JPS6242914B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel camptothecin derivative and a method for producing the same. More specifically, the present invention provides the general formula The present invention relates to a novel camptothecin derivative represented by the formula (wherein R is an alkyl group or an aralkyl group) and a method for producing the same. Camptothecin is a deciduous tree (Camptotheca).
acuminata, Nyssaceae).It has a strong nucleic acid synthesis inhibitory effect, and its action is rapid and reversible.It is unique in that it does not show cross-resistance with existing anticancer drugs. It is an antitumor substance with a mechanism of action, and is recognized to have strong anticancer effects on experimentally transplanted cancers such as murine leukemia L ₁₂₁₀ and Rat Walker 256 sarcoma. The current situation is that its usefulness as a drug is itself limited. Therefore, attempts have been made to chemically convert camptothecin into other substances, that is, to convert it into camptothecin derivatives, thereby reducing toxicity while retaining anticancer activity. However, camptothecin itself is poorly soluble in various organic solvents, and camptothecin has resistance to electrophilic substitution reactions due to the heterocycle in its structure. However, there are various obstacles, and the reality is that it is not as easy to obtain new derivatives as planned on paper. The present inventors previously succeeded in introducing a hydroxymethyl group into the 7-position of camptothecin by applying a radical reaction with methanol, and thereby produced various new camptothecin derivatives. As a result of research, camptothecin,
In the presence of metal ions, using sulfuric acid, water and peroxide, the general formula RX (where R is an alkyl group or an aralkyl group, and X is -CH ₂ OH, -COOH,
-CHO, -CO-R or

By carrying out a radical reaction with a compound represented by the following formula, we succeeded in directly introducing an alkyl group or an aralkyl group into the 7-position of camptothecin.
Therefore, the present invention provides a camptothecin derivative characterized in that camptothecin is subjected to a radical reaction with a compound represented by the aforementioned general formula, RX, using sulfuric acid, water, and peroxide in the presence of metal ions. It provides a manufacturing method for, and
The resulting general formula The present invention provides a novel camptothecin derivative represented by the formula (wherein R is an alkyl group or an aralkyl group). The present invention will be explained in detail below. The novel camptothecin derivative represented by the above formula provided by the present invention is produced by the method for producing a camptothecin derivative of the present invention as follows. The production method of the present invention uses camptothecin as a starting material, which is prepared using the general formula RX (wherein R is an alkyl group or an aralkyl group) using sulfuric acid, water, and peroxide in the presence of metal ions. ,X is-
CH ₂ OH, -COOH, -CHO, -CO-R or

It is characterized by a radical reaction with a compound represented by [formula], and the above metal ion is made to exist in the reaction system by dissolving the metal salt in water. be. Therefore, the method of the present invention involves dissolving the above-mentioned camptothecin, metal salt, sulfuric acid, and the compound represented by the general formula RX in water in any order, adding peroxide to this, and stirring. It is done by folding. Usually, the compound represented by the above general formula RX and a metal salt are dissolved in water, camptothecin is added to this solution, sulfuric acid is added, camptothecin is dissolved, and peroxide is dissolved under ice-cooling and stirring. This is done by adding, returning to room temperature, and stirring. Examples of metal salts include ferrous salts such as ferrous sulfate, ferrous chloride, and ferrous oxide. Examples of peroxides include hydrogen peroxide and tertiary butyl hydroperoxide. When using substances that are difficult to dissolve in water, such as higher alcohols, use a solubilizer. As the solubilizing agent, acetic acid or dimethylformamide is preferably used. The compound represented by the general formula RX is preferably used in a large excess relative to camptothecin, for example, in an amount of about 20 times the molar amount. The above-mentioned metal salts and peroxides are used in an excess amount, for example, about 5 to 8 times the molar amount relative to camptothecin. As the compound represented by RX, linear primary alcohols such as ethanol, propanol, butanol, n-pentanol, n-
When using octanol, n-decyl alcohol, etc., an alkyl group having one carbon atom less than the alkyl group bonded to the hydroxyl group of these alcohols can be introduced into the 7-position of camptothecin. Similarly, when using branched primary alcohols such as isoamyl alcohol, 3-methylpentanol, neopentyl alcohol, etc., the number of carbon atoms is smaller than the alkyl group bonded to the hydroxyl group of those alcohols. One less branched alkyl group can be introduced at the 7-position of camptothecin. When methanol having a cyclic alkyl group, such as cyclohexylmethanol or cyclopentylmethanol, is used, the cyclic alkyl group can be directly introduced into the 7-position of camptothecin. When using an alcohol represented by R-CH ₂ OH in which R is an aralkyl group, the aralkyl group R can be introduced into the 7-position of camptothecin. As the compound represented by RX above, R-
When using a COOH type compound, i.e., a carboxylic acid, 1 more carbon atoms than the carboxylic acid.
