JP2896612B2 - Method for producing sphingosine and intermediates - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing sphingosine useful as a physiologically active substance, and an intermediate thereof.

[0002]

2. Description of the Related Art Sphingosine is a compound constituting a part of sphingomyelin, cerebroside, ganglioside and the like, which are important physiologically active substances present in the plasma membrane. Since these compounds are involved in the mechanism of cancer development, they have many physiological activities such as anticancer effects,
Attention has been paid.

[0003] However, sphingosine is extracted from nature.
Is not easy, and its synthesis research is actively conducted.
You. (C. A. Grob, F. Gadient, Helv. Chim. Acta,Four
0, 1145 (1957); D. Shapiro et al., J. Am. Chem. So
c.,80, 1194 (1958); Y. Shoyama et al., J. Lipid Re.
s,19, 250 (1978); H. Newman, J. Am. Chem. Soc.,9
Five, 4098 (1973); B. Bernet et al., Tetrahedron Lett.,
twenty four, 5491 (1983); R. R. Schmidt et al., Angew. Chem.
Int. Ed,twenty one, 210 (1982)). But completely stereoscopic
The production method has not been reported to date.

[0004]

In recent years, when a physiologically active substance such as a drug has structural isomers, it is possible that one of the isomers is significantly superior or has a completely different activity. Therefore, it is necessary to examine the activity of each of the two enantiomers. Therefore, producing only a compound having a desirable configuration has safety,
Aspiring from both aspects of efficiency.

[0005]

According to the present invention, there is provided a compound of the general formula

[0006]

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[0007] Sharpless oxidation of a symmetrical allyl alcohol, which was impossible in the past, was carried out using the allyl alcohol represented by the following formula as a starting material to obtain an optically active epoxide.
By protecting the diol of this optically active epoxide, a compound of the general formula (I) (hereinafter, * represents an asymmetric carbon) can be obtained.

[0008]

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Next, by opening the ring of the compound of the general formula (I), it can be led to the compound of the general formula (II) (R ¹ represents a lower alkyl group and X represents a hydroxyl group). The diastereomer obtained at this time can be easily isomerized to a compound having one of the desired configurations.

[0010]

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Next, the hydroxyl group is azido-substituted and the protecting group of the diol is removed to obtain a compound represented by the formula (III).

[0012]

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This is converted to a dioxane ring derivative, and the compound of formula (I)
V) '.

[0014]

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A compound represented by the formula (IV) ′ is obtained by substituting a hydrogen of a hydroxyl group of the compound represented by the formula (IV) ′ with a leaving group such as a methanesulfonyl group to obtain a compound represented by the formula (IV) (R ² is a methanesulfonyl group, Benzenesulfonyl group, trifluoromethanesulfonyl group).

[0016]

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This is reacted with a Grignard reagent to give a compound represented by the formula (V).

[0018]

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The dioxane ring is opened under acidic conditions, and the azide is converted into an amino group by a conventional method, whereby natural or unnatural sphingosine can be obtained. The reaction temperature, via the intermediates (I) to (V) by the route described above,
Natural or unnatural sphingosine can be obtained even if the time, solvent, reagent, handling amount, etc. are different. That is, the reaction temperature, time, solvent and the like can be changed within a range that can be inferred by those skilled in the art.

The starting material is allyl alcohol
(VI) or (VII) is, for example, the method of Young et al. (J. Am.
Chem. Soc., 58 , 2274 (1936)) and can be easily obtained from acrolein.

[0021]

According to the present invention, the total yield from starting allyl alcohol to sphingosine was as high as 6% in 11 steps. Its configuration was completely controlled. According to the production method of the present invention, sphingosine of natural or non-natural type can be easily produced.

[0022]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited only by the examples. Example 1 Preparation of epoxydiol from meso-allyl alcohol 4A molecular sieve (2.0 g) was added to a solution of tetraisopropyl titanate (3.0 ml, 10 mmol) in methylene chloride (300 ml).
At −20 ° C. and a solution of (+)-diisopropyl L-tartrate (4.70 g, 20 mmol) in methylene chloride (20 ml) was added.
Stir at the same temperature for minutes. Then meso-allyl alcohol
(1.14 g, 10 mmol) in methylene chloride and after 15 minutes,
t-butyl hydroperoxide (94 ml in methylene chloride
(3.2M, 300mmol) solution and stirred for 72 hours. Water (18m
l), acetone (90 ml) was added, the temperature was returned to room temperature, and stirring was continued for 1 hour.
The insolubles are removed by filtration using. The residue on celite was treated with methylene chloride (500 ml × 1) and tetrahydrofuran (300 ml).
× 2), the mixture is stirred for 3 hours to extract the adsorbed product.

