JPH04360896A - Rapid and asymmetric production of aldose - Google Patents

Abstract

PURPOSE:To rapidly obtain the subject compounds containing an additional asymmetric carbon and useful for cyclotron nuclear medicine, etc., in a high yield by reacting a hydroxyl group-protected aldose with a substituted silylcyanide in the presence of a metal catalyst in a polar solvent, subsequently reducing and hydrolyzing it. CONSTITUTION:A hydroxyl-protected aldose (e.g. 2,3,4,5-di-O-isopropylidenD- arabinose) is reacted with a substituted silylcyanide (e.g. trimethylsilylcyanide) in the presence of a metal catalyst (e.g. zinc iodide) in a polar solvent (e.g. dichloromethane) with stirring at room temperatures to obtain a cyanhydrin. The resultant reaction mixture is subsequently filtered and the obtained filtrate is concentrated under a reduced pressure to recover a residue. After addition of ethyl alcohol, 30% formic acid and Raney nickel, the recovered residue is refluxed with heating for 10 min to be reduced and hydrolyzed. The resultant reaction mixture is filtered and the filtrate is concentrated under a reduced pressure. After desalting, the concentrated filtrate is purified by using the high- performance liquid chromatography, thus obtaining the objective aldose (e.g. D-mannose) containing an additional asymmetric carbon.

Description

[Detailed description of the invention]

0001

FIELD OF INDUSTRIAL APPLICATION The present invention is a method for producing an aldose having one more carbon atoms in a short time and in high yield using an aldose with a protected hydroxyl group as a starting material. In particular, according to the present invention, the desired aldose stereoisomer can be obtained with high stereoselectivity, and the aldose stereoisomer with a short lifetime can be obtained.
C-labeled aldose can be obtained in good yield.

0002

[Prior Art] Cyanide, such as HCN, is added to aldose.
is reacted to produce cyanohydrin, which is hydrolyzed, and then reduced with sodium amalgam etc. to obtain an aldose having one more carbon than the original aldose.
isher synthesis).

However, in this method, the yield of stereoisomers is not good, and the target aldose can only be obtained as a mixture of stereoisomers. Separation and purification of stereoisomer mixtures is extremely troublesome. In addition, labeled aldose, which uses the radioactive isotope 11C as a positron-emitting nuclide, is useful for example in cyclotron nuclear medicine, such as quantitative and dynamic diagnosis of various organs including the brain, among the radiopharmaceuticals necessary for image diagnosis of medicines. It is indispensable. However, 11C has an extremely short lifespan (its half-life is only 20 minutes), and it produces molecules with simple structures such as inorganic gases whose constituent elements are 11C synthesized using cyclotrons, etc. This is to synthesize a labeled aldose with a more complex structure using as a raw material. Therefore, it is necessary to lead to the target substance in as short a time as possible. Furthermore, since the compound has the physiological activity of labeled aldose, it is desirable that chemical stereocontrol be achieved during the synthesis process and that the labeling position can be specified. However, this is not possible with conventional methods; for example, in the case of D-glucose, a production method using a photosynthetic reaction (JF.
Lifton and M. J. Welk, Radiation Research (Radiat. Res.), 45, 35 (
(1971), but in this method, the labeling position of the target product is unspecified, and various impurities and pyrogens derived from biosynthetic reactions are present, which must be removed. There are drawbacks. Chemical synthesis has also been attempted to improve these shortcomings, and a method using Killiany-Fischer synthesis of H11CN and arabinose (
C. Y. Hsu and A. P. Wolf, Journal of Labeled Compounds Radiopharmaceuticals (J. Labeled Compd.
s. Radiopharm. ), 22, 171 (198
5) etc. are known, but in such methods, the stereocontrol in the cyanohydrination reaction is not complete, and therefore,
The disadvantage is that the target substance is a mixture of stereoisomers, making it difficult to isolate and purify it.

0004

Problems to be Solved by the Invention As described above, in the conventional method, the reaction time is long and the yield of aldose is poor. It is difficult to separate and purify impurities. Stereoisomers cannot be obtained directly without undergoing isolation and purification procedures. In particular, 11C-labeled aldose cannot be obtained in good yield. There were some drawbacks.

