroxy-Q tocopheryl benzyl ether was obtained. Obtained next S, 2'RS, 4RS
, 8'RS-2'-Hydroxy-Q tocopheryl benzyl ether in 25% pyridine was heated in an ice bath with N2
Cooled down.

Phosphorous oxychloride (2.0 g) was added and the white suspension was heated to 0.0 g at 3°C. I worshiped the candle for an hour, and then I lit it for one night without cooling it. The mixture was poured onto ice and extracted with ether. The ether solution was washed with SU's NaOH, ST's HCI, and brine, dried over sodium sulfate, and stripped of solvent. The residue is 95:5 (30~
2RS, 4RS, 8RS-2,3-dehydro-Q-tocopheryl benzyl ether and spots S, 4'RS, 58R as a yellowish resin.
A mixture of S-1',2-dehydro Q-tocopheryl benzyl ether was obtained. The resulting mixture of ethers was hydrogenated and acetylated as described in Example 25,
02RS,4'RS,8RS-Q-tocopheryl acetate was obtained as a pale yellow transparent resin having a boiling point of 210 DEG C. and a skin temperature of 0.035.

Example 27 Wave S, 2RS, 4RS, 8RS-2'-Hydroxy-Q
-Tocopheryl benzyl ether was oxidized to WaveS,4'RS,8RS-2-Oxo-Q tocopheryl benzyl ether, a pale yellow oil.

Fox S, 4'RS, 8RS-2'-oxo-o-tocopheryl benzyl ether 1.0%, potassium hydroxide 350%
A mixture of 0.25% hydrazine, 85% hydrazine and 25% diethylene glycol was heated under reflux for 1.0 hour. The mixture was distilled until an internal temperature of 20,500°C was reached. The mixture was kept at this temperature for 3 hours, cooled and extracted with ether. HC of ether solution
I and brine and dried (Na2S04
). The solvent was removed to obtain crude S, 4RS, 8RS-Q tocopheryl benzyl ether. This material was dependylated and acetylated as in Example 25, with a boiling point of 2.
00~205oo/25mm 2RS, 4'RS, 8'R
S1Q-tocopheryl acetate was obtained. The main embodiments of the present invention are as follows.

A compound of the formula '1' [wherein R is hydroxy, an ether group that can be converted to hydroxy by hydrolysis or hydrogenolysis, or an ester group that can be converted to hydroxy by hydrolysis] alkyl and R2, R3 and R4 are aryl] or a phosphorane of the formula [where R, is as above and R5 and R
6 is aryloxy or lower alkoxy to give a compound of the formula, where R and R are as above, or the compound of formula 0 above is treated with an alkali metal cyanide. and the resulting compound of formula [wherein R, is as above] and R" is hydroxy or can be converted to hydroxy by hydrolysis or hydrogenolysis. and optionally changing the hydroxy group R'' in formula IB to an ester group to obtain a compound of the formula [wherein R and R are as described above]. , and optionally the resulting formula [where R and R are as above, and m
is an integer from 0 to 1] via an acid halide of the formula [wherein R and m are as above and X is a halogen] or a compound of the formula [wherein R and m are as described above] through the aldehyde of the formula [where Z is Li or MgX, X is a halogen, and n is an integer from 0 to 1; the sum of m and n is 1] or via an aldehyde of the formula [wherein R and m are as above]; n is an integer from 0 to 1, and the sum of m and n on the formula side and X is 1]
A method for producing a chroman derivative, which comprises converting it into Q-tocopherol by phospho-organic condensation with a compound of

'2) converting the compound of formula B into compounds of formula IA and IB and, if necessary, converting the resulting compound of formula 1 to Q-tocopherol by phosphoorganic condensation with a compound of formula x via the aldehyde of formula A method according to 1 above for the production of a chroman derivative, comprising: {31. A process according to 1 or 2 above, comprising reacting a compound of formula (b) with a phosphorane of formula m in the presence of an organic solvent at an excess of about 0<0>C to about 50 qo.

'4 - A compound of formula 0 is added to an alkali metal base and a compound of formula W in an organic solvent at a temperature range of about 0°C to about 50°C.
1 above, consisting of adding to a solution of the phosphonate of
Or method 2. '51 The compound of formula 0, 3 to 7
3. A method according to 1 or 2 above, comprising treating with an alkali metal cyanide in an organic solvent at a pH range of 0.degree.

'61 consisting of hydrolyzing a compound of formula 1 to the free acid of formula [wherein R and m are as above] and halogenating the acid and rubbing it with an acid halide'. Method according to 1 or 2 above.

[7' The method according to 1 or 2 above, which comprises hydrogenating the acid halide of the formula skin and rubbing it with the aldehyde of the formula skin.

[81 The acid halide of the formula skin or the aldehyde of the formula side is condensed with the compound of the formula phantom to form a compound of the formula [wherein R is as above and the sum of m and n is 1]*,
and converting the compound of the formula into a compound of the formula: wherein R is as defined above.