After drying the combined filtrate over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was purified by column chromatography, and 332 mg (29%) of the starting material was obtained from a stream of ethyl ether to obtain 658 mg (57%; diastereomeric mixture of erythro: threo = 7: 1) of epoxydiol. The above epoxydiol (500 mg, 3.85 mmol), 2,
A solution of 2-dimethoxypropane (2.4 ml, 19.2 mmol) and pyridinium p-toluenesulfonate (97 mg, 0.38 mmol) in 5 ml of acetone is stirred at room temperature for 48 hours.

After neutralization by adding 2 ml of a saturated aqueous sodium bicarbonate solution at 0 ° C., the mixture is extracted with methylene chloride (10 ml × 3).
The organic layer is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. After column chromatography, erythro-epoxide (515 mg,
79%) and threo-epoxide (73 mg, 11%).

The physical properties of the erythro body were as follows. [Α] ^{_{D 30 -11.1 (c1.01, CHCl 3}} ) IR ν neat max 3000, 1640cm -1 1 H NMR (90MHz, CDCl 3) δ 6.00 (ddd, 1H, J = 16.8, 10.0, 6.6Hz), 5.60-5.25
(m, 2H), 4.74 (t, 1H, J = 6.6Hz), 3.77 (t, 1H, J = 6.8H
z), 3.10-2.75 (m, 2H), 2.68 (dd, 1H, J = 5.1, 2.7Hz),
1.53 (s, 3H), 1.37 (s, 3H).

The physical properties of the threo compound were as follows. [Α] ^{_{D 28 -17.9 (c 1.15, CHCl}} 3) IR ν neat max 1640cm -1 1 H NMR (90MHz, CDCl 3) δ 5.95 (ddd, 1H, J = 17.1, 9.8, 7.1Hz), 5.60-5.20 (m,
2H), 4.68 (t, 1H, J = 7.1Hz), 3.87 (t, 1H, J = 6.1Hz),
2.95 (m, 1H), 2.76 (t, 1H, J = 4.15Hz), 2.60 (dd, 1H, J =
5.12, 2.69Hz), 1.53 (s, 3H), 1.38 (s, 3H).

Example 2 Production of Epoxydiol from D, L-Allyl Alcohol (Part 1) The reaction was carried out in the same manner as in Example 1 except that the meso-allyl alcohol was changed to D, L-allyl alcohol.
R) -allyl alcohol (36%), (2R) -epoxydiol (3%), and (2R, 5R) -diepoxydiol (12%) were obtained, respectively.

Example 3 Production of Epoxydiol from D, L-Allyl Alcohol (Part 2) Diisopropyl (+)-L-tartrate of Example 1 (20 mmol)
l) was changed to (−)-D-diisopropyl tartrate (12 mmol), meso-allyl alcohol was changed to D, L-allyl alcohol, and the same reaction was carried out. (2S) -epoxydiol (9%) and ( 2S, 5S) -diepoxydiol (35%) were each obtained.

Example 4 Preparation of (2S, 3R, 4R) -1- (p-methoxy) benzyloxy-2-hydroxy-3,4-isopropylidenedioxy-5-hexyne Potassium hydride (960 mg, 24 mmol) To a suspension of the above in dimethylformamide (DMF, 20 ml) was added dropwise p-anis alcohol (2.8 ml, 24 mmol) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes.
On the other hand, a solution of erythro-epoxide (1.88 g, 11.05 mmol) obtained in Example 1 in DMF (5 ml) was added dropwise at room temperature and stirred for 1 hour. Under ice cooling, 10 ml of water was added to stop the reaction, and 50 ml of ethyl ether was added for extraction. The organic layer is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. After distilling off p-anis alcohol using a Kugelrohr at 0.1 mmHg and ~ 130 ° C, the residue was subjected to column chromatography to obtain erythro-alcohol (2.90 g, 90%).

[Α] _D ²⁸ −5.5 ° (c1.02, CHCl ₃ ) IR ν ^neat _max 3320, 1610, 1580, 1515, 1250 cm ⁻¹ NMR (90 MHz, CDCl ₃ ) δ 7.25 (d, 2H, J = 8.8Hz), 6.90 (d, 2H, J = 8.8Hz), 6.2
0-5.80 (m, 1H), 5.55-5.15 (m, 1H), 4.75-4.55 (m, 1H),
4.50 (s, 2H), 4.05 (dd, 1H, J = 6.1, 8.5Hz), 3.80 (s, 3
H), 3.70-3.40 (m, 2H ), disappears at _{2.45 (d, 1H, D 2} O), 1.5
0 (s, 3H), 1.36 (s, 3H) MS m / e 308 (M ⁺ ), 121 (100%).

