JPH04283597A - Production of 2,6-dideoxy-2-fluoro-l-talopyranose derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound for antiulcer agent having low toxicity, etc., at a low cost by hydrolyzing a specific protected deoxyfluoro-alpha-L- psychopyranoside with an acid, subjecting the hydrolyzed product to ring opening with a reducing agent, oxidizing the ring-opened substance in the presence of a metal complex to cyclize the substance, acylating the cyclized compound and separating the acylated compound. CONSTITUTION:A methyl 3-O-protected 1,5-dideoxy-5-fluoro-alpha-L-psychopyranoside expressed by formula I (Me is methyl; R<1> is benzyl, allyl, lower alkanoyl, etc.; R<2> is methyl or ethyl) is hydrolyzed with an acid and then reduced with a reducing agent such as an alkali metal borohalide to afford L-talitols expressed by formula II and D-alitols expressed by formula III and these compounds are oxidized with an oxidizing agent such as tris(trisphenylphosphine)ruthenium halide to cyclize these compounds and then acylated and separated by chromatography to give L-talopyranose expressed by formula IV (R<3> is lower alkanoyl), which is then hydrolyzed to provide 2,6-dideoxy-2-fluoro-L-talopyranose derivative expressed by formula V (R<1a> is H or R<1>).

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention provides 7-O having antitumor activity.
-(2,6-dideoxy-2-fluoro-α-L-talopyranosyl)daunomycinone or 7-O-(2,6-
dideoxy-2-fluoro-α-L-talopyranosyl)
The present invention relates to a novel method for producing 2,6-dideoxy-2-fluoro-L-talopyranose or its derivatives, which are useful as raw materials for the synthesis of adriamycinone or their 17-O-acylated derivatives.

0002

[Prior Art and Problems to be Solved by the Invention] 7-O-(2,6-dideoxy-2-fluoro-α-L-talopyranosyl)daunomycinone (compound a) represented by the following general formula (A) and 7-O-(2,6-dideoxy-2-fluoro-α-L-talopyranosyl)adriamycinone (compound b) is a novel compound with remarkable antitumor properties and low toxicity synthesized by the present inventors. It is an anthracycline derivative (see JP-A-62-145097 and European Patent Application No. 0230013). [In the formula, R is a hydrogen atom in the case of compound a, and a hydroxyl group in the case of compound b].

The present inventors further synthesized an anthracycline derivative represented by the following general formula (B) as a 14-O-acyl derivative of the anthracycline derivative of general formula (A), and further improved this derivative. It has been found that it has antitumor properties and improved water solubility, making it easier to use as an injection (Japanese Patent Laid-Open No. 63-1419).
22 and European Patent Application No. 0275431). [Wherein, R is a group -(CH2)mH (where m is 0 or 1-
6) or a group -(CH2)nCOOH (where n is 0 or an integer from 1 to 10)].

These antitumor anthracycline derivatives of general formula (A) or (B) have the following formula (C) [wherein R
' is hydrogen or hydroxyl group, or R' is group -(CH2)m
H (where m is 0 or an integer of 1 to 6) or a group -(C
H2) nCOOH (where n is 0 or an integer from 1 to 10)] for daunomycinone or adriamycinone or its 14-O-acyl derivative, 2,6-dideoxy-2-fluoro -L-talopyranose or pyranoside structure having the following formula (D
) or (D'), or a protected derivative thereof. Or, when rewritten in a plane form, [wherein A is a hydrogen atom or a hydroxyl protecting group, especially an acyl group, for example a lower alkanoyl group such as an acetyl group, or an aroyl group such as a benzoyl group, and X is a hydroxyl group,
or an alkoxy group, an acyloxy group, or a chlorine, bromine or iodine atom].

Therefore, the synthesis of the sugar compound of the above formula (D) is essential for the synthesis of the antitumor anthracycline derivatives of the above general formulas (A) and (B). This sugar compound of formula (D), namely 2,6-dideoxy-2-fluoro-
L-talopiece or its derivatives are novel sugar compounds synthesized for the first time by the present inventors, and up to now L-talopiece
-A synthesis method using fucose as a starting material was announced (see JP-A-62-145097 and JP-A-63-141992). However, since L-fucose is an expensive sugar and difficult to obtain in large quantities, it is problematic as a starting material for the production of antitumor compounds that need to be synthesized in large quantities. Therefore, there is a need for the development of a new method for synthesizing the sugar compound of formula (D) that can use as a starting material a sugar that is cheaper than L-fucose and is available in large quantities. This time, the present inventors have developed a new synthetic route for 2,6-dideoxy-2-fluoro-L-talopyranose or its protected form, which can use D-fructose, which is inexpensive and available in large quantities, as a starting material. succeeded in. Incidentally, the commercial price of L-fucose is usually about 200 times or more that of D-fructose, and the difference in these prices will of course fluctuate depending on market conditions. Furthermore, while D-fructose is extremely cheap and available in large quantities, the market supply of L-fucose is limited.

[0006]

[Means for solving the problem] 2,6-dideoxy-2
The synthetic approach carried out by the present inventors in developing a new synthetic route for -fluoro-L-talopyranose will be described below. When D-fructose is represented by a chain structural formula, it is shown by the following formula (E). This structural formula (E) is 18 on paper.
It may be rotated by 0° and expressed by the following equation (E'). The target 2,6-dideoxy-2-fluoro-L-talose is represented by the following formula (D'') when its skeleton is represented by a chain structural formula. Structural formula (E') and structural formula ( D''), 2,6-dideoxy-2-fluoro-L-talose (target compound) starting from D-fructose
For the synthesis of , at least the following five transformations are essential. Conversion (1): 6-position of D-fructose (1 of the target compound
oxidize the hydroxymethyl group at the 5-position of D-fructose (corresponding to the 2-position of the target compound) to form an aldehyde group; Conversion (2):
(corresponding to the position corresponding to the
invert the configuration of the hydroxyl group (corresponding to the position); conversion (
4): The carbonyl group at the 2-position (corresponding to the 5-position of the target compound) of D-fructose is reduced to a hydroxyl group. At that time, the epimer having the S configuration (L-configuration) is separated and recovered from the two types of epimers produced; Conversion (5)
:The 1st position of D-fructose (corresponding to the 6th position of the target compound) is deoxylated to form a methyl group.

Through the above five transformations, the basic skeleton of 2,6-dideoxy-2-fluoro-L-talose is transformed so that the 1st position (head) of D-fructose becomes the 6th position (tail) of the target compound. (D'') is synthesized. When a hemiacetal is formed between the aldehyde group and the 5-position hydroxyl group of the compound of formula (D''), ring closure occurs to form a pyranose ring. By carrying out appropriate chemical transformations such as protection of hydroxyl groups in each of the above-mentioned transformations, a plan can be devised to synthesize the target compound, that is, 2,6-dideoxy-2-fluoro-L-talopyranose.

Next, how did the present inventors actually incorporate the above five transformations into the synthesis process?
2,6-dideoxy-2-fluoro- of the above formula (D)
1 as an example of L-talopyranose and its derivatives;
Whether 3-di-O-acetyl-2,6-dideoxy-2-fluoro-α-L-talopyranose (compound 19a; see Example 16 below) was synthesized was determined by the following synthesis process chart 1 and below. This will be explained with reference to Examples 1 to 11, as well as Synthesis Process Chart 3 and Examples 12 to 18, which will be described later.

The abbreviations in the above Synthesis Process Chart 1, Synthesis Process Charts 2 and 3 to be described later, and Examples are as follows. Ac: Acetyl group -COCH3 Bn: Benzyl group -CH2C6H5 B
z: benzoyl group -COC6H5

Regarding the above synthetic process chart 1, D-fructose is used as the starting compound. A method known from this D-fructose [Robert F. Brady, Jr. , “
Carbohydrate Research” 15
Vol., pp. 35-40 (1970)], 1,2:4,5-di-O-isopropylidene-β-D-fructopyranose (Compound 1) is obtained by introducing an isopropylidene group (Step 1). The 3-hydroxyl group of this compound 1 was protected with a benzyl group (step 2), and 3-O-benzyl-1,2:4,5
-di-O-isopropylidene-β-D-fructopyranose (compound 2) is obtained. Thereafter, by elimination treatment (step 3) in which compound 2 is treated with an 80% acetic acid aqueous solution, 4,5-O-isopropylidene group among the two isopropylidene groups is selectively removed, and 3-O-benzyl -1,
2-O-isopropylidene-β-D-fructopyranose (compound 3) is obtained. Next, among the two hydroxyl groups of compound 3, acylation (step 4) in which the 5-position hydroxyl group is selectively protected with a benzoyl group produces 5-O-benzoyl-3-
O-benzyl-1,2-O-isopropylidene-β-D
- Obtain fructopyranose (compound 4). Protecting the 4-position hydroxyl group of compound 4 with a tetrahydropyranyl group (Step 5)
5-O-benzoyl-3-O-benzyl-1,2-
O-isopropylidene-4-O-tetrahydropyranyl-β-D-fructopyranose (compound 5) is produced. By removing the benzoyl group of this compound 5 (step 6), 3 is obtained as a product in which only the 5-position hydroxyl group is released.
-O-benzyl-1,2-O-isopropylidene-4-
O-tetrahydropyranyl-β-D-fructopyranose (compound 6) was obtained. Step 7 in which compound 6 is reacted with diethylaminosulfur trifluoride produces 3-O-benzyl-5-deoxy-5-fluoro-1 as a product in which fluorine is introduced with inversion of configuration.
, 2-O-isopropylidene-4-O-tetrahydropyranyl-α-L-sorbopyranose (compound 7) is obtained. Through this reaction (step 7), conversion (2) of the five conversions described above was first performed.

Further, step 8 consists of treating compound 7 with a strongly acidic cation exchange resin in methanol.
Compound 8, i.e., methyl 3-O-benzyl-5-deoxy-5-fluoro-α-L-, is a product in which both the acid-labile isopropylidene group and the tetrahydropyranyl group are eliminated and a glycosidic bond is formed. Sorbopyranoside is obtained. In step 9, the 1-position hydroxyl group, which is the primary hydroxyl group of the two liberated hydroxyl groups of compound 8, is selectively brominated with triphenylphosphine and carbon tetrabromide to produce methyl 3-O-benzyl-1-bromo. -1,5-dideoxy-5-fluoro-α-L-sorbopyranoside (compound 9) is obtained. In Step 10 of reducing Compound 9 using tributyltin hydride, methyl 3-O-benzyl-1,5-dideoxy-5-fluoro-α-L-sorbopyranoside ( Compound 10) is obtained. As a result, conversion (5) of the five conversions mentioned above has been performed.

Next, in step 11 of oxidizing the hydroxyl group at the 4-position of compound 10, methyl 3-O-benzyl-1,5-dideoxy-5-fluoro-α-L-erythro-2,4-
Hexodiuropyranoside (compound 11) is obtained. Through step 12 of reducing this compound 11, methyl 3-O-benzyl-1,5-dideoxy-5-fluoro-α-L-psychopyranoside (compound 12) is obtained as a product in which the configuration of the 4-position hydroxyl group is reversed. . This means that conversion (3) of the five conversions mentioned above has been performed.

[0013]Compared to the series of steps leading from compound 3 to compound 8 shown in synthesis process chart 1, an alternative route for synthesizing compound 8 with a reduced number of steps is shown in synthesis process chart 2 below.

That is, to explain the above synthesis process chart 2 and Examples 12 and 13 and Example 7 and Method B described later, Step 13 (13) in which compound 3 is reacted with tertiary butyldimethylsilyl chloride in pyridine ( (see Example 12), 3-O-benzyl-4-O-tert-butyldimethyl-1, which is selectively silylated at the 4-position, is produced.
2-O-isopropylidene-β-D-fructopyranose (compound 13) is obtained. Step 14 (see Example 13) of fluorinating compound 13 with diethylaminosulfur trifluoride yields 3-O-benzyl-4-O-tert-butyldimethylsilyl-5-deoxy-5-fluoro-1 ,2-O-isopropylidene-α-
L-sorbopyranose (compound 14) is obtained. The acid-labile tertiary butyldimethylsilyl group and tetrahydropyranyl group are removed by performing step 15 (see Example 7, Method B) of treating compound 14 with a strongly acidic cation exchange resin in methanol. At the same time, a glycosidic bond is generated to obtain the desired compound 8. In the above route, compared to the case shown in Synthesis Process Chart 1, the synthesis process from Compound 3 to Compound 8 can be shortened by two steps.

