JPS6247193B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel camptothecin derivatives. More specifically, the present invention relates to the general formula (In the formula, R ¹ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or an acyloxyl group,
R ² is a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group or an acyloxymethyl group, R ³ is a hydrogen atom, an alkyl group or an acyl group, and X is an oxygen atom or a sulfur atom. However, if R ¹ and R ² are both hydrogen atoms, R ³
relates to a novel camptothecin derivative represented by -OH, _-OCH3 , _-OCOCH3 ).

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 has a unique effect of not exhibiting cross-resistance with existing anticancer drugs. It is an antitumor substance with a mechanism and has been shown to have strong anticancer effects on experimentally transplanted cancers such as murine leukemia L1210 and rat Walker 256 sarcoma.
The current situation is that its usefulness as a medicine is naturally 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 it has in its chemical 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 have previously succeeded in selective oxidation and alkylation at the 5-position of camptothecin, and introduction of various carbon functional groups into the 7-position, thereby providing various new substances. However, in recent years, it has been reported that 10-hydroxycamptothecin, isolated from Camptotheca acuminata, has lower toxicity and even better anticancer activity than camptothecin (Chinese Medical Science,
1978). The present inventors have demonstrated that camptothecin or its 5-position substituted derivatives and 7-position substituted derivatives
As a result of our studies on chemical modification at the 10-position, we found that according to the present invention, camptothecin and its 5-position substituted derivatives or 7-position substituted derivatives,
Reagents having active hydrogen ⁽ R ³ By irradiating the compound with ultraviolet light, we succeeded in providing a novel camptothecin derivative represented by the above general formula.

To obtain the above-mentioned N-oxide, the following method is used. That is, camptothecin and 5
By reacting hydrogen peroxide in acetic acid with a derivative substituted at the -position or a derivative substituted at the 7-position, the corresponding N-oxide can be obtained in high yield. N-oxide can be similarly obtained by using persulfate or metachloroperbenzoic acid instead of hydrogen peroxide.

These N-oxides, i.e., camptothecin 1-oxide, 5-substituted camptothecin 1-oxide, or 7-substituted camptothecin 1-oxide, are then dissolved in a solvent such as dioxane, acetonitrile, chloroform, methylene chloride, glyme, diglyme, etc., respectively. Or dissolved in any mixed solvent thereof, the aforementioned reagents represented by the formula R ³ acid, organic sulfonic acid, Lewis acid such as trifluoride-boron ether,
Treatment is performed using an organic carboxylic acid or the like under ultraviolet irradiation. Note that good results can be obtained when the above-mentioned acids are used in an amount of 10 to 15 equivalents. When using, for example, acetic acid, propionic acid, etc. as the organic carboxylic acid, these acids can serve as a solvent. Two products are formed in the reaction mixture thus prepared. One is a small amount of deoxygenated compound and the other is a compound with formula at the 10-position.
This is a novel camptothecin derivative, which is the target substance of the present invention, into which a substituent represented by R ³ X has been introduced.

As mentioned above, camptothecin, part 5-
The position substituted derivative and the 7-position substituted derivative, respectively,
to its N-oxide, which under acidic conditions,
The novel camptothecin derivative of the present invention can be obtained by reacting it with a reagent having an active hydrogen represented by the formula R ³ XH under ultraviolet irradiation.

The novel camptothecin derivative according to the present invention is a substance useful as a pharmaceutical or an intermediate thereof.

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples.

Example 1-1 Synthesis of camptothecin 1-oxide Camptothecin (1.04 g, 3 mmol) was suspended in acetic acid (100 ml), and 30% hydrogen peroxide (15
ml) and stir at 60-70°C for 3 hours. The resulting reaction mixture is concentrated under reduced pressure to a volume of approximately 35 ml and poured into ice water (500 ml). The precipitated yellow-orange needles were collected, washed with water and then methanol, and dried under reduced pressure to yield 866 mg (90.6%
A yield of camptothecin 1-oxide is obtained. mp254゜(dec.).