Example 5 Preparation of (2R, 3S, 4R) -2-azido-1- (p-methoxy) benzyloxy-3,4-isopropylidenedioxy-5-hexene Erythro obtained in Example 4 -Alcohol (750mg, 2.5
7 mmol), pyridine (2.1 ml, 25.7 mmol) in methylene chloride (2
Trifluoromethanesulfonic anhydride (0.86 ml, 5.14 mmol) was added dropwise to the solution at 0 ° C. at 0 ° C., and the mixture was stirred at the same temperature for 5 minutes.

A saturated aqueous sodium bicarbonate solution and ethyl ether are added, and the mixture is stirred at room temperature for 30 minutes, extracted with ethyl ether, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained crude triflate is directly used for the next reaction. Crude triflate (1.2 g, about 2.57 mmol) in DMF
(15ml) Sodium azide (335mg, 5.14m) at 0 ° C
mol) and stirred at the same temperature for 2 hours. Dilute with ethyl ether, wash with saturated aqueous sodium chloride,
Dry over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain 516 mg (60%) of threo-azide.

IR ν ^neat _max 2100, 1610, 1515, 1250cm
^-1 NMR (90MHz, CDCl ₃ ) δ 7.25 (d, 2H, J = 8.8Hz), 6.90 (d, 2H, J = 8.8Hz), 6.1
5-5.75 (m, 1H), 5.35-5.10 (m, 2H), 4.70-4.40 (m, 2H),
4.45 (s, 2H), 4.20 (dd, 1H, J = 5.0, 6.2Hz), 3.82 (s, 3
H), 3.65-3.30 (m, 2H), 1.50 (s, 3H), 1.36 (s, 3H) MS m / e 333 (M ⁺ ), 121 (100%).

Example 6 Preparation of (2R, 3S, 4R) -2-azido-1- (p-methoxy) benzyloxy-3,4-dihydroxy-5-hexene The threo-azide obtained in Example 5 ( (350mg, 1.05mmol)
To a solution of this in methanol (2 ml) was added a 10% aqueous hydrochloric acid solution (1 ml), and the mixture was stirred at room temperature for 3 hours. At 0 ° C., sodium bicarbonate is added, neutralized and extracted with methylene chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain a diol (307 mg, 95%).

[Α] _D ²⁸ + 3.4 ° (c1.06, MeOH) IR ν ^neat _max 3420, 2100, 1607, 1581 cm ^-1 NMR (90 MHz, CDCl ₃ ) δ 7.25 (d, 2H, J = 8.8 Hz) ), 6.90 (d, 2H, J = 8.8Hz), 5.95
(ddd, 1H, J = 5.9, 10.2, 18.2Hz), 5.50-5.20 (m, 2H),
4.45 (s, 1H), 4.40-3.95 (m, 2H), 3.80 (s, 3H), 3.80-
3.30 (m, 3H), 2.55 (brd, 1H, J = 6.2Hz), 2.20 (brd, 1H,
J = 6.2 Hz) MS m / e 294 (M + 1), 121 (100%).

Example 7 Preparation of (2S, 4R, 5S) -5-azido-2- (p-methoxy) benzyl-4- (1-hydroxy-2-propenyl) -1,3-dioxane A dichlorodicyanoquinone (190 mg, 0.834 mmol) was added to a solution of the obtained diol (188 mg, 0.64 mmol) and 4A molecular sieve (200 mg) in methylene chloride (5 ml) at 0 ° C.
l) in one portion and stir at room temperature for 10 hours. After filtering off insolubles using Celite, the filtrate is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain a dioxane ring derivative (92 mg, 49.4%).

