JPH01233278A - Production of optically active alpha-tocotrienol - Google Patents

Abstract

PURPOSE:To industrially readily obtain the subject compound of homologue of vitamin E in high yield, by subjecting to desulfurization reaction using novel compound obtained through several intermediates from readily available nerol as a starting material. CONSTITUTION:A compound expressed by formula III (R is protect group of OH) is generated by protecting 6-position OH in chroman ring of a compound expressed by formula II obtained from nerol as a starting material, then the compound is chlorinated and aminated with dimethylamine to obtain a novel compound expressed by formula IV. Next, the compound is oxidized with persulfuric acid, hydrogenolized and chlorinated to generate a novel compound expressed by formula VII, then reacted with geranylsulfone and resultant novel compound expressed by formula IX is subjected to desulfurization reaction by adding LiHBr3 and in the presence of dichloro[1,3-bis(diphenylphosphino) propane]palladium to obtain a novel compound expressed by formula X. Finally the compound is reacted with an acid such as hydrochloric acid, thus protect group of OH is eliminated and the compound expressed by formula I is obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel method for producing industrially useful optically active α-tocotrienol.

[Prior Art and Problems to be Solved by the Invention] Tocotrienols are one of the vitamin E homologs, and their effects have attracted attention in recent years. Tocotrienols are alpha and beta like tocopherols.

Four types are known: T and δ, but among these, α-IJ enol is the most important from the viewpoint of use in pharmaceuticals and the like.

Among this α-tocotrienol, the natural optical activity d
-α-Tocotrienol has the following structural formula (1), and as is clear from this structural formula, it has an asymmetric carbon at the 2-position of the chroman ring, so it has conventional optical activity d −α
-It has been difficult to obtain tocotrienols synthetically.

As a result of considering various methods, the present inventors completed a method using (E, B, E)-geranylgeraniol as a starting material as a promising method, and filed a patent application (Japanese patent application filed). No. 206532 of 1985).

However, although this method is a powerful method, it is difficult to obtain ([E, B, E)-geranylgeraniol as a raw material, and it requires the use of expensive non-natural dimethyl tartrate when introducing a chiral point. However, the yield of the key reaction [2.3) sigmatropic rearrangement reaction is not very good.

[Means to solve the problem]

As a result of many years of intensive research into an industrial method for synthetically obtaining optically active d-α=tocotrienol, the present inventors found that it is one of the (Z)-monoterpene alcohols that can be easily used as a starting material. They discovered an industrial method using nerol and completed the present invention.

The outline of the method of the present invention is as follows.

H3 A more detailed explanation of each step is as follows.

(First step) (2R)-6-hydroxy-2 represented by formula (II)
-(4-methyl-3-pentenyl)-2゜5,7.8-
This is a step of protecting the 6-position hydroxyl group of the chroman ring of tetramethylchroman. A group commonly used as a protecting group is used. For example, benzyl group, methoxymethyl group, ethoxymethyl L p-nitrobenzyl group, t-butyldimethylsilyl group, trimethylsilyl group, triorganosilyl group such as tribenzylsilyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group. group, 1-ethoxyethyl group, etc., but methoxymethyl group is most preferred.

When protecting with methoxymethyl group, chloromethyl methyl ether is usually reacted in the presence of sodium hydroxide.

(Second Step) This reaction is a reaction in which the compound represented by formula (III) is converted into a chloride by adding, for example, trichloroincyanuric acid, and then dimethylamine is added to aminate the compound.

(Third step) This is a step of oxidizing the allylamine compound (IV) obtained in the second step to obtain compound (V).

Specifically, for example, allylamine compound (rV) is dissolved in methylene chloride, sodium carbonate is added and cooled, and then peracetic acid is added to carry out the reaction. This reaction is usually carried out at around -65°C to give preferable results.

(Fourth step) This is a step in which the obtained compound (V) is dissolved in, for example, acetic acid, zinc dust is added, and the O-N bond is hydrogenolyzed to obtain compound (VI).

(Fifth step) This is a step of chlorinating the obtained compound (Vl).

To give a preferred specific example, after nitrogen substitution using S-collidine, a chloride such as lithium chloride is added to form a chloro, chloride.

(Sixth Step) This reaction is a reaction that extends the carbon chain of the compound (VI) obtained in the fifth step.

Specifically, compound (■) is reacted in the presence of geranylsultetra n-butylammonium bromide.

(Seventh step) This reaction is a desulfurization reaction.

Specifically, dichloro[1,3-bis(diphenylphosphino)propane]palladium is added to compound (IX), and after cooling, for example, lithium triethylborohydride (L
iHBr3) is added to carry out the reaction.

(Eighth Step) This is a reaction in which the protecting group for the hydroxyl group of the compound (X) obtained in the seventh step is removed, and the reaction is usually carried out in the presence of an acid such as hydrochloric acid.

The above starting material (■) used in producing α-tocotrienol in the method of the present invention.

(V), (VT), (■), (IX),
(X) and the like are all new compounds.

Optically active substance (n) used as a starting material in the present invention
can be produced by the following method using nerol as a starting material (see Japanese Patent Application No. 61-206533).

A more detailed explanation of each step is as follows.

(First step) Nerol (XI) is subjected to enantioselective oxidation to obtain a 2,3-epoxy compound.

