JPS6160628A - Manufacture of hydroquinone derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides d-α-toferol (natural vitamin E)
The present invention also relates to a novel starting material in this process.

Although several methods of producing natural vitamin E are known, these are of only limited interest from an industrial point of view, and therefore natural vitamin E
has traditionally been extracted from natural sources. Therefore, there is a need for an industrially viable approach that can obtain natural vitamin E in excellent yield and with high optical purity.

The method according to the invention comprises: a) a compound of the general formula in which R represents an ether protecting group; (c) (dl
where R2 represents phenyl, R4 represents methyl or phenyl and R5 represents lower alkyl, aryl or aryl-lower alkyl, and optionally the general formula thus obtained In the formula, R and R1 have the above-mentioned meanings, by hydrolyzing the compound of the general formula, in which R has the above-mentioned meanings.

or reducing the compound of the general formula m to produce the compound of the general formula m, in which R has the above meaning, or b) the compound of the formula m, in which R is has the above meaning, and l (3 represents a residue of the following formula: <j) C'H! -R'' in which R2, R4 and R5 have the meanings given above, and optionally, in the general formula thus obtained, R and R5 have the meanings given above. It consists of hydrolyzing the compound to produce the compound 2) or reducing the compound of the general formula mA to give the compound of the general formula V.

The term "ether protecting group" within the scope of the present invention does not only mean hydrolytically removable groups, such as silyl groups or alkoxymethyl groups, such as methoxymethyl groups.

and also oxidatively removable groups, such as C1-C6-
means an alkyl group.

The term "lower alkyl" is used within the scope of the present invention to mean straight-chain or branched alkyl radicals of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, It means tert-butyl, pentyl, hexyl, etc. The term "aryl" refers not only to phenyl, but also to naphthyl, these groups may be substituted or unsubstituted, and the term "aryl-lower alkyl" In the terminology, aryl and lower alkyl have the meanings given above.

Furthermore, in the formulas herein, a solid tapered line "v" indicates that the corresponding residue is located above the plane of the molecule, whereas a series of "parallel lines "v" indicates that the residue is located below the plane of the molecule.

Compounds of formula 1, 2, m-A, 2 and v are new and are likewise objects of the present invention.

The reaction of a compound of formula 1 with formula (1) is conveniently carried out in an inert organic solvent at a temperature of from about -80°C to about +10°C. Preferably about -20°
It is carried out at a temperature of 0.degree. C. to about 0.degree. As solvents here in particular those which are customary in metal-organic reactions, in particular ethers, such as diethyl ether, te
Mention may be made of rk-butyl methyl ether, tetrahydrofuran and the like.

The hydrolysis of the compound (2) to the hydroxy acid of the general formula (2) can be carried out by methods known per se. This hydrolysis is conveniently carried out in a suitable organic solvent, e.g.
lower alcohols of carbon atoms, e.g. methanol,
It can be carried out using alkali metal hydroxides or alkaline earth metal hydroxides, preferably aqueous sodium or aqueous potassium, in ethanol and the like.

The reduction of a compound of formula (II) to a compound of formula V can be carried out in a manner known per se. This reduction is conveniently carried out by reducing the complex metal hydride 1, e.g. LiAlH4, LiB
It can be carried out using Ha, diimbutylaluminum hydride, and the like. Possible solvents are inert organic solvents, especially ethers, such as diethyl ether or tetrahydrofuran. The temperature and pressure at which this reduction is carried out are not critical, so the reduction can be carried out under conditions usual for the reduction of ethers to alcohols.

The ketonisel of formula (1) used as a starting material is a known compound or an analogue of a known compound that can be readily prepared by methods analogous to the preparation of known compounds. However, the compounds of formula 1, which are also used as starting materials, are new and can be prepared according to the following reaction scheme: where R has the above meaning.

The conversion of a compound of formula (1) to a Grignard reagent of formula (2) can be carried out under conditions customary for the preparation of Grignard compounds.

The reaction of a Grignard compound of formula (1) with a compound of formula VI-A can be carried out in a manner known per se. This reaction is conveniently carried out at about -80"C to about 0C, preferably about -20C. As solvents, all solvents which are likewise considered in the preparation of Grignard reagents can be used.

The reaction of a compound of the formula (1) with a compound of the formula (2) can be carried out in a manner known per se, in particular in a manner analogous to the reaction of a compound of the formula I with a ketonisel of the formula (2).