A group R (alkyl or aralkyl group) with fewer carbon atoms can be introduced at the 7-position of camptothecin. That is, for example, a methyl group can be introduced in the case of acetic acid, an ethyl group in the case of propionic acid, a propyl group in the case of lactic acid, and an isopropyl group in the case of isovaleric acid. As the compound represented by RX above, R-
When using a CHO type compound, i.e., an aldehyde, a group R (alkyl group or aralkyl group) having one carbon atom less than the number of carbon atoms of the aldehyde can be introduced at the 7-position of camptothecin. . That is, for example, in the case of acetaldehyde, a methyl group, in the case of propionaldehyde, an ethyl group, in the case of butyraldehyde, a propyl group, and in the case of octylaldehyde,
In the case of a heptyl group or capricaldehyde, a nonyl group can be introduced, respectively. As a compound represented by RX above, R—CO—
When an R-type compound, ie, a ketone, is used, the group R of the ketone can be introduced into the 7-position of camptothecin. That is, for example, a methyl group can be introduced in the case of acetone, and an ethyl group can be introduced in the case of diethyl ketone. As the compound represented by RX,

When a compound of the formula [Formula], ie, a hydroperoxide compound, is used, the group R of the hydroperoxide compound can be introduced into the 7-position of camptothecin. For example, in the case of t-butyl hydroperoxide, a methyl group can be introduced. The compound represented by RX above is R-CO-R
type compound or

[Formula] type compound, if each of the plurality of groups R is a different type of group, for example, an R ¹ -CO-R ² type compound such as methyl ethyl ketone, or

When the above-mentioned reaction is carried out using a [formula] type compound, these groups R ¹ or R ² or R ³ are usually introduced into the 7-position of camptothecin, and the substance obtained after the reaction has different groups. ^R1 ,
It becomes a mixture of multiple types of substances in which R ² and R ³ are respectively introduced. Due to its anticancer activity, the novel camptothecin derivative provided by the present invention is a chemical substance that has useful uses as a pharmaceutical that utilizes anticancer activity and as an intermediate thereof. Examples of the present invention are listed below, but the present invention is not limited to these Examples. Example 1 Production of 7-methylcamptothecin Ferrous sulfate heptahydrate (4.17 g, 15 mmole) and ethanol (3 ml, 60 mmole) were dissolved in water (30 ml), and camptothecin (700 mg, 2 mmole) was suspended. , add concentrated sulfuric acid (15 ml) little by little to dissolve. 30% hydrogen peroxide solution (1.63 ml, 16 mmole) was added dropwise to the mixture under ice-cooling and stirring. After adding the hydrogen peroxide solution, the mixture is stirred at room temperature for 6 hours. Ferrous sulfate heptahydrate (2.0 g,
7.2 mmole) was added dropwise under ice-cooling and stirring, and 30% hydrogen peroxide solution (1 ml, 9.8 mmole) was added dropwise.
