JPS6363675A - Production of 2r)-6-hydroxy-2-(4-methyl-3-pentenyl)-2,5,7,8-tetramethylchroman - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful for producing optically active alpha-tocopherol and alpha-tocotrienol of natural type in high yield without requiring dl resolution, by using nerol as a starting raw material and treating nerol by a process of eight stages. CONSTITUTION:A compound shown by formula I is subjected to enantio-selective oxidation and the prepared epoxy derivative is reductively cleft to give a compound shown by formula II, which is tosylated and reacted with isopropyl mercaptan in the presence of metal sodium to give a compound shown by formula III. Then the compound is acetylated to give a compound shown by formula IV and reacted with 4-acetoxy-2,3,5-trimethylphenol to give a compound shown by formula V. Then the compound is reductively desulfurized by the use of Raney nickel and further reductively deacetylated by the use of lithium aluminum hydride to give a compound shown by formula VI, which is directly subjected to ring formation or oxidized into a quinone derivative and subjected to ring formation to give the aimed compound shown by formula VII.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention is useful as an intermediate for producing natural α-tocopherol, α-tocotrienol, etc.
) -6-Hydroxy-2-(4-methyl-3-pentenyl) 2.5.7.8-Tetramethylchroman relates to a novel manufacturing method.

[Prior art and problems] d-α-tocopherol is the most representative vitamin E that is widely distributed in nature, and not only itself but also various derivatives are used as pharmaceuticals, foods, feeds, etc. Wide (
It is widely used and is an extremely important substance among vitamin E.

However, d-α-tocopherol must be extracted from natural products, mainly vegetable oils, and is not suitable for industrial mass production, i.e., the content of d-α-tocopherol in vegetable oils is extremely small. It requires an extremely large amount of vegetable oil, and it also requires separation and purification from homologs such as β, T, and δ, and has the drawback that isolation is also difficult.

Therefore, various attempts have been made to chemically synthesize optically active α-tocopherol, especially d-α-tocopherol (for example, HlMayler, 0.15l
er et al.+ He1v, Chin, Acta+ 4
6+650 (1963); J, W, 5cott,
W, M, Cort, H, Harley.

F, T, Bizzarro, D, R, Pan1sh
, G, 5auey+j, to.

C,S, 51.200 (1974), 52.174
(1975); He1v.

ChiIl, Acta, 5! L 290 (1976
); K., Chan, N.

Cohen et al., J. Org. Chem, 41
．． 3497.3512 (1976), arc, 3435
(1978), etc.), but the method is industrially useful.

That is, all of the conventionally proposed methods require optical resolution of the a-form using an intermediate substance at some point. The necessity of this optical resolution means that the yield is 30%.
~40)6, which is a major drawback, and it cannot be called an industrial method.

Similarly, natural α-tocotrienols containing double viscosity in the side chain at position 2 of the chroman ring are also difficult to obtain by synthesis.

[Means for solving problems]

Therefore, the present inventors have spent many years researching methods for synthetically obtaining optically active d-α-tocopherol, d-α-tocotrienol, and the like.

The present invention describes the use of (2R)-6-hydroxy-2-(4-methyl-3-pentenyl)-2,5 having the following structural formula (1) for this purpose.
, 7,8-tetramethylchroman.

Namely, the present invention is directed to enantioselective oxidation of nerol represented by the following structural formula:
idation) to obtain an epoxy compound represented by the structural formula: This compound is then reductively cleaved to obtain a compound represented by the structural formula: Next, the cough compound is tosylated to obtain the epoxy compound represented by the structural formula: The compound is then reacted with isopropyl mercaptan in the presence of sodium metal to obtain a compound represented by the structural formula: and the compound is then acetylated to obtain a compound represented by the structural formula: The compound is then reacted with 4-acetoxy-2,3,5-)limethylphenol to obtain a compound represented by the structural formula: The compound is then reacted with Raney nickel and further deacetylated. , Structural formula: (2R ) -6-Hydroxy-2-(4-methyl-3-pentenyl)-2,5,7,8-tetramethylchroman.