To give an example of a specific method, nerol,
Tartrate diester, tetraisopropyl orthotitanate, and t-butyl hydroperoxide from ~70~
Oxidation is carried out at a temperature of 30°C. Examples of tartaric acid esters that can be used include diethyl tartrate and dimethyl tartrate.

(Second step) Compound (■) in which the 2.3-epoxy compound is reductively cleaved
This is the process of obtaining For reductive cleavage, good results can be obtained using, for example, lithium aluminum hydride. At this time, as the solvent, for example, an ether solvent such as diethyl ether or tetrahydrofuran is used, and the reaction is usually carried out at about -10°C to 40°C, although the temperature is not particularly limited.

(Third step) In this step, compound (')ei) is tosylated to form compound (X
This is the process of obtaining M). The usual method is to carry out the reaction by adding p-)luenesulfonyl chloride in the presence of pyridine or the like.

(Fourth Step) This step is a step in which isopropyl mercaptan is added to the compound (XI/) obtained in the third step in the presence of metallic sodium to obtain sulfide (XV).

(Fifth step) This is an acetylation step, in which, for example, acetylation is performed using an acetylating agent such as acetic anhydride.

(Sixth step) In this step, the compound (Xllll) obtained in the fifth step is
This is a step in which 4-acetoxy-2,3,5-)limethylphenol is reacted by a (2,3]sigmatropy rearrangement reaction.

(Seventh Step) This step is a step in which the isopropylthio group of the compound (m) obtained in the sixth step is removed and deacetylated.

This process involves reductive desulfurization using Raney nickel, etc.
This is done by reductively removing the acetyl group using lithium aluminum hydride or the like.

(Eighth Step) This step is a step of obtaining the optically active compound (n) which is the final target substance. Specifically, the compound (XIX) obtained in the seventh step is directly cyclized using p-)luenesulfonic acid, anhydrous zinc chloride, etc., or oxidized to obtain a quinone compound represented by the structural formula: After this is obtained, cyclization is carried out using, for example, a palladium/carbon catalyst and p-)luenesulfonic acid or anhydrous zinc chloride.

Examples of the oxidizing agent used in the oxidation step include lead dioxide, silver oxide, hydrogen peroxide, Flemy's salt, etc., but in short, any oxidizing agent that can convert hydroquinone to quinone can be used. It is.

〔Effect of the invention〕

According to the method of the present invention, optically active α-toco)IJ enol can be easily produced without the need for dl-resolution.

Therefore, the present invention is a method for industrially producing optically active α-tocotrienol, and its value is extremely high.

〔Example〕

Examples are listed below, but it goes without saying that the present invention is not limited thereto.

Example 1 Synthesis of (2S,3R)-2,3-Epoxynerol In a 300rn 14 flask equipped with a Y-tube, a thermometer, and a syringe, 150 mj of methylene chloride was added while flowing nitrogen. was added and cooled to -20°C. First, add 4.26 g of isopropyl orthotitanate (15+y++nol),
Next, 3.40 g (16
A methylene chloride solution of 477I72 (mmol) was added at the same temperature over 3 minutes, and then stirred for 10 minutes. Nerol 2.3
1g (15mmol) methylene chloride solution 3mj! was added, and further t-butyl hydroperoxide (3,35M
1,2-dichloroethane solution) 9.00mj! (3
0 mmol) was added dropwise over 12 minutes at the same temperature, and the mixture was stirred for 4 hours. 38 mjl of 10% tartaric acid aqueous solution in the system! was added and stirred for 30 minutes, then returned to room temperature, stirred until the aqueous layer became transparent, and the organic layer and the aqueous layer were separated. Extract the aqueous layer with methylene chloride for 30rnI! ×3), Wash the organic layer thoroughly (
Water), after drying (MgSL), the solvent was distilled off and ether 1
00ml was added and cooled to 0°C. IN Hydroxide Nato'J
After stirring for 30 minutes, the organic layer and aqueous layer were separated and the aqueous layer was extracted with ether.
4) The combined organic layers were washed (water, saturated brine), dried (MgSO4), and the solvent was distilled off to give a crude product of 2.8
I got 9g. Column chromatography (silica gel 11
5g, 5-10% ethyl acetate/hexane) to obtain 2.04g of the above-titled target product.

・Yield; 80% 6[(lrJ:2°'=-16,3°(cm1.002
．． CHCI3)QIR(neat)cm-'; 3400, 2970. 1670. 1250. 1
030. 860 NMR (CCI4) δ: 1.27 (3H, s), 1.35-1.52 (2H,
+++), 1.60 (38°s), 1. ．． 65 (3
H, s), 1.87-2.27 (2H, m), 2.
03 (IH, t, J=5Hz), 3.58 (2H, d
, J=5Hz), 3.92(1!(,s), 5゜0
0 (IH, t, J=6.5Hz) Example 2 20rnI! (2S, 3R)-2,3- in an eggplant flask
Epoxy Nerol 270mg (1,6+r+mo 1
), 1.5 rllf (16 mmol) of acetic anhydride, and 1.5 ml (19 mmol) of pyridine were added, and the mixture was stirred at room temperature for 8.5 hours. After adding 2d of methanol, pour into 5ml of water, separate the organic layer and aqueous layer, and extract the aqueous layer with ether. ×4), Combine the organic layers and wash (2N hydrochloric acid,
water, saturated brine), dried (MgSO4) and evaporated. The obtained crude product was subjected to column chromatography (
Purification was performed using 6 g of silica gel (eluent: 10% ethyl acetate/hexane) to obtain 290 mg of the above-mentioned title compound.