Continue stirring for an hour. To complete the reaction, ferrous sulfate heptahydrate (4.2 g, 15 mmole) and 30% hydrogen peroxide (1.5 ml, 14.7 mmole) were added, and stirring was continued for 8 hours at room temperature. The reaction mixture is diluted with ice water (2.5) and extracted with chloroform (3). The chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue was purified by silica gel (10 g) column chromatography (chloroform) and further recrystallized from n-hexane-chloroform to give the title compound 127 mg (yield:
17.5%) is obtained as yellow needles. mp280−281℃ IRν ^KBr _nax cm ^-1 : 3350, 2920, 1755, 1650, 1600
，
1470, 1155, 765. NMR (in DMSO−d ₆ ) δ: 0.91 (3H, t, J=
7.5Hz), 1.88 (2H, q, J = 7.5Hz), 2.79
(3H, s), 5.26 (2H, s), 5.41 (2H,
s), 6.43 (1H, s, D ₂ O - change), 7.34
(1H, s), 7.57-8.32 (4H, m). MS: m _/ e362 (M ⁺ ) ( _{as C21H18N2O4} = _362.37 ). Example 2 Preparation of 7-methylcamptothecin Ferrous sulfate heptahydrate (2.0 g, 7 mmole) is dissolved in water (15 ml) and acetic acid (1.5 ml, 25 mmole) is added. Add camptothecin (500 mg,
1.43 mmole) was suspended, and concentrated sulfuric acid (8 ml) was added little by little to dissolve. Then, under ice-cooling and stirring,
Butyl-hydroperoxide (900mg,
10 mmole) is added dropwise little by little. After addition of t-butyl hydroperoxide, stirring is continued for 1 hour at room temperature. The reaction mixture is diluted with ice water (500ml) and extracted with chloroform (1.5ml). This chloroform layer was dried with magnesium sulfate,
Filter and dry under reduced pressure. Wash the residue thoroughly with acetone to obtain 440 mg (84.4% yield) of crude crystals. When the crude crystals are purified by recrystallization from pyridine-methanol, 300 mg (yield 57.6%) of the title compound is obtained as pale yellow-white needle crystals. The analytical data of this product were consistent with that of the compound obtained in Example 1. Example 3 Production of 7-ethyl camptothecin Camptothecin (1.00 g, 2.87 mmole), ferrous sulfate heptahydrate (5.60 g, 20.1 mmole) and 1
- Dissolve propanol (6 ml, 86.1 mmole) in a sulfuric acid aqueous solution (30 ml of water, 15 ml of concentrated sulfuric acid), and add 30% hydrogen peroxide solution (2.1 ml, 20.1 mmole) little by little while stirring on ice. After adding the hydrogen peroxide solution, stirring was continued for 1 hour at room temperature. Pour the reaction mixture into ice water (2)
and extract with chloroform (2.5).
This chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue is separated and purified by silica gel (15 g) column chromatography (chloroform), and then recrystallized from n-hexane-chloroform. 265 mg of the title compound (yield
25.3%) is obtained as pale yellow-white needles. mp258−261℃ IRν ^KBr _nax cm ^-1 : 3370, 2920, 1750, 1650, 1600
，
1460, 1150, 760. NMR (in DMSO-d ₆ - CDCl ₃ ) δ: 0.97 (3H,
t, J = 7Hz), 1.39 (3H, t, J = 7
Hz), 1.91 (2H, q, J = 7Hz), 3.21
(2H, q, J=7Hz), 5.21 (2H, s),
5.24 (1H, d, J = 16Hz), 5.57 (1H,
d, J=16Hz), 7.49 (1H, s), 7.44−
8.21 (4H, m). MS: m/e376.1399 (M ⁺ ) (C ₂₂ H ₂₀ N ₂ O ₄ =
376.1422). Example 4 Production of 7-ethylcamptothecin Ferrous sulfate heptahydrate (350 mg, 1.25 mmole)
was dissolved in water (10 ml), propionaldehyde (144 mg, 2.48 mmole) was added, and acetic acid (10
ml). Camptothecin (175 mg, 0.5 mmole) was suspended in this, and concentrated sulfuric acid (2 ml) was added.
Add little by little and dissolve. Add 30% hydrogen peroxide solution (144 mg, 1.27 mmole) to this while stirring on ice.
