JP2562782B2 - Method for producing triol derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

SUMMARY OF THE INVENTION The present invention provides an intermediate for producing sphingosine.
Known triol derivative production method . See general formula

Embedded image (In the formula, R'represents a methyl group, an ethyl group, a phenyl group, and a benzyl group.) The phosphonate derivative represented by the general formula is reacted with an aldehyde in the presence of a base.

Embedded image (In the formula, R represents an alkyl group, an alkenyl group, an alkynyl group having 30 or less carbon atoms, or a phenyl group, a methoxyphenyl group, a methylphenyl group, a phenylethyl group, and a benzyl group.) (4E) -1 , 2-isopropylidene-3-oxo-4-alkene-1,2-diol derivative, and then reducing the obtained diol derivative
A general formula characterized by

Embedded image (Wherein R is an alkyl group having 30 or less carbon atoms, an alkenyl group, an alkynyl group or a phenyl group, methoxyphenyl group, methylphenyl group, phenylethyl group, a benzyl group.) Sphingosine production intermediate represented by
(4E) -1,2-isopropylidene-4-alkene-
The present invention relates to a method for producing a 1,2,3-triol derivative.

[0002]

2. Description of the Related Art Sphingosine is an essential structure of glycosphingolipids. Recently, it has become clear that glycosphingolipids have important functions in the living body. For example, it has been reported that a glycosphingolipid called ganglioside GQ1b is deeply involved in the differentiation of nerve cells. However, very small amounts of these glycosphingolipids are obtained from nature, and development of a synthetic method thereof is indispensable for utilizing them as medicines, and synthesis of various sphingosines has already been reported.
[D.Shapiro, “Chemistry of Sphingo-lipids”; Herman
n: Paris, France, 1969; H. Newmann, J. Am. Chem. Soc., 95 , 40
98 (1973); RS Garigipati and SMWeinreb, ibid., 105 ,
4499 (1983); MA Findeis and GM Whitesides, J.Org.Ch
em., 52 , 2838 (1987); K.Koike, M.Numata, and T.Ogawa, Ca
rbohydr.Res., 158 , 113 (1986); M.Kiso, A. Nakamura, Y. Tom
ita, and A. Hasegawa, ibid., 158 , 101 (1986).]

[0003]

In these synthetic methods, stereoisomers and geometrical isomers are remarkably mixed, and particularly in the synthesis of the olefin part, a mixture of (E) -olefin and (Z) -olefin is obtained. Therefore, it is hard to say that it is an industrially superior method.

On the other hand, when the glycosphingolipid is put to practical use as a medicine or the like, the synthesis of these analogs is essential. However, in order to produce isomers of sphingosine by the conventional synthetic method, different raw materials are required for each isomer.

[0005]

As a result of intensive studies from the above viewpoints, the present inventors have found that the objective can be achieved through a specific triol derivative and have reached the present invention.

The present invention will be described in detail below.

First, (4E)-shown in the general formula 2
A method for producing a 1,2-isopropylidene-3-oxo-4-alkene-1,2-diol derivative will be described.

The phosphonate derivative represented by the general formula 1 as a raw material can be synthesized from isopropylideneglycerate and methylphosphonate diester by a conventional method.

Well-known derivatives can be used as isopropylidene glycerate. Specific examples include corresponding methyl ester, ethyl ester, benzyl ester and the like.

Well-known derivatives of methylphosphonate can also be used. Specific examples thereof include dimethyl ester, diethyl ester, diphenyl ester, dibenzyl ester and the like.

Well-known aldehydes can be used as other raw materials. That is, either an aliphatic aldehyde or an aromatic aldehyde can be used. Specific examples of the aliphatic aldehyde include formaldehyde, acetaldehyde, propyl aldehyde, butyraldehyde, pentyl aldehyde, decyl aldehyde, tridecyl aldehyde, tetradecyl aldehyde, pentadecyl aldehyde and hexadecyl aldehyde.
As the aromatic aldehyde, benzaldehyde,
Examples thereof include benzyl aldehyde and phenyl ethyl aldehyde. Needless to say, these aldehydes can be used even if they contain other functional groups.