The compounds of formula (1) used as starting materials are known. However, the compounds of formula (1) used as starting materials are also new and are likewise an object of the present invention. They can be prepared as shown in the following reaction scheme: 10 XTl1-A or 10XM-A or 4-xv-A' or +V■
-A or XV-A x■-A
CH, -R''X■-AX■-A In the formula, R, R2, R4 and R5 have the above meanings.

The reaction of compounds of formula X with pyruvic acid can be carried out in a manner known per se. This reaction is conveniently carried out in an aqueous
It is carried out in an alcoholic medium with the addition of a base, for example potassium hydroxide or sodium hydroxide. The reaction between the compound of Ikari and the compound of I) can also be carried out catalytically in a manner known per se, preferably in the presence of a base. In particular, noradium can be used as a catalyst. As base it is possible to use inorganic bases such as potassium hydroxide or also organic bases such as HL, triethylamine and the like.

The reaction of the compound 2) with the compound of the formula -A-XVI[-A can be carried out in a manner conventional for the preparation of esters from acids and alcohols. Esterification is
Preferably, this is carried out by first converting the acid into an imidazolide and then reacting this with the alcohol.

A compound of the formula (1) can, for example, be converted into a known compound of the formula and this can be converted into natural vitamin E in a manner known per se. The conversion of compound 2) into a compound of formula X2 can be carried out in a manner known per se. This conversion is conveniently carried out in aqueous acetonitrile.
It is carried out by oxidation using (NO3)6.

Compounds of formula V can be prepared, for example, by converting a compound of formula V into an epoxide, reacting the resulting epoxide with a Grignard compound of general formula, in which R has the above meaning, and thus (1
) is converted into natural vitamin E by converting the thus obtained known compound of the general formula can be transformed.

The conversion of compounds of formula V into epoxides of formula XX can be carried out in a manner known per se. For this purpose, the primary hydroxy group in the compound of formula V is first converted into a leaving group,
For example, halides (chlorine, bromine and iodine are considered halogens) or sulfonic esters (
for example, tosylate or mesylate).

This can be carried out in a manner known per se. The compound thus obtained is subsequently treated with a base. As bases, not only inorganic bases but also organic bases are suitable, preferably, for example, especially sodium hydroxide or potassium hydroxide.

The reaction of an epoxide of the formula XX with a Grignard compound of the formula XxI can be carried out in a manner known per se. However, it is preferred to carry out this reaction in the presence of a copper(I)-catalyst, especially II(I)-n-propylacetylide or a copper(I) halide-dimethylsulfide complex.

Suitable solvents for this reaction are all the solvents customary for Grignard reactions.

Compounds of general formula xxn are known and can be converted to d-α-tocopherol in known ways.

-X挌A↓- 18.6 mmol of 2-(2',5'-dimethoxy-3' in 20 ml of tetrahydrofuran.

A solution of 4°,6'-)-dimethylphenyl)-dityltriisobroboxytitanium was added with stirring at -20"0 to 3.12 g (10,3 mmol) of (-)
It was treated dropwise with -8-phenylmethylbilibate and the mixture was subsequently left at -20 DEG C. for a further 16 hours. 50 ml of aqueous sodium dihydrogen phosphate solution (
After addition of 10%), the mixture is extracted three times with 50 ml of ether each time.The combined organic phases are dried over sodium sulfate and the solvent is then removed on a rotary evaporator.

6.76 g of (-)-8-phenylmethyl (S)-4-
(2', 5'-dimethoxy-3', 4°.

6'-)limethylphenyl)-2-hydroxy-2-methylbutanoate is obtained.

2-(2′,5′-dimethoxy-3°,4′,6°-trimethylphenyl)-dityltriisoproboxytitanium used as starting material can be prepared as follows: 5 .34 g (18,6 mmol) of 1
-(2-bromoethyl)-2,5-dimethoxy-3,4
6-Trimethylbenzene is heated under reflux with 0.50 g (20.8 mmol) of magnesium in 20 ml of dry tetrahydrofuran for 1 hour, then 4.
71 ml (19.0 mmol) of chloro-triisopropoxytitanium are added at -20°C. This results in 2-(2'.

5″-dimethoxy-3′,4′,6°-trimethylphenyl)-dityltriisoproboxytitanium is treated directly.

0.907 g (approximately 1.35 mmol) of (-)-8-phenylmethyl (S)-4-(
A solution of 2',5'-dimethoxy-3',4',6'-)limethylphenyl)-2-hydroxy-2-methylbutanoate was treated with 1 ml of 28% sodium hydroxide solution.