Add dropwise little by little, and continue stirring for 15 minutes under ice cooling. The reaction mixture is diluted with ice water (500 ml) and extracted with chloroform (800 ml). The chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue was separated and purified by silica gel (10 g) column chromatography (chloroform) to yield 105 mg of the title compound (yield 55.8%).
is obtained as pale yellowish white crystals. The analytical data of the material obtained were consistent with that obtained in Example 3. Example 5 Production of 7-ethylcamptothecin Ferrous sulfate heptahydrate (1.0g, 3.59mmole)
was dissolved in water (10 ml), diethyl ketone (1.29 g, 15 mmole) was added thereto, and acetic acid (6 ml) was added and dissolved. Camptothecin (175
mg, 0.5 mmole) was suspended and dissolved by adding concentrated sulfuric acid (2 ml). Then, 30% hydrogen peroxide solution (560 mg, 5 mmole) was added dropwise little by little while stirring on ice.
After adding the hydrogen peroxide solution, stir at room temperature for 48 hours.
The reaction mixture is diluted with ice water (500 ml) and extracted with chloroform (500 ml). The chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue was separated by silica gel (10 g) column chromatography (chloroform) to obtain 17 mg (yield 13.8%) of the title compound and 61 mg of unreacted camptothecin. The analytical data for 7-ethylcamptothecin obtained were consistent with that obtained in Example 3. Example 6 Production of 7-propylcamptothecin Ferrous sulfate heptahydrate (2.8g, 10.1mmole)
and 1-butanol (3 ml, 43 mmole) in water (30
ml) and add camptothecin (500 mg,
1.43 mmole) was suspended, dissolved by adding concentrated sulfuric acid (15 ml), and then 30% hydrogen peroxide solution (1.1 ml, 10.1 mmole) was added dropwise in small portions under ice-cooling and stirring, and the mixture was stirred at room temperature for 4 hours. Continue stirring. The reaction mixture is diluted with ice water (1.5) and extracted with chloroform (2). Dry the chloroform layer over magnesium sulfate, filter, and dry under reduced pressure. After separating and purifying the residue by silica gel (15 g) column chromatography (chloroform), further n-hexane-
Recrystallization from chloroform gives 110 mg (yield 21.0%) of the title compound as pale yellow-white needles. mp260−261℃. IRν ^KBr _nax cm ^-1 :3400, 2930, 1745, 1650, 1600
，
1455, 1155, 760. NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7Hz),
1.08 (3H, t, J=8Hz), 1.25−2.05
(4H, m,), 3.26 (2H, t, J=8Hz),
5.24 (2H, s), 5.52 (2H, dxd, J=17
Hz), 7.67 (1H, s) 7.55−8.29 (4H,
m). MS: m _/ e390 (M ⁺ ) ( _{as C23H22N2O4} = _390.43 ). Example 7 7-Propylcamptothecin ferrous sulfate heptahydrate (800 mg, 2.88 mmole)
was dissolved in water (10 ml), butyraldehyde (260 mg, 3.61 mmole) was added to this solution, and acetic acid (17
ml). This is combined with camptothecin (500
mg, 1.44 mmole) was suspended and dissolved by adding concentrated sulfuric acid (2 ml) little by little. While stirring and cooling on ice, 30% hydrogen peroxide (333 mg, 2.93 mmole) was added dropwise little by little, and stirring was continued for 20 minutes under ice cooling. The reaction mixture was diluted with ice water (1) and chloroform (1)
Extract with The chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue was separated and purified by silica gel (15 g) column chromatography (chloroform) to obtain 333 mg (yield 59.3%) of the title compound as yellow-white crystals. When this product is purified by recrystallization from ethanol, pale yellow prism crystals are obtained. The analytical data for this were consistent with that obtained in Example 6. Example 8 Production of 7-butylcamptothecin Ferrous sulfate heptahydrate (3.0g, 10.7mmole)
was dissolved in water (30 ml), camptothecin (500 mg, 1.43 mmole) was suspended in this, and concentrated sulfuric acid (20 ml) was added.
Add and dissolve. Add 1-amyl alcohol (4.6 ml, 43 mmole) to the mixture and stir under ice cooling for 30 min.
