JPH0788376B2 - Process for producing optically active α-tocotrienol - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for industrially useful production of optically active α-tocotrienol.

[Conventional technology and problems]

Tocotrienol is one of the vitamin E homologues, and its action has recently attracted attention. Similar to tocopherol, four types of α, β, γ, δ are known as tocotrienols, but α-tocotrienol is the most important of these.

Among these α-tocotrienols, the naturally-occurring optically active d
-Α-tocotrienol has the following structural formula (I), As is clear from this structural formula, since it has an asymmetric carbon atom at the 2-position of the chroman ring, it has conventionally been optically active d-α.
-It was difficult to obtain tocotrienols synthetically.

[Means for solving problems]

Therefore, the present inventors have conducted many years of research on a method for synthetically obtaining optically active d-α-tocotrienol, and as a result,
The inventors have found that this is possible by the method shown below, and have completed the present invention.

That is, the present invention has the structural formula: (Where R ¹ is the formula The geranylgeraniol represented by is represented by the enantio-selective oxidati
on) and the structural formula: An epoxy compound represented by the following formula is obtained, and then the compound is reductively cleaved to obtain a structural formula: A compound represented by the formula: [In the formula, Ts is a tosyl group Represents The same applies to the following], and then the compound is reacted with isopropyl mercaptan in the presence of metallic sodium to give a structural formula: A compound represented by the following formula is obtained, and then the compound is acetylated to obtain the structural formula: (Wherein Ac represents an acetyl group; the same applies hereinafter), and then the compound is reacted with 4-acetoxy-2,3,5-trimethylphenol to give a structural formula: A compound represented by the following formula is obtained, and then the compound is reacted with Raney nickel and further deacetylated to obtain a structural formula: The compound represented by the formula (1) is obtained, and then the compound is directly cyclized, or is oxidized to obtain a quinone body and then cyclized, and the structural formula: The present invention relates to a method for producing an optically active d-α-tocotrienol represented by

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

Each step will be described in more detail below.

(Step 1) Geranylgeraniol is subjected to an enantioselective oxidation operation to obtain a 2,3-epoxy compound.

If an example of a specific method is shown, geranylgeraniol, a tartaric acid diester, tetraisopropyl orthotitanate, and t-butyl hydroperoxide are heated at a temperature of −70 to 30 ° C. in a halogen-based hydrocarbon such as dichloroethane or trichloroethane. To oxidize. As the tartrate ester, for example, diethyl tartrate, dimethyl tartrate or the like can be used.

(Second step) This is a step of reductively cleaving the 2,3-epoxy compound to obtain the compound (IV). For reductive cleavage, good results can be obtained by using, for example, lithium aluminum hydride. At this time, an ether solvent such as diethyl ether or tetrahydrofuran is used as a solvent, and the temperature is not particularly limited, but the reaction is usually performed at about -10 ° C to 40 ° C.

(Third Step) This step is a step of tosylating compound (IV) to obtain compound (V). The usual method is in the presence of pyridine, etc.
The reaction is carried out by adding p-toluenesulfonyl chloride.

(Fourth Step) This step is a step of adding isopropylmercaptan to the compound (V) obtained in the third step in the presence of metallic sodium to obtain a sulfide.

(Fifth Step) In the acetylation step, acetylation is performed with an acetylating agent such as acetic anhydride.

(Sixth Step) In this step, the compound (VII) obtained in the fifth step is treated with 4-
This is a step of reacting acetoxy-2,3,5-trimethylphenol.

(Seventh Step) This step is a step of removing the isopropylthio group and deacetylating the compound (IX) obtained in the sixth step. This step is performed by a method such as reductively desulfurizing with Raney nickel or the like and reductively removing the acetyl group with lithium aluminum hydride or the like.