・Yield: 95%, 80%e, e.

・IR(neat)cm-'; 2960, 1740.1230.1030.880・N
MR (CCI4) δ; 1.31 (3H, s), 1.40-1.55 (21
(, m), 1.64 (3H.

s), 1.71 (3H, s), 1.91-2.
29(2)1. m), 2.06 (3H, s),
2.81 (IH, t, J=6Hz), 3.92 (L
H, dd.

J=6Hz, 12Hz), 4.22 (IH, d
d, J=6Hz, 12Hz).

5, 12 (1)1. t, J = 6.6 Hz) diol IH 100% tetrahydrofuran in a 500 m 14 round flask equipped with an Aline condenser, thermometer, dropping funnel and nitrogen method.
mj! and 2.58g of lithium aluminum hydride.
(68 mmol) was added and suspended. Cool to 0°C, (2R,3R)-2,3-epoxynerol 8.4
A solution of 3 g (49.5 mmol) in tetrahydrofuran (40 mf) was added dropwise, refluxed for 10 minutes, cooled to 0°C, and water-tetrahydrofuran (1:1) 16rd!
Excess lithium aluminum hydride was quenched with.

Add 2N hydrochloric acid (150°C) to separate the organic layer, extract the aqueous layer with ether (130ml x 4), combine the organic layers, wash (saturated brine), dry (MgSO4), and evaporate the solvent to obtain the above-mentioned purpose. 8.28g of the product was obtained. The purity of this product was confirmed by C, IR, and NMR spectra.

・Yield; 97% ・[α]67=-2.79° (C=2.19.CHC
l,)・IR(neat)cm'; 3330, 2920.1120. 1060. 83
0-NMR (CC14) δ; 1.17 (31 (, s), 1.32-2J3 (6H,
m), 1.59 (3H.

s), 3.72 (2H, t, J=7Hz), 4.4
0(2H,s), 5.03(LH,t, J=6Hz
) In a 50 ml eggplant flask equipped with an IH calcium chloride tube (3
R) -3,7-dimethyl-6-octene-1,3-diol 7.98g (46mmol), pyridine 15m
j! was added and cooled to 0℃, and 11.5 g of tosyl chloride was added.
(60 mmol) was added little by little. The mixture was stirred at the same temperature for 1.5 hours, poured into 110 rn1 of ice-cooled water, and the organic layer was separated.

The aqueous layer was extracted with ether (60ml x 4), the organic layers were combined and washed (2N hydrochloric acid, water, saturated brine), dried (M
gSOn), the solvent was distilled off to obtain the above-titled target product in 15.
I got 1g. It was confirmed that this was pure by TLC, IR, and NMR spectra.

O yield; quant.

OIR(neat)cm-'; 3550, 2980.1600.1360.1190.
1180°960, 820 ・NMR (CCI 4) δ; 1.10 (3) 1. s), 1.23-2.10 (6H
, m), 1.55(3)1゜s), 1.63(3
H, s), 2.17 (3tl, s), 2.50
(LH,s).

4.43 (2tl, t, J=7Hz), 4.9
7 (IH, t, J=7Hz).

7.20 (2tl, d, J=8Hz), 7.61 (
2H, d, J = 8Hz) JH Aline 500r with cooler, thermometer and dropping funnel
rtl! Put methanol 140- into four Lof flasks,
7.03 g (92 mmol) of inpropyl mercaptan was dissolved by dissolving 2.12 g (92 mg atoms) of metallic sodium.
) and then stirred at room temperature for 30 minutes. (3R) -
A methanol solution of 27.4 g (84 mmol) of 3.7-dimethyl-3-hydroxy-6-octynyl tosylate was added dropwise at room temperature over 45 minutes, and the mixture was stirred at 50° C. for 2 hours. Pour into 400ml of water and extract ether, 230ml.
After washing (IN sodium hydroxide, lithium aqueous solution, saturated brine) and drying (MgS[14), the solvent was distilled off to obtain 18.5 g of a crude product. Column chromatography (
Purify with 600g of silica gel to obtain 1 of the above-titled target product.
7.4g was obtained.

・Yield; 90% −[al:” = −0,75°(cm3.73.C
OCl2)OIR(neat)cm-'; 3420, 2970.1160.920.840ONM
R(CC1,) δ; 1.16 (3H, s), 1.25 (6H, d, J=7
Hz), 1.37-2.21 (6H, m), 1.6
0(3H,s), 1.65(3)1. s).

2.4(1~2.57(2f(,rn), 2.47<
II (, s), 2.88 (IN.

hept,, J=7Hz), 5.07(IH,t,J
= 6Hz) in a 100ml eggplant flask (3R) -3,
Add 9.26 g (40 mmol) of 7-dimethyl-3-hydroxy-6-octenyl isopropylsulfide and 5.33 g (52 mmol) of acetic anhydride, and add 0.23 g (1.2 mmol) of p-)luenesulfonic acid hydrate.
After adding, the mixture was stirred at room temperature for 1 hour. Add the reaction solution to 110% water.
After separating the organic and aqueous layers, the aqueous layer was extracted with ether at 60 mI! ×4), combine the organic layers and wash (&
81 hydrated NaHCO, aqueous solution, water, saturated brine), after drying (MgS [14), the solvent was evaporated to give 10.7 g of crude product.
I got it. Column chromatography (silica gel 330
15-40% methylene chloride/hexane) to obtain 10.4 g of the above-mentioned title product.