%-Hydrogen peroxide solution (1.1 ml, 10.7 mmole) is added dropwise little by little. After adding the hydrogen peroxide solution, the mixture was stirred at room temperature for 4 hours. The reaction mixture is diluted with ice water (1.5) and extracted with chloroform (2). The chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. Remove the residue with silica gel (10
g) Separation and purification by column chromatography (chloroform) and further purification by recrystallization from n-hexane-chloroform yielded 54mg of the title compound.
(Yield 9.3%) is obtained as pale yellowish white needles. mp206−207℃ IRν ^KBr _nax cm ^-1 : 3350, 2930, 1745, 1680, 1600
，
1450, 1150, 755. NMR ( _CDCl3 ) δ: 0.80−2.04 (12H, m), 3.14
(2H, t, J=7Hz), 5.20 (2H, s),
5.26 (1H, d, J = 17Hz), 5.73 (1H,
d, J=17Hz), 7.62 (1H, s), 7.28−
7.88 (2H, m), 7.96-8.26 (2H, m). MS: m _/ e404 (M ⁺ ) (as _{C24H24N2O4 = 404} ). Example 9 Production of 7-butylcamptothecin Ferrous sulfate heptahydrate (300 mg, 1.07 mmole)
Dissolve in water (10ml), layer with n-amyl alcohol (310μ, 2.86mmole), add dimethylformamide (6ml) and dissolve. Camptothecin (50 mg, 0.143 mmole) was suspended in this, and then concentrated sulfuric acid (1.5 ml) was added to dissolve. Under ice-cooling and stirring, 30% hydrogen peroxide solution (110μ,
1.07 mmole) was added dropwise little by little. After adding the hydrogen peroxide solution, stir at room temperature for 4 hours. The reaction mixture was diluted with ice water (100ml) and chloroform (300ml).
Extract with The chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue was separated and purified by silica gel (4 g) column chromatography and further purified by recrystallization from n-hexane-chloroform to obtain the title compound 18.
mg (yield 32%) is obtained as pale yellow-white needles.
The analytical data for this was consistent with that obtained in Example 8. Example 10 Production of 7-heptylcamptothecin Ferrous sulfate heptahydrate (800 mg, 2.88 mmole)
was dissolved in water (10 ml) and octanal (459 mg,
3.56 mmole) and dissolve in acetic acid (20 ml).
Camptothecin (500 mg,
1.44 mmole) was suspended, and concentrated sulfuric acid (4 ml) was added little by little to dissolve it. While stirring on ice, add 30% hydrogen peroxide (333 mg, 2.94 mmole) little by little dropwise. After adding the hydrogen peroxide solution, continue stirring for 15 minutes under ice cooling. The reaction mixture was diluted with ice water (1) and extracted with chloroform (600 ml). This chloroform layer was dried with magnesium sulfate,
Filter and dry under reduced pressure. Remove the residue from silica gel (15
g) Column chromatography (chloroform)
The title compound was separated and purified by 334 mg (yield:
53.5%) is obtained as a yellow-white solid. When this product is purified by recrystallization from ethanol, yellow-white needle crystals are obtained. mp245−246℃ IRν ^KBr _nax cm ^-1 : 3380, 2920, 1750, 1655, 1600
，
1460, 1160, 763. NMR (in CDCl ₃ ) δ: 0.80−2.05 (18H, m),
3.16 (2H, br.t, J=8Hz), 5.23 (2H,
s), 5.30 (1H, d, J = 17Hz), 5.72
(1H, d, J=17Hz), 7.65 (1H, s),
7.30-7.85 (2H, m), 8.02-8.30 (2H,
m). MS: m _/ e446 (M ⁺ ) ( _{as C27H30N2O4} = _446.22 ). Example 11 Production of 7-heptylcamptothecin Ferrous sulfate heptahydrate (800 mg, 2.88 mmole)
was dissolved in water (10 ml), and octanal (459 mg,
3.56 mmole) and dissolve in acetic acid (20 ml).
Camptothecin (500 mg,
1.44 mmole) was suspended and dissolved by adding concentrated sulfuric acid (4 ml) little by little. While cooling with ice and stirring, 30% hydrogen peroxide (333 mg, 2.94 mmole) is added dropwise little by little.