This mixture is then left to stand at room temperature for 16 hours.Then, this mixture is diluted with 50 ml of wood, each time 50 ml of
Extract 3 times with 1 ether. The aqueous phase is acidified (pH 2) with 10% phosphoric acid and extracted three times with 50 ml of ether each time.The combined organic phases are dried over sodium sulfate and the solvent is then removed on a rotary evaporator. 212mg(S)
-4-(2',5'-dimethoxy-3',4',6
°-Trimethylphenyl)-2-hydroxy-2-methylbutanoic acid is obtained.

6.76 g (approximately 10.
3 mmol) of (S)-4-(2',5'-dimethoxy3'',4°,6'-)lyntylphenyl)-
A solution of 2-human axy-2-methylbutanoate was added to 1
Add in portions to a suspension of 0.380 g (9.98 mmol) LiAlH4 in 0 ml of ether without stirring.

After stirring for a further 2 hours at room temperature, 10 ml of ethyl acetate was added (to decompose the LiAIHs).
Subsequently, 10 ml of 10% aqueous sodium dihydrogen phosphate solution are added in full. This reaction mixture was added 5 times each time.
Extracted three times with 0 ml of ether, the combined organic phases were dried over sodium sulfate and the solvent was then removed on a rotary evaporator, which yielded 4.61 g of crude (S)-4-(2°
, 5°-dimethoxy-3゛.

4′,6°-trimethylphenyl)-2-methyl-1,
2-methanediol is obtained. 10 of this crude product
Reprecipitation from ml ether and 40 ml hexane gives the pure seal as a white product.

chiral shift test fi
I using (Eu(HFC)3 as agent)
In H-NMR (60MH2), this compound is
Optically pure (e, e, >90%) as acetonide
It turned out to be.

- 0.78 mmol of 2-(2',5'-dimethoxy-3',4',6) in 10 ml of dry tetrahydrofuran
A solution of '-trimethylphenyl)-dityltriisoproboxytitanium (manufactured by tJ according to Example 1) was prepared at -20
It was treated with 0.30 H (0.95 mmol) of (+)-cis-3-benzylbornylpyrivate at -20° C. with stirring, and the mixture was subsequently left at -20° C. for a further 16 hours. The treatment was carried out in a manner analogous to that described in Example 1, and (+)-cis-3
-Benzylbornyl(S)-4-(2°,5'-dimethoxy-3',4',6'-trimethylphenyl)-
2-Hydroxy-2-methylbutanoate is obtained, which is directly saponified in a manner analogous to that described in Example 2. The resulting aqueous phase was mixed with 0.5 ml of dimethyl sulfate and 20 mg of Aliquat.
336 [phase change catalyst from Fluka/CH] and stir the mixture for 1 hour at room temperature. Add 1 ml of 25% ammonia and stir the resulting mixture for a further 1 h at room temperature (removal of excess dimethyl sulfate). Extract the reaction mixture with ether and
By drying the ether phase with sodium sulfate and removing the solvent, 150 mg of methyl (S)-4-(
2',5'-dimethoxy-3°,4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoate is obtained. “Pirkle Phase”
hase) J c7) Optical purity according to HPLC = 95%
e, e,.

The (+)-cis-3-benzylbornyl birivate used as starting material can be prepared as follows: A solution of 0.88 g (10 mmol) of pyruvic acid in 20 ml of dry methylene chloride. 2.2g (10 mmol)
of caribonylciimiguzole and the mixture is stirred until gas evolution ceases (approximately 10 minutes). To the solution thus obtained of imidazole biribate is added 3.7 g (10 mmol) of (+)-cis-3-benzylborneol in dry methylene chloride together with 1 mmol of lithium imidazole as a catalyst. .

The mixture is stirred overnight at room temperature and subsequently taken up in water and ether, the Ninyl phase is filtered through silica gel, the filtrate is concentrated and the residue is distilled in a high vacuum (10-21-l) at about 190 complexes. do. 4.5g (+)
-cis-3-benzylbornyl birivate is obtained.

Thin layer chromatography: (silica gel: toluene/ethyl acetate lO:1): Rf = 0.4 - 14 g (2,
68 mmol) of (-)-cis-3-benzylbornyl (S)-4-(2',5'-dimethoxy-3',4',
6′-Trimethylphenyl)-2-ketobutanoate was treated with 3 mmol of methyl-triisopropoxytitanium in 1 ml of hexane with stirring at −20° C., and the mixture was subsequently heated at −20° C. Leave for a further 16 hours. The treatment was carried out in a manner analogous to that described in Example 1 and (-)-cis-
3-Benzylbornyl (S)-4-(2″,5°-dimethoxy-3′,4′,6″-trimethylphenyl)-2-hydroxy-2-methylbutanoate was obtained, which was used in Example Directly converted to the methyl ester in a manner analogous to that described in 4.