{91 A compound of the formula
], and then change the compound of formula × m to the compound of formula ×
8. The method according to 8 above, consisting of converting into a V★ compound.

[IQ Shikari compound has the formula [wherein R is as above, and the sum of m and n is 1]
and converting the compound of formula V into a compound of formula V.

(11) condensing an aldehyde of formula value with a compound of formula 8. The method according to 8 above, consisting of converting into a compound of formula xV.

(12) The method according to 1 or 2 and 6 above, which comprises resolving the acid of formula with an optically active base to obtain the phantom and 2R enantiomers.

(13) Formula for division [In the formula, R is as above] The method according to 6 and 12 above, using the acid of

(1-core acid of formula A is divided into enantiomers of formula [wherein R is as above] and 2R enantiomers of formula [wherein R is as above].

Method according to 13 above. (15) Formula for division [In the formula, R is as above] The method according to 6 and 12 above, using the acid of

(16) The method according to 15 above, in which the acid of formula WB is divided into enantiomers of the formula [wherein R is as above] and globular enantiomers of the formula [wherein R is as above] .

(17) The method according to 13 or 15 above, which is carried out in an organic solvent using resolved q-methyl-benzylamine. (
18) Enantiomers of the formula Aa and WAb and fox acids of the formula are halogenated to form the formula [wherein R and X are as above] and the formula [wherein R and X are as above] 1, 2, 6 and 14 above, consisting of making the fox enantiomer of
method.

(Ba and WBb of formula 19D are halogenated to give the formula [wherein R and X are as above]
The process according to 1, 6 and 16 above, comprising forming an enantiomer of the same type and a globular enantiomer of the formula: in which R and X are as defined above.

(20) Hydrogenation of formula plate Aa and Kajinoru and 2R acid halide to obtain the enantiomer of formula [wherein R is as above] and the formula [wherein R is as above] of The above 1, 2,
Methods according to 7 and 18.

(21) After formula plate Ba and skin Bb and fox acid halide are hydrogenated to form the formula [wherein R is as above] and the enantiomer and formula* [wherein R is as above] 1, 2, above, consisting of making a wave enantiomer of
Methods according to 7 and 19.

(22) Shikihata's aldehyde is split with an optically active base to produce the $ enantiomer of Shikihata and dish Ba, and Shikihata A.
The method according to 1 and 7 above, consisting of obtaining a love enantiomer of skin Bb and skin Bb.

(23) The method according to 22 above, wherein the resolution is carried out using Q-methyl-penzylamine in an organic solvent. (2) The dehydration product of phytol is treated with ozone gas and the resulting ozonide is treated with a tsuba metal hydride reducing agent to produce a mixture containing a compound of formula, and the mixture is subjected to fractional distillation to form a compound of formula 3. The method according to 1 or 2 above, which comprises producing a compound of the formula: [wherein n is an integer from 0 to 1] by isolating the compounds of *Aa and KAb*.

(25) The compound of formula ×A is treated with a halogenating agent to give the formula [
25. The method according to 1 or 2 and 24 above, comprising producing a compound of the formula: wherein X is halogen and n is an integer from 0 to 1.

(2 clauses The compound of formula X is a Grignard compound or the formula [where Z is MgX,
is an integer from 0 to 1].

(27) The aldehyde of formula Aa is condensed with the compound of formula ×A when n is 0, or the aldehyde of formula W & is condensed with the compound of formula ×A when n is 1, and natural Q The process according to 1 or 2 above, consisting of obtaining tocopherol [arc, 4R, 8R-Q-tocopherol].

(28) An acid halide of formula WAa or an aldehyde of formula Aa is condensed with a compound of formula KA when n is 0, or an acid halide of formula Ba or an aldehyde of formula Aa is condensed with a compound of formula KA when n is 0. 1, the natural Q-tocopherol [2R,4'R,8
1 above, consisting of obtaining R-Q-tocopherol]
method.

Claims (1)

[Claims] 1 Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R is hydroxy, an ether group that can be converted to hydroxy by hydrolysis or hydrogenolysis, or an ester group that can be converted to hydroxy by hydrolysis. be〕
When the compound of is treated with an alkali metal cyanide, the resulting formula ▲ There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R is as above] The compound of formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Chroman derivatives of the above formula IB^-, characterized in that R_1 is lower alkyl, and R'' is hydroxy or an ether group that can be converted to hydroxy by hydrolysis or hydrogenolysis. Manufacturing method. 2 Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R is hydroxy, an ether group that can be converted to hydroxy by hydrolysis or hydrogenolysis, or an ester group that can be converted to hydroxy by hydrolysis]
When the compound of is treated with alkali metal cyanide, the resulting formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is as above] The compound of formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Formula where R_1 is lower alkyl and R'' is hydroxy or an ether group that can be converted to hydroxy by hydrolysis or hydrogenolysis, and the hydroxy group R'' in formula IB^- is changed to an ester group. Formulas that are characterized by changing ▲ There are mathematical formulas, chemical formulas, tables, etc. and R_1 is as described above].