Example 1-2 Synthesis of 10-[(carboethoxymethyl)thio]camptothecin Camptothecin 1-oxide (75 mg, 0.206 m
mol) in ethanol-free chloroform (50
ml) and dioxane (50 ml), add boron trifluoride (50 μl) and ethyl thioglycolate (5 g), and irradiate with light for 40 minutes. The reaction mixture is concentrated under reduced pressure, then water (100 ml) is added and extracted with chloroform (100 ml x 3). After drying the chloroform layer with magnesium sulfate,
The residue was filtered and dried under reduced pressure with silica gel (5
g) and high performance liquid chromatography (RiChrosorb SI-60 column, 10% acetone).
When purified with chloroform), camptothecin 22
mg along with 20 mg (20.8%) of the title compound are obtained.

Yellow needles, mp228-231 (dec.) [chloroform- n -hexane] NMR (in CDCl ₃ ): 1.04 (3H, t, J = 7.8Hz),
1.25 (3H, t, J = 7.3Hz), 1.90 (2H, q, J
=7.8Hz), 3.81 (2H, s), 4.21 (2H, q, J
= 7.3Hz), 5.28 (1H, d, J = 16.6Hz), 5.27
(2H, s), 5.75 (2H, d, J=16.6Hz), 7.64
(1H, s), 7.70 (2H, m), 8.17 (1H, d, J
= 9 Hz), 8.26 (1H, br, s) MS: m/e 466 [M ⁺ ] (as C ₂₄ H ₂₂ N ₂ O ₆ S = 466) Example 2-1 Synthesis of 5-methylcamptothecin 1-oxide 5-methylcamptothecin (362mg, 1m
mol) in acetic acid (25 ml), add 30% hydrogen peroxide (2.5 ml, 0.0245 mol), and heat at 65-70°C for 3 hours. The reaction mixture was concentrated to about 1/5 volume under reduced pressure, diluted with ice water (250 ml), and the precipitated yellow-orange needles were collected and dried under reduced pressure at 60°C for 6 hours to give 5-methylcamptothecin 1- Oxide, 234 mg is obtained (yield 62.0%) mp226~
(dec.).

MS: m/e 378 [M ⁺ ] (as C ₂₁ H ₁₈ N ₂ O ₅ = 378) Example 2-2 Synthesis of 10-hydroxy-5-methylcamptothecin 5-methylcamptothecin 1-oxide (27
mg, 0.0714 mmol) was dissolved in acetonitrile (20 ml), dioxane (25 ml), and water (5 ml), and concentrated sulfuric acid (50 μ) was added thereto and irradiated with light for 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with water (50 ml), the insoluble material was removed, dried, and purified by silica gel column chromatography (2% methanol-chloroform) to give the title compound along with 5 mg of 5-methylcamptothecin. of target product 11 mg (yield: 50.6
%) is obtained as pale yellow-white crystals.

NMR (in DMSO−d ₆ ) δ: 0.87 (3H, t, J=
7Hz), 1.77 (3H, br d, J=6Hz, _C5-
CH ₃ ), 1.84 (2H, q, J = 7Hz), 5.36
(2H, br s, C ₁₇ − H ₂ ), 5.60 (1H, m, C ₅ −
H), 6.43 (1H, br s, D ₂ O−
exchangeable), 7.07 (2H, m, C ₉ −H and
C ₁₄ −H), 7.14 (1H, d×d, J=9Hz, 2
Hz, C ₁₁ −H), 7.84 (1H, d, J=9Hz, C ₁₂
-H), 8.41 (1H, br s, C ₇ -H), 10.34
(1H, s, _D2O -exchangeable).

MS: m/e 378 [M ⁺ ] (as C ₂₁ H ₁₈ N ₂ O ₅ = 378) Example 3-1 Synthesis of 5-methoxycamptothecin 1-oxide 5-methoxycamptothecin (190 mg, 0.5 m
mol) in acetic acid (15 ml), to which 30% hydrogen peroxide (1.25 ml, 0.0125 mol) was added, and 65 to 70
Stir at ℃ for 3 hours. Reduce the reaction mixture to about 1/4 under reduced pressure.
Concentrate to volume, dilute this with ice water (200 ml), collect the precipitated yellow-orange needles, and incubate at 60°C under reduced pressure.
After drying for 6 hours, 145 mg (yield: 73.6%) of 5-methoxycamptothecin 1-oxide is obtained. mp208゜～(dec.) NMR (in CDCl ₃ ): 1.03 (3H, t, J=7Hz),
1.92 (2H, q, J = 7Hz), 3.51, 3.66 (1.5H
×2, s, s), 5.30 (1H, d, J = 16Hz),
5.59 (1H, d, J = 16Hz), 6.73, 6.85 (0.5H
×2, s, s), 7.72−8.01 (4H, m), 8.24
(1H, s), 8.76 (1H, m) MS: m/e 394 [M ⁺ ] (as C ₂₁ H ₁₈ N ₂ O ₆ = 394) Example 3-2 Synthesis of 10-hydroxy-5-methoxycamptothecin 5-methoxycamptothecin 1-oxide (98
mg, 0.248 mmol) was dissolved in acetonitrile (50 ml), dioxane (50 ml), and water (5 ml), concentrated sulfuric acid (100 μ) was added thereto, and the mixture was irradiated with light for 30 minutes.
The reaction mixture is concentrated under reduced pressure and diluted with water (100ml). The insoluble matter is removed, dried, and purified by silica gel column chromatography (2% methanol-chloroform) to obtain 23.5 mg (yield: 26.1%) of the desired product along with 7 mg of 5-methoxycamptothecin.