The solvent used is not particularly limited. Specifically, methanol, isopropyl alcohol, diethyl ether, benzene, toluene, tetrahydrofuran,
Dichloromethane, dioxane, chloroform and the like can be mentioned. Alcohol solvents, especially isopropyl alcohol, are particularly preferable.

Well-known bases can be used as the base. For example, sodium hydride, triethylamine, sodium hydroxide, potassium carbonate, cesium carbonate, butyl lithium and the like can be mentioned. Of these, carbonates, especially cesium carbonate, are particularly effective.

In the reaction, the molar ratio of the phosphonate derivative represented by the general formula 1 to the aldehyde and the base is not particularly limited. However, usually equimolar amounts or 1.1 to 1.3 equivalents of aldehyde are usually used. Needless to say, the phosphonate derivative or the aldehyde can be used in excess or in large excess.

The reaction temperature is not particularly limited, but usually -1.
It is in the range of 00 ° C to 60 ° C. Particularly, the range of −80 ° C. to 30 ° C. is preferable. The reaction time is in the range of several hours to several tens of hours.

All of the 1,2-isopropylidene-3-oxo-4-alkene-1,2-diol derivatives synthesized as described above are (E) -olefins, and (Z) -olefins as in the conventional method. No body contamination was observed.

Next, (4E) -1, represented by the general formula 3,
A method for producing a 2-isopropylidene-4-alkene-1,2,3-triol derivative will be described.

(4E) -1,2-isopropylidene-3-oxo- represented by the general formula 2 synthesized as described above.
The carbonyl group of the 4-alkene-1,2-diol derivative is reduced with a known reducing agent to give a (4E) -1,2-isopropylidene-4-alkene-1,2,3-triol derivative. Well-known reducing agents can be used as the reducing agent. Specifically, sodium borohydride, lithium tri-tert-butylborohydride, sodium tri-tert-butylborohydride, diisobutylaluminum hydride, 9-
Borabicyclo [3.3.1] nonane and the like can be mentioned. In addition, additives such as zinc bromide and magnesium bromide can be made to coexist in order to enhance stereoselectivity.

The solvent used is not particularly limited. Specifically, the above-mentioned organic solvent can be used. Of these, tetrahydrofuran is particularly effective.

The molar ratio of the reducing agent to be reacted is not particularly limited. However, it is usually in the range of 1.0 to 10 equivalents with respect to the carbonyl group.

The reaction temperature is not particularly limited, but is usually -10.
It is in the range of 0 ° C to 50 ° C. It is particularly preferable to carry out the reaction at a low temperature in order to enhance the stereoselectivity. For example, derived from methyl (R) -isopropylideneglycerate (2
R, 4E) -1,2-isopropylidene-3-oxo-
When the 4-octadecene-1,2-diol derivative was reacted in tetrahydrofuran at −78 ° C. with lithium tritert-butylborohydride, the 3R compound had an asymmetric yield of 90% d.
Obtained by e. It is also possible to selectively synthesize the 3S form.

Two of the derivatives used in the above two steps
The stereotype at the -position is not particularly limited, and may be any of the (R) -form and the (S) -form, and a mixture thereof may be used. Further, these are easily available, and by combining the above reduction reaction and the raw materials, it is possible to produce preferable stereoisomers.

(4E) -1, synthesized as described above,
When a 2-isopropylidene-4-alkene-1,2,3-triol derivative is deisopropylidated and benzylidene-ized by a conventional method, (4E) -1,3-benzylidene-4-alkene-1,2,3- Can be induced to triol. This induction of (4E) -1,3-benzylidene-4-alkene-1,2,3-triol to sphingosine is already known. [RRSchmidt and P.Zimmerma
nn, Tetrahedron Lett., 27 , 481 (1986).]