・Yield; 95% ・[ffl^' = -2,02° (cm3.34.C
OCl2)OIR(neat)cm-'; 2960, 1?30.1240.830・NMR(CD
CI,)δ; 1.26(6)1. d, J=6.8Hz), 1.44
(3H,s), 1.60(3H,s), 1.68(
3H, s), 1.72-2.18 (6H, m).

1.98 (3H, s), 2.38-2. L2(2)1
．． m), 2.94(1)1゜hept,, J=6.8
Hz), 5.09 (LH, m> (A method) 7-shaped tube, injection pipe, 30mji side tube with drip side tube, 10
0 mf 4-hole flask was heated and dried in advance, cooled to room temperature while flowing nitrogen, and trimethylhydroquinone-4-
3.53g (18mmol) of acetate and 15mj of methylene chloride! Dissolve in 3-acetoxy-3゜7-dimethyl-6-octenyl isopropylsulfide 1.6
5 g (6 mmo I) in 8 ml of methylene chloride solution, S
- After adding 1.10 g (9 mmol) of collidine, -5
Cooled to 0°C. Sulfuryl chloride 0.98g (7m
After stirring at the same temperature for 15 minutes, 13 ml of a methylene chloride solution containing 3.68 g (36 mmol) of triethylamine was added dropwise over 1.5 minutes, stirring at the same temperature for 30 minutes, and gradually returning to room temperature. The reaction solution was poured into 90 mt of ice-cooled IN hydrochloric acid, the organic layer was separated, the aqueous layer was extracted with ether, and the organic layers were combined and washed (saturated NaH
CO3 aqueous solution, saturated brine), after drying (MgSO4)
The solvent was distilled off to obtain 5.24 g of a crude product.

Column chromatography (220 g of silica gel.

Purification with eluent (5% ethyl acetate/hexane) gave 0.90 g of the above-titled target product.

・Yield: 40% (Method B) Y-tube, 30mj! 3 Lof flasks, 100m! Heat and dry four flasks in advance, cool to room temperature while flowing nitrogen, and add trimethylhydroquinone (4-acetate) 2
．． Dissolve 91 g (15 mmol) in methylene chloride 15-, and 1.36 g (5 mmol) of 3-acetoxy-3,7-dimethyl-6-octenyl isopropylsulfide.
, 0.72 g (6 mmol) of S-collidine was added, and the mixture was cooled to -40°C. Sulfuryl chloride 0.81g (6m
mol) was added dropwise and stirred at the same temperature for 10 minutes, and the reaction solution was added with triethylamine 5, which had been cooled in advance to -30°C.
．． 06g (50mmol) methylene chloride solution 10-
The temperature was gradually raised to 0°C. Pour the reaction solution into a 70-mole tube of ice-cooled 2N hydrochloric acid, separate the organic layer, and extract the aqueous layer with chloroform. X3), the organic layers were combined, washed (NaHCO* aqueous solution), dried (MgSOJ), and the solvent was distilled off to obtain a crude product. Column chromatography (
Purification was performed using 300 g of silica gel (eluent: 5% ethyl acetate/hexane) to obtain 1.20 g of the above-mentioned target product.

(Improved method) The reaction operation was carried out in the same manner as in Method B, and the mixture was poured into a methylene chloride solution of triethylamine, and the temperature was gradually raised to 0°C. The reaction solution was filtered under reduced pressure to remove the salt, and the filtrate was poured into water to separate the organic layer. Extract the aqueous layer with ether (20m 1' x 2)
After combining the organic layers and drying (MgSO4), the solvent was distilled off to obtain 6 g of crude product. Column chromatography (
Purification was performed using 60 g of silica gel (1 eluent; 5% ethyl acetate/hexane) to obtain 1.64 g of the above-mentioned title compound.

- Yield; 71% oIR (neat) cm-'; 3180, 2930.1760.1730.1240.
830 NMR (CDCI, δ; 1.09. 1.206)1. each d, J=7)
1z), 1.3H3)1°S), 1.51(3H
,s), 1.603H,s), 1.68(4H,m
).

1.82 (3H, s), 1.94 (2H, m), 2
．． 00 (3H, s).

2.14 (6tl, s), 2.25 (3H, s),
2.46-3.03 (LH.

m), 4.57 (LH, t, J=6Hz), 4.9
3 (LH, m), 7.57 (IH, S) 1.84 g of the above-titled target product was obtained by the same operation as the improved method described in Tate Example 7.

・Yield; 79% ・Figure Δ' = 13.1" (C=1.18. CH
Cl3) Example 9 Ethanol 20rd, Raney nickel (W4) in a 5 (1 mj! 2 Lof flask) equipped with an Aline condenser and a thermometer.
9 g was added and refluxed for 20 minutes. After returning to room temperature, the rearrangement product obtained in Example 8 was 0.848 (L 8 mmo
10 ml of the ethanol solution of 1) was added and stirred for 45 minutes.