An outline of the synthesis method of the present invention is as follows.

A more detailed explanation of each step is as follows.

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

To give an example of a specific method, nerol, tartaric acid diester, tetraisopropyl orthotitanate, and t-butyl hydroperoxide are mixed in a hydrogenated hydrocarbon such as dichloroethane or trichloroethane.
The 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) The 2.3-epoxy compound is reductively cleaved to form a compound (IV
). For reductive cleavage, good results can be obtained using, for example, lithium aluminum hydride. In this case, as a solvent, for example, diethyl ether,
The reaction is usually carried out using an ether solvent such as tetrahydrofuran at a temperature of about -10°C to 40°C, although the temperature is not particularly limited.

(Third step) This step is a step of tosylating compound (IV) to obtain compound (V). The usual method is to carry out the reaction by adding p-toluenesulfonyl 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 (V) obtained in the third step in the presence of metallic sodium to obtain a sulfide.

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

(Sixth Step) This step is a step in which the compound (■) obtained in the fifth step is reacted with 4-acetoxy-2,3,5-trimethylphenol.

(Seventh Step) This step is a step in which the isopropylthio group of compound (IX) obtained in the sixth step is removed and deacetylated. This step is carried out by reductive desulfurization using Raney nickel or the like and reductive removal of acetyl groups using lithium aluminum hydride or the like.

(Eighth Step) This step is a step of obtaining the optically active compound (1) which is the final target substance. Specifically, the compound (X) obtained in the seventh step is directly cyclized using p-)luenesulfonic acid, anhydrous zinc chloride, etc., or oxidized to produce a quinone represented by the structural formula: After obtaining the compound, cyclization is carried out using, for example, a palladium/carbon catalyst and p-toluenesulfonic 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〕

(2R)-6-hydroxy- obtained by the present invention
2-(4-methyl-3-pentenyl)-2゜5.7.8
-Tetramethylchroman is an intermediate for producing natural d-α-tocopherol and d-α-tocotrienol, and this intermediate can easily be used to produce d-α-tocopherol,
d-α-tocotrienol. According to this method, natural optically active α-tocopherol and α-tocotrienol can be produced industrially in high yield without requiring a-resolution, and therefore the value of the present invention is extremely high. .

〔Example〕

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

Example 1 Methylene chloride 1 cooled to -20°C under nitrogen atmosphere
Tetraisopropyl heorthotitanate in 50ml 4.2
6g (15mmol) and L-(+)-ethyl tartrate 3
．． 40 g (16 mmol) was added and stirred at the same temperature for 10 minutes. Next, 2.31 g (151 mmol) of nerol was added, and 9.0 ml (2,69 g) of L2-dichloroethane solution (3,35 M) of t-butyl hydroperoxide was added.
, 30 m+wol) was added dropwise over 12 minutes at the same temperature and stirred for 4 hours. Then 38ml of 10% tartaric acid aqueous solution
was added, stirred at the same temperature for 30 minutes, and then warmed to room temperature.

The organic layer was separated, the aqueous layer was extracted with methylene chloride, the extract and the organic layer were combined, washed with water, dried (MgSOe), and the solvent was distilled off to obtain 6.77 g of a crude product. This was dissolved in 100 ml of ether, and 45 ml of IN sodium hydroxide aqueous solution was added at 0°C, followed by stirring for 30 minutes. The aqueous layer was extracted with ether, and the extract was combined with the first organic layer, washed (water, saturated brine), dried (MgSO,), and the solvent was distilled off to obtain 2.89 g of a crude product. This was purified by column chromatography (115 g of silica gel, eluent 10% ethyl acetate/hexane) to obtain the desired (2S, 3R)
-2,3-epoxynerol 2.04g (yield 94χ
) was obtained.