NMR (in DMSO−d ₆ ) δ: 0.87 (3H, t, J=
7Hz), 1.83 (2H, q, J=7Hz), 3.46, 3.54
(1.5H×2, s, s, C ₅ −OCH ₃ ), 5.39 (2H,
br s, C ₁₇ −H), 6.28 (1H, br s, D ₂ O−
exchangeable), 6.80, 6.86 (0.5H×2, s,
s, C ₅ −H), 7.02 (1H, d, J=2Hz, C ₉ −
H), 7.21 (1H, br s, _C14 -H), 7.25
(1H, d, d, J = 9Hz, 2Hz, C ₁₁ −H),
7.90 (1H, d, J=9Hz, _C12 -H), 8.48
(1H, br s, C ₇ −H), 10.36 (1H, s, D ₂ O
−exchangeable).

MS: m/e 394 [M ⁺ ] (as C ₂₁ H ₁₈ N ₂ O ₆ = 394) Example 4-1 Synthesis of 7-ethylcamptothecin 1-oxide 7-ethylcamptothecin (1.00 g, 2.65 m
mol) in acetic acid (300 ml) and add 30%
− Add hydrogen peroxide (7.5 ml, 0.0736 mol), 65 ~
Stir at 70° for 3 hours. The reaction mixture was heated under reduced pressure to approximately 1/2
Concentrate to 4 volumes, dilute with ice water (500 ml), collect precipitated yellow-orange needles, and dry under reduced pressure at 60°C for 6 hours to obtain 808 mg of 7-ethylcamptothecin 1-oxide (yield: 77.7%). can get.

mp255゜～(dec.) NMR (in DMSO−d ₆ ): 0.87 (3H, t, J=7
Hz), 1.28 (3H, t, J=7Hz), 1.84 (2H,
q, J=7Hz), 3.10 (2H, q, J=7Hz),
5.26 (2H, s), 5.36 (2H, s), 6.24 (1H,
s, D ₂ O-exchangeable), 7.80 (3H, m),
8.10 (1H, s), 8.35 (1H, m) MS: m/e 392 [M ⁺ ] (as C ₂₂ H ₂₀ N ₂ O ₅ = 392) Example 4-2 of 7-ethyl-10-hydroxycamptothecin Synthesis 7-ethylcamptothecin 1-oxide (100
mg, 0.255 mmol) was dissolved in acetonitrile (65 ml), dioxane (30 ml), and water (5 ml), to which concentrated sulfuric acid (0.1 ml) was added and irradiated with light for 25 minutes. The reaction mixture was concentrated under reduced pressure, water (100 ml) was added, and the mixture was extracted with chloroform (100 ml x 3).
Dry the chloroform layer with magnesium sulfate,
The residue was purified by silica gel column chromatography (2% methanol-chloroform) to give 12 mg of 7-ethylcamptothecin as well as 43 mg of the title compound (yield:
49.1%) is obtained as pale yellow-white crystals. m.
p.231゜〜(dec.) [EtOH] NMR (in CDCl ₃ ) δ: 0.98 (3H, t, J=7
Hz), 1.38 (3H, t, J=7Hz), 1.90 (2H,
q, J=7Hz), 3.08 (2H, q, J=7Hz),
5.17 (2H, s), 5.23 (1H, d, J=16Hz),
5.54 (1H, d, J = 16Hz), 7.34 (2H, m),
7.39 (1H, s), 7.92 (1H, d, J = 9Hz) MS: m/e 392 [M ⁺ ] (as C ₂₂ H ₂₀ N ₂ O ₅ = 392) Example 4-3 7-ethyl-5・Synthesis of 10-dihydroxycamptothecin Dissolve 7-ethyl-10-hydroxycamptothecin (50 mg, 0.128 mmol) in DMF (20 ml),
This is combined with anhydrous potassium carbonate (150mg) and iodine (40mg).
mg, 0.157 mmol) and stirred at room temperature for 5 hours.
Thereafter, insoluble matter was removed by filtration, the liquid was dried and the residue was purified by silica gel column chromatography to obtain 35 mg (67.0 mg) of the title compound.
%) is obtained.