The catalyst was filtered through Celite and the solvent was evaporated to obtain the crude product. This was purified by column chromatography (35 g of silica gel, 1 eluent; 5% ethyl acetate/hexane) to obtain 0.63 g of the above-titled target compound.

・Yield: 89% ・Same name 6 = +15.4° (cm2.72. CHCI
3) OIR (neat) cm-'; 3500, 2930. 1760. 1730. 1
210. 1070. 840 NMR (CDCl2)
δ; 1.48 (3H, s), 1.6H3H, s),
1.69 (3H, s).

1.75-1.98 (6H, m), 2.03 (3H,
s), 2.05 (3H.

s), 2.07 (3H, s), 2.13 (3H
,s), 2.33(3H,s).

2.58 (2H, t, J=8Hz), 5.09 (L
H, m), 5.34 (LH.

S) Example 1〇1ヱ200m1 equipped with a thermometer and nitrogen bulb! 45 ml of diethyl ether was placed in a four-bottle flask, and 0.59 g (16 mmol) of lithium aluminum hydride was added and suspended. Desulfurized product 2.0 obtained in Example 9 was cooled to 0°C.
3g (5,2n+n+o l) in 8ml of diethyl ether solution! was added dropwise, and the mixture was stirred at room temperature for 1 hour. 0℃ again
The excess lithium aluminum hydride was quenched by adding water little by little, followed by 70mj of 2N hydrochloric acid!
was added and the organic layer was separated. Extract the aqueous layer with ether 2
After drying (MgSD
), the solvent was distilled off to obtain 59 g of crude product 1.

100m14 with Aline cooler, thermometer and nitrogen bulb
1.59 g of crude product (5.2 mmol
) and 30mj of benzene! and further p-
Toluenesulfonic acid hydrate 99 mg (0.52 mmol
) was added. After stirring at 55° C. for 2 hours, 30 ml of water was added and the organic layer was separated. Extract the aqueous layer with ether 15-
X3), the organic layers were combined, washed (saturated aqueous NaHC[]3, saturated brine), dried (MgSOs) and evaporated to obtain the crude product. Column chromatography (
Purification was performed using 45 g of silica gel (1 eluent; 1% ethyl acetate/hexane) to obtain 1.39 g of the above-titled target product.

・Yield: 93% ・Melting point: 4g, 5-50°C -[ff1g' = -4,71°(cm1.40.C
HCI3)61R(KBr)cm-'; 3430, 2920. 1260. 1080. 8
55 NMR (CDC13) δ; 1.24 (3H, s), 1.54 (2H, m), 1
．． 60 (3H, s).

1.67 (3H, s), 1.77 (2H, t, J=7
Hz), 1.99 (2H.

m), 2.10 (6H, s), 2.14 (3) 1.
s), 2.60 (2H, t.

J=7Hz), 4.29(1)1. s), 5.1
2 (LH, t, J=7Hz)ヱヱ50ml with calcium chloride pipe! (2R)-6-chromanol 309 obtained in Example 1O in an eggplant flask
mg (1.1 mmol), acetic anhydride 219 mg (2
, 1 mmol) and 6 mg (0.03 mmol) of p-toluenesulfonic acid hydrate were added thereto, and the mixture was stirred at room temperature for 1 hour. 1.5 methanol was added, and the mixture was poured into 20 ml of water, and the organic layer was separated. Extract the aqueous layer with ether at 10mfx
3) The combined organic layers were washed (saturated aqueous NaHCO3, saturated brine), dried (MgSO4), and the solvent was evaporated to obtain 355 mg of crude product. This was purified by column chromatography (18 g of silica gel, eluent: 1% ethyl acetate/hexane) to obtain 326 m
I got g.

・Yield; 92% iR (neat) cm-'; 2940, 1?55.1210.1080.850・N
MR (CDC13) δ; 1.20 (3H, s), 1.58 (3f1.s),
1.64 (3H, s).

1.90 (3H, s), 1.96 (3H, s),
2.07 (3H, s).

2.17 (3H, s), 1.41-2.33 (6H
, m), 2.38 (2H.

t, J = 7 Hz), 5.10 (lft, m) 320 mg (0.97 mmol) of (2R)-6-acetoxychroman obtained in Example 11 was placed in a 30 mN three-low flask equipped with a glass tube, a calcium chloride tube, and a thermometer. ), methylene chloride 5- was added, cooled to -60℃ and ozone oxygen (3,
6 mg/R gas) was flowed at 8.5 f/h for 1 hour. Thereafter, ozone was expelled with nitrogen, 120 mg (1.94 mmol) of dimethyl sulfide was added at the same temperature, the temperature was gradually returned to room temperature, and the mixture was poured into 20 rnl of water to separate the organic layer. 7rrti to extract the aqueous layer with ether! X3), the combined organic layers were washed (water, saturated brine), and after drying (Mg
SO4) and the solvent was distilled off to obtain 343 mg of crude product.

Column chromatography (silica gel 16g)
Purification was performed to obtain 178 mg of the above-mentioned target product.

