JPH0575759B2

JPH0575759B2 -

Info

Publication number: JPH0575759B2
Application number: JP32841391A
Authority: JP
Inventors: Tadashi Fujii; Yukio Chikui
Original assignee: Nippon Kayaku Co Ltd
Current assignee: Nippon Kayaku Co Ltd
Priority date: 1991-11-18
Filing date: 1991-11-18
Publication date: 1993-10-21
Also published as: JPH0525192A

Claims

[Claims]

Claim 1: Formula [Chemical 1] ■■■ Turtle Shell [1245] ■■■ [In the formula, R ₁ represents -COCHX ₂ or -COCX ₃ (X represents a halogen atom). ] β-D-glucose represented by: Detailed Description of the Invention [0001] [Industrial Application Field] The present invention provides β-D-
Regarding glucose. Etoposide exhibits antitumor activity and is a useful substance as an anticancer agent. [Prior Art] The following process is already known as a method for producing compound (1). (Tokuko Showa 46
-Refer to Publication No. 37837) [0002] [Chemical formula 2] ■■■ Turtle shell [1246] ■■■ [0003] (In the formula, A is formyl or acetyl, B
(represents benzyloxycarbonyl) [Problems to be Solved by the Invention] However, the above method requires two steps: removing A and then removing B, and moreover, the removal of A requires a long time (for example, 20 The reaction is not completed even after being allowed to react for up to 30 hours), and the quality of etoposide obtained is poor due to the increase in by-products such as colored substances, and the yield is also low. [Means for Solving the Problems] Therefore, the present inventors investigated various new methods for producing etoposide, and found that the formula (3) obtained using di- or trihalogenoacetyl halides [0004] [Chemical formula 3] ■■ Turtle Shell [1247] ■■■ [0005] [In the formula, R ₁ and R ₂ are the same or different and represent the formula -COCHX ₂ or -COCX ₃ (in the formula, X represents a halogen atom). ] When the compound represented by is reacted with alcohols, amines and/or ammonia, R ₁ and R ₂ are removed at once to obtain etoposide, and the obtained etoposide has few impurities and is easy to purify. It was found that the formula (6) [0006] ■■■ Tortoise shell [1248] ■■■ [0007] [In the formula, R ₁ is −COCHX ₂ or −
COCX ₃ (X represents a halogen atom). ] It has been found that β-D-glucose represented by the following is useful as an intermediate for etoposide. In the above formula (6), examples of X in R ₁ include fluorine, chlorine, bromine, and iodine, with chlorine or bromine being practically preferred. Examples of R ₁ include difluoroacetyl, dichloroacetyl, dibromoacetyl, diiodoacetyl, trifluoroacetyl, trichloroacetyl, tribromoacetyl, triiodoacetyl, and the like. [0008] Here, compound (6) is a new compound,
Known 4,6-O-ethylidene-1-O-benzyloxycarbonyl-β-D-glucopyranose
It is synthesized using (7) as a raw material, for example, through the following reaction route. [0009] [Chemical formula 5] ■■■ Turtle shell [1249] ■■■ [0010] (In the formula, R ₁ is the same as above.) That is, 4,6-O-ethylidene-1-O-penzyloxy 4, obtained by reacting carbonyl-β-D-glucopyranose (7) with dihalogen or trihalogenoacetyl chloride in an inert solvent.
6-O-ethylidene-1-O-benzyloxycarbonyl-2,3-di-O-halogenoacetyl-
Compound (6) can be obtained by hydrogenolyzing β-D-glucopyranose (8). Although some α-form is unavoidable during hydrogenolysis, since only the β-form of compound (6) selectively crystallizes from the reaction solution, it is difficult to separate the α- and β-forms. It has the property of being easy to use. Furthermore, the β-form of compound (6) has good stability and isomerization to the α-form is hardly observed, so it can be stored for a long time. [Example] Example 1 (a) 4,6-O-ethylidene-1-O-benzyloxycarbonyl-2,3-di-O-dichloroacetyl-β-D-glucopyranose (8) ( R ₁
= _COCHCl2 ) 4,6-O-ethylidene-1-O-benzyloxycarbonyl-β-D-glucopyranose (7)
Suspend 34.0g in 340ml of 1,2-dichloroethane,
After adding 23.7 g of pyridine, the mixture is cooled to 0-5°C.
Add 32.4g of dichloroacetyl chloride to this about 1
After the dropwise addition over time, stirring is continued for an additional 0.5 hour. Then, the reaction solution was washed with water, the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound (8).
51.0 g of (R ₁ =COCHCl ₂ ) was obtained (yield 90.7%). mp150～151℃ IRν _nax (KBr) 1770, 1255, 1100, 820cm ^-1 (b) 4,6-O-ethylidene-2,3-di-O-
