JPH032875B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a raw material for producing a substance useful as an anticancer agent in good yield.

(Prior art) As a method for producing 4'-demethyl-epipodophyllotoxin-β-D-ethylidene glycoside, which is a compound useful as an anticancer agent,
No. 38258 and Special Publication No. 46-37837 are known.

(Problems to be Solved by the Invention) However, in these methods, since the protecting group of the aglycone and that of the sugar are different, two steps are required for their removal. That is, aglycone 4
Hydrogenolysis is carried out using palladium-carbon as a catalyst to remove the benzyloxycarbonyl group which is the protective group at position ', and zinc acetate is used to remove the acetyl or formyl group which is the sugar protective group. In particular, the removal of sugar protecting groups requires high temperatures and long periods of time; for example, the reaction is not completed even after 20 to 30 hours, and further reaction increases by-products, resulting in lower yields and lower industrial performance. This is not a good manufacturing method.

(Means for Solving the Problems) Therefore, the present inventors conducted various studies to overcome the above-mentioned drawbacks, and found that by reacting a specific raw material compound with an amine and/or ammonia at 0° to room temperature for several hours, Protecting groups at the 4'-position of the aglycone and the 2- and 3-positions of the sugar can be removed all at once and safely, allowing highly purified 4'-demethyl-epipodophyllotoxin-β-D-ethylidene glucoside to be produced in high yield. The present invention was completed based on the discovery that the present invention can be obtained.

That is, the present invention provides 4'-halogenoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,
Regarding 3-di-O-halogenoacetyl-4,6-O-ethylidene glucoside (), the halogenoacetyl group is removed by reacting it with an amine and/or ammonia to produce 4'-demethyl-epipodophyllotoxin- β-D-ethylidene glucoside ().

[In the formula, R represents a halogenoacetyl group represented by -COCH ₂ X (in the formula, X represents a halogen)]
The compound represented by the above formula () is called VP16-213, and is a substance useful as an anticancer agent that exhibits antitumor activity.

In the present invention, the 4′ position of the aglycone and the 2′ position of the sugar
The halogenoacetyl groups R at the positions R and 3 may be the same or different. Examples of the halogen for X include chlorine and bromine.

The amines to be reacted with the compound () include aliphatic primary amines such as methylamine, ethylamine, n-propylamine, and n-butylamine;
Examples include aliphatic secondary amines such as dimethylamine, diethylamine, di-n-propylamine, and di-n-butylamine, cyclic amines such as pyrrolidine, piperidine, and morpholine, and aliphatic diamines such as ethylenediamine. When using these amines and/or ammonia, it is natural that they may be added to the reaction system as they are, but
For example, in the presence of a base such as pyridine or triethylamine, an acetate or hydrochloride of an amine and/or ammonia may be added to prepare a free amine and/or ammonia in the reaction system, and the reaction may be performed. The amount used is 3 to 3 for the compound ()
A ratio of 10 moles is appropriate.

The reaction temperature can vary depending on the type of amine.
A temperature of 10 to 100°C is preferred, and a temperature of 0 to 70°C is particularly suitable. The time required for the reaction varies depending on the type of amine and the reaction temperature, but is usually 0.5 to 5 hours.

The solvent to be used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include chloroform, ethylene chloride, methanol, ethanol, and pyridine.

According to this method, the halogenoacetyl group R can be easily removed in a short time and under mild conditions, and compound () can be obtained from compound () in high yield. Therefore, purification after the completion of the reaction is easy; for example, pure compound (2) can be obtained by simply washing the reaction solution with water and performing simple recrystallization, making this method extremely advantageous as an industrial production method.

The compound of formula () of the present invention
4′-demethyl-epipodophyllotoxin () obtained from podophyllotoxin, an antitumor active substance produced by Podophyllumemodi Wall
6469) as a raw material, it is synthesized, for example, through the following reaction history.

[In the formula, R is the same as above] That is, 4'-halogenoacetyl- obtained by reacting 4'-demethyl-epipodophyllotoxin () with halogenoacetyl chloride in an inert solvent.
4'-Demethyl-epipodophyllotoxin (2018) was dissolved in 4,6-O-ethylidene-2,3-di-O in an inert solvent in the presence of boron trifluoride ethyl etherate at a temperature below 0°C. -halogenoacetyl-β-
Compound () is obtained by condensation with D-glucopyranose (). Here, compound () is a new compound, 4,6-ethylidene-1-O-benzyloxycarbonyl-β-D-
It is synthesized using glucopyranose () as a raw material, for example, through the following reaction route.

[In the formula, R is the same as above] That is, obtained by reacting 4,6-O-ethylidene-1-O-benzyloxycarbonyl-β-D-glucopyranose () with halogenoacetyl chloride in an inert solvent. 4,6-O-ethylidene-1-O-benzyloxycarbonyl-2,3
Compound () is obtained by hydrogenolyzing -di-O-halogenoacetyl-β-D-glucopyranose ().