・Yield: 60% (Ozone standard yield: 91%) OIR(neat) cm-'; 2930, 2
720. 1745. 1720. 1215. 11
95° NMR (CDC13) δ; 1.21 (3H, s), 1.77 (2H, t, J = 6
．． 8Hz), 1.84-1.97 (2H, m), 1
．． 97 (3H, s), 2. Old (3t1.s).

2,30 (3H,s), 2.60 (4H,m)
, 9.74 (18, t, J = 1, 6 Hz) 50m1 with a trap ball containing Molekinilar Thieves 4A and Jim Roth! In an eggplant flask, 150 mg (0.49 mmol) of the (2S)-aldehyde obtained in Example 12 was added.
), benzene 15mj! , ethylene glycol 37m
g (0.59 mmol 1) and further 6 mg (0.03 mmol) of p-toluenesulfonic acid hydrate were added thereto and the mixture was refluxed for 2 hours.

Return to room temperature and wash (IN NazCO, aqueous solution, water),
After drying (MgSOl), the solvent was distilled off to give a crude product of 166m
g was obtained, and column chromatography (6 g of silica gel,
Purification was performed using 10% ethyl acetate/hexane (eluent: 10% ethyl acetate/hexane) to obtain 143+ng of the above-mentioned title object.

・Yield: 84% ・Melting point: 131-132°C -NMR (CDCI,) δ: 1.24 (3H, s), 1.76 (4H, m), 1
．． 78(2)1. t, J=6.6Hz), 1.97(
3H,s), 2.0H3H,s), 2.08(3H
,s), 2.32(3H,s), 2.61(2H,
t, J=6.6Hz).

3.73-3.89 (2H, m), 3.93-4.
08(2)1. m).

4,87 (IH, m) Diethyl ether 6rd in a 30m 13-hole flask equipped with a thermometer and nitrogen method! , lithium aluminum hydride 2
2 mg was added and suspended. Cool to 0°C, Example 13
135 mg (0.35 m
mol) of diethyl ether-methylene chloride solution 4- was added dropwise, and the mixture was stirred at room temperature for 40 minutes. Cool again to 0℃ and add 1ml of water! Quench excess lithium aluminum hydride with 8 ml of 2N hydrochloric acid! was added to separate the organic layer.

The aqueous layer was extracted with ether (7rdX3), the organic layers were combined, washed (water), dried (MgSO4), and the solvent was distilled off to obtain a crude product. This was subjected to column chromatography (4 g of silica gel, eluent: 10% ethyl acetate/hexane).
Purification was performed to obtain 113 mg of the above-mentioned target product.

・Yield: 95% ・Melting point: 102.5-104°C ・IR (KBr) cm-'; 3480, 2920.1240.1130.920・N
MR(CDC13)δ; 1.23(3)1. s), 1.75 (4H, m),
1.79 (2H, t, J=7Hz), 2.10 (6H
,s), 2.14(31(,s), 2.61(2H
.

t, J=7Hz), 3.73-3.88 (28, m)
, 3.93-4.08 (2N, m), 4.29 (L
11 hg (0.36 mmol) of the (2S)-acetal obtained in Example 14, 8 ml of acetone, and 180 μA of IN hydrochloric acid were added to a 20 ml eggplant flask equipped with a 4.86 (IH, m) Dimroth. Refluxed for an hour. The temperature was returned to room temperature, saturated aqueous sodium hydrogen carbonate solution 2- was added, and the organic layer was separated. Extract the aqueous layer with ether 6 m
1l! X3), combine the organic layers and wash (saturated NaHCO
After drying (MgSIL), the solvent was distilled off to obtain a crude product. Column chromatography (
Purify with 4g of silica gel to obtain 76m of the above-titled target product.
I got g.

・Yield: 81% ・Melting point: 88-89.5°C ・[(rlRo' = 13.4° (cm1.15.
C5Hs), 79%e, e.

Literature value> Melting point; 90.5-92.5°C [ff1a5=-17,02° (cm0.9398.
C, H6) 1.62 g of 6-chromanol obtained in Example 10 (5.6 mm
ol) and 16 mI of tetrahydrofuran! , dissolved in 0.32 ml of dimethyl sulfoxide, added 149 g (llmmol) of sodium hydride (55%),
After reacting at room temperature for 30 minutes, 0.958 (llmmol) of chloromethyl methyl ether was added dropwise and stirred for 0.5 hour. The reaction solution was poured into water, the organic layer was separated, the aqueous layer was extracted with methylene chloride, the organic layers were combined, washed (saturated brine), dried (MgSO4), and the solvent was distilled off to obtain a crude product. This was purified by column chromatography (30 g of silica gel, 1 eluent; 2% ethyl acetate/hexane) to obtain 1.83 g of the above-titled target product.

・Yield: 98% OI R(neat) cnr'; 2920, 1
260.1160.1050.980 NMR (CDC
Iri δ; 1.24 (3H, s), 1.54 (2H, m),
1.58 (3H, s).

1.67 (3H, s), 1.77 (2) 1. t, J
=7Hz), 2.09 (3N.

s), 2.14 (3H, s), 2.18 (3H
,s), 2.57(2H,t.