“Pirkle Phase”
7) Optical purity according to HPLC = 70% e, e,.

Experiments performed with optically pure (+)-borneol in a manner similar to the above yielded the corresponding (R)-methyl ester with an optical purity of 95% e,e.

(-)-cis-3-benzylbornyl (S)-4-(2°,5″-dimethoxy-3°,
4°, 6′-) lymphenyl)-2-ketobutanoate is 4-(2′-).

5'-dimethoxy-3',4',6°-trimethylphenyl)-2-ketobutanoic acid and (-)-cis-3-
It can be prepared starting from benzylborneol.

4-(2',5'-dimethoxy-3' as described above).

4',6'-Trimethylphenyl)-2-ketobutanoic acid can be prepared as follows: 3.7 g (17,6 mmol) of 2,5-dimethoxy- in 20 ml of methanol 3,4,6-trimethylhenzaldehyde and 5.0 g (53,2 mmol)
of sodium biribate Q54 solution at 0.1[(1,8
mmol) and the mixture was subsequently heated under reflux for 5 hours, resulting in a yellow solution. The reaction mixture was poured onto ice-water and the resulting 4-(2′,5°-dimethoxy-3′,4′,6′-trimethylphenyl)-2-keto-3-butanoic acid was stirred by the addition of sulfuric acid. Precipitate by The BS solution is stirred for 1 hour, filtered, and the reading residue is washed with water and dried. In this way, 4-(2′,5°-dimethoxy-3″,4′,6′-1
-Lynthylphenyl)-2-keto-3-butanoic acid is obtained in the form of a yellow powder jAi with a melting point of 126-127°C.

1.02 g (3.5 mmol) of this powder in 80 ml of water was subjected to thin layer chromatography by adding 10 ml of IN water-dissolving sodium solution at normal pressure in the presence of 400 mg of Pcl/C (5%). Hydrogenate until graphic control indicates complete hydrogenation. The catalyst is filtered and the filtrate is acidified to pH 4 with phosphoric acid and extracted with ether.

Evaporation of the nityl extract and drying over sodium sulfate yielded 0.75 g of 4-(2').

5'-dimethoxy-3',4°,6'-)lymphenyl)-2-ketobutanoic acid is obtained.

In a method similar to that described in Example 5, (I
S)-1-benzylcarbamyl-ethyl 4-(2',5
'-Dimethoxy-3°, 4'.

6'-trimethylphenyl)-2-ketobutanoate was reacted first with methyl-triisopropoxytitanium at -78°C for 5 hours, then at -20°C for 16 hours, and the reaction product was reacted with methyl ester diconverted sulfur, This optical purity is determined by the “Burkle phase”.
Ph a 5e) J (7) 95% according to HPLC
e, e, that's it.

(IS)-1-Benzylcarbamyl-ethyl 4-(2″,5′-dimethoxy-3′, used as starting material)
4',6''-trimethylphenyl)-2-ketobutanoate is 4-(2',5'-dimethoxy-3°4
+ , 5 + -trimethylphenyl)-2-ketobutanoic acid and (IS)-1-(benzylcarbamyl)ethanol C=L-milk mbenzylamide) prepared in a manner analogous to that described in Example 4 be able to.

148 mg (0.5 mmol) of (S)-4-(2'
, 5°-dimethoxy-3′,4″,6°-trimethylphenyl)-2-hydroxy-2-methylbutanoic acid (prepared according to Example 2) was dissolved in 2 ml of acetonitrile and the solution was dissolved in 2 ml of water. of 560 mg (1 mmol) of Ce(NH4)2 (NO3)6 with stirring and the mixture was subsequently treated with a further 1 mmol of Ce(NH4)2 (NO3)6 at room temperature.
Stir for 0 min. The mixture is then treated with 50 ml of water and extracted 3 times with 50 ml of chloroform each time. After drying over sodium sulfate, the combined organic phases were concentrated to yield 111 mg of (+)-(S)-2-hydroxy-2
-Methyl-4-(2'.

4゛,5°-trimethyl-31,6“-dioxo-1′
, 4°-cyclohexadien-1'-yl)butanoic acid is obtained.

Melting point 115-117°C; [α] = +11° (C
=0.2%, chloroform); "Burkle phase (Pirk
l=”hase)Jc7) Optical purity according to HPLC=
95% e, e,.

The product obtained after catalytic hydrogenation and subsequent acidic cyclization, namely (di)-(S)-6-hydroxy-2,
5,7,9-Tetramethylchroman-2-carboxylic acid is optically pure after crystallization from toluene.