[0005]

[Means for Solving the Problems] The present invention provides that in a polar solvent,
This is a method for producing an aldose with an increased number of asymmetric carbon atoms by one, which is characterized by reacting an aldose with a protected hydroxyl group with a trisubstituted silyl cyanide in the presence of a metal catalyst to produce cyanohydrin, and then reductively hydrolyzing this. .

Raw material, aldose with protected hydroxyl group (
The aldose in (I) (hereinafter sometimes referred to as protected aldose) may be any monosaccharide having an aldehyde group. Examples include aldtriose, aldotetrose, aldopentose, aldohexose, and aldoheptose. Further, as the protecting group, all those used in this field can be used, but for example, isopropylidene group is preferable. Protected aldoses are, for example, Helmut Chinner, Ecardo
Wittenberg and Gerhard Lembarz, Chem. Ber. 92, 1614.
(1959) or a method analogous thereto. In addition, the substituted silyl cyanide preferably has a bulky substituent in order to obtain a stereoisomer as the aldose of the target substance, such as trialkylsilyl cyanide, more preferably tri-lower alkylsilyl cyanide, such as trimethylsilyl cyanide. can be mentioned. The polar solvent is preferably one that dissolves the protected aldose and aldose, but does not dissolve the metal catalyst at all or hardly dissolves it. Examples of such a solvent include alkyl halides (dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dibromomethane, etc.). ) and tetrahydrofuran. Metal catalysts include inorganic metal salts and organic metals commonly used in nucleophilic addition reactions to carbonyl groups, especially zinc halides (e.g. zinc iodide, zinc bromide, etc.), magnesium halides (e.g. magnesium bromide, etc.), and Metal cyanide (
Examples include cuprous cyanide, etc.). The reaction molar ratio between the protected aldose and the trisubstituted silyl cyanide is not particularly limited, but is usually about 1:3. Further, the amounts of the polar solvent and the metal catalyst to be used are not particularly limited, but each may be about the same mole of the protected aldose as the raw material. The reaction may be carried out at room temperature under normal pressure, but may also be carried out under heating and pressure, if desired. The reaction time is generally very short, at most within a few minutes. The cyanohydrin (II) produced by this reaction is then reductively hydrolyzed to produce the target substance, an aldose (hereinafter sometimes referred to as the target aldose), which has one more carbon number than the original aldose. Generate. Reductive hydrolysis is the reduction of a cyano group to an aldehyde group and the removal of a protecting group from a hydroxyl group, and can be easily carried out by conventional methods in this field. Reduction can be carried out using, for example, a heterogeneous metal catalyst such as Raney nickel, an aluminum-based reducing agent such as diisobutylaluminum hydride, or a boron-based reducing agent such as sodium borohydride. Hydrolysis can also be carried out using, for example, an organic acid such as formic acid or acetic acid, or a mineral acid such as hydrochloric acid. Although reduction and hydrolysis can be carried out individually, it is preferable for convenience to carry them out all at once. For example, lower alcohols (methanol, ethanol, etc.)
may be used as a solvent, and heated under reflux in the presence of formic acid and Raney nickel. The target aldose can be collected by a conventional method, but especially in the present invention, since no by-products are produced, the solution or syrupy solution obtained by simply removing the solid content from the produced solution is used as the target aldose-containing product. It can be used for the following purposes:

The present invention can be represented by the following reaction formula.

[Formula 1] (wherein, R is a hydroxyl protecting group, and n is 0 or a positive integer.)

[0008]

According to the present invention, the desired aldose can be produced in high yield through a short reaction time. In particular, it has stereospecificity with an S configuration/R configuration ratio of 3 or more,
No isolation and purification of stereoisomers is required. In particular, when the target aldose is a 11C-labeled compound, the reaction time is short and no purification is required, making it possible to make maximum use of short-lived compounds. Furthermore, since the reaction can be performed at a low efficiency, the reaction purified product containing the target labeled aldose can be applied as it is for the purpose of cyclotron nuclear medicine. It can produce excellent effects.