J=7Hz), 3.60 (3H, s), 4.8
4 (2H, s), 5.12 (LH, m) 0.60 g (1.8 mmol) of the methoxymethyl ether obtained in Example 16 was placed in a 20 ml eggplant flask,
Trichloroisocyanuric acid was dissolved in 3.5 rnfl of hexane and cooled in a water bath. l1g (0,48+++m
ol) was added and stirred for 3.5 hours. Filter the reaction solution and wash the organic layer (Na2S203 aqueous solution, saturated brine)
After drying (MgSO<), the solvent was distilled off to give 0.0% chloride.
66g was obtained.

0.43 g (2 mmol) of the chloride was placed in a 30-bottom eggplant flask, dissolved in 6 ml of methanol, and 3.4-ml of a 50% aqueous dimethylamine solution was added, followed by stirring at room temperature for 6 days. After distilling off the solvent, IN sodium hydroxide was added. After pouring into the aqueous solution 5rd!, extracting with ethyl acetate and drying (MgSOs), the solvent was distilled off to obtain a crude product. This was purified by column chromatography (8 g of silica gel, 1 eluent; 50% ethyl acetate/hexane). 0.22 g of the above-titled target product was obtained.

-Yield; 60% iR(neat)cm-'; 2920, 1660. 1240. 1160. 1
050. 980 NMR (CDCl2) δ: 1.203H, s), 1.44-1.93 (6H, m
), 1.68(3)1. s), 2.08(3)1.
s), 2.14(3H,s), 2.18(3H,s
), 2.2H6H,s), 2.30-2.81 (3
H, m).

3.6H3H,s), 4.80(IH,s), 4.
86(3H,s)Xymethoxy-2,5,7,8-tetramethylchromade 50mj with calcium chloride tube! 0.32 g of allylamine obtained in Example 17 (0.8
5 mmol), dissolved in 12-methylene chloride, and added 0.18 g (1.7 mmol) of sodium carbonate.
Cooled to ℃. At the same temperature, 0.32 g of 40% peracetic acid (
After stirring for 1 hour, the temperature was slowly raised to 0°C, and 0.16 g (1.27 mmol) of sodium sulfite was added.
A 5 mj aqueous solution of mol) was added. After separating the organic layer, salt was added to the aqueous layer, extracted with ethyl acetate, and after drying (MgS
O, ), heated to 40-50°C and reacted for 1 hour.

The crude product obtained by distilling off the solvent was subjected to column chromatography (5.5 g of silica gel, eluent: 8% ethyl acetate/
Hexane) to obtain 0.20 g of the above-mentioned target product.

- Yield; 61% OIR (neat) cm-'; 2900, 1210. 860 ・NMR (CDC13) δ; 1.25 (3H, s), 1.66 (3H, s),
1.50-1.86 (4N.

m), 2.09 (3H, s), 2.14 (3H
,s), 2.18(3H,s).

2.57 (6H, s), 2.54-2.66 (2)
1. m), 3.61 (3H.

s), 4.04 (2H, s), 4.85 (28
, s), 5.44 (IH, t.

J = 6.3 Hz) 0.19 g (0.49 mmol) of allyloxyamine obtained in Example 18 was placed in a 10-bottom flask, and acetic acid-
0.90g of zinc powder dissolved in 5.4ml of water (1:1)
(14 mmol) was added. After stirring at room temperature for 40 hours, the zinc dust was filtered off, and the filtrate was extracted with ether and washed (saturated N
aHCOs aqueous solution, saturated brine), after drying (M g
S 04 ) and the solvent was distilled off to obtain a crude product. This was purified by column chromatography (4.7 g of silica gel, eluent: 10% ethyl acetate/hexane) to obtain 0.12 g of the title target compound.

The above-mentioned zinc powder used was one that was stirred in 5% hydrochloric acid for several minutes, filtered, and then washed (distilled water x 3, methanol x 3, ether x 3).

・Yield; 73% OIR(neat) cm-'; 3350, 2
900. 1240. 1160. 1060. 85
0.NMR (CDCI,) δ; 1.26 (3H, s), 1.58 (LH, s), 1
．． 65 (3tl, s).

1.51-1.65 (28, m), 1.80 (2N,
t, J=7Hz).

2.09 (3H, s), 2.14 (3H, s), 2
．． 18 (3tl, s).

2.59 (2H, t, J=7Hz), 3.61 (3H
, s), 3.97 (2H.

S), 4.85 (2H, s), 5.40 (lft,
m) pentenyl)-6-medoxymethoxy 2.5.7
Obtained in Example 19 (EE) in a 10 ml eggplant flask
-Allyl alcohol 120rig (0,34+n+n
ol), S-:1 lysine 92 mg (0,75 mm
o 1) was added and the atmosphere was replaced with nitrogen. In addition, lithium chloride29
mg t'o, 69 mmo I) in dimethylpolamide solution 1.5 mj! was added and cooled in a water bath, then 79 mg (0.69 mmol) of methanesulfonyl chloride was added, and the mixture was stirred for 3.5 hours while being cooled in a water bath. 30% of the reaction solution
- Pour into ice water, extract with ether, wash (saturated Cu(NO)
3), aqueous solution, saturated Na)lc[Is aqueous solution, water), and after drying (MgSIL), the solvent was distilled off to obtain 126 mg of the above-titled target product. This product was confirmed to be pure by TLC, IR, and NMR.

0 yield; quant.

eIR(neat)cm-'; 2920, 1250.1160.1060.800.7
50.680 NMR (CDCI,) δ; 1, 24 (3H, s), 1.72 (3N, s),
1.57-1.88 (48゜), 2.07 (3H,
s), 2.13(3H,s), 2.16(3H,s
).