Furthermore, using the above compound 12 obtained by the method shown in the above synthetic process chart 1, the 3-O-benzyl group was removed by an appropriate deprotection method, and the methyl composing aglycon was removed. When the group is removed by hydrolysis, a compound of the following formula can be generated. After the hydroxyl group at the 2-position of the compound of formula (F) is alkylated with a methyl group or an ethyl group to give psicopyranoside, the hydroxyl group at the 3-position is further changed to a suitable protecting group, such as a benzyl group or an allyl group.
l) group, a lower alkanoyl group (e.g. acetyl group) or a benzoyl group, the following general formula (I): [wherein Me is a methyl group and R1 is a benzyl group, an allyl group, a lower alkanol group or is a benzoyl group, R
2 is a methyl group or an ethyl group] Methyl or ethyl 3-0-protected-1,5-dideoxy-5
-Fluoro-α-L-psychopyranoside can be prepared.

The process from the compound of general formula (I) to the formation of a 2,6-dideoxy-2-fluoro-L-talopyranose skeleton is shown in the synthesis process chart 3 below and Examples 14 to 16 below. This will be explained below with reference to .

Regarding synthesis process chart 3, the general formula (I
) When the glycosidic bond is cleaved in step A of acid hydrolysis of compound (I), that is, the aglycone group (R2
) is eliminated, the hemiacetal compound (
II), for example 3-O-benzyl-1,5-dideoxy-5-fluoro-L-psychopyranose (compound 15;
(see Example 14) is obtained. This compound 15 is α-L
and in the form of a mixture of β-L anomers. In addition, a small amount of a compound formed by ring opening of hemiacetal to form a chain structure also exists as an equilibrium mixture. In step B of reducing compound (II), compound (III), such as 4-O-benzyl-
2,6-dideoxy-2-fluoro-L-talitol (
Compound 16a) is produced as the main product, and also compounds (III'), such as 4-O-benzyl-2,6-dideoxy-2-fluoro-D-allitol (compound 16b
) [However, the position numbers of the compounds after Compound 16 are assigned according to the final target compound, and are different from those before Compound 15; that is, before Compound 15 and after Compound 16, the position numbers for the same carbon atom are different. position number is given] is produced as a by-product (Example 15 below)
reference). This results in three of the five transformations mentioned earlier.
Conversion (4) is then performed. However, it was not possible at this stage to separate the epimer having the 5S configuration (corresponding to compound 16a) among the above two types of epimers.

Synthesis process chart 3 shows L-talitol derivative (III) and D-allitol derivative (III).
') is subjected to step C in which the hydroxymethyl group at the 1st position is selectively oxidized with a specific oxidizing agent while leaving three hydroxyl groups free, and the hydroxymethyl group becomes an aldehyde group.

That is, for example, when the mixture of Compound 16a and Compound 16b is oxidized with tris(triphenylphosphine)ruthenium(II) chloride in benzene while leaving three hydroxyl groups free (Step C), 1 Only the hydroxymethyl group at the position is selectively oxidized to become an aldehyde group [conversion (1) is performed here].

Next, the obtained aldehyde compound forms a hemiacetal ring between the aldehyde group and the hydroxyl group at the 5-position, so that 4-O-benzyl-2,6-dideoxy-2-fluoro-L-talopyranose is formed. (Compound 17a)
An inseparable mixture of and its 5-epimer (compound 17b) is obtained. Generally, a mixture of compound (IV) and compound (IV') shown in Synthesis Process Chart 3 is obtained. This mixture was acylated (acyl group R3,
For example, if Step D is carried out (for example, introduction of an acetyl group), and separation and purification is performed by a chromatographic separation method, such as silica gel column chromatography, the general formula (V
), such as 1,3-di-O-acetyl-4-O
-benzyl-2,6-dideoxy-2-fluoro-L-
Talopyranose (compound 18) can be obtained. For example, compound 18 is 1,3-di-O-acetyl- which is the α-L-anomer and β-L-anomer, respectively.
4-O-benzyl-2,6-dideoxy-2-fluoro-α-L-talopyranose (compound 19a) and 1,3-
It is a mixture with di-O-acetyl-4-O-benzyl-2,6-dideoxy-2-fluoro-β-L-talopyranose (compound 19b). Removal of the benzyl group from compound 19a isolated from this mixture results in 1,3-di-O-acetyl-2,6-dideoxy-2-fluoro-
α-L-talopyranose (compound 20a) is obtained, which is then acetylated to provide the 1,3,4-tri-O-acetyl-2,6-
dideoxy-2-fluoro-α-L-talopyranose (
Compound 21a) is obtained. Compound 21a has the above formula (A)
Alternatively, it is a compound actually used as an intermediate in the synthesis of the antitumor anthracycline derivative of formula (B) (see JP-A-62-145097). Separately separated β-L
Compound 19b as an anomer was also prepared by 1,,3,4-tri-O-acetyl-2,6-dideoxy-2-fluoro-β-L-talopyranose (Compound 21b ). This compound 21b is also a compound already synthesized by the present inventors [K. OK, Y. Takagi, T. Tsuchi
ya, S. Umezawa, and H. Umezawa
Carbohydrate Research”16
9, pp. 69-81 (1987)], and compound 2
Like 1a, it can be used as an intermediate for the synthesis of antitumor anthracycline derivatives.

In this way, by following the synthesis routes shown in the synthesis process charts 1 and 3 above, D-
The present inventors have now discovered that the desired 2,6-dideoxy-2-fluoro-L-talopyranose compound can be obtained using fructose as a starting material.

Generally speaking, the treatment of compound (V) shown in the above synthetic process chart 3 is as follows: The O-acyl groups (R3) at the 1st and 3rd positions of this compound (V) are When step E of elimination by hydrolysis or alcoholysis is carried out, compound (VI), i.e. 4-O-protected-2,6
-dideoxy-2-fluoro-α,β-L-talopyranose is produced. From this compound (VI), when step F of removing the protecting group (R1) of the 4-position hydroxyl group is carried out by a conventional method, compound (VII) is obtained, i.e., 2,6-dideoxy-2-fluoro-α,β-L - Talopyranose is produced. On the other hand, regarding compound (VI), a protecting group for the 4-position OH group (
Elimination of R1), introduction of a new hydroxyl protecting group (A), halogenation of the 1-position OH group (introduction of halo group X),
When step G, which includes the introduction of an aglycone (e.g., introduction of a methyl group can.

Furthermore, the compound (V) shown in synthesis process chart 3, namely 1,3-di-O-acyl-4-
O-protected-2,6-dideoxy-2-fluoro-L-talopyranose is now a protecting group for the 4-position hydroxyl group (R1)
is subjected to step Q of elimination using a conventional method, the following compound (VIa) is obtained: 1,3-di-O-acyl-2,6
-dideoxy-2-fluoro-L-talopyranose is produced. This step (Q) is represented by the following reaction formula.

[0024] The reaction of this step (Q) is carried out in Example 17 below, in which 1,3-di-O-acetyl-4-O-benzyl-2,6-dideoxy-2-fluoro-α-L-
Illustrated by the example of debenzylation of talopyranose (compound 19a) by catalytic reduction to yield 1,3-di-O-acetyl-2,6-dideoxy-2-fluoro-α-L-talopyranose (compound 20a). Ru.

Separately, using a mixture of the L-talitol derivative (compound III) and the D-allitol derivative (compound III') shown in the synthesis process chart 3, 2,6-dideoxy-2-fluoro- α, β-L-
The present inventors also invented a second route for synthesizing talopyranose (Compound VII).
This will be explained below with reference to 3.

Regarding this synthesis process chart 4, L-talitol derivative (III) and D-allitol derivative (I
II'), such as the specific compound 16 above.
Of the three free hydroxyl groups in the mixture of a and compound 16b, the 1st-position hydroxyl group, which is a primary hydroxyl group, is the only hydroxyl group at position 3.
The present inventors have discovered in the present study that it is possible to selectively protect with a butyldimethylsilyl group, generally a trialkylsilyl group.

That is, compound (III) and compound (I
Step H of selectively protecting the 1-position hydroxyl group of II') with a trialkylsilyl group (R4) as a special protecting group and subjecting the obtained protected product to silica gel chromatography.
When carrying out
-O-tertiary butyldimethylsilyl-2,6-dideoxy-2-fluoro-L-talitol (compound 22a),
It can be separated from the corresponding 5R epimer (compound 22b) by silica gel column chromatography (see Example 20). Next, when step I is performed in which the two free hydroxyl groups at the 3- and 5-positions of compound (VIII), for example, compound 22a, are protected with a divalent hydroxyl protecting group (R5), for example, an isopropylidene group, the compound (
IX), for example 4-O-benzyl-1-O-tert-butyldimethylsilyl-2,6-dideoxy-2-fluoro-3,5-O-isopropylidene-L-talitol (compound 23) is obtained (See Example 21). Then, when step J of eliminating the trialkylsilyl group (R5) is performed (see Example 22), a compound in which only the 1-position hydroxyl group is released (
X), for example 4-O-benzyl-2,6-dideoxy-
2-fluoro-3,5-O-isopropylidene-L-talitol (compound 24) was obtained. When step K of oxidizing the 1-position hydroxyl group of compound (X) is performed, the aldehyde compound (X
I) is obtained. When this compound is subjected to step L, which involves removal of the divalent hydroxyl protecting group (R5), e.g. isopropylidene group, by acid hydrolysis and formation of a hemiacetal ring as in Example 23, compound (VI), e.g. -O-benzyl-2,6-dideoxy-2-fluoro-L-talopyranose is obtained as a mixture of α-L- and β-L-anomers (see Example 23).

At this stage, conversion (1) of the five conversions described above has been achieved in the case of synthesis process chart 4, and the target 2,6-dideoxy-2-fluoro-L- This means that the basic skeleton of talopyranose has been achieved.

Furthermore, using the mixture of L-talitol derivative (compound III) and D-allitol derivative (compound III') shown in the synthesis process chart 3, 2,6-dideoxy-2-fluoro- α, β-L
-A third route by which Talopyranose (Compound VII) can be synthesized has also been invented by the inventors. This third route will be explained below with reference to Synthesis Process Chart 5 below and Examples 25 and 26 below.

To explain the above synthetic process chart 5, the mixture of the L-talitol derivative (compound III) and the D-allitol derivative (compound III') shown in the synthetic process chart 3 is When chlorotrimethylsilane is reacted, all of the unprotected hydroxyl groups of compound (III) and compound (III') are protected with trimethylsilyl group (Y) (step M) to form compound (III).
1,3,5-tri-O-trimethylsilyl derivatives of (III') and (III'), ie, a mixture of compound (XII) and compound (XII'), are obtained. This mixture is
It is a compound represented by the following general formula [wherein R1 has the above-mentioned meaning and Y is a trimethylsilyl group]. This compound (X
When the methyl group (-CH2OY) with a primary trimethylsilyloxy group in the 1-position of IIa) is treated with chromium trioxide (CrO3), it can be selectively oxidized and converted to an aldehyde group, but other It has been discovered by the inventor that the trimethylsilyloxy group in position does not undergo oxidation. Therefore, selective oxidation of compound (XIIa) with chromium trioxide produces an inseparable mixture of aldehyde compounds of the following formula. This mixture is an aldehyde compound of the following general formula, in which R1 and Y have the same meanings as above. This aldehyde compound (XIIIa
), when the trimethylsilyl groups (Y) at the 3- and 5-positions are removed by acid treatment, a 4-O-protected-2,6-dideoxy-2-fluoro-L- Talopyranose (Compound IV) and Part 5
- epimer form (compound IV') is produced as a mixture that cannot be separated from each other. This compound (IV) and the compound (
The mixture with IV') can be separated by chromatography after acylation of the 1- and 3-position hydroxyl groups of the compound (introduction of acyl group R3), as explained in the synthesis process chart 3 above. When subjected to process D including 1,
3-di-O-acyl-4-O-protected-2,6-dideoxy-2-fluoro-L-talopyranose (ie, compound V) can be obtained.