^1H -NMR (in DMSO- _d6 ) δppm: 0.90 (3H,
t, J=7.5Hz), 1.30 (3H, t, J=7.5Hz),
1.90 (2H, q, J = 7.5Hz), 3.30 (2H, q, J
=7.5Hz), 5.40 (2H, s), 6.50 (1H, s),
7.0−8.0 (6H, m), 10.30 (1H, s).

MS: m/e 408 [M ⁺ ], (as C ₂₂ H ₂₀ N ₂ O ₆ = 408) Example 4-4 Synthesis of 7-ethyl-10-hydroxy-5-methoxycamptothecin 7-ethyl-5・10 - Dihydroxycamptothecin (20 mg, 0.049 mmol) in methanol (30 ml)
Add concentrated sulfuric acid (0.5 ml) and stir for 48 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and washed with water. The chloroform layer is dried over anhydrous magnesium sulfate, dried under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound (18 mg, 87.0%).

^1H -NMR (in CDCl ₃ ) ppm: 1.00 (3H, t, J
= 7.5Hz), 1.25 (3H, t, J = 7.5Hz), 1.95
(2H, q, J=7.5Hz), 3.40 (2H, q, J=7.5
Hz), 4.00 (3H, s), 5.44 (2H, ABq), 6.80
−8.10 (5H, m).

MS: m/e: 422M ⁺ (as C ₂₃ H ₂₂ N ₂ O ₆ = 422) Example 5 Synthesis of 7-ethyl-10-methoxycamptothecin 7-ethylcamptothecin 1-oxide (100
mg, 0.255 mmol) in methanol (50 ml)-dioxane (50 ml), and concentrated sulfuric acid (0.1
ml) and irradiate with light for 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with water (100 ml), extracted with chloroform (100 ml x 3), the chloroform layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure, and the residue was purified with silica gel (5 g). High performance liquid chromatography (RiChrosorb SI-60 column, 10%
-acetone-chloroform)
27mg with 18mg 7-ethylcamptothecin
The title target product (yield: 33.2%) is obtained. Pale yellow-white needle crystals, mp261°~(dec.) [ n -hexane-chloroform] NMR (in _CDCl3 ) δ: 1.28 (3H, t, J=7
Hz), 1.49 (3H, t, J=7Hz), 1.97 (2H,
q, J=7Hz), 3.24 (2H, q, J=7Hz),
4.30 (3H, s), 5.27 (2H, s), 5.25 (1H,
d, J=16Hz), 5.70 (1H, d, J=16Hz),
7.20 (1H, d, J = 3Hz), 7.47 (1H, d×
d, J=9Hz, 3Hz), 7.72 (1H, s), 8.53
(1H, d, J = 9Hz) MS: m/e 406 [M ⁺ ] (as C ₂₃ H ₂₂ N ₂ O ₅ = 406) Example 6-1 Synthesis of 7-propylcamptothecin 1-oxide 7-propylcamptothecin (390mg, 1m
mol) in acetic acid (55 ml) and add 30% -
Add hydrogen peroxide (3 ml, 0.0294 mol) to 65-70
Stir at ℃ for 4 hours. The reaction mixture was heated under reduced pressure for approximately 10 min.
Concentrate to a volume of 60 ml, dilute with ice water (250 ml), remove the precipitated yellow-orange needles, and boil for 60 mL under reduced pressure.
After drying for 6 hours at <0>C, 278 mg (yield: 68.4%) of 7-propylcamptothecin 1-oxide is obtained. mp238゜～(dec.), MS: m/e 406
[M ⁺ ] (as C ₂₃ H ₂₂ N ₂ O ₅ = 406) Example 6-2 Synthesis of 10-hydroxy-7-propylcamptothecin 7-propylcamptothecin 1-oxide (200 mg, 0.493 mmol) was dissolved in dioxane (60 ml) - Dissolve in acetonitrile (20 ml) - water (5 ml), add concentrated sulfuric acid (100μ), and irradiate with light for 30 minutes. The reaction mixture was concentrated under reduced pressure and added to water (100ml).
Dilute with The insoluble matter is removed, dried, and purified by silica gel column chromatography (2% methanol-chloroform) to obtain the title target compound (121 mg, yield 60.5%) along with 11 mg of 7-propylcamptothecin.