[α) o”=-17,0” (cm1.9.Cl
ICl5), 80%ee (by NMR) nn"=1.4622 ir(neat)cm-': 3410.2960
．． 1670.1030.860ns+r(CCL)δ:
1.33 (3H, s), 1.42-1.50 (2)
1. m).

1.62(3i(,s), 1.68(3H,s),
1.92-2.17 (2H.

m), 2.92 (LH, t, J=5Hz), 3.68 (
IH,s), 3.8H2Ld, J=5Hz), 5.08
(LH, t, J-6Hz) Example 2 H 8.1 g of lithium aluminum hydride (0,21@ol
) and (3R)-2,3-epoxynerol 2
100 ml of a solution of 6.7 g (0.16+g) in tetrahydrofuran was added dropwise over 1 hour, and the mixture was refluxed for 10 minutes.

Cool to 0°C and add 40ml of 50% tetrahydrofuran aqueous solution.
1 was added dropwise to deactivate the remaining reducing agent, and 2N salt H390m
Added l. Separate the organic layer and extract the aqueous layer with ether (
The extract was combined with the organic layer, washed (saturated saline), dried and washed, and the solvent was distilled off to obtain 27.0 g of the target compound '#yJ (yield quantitative). Ta.

This was confirmed to be a pure product by TLC, IR and NMR spectra.

[α]. ”--2,79° (C=2.2.CHC
h) no"=1.4699 tr(neat)am-': 3340.2
920. 1670. 1i10. 1050°102
0.820 nmr (CC1a) δ: 1.1? (3H,s),
1.41-2.2H6Lm).

1.60(31(,s), 1.67(3H,s),
3.75 (2H, t, J=6Hz).

4.40<18. bs), 4.67 (IH, bs)
, 5.10 (IH, t, J=6Hz) Example 3 H (3R) -3,7-dimethyl-6-octene-1.3
- 15.6 g (91 m++ol) of diol in pyridine 3
23.4 g (123 mmol) of p-toluenesulfonyl chloride was added over 40 minutes at 0°C, and the mixture was stirred at the same temperature for 1.5 hours. Pour the reaction solution into ice water 200 ml
ml, separate the organic layer, extract the aqueous layer with ether,
The extract was combined with the organic layer, washed (2N hydrochloric acid, saturated saline) and dried (MgSOa), and then the solvent was distilled off to obtain 26.7 g (quantitative yield) of the target compound. This is TLC,
N? It was confirmed by IR and Il+ spectra that it was a pure product.

ir(neat)cm-': 3540.3450
．． 2970.1600.1500゜1360, 1190
．． 1175.955.815 nmr (CC1m) δ:
1.07 (3H, s), 1.30 (4H, m), 1.
52 (3H, s), 1.60 (3H, s), 1.7
4-2.11 (2H, m).

2.33 (311, s), 2.51 (IH, s),
4.07 (2H, t, J=6Hz), 4.94 (IH
, t, J=6Hz), 7.19(2H, d, J=8H
z).

”,,63 (2H, d, J=8Hz) Example 4 H methanol! 1.6g of metallic sodium in 10ml (
69 mg atom) was added and dissolved, and 5.26 g (69 m+aol) of isopropyl mercaptan was added dropwise.
Stirred at room temperature for 30 minutes. (3R) -3-hydroxy-3,7-dimethyl-6-octenyl tosylate 20.
A solution of 5 g (63 mmol) in methanol (50 sol) was added dropwise at room temperature over 40 minutes, and the mixture was further stirred at 50° C. for 1.5 hours.

Cooled to room temperature, poured into 320W+1 water, salted out, extracted with ether (6 times), washed (0, IN sodium hydroxide, saturated brine), dried (MgSO,), concentrated, and the crude product IS, 5g was obtained. Column chromatography (
The product was purified using silica gel (400 g) to obtain 14.2 g (yield: 98.chi.) of the target product.