Colorless needles (Et ₂ O-n-hexane) mp. 78
-80 ° C. [α] ^{_{D 27 -46.0 ° (c 0.67,}} CHCl 3) IR ν neat max 3435, 2108, 1610, 1515cm -1 NMR (90MHz, CDCl 3) δ 7.25 (d, 2H, J = 8.8Hz) , 6.90 (d, 2H, J = 8.8Hz), 6.05
(ddd, 1H, J = 4.88, 10.25, 15.4Hz), 5.54 (s, 1H), 5.53
-5.15 (m, 2H), 4.52 (dd, 1H, J = 1.46, 12.45Hz), 4.40
(m, 1H), 4.20 (dd, 1H, J = 1.46, 12.45Hz), 3.90 (d, 1H,
J = 1.7Hz), 3.86 (s, 3H), 3.30 (d, 1H, J = 1.7Hz), 2.10
(d, 1H, J = 3.2Hz) Analytical value Calculated value C ₁₄ H ₁₇ N ₃ O ₄ C 57.72; H 5.88; N 14.
42 found C 57.98; H 5.98; N 14.27.

Example 8 (2S, 4R, 5S) -5-Azido-2- (p-methoxy) benzyl-4- (1-methanesulfonyloxy-2
Production of -propenyl) -1,3-dioxane The dioxane ring derivative obtained in Example 7 (79 mg, 0.27 mm
ol) and 4-dimethylaminopyridine (335 mg, 2.7 mmol) in methylene chloride (5 ml), methanesulfonyl chloride (0.28 ml, 2.44 mmol) was added dropwise at 0 ° C, and the mixture was further stirred at the same temperature for 1 hour. After adding methylene chloride for dilution,
Wash with water, saturated aqueous sodium chloride and dry over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography to obtain mesylate (88 mg, 88%).

IR ν ^neat _max 2086, 1576, 1479, 1365 cm
^-1 NMR (90 MHz, CDCl ₃ ) δ 7.40 (d, 2H, J = 8.8 Hz), 6.85 (d, 2H, J = 8.8 Hz), 6.20
-5.80 (m, 1H), 5.70-5.15 (m, 4H), 4.70-4.00 (m, 3H),
3.80 (s, 3H), 3.20 (d, 1H, J = 1.7Hz), 3.00 (s, 3H).

Example 9 (2S, 4R, 5R) -5-Azido-2- (p-methoxy) benzyl-4- (1E-pentadecenyl) -1,3
Preparation of dioxane To a solution of cuprous iodide (38 mg, 0.2 mmol) in 2 ml of tetrahydrofuran (THF) was added dropwise lauryl magnesium bromide (0.67 M solution in THF, 0.60 ml: 0.4 mmol) at -30 ° C. Stir at 0 ° C. for 15 minutes. During this time, the gray suspension turns brown. A solution of the mesylate (37 mg, 0.1 mmol) obtained in Example 8 in THF (1 ml) was added dropwise to the solution cooled to −30 ° C. again, and the solution was further added at the same temperature for 15 minutes.
Stir at 5 ° C. for 1 hour. After terminating the reaction with a saturated aqueous ammonium chloride solution (1 ml) and diluting with ethyl ether, the organic layer is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain E-olefin (31 mg, 70%).

[Α] _D ²⁸ −69.1 ° (c 0.92, CHCl ₃ ) IR ν ^neat _max 2794, 2078, 1565, 1475, 1423 cm ⁻¹ NMR (90 MHz, CDCl ₃ ) δ 7.45 (d, 2H, J = 8.8Hz), 6.95 (d, 2H, J = 8.8Hz), 6.20
-5.50 (m, 2H), 5.59 (s, 1H), 4.60-4.10 (m, 3H), 3.79
(s, 3H), 2.89 (brd, 1H, 1.7Hz), 2.20-1.80 (m, 2H), 1.
65-1.00 (m, 22H), 0.88 (brd, 3H).

Example 10 Preparation of (2R, 3R, E) -2-azido-1,3-dihydroxy-2-octadecene E-olefin obtained in Example 9 (32 mg, 72 mmol)
A mixture of methanol (1 ml) and 10% aqueous hydrogen chloride (0.5 ml) was stirred at room temperature for 2 hours. At 0 ° C. carefully add sodium bicarbonate, neutralize and extract with methylene chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give azide (22 mg,
95%).

[Α] _D ²⁸ −0.28 (c0.71, CHCl ₃ ) IR ν ^neat _max 3400, 2080 cm ^{−1 1} H NMR (500 MHz, CDCl ₃ ) δ 5.81 (dt, 1H, J = 15.3 Hz, J = 6.1Hz), 5.52 (ddt, 1H, J
= 15.3Hz, 8.5Hz, J = 1.2Hz), 4.22 (t, 1H, J = 6.1Hz), 3.8
2 (dd, 1H, J = 11.6Hz, J = 4.3Hz), 3.71 (dd, 1H, J = 11.6H
z, J = 6.7Hz), 2.10 (brs, 2H), 2.05 (dd, 2H, J = 7.3, J =
6.7Hz), 1.38 (m, 2H), 1.26 (brs, 20H), 0.88 (t, 3H, J =
7.3Hz).