2, 47 (2)1. Ql), 2.58 (2H
, t, J=7Hz), 3.57 (3H.

s>, 3.96 (2) 1. s), 4.80(2H,s
), 5.50 (IH, t.

J=7Hz) Obtained in Example 20 (B) - Black Jl/Body L26mg
(0,341T1moI), geranyl sulfone 200m
g (0.69 mmol), 50% hydroxide) IJ
Mix 0.44 g of tetra-n-butylammonium aqueous solution and add 8 mg of tetra n-butylammonium puromy Y (0,024+y++nol).
was added and stirred vigorously for 1.5 hours using a mechanical stirrer. Add 10 mf of water to the reaction solution, extract with ether,
After washing (saturated brine), drying (MgSO3) and evaporation, the crude product was obtained.

This was purified by column chromatography (6 g of silica gel, eluent: 10% ethyl acetate/hexane) to obtain 179 mg of the above-mentioned target compound.

・Yield: 84% oIR (neat) cm-'; 2920, 1600.1300.1140.810・N
MR(CD[l'13)δ; 1.20(6)1. s), 1.50 (3H, s),
1.59 (3H, s).

1.68 (3H, s), 1.64 (2)! , m),
1.75 (2H, t, J=6.6Hz), 1.9
0 (6H, m), 2.06 (3H, s), 2.13
(3N, s), 2.17 (3H, s), 2.43 (
3)1. s), 2.56 (2H, t, J=6.6Hz
), 2.73-2.94 (2H, m), 3.61 (
38,s), 3.70-3.83(IH,m), 4
．． 84(2)1. s).

4.90-5.23 (3H, m), 7.28 (2H,
d, J=8°3Hz).

7, 71 (2H, -d, J=8.3Hz) Example 2
2 (2R, 3'ε, 7'E)-6-medoxymethoxy 2
．． 5.7.81ヱ30mj! In an eggplant flask were placed 175 mg (0.28 mmol) of the coupling product obtained in Example 21 and 0 (1
,3-bis(diphenylphosphino)furopane]haladium(n) 13 mg (0,022 mmol) was added,
Add 14 ml of tetrahydrofuran and replace with nitrogen.
Cooled to . Lithium triethylborohydride (1,0 M solution in tetrahydrofuran) 1.4 d (1,4
mmol) was added, the mixture was returned to room temperature and stirred for 3 hours, and then 20 ml of water was added to quench excess lithium triethylborohydride. The reaction solution was extracted with ether, washed (saturated brine), dried (MgSO4), and the solvent was distilled off to obtain a crude product. This was purified by column chromatography (1.5 g of silica gel, eluent: 5% ethyl acetate/hexane) to obtain 115 mg of the above-mentioned title compound.

・Yield; 87% 'IR(neat)Cm-'; 2900, 1250.1160.1060・NMR(C
DC13) δ; 1.25 (3H, s), 159 (9N, s),
1.68 (3tl, s).

1, 79 (2H, t, J=6.8Hz), 1.43
~1.86 (2H, m).

2.00(10)1. s), 2.09(3)1. s)
, 2.14 (3H, s).

2.18 (3H, s), 2.59 (2H, t, J=6
．． 8Hz), 3.61 (3H, s), 4.85 (2
H,s), 5.1HIH,m)(2R,3'8.7°
E) -α-Tocotrienol 110 fng (0.23 mmol) of the α-tocotrienol methoxymethyl ether obtained in Example 22 was placed in an O-bottom flask, and 3.5 mj of isopropyl alcohol was added. Dissolve in 4N hydrochloric acid 0
．． 6- was added and stirred at room temperature for 20 hours. Add 20% of the reaction solution to water.
After extraction with ether, washing (water), and drying (M
gSL) and the solvent was distilled off to obtain a crude product. This was subjected to column chromatography (2 g of silica gel, eluent:
(ethyl acetate/hexane) to obtain the above title (2R,
93 mg of 3°E, 7′ε)-α-tocotrienol was obtained.

・Yield; 93% ・[α]P-4,53°(Cm1.61.CHCl3
), 79% e, e.

Literature value> [α3g5=-5,71°(Cm1°01155.C
H[”L)oIR(neat)c+n'; 345
0.NMR (CDC13) δ; 1.26 (38, s), 1.59 (9H, s), 1
．． 68 (3H, s>.

180 (2H, t, J = 7) 1z), 2.00 (3)
1. s), 2.11(3)l.

s), 2.16(3)1. s), 2.00-2.1
6 (12N, m).

2.61 (2H, t, J=7Hz), 4.18 (LH
, s), 5.13 (3H.

m)

Claims (1)

[Claims] 1 A compound represented by the general formula ▲ includes numerical formulas, chemical formulas, tables, etc. ▼ (in the formula, R represents a protecting group for a hydroxyl group) is subjected to a desulfurization reaction to produce the following general formula ▲ mathematical formula, There are chemical formulas, tables, etc. ▼ (In the formula, R has the above meaning) The following structural formula is characterized by obtaining a compound represented by and then removing the protecting group of the hydroxyl group of the obtained compound. (
A method for producing optically active α-tocotrienol represented by I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I)