Next, this compound (V) is subjected to hydrolysis or alcoholysis of the O-acyl groups (R3) at the 1st and 3rd positions from the compound (V), as in the case of the synthesis route in Synthesis Process Chart 3. When subjected to step E of elimination by 4-O-
Protected-2,6-dideoxy-2-fluoro-α,β-L
- produces talopyranose (compound VI). Moreover, when this compound (VI) is subjected to step F of elimination of the 4-position hydroxyl group (R1), 2,6-dideoxy-2-fluoro-L
- Talopyranose (Compound VII) is produced. On the other hand, when the above compound (V) is subjected to step Q of removing the protecting group (R1) of the hydroxyl group at the 4-position, 1,3-di-O
-acyl-2,6-dideoxy-2-fluoro-L-talopyranose (compound VIa) can be produced.

As mentioned above, the present inventors have developed D-
Starting from fructose, several new methods have been developed that allow the synthesis of sugar compounds with 2,6-dideoxy-2-fluoro-α,β- or -α-L-talopyranose structures by various routes. .

[0033] In relation to the synthesis route shown in Synthesis Process Chart 3 above, the following manufacturing method is provided according to the first invention. That is, the following formula [wherein Me is a methyl group, R1 is a benzyl group, allyl group, lower alkanol group or benzoyl group, and R
2 is a methyl group or an ethyl group] methyl or ethyl 3-0-protected-1,5-dideoxy-5-fluoro-α-L-psychopyranoside is acid-hydrolyzed to form the following formula [where Me and R1 has the same meaning as above] 3-0-
Protected-1,5-dideoxy-5-fluoro-α,β-L
- Step (A) of producing psychopyranose and formula (II
) by reducing the compound with a reducing agent selected from alkali metal borohydride, lithium aluminum hydride and dialkylaluminium hydride to open the ring to form the compound of the following formula [wherein Me and R1 have the same meanings as above]. 4-
O-protected-2,6-dideoxy-2-fluoro-L-talitol and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allitol.
) 1-position hydroxymethyl group (-CH2OH) of the compound
is oxidized with tris(triphenylphosphine)ruthenium(II) halide as an oxidizing agent, thereby converting it into an aldehyde group (-CHO), and at the same time forming a hemiacetal ring between the aldehyde group and the 5-position hydroxyl group. With cyclization by reaction, 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-L-talopyranose and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allopyranose, a step (C) of producing a hybrid stereoisomer mixture from the compound of formula (IV) and the compound of formula (IV 1-position hydroxyl group and 3-position hydroxyl group of each compound of formula (IV') are acylated with a lower alkanoyl group or benzoyl group, and the resulting acylated product of the compound of formula (IV) and the compound of formula (IV') are acylated. The following formula [wherein M
4-O-protected-1,3-di-O-acyl-2,6 in which e and R1 have the same meanings as above, and R3 is an acyl group selected from the lower alkanoyl group and benzoyl group used. Step (D) of isolating -dideoxy-2-fluoro-α,β-L-talopyranose and hydrolysis or alcoholysis of the compound of formula (V) to remove the acyl group (R3) from the compound of formula (V). Alternatively, both the acyl group (R3) and the group R1 in the case of an acyl group are eliminated, thereby producing 4-O of the following formula [wherein Me is a methyl group and R1a is the same as R1 or is hydrogen] -Protected or non-protected-2,6-
and a step (E) of producing dideoxy-2-fluoro-α,β-L-talopyranose.
A method for preparing 4-O-protected or unprotected-2,6-dideoxy-2-fluoro-α,β-L-talopyranose of formula (VI) is provided.

In the method of the first invention, the formula (
Step A of producing the compound of formula (II) by hydrolyzing the compound of formula (II) with an acid can be carried out specifically as shown in Example 14 below, but generally it is carried out using an 80% aqueous acetic acid solution or 0.1N to 1N hydrochloric acid aqueous solution or 0.0
It can be hydrolyzed in a 5N to 1N aqueous sulfuric acid solution. Instead of the aqueous solution, a dioxane-aqueous solution or a tetrahydrofuran aqueous solution may be used. Reaction temperature is 30°~80°
can be.

Next, a step of reducing the compound of formula (II) with a reducing agent to produce a mixture of the ring-opened L-talitol derivative of formula (III) and the D-allitol derivative of formula (III') Although B can be carried out specifically as shown in Example 15 below, in general, a reducing agent is selected which gives the L-talitol derivative of formula (III) as the main product from the compound of formula (II). This is an important point. Preferred reducing agents are lithium borohydride, sodium borohydride, sodium borohydride plus lithium chloride, lithium aluminum hydride or potassium borohydride. On the other hand, when diisobutylaluminum hydride is used as the reducing agent, undesirable D-allitol derivatives may become the main product. The reaction solvent may be dimethoxyethane, tetrahydrofuran, dioxane or diglyme, and when lithium borohydride, sodium borohydride, or potassium borohydride is used as the reducing agent, ethanol, 2-propanol, or a water-containing solvent thereof may also be used. The reaction temperature is -
It is in the range of 30°C to +50°C.

Next, the compound of formula (III) and the compound of formula (III
') The 1-position hydroxymethyl group of the mixture of compounds of formula (IV
) and the 2-fluoro-L-talopyranose derivative of formula (I
Step C of producing a mixture of V') with the 2-fluoro-D-allopyranose derivative can be carried out specifically as shown in Example 16 below, but generally it is carried out in anhydrous benzene or toluene. Tris (
This can be carried out by an oxidation method using tris(triphenylphosphine)ruthenium(II) halide, preferably tris(triphenylphosphine)ruthenium(II) chloride.

The step (part of step D) of acylating the 1- and 3-position hydroxyl groups of the compound of formula (IV) and the compound of formula (IV') (inseparable from each other) produced in step C is as follows:
Although it can be carried out as shown in Example 16 and Example 26 (c) below, generally, acetic anhydride, acetyl chloride, propionyl chloride, benzoyl chloride, etc. are used as an acylating agent in an anhydrous organic solvent such as anhydrous pyridine. It can be implemented using In addition to pyridine, 4-
Dimethylaminopyridine-dichloromethane or the like can be used, and the reaction can be carried out at a reaction temperature of 10°C to 80°C.

A compound of the following formula (V) and a compound of the following formula as acylated products produced in this acylation reaction are separated by a chromatographic separation method (part of step D) using, for example, toluene-acetic acid as a developing solvent. They can be separated from each other by silica gel column chromatography using an ethyl mixed system, and the 2-fluoro-L-talopyranose protected derivative of formula (V) can be isolated and recovered.

The compound of formula (V) obtained from the above step D has a protecting group (R1) at the 4-position and/or
The acyl groups (R3) at the 1st and 3rd positions can be removed from the compound (V) by a conventional deprotection method. For example, the acyl group (R3) of the compound of formula (V) and the protecting group (R1) at the 4-position in the case of an acyl group can be obtained by converting the compound (V) into sodium hydroxide or sodium methoxyhydroxide in methanol at room temperature. They can be eliminated together by carrying out Step E of hydrolysis or alcoholysis in the presence of a compound using a conventional method. If desired, the formula (
From the compound of V), the acyl groups (R3) at the 1st and 3rd positions can be removed, and then the protecting group (R1) at the 4th position can be removed, or the protecting group (R1) at the 4th position can be removed in the reverse order. ) can be eliminated, and then the two acyl groups (R3) at the 1st and 3rd positions can be eliminated.

The above-mentioned step E in the first method of the present invention
The compound of formula (V) is subjected to hydrolysis or alcoholysis, thereby removing the two acyl groups (R3) at the 1st and 3rd positions, and converting the protecting group (R1) at the 4th position into a compound such as an acetyl group or a benzoyl group. In the case of protection of the acyl type, this acyl type group (R1) is also removed at the same time to produce the compound of formula (VI) when the 4-position is not protected as the final product of this method. . However, the protecting group at position 4 of the compound of formula (V) (
If R1) is not an acyl type group, i.e. the group R1
is a benzyl group or an allyl group, it cannot be eliminated by the hydrolysis or alcoholysis in the above step E, so it remains and forms a compound of the formula (VI) in which the group R1a is a benzyl group or an allyl group. ) produces the compound. Such a compound of formula (VI) can be obtained by removing the protected benzyl or allyl group (R1) of the 4-position hydroxyl group in a conventional manner as in Step F shown in Synthesis Process Chart 3 to form 2,6-dideoxy-2 -Fluoro-L-talopyranose (Compound V
II) can be generated. In this step F, de-O-benzylation or de-O-allylation, which is a reaction for eliminating a benzyl group or an allyl group as the group R1 protecting the 4-position hydroxyl group, is carried out using reaction means and conditions commonly used in the deprotection method. It can be carried out with For example, de-O-benzylation can be achieved by hydrogenation using palladium black or palladium-activated carbon catalysts in aqueous dioxane or aqueous tetrahydrofuran, optionally in the presence of an acid such as acetic acid or hydrochloric acid ( (See Example 19 below). Alternatively, de-O-allylation can be achieved by reacting tris(triphenylphosphine)rhodium chloride in the presence of diazabicyclo[2.2.2]octane in aqueous ethanol followed by acid hydrolysis.

In the method of the first invention, formula (V)
Step E is carried out in which the O-acyl groups (R3) at the 1st and 3rd positions of the compound are eliminated by hydrolysis or alcoholysis to produce the compound of the formula (VI). ) The compound of formula (VIa), i.e. The method can be modified to produce 1,3-di-O-acyl-2,6-dideoxy-2-fluoro-L-talopyranose (Examples 16 and 17 below).
reference). Separately, the reaction of converting the 1-position acyloxy group (OR3) of the compound of formula (V) into a halogen is performed by reacting titanium tetrahalide, such as titanium tetrabromide, tetrachloride, or tetraiodide, in dichloromethane or ethyl acetate. Alternatively, it can be carried out by reacting hydrogen bromide or hydrogen chloride in acetic acid (see Example 3 of JP-A-62-145096).

Furthermore, in connection with the combination of a part of the synthesis route shown in the synthesis process chart 3 and the synthesis route shown in the synthesis process chart 4, according to the second invention, the following production process is performed. law is provided. That is, the following equation

004
3] Methyl or ethyl [wherein Me is a methyl group, R1 is a benzyl group, allyl group, lower alkanol group, or benzoyl group, and R2 is a methyl group or ethyl group] 3-0-Protected- Acid hydrolysis of 1,5-dideoxy-5-fluoro-α-L-psychopyranoside yields the following formula:

Step of producing 3-0-protected-1,5-dideoxy-5-fluoro-α,β-L-psychopyranose [wherein Me and R1 have the same meanings as above] (
A) and the compound of formula (II) are ring-opened by reducing the compound of formula (II) with a reducing agent selected from alkali metal borohydride, lithium aluminum hydride and dialkyl aluminum hydride to obtain the following formula:

4-O-protected-2,6-dideoxy-2-fluoro-L-talitol [wherein Me and R1 have the same meanings as above] and the following formula [wherein Me and R1 have the same meanings as above] 4-, which has the same meaning as
O-protected-2,6-dideoxy-2-fluoro-D-allitol, a compound of formula (III) in the mixture and a compound of formula (III') ) of the 1-position hydroxymethyl group (-
The hydroxyl group in CH2OH) is selectively protected with a tertiary-butyl-di(lower) alkylsilyl group or a tertiary-butyl-diphenylsilyl group to form the following formula [where Me and R1 have the same meanings as above, and R4 is 3 1-O-, which is a butyl-di(lower)alkylsilyl group or a tertiary-butyl-diphenylsilyl group.
Protected-4-O-protected-2,6-dideoxy-2-fluoro-L-talitol and 1-O-protected-4-O-protected-2
, 6-dideoxy-2-fluoro-D-allitol to form a mixed stereoisomer mixture, which is then subjected to chromatographic separation to produce the following formula:

0046
A step of isolating 1-O-protected-4-O-protected-2,6-dideoxy-2-fluoro-L-talitol [wherein Me, R1 and R4 have the same meanings as above] ( H)
and the 3-position hydroxyl group and the 5-position hydroxyl group of the compound of formula (VIII) are simultaneously protected with an alkylidene group, cycloalkylidene group, benzylidene group, or tetrahydropyranylidene group as a divalent hydroxyl protecting group to obtain the following formula:

0047
[In the formula, Me, R1 and R4 have the same meanings as above, and R5 is an alkylidene group, a cycloalkylidene group, a benzylidene group or a tetrahydropyranylidene group]
4-O-protected-1-O-trialkylsilyl (or alkyldiphenylsilyl)-2,6-dideoxy-2-
Step (I) of producing fluoro-3,5-O-protected-L-talitol and reacting a compound of formula (IX) with tetrabutylammonium fluoride or a mixture of tetrabutylammonium chloride and potassium fluoride. The protecting group (R4) of the 1-position hydroxyl group is selectively removed, thereby creating the following formula

4-O-protected-2,6-dideoxy-2 [wherein Me, R1 and R5 have the same meanings as above]
Step (J) of producing -fluoro-3,5-O-protected-L-talitol and converting the hydroxymethyl group (-CH2OH) at the 1-position of the compound of formula (X) to an aldehyde group (-CHO
) to form the following formula:

Step (K) of producing an aldehyde compound [wherein Me, R1 and R5 have the same meanings as above]
and the compound of formula (XI) is hydrolyzed to remove the hydroxyl protecting group (R5) or the group R5 and the group R1, and at the same time, between the aldehyde group at the 1-position and the deprotected hydroxyl group at the 5-position. With cyclization by a hemiacetal ring formation reaction, 4-O-protected or unprotected-2,6- of the following formula:
A step (L) of producing dideoxy-2-fluoro-α,β-L-talopyranose,
A method for preparing 4-O-protected or unprotected-2,6-dideoxy-2-fluoro-α,β-L-talopyranose of formula (VI) is provided.