After adding the hydrogen peroxide solution, continue stirring for 15 minutes under ice cooling. The reaction mixture was diluted with ice water (1) and extracted with chloroform (600 ml). The chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue was separated and purified by silica gel (15 g) column chromatography (chloroform) to yield 334 mg (yield 53.5%) of the title compound.
is obtained as a yellow-white solid. When this product is purified by recrystallization from ethanol, yellow-white needle crystals are obtained. The analytical data of this were consistent with the data of the compound obtained in Example 10. Example 13 Production of 7-nonylcamptothecin Ferrous sulfate heptahydrate (800 mg, 2.88 mmole)
Dissolve in water (10 ml), add n-decylaldehyde (560 mg, 2.94 mmole), and dissolve with acetic acid (32 ml). Camptothecin (500 mg,
1.44 mmole) was suspended and dissolved by adding concentrated sulfuric acid (4 ml) little by little. Add 30% hydrogen peroxide (333 mg, 2.94 mmole) little by little while stirring on ice. After adding the hydrogen peroxide solution, continue stirring for an additional 30 minutes under ice cooling. The reaction mixture is diluted with ice water (1) and extracted with chloroform (1). The chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform), and the title compound was obtained as a yellowish-white solid.
261 mg (yield 38.3%) is obtained. This product is purified by recrystallization from methanol to obtain yellowish-white needles. mp205−207℃. IRν ^KBr _nax cm ^-1 :3420, 2930, 1750, 1655, 1595
，
1460, 1160, 762. NMR (in CDCl ₃ ) δ: 0.78−2.02 (22H, m),
3.16 (2H, br.t, J=7Hz), 5.24 (2H,
s), 5.30 (1H, d, J = 17Hz), 5.72
(1H, d, J=17Hz), 7.68 (1H, s),
7.50-7.90 (2H, m), 8.02-8.30 (2H,
m). MS: m _/ e474 (M ⁺ ) ( _{as C29H34N2O4} = _474.25 ). Example 14 Production of 7-isobutylcamptothecin Ferrous sulfate heptahydrate (2.80g, 10.1mmole)
Dissolve in water (30 ml), layer with isoamyl alcohol (3.5 ml, 39 mmole), add dimethylformamide (10 ml) and dissolve. Camptothecin (500 mg, 1.43 mmole) is suspended in this solution and dissolved by adding concentrated sulfuric acid (15 ml). Under ice-cooled stirring, 30
%-Hydrogen peroxide (1.1 ml, 10.1 mmole) is added dropwise. 40 at room temperature after addition of hydrogen peroxide solution
Stir for a minute. The reaction mixture is diluted with ice water (1.5) and extracted with chloroform (1.5). This chloroform layer was dried with magnesium sulfate,
Filter and dry under reduced pressure. Remove the residue from silica gel (15
g) Separation and purification by column chromatography (chloroform) and further purification by recrystallization from n-hexane-chloroform yields 95 mg (yield 16.7%) of the title compound as pale yellow-white needle crystals. mp198−200℃. IRν ^KBr _nax cm ^-1 :3400, 2930, 1740, 1650, 1595
，
1450, 1155, 760. NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7Hz),
1.07 (6H, d, J = 7Hz), 1.93 (2H,
q, J = 7Hz), 2.12-2.40 (1H, m),
3.09 (2H, d, J=7Hz), 5.28 (2H,
s), 5.54 (2H, dxd, J=17Hx), 7.68
(1H, s), 7.55-8.29 (4H, m). MS: m _/ e404 (M ⁺ ) (as _{C24H24N2O4 = 404} ). Example 15 Production of 7-benzylcamptothecin Ferrous sulfate heptahydrate (3.40g, 12.2mmole)
was dissolved in water (30 ml), layered with β-phenethyl alcohol (3.20 g, 28.6 mmole), and acetic acid (27
ml) and dissolve. Camptothecin (500 mg, 1.43 mmole) was suspended in this and concentrated sulfuric acid (30 ml) was added.
Add and dissolve. Add 30% to the mixture under ice-cooling and stirring.