¹³ C NMR (500 MHz, CDCl ₃ ) 135.6 (d), 128.3 (d), 73, 6 (d), 67.6 (d), 62.9 (t), 32.
3 (t), 31.9 (t), 29.7 (t), 29.6 (t), 29.5 (t), 29.4 (t),
29.2 (t), 28.9 (t), 22.7 (t), 14.2 (q). MS m / e 325 (M ⁺ ), 135 (100%).

Example 11 Preparation of D-threo-sphingosine Azide (33 mg, 0.102 mmol) obtained in Example 10, propanedithiol (102 μl, 1.02 mmol) in methanol (0.5 ml)
Triethylamine (0.14 ml, 1.0 mmol) is added to the solution at room temperature, and the mixture is stirred for 48 hours. After distilling off methanol, crude threo-sphingosine was obtained.

Next, this was dissolved in methylene chloride (1 ml), and 4-dimethylaminopyridine (50 mg, 0.40
6 mmol) and acetic anhydride (0.1 ml, 1.015 mmol) are added and stirred at room temperature for 1 hour. The mixture is diluted with ethyl ether, washed successively with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain threo-triacetylsphingosine (39 mg, 90%: two steps). This compound was in good agreement with the specific rotation of the known threo-triacetylsphingosine.

[Α] _D ²⁹ −8.5 ° (c 0.79, CHCl ₃ ), (literature [α] _D ²⁴ −8.9 (CHCl ₃ )) IR ν ^neat _max 1710, 1670 cm ^{−1 1} H NMR (500 MHz, CDCl ₃ ) δ 5.75 (dt, 1H, J = 14.6Hz, J = 6.7Hz), 5.69 (brd, 1H,
J = 9.2Hz), 5.42-5.34 (m, 2H), 4.38 (m, 1H), 4.06 (ddd, 2
H, J = 11.6, 5.5, 3.7Hz), 2.06 (s, 3H), 2.05 (s, 3H),
2.00 (m, 2H), 1.98 (s, 3H), 1.33 (m, 2H), 1.23 (s, 2O
H), 0.86 (t, 3H, J = 6.7Hz).

¹³ C NMR (500 MHz, CDCl ₃ ) 170.7 (s), 170.1 (s), 169.9 (s), 137.4 (d), 124.1 (d),
73.1 (d), 63.1 (t), 50.9 (d), 32.3 (t), 31.9 (t), 29.9
(t), 29.73 (t), 29.70 (t), 29.69 (t), 29.47 (t), 29.39
(t), 29.19 (t), 23.29 (t), 22.73 (q), 21.12 (q), 20.79
(q), 14.16 (q).

Example 12 Preparation of (2S, 3S, 4R) -1- (p-methoxy) benzyloxy-2-hydroxy-3,4-isopropylidenedioxy-5-hexene 1.72 g (43.0 mmol) of potassium hydride 5.40 ml (43.0 mmol) of p-anis alcohol was added dropwise to a suspension of 40 ml of DMF at 0 ° C., and the mixture was stirred until hydrogen evolution ceased. And stirred for 6 hours. Water is added and the mixture is extracted with ethyl ether. The organic layer is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to distillation under reduced pressure to remove excess p-anis alcohol,
The residue was subjected to column chromatography using silica gel to obtain 1.13 g (90%) of alcohol.

[0050] [α] ^{_{D 28 + 1.03 ° (c1.03,}} CHCl 3) IR (film) ν max 3474, 1613cm -1 1 H NMR (90MHz, CDCl 3) δ 7.25 (d, 2H, J = 8.80 Hz, Ar), 6.90 (d, 2H, J = 8.80H
z, Ar), 6.05-5.60 (m , 1H, CH = CH 2), 5.50-5.15 (m, 2H,
_{CH = CH 2), 4.48 (} s, 2H, OCH 2 Ar), 4.60-4.25 (m, 1H, C 4 -
H), 3.81 (s, 3H, OCH ₃ ), 3.80-3.60 (m, 2H, C ₃ -H, C _2-
H), 3.50 (d, 2H, J = 5.1Hz, C ₁ -H ₂ ), 2.38 (d, 1H, J = 6.4H
z, OH), 1.43 (s , 6H, CH 3).