(Eighth Step) This step is a step of obtaining optically active d-α-tocotrienol (I) as a final target substance. Specifically, the compound (X) obtained in the seventh step is treated with p-toluenesulfonic acid,
Cyclization is carried out directly using anhydrous zinc chloride or the like, or by oxidation to give the structural formula: After the quinone compound represented by the formula (1) is obtained, it is cyclized with, for example, a palladium / carbon catalyst and p-toluenesulfonic acid or anhydrous zinc chloride.

Examples of the oxidizing agent used in the oxidizing step include lead dioxide, silver oxide, hydrogen peroxide, and Flemmy's salt. In short, any oxidizing agent capable of converting a hydroquinone form to a quinone form can be used. Is.

〔The invention's effect〕

The method of the present invention is a method which can industrially produce a naturally-occurring optically active α-tocotrienol in a high yield without requiring dl resolution, and therefore the value of the present invention is extremely high.

〔Example〕

Examples will be given below, but it goes without saying that the present invention is not limited thereto.

Example 1 Synthesis of (2R, 3R) -2,3-epoxygeranylgeraniol 1.80 g (10 mmol) of dimethyl D-(-)-tartrate was dissolved in 110 ml of methylene chloride and cooled to -20 ° C. 2.84 g (10 mmol) of tetraisopropyl orthotitanate was added and stirred for 10 minutes, and then 2.90 g (10 mmol) of geranylgeraniol was added. tert-Butyl hydroperoxide 1,2-
Dichloroethane solution (3.35M) 5.97ml (1.80g, 20mmol)
Was added dropwise over 30 minutes and stirred for 3 hours. 10% L-(+)-
250 ml of an aqueous tartaric acid solution was added, and the mixture was stirred for 30 minutes while continuing cooling with a dry ice-carbon tetrachloride bath. After removing the bath, stirring was continued for another 2.5 hours. After separation, extraction and drying,
Crystals precipitated upon concentration. After filtration and washing, the mother liquor was concentrated and purified by silica gel column chromatography to obtain (2R, 3R) -2,3-epoxygeranylgeraniol 2.89.
g (Y = 94%) was obtained.

[Α] _D ¹⁷ = + 4.81 ° (C = 2.9, CHCl ₃ ), 95% een _D ²⁵ =
1.4887 ir (neat) cm ^-1 : 3400,2910,2850,1660,1440,1380,1025,
850 ¹ Hnmr (CCl ₄ ) δ: 1.23 (3H, s), 1.57 (9H, s), 1.65 (3
H, s), 1.81 to 2.22 (12H, m), 2.84 (1H, t, J = 5.4Hz), 3.
60 (2H, d, J = 5.4Hz), 3.92 (1H, s), 4.77 to 5.23 (3H, b
m) ¹³ Cnmr (CDCl ₃ ) δ: 15.71 (2C), 16.46, 17.33, 23.29, 2
5.35,26.32 (2C), 26.54,38.35,39.44 (2C), 60.89,63.
05,123.08,123.84,124.16,130.66,134.56,135.22 Example 2 (3R) -3,7,11,15-tetramethylhexadeca-6,10,14
-Triene-1,3-diol synthesis Equipped with a dropping funnel with a side tube, an arene cooling tube, and a nitrogen ball
250 ml of tetrahydrofuran was placed in a 500 cc three-necked flask, and 4.10 g (108 mmol) of lithium aluminum hydride was suspended. Thereto, 22.1 g (72 mmol) of (2R, 3R) -2,3-epoxygeranylgeraniol was added to 50 ml of tetrahydrofuran.
The solution dissolved in was added dropwise at room temperature for 15 minutes and refluxed for 4 hours. The reaction product was cooled to 0 ° C., 25 ml of a 1: 1 solution of water and tetrahydrofuran was added little by little to quench unreacted lithium aluminum hydride, 130 ml of 3N hydrochloric acid was added, and the mixture was extracted with ether. Wash the extract with saturated saline,
After drying over magnesium sulfate, the solvent was distilled off and the residue was purified by column chromatography to obtain 20.3 g of the desired product (Y = 92
%) Was obtained.