(ff) D"=-0,75" (C=3.7.
CHClm)no"=1.4851 ir(neat)cm-': 3400.2960
．． 1150.920.830 nmr (CCL) δ: 1
．． 15(3)1. s), 1.25 (6H, d, J=6
．． 8Hz).

1.38-1.54 (4Hm), 1.51 (38,s
), 1.65 (3H.

s), 1.81-2.24 (2B, +w), 2.5
6 (2M, t, J=511z).

2.68 (LH, s), 2.76 (IH, hept,
J=6.8Hz), 5.08(IH,t, J=6H
z) Example 5 (3R) -3-acetoxy-3,7-dimethyl-6-
Synthesis of octenyl isopropylsulfide (3R)-1
- Isopro and Lunao 3.7-dimethyR/- 13.9 g (60 mmol) of 6-octen-3-ol and 8.01 g (78 mmol) of acetic anhydride were mixed, and p-) was prepared at room temperature.
Luenesulfonic acid hydrate 344+*g (1,8m+5
ol) was added over 20 minutes. Stir at the same temperature for 30 minutes,
The reaction solution was poured into 150 ml of water, the organic layer was separated, the aqueous layer was extracted with ether, and the extract was combined with the organic layer and washed (
After drying (MgSOn), the solvent was distilled off to give 16.6 g of crude product.
I got it. This was purified by column chromatography (500 g of silica gel) to yield 15.6 g of the target product (yield: 95 g).
I got it.

[α]. "=-2,02° (C=3.3. CHCl3
)ir(neat)cs+-': 2960.17
30.1240nmr(CC1*)δ: 1.2G(6
11,d, J-6,8Hz), 1.38(3H.

s), 1.58 (3Ls), 1.65 (3Ls),
1.82-2.17 (6H, m), 1.89 (3H
, s), 2.32-2.60 (2H, m).

2.86<ILhept, J-6,811z), 5
．． 07(1)1. t, J=6Hz) Example 6 Yoshikei 4-acetoxy-2,3,5-)limethylphenol 3
．． 53g (18s+mol), (3R)-3-7 setoxy 3.7-dimethyl-6-octenyl isopropylsulfide 1.65g (6w+mol) and S-collidine 1.10g (9+amol) were dissolved in methylene chloride 23m
0.98 g of sulfuryl chloride (
After stirring at the same temperature for 15 minutes, a solution of 3.68 g (36 mmol) of triethylamine in methylene chloride (13 ml) was added dropwise over 1.5 minutes, followed by stirring at the same temperature for 30 minutes. Thereafter, the temperature was gradually raised to room temperature, the reaction solution was poured into 90 ml of ice-cooled IN hydrochloric acid, the organic layer was separated, and the aqueous layer was extracted with ether. The extract and the previous organic layer were combined, washed (saturated sodium bicarbonate, saturated saline), dried (MgSOn), the solvent was distilled off, and column chromatography (silica gel 220g% eluent 5% ethyl acetate/hexane) The target product was separated in an amount of 945+mg (yield: 42χ).

[α) @”= −13,1” (C=1.2.CH
Ch)ir(neat)cm-' = 3240.
2970. 1?60. 1730. 1363°1
240.1200 nmr (CDC1x) δ: 1.09 (3H, d, J=
7Hz), 1.21 (3H, d.