Pale yellow-white needle crystals, mp237゜~ (dec.) [Toluene] NMR (in DMSO- _d6 ) δ: 0.89 (3H, t, J=
7Hz), 1.06 (3H, t, J=7Hz), 1.60−1.90
(5H, m), 3.00 (2H, t, J=7Hz), 5.24
(2H, s), 5.40 (2H, s), 6.24 (1H, s,
D ₂ O−exchangeable), 7.35 (1H, s), 7.30
(2H, m), 7.99 (1H, d, J = 9Hz) MS: m/e 406 [M ⁺ ] (as C ₂₃ H ₂₂ N ₂ O ₅ = 406) Example 7-1 7-Benzylcamptothecin 1- Synthesis of oxide 7-benzylcamptothecin (250mg, 0.570m
mol) in acetic acid (50 ml) and add 30% -
Add hydrogen peroxide (2 ml, 0.0196 mol) to 65-70
Stir at ℃ for 3 hours. The reaction mixture was heated under reduced pressure for approximately 10 min.
Concentrate to ml volume, then ice water (250ml)
Dilute with After this was left at room temperature for 12 hours, the yellow-orange needle crystals that had precipitated were removed and heated at 60℃ under reduced pressure for 6 hours.
When dried for an hour, 7-benzylcamptothecin 1
-164 mg (yield: 63.5%) of oxide are obtained.

mp220゜～(dec.) NMR (in CDCl ₃ ): 1.09 (3H, t, J = 7.5Hz),
1.87 (2H, q, J = 7.5Hz), 4.48 (2H, s),
5.16 (2H, s), 5.20 (1H, d, J=16Hz),
5.64 (1H, s, J=16Hz), 7.05−8.12 (8H,
m), 8.32 (1H, s), 8.80 (1H, m).

MS: m/e 457 [M ⁺ ] (as C ₂₇ H ₂₂ N ₂ O ₅ = 454) Example 7-2 Synthesis of 10-acetoxy-7-benzylcamptothecin 7-Benzylcamptothecin 1-oxide (100 mg, 0.22 mmol ) in acetic acid (100ml),
Irradiate with light for 1 hour. The reaction mixture was dried under reduced pressure, decolorized with silica gel (5 g), and then subjected to high performance liquid chromatography [RiChrosorb SI-60 column, 4
%-acetone-chloroform] to obtain 28 mg (yield: 29.9%) of the desired product along with 14 mg of 7-benzyl-camptothecin.
When this product is recrystallized from n -hexane-chloroform, pale yellow-white needle crystals are obtained.

m.p.226゜~ (dec.).

NMR (in CDCl ₃ ) δ: 1.03 (3H, t, J = 7.3
Hz), 1.85 (2H, q, J = 7.3Hz), 2.37 (3H,
s), 4.52 (2H, s), 5.11 (2H, s), 5.26
(1H, d, J=16Hz), 5.73 (1H, d, J=16
Hz), 7.10 (5H, m), 7.53 (1H, d×d, J
=9Hz, 3Hz), 7.65 (1H, s), 7.89 (1H,
d, J = 3 Hz), 8.27 (1H, d, J = 9 Hz) MS: m/e 496 [M ⁺ ] (as C ₂₉ H ₂₄ N ₂ O ₆ = 496) Example 8-1 7-acetoxymethylcamptothecin Synthesis of 1-oxide 7-acetoxymethylcamptothecin (1.0
g, 2.38 mmol) was dissolved in acetic acid (150 ml), 30% hydrogen peroxide (10 ml, 0.0981 mol) was added thereto, and the mixture was stirred at 65-70°C for 3.5 hours. The reaction mixture is concentrated under reduced pressure to approximately 50 ml, diluted with ice water (350 ml) and extracted with chloroform (3 x 300 ml).
The chloroform layer was washed with a 7% aqueous sodium bicarbonate solution, then dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by reprecipitation with chloroform- n -hexane to give 7-
Acetoxymethylcamptothecin 1-oxide
679 mg (yield: 65.9%) are obtained as yellow needles.