n _D ²⁵ = 1.4908 ir (neat) cm ^-1 : 3330,2910,1660,1440,1370,1020,880 nmr (CCl ₄ ) δ: 1.17 (3H, s), 1.57 (9H, s), 1.63 (3H ,
s), 1.37 ~ 1.85 (4H, m), 1.85 ~ 2.36 (10H, m), 3.76 (2
H, d, J = 6 Hz), 4.61 (2H, s), 4.87 to 5.27 (3H, bm) Example 3 (3R) -3-hydroxy-3,7,11,15-tetramethylhexadeca-6, Synthesis of 10,14-trienyl tosylate In a 200 cc eggplant-shaped flask equipped with a soda lime tube, (3
R) -3,7,11,15-tetramethylhexadeca-6,10,14-
18.5 g (60 mmol) of triene-1,3-diol was added to pyridine 20
It was dissolved in ml and cooled to 0 ° C. 17.2 g (90 mmol) of p-toluenesulfonyl chloride was added thereto, and the mixture was stirred at 0 ° C. for 1.5 hours, 200 ml of ice water was added, and the mixture was extracted with methylene chloride.
The extract was washed with 0% sulfuric acid, aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and the solvent was distilled off to obtain 26.5 g of the desired product (Y = 95%). It was confirmed to be pure by TLC, NMR spectrum and IR spectrum.

n _D ²⁵ = 1.5128 ir (neat) cm ^-1 : 3540,2930,1670,1600,1450,1360,1180,
1100,890 nmr (CCl ₄ ) δ: 1.09 (3H, s), 1.56 (9H, s), 1.62 (3H,
s), 1.70 to 1.81 (4H, m), 1.81 to 2.27 (10H, m), 2.37 (3
H, s), 2.58 (1H, s), 4.08 (2H, t, J = 7Hz), 4.80-5.19
(3H, bm), 7.22 (2H, d, J = 8Hz), 7.66 (2H, d, J = 8Hz) Example 4 (3R) -3-hydroxy-3,7,11,15-tetramethylhexadeca -6,10,14-Trienyl isopropyl sulfide 130 ml of methanol was placed in a 300 cc eggplant-shaped flask, and 1.5 g (65 mg-atom) of metallic sodium was added and dissolved therein. 4.95 g (65 mmol) of isopropyl mercaptan was added, and the mixture was stirred at room temperature for 10 minutes. There (3R) -3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-
A solution of 21.7 g (47 mmol) of trienyl tosylate in 100 ml of methanol was added dropwise, and the mixture was stirred at 50 ° C for 1 hour.
After cooling to room temperature, it was poured into 200 ml of water, extracted with ether, washed with 1N-sodium hydroxide aqueous solution, water and saturated saline, and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography to obtain 15.1 g of the desired product (Y = 84
%) Was obtained.

n _D ²⁵ = 1.4978 ir (neat) cm ^-1 : 3440,2930,1660,1450,1380,930 ¹ Hnmr (CCl ₄ ) δ: 1.15 (3H, s), 1.25 (6H, d, J = 7Hz),
1.60 (9H, s), 1.66 (3H, s), 1.43 to 1.88 (4H, m), 1.88
~ 2.21 (10H, m), 2.37 ~ 2.74 (2H, m), 2.63 (1H, bs),
2.90 (1H, hept, J = 7Hz), 4.78-5.24 (3H, bm) Example 5 (3R) -3-acetoxy-3,7,11,15-tetramethylhexadeca-6,10,14-tri Synthesis of enylisopropyl sulfide In a 250cc eggplant-shaped flask equipped with a calcium chloride tube (3
R) -3-Hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienylisopropyl sulfide 14.
7g (40mmol), acetic anhydride 45.9g (450mmol), pyridine 3
5.6 g (450 mmol), N, N-dimethylaminopyridine 2.44 g
(20 mmol) were mixed and stirred at room temperature for 18 hours. After adding 30 ml of methanol to quench excess acetic anhydride, water 35
It was poured into 0 ml and extracted with ether. After washing with dilute hydrochloric acid and saturated saline and drying over magnesium sulfate, the solvent was distilled off,
Purify by column chromatography 14.1 g (Y
= 87%).