[0024]

As described above, according to the method of the present invention, a derivative of glycerin is passed through a (4E) -1,2-isopropylidene-3-oxo-4-alkene-1,2-diol derivative represented by the general formula 2 However, (4E) -1,2-shown in the general formula 3 which is known as an intermediate for the production of sphingosine.
The isopropylidene-4-alkene-1,2,3-triol derivative has the advantage that it can be produced in good yield and with almost no mixing of stereoisomers and geometric isomers. It is also possible and its industrial value is great. Hereinafter, the present invention will be described in more detail with reference to Examples and the like, but the present invention is not limited by the following Examples and the like as long as the gist thereof is not exceeded.

[0025]

[Reference Example 1] Dimethyl methylphosphonate 506.8 mg
(4.08 mmol) was dissolved in 5 ml of tetrahydrofuran, cooled to -78 ° C, and 1.5 M butyllithium / hexane solution was added dropwise thereto. Then (R) -1,2-
Methyl isopropylidene glycerate 511 mg (3.2
3 mmol) was added. The reaction temperature was raised to room temperature overnight, and the mixture was extracted with ethyl acetate by a conventional method. When the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, (R) -1,2-isopropylideneglyceroylmethylphosphonate dimethyl was obtained as an oily substance in an amount of 525.9 mg (3.
18 mmol; 98%) was obtained. ¹ H NMR (CDC
l ₃ ) δ1.42 (3H, s), 1.46 (3H,
s), 3.33 (2H, dd, J = 9, 22Hz),
3.78 (6H, d, J = 11Hz), 4.10 (2
H, d), 4.53 (1H, t); Specific rotation [α] _D ³⁰
+ 77.6 ° (c1.6, CHCl ₃ )

[0026]

Example 1 Phosphonate 1 synthesized in Reference Example 1
45 mg (0.57 mmol), lithium chloride 29.3 mg
(0.69 mmol) and molecular sieves 3A powder were suspended in 5.3 ml of tetrahydrofuran, and 0.088 ml (0.63 mmol) of triethylamine and 0.058 ml (0.57 mmol) of benzaldehyde were added thereto and reacted overnight. It was extracted with ethyl acetate by a conventional method, and the solvent was dried over anhydrous sodium sulfate overnight. The solvent was distilled off under reduced pressure and purified by silica gel thin layer chromatography for adjustment (2
R, 4E) -1,2-isopropylidene-3-oxo-
43.5-phenyl-4-pentene-1,2-diol.
7 mg (0.19 mmol; 33%) was obtained. ¹³ C NM
R (CDCl ₃ ) δ 25.4, 26.1, 66.8, 79.
9, 111.0, 120.9, 128.6, 128.9, 1
30.8, 134.6, 144.5, 198.3

[0027]

Example 2 Phosphonate 1 synthesized in Reference Example 1
26.1 mg (0.48 mmol) and cesium carbonate 162.
2 mg was suspended in 1.5 ml of isopropyl alcohol, and 36.9 mg (0.51 mmol) of butyraldehyde was added thereto and reacted overnight. Then, the same procedure as in Example 1 was conducted to obtain 47.4 mg (50%) of (2R, 4E) -1,2-isopropylidene-3-oxo-4-nonene-1,2-diol.
%) Obtained. ¹ H NMR (CDCl ₃ ) δ 0.94 (3
H, t), 1.42 (3H, s), 1.46 (3H,
s), 6.52 (1H, bd, J = 17Hz), 7.05
(1H, dt, J = 17,9 Hz); ¹³ C NMR (C
DCl ₃ ) δ 13.7, 21.3, 25.4, 26.1, ₃
4.7, 66.7, 79.6, 110.9, 125.3, 1
50.0, 198.1

[0028]

Example 3 Phosphonate 1 synthesized in Reference Example 1
16.1 mg (0.46 mmol) and cesium carbonate 163.
3 mg was suspended in 1.5 ml of isopropyl alcohol, and 36.9 mg (0.51 mmol) of butyraldehyde was added thereto and reacted overnight. Then, the same procedure as in Example 1 was carried out to obtain 66.7 mg (73%) of (2R, 4E) -1,2-isopropylidene-3-oxo-4-nonene-1,2-diol.
%) Obtained.

