JPH0525192A - Beta-d-glucose - Google Patents

Abstract

PURPOSE:To provide a novel beta-D-glucose having an antitumor activity, useful as an intermediate for synthesizing a carcinostatic agent: etoposide, and giving the easily purified etoposide in a high purity and a good yield. CONSTITUTION:beta-D-Glucose of formula I [R1 is COCHX2. COCX3 (X is halogen)@{947/28}, e.g. 4,6-O-ethylidene-1-O-benzyloxycarbonyl-2,3-di-O- dichloroacetyl-beta-D-glucopyranose. The compound of formula I is produced, e.g. by reacting 4,6-O-ethylidene-1-O-benzyloxycarbonyl-beta-D-glucopyranose with dihalogeno or trihalogenoacetyl chloride, etc., in an inert solvent such as dichloroethane and subsequently hydrogenatingly demasking the produced compound of formula III in the presence of palladium black, etc., in a solvent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to β-D-glucose represented by the following formula (6) which is useful as an intermediate for etoposide. Etoposide exhibits antitumor activity and is a useful substance as a carcinostatic agent.

2. Description of the Related Art As a method for producing the compound (1), the following steps are already known. (Japanese Patent Publication No. 46-378
(See Japanese Patent No. 37)

[0002]

[Chemical 2]

(In the formula, A represents formyl or acetyl, and B represents benzyloxycarbonyl.)

However, the above-mentioned method requires two steps of removing A and then B, and the removal of A takes a long time (for example, 20 to 30).
However, the quality of the obtained etoposide is poor and the yield is low.

The inventors of the present invention have made various investigations on new methods for producing etoposide, and as a result, formula (3) obtained by using di- or trihalogenoacetyl halides has been investigated.

[0004]

[Chemical 3]

[Wherein R ₁ and R ₂ are the same or different and are represented by the formula-
COCHX ₂ or —COCX ₃ (wherein X represents a halogen atom) is shown. ] When a compound represented by the following formula is reacted with alcohols, amines and / or ammonia, R ₁
And R ₂ are removed at once to obtain etoposide,
The obtained etoposide was found to have few impurities and to be easily purified.

[0006]

[Chemical 4]

[Wherein R ₁ is --COCHX ₂ or --CO
CX ₃ (X represents a halogen atom) is shown. ] The β-D-glucose represented by the formula] was found to be useful as an intermediate for etoposide. In the above formula (6),
Examples of X in R ₁ include fluorine, chlorine, bromine, iodine and the like, but chlorine or bromine is practically preferable. Examples of R ₁ include difluoroacetyl, dichloroacetyl, dibromoacetyl, diiodoacetyl, trifluoroacetyl, trichloroacetyl, tribromoacetyl, triiodoacetyl and the like.

The compound (6) is a novel compound,
For example, the known 4,6-O-ethylidene-1-O-benzyloxycarbonyl-β-D-glucopyranose (7) is used as a starting material and is synthesized through the following reaction route.

[0009]

[Chemical 5]

(In the formula, R ₁ is the same as above.)
4,6-O-ethylidene-1-O-pentyloxycarbonyl-β-D-glucopyranoose (7) obtained by reacting dihalogeno or trihalogenoacetyl chloride in an inert solvent -Ethylidene-1-O-
Compound (6) can be obtained by hydrogenolysis of benzyloxycarbonyl-2,3-di-O-halogenoacetyl-β-D-glucopyranose (8). Although a small amount of α-form is inevitable during the hydrogenolysis, only β-form of compound (6) crystallizes selectively from the reaction solution, and therefore α-form and β-form are separated. Has the property that it is easy. In addition, β- of compound (6)
Since the body has good stability and almost no isomerization to the α-form is observed, it can be stored for a long period of time.

[0011]

【Example】

 Example 1 (a) 4,6-O-ethylidene-1-O-benzyloxy
Cycarbonyl-2,3-di-O-dichloroacetyl-β
-D-glucopyranose (8) (R₁= COCHC
l₂) 4,6-O-Ethylidene-1-O-benzyloxycal
34.0 g of bonyl-β-D-glucopyranose (7)
Suspended in 340 ml of 1,2-dichloroethane, pyridine
After adding 23.7 g, cool to 0-5 ° C. Jiku
Add 32.4 g of loroacetyl chloride over about 1 hour.
After dropping, the stirring is continued for another 0.5 hour. Then the reaction liquid
Washed with water, dried the organic layer over anhydrous magnesium sulfate, and then reduced.
Compound (8) (R₁= COCHCl₂) 5
1.0 g was obtained (yield 90.7%). m. p. 150-151 ° C IR ν_max(KBr) 1770, 1255, 1100, 820cm^-1  (B) 4,6-O-ethylidene-2,3-di-O-dicu
Loloacetyl-β-D-glucopyranose (6) (R₁
= COCHCl₂) Compound (8) (R₁= -COCHCl₂) 10.0 g
Dissolve in 50 ml of acetone and add 1.0 g of palladium black.
Then, hydrogenolysis is performed under pressure at -5 to 10 ° C. End of reaction
After completion, the catalyst is filtered off and the solvent is distilled off under reduced pressure. Di residue
Add 17 ml of isopropyl ether, cool to 0 ° C, and suck.
Compound (6) (R₁= -COCHCl₂)
7.3 g was obtained (yield 95.9%). m. p. 133-135 ° C IR ν_max(KBr) 3445, 1775, 1305, 1165, 1095, 10
05, 815cm^-1