In this second method of the present invention, step A and step B can be carried out in exactly the same manner as in the first method of the present invention.

In the next step H in the second method of the present invention, in the first half of step H, the hydroxyl group at the 1-position of the L-talitol derivative of formula (III) and the D-allitol derivative of formula (III') is , a specific trisubstituted silyl group (R
Protection is achieved by selectively introducing 4), and specifically, this is carried out, for example, as shown in Example 20 below. Generally, the selective introduction of the trisubstituted silyl group (R4) is carried out using tertiary butyl-dimethylsilyl as a reaction reagent.
chloride, tertiary butyl-dimethylsilyl trifluoromethanesulfonate or tertiary butyl-diphenylsilyl chloride, and imidazole as the base.
4-dimethylaminopyridine, 2,6-lutidine or N
, N-diisopropylethylamine and the like in a solvent such as N,N-dimethylformamide pyridine or dichloromethane at a reaction temperature of 0°C to +50°C.

As a result, the 1-O-protected-L-talitol derivative of formula (VIII) and the corresponding 1-O-
An inseparable mixture with the protected-D-allitol derivative is produced. The second half of step H, in which the L-talitol derivative of formula (VIII) is isolated from the mixture by a chromatographic separation method, involves separating the mixture by silica gel column chromatography using, for example, a hexane-ethyl acetate mixed system as a developing solvent. (See Example 20 below). The above step H
The compound of formula (VIII) obtained from
5) Subject to step I of protection by introduction of one. In this step I, 2,
Using 2-dimethoxypropane, 2-methoxypropene, cyclohexanone dimethyl acetal, benzaldehyde or benzaldehyde dimethyl acetal, etc. and as a catalyst a weak acid salt such as pyridinium p-toluenesulfonate, an organic acid such as p-toluenesulfonic acid,
A solvent such as dichloromethane, 1
, 2-dichloroethane or N,N-dimethylformamide, etc. at a temperature of 20°C to 80°C.

In the next step J, the compound of formula (IX) obtained from step I above is added to one of the compounds of formula (IX).
The hydroxyl group is protected by a treatment for selective removal of the trisubstituted silyl group (R4). This selective deprotection treatment in step J is carried out, for example, as shown in Example 22 below, but generally, for the compound of formula (IX),
The treatment can be carried out by using tetrabutylammonium fluoride or a mixture of tetrabutylammonium chloride and potassium fluoride as a treatment agent in a solvent such as tetrahydrofuran, dioxane or acetonitrile at a temperature of -10°C to 50°C.

Next, the L-talitol protected derivative of formula (X) obtained in Step J is converted into an aldehyde group by oxidizing the 1-position hydroxymethyl group of the compound to form an aldehyde compound of formula (XI). It is subjected to step K to generate it. This process K
Although the oxidation reaction can be carried out, for example, as shown in Example 23 below, it is generally carried out using an oxidizing agent that is used in a normal organic chemical reaction in which a primary hydroxymethyl group is oxidized to an aldehyde group. can. For example, using dimethyl sulfoxide as the oxidizing agent, dicyclohexylcarbodiimide-pyridinium trifluoroacetate, or phosphorus pentoxide, or oxalyl chloride-triethylamine as the reaction promoter, in benzene, N,N-dimethylformamide or dichloromethane as the solvent. Can be implemented. Alternatively, the reaction can be carried out in dichloromethane, 1,2-dichloroethane, etc. as a solvent, using pyridinium chlorochromate as an oxidizing agent, and in some cases, coexisting Moleculer sieves. Alternatively, the reaction is carried out in a solvent such as dichloromethane or 1,2-dichloroethane in the presence of pyridine using chromium trioxide as an oxidizing agent. The reaction temperature can range from -70°C to +50°C depending on the above reaction conditions.

The aldehyde compound of formula (XI) obtained from the above step K is then subjected to step L in which the protecting group (R5) is removed and the pyranose ring is closed. In this step L, the aldehyde compound of formula (XI) is used, for example in Example 2 below.
Although the aldehyde compound of formula (XI) is generally treated with an 80% aqueous acetic acid solution, a 0.1-1N aqueous hydrochloric acid solution, or a 0.05-1N aqueous sulfuric acid solution, It can be implemented by However, a dioxane-aqueous solution or a tetrahydrofuran-aqueous solution may be used instead of the aqueous solution. This reaction can be carried out at temperatures ranging from 20<0>C to 100<0>C. Through this step L, the formula (VI
) of 4-O-protected or unprotected-2,6-dideoxy-2
-Fluoro-L-talopyranose is produced as the desired product.

Furthermore, in connection with the combination of a part of the synthesis route shown in the synthesis process chart 3 and the synthesis route shown in the synthesis process chart 5, according to the third invention, the following method is performed. is provided. That is, in the third invention, R
2 is a methyl group or an ethyl group] methyl or ethyl 3-0-protected-1,5-dideoxy-5-fluoro-α-L-psychopyranoside is acid-hydrolyzed to form the following formula [where Me and R1 has the same meaning as above] 3-0-
Protected-1,5-dideoxy-5-fluoro-α,β-L
- Step (A) of producing psychopyranose and formula (II
) by reducing the compound with a reducing agent selected from alkali metal borohydride, lithium aluminum hydride and dialkylaluminium hydride to open the ring to form the compound of the following formula [wherein Me and R1 have the same meanings as above]. 4-
O-protected-2,6-dideoxy-2-fluoro-L-talitol and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allitol, a compound of formula (III) in the mixture and a compound of formula (III') ) of the 1-position hydroxymethyl group (-
The hydroxyl group, the 3rd-position hydroxyl group, and the 5th-position hydroxyl group in CH2OH) are protected with a trimethylsilyl group or a triethylsilyl group to form the following formula [where Me and R1 have the same meanings as above, and Y is a trimethylsilyl group or a triethylsilyl group. ] of 4
-O-protected-1,3,5-tri-O-silyl-2,6-
Dideoxy-2-fluoro-L-talitol and 4-O-protected-1,3,5-tri-O-silyl-2,6- of the following formula [wherein Me and Y have the same meanings as above] dideoxy-2-fluoro-D-allitol, and converting the compound of formula (XII) and the compound of formula (XII') in the mixture to chromium trioxide ( CrO3)-pyridine complex to form the formula (
The trimethylsilyloxymethyl group at position 1 or the triethylsilyloxymethyl group at position 1 of each compound of XII) and (XII') is oxidized to an aldehyde group (-CHO), whereby the following formula [wherein Me, R1 and Y has the same meaning as above] and 4-O-protected-2,6-dideoxy-2-fluoro-3,5-di-O-silyl-aldehyde-L-talose and the following formula [wherein, Me, R1 and Y have the same meanings as above] 4-O-protected-2,6-dideoxy-2-fluoro-3,5-di-O-silyl-aldehyde-D-allose step (N) of producing a stereoisomer mixture of
) and at the same time with the formation of a hemiacetal ring between the aldehyde group at the 1st position and the deprotected hydroxyl group at the 5th position, the following formula [wherein Me and R1 have the same meanings as above] ] No. 4-
O-protected-2,6-dideoxy-2-fluoro-L-talopyranose and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allopyranose, a step (O) of producing a hybridized stereoisomer mixture from a compound of formula (IV) and a compound of formula (IV) in the mixture; 1-position hydroxyl group and 3-position hydroxyl group of the compound of formula (IV') are acylated with a lower alkanoyl group or benzoyl group, and the resulting acylated product of the compound of formula (IV) and the compound of formula (IV') are acylated. The following formula [wherein M
4-O-protected-1,3-di-O-acyl-2,6 in which e and R1 have the same meanings as above, and R3 is an acyl group selected from the lower alkanoyl group and benzoyl group used. Step (D) of isolating -dideoxy-2-fluoro-α,β-L-talopyranose, and hydrolysis or alcoholysis of the compound of formula (V) to remove the acyl group (R3) from the compound of formula (V). Alternatively, both the acyl group (R3) and the group R1 in the case of an acyl group are eliminated, thereby producing 4-O of the following formula [wherein Me is a methyl group and R1a is the same as R1 or hydrogen] -Protected or non-protected-2,6-
and a step (E) of producing dideoxy-2-fluoro-α,β-L-talopyranose.
A method for preparing 4-O-protected or unprotected-2,6-dideoxy-2-fluoro-α,β-L-talopyranose of formula (VI) is provided.

In this third method of the present invention, step A and step B can be carried out in exactly the same manner as in the first method of the present invention. The mixture of L-talitol derivative of formula (III) and D-allitol derivative of formula (III') obtained from step B is then protected with all hydroxyl groups present in these derivatives with trimethylsilyl group or triethylsilyl group. to step M. In this step M, except for using trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate, or triethylsilyl chloride or triethylsilyl trifluoromethanesulfonate as a reagent for introducing a trimethylsilyl group or a reagent for introducing a triethylsilyl group, It can be carried out in the same manner as the first half of step H of the second method of the present invention described above at a temperature of 0 to 50° C. in a solvent such as N,N-dimethylformamide or pyridine in the presence of a suitable base. The tri-O-trimethyl (or triethyl) silylation reaction carried out in this step M allows the formula (X
II) L-talitol derivative and D- of formula (XII')
A mixture with allitol derivatives is produced.

In the next step N, the mixture of compounds of formula (XII) and formula (XII') is immediately subjected to an oxidation reaction with a chromium trioxide-pyridine complex as the oxidizing agent. As a result, only the tolumethyl (or ethyl)silyloxymethyl group (-CH2OY) at the 1-position is selectively oxidized to an aldehyde group, producing an aldehyde compound (hybrid) of formula (XIII). This oxidation reaction can be carried out, for example, as shown in Example 26 (a) below, but generally, except for the need to use a specially selected chromium trioxide-pyridine complex as the oxidant, It can be carried out in the same manner as step K of the method of the present invention. This third
The method of the present invention can reduce the number of steps in that it does not require the step of eliminating trisubstituted silyl (R4) from the compound of formula (IX) as in step J of the second method of the present invention. There are advantages.

In the next step O, the trimethyl (or ethyl)silyl group (Y) is removed from the aldehyde compounds (in the form of a hybrid) of formula (XIII) and formula (XIII') produced in step N. To achieve this, acid hydrolysis is performed. The acid hydrolysis reaction in step O can be carried out in the same manner as in step L of the second method of the present invention. The L-talopyranose derivative of formula (IV) and the D-allopyranose derivative of formula (IV') (in the form of a mixture) obtained in the above step O are then step D, in which the compound of formula (V) is isolated from the resulting 1,3-di-O-acylated product by chromatographic separation. This step D can be carried out in exactly the same manner as step D of the first method of the present invention.