(Example) The present invention will be specifically described below with reference to Examples.

Example 1 4'-demethyl-epipodophyllotoxin-β-
Process for producing D-ethylidene glucoside () 4'-chloroacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-O-chloroacetyl-4,6-O-ethylidene glucoside () (R=-COCH ₂ Cl) 8.2g pyridine 50
ml and cooled to 0°C. 70% ethylamine
Add 4.5g dropwise and stir at 0°C for 1 hour. After the reaction is complete, add 200 ml of chloroform, neutralize with 2N hydrochloric acid, wash with water, and dry over anhydrous sodium sulfate. The crude crystals obtained by distilling off the solvent under reduced pressure were recrystallized from chloroform to obtain 4.9 g of crystals. (Yield 83.1%) Rf value of TCL of the crystal obtained here (silica gel,
Developing solvent chloroform:methanol=9:1),
IR, NMR, and optical rotation were the same as those of the material obtained by the method of Japanese Patent Publication No. 46-37837.

mp259-262℃, Rf=0.44 Example 2 4'-demethyl-epipodophyllotoxin-β-
Method for producing D-ethylidene glucoside () In Example 1, the reaction was carried out in the same manner as in Example 1 using 4.5 g of pyrrolidine instead of ethylamine, to obtain 4.6 g of compound (). (yield
78.0%) Example 3 4'-demethyl-epipodophyllotoxin-β-
Method for producing D-ethylidene glucoside (2) A reaction was carried out in the same manner as in Example 1 except that 2.0 g of 98% ethylenediamine was used in place of ethylamine to obtain 4.9 g of compound (2). (Yield 83.1%) Example 4 4'-demethyl-epipodophyllotoxin-β-
Method for producing D-ethylidene glucoside () 8.2 g of compound () (R=-COCH ₂ Cl) was dissolved in a mixed solvent of 150 ml of chloroform and 50 ml of methanol, 6.6 g of diethylamine was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was treated in the same manner as in Example 1 to obtain 3.6 g of compound (). (Yield 61.0%) Example 5 4'-demethyl-epipodophyllotoxin-β-
Method for producing D-ethylidene glucoside () 8.2 g of compound () (R=-COCH ₂ Cl) is suspended in 150 ml of methanol, 10 ml of pyridine and 5.0 g of ammonium acetate are added, and the mixture is refluxed for 1 hour. After methanol was distilled off under reduced pressure, the residue was treated in the same manner as in Example 1 to obtain 4.5 g of compound (). (Yield 76.3%) Example 6 4'-demethyl-epipodophyllotoxin-β-
Method for producing D-ethylidene glucoside () Dissolve 8.2 g of compound () (R=-COCH ₂ Cl) in a mixed solvent of 150 ml of chloroform and 50 ml of methanol, add 10 ml of triethylamine and 3.5 g of ammonium chloride, and stir at room temperature for 4 hours. . After the reaction was completed, the same treatment as in Example 1 was carried out to obtain the compound ().
4.9g was obtained. (Yield 83.1%) Example 7 4'-demethyl-epipodophyllotoxin-β-
Method for producing D-ethylidene glucoside () In Example 6, the compound () (R=-
4'-bromoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2 instead of COCH ₂ Cl),
3-di-O-bromoacetyl-4,6-O-ethylidene glucoside () (R=-COCH ₂ Br) 9.5
When the reaction was carried out in the same manner as in Example 6 using g, 4.8 g of compound () was obtained. (Yield 81.8%) Example A 4'-chloroacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-O-chloroacetyl-4,6-O-ethylidene glucoside ( ) (R=-COCH ₂ Cl) (a) Process for producing 4'-chloroacetyl-4'-demethyl-epipodophyllotoxin () (R=-COCH ₂ Cl) 4'-demethyl-epipodophyllotoxin Irotoxin ()
40.0 g was suspended in 750 ml of anhydrous ethylene chloride, and 11.9 g of anhydrous pyridine was added thereto, followed by cooling to -20°C.
15.4 g of 95% chloroacetyl chloride was added dropwise to this solution over a period of 1.5 hours, and the mixture was further stirred for 0.5 hour. After the reaction is completed, the reaction solution is washed with water and the organic layer is dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from methanol to obtain 43.4 g of compound () (R=-COCH ₂ Cl). (yield
91.1%) mp238~240℃ IRν ^KBr _nax 3550, 1783, 1765 (sh), 1483, 1230,