[0029]

Example 4 127.5 mg (0.51 mmol) of the phosphonate ester synthesized in Reference Example 1 and 16 cesium carbonate
1.2 mg was suspended in 5 ml of isopropyl alcohol, and 206.1 mg (0.5%) of 80% tetradecyl aldehyde was added to the suspension.
4 mmol) was added and reacted overnight. Thereafter, the same procedure as in Example 1 was carried out to obtain 128.9 mg (75%) of (2R, 4E) -1,2-isopropylidene-3-oxo-4-octadecene-1,2-diol. ¹³ C NMR
(CDCl ₃ ) δ 14.1, 22.7, 25.4, 26.
1,28.1,29.3 to 29.7 (m), 32.0,6
6.7, 79.6, 110.9, 125.0, 150.1,
198.0; Specific rotation [α] _D ³⁰ + 77.6 ° (c1.6,
CH Cl ₃ ) + 7.7 ° (c1.3, EtOH)

[0030]

[Example 5] 2.1 The diol derivative synthesized in Example 4
0 g (6.2 mmol) was dissolved in 70 ml of tetrahydrofuran, and 6.8 ml (7.4 ml) of a 1.1M lithium tri-tert-butyl borohydride / tetrahydrofuran solution at -78 ° C.
4 mmol) was added dropwise. The reaction temperature was raised to room temperature overnight, and the mixture was extracted with diethyl ether by a conventional method. The organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure and purified by silica gel column chromatography (2R, 4E)-
1,2-isopropylidene-4-octadecene-1,2,
1.85 g (88%) of 3-triol was obtained. ¹³ C
The stereochemistry at the 3-position determined by NMR was 95% for the R form,
The S form was 5%. (Asymmetric yield is 90% de) 3-R
Body; ¹³ C NMR (CDCl ₃ ) δ14.1, 22.7, 2
5.4, 26.9, 29.1 to 29.7 (m), 32.0,
32.4, 66.1, 74.4, 75.7, 79.3, 12
7.9,135.33-S form; 127.4,134.4

[0031]

Example 6 The diol derivative 20 synthesized in Example 4
3.1 mg (0.6 mmol) and magnesium bromide etherate 160.0 mg (0.6 mmol) were dissolved in 3 ml of tetrahydrofuran, and 1.1 M trihydrogenated secondary at -78 ° C.
Butylboron lithium / tetrahydrofuran solution 0.6
6 ml (0.72 mmol) was added dropwise. The reaction temperature was raised to room temperature overnight, and the mixture was extracted with diethyl ether by a conventional method. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by silica gel column chromatography (2
R, 4E) -1,2-isopropylidene-4-octadecene-1,2,3-triol 152.5 mg (75%)
Obtained. The stereochemistry at the 3-position determined by ¹³ C NMR was 95% for the R isomer and 5% for the S isomer. (The irregular yield is 90
% De)

[0032]

Example 7 The diol derivative 20 synthesized in Example 4
3.1 mg (0.6 mmol) was dissolved in 6 ml of tetrahydrofuran and 0.72 ml (0.72 ml) of 1.0 M diisobutylaluminum hydride / tetrahydrofuran solution was dissolved at -78 ° C.
mmol) was added dropwise. The reaction temperature was raised to room temperature overnight, and the mixture was extracted with diethyl ether by a conventional method. The organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure and purified by silica gel column chromatography (2R, 4E)-
1,2-isopropylidene-4-octadecene-1,2,
152.5 mg (75%) of 3-triol was obtained. ¹³
The stereochemistry at the 3-position determined by C NMR is 90 for the R-form.
%, S-form was 10%. (Asymmetric yield is 80% de)

[0033]

Example 8 The diol derivative 20 synthesized in Example 4
3.1 mg (0.6 mmol) was dissolved in 8 ml of tetrahydrofuran, and 0.5 M, 9-borabicyclo [3.
3.1] Nonane / tetrahydrofuran solution 1.44 ml
(0.72 mmol) was added dropwise. The reaction temperature was raised to room temperature overnight, and the mixture was extracted with diethyl ether by a conventional method. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by silica gel column chromatography (2R,
4E) -1,2-isopropylidene-4-octadecene-1,2,3-triol was obtained in an amount of 28.4 mg (13%).