[Α] _D ¹⁷ = -2.49 ° (C = 3.0, CHCl ₃ ) n _D ²⁵ = 1.4917 ir (neat) cm ^-1 : 2920,1730,1660,1450,1360,1240 ¹ Hnmr (CCl ₄ ) δ: 1.21 (6H, d, J = 6Hz), 1.39 (3H, s),
1.57 (9H, s), 1.65 (3H, s), 1.77 to 2.40 (14H, m), 1.90
(3H, s), 2.40 to 2.70 (2H, m), 2.85 (1H, hept, J = 6H
z), 4.78-5.29 (3H, bm) Example 6 (3'R) -2- (3'-acetoxy-1'-isopropylthio-3 ', 7', 11 ', 15'-tetramethylhexadeca Synthesis of -6 ', 10', 14'-trienyl) -3,5,6-trimethylhydroquinone-4-acetate In a 300cc four-necked flask equipped with a Y-tube, thermometer, and calcium chloride tube, (3R) -3-acetoxy-3,7,11,15-
Tetramethylhexadeca-6,10,14-trienyl isopropyl sulfide 6.54 g (16 mmol), 4-acetoxy-
4.32 g (48 mmol) of 2,3,5-trimethylphenol was dissolved in 50 ml of methylene chloride, and 2.30 g of s-collidine (19 mmo
l) was added and the atmosphere was replaced with nitrogen. This solution was cooled to −50 ° C., 2.29 g (17 mmol) of sulfuryl chloride was added, and the mixture was stirred at −50 ° C. for 1 hour.
Stir for 0 minutes. This solution was added dropwise to a solution of 9.31 g (96 mmol) of triethylamine cooled in -40 ° C. in 50 ml of methylene chloride, and after normal treatment, purified by column chromatography to obtain 4.90 g of the desired product (Y = 51%). .

[Α] _D ¹⁷ = -12.8 ° (C = 1.0, CHCl ₃ ) n _D ²⁵ = 1.5207 ir (neat) cm ^-1 : 3220,2920,1760,1730,1445,1360,1240,
1200 ¹ Hnmr (CDCl ₃ ) δ: 1.09 (3H, d, J = 6Hz), 1.23 (3H, d, J
= 6Hz), 1.32 (3H, s), 1.58 (9H, s), 1.65 (3H, s), 1.8
2 (3H, s), 2.02 (6H, s), 2.14 (3H, s), 2.26 (3H, s),
1.72 to 3.00 (15H, m), 4.61 (1H, t, J = 6Hz), 4.80 to 5.30
(3H, bm), 7.71 (1H, s) mass m / e600 (M ⁺ ) Example 7 (3'R) -2- (3'acetoxy-3 ', 7', 11 ', 1
Synthesis of 5'-tetramethyl-6 ', 10', 14'-hexadecatrienyl) -3,5,6-trimethylhydroquinone-4-acetate 20 ml ethanol, Raney nickel (W4) 8.8 g in a 50 ml two-necked flask equipped with an arene condenser and a calcium chloride tube.
Was added, the mixture was refluxed for 15 minutes, then cooled to room temperature, and (3 '
R) -2- (3'-acetoxy-1'-isopropylthio-3 ', 7', 11 ', 15'-tetramethylhexadeca-
A solution of 1.00 g (1.67 mmol) of 6 ', 10', 14'-trienyl) -3,5,6-trimethylhydroquinone-4-acetate in 10 ml of ethanol was added, and the mixture was stirred at room temperature for 1 hour, and further 30 ° C. The mixture was stirred for 2.5 hours. Then, the catalyst was filtered through Celite and the solvent was distilled off.
g (Y = 95%) were obtained. It was confirmed to be pure by TLC, ¹ H-NMR, and IR spectrum.