Add hydrogen peroxide solution (1.5 ml, 14.7 mmole) dropwise little by little. After adding the hydrogen peroxide solution, continue stirring at room temperature for 16 hours. The reaction mixture is diluted with ice water (1.5) and extracted with chloroform (1.5). This chloroform layer was dried with magnesium sulfate,
Filter and dry under reduced pressure. The residue was thoroughly washed with n-hexane, separated and purified by column chromatography (chloroform) using silica gel (10 g), and further purified by recrystallization from n-hexane-chloroform, yielding 202 mg (yield 50.6%) of the title compound in a pale form. Obtained as yellowish-white needles. mp263−265℃. IRν ^KBr _nax cm ^-1 :3360, 2800, 1735, 1650, 1590
，
1440, 1145, 755, 695. NMR (in CDCl ₃ ) δ: 1.03 (3H, t, J = 7.5
Hz), 1.89 (2H, q, J = 7.5Hz), 4.58
(2H, s), 5.14 (2H, s), 5.26 (1H,
d, J = 16.2Hz), 5.73 (1H, d, J =
16.2Hz), 7.00−7.34 (5H, m) 7.68
(1H, s), 7.55-8.32 (4H, m). MS: m _/ e438 (M ⁺ ) ( _{as C27H22N2O4} = _438.47 ). Example 16 Production of 7-β-phenethylcamptothecin Camptothecin (350 mg, 1 mmole) and ferrous sulfate heptahydrate (2.0 g, 7.2 mmole) were dissolved in an aqueous sulfuric acid solution (water, 25 ml, concentrated sulfuric acid 10 ml). Then, layer 3-phenylpropanol (1.5 g, 11.0 mmole) and dissolve by adding dimethylformamide (10 ml). Add 30% hydrogen peroxide solution (740 μ, 7.2 mmole) little by little to the mixture while stirring on ice, and after adding the hydrogen peroxide solution, stir at room temperature for 20 hours. Ferrous sulfate heptahydrate (2.0 g,
7.2 mmole), 3-phenylpropanol (1.5
g, 11.0 mmole) and dimethylformamide (35
ml), add 30% hydrogen peroxide solution (740 μ, 7.2 mmole) under ice-cooling and stirring, and stir at room temperature for further 20 hours. The reaction mixture is diluted with ice water (1.5), extracted with chloroform (2.0) and dried over magnesium sulfate. This chloroform layer was filtered, dried under reduced pressure, and the residue was collected using silica gel (10 g).
Separation and purification by column chromatography (chloroform) and further purification by recrystallization from n-hexane-chloroform yielded 66 mg of the title compound,
(Yield 14.2%) is obtained as pale yellowish white needle crystals. mp260−262℃. IRν ^KBr _nax cm ^-1 :3370, 2920, 1745, 1655, 1600
，
1450, 1155, 755, 700. NMR (in CDCl ₃ ) δ: 1.02 (3H, t, J = 7.5
Hz), 1.89 (2H, q, J = 7.5Hz), 3.47
(2H, t, J = 7Hz), 3.80 (2H, t, J
=7Hz), 4.78 (2H, s) 5.24 (1H, d,
J = 17Hz), 5.70 (1H, d, J = 17Hz),
6.98−7.40 (5H, m), 7.61 (1H, s),
7.51−8.38 (4H, m). MS: m _/ e452 (M ⁺ ) ( _{as C28H24N2O4} = _452.49 ). Example 17 Production of 7-isopropylcamptothecin Ferrous sulfate heptahydrate (2.0 g, 7.5 mmole) was dissolved in water (20 ml), and isobutanol (2.75 ml,
30 mmole) and dissolve by adding acetic acid (6 ml). This includes camptothecin (350mg, 1mmole)
Suspend and dissolve by adding concentrated sulfuric acid (17ml). Under ice-cooling and stirring, 30% hydrogen peroxide solution (760μ,
7.5 mmole) was added dropwise little by little, and after addition of hydrogen peroxide solution, the mixture was stirred at room temperature for 30 minutes. The reaction mixture is diluted with ice water (1) and extracted with chloroform (1.5). The chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue is separated and purified by silica gel (10 g) column chromatography (chloroform) and further purified by recrystallization from n-hexane-chloroform to obtain 128 mg (yield 32.8%) of the title compound as pale yellow-white needles. . mp258−259℃ IRν ^KBr _nax cm ^-1 : 3400, 2950, 1750, 1645, 1595