[0034]

Example 9 The diol derivative 20 synthesized in Example 4
3.1 mg (0.6 mmol) was dissolved in 3 ml of tetrahydrofuran, and 22.7 mg of sodium borohydride was added at 0 ° C.
(0.6 mmol) was added. After 30 minutes 5 ml of methanol
Was added to stop the reaction, and the mixture was extracted with diethyl ether by a conventional method. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 197.4 mg (97%) of a crude product of (2R, 4E) -1,2-isopropylidene-4-octadecene-1,2,3-triol. ) Got it. Then, it was benzylated with sodium hydride and benzyl bromide by a conventional method and purified by silica gel thin layer chromatography for adjustment (2R,
4E) -1,2-isopropylidene-4-octadecene-1,2,3-triol has a 3-benzyl R-form of 7
6.7 mg (30%) and 67.0 mg (27%) of S form were obtained. R form; ¹³ C NMR (CDCl ₃ ) δ 14.1,
22.7, 25.5, 26.0, 32.4, 66.1, 69.
9,78.0,81.0,109.7,126.0,12
7.4 to 137.4 (m), 138.7

[0035]

[Example 10] Synthesized in Examples 5 to 7 (2R, 3R,
4E) -1,2-isopropylidene-4-octadecene-1,2,3-triol 306.5 mg (0.9 mmol)
Was dissolved in a mixed solvent of methanol and tetrahydrofuran (3.5 ml each), and 1N hydrochloric acid (0.6 ml) was added thereto. The reaction was carried out overnight at room temperature and the solvent was distilled off under reduced pressure. Then, the residue was redissolved in 3 ml of dimethylformamide, and 150.7 mg (0.99 mmol) of benzaldehyde dimethyl acetal and 0.5 mg (0.0024 mmol) of p-toluenesulfonic acid were added. The mixture was reacted at 60 ° C. under reduced pressure for 2.5 hours, extracted with ethyl acetate by a conventional method, and purified by silica gel thin layer chromatography for adjustment (2R, 3R, 4E) -1,3-benzylidene-4-octadecene-1, 2,3-triol is 16
Obtained 3.6 mg (47%). ¹³ C NMR (CDC
l ₃ ) δ14.1, 22.7, 29.0 to 29.7 (m),
32.0, 32.3, 32.5, 61.6, 66.5, 72.
5, 78.8, 80.7, 82.8, 101.5, 103.
6, 126.1, 128.3, 128.4, 129.0, 1
29.3, 135.1, 136.6, 138.1

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area C07M 7:00

Claims (1)

(57) [Claims] 1. A general formula : (In the formula, R'is a methyl group, an ethyl group, a phenyl group, benzyl
Represents a radical. ) And a phosphonate derivative represented by
An aldehyde is reacted in the presence of a base to give a compound of the general formula : (In the formula, R is an alkyl group having 30 or less carbon atoms, alkenyl
Group, alkynyl group, or phenyl group, methoxyphen
Nyl group, methylphenyl group, phenylethyl group, benzyl
Represents a radical. ) Represented by (4E) -1,2-isopro
Pyridene-3-oxo-4-alkene-1,2-dio
And then reduce the resulting diol derivative.
The general formula [Chemical formula 3] characterized by (In the formula, R is an alkyl group having 30 or less carbon atoms, alkenyl
Group, alkynyl group, or phenyl group, methoxyphen
Nyl group, methylphenyl group, phenylethyl group, benzyl
Represents a radical. ) Sphingosine production intermediate represented by
(4E) -1,2-isopropylidene-4-alkene-
Method for producing 1,2,3-triol derivative .