Finally, the compound of formula (V) obtained in step D is subjected to step E of hydrolysis or alcoholysis to obtain the target compound of formula (VI), ie 4-O-protected- or unprotected- 2,6-dideoxy-2-fluoro-L-talopyranose is produced. This step E can be carried out in exactly the same manner as step E of the first method of the present invention.

[0061] Also in this third method of the present invention, the above step E is omitted, and instead, the protecting group (R1) for the hydroxyl group at the 4-position is immediately removed from the compound of formula (V). It is possible to modify the method to carry out the desorption step Q (described above in connection with the first method of the invention). Furthermore, in the method of the first invention, L- of formula (II)
The psicopyranose derivative is reduced with a reducing agent, thereby forming the L-talitol derivative of formula (III) and the formula (III').
We have repeatedly researched the method of step B to produce the D-allitol derivative of hydride and in an organic solvent such as dimethoxymethane, tetrahydrofuran, dioxane, diglyme at -30℃~
When the reduction reaction is carried out at a reaction temperature of +50°C, the desired L-talitol derivative of formula (III) is preferentially produced at a higher rate than the undesired D-talitol derivative of formula (III'). I found that I can get it.

According to the fourth aspect of the present invention, the following method is provided. That is, in the fourth invention, the following formula

[
1,5-dideoxy-5-fluoro-α,β [wherein Me is a methyl group, R1 is a benzyl group, an allyl group, a lower alkanoyl group or a benzoyl group]
-L-psicopyranose in a non-reactive organic solvent-
characterized in that it consists of reduction with lithium borohydride or sodium borohydride or potassium borohydride or both sodium borohydride and lithium chloride or lithium aluminum hydride at a temperature of 30 ° C to 50 ° C.

[0064]
4-O in which Me and R1 have the same meanings as above
-Protected-2,6-dideoxy-2-fluoro-L-talitol and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allitol and a stereoisomer mixture containing the compound of formula (III) in a proportion of 3 times or more that of the compound of formula (III'). A manufacturing method is provided.

Furthermore, in the above-mentioned first, second or third method of the present invention, the compound of formula (III) obtained in step A and the compound of formula (III') are sterically inseparable from each other. It is a mixture of isomers and can be considered as one compound, and is also an important intermediate in synthesizing the target compound by the method of the present invention. Therefore, in the fifth aspect of the invention, 4 of the following formula [wherein Me is a methyl group and R is hydrogen, a benzyl group, an allyl group, an acetyl group or a benzoyl group]
-O-protected or unprotected-2,6-dideoxy-2-fluoro-L-talitol and 4-O of the following formula [wherein Me and R have the same meanings as above]
- protected or unprotected -2,6-dideoxy-2-fluoro-D-allitol, which is a mixture of mutually inseparable stereoisomers of the following general formula [wherein Me and R are There is provided a hexitol derivative represented by: This compound (II
An example of Ic) is shown in Example 27 below.

[0066] The present invention will be explained below with reference to examples. Example 1 Preparation of 3-O-benzyl-1,2:4,5-di-O-isopropylidene-β-D-fructopyranose (Compound 2)

1,2:4,5-di-O-isopropylidene-β-D-fructopyranose (compound 1) [Rob
ert F. Brady, Jr. , “Carbohy
drate Research” Volume 15, 35-40
(1970)] was dissolved in 23 ml of anhydrous N,N-dimethylformamide, and
Sodium hydride (oil-based, 60%) 70% under nitrogen atmosphere
After adding 0 mg and stirring at room temperature for 30 minutes, 1.92 ml of benzyl bromide was added and the mixture was further stirred at room temperature for 1 hour to effect benzylation of the 2-position hydroxyl group. After adding water to the reaction solution,
After extraction with chloroform, the extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The obtained residue was subjected to silica gel column chromatography (developing system: toluene-ethyl acetate, 20 ml).
), the title compound was purified as syrup, 5.33g (
99%) obtained. [α]D23-89° (c2, chloroform) Elemental analysis Theoretical value as C19H26O6: C, 65.13; H, 7.48% Analysis value:
C, 65-37; H, 7.47%. In addition, this compound is H. Steinlin, L. Cama
rda and A. Vasella “Helvetic”
a Chimica Acta” Volume 62, 378-
Although it is briefly described in the experimental section on page 390 (1979), there is no description of the data.

Example 2 3-O-benzyl-1,2-O-isopropylidene-β
-Production of D-fructopyranose (compound 3)

007
0] 3-O-benzyl-1,2:4,5-di-O-isopropylidene-β-D-fructopyranose (compound 2
) was dissolved in 30 ml of an 80% acetic acid aqueous solution and allowed to stand at room temperature for 15 hours to cause hydrolysis to eliminate one isopropylidene group. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (developing system: hexane-acetone, 2:1) to obtain 827 mg (90%) of crystals of the title compound. [α]D23-115° (c1.5, chloroform) Melting point 99-101°C
etica Chimica Acta” Volume 62,
378-390 (1979)], including data, the specific optical rotation is +113.2° (c1.
1, chloroform), and the sign is opposite to that of the compound obtained in this example.

Example 3 5-O-benzoyl-3-O-benzyl-1,2-O-
Production of isopropylidene-β-D-fructopyranose (compound 4)

3-O-benzyl-1,2-O-isopropylidene-β-D-fructopyranose (compound 3) 4
53 mg was dissolved in a mixed solvent of 15 ml of anhydrous dichloromethane and 0.35 ml of anhydrous pyridine, and after cooling to -78°C, 0.18 ml of benzoyl chloride was added, and at the same temperature 1.
The 5-position hydroxyl group was benzoylated by standing for a period of time. After adding water to the reaction solution, it was extracted with chloroform, and the extract was diluted with 2
After washing successively with a 0% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and water, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

The obtained residue was subjected to silica gel column chromatography (developing system: toluene-ethyl acetate, (0:1
) to separate and purify the title compound as syrup, 454m
g (75%) was obtained. [α]D24-155° (c1, chloroform) H-N
MR spectrum (deuterochloroform): δ 3.79 (
1H, d, H-3) 4.31 (1H, dd, H-4) 5.42 (1H, dt, H-5) 7.25-8.1 (10H, m, C6H5x2).

Example 4 5-O-benzoyl-3-O-benzyl-1,2-O-
Isopropylidene-4-O-tetrahydropyranyl-β
-Production of D-fructopyranose (compound 5)

007
5] 5-O-benzoyl-3-O-benzyl-1,2-
O-isopropylidene-β-D-fructopyranose (
416 mg of compound 4) was dissolved in 5 ml of anhydrous dichloromethane, and 0.2 ml of 3,4-dihydro-2H-pyran was added to the solution.
8 ml and 25 mg of pyridinium P-trienesulfonate were added and reacted at room temperature for 4 hours (4-O-
(Introduction of tetrahydropyranyl group). The reaction solution was diluted with chloroform, washed successively with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 500 mg of the title compound as a syrup.
(Quantitative) Obtained. This compound was obtained as a mixture of two types of diastereomers based on the stereoisomerism of the tetrahydropyranyl group. Elemental analysis Theoretical value as C28H34O8: C, 67.45; H, 6.87% Analysis value: C,
67.22; H, 6.89%.

Example 5 3-O-benzyl-1,2-O-isopropylidene-4
Production of -O-tetrahydropyranyl-β-D-fructopyranose (compound 6)

5-O-benzoyl-3-O-benzyl-
4-O-tetrahydropyranyl-1,2-O-isopropylidene-β-D-fructopyranose (compound 5) 4
Dissolve 90 mg in 4 ml of anhydrous methanol, and add 2
8% sodium methoxide-methanol solution 0.06m
After adding 1, the mixture was allowed to stand at room temperature for 4 hours (elimination of 5-O-benzoyl group). After introducing carbon dioxide gas into the reaction solution, it was concentrated under reduced pressure. Chloroform was added to the residue, and the chloroform solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing system: hexane-acetone, 3:1) to give 369 mg (95%) of the title compound as a syrup.
)Obtained. This compound is obtained as a mixture of two types of diastereomers based on the stereoisomerism of the tetrahydropyranyl group. H-NMR spectrum (deuterochloroform): δ 4.
04 (dd, H-4 of one diastereomer) 4.27 (dd, H-4 of the other diastereomer) 4
．． 09 (m, H-5 of both diastereomers).

Example 6 3-O-benzyl-5-deoxy-5-fluoro-1,
Production of 2-O-isopropylidene-4-O-tetrahydropyranyl-α-L-sorbopyranose (compound 7)

[
224 mg of 3-O-benzyl-1,2-O-isopropylidene-4-O-tetrahydropyranyl-β-D-fructopyranose (compound 6) was dissolved in a mixture of 3 ml of anhydrous benzene and 0.4 ml of anhydrous pyridine. Then, 0.28 ml of diethylaminosulfur trifluoride was added to this solution under ice cooling, and the mixture was reacted at 65° C. for 7 hours (introduction of 5-fluoro group). After the reaction solution was cooled to room temperature, it was added dropwise to an ice-cooled saturated aqueous sodium hydrogen carbonate solution. Extraction was performed with ethyl acetate, and the extract was washed successively with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The obtained residue was subjected to silica gel column chromatography (developing system: toluene-ethyl acetate, 20:1).
), the title compound was purified as a syrup and 158 mg (
70%). This compound is obtained as a mixture of two diastereomers based on the stereoisomerism of the tetrahydropyranyl group. 19F-NMR spectrum (deuterochloroform, CFCl
3 internal standard): δ -197.4 (ddd, F of one diastereomer) JF, H-5 50, JF, H-4 14.5, J
F,H-6ax4Hz δ -196.5 (broad dd, F of the other diastereomer) JF,H-5 50.5, JF,H-4 14.5
Theoretical value as Hz elemental analysis C21H29FO6: C, 63.62; H, 7.37; F, 4.79
% Analysis value: C, 63.74; H, 7.33; F, 4.99
%.

Example 7 Preparation of methyl 3-O-benzyl-5-deoxy-5-fluoro-α-L-sorbopyranoside (compound 8)

[
Method A 3-O-benzyl-5-deoxy-5-fluoro-1,
2-O-isopropylidene-4-O-tetrahydropyranyl-α-L-sorbopyranose (compound 7) 67 mg
was dissolved in 0.5 ml of anhydrous methanol, 80 mg of dried DOWEX 50W x 1 (H+ type) resin was added thereto, and the mixture was stirred at room temperature for 24 hours. After removing the ion exchange resin by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing system: toluene-acetate ether, 3
:1) to obtain 34 mg (71%) of crystals of the title compound.
Obtained. Melting point 97.5-98.5°C [α]D22 -37° (c1.3, chloroform)
1H-NMR spectrum (deuterochloroform): δ 1
．． 80 (1H, dd, OH-1) 2.35 (1H, d,
OH-4) 3.32 (3H, s, OCH3) 19F-NMR spectrum (deuterochloroform CFC
l3 internal standard): δ -200.4 (ddd) JF, H-5 50.
5, JF, H-4 15.5 JF, H-6ax
4.5Hz

Method B 3-O-benzyl-4-O obtained in Example 13 below
-tert-butyldimethylsilyl-5-deoxy-
5-Fluoro-1,2-O-isopropylidene-α-L
- 396 mg of sorbopyranose (compound 14) was reacted with Dowex 50W x 1 (H+ form) resin in anhydrous methanol under the same conditions as in method A above, and post-treatment was performed to give 201 mg of crystals of the title compound ( 76%). The melting point, optical rotation and spectral data were consistent with the values for the compound obtained with Method A.

