JPH0678325B2 - Process for producing sphingosine derivative, intermediate and process for producing the same - Google Patents

Description

The present invention relates to a method for producing a sphingosine derivative, an intermediate and a method for producing the same. Specifically, the intermediate represented by the general formula (I) and the intermediate represented by the general formula (II) (R and R ″ represent a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group and aralkyl group, and R ′ represents an amino-protecting group.), Then, it relates to a method for producing a sphingosine derivative represented by the general formula (III), in which the intermediate (I) is reduced.

(R is a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group,
R'represents an amino protecting group. ) 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 Sphingolipi
ds "; Hermann: Paris, France, 1969; H. Newmann, J. Am. Chem.
Soc., 95, 4098 (1973); RS Garigipati and SMWeinre
b, ibid., 105,4499 (1983); MAFindeis and GM Whit
esides, J.Org.Chem., 52,2838 (1987); K.Koike, M.Numat
a, and T.Ogawa, Carbohydr.Res., 158,113 (1986); M.Kis
o, A.Nakamura, Y.Tomita, and A.Hasegawa, ibid., 158,101
(1986). Reference] In these synthetic methods, stereoisomers and geometrical isomers are significantly mixed, and particularly in the synthesis of the olefin part, a mixture of (E) -olefin and (Z) -olefin is obtained, which is an industrially excellent method. It is hard to say.

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

As a result of earnest research from the above viewpoints, the present inventors have found that the objective can be achieved via a specific intermediate, and have reached the present invention.

That is, the gist of the present invention is to provide an aldehyde selected from alkyl aldehydes, alkenyl aldehydes, alkynyl aldehydes, aryl aldehydes, and aralkyl aldehydes substituted or unsubstituted with the phosphonate derivative represented by the general formula (II) in the presence of a base. It is a method for producing the sphingosine derivative represented by the general formula (III) by reducing the intermediate (I) obtained by reacting the resulting intermediate represented by the general formula (I).

Hereinafter, the present invention will be described in detail.

First, a method for producing the intermediate represented by the general formula (I) will be described.

The phosphonate derivative represented by the general formula (II) as a raw material can be synthesized from N-protected-N, OO-isopropylidene serine ester and methylphosphonate diester by a conventional method.

Well-known derivatives can be used as the N-protected-N, O-isopropylidene serine ester. Specific examples include corresponding methyl ester, ethyl ester, benzyl ester and the like. Also, the third amino protecting group is
Well-known protecting groups such as butyloxycarbonyl (Boc) group, benzyloxycarbonyl group and p-methoxybenzyloxycarbonyl group can be used. Serine is L-form, D
It goes without saying that there are bodies, any of which or mixtures thereof can be used.

Well-known derivatives of methylphosphonate can also be used. Specifically, dimethyl ester, diethyl ester,
Examples thereof include diphenyl ester and dibenzyl ester.

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. Examples of aromatic aldehydes include benzaldehyde, benzyl aldehyde, phenylethyl aldehyde and the like. Needless to say, these aldehydes can be used even if they contain other functional groups.

The solvent used is not particularly limited. Specific examples include methanol, isopropyl alcohol, diethyl ether, benzene, toluene, tetrahydrofuran, dichloromethane, dioxane and chloroform. Alcohol solvents, especially isopropyl alcohol, are particularly preferable.

Well-known bases can be used as the base to be used. 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 (II) to the aldehyde and the base is not particularly limited. However, usually equimolar amounts or 1.1 to 1.3 equivalents of aldehyde are used, respectively. 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 is usually in the range of -100 ° 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 intermediates (I) synthesized as described above were (E) -olefins, and no contamination of (Z) -olefins was observed as in the conventional method.

Next, a method for producing the sphingosine derivative represented by the general formula (III) will be described.

The sphingosine derivative (III) can be obtained by reducing the carbonyl group of the intermediate represented by the general formula (I) synthesized as described above with a known reducing agent. Well-known reducing agents can be used as the reducing agent. Specific examples include sodium borohydride, lithium tri-tert-butylborohydride, sodium tri-tert-butylborohydride, diisobutylaluminum hydride, 9-borabicyclo [3.3.1] nonane, and the like. In addition, additives such as zinc bromide, magnesium bromide and cerium chloride 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 and a mixed solvent of tetrahydrofuran and an alcohol solvent are particularly effective.

There is no particular limitation on the molar ratio of the reducing agent to be reacted. 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 in the range of -100 ° C to 50 ° C.