Example 2 (a) 4,6-O-ethylidene-1-O-benzyloxycarbonyl-2,3-di-O-dibromoacetyl-β
-D- glucopyranose - scan (8) (R ₂ = COCHB
r ₂ ) 4,6-O-ethylidene-1-O-benzyloxycarbonyl-β-D-glucopyranose (7) (5.1 g) was suspended in 51 ml of 1,2-dichloroethane to prepare pyridine.
After adding 6 g, cool to 0-5 ° C. 7.8 g of dibromoacetyl chloride was added dropwise thereto over about 1 hour, and stirring was continued for another 30 minutes. Then, wash the reaction solution with water,
The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to 25 ml to give compound (8) ((R ₁
= COCHBr ₂₎ of 1.2 to obtain a dichloroethane solution. (B) 4,6-O-ethylidene-2,3-di-O-dipromoacetyl-β-D-glucopyranose (6) (R ₁
= -COCHBr ₂₎ Compound _{(8) (R 1 = -COCHBr} 2) 1,2-dichloroethane solution 25ml to hydrogenation at -10 to-5 ° C. by the addition of palladium black 0.4g under pressure of (a) I do. After completion of the reaction, the catalyst was filtered off and the compound (6) (R ₁ =-
A 1,2-dichloroethane solution of COCHBr ₂ ) was obtained.

Example 3 (a) 4,6-O-ethylidene-1-O-benzyloxycarbonyl-2,3-di-O-trichloroacetyl-
β-D-glucopyranose (8) (R ₁ = -COCCl
₃ ) Using 2.5 g of trichloroacetyl chloride instead of dibromoacetyl chloride in Example 2 (a), 25 ml of a 1,2-dichloroethane solution of compound (8) (R ₁ = COCCl ₃ ) was obtained. (B) 4,6-O-ethylidene-2,3-O-trichloroacetyl-β-D-glucopyranose (6) (R ₁ =
-COCCl ₃₎ using the resulting solution 25ml in (a), to obtain a 1,2-dichloroethane solution 25ml of compound in the same manner as in Example 2 (6) (6) ( R 1 = -COCCl 3).

Reference Example (a) 4'-Dichloroacetyl-4'-demethyl-epi
Podophyllotoxin (5) (R₂= COCHCl₂) 4'-demethyl-epipodophyllotoxin (4) 8 g
Dissolve in 160 ml of acetone and add 3.2 g of pyridine.
After that, it is cooled to -5 to -10 ° C. Dichloro acetyl
4.1 g of luchloride was added dropwise over about 1.5 hours, and
Stir for 0.5 hours. Then, distill off acetone under reduced pressure.
The solid obtained was removed and 1,2-dichloroethane (160 m)
It is dissolved in 1 and washed with water. Then this 1,2-dichloro
The ethane solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
Compound (5) (R₂= -COCHCl₂) 9.5
g was obtained (yield 93.4%). m. p. 207-208 ° C IR ν_max(KBr) 3540, 1775, 1600, 1485, 1235, 1
130 cm^-1  (B) 4'-dichloroacetyl-4'-demethyl-epi
Podophyllotoxin-β-D-2,3-di-O-diclo
Roacetyl-4,6-O-ethylidene glucoside (3)
(R₁, R₂= -COCHCl₂) Compound (5) (R₂= -COCHCl₂) 3.0 g
Dissolve in 60 ml of 1,2-dichloroethane, then combine
Thing (6) (R₁= -COCHCl₂) Add 2.5g
Cool to -10 ° C. Boron trifluoride ethyl ether
1.1g was added dropwise over about 1.5 hours, and after the completion,
Continue stirring for 0.5 hour. Pyridine 0.8g inside temperature -5
While maintaining at -10 ℃, add water and wash.
It After drying the organic layer over anhydrous magnesium sulfate,
Concentrate and recrystallize the residue from methanol to give compound (3)
(R₁, R₂= -COCHCl₂) 4.4 g were obtained (yield
81.4%). m. p. 207-208 ° C (c) 4'-dichloroacetyl-4'-demethyl-epi
Podophyllotoxin-β-D-2,3-di-O-diclo
Roacetyl-4,6-O-ethylidene glucoside (3)
(R₁, R₂= -COCHCl₂) 1 g and ammonium acetate
1 g of um was dissolved in 20 ml of methanol, and 1.5 was dissolved at room temperature.
Stir for hours. After completion of the reaction, concentrate methanol to 10 ml.
0.55 g of crystals of etoposide after shrinking and cooling
Was obtained (yield 86.1%). Rf value of TLC of the crystals obtained here (silica gel, developed solution)
Medium chloroform: methanol = 9: 1), IR, NMR
And the optical rotation are obtained by the method of Japanese Examined Patent Publication No. 46-37837.
It was identical to that of the substance given. m. p. 259 to 260 ° C., Rf = 0.44

[0015]

[Effect] As is apparent from the above reference example, β-D of the present invention
-By using glucose, etoposide can be obtained with high purity and high yield in a small number of steps.

Claims (1)

What is claimed is: Claims 1 Wherein, R ₁ is -COCHX ₂ or -COCX ₃ (X in. Which a halogen atom) shows a. ] -D represented by
-Glucose