Example 8 Methyl 3-O-benzyl-1-bromo-1,5-dideoxy-5-fluoro-α-L-sorbopyranoside (
Production of compound 9)

4.39 g of methyl 3-O-benzyl-5-deoxy-5-fluoro-α-L-sorbopyranoside (compound 8) was dissolved in 270 ml of anhydrous pyridine.
To this, 9.3 g of triphenylphosphine and 5.85 g of carbon tetrabromide were added and reacted at 100° C. for 8 hours (bromination). After cooling the reaction solution to room temperature, add 40ml of methanol.
1 was added, stirred for 10 minutes, and then concentrated under reduced pressure. Add chloroform to the obtained residue and dilute the chloroform solution to 20
After sequentially washing with % potassium hydrogen sulfate aqueous solution, saturated sodium hydrogen carbonate aqueous solution, and water, drying with anhydrous sodium sulfate,
It was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (developing system: toluene-ethyl acetate, 10:1) to obtain 3.01 g (56 g) of the title compound as a syrup.
%)Obtained. [α]D22 -28° (c3.3, chloroform)
Theoretical value as elemental analysis C14H18BrFO4: C, 48.15; H, 5.20; Br, 22.
88; F, 5.44% Analysis value: C, 47.93; H, 5.22; Br, 22.
71; F, 5.72%

Example 9 Methyl 3-O-benzyl-1,5-dideoxy-5
-fluoro-α-L-sorbopyranoside (compound 10)
Manufacturing of

2.92 g of methyl 3-O-benzyl-1-bromo-1,5-dideoxy-5-fluoro-α-L-sorbopyranoside (compound 9) was dissolved in anhydrous dioxane 7
6 ml of the solution, 13.5 ml of tributyltin hydride and 275 mg of α,α'-azobisisobutyronitrile were added, and the mixture was reacted at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing system: chloroform-ethyl acetate, 40:1) to give 1.66 g (73%) of the title compound as a syrup.
)Obtained. [α]D21 -42° (c3.6, chloroform)
1H-NMR spectrum (deuterochloroform): δ 1
．． 31 (3H, s, CH3) δ 3.24 (1H, s, OCH3) δ 4.16
(1H, ddt, H-4) J4, F16, J3, 4
9.5J4,5 8.5,J4,OH 3Hz.

Example 10 Methyl 3-O-benzyl-1,5-dideoxy-5
-Production of fluoro-α-L-erythro-2,4-hexodiuropyranoside (compound 11)

Methyl 3-O-benzyl-1,5-dideoxy-5-fluoro-α-L-sorbopyranoside (
1.35 g of compound 10) was dissolved in 10 ml of anhydrous benzene, 1.4 ml of dimethyl sulfoxide, 1.55 g of dicyclohexylcarbodiimide, and 0.25 g of pyridinium trifluoroacetate were added thereto, and the mixture was stirred at room temperature for 3 hours to perform an oxidation reaction. Ta. Saturated oxalic acid in the reaction solution
After adding the methanol solution, insoluble matter was removed by filtration and washed with benzene. The filtrate and washing liquid were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution, a 20% aqueous potassium hydrogen sulfate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing system: toluene-ethyl acetate, 15:1) to obtain 1.07 g (80%) of the title compound as crystals. Melting point 139.5-140°C [α]D22 +44° (c0.7, chloroform)
IR spectrum (KBr): 1750 cm-1 (C=0)

Example 11 Methyl 3-O-benzyl-1,5-dideoxy-5
-fluoro-α-L-psychopyranoside (compound 12)
Manufacturing of

Methyl 3-O-benzyl-1,5-dideoxy-5-fluoro-α-L-erythro-2,4-
43 mg of hexodiuropyranoside (compound 11) was dissolved in 1 ml of anhydrous tetrahydrofuran, cooled to -78°C, 12 mg of lithium aluminum hydride was added to this solution, and the mixture was stirred at the same temperature for 1 hour to perform a reduction reaction. . After adding a saturated aqueous ammonium chloride solution to the reaction solution, insoluble materials were removed by filtration and washed with chloroform. A chloroform solution of the filtrate and washing solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing system: toluene-ethyl acetate, 10:1) to give the title compound as crystals.
mg (95%) was obtained. Melting point 66.5-67.5°C [α]D22 +24° (c0.8, chloroform)
1H-NMR spectrum (deuterochloroform + heavy water): δ
3.16 (1H, dd, H-3) J3,4 3,
J3, F 1.5Hz4.47 (1H, m, H-4)

Example 12 Structure of 3-O-benzyl-4-O-tertiary butyldimethylsilyl-1,2-O-isopropylidene-β-O-fructopyranose (13)

3-O-benzyl-1 obtained in Example 2
, 388 mg of 2-O-isopropylidene-β-D-fructopyranose (compound 3) was dissolved in 2.6 ml of pyridine, 245 mg of tertiary-butyldimethylsilyl chloride was added, and the mixture was reacted at 80°C for 15 hours. (abbreviated as TBDMS)]. After the reaction solution was cooled to room temperature, a small amount of water was added to decompose excess reagent, and then diluted with ethyl acetate. This solution was washed successively with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (
Separation and purification using a developing system (toluene-ethyl acetate, 10:1) yielded 293 mg (55%) of the title compound as a syrup.
Obtained. 1H-NMR spectrum (deuterochloroform): δ 0
．． 09 and 0.13 (3H, s, Si-CH
3) 0.94 (9H,s,Si-C-CH3×
3) 1.41 and 1.48 (3H, s, CH3 of isopropylidene group, respectively) 3.82 (1H, m, H-5) 4.10
(1H, dd, H-4)

Example 13 Preparation of 3-O-benzyl-4-O-tertiary-butyldimethylsilyl-5-deoxy-5-fluoro-1,2-O-isopropylidene-α-L-sorbopyranose (14)

[
3-O-benzyl-4-O-tertiary butyldimethylsilyl-1,2-O-isopropylidene-β-D-
380 mg of fructopyranose (compound 13) was dissolved in a mixture of 6.6 ml of anhydrous benzene and 0.36 ml of anhydrous pyridine, and 0.27 ml of diethylaminosulfur trifluoride was added in an ice bath. After that, add the reaction solution to 6
It was left at 0° C. for 5 hours (introduction of fluoro group). The reaction solution was cooled to room temperature, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added and stirred. The organic layer was washed successively with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (
The residue was purified using a developing system (toluene-ethyl acetate, 30:1) to obtain 229 mg (60%) of the title compound as a syrup. 1H-NMR spectrum (deuterochloroform): δ 4
．． 09 (1H, dt, H-4) 4.37 (1H, ddd
d, H-5) J5, F 50, J5, 4 8.5,
J5,6eq 6.5,J5,
6ax 10.5Hz 19F-NMR spectrum (deuterochloroform, CFCl
3 internal standard): δ -195.8 (br.dd)

Example 14 3-O-benzyl-1,5-dideoxy-5-fluoro-L-psychopyranose (compound 15) of the following formula (II')
)Manufacturing of

Methyl 3-O-benzyl-1,5-dideoxy-5-fluoro-α-L-psychopyranoside (
40 mg of compound 12) was dissolved in 4 ml of 80% acetic acid aqueous solution and reacted at 50°C for 4 hours for hydrolysis (Step A).
I did it. The reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography (developing system: toluene-ethyl acetate, 2:
1), and the crystals of the title compound were purified by α-L and β-L.
33 mg (87%) was obtained as an equilibrium mixture of the anomer and trace amounts of linear compounds. Theoretical value as elemental analysis C13H17FO4: C, 60.93; H, 6.69; F, 7.41
% Analysis value: C, 60.62; H, 6.60; F, 7.11
% The above chain compound has the following formula.

Example 15 4-O-benzyl-2,6-dideoxy-2-fluoro-L-talitol (compound 16a) of the following formula (III-1)
) and 4-O-benzi-2 of the following formula (III'-1),
Production of 6-dideoxy-2-fluoro-D-allitol (compound 16b)

3-O-benzyl-1,5-dideoxy-
196 mg of 5-fluoro-L-psicopyranose (compound 15) was dissolved in 7.4 ml of tetrahydrofuran, cooled to 0°C, 33 mg of lithium borohydride was added, and the mixture was stirred at the same temperature for 1 hour for reduction (Step B). I did it. After adjusting the pH to 6 by adding 2N hydrochloric acid to the reaction solution, insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, methanol and silica gel were added to the residue, and the mixture was stirred at room temperature for 2 hours to decompose the chelate compound generated during the reaction. The residue obtained by filtering and concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (developing system: toluene-ethyl acetate,
1:2) to obtain 175 mg (89%) of the title compound mixture as a syrup. Although this mixture could not be separated by silica gel column chromatography, it was found from the 19F-NMR spectrum that the abundance ratio of the L-talitol derivative and the D-allitol derivative was 3.2:1. 19F-NMR spectrum (deuterochloroform, CFCl
3 internal standard): δ-198.2 (br.dddd, L-talitol derivative) JF, H-1 26, JF, H-1' 23, JF
, H-2 48, JF, H-3 8.5Hz-19
7.5 (dddd, D-allitol derivative) JF, H-
1 26, JF, H-1' 23, JF, H-2
46, JF, H-3 12Hz

Example 16 The following formula (
V-1) Production of 1,3-di-O-acetyl-4-O-benzyl-2,6-dideoxy-2-fluoro-α-L-talopyranose (compound 19a)

4-O-benzyl- obtained in Example 15
2,6-dideoxy-2-fluoro-L-talitol (
Compound 16a) and 4-O-benzyl-2,6-dideoxy-2-fluoro-D-allitol (Compound 16b)
) was dissolved in 8 ml of anhydrous benzene,
Tris (triphenylphosphine) is added to this as an oxidizing agent.
262 mg of ruthenium (II) chloride was added, and the mixture was stirred at room temperature for 3 days to perform oxidation (Step C). Ether was added to the reaction solution, the insoluble portion was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (developing system: hexane-ethyl acetate, 1:1) to obtain 4-O-benzyl-2,6-dideoxy-2-fluoro, which belongs to the compound of formula (IV). -L-talopyranose (compound 17a) and the 5-epimer of compound 17a (compound 17b) belonging to the compound of formula (IV')
20 mg of a mixture consisting of This mixture was dissolved in 0.6 ml of anhydrous pyridine, 0.075 ml of acetic anhydride was added, and the hydroxyl groups at the 1st and 3rd positions were acetylated (part of step D) by leaving the mixture at room temperature for 15 hours.
1,3-di-O-acetyl-4- belonging to the compound V)
O-benzyl-2,6-dideoxy-2-fluoro-α
, β-L-talopyranose (compound 18) was produced. After adding a small amount of water to the reaction solution containing the acetylated product and allowing it to stand, diluted with ethyl acetate, this solution was washed successively with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and water, and then dried over anhydrous sodium sulfate. and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (developing system: toluene-ethyl acetate, 20:1) (part of step D), and 13 mg of the title compound 19a (compound 16a and 1
A yield of 10% from the mixture of 6b was obtained. The melting point, optical rotation, 1H and 19F-NMR spectra of the obtained compound matched those values of Compound 19a obtained in Example 24 described later.

Note that when the above compound 19a is dissolved in methanol, sodium methoxide is added, and the mixture is left to stand at room temperature, deacetylation (Step E) occurs, and 4-O-benzyl-2,6-dideoxy-2-fluoro- α,β-L-talopyranose (belonging to the compound of formula (VI)) was obtained as a syrup or solid.

Example 17 1,3-di-O-acetyl-2,6-dideoxy-2-
Production of fluoro-α-L-talopyranose (compound 20a)

1,3-di-O-acetyl-4-O-benzyl-2,6-dideoxy-2- obtained in Example 16
31 mg of fluoro-α-L-talopyranose (compound 19a) was dissolved in 0.9 ml of a mixture of dioxane-acetic acid-water (10:1:1), and catalytic reduction was performed at normal pressure in the presence of palladium black. The benzyl group was removed. The title compound 20a was obtained by filtering the reaction solution and concentrating the filtrate under reduced pressure.
Obtained 21 mg (92%) as a hard syrup. [α]D21 -103° (c2, chloroform)

[
Example 18 1,3,4-tri-O-acetyl-2,6-dideoxy-2-fluoro-α-L-talopyranose (compound 21
a) Manufacture

20 mg of 1,3-di-O-acetyl-2,6-dideoxy-2-fluoro-α-L-talopyranose (compound 20a) obtained in Example 17 was dissolved in 0.3 ml of anhydrous pyridine. , 0.04 ml of acetic anhydride was added, and the mixture was allowed to stand at room temperature for 15 hours to carry out acetylation. After adding a small amount of water to the reaction solution, diluted with ethyl acetate, this solution was diluted with 2
The mixture was washed successively with a 0% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 23 mg (97%) of the title compound 21a as crystals. Melting point 101-102° [Literature value 1) 102-1
03°] [α]D23-108° (c0.6, chloroform) [
Literature value 1) 111° (c1, chloroform)] Literature 1)
(a) K. Ok, Y. Takagi, T. Tsuchi
ya, S. Umezawa and H. Umez
awa, “Carbohydrate Resear
Ch. ”, vol. 169, pp. 69-81, 1987
Year (b) JP-A-62-145097 Specification Reference Example 2-
(1) The H-NMR spectrum and 19F-NMR spectrum also completely matched the spectrum described in the above-mentioned document 1).