By combining the above reduction reaction and the raw materials, it is possible to produce a preferable stereoisomer.

The sphingosine derivative synthesized as described above (II
Deprotection of I) by a conventional method can induce sphingosine. This deprotection is already known. [P.
Garner, JMPark, and E.Malecki, J.Org.Chem., 53,4395
(1988). Reference] As described above, in the method of the present invention, a compound represented by the general formula (III) known as a sphingosine derivative is obtained from a derivative of serine via an intermediate represented by the general formula (I) in good yield and stereoisomers and It has an advantage that it can be produced with almost no mixing of geometrical isomers, and in addition, stereoisomers can be produced separately, 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.

Reference Example 1 1.49 g (12 mmol) of dimethyl methylphosphonate was dissolved in 40 ml of tetrahydrofuran and cooled to −78 ° C., and 1.
7.7 ml of 57M butyllithium / hexane solution was added dropwise. Then 2.59 g (10 mmol) of N-Boc-N, O-isopropylidene-L-serine methyl ester was added. The reaction temperature was raised to room temperature overnight, and the mixture was extracted with ethyl acetate by a conventional method. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain N-Boc-N, O-isopropylidene-L-
Dimethyl cerylmethylphosphonate 1.93 as an oil
g (55%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
1.51 (3H, s), 1.65 (3H, s), 3.33 (2H, dd, J = 9,22Hz),
3.80 (6H, d, J = 11Hz).

Example 1 0.73 g of phosphonate synthesized in Reference Example 1 under ice cooling
(2.1 mmol) and cesium carbonate 0.78 g (2.4 mmol) were suspended in isopropyl alcohol 9 ml, and tetradecyl aldehyde 0.67 g (3.2 mmol) was added thereto and reacted overnight at room temperature. After extraction with ethyl acetate by a conventional method and purification by column chromatography, 0.79 g (86
%) Obtained. ¹³ C NMR (CDCl ₃ ) δ 14.1, 22.7, 24.3, 25.
3,26.1,27.5,28.1,28.3,29.2,29.4,29.6,32.0,32.7,33.
8,64.1,64.8,65.8,80.5,95.1,125.6,149.4,151.6,196.
3.

Example 2 56.5 mg (0.13 mmol) of the olefin compound synthesized in Example 1
It was dissolved in 0.33 ml of 0.4 M cerium chloride / tetrahydrofuran-methanol (2: 1) solution. To this was added sodium borohydride 5 mg (0.13 mmol) at room temperature. 5 minutes later 5
%, The reaction was stopped with a citric acid solution, extraction with ether was carried out by a conventional method, and purification by silica gel column chromatography revealed that N-Boc-N, O-isopropylidene-D-erythro-C.
18-sphingosine as a mixture with its threo body 92
% Obtained. ^The isomer ratio determined by ¹³ C NMR was 5: 1 and erythr.
o My body was my priority. ¹³ C NMR (CDCl ₃ ) δ135.2 (thre
o), 133.4 (erythro).

Example 3 131.2 mg (0.3 mmol) of the olefin compound synthesized in Example 1 was dissolved in 4 ml of tetrahydrofuran, and 0.33 ml (0.36 mmol) of a 1.1 M lithium tri-tert-butylborohydride / tetrahydrofuran solution was added dropwise at -78 ° C. . The reaction temperature was raised to room temperature overnight, and the mixture was extracted by a conventional method and purified in the same manner as in Example 2. The yield was 90%, and the threo form was preferential with a isomer ratio of 3: 1.

Claims (5)

[Claims] 1. A sphingosine synthetic intermediate represented by the general formula (I). (R is a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group,
R'represents an amino protecting group. ) 2. The intermediate according to claim 1, wherein the amino protecting group represented by R'is a tert-butyloxycarbonyl group. 3. A phosphonate derivative represented by the general formula (II) and an aldehyde selected from a substituted or unsubstituted alkyl aldehyde, alkenyl aldehyde, alkynyl aldehyde, aryl aldehyde and aralkyl aldehyde in the presence of a base. The method for producing an intermediate according to claim 1, wherein the intermediate is reacted. (R and R ″ represent a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group and aralkyl group, and R ′ represents an amino protecting group.) 4. The method according to claim 3, wherein cesium carbonate is used as the base. 5. A sphingosine represented by the general formula (III), characterized by reducing the phosphonate derivative according to claim 3 to the intermediate according to claim 1 and reducing the intermediate. Method for producing derivative. (R is a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group,
R'represents an amino protecting group. )