[0009]

【Example】

Example 1 (Synthesis and isolation example of D-mannose) 2,3:4,5-di-
O-isopropylidene-D-arabinose (V) (20
mg, 0.087 mmol) in dry dichloromethane (0.
．． Zinc iodide (31 mg, 0.09
7 mmol) was added. Trimethylsilyl cyanide (37 μl, 0.28 μl) was added to this mixture while stirring at room temperature.
mmol) was added dropwise, and the mixture was stirred at room temperature for 3 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. Ethyl alcohol (1 ml) and 30% formic acid (1 ml) were added to this residue.
) and Raney nickel (80 mg) at 100°C.
The mixture was refluxed for 10 minutes at a lower temperature. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in distilled water (3 ml) using a desalting device (manufactured by Asahi Kasei Corporation, Microacylizer S).
D-mannose (11 mg, 7
0%) was obtained as syrup. The obtained compound was identified by comparative analysis with a standard product using high performance liquid column chromatography. High performance liquid column chromatography analysis: Pump: Shimadzu Corporation, LC-9A differential refractive index detector: Showa Denko KK, RISE-61 ion exchange resin column: Showa Denko KK, Ionpack KS-801 type Developing solvent: Decarbonated water Flow rate: 1.0ml/min. Column temperature: 70°C Retention time: 8.46min.

Example 2 (Analysis example of cyanohydrin derivative) 2,3:4,5-di-O-isopropylidene-D-arabinose (IV) (
After dissolving 20 mg, 87 μmol) in each solvent (500 μl), each metal catalyst (1.1 equivalent) was added at room temperature, followed by trimethylsilyl cyanide (37 μl, 0.28 mm
After stirring at room temperature for 3 minutes, take 50 μl of the reaction solution and add 1.0 M n-Bu4NF THF solution:
10% citric acid methanol solution = 1:3 mixture (150
After treatment, HPLC analysis was performed. Note that under these desilylation conditions, racemization of the cyanohydrin derivative progresses gradually, so all HPLC analyzes were performed after treatment at room temperature for 1 minute (see Table 1). High performance liquid column chromatography analysis: Pump: manufactured by Shimadzu Corporation, LC-9A type differential refractive index detector: manufactured by Shimadzu Corporation, RID-6A type column: Waters
Radial Pack C18 (8mm x 10cm, 5μ) Developing solvent: Acetonitrile: 0.003M KH2P
O4 aqueous solution = 2:3 flow rate: 1.5ml/min. Column temperature: room temperature holding time: 3,4:5,6-di-O-isopropylidene-D-glucononitrile (R form, V): 6.5616 min. Retention time: 3,4:5,6-di-O-isopropylidene-D-mannononitrile (S form, VI): 6.035 min.

Table 1 Cyanohydrination reaction conditions Reaction example Metal catalyst
Solvent VI/V
1 Znl2
CH2Cl2 6.01 2
Znl2 ClCH2CH2C
l 3.34 3 Z
nl2 CHCl3 1
6.7 4 Znl2
CCl4 4.0
5 ZnBr2
CH2Cl2 11.0 6
ZnBr2 CCl4
6.80 7
MgBr2 CH2Cl2
6.44 8 CuCN
CH2Cl2 6.5
0

[Chemical 2]

Claims (8)

[Claims] [Claim 1] A method having one asymmetric carbon, characterized by reacting an aldose with a protected hydroxyl group with a substituted silyl cyanide in a polar solvent in the presence of a metal catalyst to produce cyanohydrin, which is then reductively hydrolyzed. Method for producing increased aldoses. 2. The method according to claim 1, wherein the aldose with a protected hydroxyl group is protected with an isopropylidene group. 3. The method according to claim 1, wherein the substituted silyl cyanide is a trialkylsilyl cyanide. 4. The method according to claim 1, wherein the polar solvent is an alkyl halide. 5. The method according to claim 1, wherein the metal catalyst is zinc halide. 6. The production method according to claim 1, wherein the reaction is carried out continuously without separating the intermediate cyanohydrin. 7. The method according to claim 1, wherein the aldose is a stereoisomer. 8. The production method according to claim 1, wherein the target substance 11C-labeled aldose is obtained using 11C cyanide as the substituted silyl cyanide.