Example 19 1,3,4-tri-O-acetyl-2,6-dideoxy-2-fluoro-β-L-talopyranose (compound 21
b) Manufacture

4 of 1,3-di-O-acetyl-4-O-benzyl 2,6-dideoxy-2-fluoro-β-L-talopyranose (compound 19b) obtained in Example 16
8 mg was subjected to catalytic reduction under the same conditions as described in Example 17 to obtain 1,3-di-O-acetyl-2,6-dideoxy-2-fluoro-β-L-talopyranose (20b
) was obtained. This compound was acetylated under the same conditions as described in Example 18 to obtain 36 mg of the title compound 21b as a solid (87% yield from compound 19b). The 1H-NMR spectrum of the obtained compound completely matched the spectrum described in Example 18, Document 1(a).

Example 20 Preparation of 4-O-benzyl-1-O-tertiary butyldimethylsilyl-2,6-dideoxy-2-fluoro-L-talitol (compound 22a)

4-O-benzyl- obtained in Example 15
2,6-dideoxy-2-fluoro-L-talitol (
Compound 16a) and -D-allitol (Compound 16b)
) (3.2:1) was dissolved in a mixture of 2 ml of anhydrous dichloromethane and 0.2 ml of anhydrous pyridine,
To this solution, 113 mg of tertiary-butyldimethylsilyl chloride and 38 mg of N,N-dimethylaminopyridine were added, and the mixture was reacted at room temperature for 15 hours to perform the step of introducing a tertiary-butylditylsilyl group (step H). After adding a small amount of water to the reaction solution, it was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (developing system: hexane-ethyl acetate,
3:1) to obtain the title compound 22a,
Separation from the corresponding D-allitol derivative yielded 152 mg (66%) of the title compound 22a as a syrup. [α]D22 -6° (c0.7, chloroform) 1
9F-NMR spectrum (deuterochloroform, CFCl3
internal standard): δ -196.2 (dddd) JF, H-1 30
．． 5, JF, H-1' 23, JF, H-2 46
．． 5, JF, H-3 9Hz elemental analysis Theoretical value as C19H33FSiO4: C, 61.42; H, 8.95; F, 5.11
% Analysis value: C, 61.44; H, 8.86; F, 5.54
%

Example 21 Preparation of 4-O-benzyl-1-O-tertiary butyldimethylsilyl-2,6-dideoxy-2-fluoro-3,5-O-isopropylidene-L-talitol (compound 23)

4-O-benzyl-1-O-tertiary butyldimethylsilyl-2,6-dideoxy-2-fluoro-L
- 188 mg of Talitol (compound 22a) anhydrous 1,
Dissolve in 5 ml of 2-dichloroethane and add 2,2-
0.25 ml of dimethoxypropane and pyridinium p
- Add 38 mg of toluene sulfonate and heat at 60°C for 1.
After standing for 5 hours, isopropylidene groups were introduced (according to step I). After cooling the reaction solution to room temperature, chloroform was added, and the chloroform solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 200 mg of the title compound (
96%). 1H-NMR spectrum (deuterochloroform): δ 0
．． 06(6H,s,Si-CH3×20.90(9H,
s, Si-C-CH3 x 31.25 (3H, d, CH3
-6 1.32 and 1.39 (3H, s, CH3 of isopropylidene group, respectively)

Example 22 Preparation of 4-O-benzyl-2,6-dideoxy-2-fluoro-3,5-O-isopropylidene-L-talitol (compound 24)

4-O-benzyl-1-O-tertiary
203 mg of butyldimethylsilyl-2,6-dideoxy-2-fluoro-3,5-O-isopropylidene-L-talitol (compound 23) was mixed with 2.0 mg of tetrahydrofuran.
0.6 ml of 1 molar tetrabutylammonium fluoride-tetrahydrofuran solution at 0°C.
1 and left at the same temperature for 1 hour, the TBDMS group was eliminated (according to step J). The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing system: toluene-ethyl acetate, 5:1) to obtain 119 mg (81%) of the title compound 24 as crystals. Melting point 82-83°C [α]D23 -19° (c0.9, chloroform)

Example 23 Preparation of 4-O-benzyl-2,6-dideoxy-2-fluoro-L-talopyranose (Compound 25)

0116
] 4-O-benzyl-2,6-dideoxy-2-fluoro-3,5-O-isopropylidene- obtained in Example 22
103 mg of L-talitol (compound 24) was dissolved in a mixture of 1.8 ml of anhydrous benzene and 0.15 ml of anhydrous pyridine, and 0.4 ml of dimethyl sulfoxide, 214 mg of dicyclohexylcarbodiimide, and 33 mg of pyridinium trifluoroacetate were added thereto, and the mixture was stirred at room temperature for 1 hour. Stirring and oxidation of the hydroxymethyl group at position 1 (according to step K)
I did this. A dioxane solution of 90 mg of oxalic acid (0.5 mg) was added to the reaction solution containing the generated aldehyde compound (XI').
ml was added to decompose excess dicyclohexylcarbodiimide, and insoluble matter was removed by filtration and washed with benzene. A benzene solution obtained by combining the filtrate and the washing liquid was washed successively with a 10% aqueous potassium hydrogen sulfate solution and a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

1.7 ml of a water-dioxane (1:5.5) mixture containing 80 mmol of sulfuric acid was added to the residue, and the mixture was heated at 70°C to 1.7 ml.
The reaction was carried out for a period of time to remove the isopropylidene group and simultaneously cyclize to pyranose (according to step L). The reaction solution was neutralized by adding saturated aqueous sodium hydrogen carbonate solution, and then extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing system: chloroform-
Separation and purification with ethyl acetate (2:1) yielded the title compound 25.
62 mg (70%) of syrup was obtained as a mixture of α-L- and β-L-anomers. 1H-NMR spectrum (deuterochloroform): δ 1
．． 33 (d, α-L-anomer CH3-6) 1.38
(d, β-L-anomer CH3-6) 5.45 (dd
d, α-L-anomer H-1) J1,2 1.5,
J1,OH 4,J1,F 9Hz elemental analysis Theoretical value as C13H17FO4: C, 60.93; H, 6.68; F, 7.41
% Analysis value: C, 60.69; H, 6.64; F, 7.50
%

Further, when this compound 25 is subjected to catalytic reduction in the same manner as in Example 17 to eliminate the 4-O-benzyl group,
The desired 2,6-dideoxy-2-fluoro-L-talopyranose (Compound VII) was obtained.

Example 24 1,3-di-O-acetyl-4-O-benzyl-2,6
-dideoxy-2-fluoro-α-L-talopyranose (compound 19a) and 1,3-di-O-acetyl-4
-O-benzyl-2,6-dideoxy-2-fluoro-
Production of β-L-talopyranose (compound 19b)

01
20. 62 mg of 4-O-benzyl-2,6-dideoxy-2-fluoro-L-talopyranose (compound 25)
was dissolved in 2 ml of anhydrous pyridine, and 0.23 ml of acetic anhydride was added.
was added and left at room temperature for 15 hours to carry out acetylation. After adding a small amount of water, the mixture was diluted with ethyl acetate, and the solution was washed successively with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing system: hexane-acetone,
4:1) to obtain 64 mg (78%) of the α-L-anomer (Compound 19a) of the title compound as crystals and 12 mg (15%) of the β-L-anomer (Compound 19b) as a solid. Ta. α-L-anomer (compound 19a): Melting point 101-101.5°C [α]D21-90° (c2.8, chloroform) 1H
-NMR spectrum (deuterochloroform): δ 6.3
3 (1H, dd, H-1) 4.58 (1H, dddd,
H-2) 19F-NMR spectrum (deuterochloroform, CFCl
3 internal standard): δ -201.9 (ddd) JF, H-2 49,
JF, H-3 31.5, JF, H-1 8.5H
zβ-L-anomer (compound 19b): [α]D21 -10° (c1, chloroform) 1H
-NMR spectrum (deuterochloroform): δ 5.6
9 (1H, dd, H-1) 4.74 (1H, brd, H
-2) 19F-NMR spectrum (deuterochloroform, CFCl
3 internal standard): δ -218.7 (ddd) JF, H-2 51.
5JF, H-330.5, JF, H-1 19.5H
z

Example 25 4-O-benzyl-2,6-dideoxy, 1,3,5-tri-O-trimethylsilyl of 2-fluoro-L-talitol (compound 16a) and -D-allitol (compound 16b) reaction

L-talitol derivative (compound 16a) and D-talitol derivative (compound 1) obtained in Example 15
6b) was dissolved in 4.6 ml of anhydrous pyridine, and 0.8 ml of chlorotrimethylsilane was added to the mixture under ice cooling.
After adding 9 ml and 48 mg of 4-dimethylaminopyridine, the mixture was reacted at room temperature for 15 hours (Step M). The reaction solution was ice-cooled, water was added, and then extracted with ethyl acetate. The extract was dried using anhydrous sodium sulfate, concentrated under reduced pressure,
A mixture of 1,3,5-tri-O-trimethylsilyl compound (26a) and compound (26b) was obtained as a syrup.

Example 26 Selective oxidation reaction of the primary trimethylsilyloxymethyl group of compounds (26a) and (26b) and subsequent acid treatment to produce 1,3-di-O-acetyl-4-O-benzyl-2, 6
-Production of dideoxy-2-fluoro-α-L-talopyranose (compound 19a)

(a) Compound (26) obtained in Example 25
a) A selective oxidation reaction of the primary trimethylsilyloxymethyl group of the mixture of compound (26b) was carried out. i.e. 468 mg of chromium trioxide and 0.76 ml of pyridine
was added to 15.5 ml of anhydrous dichloromethane and stirred at room temperature for 30 ml.
The above compound (26a),
A solution prepared by dissolving the mixture of (26b) in 1.3 ml of anhydrous dichloromethane was added under ice cooling. After stirring for 1 hour under ice-cooling to perform the oxidation reaction of the trimethylsilyloxymethyl group at the 1st position (Step N), the reaction solution containing the two types of aldehyde compounds (27a) and (27b) produced was poured into silica gel. Pour onto a bed of water and filter. By concentrating the filtrate under reduced pressure, aldehyde compounds (27a) and (27b) [formula (XIII)] in which the 1-position was converted to an aldehyde group
, belonging to the compound of formula (XIII')] was obtained.

(b) This syrup was dissolved in 4 ml of a water-dioxane (1:5.5) mixture containing sulfuric acid at a concentration of 80 mmol, and treated with acid by reacting at 70° C. for 1 hour.
The trimethylsilyl group was removed and cyclization into a pyranose ring was performed (Step O). After the reaction solution containing the generated 4-O-benzyl-2,6-dideoxy-2-fluoro-L-talopyranose (Compound 17) was cooled to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added to neutralize it. After extraction with chloroform, the chloroform layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-O-benzyl-2,6-dideoxy-2-fluoro-L-talopyranose (compound 17a) and its 5- Epimer (
A syrup containing compound 17b) as the main component was obtained.

(c) This syrup is mixed with anhydrous pyridine 3.6
ml, add 0.74 ml of acetic anhydride, and stir at room temperature for 15 minutes.
Acetylation was carried out by standing for a period of time (part of step D). After adding water to the reaction solution containing the acetylated sugar produced, it was extracted with ethyl acetate, and the extract was washed sequentially with a 20% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and water, and then extracted with anhydrous sodium sulfate. and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (
Separation and purification with a developing system: hexane-ethyl acetate, 3:1) yielded 94 mg of the title compound 19a (compounds 16a and 16
A yield of 36% was obtained from the mixture of b. The physical constants and NMR spectrum of the obtained compound 19a are as shown in Example 24.
These values were consistent with those of compound 19a obtained in .