，
1460, 1155, 760. NMR (in CDCl ₃ ) δ: 1.04 (3H, t, J = 7.5
Hz), 1.54 (6H, d, J = 7Hz), 1.90
(2H, q, J = 7.5Hz), 4.00 (1H,
heptet, J = 7Hz), 5.29 (1H, d, J =
17Hz), 5.37 (2H, s), 5.75 (1H, d,
J=17Hz), 7.63 (1H, s), 7.45−8.36
(4H, m). MS: m _/ e390 (M ⁺ ) (as _{C23H22N2O4 = 390} ). Example 18 Production of 7-cyclohexylcamptothecin Ferrous sulfate heptahydrate (3.0g, 10.73mmole)
was dissolved in water (30 ml), layered with cyclohexylmethanol (1.63 g, 14.3 mmole), and acetic acid (22 ml) was added and dissolved under stirring. Camptothecin (500 mg, 1.43 mmole) was suspended in this solution and dissolved by adding concentrated sulfuric acid (8 ml). Add 30% hydrogen peroxide solution (1.1 ml,
10.73 mmole) was added dropwise little by little, and after addition of hydrogen peroxide solution, stirring was continued for 30 minutes at room temperature. The reaction mixture was diluted with ice water (1) and chloroform (1.5
) to extract. The chloroform layer is dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue was separated and purified by silica gel (10 g) column chromatography (chloroform), and further n-
Purification by recrystallization from hexane-chloroform yields 181 mg (yield 29.4%) of the title compound as pale yellow-white needles. mp260−261℃. IRν ^KBr _nax cm ^-1 :3380, 2920, 1745, 1655, 1595
，
1440, 1155, 765. NMR (in CDCl ₃ ) δ: 1.04 (3H, t, J=8
Hz), 1.20-2.18 (12H, m), 3.70 (1H,
m), 5.30 (1H, d, J = 17Hz), 5.39
(2H, s), 5.72 (1H, d, J=17Hz),
7.67 (1H, s), 7.50−7.85 (2H, m),
8.16−8.27 (2H, m). MS: m _/ e430 (M ⁺ ) ( _{as C26H26N2C4} = _430.19 ). Example 19 Production of 7-ethylcamptothecin Ferrous sulfate heptahydrate (1.20g, 4.31mmole)
and propionic acid (990 mg, 13.4 mmole) were dissolved in water (15 ml) and camptothecin (300 mg,
0.862 mmole) was suspended and dissolved by adding concentrated sulfuric acid (6 ml) little by little. Add 30% to the mixture under ice-cold stirring.
- Add hydrogen peroxide solution (1 ml, 9.81 mmole) dropwise little by little over about 10 minutes. After adding the hydrogen peroxide solution, continue stirring at room temperature for 16 hours. The reaction mixture was diluted with ice water (300
ml) and extracted with chloroform (400 ml). The chloroform layer is dried over magnesium sulfate, filtered, and the chloroform is dried under reduced pressure.
The residue was separated and purified by silica gel (10 g) column chromatography (chloroform).
73 mg of the title compound as a yellow-white solid (yield 22.5
%)can get. The analytical data of this were consistent with the data of the compound obtained in Example 3.

Claims (1)

[Claims] 1. General formula (In the formula, R is an alkyl group or an aralkyl group.) A camptothecin derivative represented by: 2 camptothecin in the presence of metal ions,
Using sulfuric acid, water and peroxide, the general formula, RX (where R is an alkyl group or an aralkyl group, and X is -CH ₂ OH, -COOH, -CHO, -CO-R or [formula] A general formula characterized by a radical reaction with a compound represented by A method for producing a camptothecin derivative represented by the formula (wherein R is an alkyl group or an aralkyl group).