MS m / e 308 (M ⁺ ), 121 (100%). Analysis Calculated _{C 17 H 24 O 5 C,} 66.21; H, 7.84 Found C, 66.07; H, 7.82. Example 13 Preparation of (2R, 3R, 4R) -2-azido-1- (p-methoxy) benzyloxy-3,4-isopropylidenedioxy-5-hexene 930 mg (3.02 mmol) of the alcohol obtained in Example 12 ), 0.28 ml (3.63 mmol) of methanesulfonyl chloride was added dropwise to a solution of 520 mg of dimethylaminopyridine in 50 ml of methylene chloride at 0 ° C, and the mixture was stirred for 30 minutes. A saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl ether, dried over magnesium sulfate, and evaporated to give a crude mesylate. To a solution of the crude mesylate in 25 ml of DMF is added 3.63 g (55.8 mmol) of sodium azide, and the mixture is heated for 40 hours. Ethyl ether is added to the reaction solution, which is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 15 g of silica gel to give 720 mg (77.5%) of azide
I got

[Α] _D ²⁷ −1.26 ° (c1.06, CHCl ₃ ) IR (film) ν _max 2098, 1613 cm ^{−1 1} H NMR (90 MHz, CDCl ₃ ) δ 7.25 (d, 2H, J = 8.80 Hz , Ar), 6.90 (d, 2H, J = 8.80H
z, Ar), 5.85 (ddd, 1H, J = 6.59, 9.77, 16.9Hz, CH = C
H ₂ ), 5.42 (dd, 1H, 0.7, 16.9Hz, CH = CH), 5.27 (dd, 1H,
J = 0.5, 9.8Hz, CH = CH), 4.70-4.40 (m, 2H, C 3 -H, C 4 -
H), 4.50 (s, 2H , OCH 2 Ar), 4.50-4.25 (m, 2H, C 3 -H, C 4 -
H), 3.82 (s, 3H, OCH ₃ ), 3.90-3.45 (m, 3H, C ₁ -H ₂ , C _2-
H), 1.45 (s, 3H , CH 3), 1.36 (s, 1H, CH 3).

MS m / e 333 (M ⁺ ), 121 (100%). Analytical value C ₁₇ H ₂₃ N ₃ O ₄ Calculated C, 61.24; H, 6.95; N, 12.
61 Found C, 61.36; H, 7.02; N, 12.36. Example 14 Production of (2R, 3R, 4R) -2-azido-1- (p-methoxy) benzyloxy-3,4-dihydroxy-5-hexene 680 mg (2.04 mmol) of azide obtained in Example 13, A solution of Amberlyst-15, 20 ml of methanol is stirred at room temperature for 20 hours. Neutralize with saturated aqueous sodium bicarbonate and extract with methylene chloride. After drying over magnesium sulfate,
The solvent was distilled off, and the residue was subjected to column chromatography using silica gel to obtain 307 mg (95%) of a diol.

[Α] _D ³⁰ −45.1 ° (c1.04, CHCl ₃ ) IR (film) ν _max 3412, 2098, 1613 cm ^{−1 1} H-NMR (90 MHz, CDCl ₃ ) δ 7.28 (d, 2H, J = 8.80Hz, Ar), 6.86 (d, 2H, J = 8.80H
z, Ar), 5.92 (ddd, 1H, J = 5.70, 10.0, 17.2Hz, CH = C
H ₂ ), 5.55-5.15 (m, 2H, CH = CH ₂ ), 4.50 (s, 2H, OCH ₂ Ar),
_{4.23 (m, 1H, C 4} -H), 3.880 (s, 3H, OCH 3), 3.90-3.50
_{(m, 4H, C 4 -H} , C 1 -H 2, C 2 -H), 2.55 (s, 2H, OH).

MS m / e 294 (MH ⁺ ), 121 (100%). HRMS calculated value C ₁₄ H ₁₉ NO ₄ (MN ₂ ) 265.1314, measured value 26
5.1310. Example 15 Preparation of (2R, 4R, 5R) -5-azido-2- (p-methoxy) benzyl-4- (1-hydroxy-2-propenyl) 1,3-dioxane 150 mg of the diol obtained in Example 14 To a suspension of 0.51 mmol (0.51 mmol) and 500 mg of 4A-molecular sieve in 5 ml of methylene chloride was added 128 mg (0.56 mmol) of dichlorodicyanoquinone at 0 ° C and the mixture was stirred for 10 hours. After filtration through Celite, the filtrate is washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and the solvent is distilled off. The residue was subjected to column chromatography using silica gel to obtain 107 mg (72%) of an acetal.