[0127] In this example, the overall yield was more than three times that of Example 16. Also compounds 16a and 16b
Examples 20, 21, 22, 23, 24 using a mixture of
Compound 1 via (according to the route of synthesis process chart 4)
Compared to the case of synthesizing 9a, the number of steps was fewer and the overall yield was also improved.

Example 27 2,6-dideoxy-2-fluoro-L-talitol (
Preparation of a mixture of compound 28a) and 2,6-dideoxy-2-fluoro-D-allitol (compound 28b)

[
4-O-benzyl-2 obtained in Example 15
, 6-dideoxy-2-fluoro-L-talitol (compound 16a) and 4-O-benzyl-2,6-dideoxy-2-fluoro-D-allitol (compound 16b)
41 mg of a mixture of dioxane-acetic acid-water (10:1:
The mixture was dissolved in 4 ml of the mixture of 1) and subjected to catalytic reduction with hydrogen gas at normal pressure in the presence of palladium black for 3 hours to remove the benzyl group. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of the title compound as a syrup of 23 m
g (87%) was obtained. Since this mixture could not be separated into its component isomers by silica gel column chromatography, it could be considered to be a hexitol derivative, which is a single compound represented by the above formula (IIIc). 1H-NMR spectrum (heavy methanol): δ 1.
21 (Me of d,L-talitol derivative) J5,66.
5Hz δ 1.20 (Me of d,D-allitol derivative)J
5,6 6.5Hz 19F-NMR spectrum (heavy methanol, CFCl3
internal standard):

Claims (5)

[Claims] Claim 1: A compound of the following formula [wherein Me is a methyl group, R1 is a benzyl group, allyl group, lower alkanol group or benzoyl group, and R
2 is a methyl group or an ethyl group] methyl or ethyl 3-0-protected-1,5-dideoxy-5-fluoro-α-L-psychopyranoside is acid-hydrolyzed to form the following formula [where Me and R1 has the same meaning as above] 3-0-
Protected-1,5-dideoxy-5-fluoro-α,β-L
- Step (A) of producing psychopyranose and formula (II
) by reducing the compound with a reducing agent selected from alkali metal borohydride, lithium aluminum hydride and dialkylaluminium hydride to open the ring to form the compound of the following formula [wherein Me and R1 have the same meanings as above]. 4-
O-protected-2,6-dideoxy-2-fluoro-L-talitol and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allitol, a step (B) of producing a mixed stereoisomer mixture from a compound of formula (III) and a compound of formula (III');
) 1-position hydroxymethyl group (-CH2OH) of the compound
is oxidized with tris(trisphenylphosphine)ruthenium(II) halide as an oxidizing agent, thereby converting it into an aldehyde group (-CHO) and simultaneously converting it into the hemiacetal ring between the aldehyde group and the hydroxyl group at the 5-position. With cyclization by formation reaction, 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-L-talopyranose and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allopyranose, a step (C) of producing a hybrid stereoisomer mixture from the compound of formula (IV) and the compound of formula (IV 1-position hydroxyl group and 3-position hydroxyl group of each compound of formula (IV') are acylated with a lower alkanoyl group or benzoyl group, and the resulting acylated product of the compound of formula (IV) and the compound of formula (IV') are acylated. The following formula [wherein M
4-O-protected-1,3-di-O-acyl-2,6, where e and R1 have the same meanings as above, and R3 is an acyl group selected from the lower alkanoyl group and benzoyl group used. Step (D) of isolating -dideoxy-2-fluoro-α,β-L-talopyranose and hydrolysis or alcoholysis of the compound of formula (V) to remove the acyl group (R3) from the compound of formula (V). Alternatively, both the acyl group (R3) and the group R1 in the case of an acyl group are eliminated, thereby producing 4-O of the following formula [wherein Me is a methyl group and R1a is the same as R1 or is hydrogen] -Protected or non-protected-2,6-
and a step (E) of producing dideoxy-2-fluoro-α,β-L-talopyranose.
A method for producing 4-O-protected or unprotected-2,6-dideoxy-2-fluoro-α,β-L-talopyranose of formula (VI). [Claim 2] The following formula [wherein Me is a methyl group, R1 is a benzyl group, allyl group, lower alkanol group or benzoyl group, and R2
is a methyl group or an ethyl group]
3-O-protected-1,5-dideoxy-5-fluoro-
3-O-protected-1,5-dideoxy-5-fluoro-α,β-L of the following formula [wherein Me and R1 have the same meanings as above] is obtained by acid hydrolysis of α-L-psychopyranoside. −
Step (A) of producing psicopyranose and formula (II)
By reducing the compound with a reducing agent selected from alkali metal borohydride, lithium aluminum hydride and dialkyl aluminum hydride, the ring is opened to obtain 4 of the following formula [wherein Me and R1 have the same meanings as above] −
O-protected-2,6-dideoxy-2-fluoro-L-talitol and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allitol, a compound of formula (III) in the mixture and a compound of formula (III') ) of the 1-position hydroxymethyl group (-
The hydroxyl group in CH2OH) is selectively protected with a tertiary-butyl-di(lower) alkylsilyl group or a tertiary-butyl-diphenylsilyl group to form the following formula [where Me and R1 have the same meaning and R4 is tertiary-butyl]. -di(lower)alkylsilyl group or tertiary butyl-diphenylsilyl group]
4-O-protected-2,6-dideoxy-2-fluoro-L
-Talitol and 1-O-protection-4-O-protection-2,6-
A mixed stereoisomer mixture is produced from dideoxy-2-fluoro-D-allitol, and the mixture is then subjected to chromatographic separation to produce the following formula [wherein Me, R1 and R4 have the same meanings as above]
1-O-protected-4-O-protected-2,6-dideoxy-
Step (H) of isolating 2-fluoro-L-talitol, and simultaneously using an alkylidene group, cycloalkylidene group, or benzylidene group as a divalent hydroxyl protecting group for the 3-position hydroxyl group and the 5-position hydroxyl group of the compound of formula (VIII) Or protected with a tetrahydropyranylidene group to form the following formula [wherein, Me
, R1 and R4 have the same meanings as above, and R5 is an alkylidene group, a cycloalkylidene group, a benzylidene group, or a tetrahydropyranylidene group]. )-2,6-dideoxy-2-fluoro-3,
Step (I) of producing 5-O-protected-L-talitol and reacting the compound of formula (IX) with tetrabutylammonium fluoride or a mixture of tetrabutylammonium chloride and potassium fluoride to form the 1-position hydroxyl group. The protecting group (R4) is selectively removed, thereby providing 4-O-protected-2,6 of the following formula [wherein Me, R1 and R5 have the same meanings as above].
-dideoxy-2-fluoro-3,5-O-protected-L-
Step (J) of producing Talitol and oxidizing the hydroxymethyl group (-CH2OH) at the 1-position of the compound of formula (X) to an aldehyde group (-CHO) to form the following formula [where Me, R1 and R5 are has the same meaning as above]
Step (K) of producing an aldehyde compound of formula (XI
) to form a hydroxyl protecting group (R5)
or leaving off the group R5 and the group R1 and combining it with 1
With cyclization by a hemiacetal ring formation reaction between the aldehyde group at position and the deprotected hydroxyl group at position 5, the following formula [where Me is a methyl group and R1a is the same as R1 or hydrogen] ] of 4-O-protected or unprotected-2,6-
A step (L) of producing dideoxy-2-fluoro-α,β-L-talopyranose,
A method for producing 4-O-protected or unprotected-2,6-dideoxy-2-fluoro-α,β-L-talopyranose of formula (VI). 3. The following formula [wherein Me is a methyl group, R1 is a benzyl group, allyl group, lower alkanol group or benzoyl group, and R
2 is a methyl group or an ethyl group], methyl or ethyl 3-O-protected-1,5-dideoxy-5-fluoro-α-L-psychopyranoside was acid-hydrolyzed to form the following formula [where Me and R1 has the same meaning as above] of 3-O-
Protected-1,5-dideoxy-5-fluoro-α,β-L
- Step (A) of producing psychopyranose and formula (II
) by reducing the compound with a reducing agent selected from alkali metal borohydride, lithium aluminum hydride and dialkylaluminium hydride to open the ring to form the compound of the following formula [wherein Me and R1 have the same meanings as above]. 4-
O-protected-2,6-dideoxy-2-fluoro-L-talitol and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allitol, a compound of formula (III) in the mixture and a compound of formula (III') ) of the 1-position hydroxymethyl group (-
The hydroxyl group, the 3rd-position hydroxyl group, and the 5th-position hydroxyl group in CH2OH) are protected with a trimethylsilyl group or a triethylsilyl group to form the following formula [where Me and R1 have the same meanings as above, and Y is a trimethylsilyl group or a triethylsilyl group. ] of 4
-O-protected-1,3,5-tri-O-silyl-2,6-
Dideoxy-2-fluoro-L-talitol and 4-O-protected-1,3,5-tri-O-silyl-2,6- of the following formula [wherein Me and Y have the same meanings as above] dideoxy-2-fluoro-D-allitol, and converting the compound of formula (XII) and the compound of formula (XII') in the mixture to chromium trioxide ( CrO3)-pyridine complex to form the formula (
The trimethylsilyloxymethyl group at position 1 or the triethylsilyloxymethyl group at position 1 of each compound of XII) and (XII') is oxidized to an aldehyde group (-CHO), whereby the following formula [wherein Me, R1 and Y has the same meaning as above] and 4-O-protected-2,6-dideoxy-2-fluoro-3,5-di-O-silyl-aldehyde-L-talose and the following formula [wherein, Me, R1 and Y have the same meanings as above] 4-O-protected-2,6-dideoxy-2-fluoro-3,5-di-O-silyl-aldehyde-D-allose step (N) of producing a stereoisomer mixture of
) and simultaneously with the formation of a hemiacetal ring between the 1-position aldehyde group and the deprotected 5-position hydroxyl group, the following formula [wherein Me and R1 have the same meanings as above] ] No. 4-
O-protected-2,6-dideoxy-2-fluoro-L-talopyranose and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allopyranose, a step (O) of producing a hybridized stereoisomer mixture from a compound of formula (IV) and a compound of formula (IV) in the mixture; 1-position hydroxyl group and 3-position hydroxyl group of each compound of formula (IV') are acylated with a lower alkanoyl group or benzoyl group, and the resulting acylated product of the compound of formula (IV) and the compound of formula (IV') are acylated. The following formula [wherein M
4-O-protected-1,3-di-O-acyl-2,6, where e and R1 have the same meanings as above, and R3 is an acyl group selected from the lower alkanoyl group and benzoyl group used. Step (D) of isolating -dideoxy-2-fluoro-α,β-L-talopyranose and hydrolysis or alcoholysis of the compound of formula (V) to remove the acyl group (R3) from the compound of formula (V). Alternatively, both the acyl group (R3) and the group R1 in the case of an acyl group are eliminated, thereby forming 4- of the following formula [wherein Me is a methyl group and R1a is the same as R1 or hydrogen] O-protected or unprotected-2,6
-dideoxy-2-fluoro-α,β-L-talopyranose. A method for producing -2-fluoro-α,β-L-talopyranose. 4. The following formula [wherein Me is a methyl group, and R1 is a benzyl group, allyl group, lower alkanoyl group or benzoyl group]
1,5-dideoxy-5-fluoro-α,β-L-psychopyranose was heated at -30°C to
characterized in that it consists of reduction with lithium borohydride or sodium borohydride or potassium borohydride or both sodium borohydride and lithium chloride or lithium aluminum hydride at a temperature of 50° C. 4-O of [Me and R have the same meanings as above]
-Protected-2,6-dideoxy-2-fluoro-L-talitol and 4- of the following formula [wherein Me and R1 have the same meanings as above]
O-protected-2,6-dideoxy-2-fluoro-D-allitol and a stereoisomer mixture containing the compound of formula (III) in a proportion of 3 times or more that of the compound of formula (III'). Production method. 5. 4 of the following formula [wherein Me is a methyl group and R is hydrogen, a benzyl group, an allyl group, an acetyl group, or a benzoyl group]
-O-protected or unprotected-2,6-dideoxy-2-fluoro-L-talitol and 4-O of the following formula [wherein Me and R have the same meanings as above]
- protected or unprotected -2,6-dideoxy-2-fluoro-D-allitol, which is a mixture of mutually inseparable stereoisomers of the following general formula [wherein Me and R are A hexitol derivative represented by