J=711z), 1.31 (3t1.s), 1.5
1 (38,s), 1.61 (38,s), 1.6
8 (4H, m), 1.82 (3H, s), 1.
94 (2Lm), 2.00 (3H, s), 2.
14 (6Ls), 2.25 (38,s), 2.4
6-3.03 (1B, m), 4.57 (111, t,
J=6H2), 4.93 (18, bs), 7.57
(IH,s) Example 7 A of rhotrimethylphenol 10 ml of ethanol was added to 3.6 g of freshly prepared Raney nickel (W4) and heated under reflux for 10 minutes. 3-acetoxy-l-isopropylthio-3,7-dimethyl-6-octenyl)-4
-acetoxy-3,5,6-)limethylphenol 28
6 mg (0,62+m5 ol) of ethanol (5 ml
) solution was added and stirred at 50°C for 30 minutes. After that, the reaction solution was filtered through Celite, the solvent was distilled off, and the target product 22
9 mg (yield: 95x) was obtained. Is this TLC and N?
It was confirmed by IR spectrum that it was almost pure.

nmr (CCL) δ: 1.40 (3H, s), 1.
57 (311, s), 1.63 (3H, s), 1.
57-1.92 (6H, +*), 1.92 (12) 1
．． s).

2.18 (3H,s), 2.37 (2i1.bs),
5.00 (III, bs).

5.52 (1B, s) Example 8 Futatekujira! Lithium aluminum hydride 128 mg (3,4+++
+5 ol) was suspended in 11 ml of ether, and (3'R)-4-acetoxy-2-(3-7
Setoxy-3,7-dimethyl-6-octenyl)-3,
A solution of 016-trimethylphenol in ether (5 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Cool to 0°C again, gradually add 111 liters of water to deactivate the excess reducing agent, add 15 wl of 2N hydrochloric acid, separate the active layer, extract the aqueous layer with methylene monochloride, and extract the extract. Combine with the previous organic layer, wash (water, sodium thiosulfate aqueous solution, saturated saline), and dry (MgSOe).
Thereafter, the solvent was distilled off to obtain 173 mg of a crude product.

Next, 173 mg (0.56 mn+ol) of this crude product was dissolved in 10 ml of benzene under a nitrogen atmosphere, and P-)toluenesulfonic acid-elongate 12B (0.06 mmol) was added, and the mixture was heated at 50°C for 1 hour, and then at 70°C. The mixture was stirred for 1.5 hours. 10 ml of water was added to separate the organic layer, and the aqueous layer was extracted with methylene chloride. Combine the extract and the organic layer and wash (
saturated sodium bicarbonate aqueous solution, water, saturated saline),
Dry (MgS(lt)), concentrate to obtain crude product 168+w
I got g. This was purified by column chromatography (silica gel 9gS eluent 0.5z ethyl acetate/hexane) to obtain 147mg of 6-chromanol (yield 91χ).
I got it.

ir(neat)c+++-': 3430. 2
930, 1260. 1210, 1160.

1080, 855 n+sr (CC 1 t) δ: 1.18 (3H.s
), 1.43-1.77 (4H, m).

1,55(3H,s), 1.61(3H,s),
2.00 (IIH, s).

2, 48 (2) 1. t. J-7Hz), 4.07(1
8,), 5.00(1)1,t.

J=61(z)

Claims (1)

[Claims] 1 Structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Nerol represented by enantioselective oxidation
dation) to obtain the epoxy compound represented by the structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and then the compound is reductively cleaved to produce the structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by is obtained, and then the compound is tosylated to form a structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Ts represents a tosyl group (▲There are mathematical formulas, chemical formulas, tables, etc.). The same applies hereafter] A compound represented by is obtained, and then the compound is reacted with isopropyl mercaptan in the presence of metallic sodium to obtain a compound represented by the structural formula: ▲ Numerical formula, chemical formula, table, etc. ▼ Acetylate a compound to obtain a compound represented by the structural formula: ▲Mathematical formula, chemical formula, table, etc.▼, and then react the compound with 4-acetoxy-2,3,5-trimethylphenol to obtain the structural formula : ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Obtain the compound represented by , and then the compound is reacted with Raney nickel and further deacetylated to obtain the structural formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The compound is characterized in that the compound is directly cyclized or oxidized to obtain a quinone compound and then cyclized. A method for producing (2R)-6-hydroxy-2-(4-methyl-3-pentenyl)-2,5,7,8-tetramethylchroman.