[Α] _D ²⁸ −26.1 ° (c 0.52, CHCl ₃ ) IR (film) ν _max 3464, 2110, 1614 cm ^{−1 1} H-NMR (90 MHz, CDCl ₃ ) δ 7.38 (d, 2H, J = 8.80Hz, Ar), 6.90 (d, 2H, J = 8.80H
z, Ar), 6.05 (ddd, 1H, J = 5.62, 10.0, 15.6Hz, CH = C
_{H 2), 5.45 (s,} 1H, O-CH-O), 5.55-5.20 (m, 2H, CH = CH 2),
_{4.45 (s, 2H, OCH 2} Ar), 4.55-4.20 (m, 2H, C 3 -H, C 4 -H),
3.81 (s, 3H, OCH ₃ ), 4.10-3.45 (m, 3H, C ₁ -H ₂ , C ₂ -H), 2.
20 (br d, 1H, J = 8.8Hz, OH), 2.20 (br d, 1H, J = 6.20H
z, OH).

MS m / e 291 (MH ⁺ ), 135 (100%). HRMS calculated C ₁₄ H ₁₇ N ₃ O ₄ (M ⁺ ) 291.1219, found 29
1.1209. Example 16 (2S, 4S, 5R) -5-Azido-2- (p-methoxy) benzyl-4- (1E-pentadecenyl) -1,3
-Production of dioxane 70 mg (0.24 mmol) of the alcohol obtained in Example 15, dimethylaminopyridine 105 mg (0.84 mmol) of methylene chloride 25 ml
To the solution was added 47 μl of methanesulfonyl chloride (0.60 m
mol) is added dropwise and stirred for 1 hour. Add water, extract with methylene chloride and wash with saturated aqueous sodium chloride. After drying over magnesium sulfate, the solvent was distilled off to obtain a crude mesylate.

1 mg of iodine was added to a suspension of 1.82 g of magnesium in 50 ml of THF, and 12 ml of lauryl bromide was added dropwise while heating with a dryer so that the reaction solution was gently refluxed, and further heated under reflux for 1 hour. Cuprous iodide 92mg (0.20mmol)
1.35 ml (0.96 mmol) of laurylmagnesium bromide was added dropwise to a suspension of the above in 8 ml of THF at -30 ° C, and the mixture was stirred at 0 ° C for 10 minutes and then cooled again to -30 ° C. A solution of the crude mesylate in 1 ml of THF is added dropwise at 0 ° C, and the mixture is stirred for 15 minutes and at -5 ° C for 1 hour. A saturated aqueous ammonium chloride solution is added to the reaction solution, and the mixture is extracted with Et ₂ O. The organic layer is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 3 g of silica gel to give E-olefin (82 mg, 77%).
I got

[0059] [α] ^{_{D 27 + 2.10 ° (c1.05,}} CHCl 3) IR (film) ν max 2106, 1616cm -1 1 H NMR (500MHz, CDCl 3) δ 7.41 (d, 2H, J = 8.54 Hz, Ar), 6.88 (d, 2H, J = 8.54H
z, Ar), 5.98 (dt , 1H, J = 15.3, 6.7Hz, C 5 -H), 5.58 (dd,
1H, J = 15.3, 7.3Hz, C 4 -H), 5.45 (s, 1H, OCHO), 4.32
(dd, 1H, J = 5.5, 11.0Hz), 4.04 (dd, 1H, J = 7.9, 7.9H
z), 3.80 (s, 3H, OCH ₃ ), 3.59 (dd, 3H, J = 11.0, 11.0),
3.45 (dt, 1H, J = 5.5, 9.8Hz), 2.10 (q, 1H, J = 7.3Hz),
1.42 (m, 2H), 1.25 (br s, 20H), 0.88 (t, 3H, J = 6.7Hz)
.

MS m / e 294 (MH ⁺ ), 121 (100%). Analysis Calculated _{C 26 H 41 N 3 O 3} : C, 70.38; H, 9.32; N,
9.48 found: C, 70.48; H, 9.47; N, 9.01. Example 17 Preparation of (2R, 3S, E) -2-azido-1,3-dihydroxy-4-octadecene 40 mg (72 μmol) of the E-olefin obtained in Example 16, 0.1 ml of a 10% aqueous hydrogen chloride solution, 1 ml of methanol The solution is stirred at room temperature for 2 hours. Neutralize with saturated aqueous sodium bicarbonate and extract with methylene chloride. After drying over magnesium sulfate, the solvent was distilled off, and the residue was subjected to column chromatography using 3 g of silica gel to obtain 28 mg (96%) of azide.