Dichloroacetyl-β-D-glucopyranose
(6) (R ₁ = COCHCl ₂ ) Compound (8) (R ₁ = -COCHCl ₂ ) 10.0 g was dissolved in 50 ml of acetone, 1.0 g of palladium black was added and -
Hydrogenolysis is carried out under pressure at 5-10°C. After the reaction is completed, the catalyst is filtered off and the solvent is distilled off under reduced pressure. Add 17 ml of diisopropyl ether to the residue, cool to 0°C, and filter with suction to obtain compound (6) (R ₁ = -COCHCl ₂ ).
7.3g was obtained (yield 95.9%). mp133～135℃ IRν _nax (KBr) 3445, 1775, 1305, 1165,
1095, 1005, 815 cm ^-1 [0012] Example 2 (a) 4,6-O-ethylidene-1-O-benzyloxycarbonyl-2,3-di-O-dibromoacetyl-β-D-glucopyranose ( 8)( _R2
= _COCHBr2 ) 4,6-O-ethylidene-1-O-benzyloxycarbonyl-β-D-glucopyranose (7)
Suspend 5.1 g in 51 ml of 1,2-dichloroethane, add 3.6 g of pyridine, and cool to 0-5°C. 7.8 g of dibromoacetyl chloride was added dropwise to this over about 1 hour, and stirring was continued for an additional 30 minutes. Then, the reaction solution was washed with water, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to a volume of 25 ml to obtain compound (8) ((R ₁ = COCHBr ₂ ).
A 1,2-dichloroethane solution of was obtained. (b) 4,6-O-ethylidene-2,3-di-O-
Dipromoacetyl-β-D-glucopyranose
(6) (R ₁ = -COCHBr ₂ ) 1,2- of compound (8) (R ₁ = -COCHBr ₂ ) of (a)
Add 0.4 g of palladium black to 25 ml of dichloroethane solution and perform hydrogenation under pressure at -10 to -5°C.
After the reaction was completed, the catalyst was filtered off and 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 ) In Example 2(a), 3.5 g of trichloroacetyl chloride was used instead of dibromoacetyl chloride.
Using this, 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 25 ml of the solution obtained in (a), 25 ml of a 1,2-dichloroethane solution of compound (6) (R ₁ = -COCCl ₃ ) was prepared in the same manner as in Example 2 (6). I got it. [0014] Reference example (a) 4'-dichloroacetyl-4'-demethyl-epipodophyllotoxin (5) (R ₂ = COCHCl ₂ ) 4'-demethyl-epipodophyllotoxin (4) 8 g
was dissolved in 160 ml of acetone, 3.2 g of pyridine was added, and the mixture was cooled to -5 to -10°C. 4.1 g of dichloroacetyl chloride was added dropwise to this over about 1.5 hours, and the mixture was further stirred for 0.5 hour. Then, acetone is distilled off under reduced pressure, and the resulting solid is dissolved in 160 ml of 1,2-dichloroethane and washed with water. Next, this 1,2-dichloroethane solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain compound (5) (R ₂
= _-COCHCl2 ) 9.5g was obtained (yield 93.4%). mp207～208℃ IRν _nax (KBr) 3540, 1775, 1600, 1485,
1235, 1130cm ^-1 (b) 4'-dichloroacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-O
-dichloroacetyl-4,6-O-ethylidene glucoside (3) (R ₁ , R ₂ = -COCHCl ₂ ) Compound (5) (R ₂ = -COCHCl ₂ ) 3.0 g to 1,2-
Dissolve in 60ml of dichloroethane, then compound (6)
Add 2.5 g (R ₁ =-COCHCl ₂ ) and cool to -10°C. Boron trifluoride ethyl etherate 1.1g
was added dropwise over about 1.5 hours, and stirring was continued for an additional 0.5 hours. 0.8g of pyridine at an internal temperature of -5 to -10℃
After dripping while maintaining the temperature, wash by adding water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain the compound.
(3) 4.4 g of (R ₁ , R ₂ = -COCHCl ₂ ) was obtained (yield
81.4%). mp207-208℃ (c) 4'-dichloroacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-O
1 g of -dichloroacetyl-4,6-O-ethylidene glucoside (3) ( _R1 , _R2 = _-COCHCl2 ) and 1 g of ammonium acetate are dissolved in 20 ml of methanol and stirred at room temperature for 1.5 hours. After the reaction was completed, methanol was concentrated to 10 ml and cooled to obtain 0.55 g of etoposide crystals (yield: 86.1
%). TLC Rf value of the crystal obtained here (silica gel,
Developing solvent chloroform:methanol=9:1),
The IR, NMR and optical rotation were the same as those of the material obtained by the method of Japanese Patent Publication No. 46-37837. mp259-260°C, Rf=0.44 [0015] [Effect] As is clear from the above reference examples, etoposide can be obtained with high purity and high yield in a small number of steps by using the β-D-glucose of the present invention. .