[Α] _D ²³ = + 15.8 ° (C = 2.3, CHCl ₃ ) ir (neat) cm ^-1 : 3480,2930,1760,1730,1220,1075,840 ¹ Hnmr (CCl ₄ ) δ: 1.43 (3H , s), 1.58 (9H, s), 1.63 (3
H, s), 1.97 (12H, s), 2.23 (3H, s), 1.58 to 2.34 (16H,
m), 5.03 (3H, bm), 5.35 (1H, s) Example 8 Synthesis of d-α-tocotrienol Ether in a 50 ml four-necked flask equipped with a thermometer and nitrogen bulb.
Put 15 ml, and 153 mg of lithium aluminum hydride
(4.0 mmol) was added and suspended. It is cooled to 5 ° C. and (3′R) -2- (3′-acetoxy-3 ′, 7 ′, 1
1 ', 15'-Tetramethyl-6', 10 ', 14'-hexadecatrienyl) -3,5,6-trimethylhydroquinone-4-
A solution of 350 mg (0.66 mmol) of acetate in 7 ml of ether was added dropwise, and the mixture was stirred at room temperature for 1 hour. Then, after cooling to 0 ° C., 2 ml of water was added little by little to quench excess lithium aluminum hydride. 3N-hydrochloric acid (15 ml) was added to separate the organic layer, and then ether was extracted.The organic layer was separated, washed with an aqueous sodium thiosulfate solution and saturated saline, dried over sodium sulfate, and then the ether was distilled off. , 295 mg of the target crude product was obtained. This was used as it was in the next reaction.

After placing 295 mg of the crude product (deacetylated product) and 10 ml of benzene in a 50 ml two-necked flask equipped with an arene condenser and a nitrogen bulb, 14 mg (0.07 mmol) of p-toluenesulfonic acid monohydrate was added, and then 70 ° C. And stirred for 30 minutes. 10 ml of water was added to this to separate the organic layer, and the aqueous layer was extracted with ether and combined with the previous organic layer. This was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated to give the desired crude product (299 mg). This was purified by column chromatography (silica gel 20 g) to give d-α.
251 mg (Y = 89%) of tocotrienols were obtained.

[Α] _D ²⁰ = -5.14 ° (C = 0.35, CHCl ₃ ), 90% eemass m
/ e424 (M ⁺ ) ir (neat) cm ^-1 : 3450,2930,1255,1215,1165,1085,855 ¹ Hnmr (CDCl ₃ ) δ: 1.26 (3H, s), 1.59 (9H, s), 1.68 (3
H, s), 1.80 (2H, t, J = 7Hz), 2.00 (3H, s), 2.11 (3H,
s), 2.16 (3H, s), 2.00 to 2.16 (12H, m), 2.61 (2H, t, J
= 7Hz), 4.18 (1H, s), 5.13 (3H, bm)

Claims (1)

[Claims] 1. A structural formula: (Where R ¹ is the formula The geranylgeraniol represented by is represented by the enantio-selective oxidati
on) and the structural formula: An epoxy compound represented by the following formula is obtained, and then the compound is reductively cleaved to obtain a structural formula: A compound represented by the formula: [In the formula, Ts is a tosyl group Represents The same applies to the following], and then the compound is reacted with isopropyl mercaptan in the presence of metallic sodium to give a structural formula: A compound represented by the following formula is obtained, and then the compound is acetylated to obtain the structural formula: (Wherein Ac represents an acetyl group; the same applies hereinafter), and then the compound is reacted with 4-acetoxy-2,3,5-trimethylphenol to give a structural formula: A compound represented by the following formula is obtained, and then the compound is reacted with Raney nickel and further deacetylated to obtain a structural formula: The compound represented by the formula (1) is obtained, and then the compound is directly cyclized, or is oxidized to obtain a quinone body and then cyclized, and the structural formula: The manufacturing method of optically active d- (alpha) -tocotrienol represented by these.