mp250゜～(dec.) NMR (in DMSO−d ₆ ): 0.87 (3H, t, J=7
Hz), 1.83 (2H, q, J=7Hz), 2.05 (3H,
s), 5.42 (4H, br s), 5.61 (2H, s), 6.42
(1H, s, D ₂ O−exchangeable), 7.80 (2H,
m), 7.91 (1H, s), 8.20 (1H, m), 8.63
(1H, m), MS: m/e 436 [M ⁺ ] (as _C23H20N2O7 =436) Example 8-2 Synthesis of 7- _{acetoxymethyl} - ₁₀ - _{hydroxycamptothecin} 7-acetoxymethylcamptothecin 1-oxide (75mg, 0.172mmol) in dioxane (40ml)
- Acetonitrile (50 ml) - Dissolve in water (10 ml), add concentrated sulfuric acid (0.1 ml), and irradiate with light for 45 minutes. The reaction mixture was concentrated to about half its volume under reduced pressure.
Dilute with water (100 ml) and chloroform (200 ml
2) Extract. The chloroform layer was dried over magnesium sulfate, filtered and dried under reduced pressure, and the residue was subjected to silica gel column chromatography (2%
-methanol-chloroform) to give 24 mg (yield: 32%) of the title compound along with 7-acetoxymethylcamptothecin (22 mg).

Pale yellow-white needles, mp257° (dec.) [ n -hexane-chloroform] NMR (in DMSO- _d6 ) δ: 0.98 (3H, t, J=
7Hz), 1.38 (3H, t, J=7Hz), 1.90
(2H, q, J=7Hz), 3.08 (2H, q, J=7
Hz), 5.17 (2H, s), 5.23 (2H, s), 5.54
(2H, s), 6.34 (1H, br, D ₂ O−
exchangeable), 7.34 (2H, m), 7.39 (1H,
s), 7.92 (1H, d, J = 9Hz) MS: m/e 436 [M ⁺ ] (as C ₂₃ H ₂₀ N ₂ O ₇ = 436) Example 9-1 of 7-hydroxymethylcamptothecin 1-oxide Synthesis 7-hydroxymethylcamptothecin (300
mg, 0.794 mmol) in glacial acetic acid (70 ml), added 30% hydrogen peroxide (30 ml), and
Stir for 1 hour. Add to this 30% hydrogen peroxide (20
ml) and continue stirring at 70-80°C for an additional 1.5 hours. The reaction mixture was concentrated under reduced pressure to a volume of 40 ml, added with ice water (60 ml) and left for 12 hours. The precipitated yellow crystals are collected and dried under reduced pressure.
142 mg (yield: 45.4%) of the title compound is obtained as yellow needles.

mp255−260℃(dec.) IRν ^KBr _nax cm ^-1 ; 3400, 2940, 1755, 1650, 1600
,
1460, 1160, 1100, 765 Example 9-2 Synthesis of 7-hydroxymethyl-10-hydroxycamptothecin 7-hydroxymethylcamptothecin 1-oxide (50 mg, 0.127 mmol) was dissolved in dioxane (40 mg, 0.127 mmol).
ml), acetonitrile (40 ml), and water (10 ml), add concentrated sulfuric acid (3 drops), and irradiate with light for 10 minutes. The reaction mixture was concentrated under reduced pressure, water (20 ml) was added to the residue, and the insoluble matter was dried to obtain 40 mg (80%) of the title compound. This was purified by silica gel chromatography.

mp260−263℃(dec.) IRν ^KBr _nax cm ^-1 ; 3400, 2980, 1735, 1650, 1590
,
1240, 1160, 1100, 800, 775

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or an acyloxyl group,
R ² is a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group or an acyloxymethyl group, R ³ is a hydrogen atom, an alkyl group or an acyl group, and X is an oxygen atom or a sulfur atom. However, if R ¹ and R ² are both hydrogen atoms, R ³
is not -OH, _-OCH3 , _-OCOCH3 ).