[0061] [α] ^{_{D 26 + 34.9 ° (c0.98,}} CHCl 3) IR (film) ν max 3400, 2080cm -1 1 H NMR (500MHz, CDCl 3) δ 5.81 (dt, 1H, J = 15.3 , 6.7Hz, C ₅ -H), 5.52 (dd, 1H,
J = 15.9, 7.3Hz, C ₄ -H), 4.24 (dd, 1H, J = 6.10, 6.10Hz,
C ₃ -H), 3.78 (m, 2H, C ₁ -H, C ₃ -H ₂ ), 3.50 (dd, 1H, J = 5.
5, 10.4Hz), 3.71 (dd, 1H, J = 6.70Hz, C ₁ -H), 2.50 (br
d, 2H, OH), 2.06 (dd, 1H, J = 6.7, 14.0Hz, C 2 -H), 1.38
(m, 2H, C ₆ -H ₂ ), 1.25 (br s, 20H), 0.87 (t, 3H, J = 6.7H
z, C ₁₈ -H _3).

¹³ C-NMR (127 MHz, CDCl ₃ ) δ 136.1 (d), 128.1 (d), 73.8 (d), 66.8 (d), 62.7 (t),
32.4 (t), 32.0 (t), 29.7 (t), 29.7 (t), 29.5 (t), 29.4
(t), 29.3 (t), 29.0 (t), 22.8 (t), 14.2 (q). MS m / e 294 (MH ^<+> ), 121 (100%).

Analytical value Calculated value C ₁₈ H ₃₅ N ₃ O ₂ : C, 66.41;
H, 10.84; N, 12.38 Found: C, 66.53; H, 10.52; N, 12.87. Example 18 Preparation of L-erythro-sphingosine Lizide was added to 42 ml (143 μmol) of azide obtained in Example 17 in 1 ml of THF.
Add 19 mg (0.50 mmol) of AlH _{4 and} stir for 30 minutes. After adding a saturated ammonium hydroxide solution and stirring, the mixture is filtered through celite. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methylene chloride-n-hexane to give L-erythro-sphingosine (31 mg, 85 mg).
%).

Mp. 80-82 ° C. (Α) _D ²⁶ −2.72 ° (c0.81, CHCl ₃ ) (literature mp 81-82 ° C., (α) _D ²⁴ −2.8 ° (CHCl ₃ )) IR (film) ν _max 3400cm ^{−1 1} H NMR (90MHz, CDCl ₃ ) δ 5.75 (dt, 1H, J = 15.3, 7.5Hz, C ₅ -H), 5.45 (dd, 1H,
J = 15.3, 7.0Hz, C ₄ -H), 4.05 (t, 1H, J = 6.1Hz, C ₃ -H),
3.70 (m, 1H, C ₁ -H), 3.58 (dd, 1H, J = 6.1, 10.5Hz C _1-
H), 2.85 (q, 1H, J = 5.0Hz, C ₂ -H), 2.00 (br s, 4H, NH ₂ ,
OH), 2.06 (m, 2H , C 17 -H), 1.25 (br s, 22H), 0.87 (t,
_{3H, J = 6.7Hz, C 18} -H 3).

Continuation of the front page (51) Int.Cl. ⁶ identification symbol FI C07D 319/06 C07D 319/06 407/04 303 407/04 303 (58) Investigated field (Int.Cl. ⁶ , DB name) CA (STN ) CAOLD (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A compound of the general formula (* Indicates an asymmetric carbon). 2. A compound of the general formula (In the above formula, * represents an asymmetric carbon; R ¹ represents a lower alkyl group; X represents a hydroxyl group or an azide.) 3. A compound of the general formula (In the above formula, * represents an asymmetric carbon; R ¹ represents a lower alkyl group.) 4. A compound of the general formula (In the above formula, * represents an asymmetric carbon. R ¹ represents a lower alkyl group, and R ² represents hydrogen, a methanesulfonyl group, a toluenesulfonyl group, a benzenesulfonyl group, or a trifluoromethanesulfonyl group.) Sphingosine intermediate. 5. A compound of the general formula (In the above formula, * represents an asymmetric carbon; R ¹ represents a lower alkyl group.) 6. A compound of the general formula Asymmetric epoxidation is carried out using an allyl alcohol represented by as a starting material, via an intermediate according to claims 1 to 5,
A method for producing natural or unnatural sphingosine, comprising opening the dioxane ring of the intermediate represented by the general formula (V) according to claim 5 and substituting an azide with an amino group.