).

A) 237 mg of tosyl chloride and 350 mg of (
S)-4-(2',5'-dimethoxy-3'.

4',6'-)rifthyl-2enyl)-2-methyl-1,
2-Butanediol is dissolved in 1 ml of methylene chloride, then 180 ml of pyridine is added in bulk at 0°C, and the mixture is left for 1 hour at 0°C and then for 16 hours at room temperature. Then 1 g of ice and 0.3 ml of concentrated hydrochloric acid are added. The mixture is then extracted with methylene chloride and the extract is dried and emulsified. 511 mg of (S)-4-(2',5'-dimethoxy-3',4°,6''-trimethylphenyl)-2-methyl-1-toluenesulfonyloxy-2-butanediol are obtained.

).

b) 177 mg of (S)-4-(2′,5°-dimethoxy-3°,4′,6”-trimethylphenyl)-
2-Methyl-1-toluenesulfonyloxy-2-butanediol was dissolved in 1 ml of ethanol and this solution was dissolved in 0.3 ml of an alcoholic solution of sodium hydroxide (1 ml).
, 2N).

This mixture was left at room temperature for 10 minutes, then 30 minutes
m] of JQ methylene is added, and the mixture is dried over 6 m of sodium sulfate and concentrated. 105 mg of (S)-4-
(2', 5'-dimethoxy-3', 4', 6°-
Trimethylphenyl)-2-methyl-1,2-epoxybutane is obtained. Melting point 47-48°C.

Holm).

c) 5.8 mmol of (3R,7R)-3,7°11-
Trimethyldodecyl bromide is heated under reflux for 15 minutes with calcined magnesium in 20 ml of ethyl acetate, then 1 g of (S)-4-(2',5'-dimethoxy-3',4',8°-trimethyl phenyl)-2-methyl-1,2-epoxybutane and 0.9 g of '1i
f4(1) -2-propylacetylide [or j bromide
O(I)/dimethyl sulfide complex] is added at 0°C. The temperature of the reaction mixture is subsequently raised to room temperature and the mixture is stirred overnight. Then 1 ml of ammonium chloride is added and the mixture is extracted with ethyl ether. The extract is dried, concentrated, and the residue is distilled in a bulb-tube (melting point, O, O1 mmHg = 140 °C), 1.28 g (7
2%) [or 1.41g (79%)] of (3R,7R
,11R) -1-(2',5'-dimethoxy-3'
, 4', 6'-trimethylphenyl)-3,7,11
, 15-tetramethylhexadecane-3-ol is obtained as a colorless oil.

Holm).

C31H5603 (476, 79) Measured value: C=78.09 H=11.84° Actual value:
C=77.92 H=11.88゜Patented Large F-Hofmann Roche Land Company Akchengesellschaft

Claims (1)

[Claims] 1, a) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R represents an ether protecting group. In the middle, R^1 represents the residue of the following formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼(c) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(d) or ▲There are mathematical formulas, chemical formulas, tables, etc.▼(e) Here, R^2 represents phenyl, and R^4 represents methyl or phenyl. and R^5 is lower alkyl,
Representing aryl or aryl-lower alkyl, is reacted with the ketoester of Hydrolyzing a compound having the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ IV where R has the above meaning, or reducing the compound having the general formula III. , general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ V In the formula, R has the above meaning, or b) the compound of the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ VI, General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼V In the formula, R has the above meaning, and R^3 represents the residue of the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼( f) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (g) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (h) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (i) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼(j) or ▲Mathematical formulas, chemical formulas, tables, etc.▼(k) Here, R^2, R^4 and R^5 have the above meanings, and react with the compound, and as necessary. Then, the general formula thus obtained ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ III-A In the formula, R and R^5 have the above meanings. , or a method for producing a hydroquinone derivative, which comprises reducing a compound of general formula III-A to give general formula V. 2. The reaction of the compound of formula I with the ketoester of formula II at a temperature of from about -80°C to about +10°C, preferably from about -20°C to about 0°C.
2. A method according to claim 1, which is carried out at a temperature of . 3. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ I In the formula, R represents an ether protecting group. 4. A compound of the general formula ▲ Numerical formulas, chemical formulas, tables, etc.▼III In the formula, R and R^1 have the meanings described in claim 1. 5. General formula ▲ Numerical formula, chemical formula, table, etc. ▼III-A In the formula, R and R^3 have the meanings described in claim 1. 6. General formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ IV In the formula, R represents an ether protecting group. 7. A compound of the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ VII In the formula, R and R^3 have the meanings described in claim 1.