1130cm ^-1 (b) 4,6-O-ethylidene-1-O-benzyloxycarbonyl-2,3-di-O-chloroacetyl-β-D-glucopyranose () (R
=-COCH ₂ Cl) 51.0 g of 4,6-O-ethylidene-1-O-benzyloxycarbonyl-β-D-glucopyranose () was suspended in 500 ml of anhydrous chloroform, and 35.6 g of anhydrous pyridine was added. Cool to 0°C. Add 42.8g of 95% chloroacetyl chloride to this solution.
After the dropwise addition over a period of time, the mixture was stirred at room temperature for 0.5 hour. After the reaction is completed, the reaction solution is washed with water and the organic layer is dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from isopropyl ether to obtain 66.6 g of compound () (R=-COCH ₂ Cl). (Yield 90.1%) mp130-131℃ IRν ^KBr _nax 1765, 1255, 1098, 700cm ^-1 (c) 4,6-O-ethylidene-2,3-diO-
Method for producing chloroacetyl-β-D-glucopyranose () (R=-COCH ₂ Cl) 49.3 g of the compound () (R=-COCH ₂ Cl) was dissolved in 500 ml of dry acetone, and 10% palladium-carbon was added.
Add 10g and perform hydrogenation at -10 to 15°C under normal pressure. After the reaction is complete, separate the catalyst and add 100ml of dry acetone.
After washing with
35.6 g of -COCH ₂ Cl) were obtained as a white foam.
(Yield 99.2%) IRν ^CHCl3 _nax 3600, 1765, 1282, 1130, 1095 cm ^-1 (d) 4'-chloroacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di- O-
Method for producing chloroacetyl-4,6-O-ethylidene glucoside () (R=-COCH ₂ Cl) 11.9 g of compound () (R=-COCH ₂ Cl) was dissolved in 150 ml of anhydrous ethylene chloride, and then compound ()
Add 9.9 g (R=-COCH ₂ Cl) and cool to -20°C. After 5.3 g of boron trifluoride ethyl etherate was added dropwise, the mixture was stirred at -20°C for 0.5 hour. After the reaction is complete, 4.0 g of pyridine is added dropwise, the reaction solution is washed with water, and the organic layer is dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from methanol to obtain 16.4 g of compound () (R=-COCH ₂ Cl). (Yield 80.3%) mp244-246℃ IRν ^KBr _nax 1775, 1601, 1483, 1232, 1126cm ^-1 Example B 4'-bromoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2, Process for producing 3-di-O-bromoacetyl-4,6-O-ethylidene glucoside () (R=-COCH ₂ Br) (a) 4'-bromoacetyl-4'-demethyl-epipodophyllotoxin () (R= _-COCH2Br )
The crude product obtained in Example A-(a) using 20.9 g of 98% bromoacetyl chloride in place of chloroacetyl chloride was recrystallized from benzene to obtain the compound () (R=-COCH ₂ Br) 47.0g was obtained. (yield
90.2%) mp220~222℃ IRν ^KBr _nax 3540, 1782, 1765, 1601, 1483, 1232,
1124 cm ^-1 (b) 4,6-O-ethylidene-1-O-benzyloxycarbonyl-2,3-di-O-bromoacetyl-β-D-glucopyranose () (R
=-COCH ₂ Br) Preparation method In Example A-(b), 98% bromoacetyl chloride (53.0 g) was used instead of chloroacetyl chloride to obtain 76.2 g of compound () (R=-COCH ₂ Br). (Yield 87.3%) mp140-142℃ IRν ^KBr _nax 1770, 1760, 1243, 1122cm ^-1 (c) 4,6-O-ethylidene-2,3-di-O-
Process for producing bromoacetyl-β-D-glucopyranose () (R=-COCH ₂ Br) In Example A-(c), compound () (R=-
COCH ₂ Cl) instead of compound ()(R=-
_Compound () (R=-
Obtained as a foam using 44.4 g of COCH ₂ Br). (Yield 98.9%) IRν ^CHCl3 _nax 3575, 1758, 1275, 1125, 1095 cm ^-1 (d) 4'-bromoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di- O-
Process for producing bromoacetyl-4,6-O-ethylidene glucoside () (R=-COCH ₂ Br) In Example A-(d), compound () (R=-
COCH ₂ Cl) instead of compound ()(R=-
Using 13.0 g of COCH ₂ Br), compound () (R=-
COCH ₂ Cl) instead of compound ()(R=-
_Compound () (R=-
18.8 g of COCH ₂ Br) was obtained. (Yield 79.7%) mp201-203℃ IRν ^KBr _nax 1770, 1763 (sh), 1603, 1483, 1232,
1120cm ^-1 (Effects of the Invention) By using the compound () of the present invention, the compound () can be easily obtained in high yield.

Claims (1)

[Claims] 1 formula 4'-halogenoacetyl-4'-demethyl-epipodophyllotoxin-β [wherein R represents a halogenoacetyl group represented by the formula -COCH ₂ X (wherein X represents a halogen)] -D-2,
3-di-O-halogenoacetyl-4,6-O-ethylidene glucoside.