Pyranoindolizine derivatives and preparation process thereof

Description: TECHNICAL FIELD [Detailed description of the invention]

[Industrial application field] The present invention is based on the following formula (I), which is useful as a synthetic intermediate for a novel pyranoindolidin derivative, more specifically, a camptothecin derivative having an anticancer activity.<img file="JPH0737460B2_D0001.tif" />(In the formula, R is a hydrogen atom or a hydroxyl group, Q is C = O or<img file="JPH0737460B2_D0002.tif" />Is shown. However, this does not apply when R is a hydrogen atom and Q is C = O. ) It relates to a pyranoindolizine derivative represented by. [Conventional technology and its problems] Conventionally, the following equation (II) or (III)<img file="JPH0737460B2_D0003.tif" />The camptothecin derivative represented by (1) is known to have an excellent anticancer activity (Japanese Patent Laid-Open No. 58-39683, Tetrahedron 37,1047 (1981)), and a synthetic intermediate for advantageously synthesizing the compound is provided. Was desired. Also, the following equation (IV)^*) <img file="JPH0737460B2_D0004.tif" />The natural camptothecin represented by is known to have an S-coordination at its 20th position, and therefore, a synthetic intermediate capable of advantageously producing a natural camptothecin having an S-coordination or a derivative thereof. The donation of the body was desired. [Means to solve problems] As a result of conducting various studies to advantageously produce such a camptothecin derivative, the present inventor has industrially advantageous from the pyranoindolidin derivative represented by the formula (I), which was synthesized for the first time by the present inventor. We have found that the above camptothecin derivative can be derived, and completed the present invention. In addition, the following formula (I) in which the steric coordination at the 4-position of compound (I) is S^*) <img file="JPH0737460B2_D0005.tif" />(In the formula, Q and R have the above meanings) The present invention was completed by finding that natural camptothecin can be easily derived from the pyranoid lysine derivative represented by. Therefore, an object of the present invention is to provide a pyranoindolizine derivative useful as a synthetic intermediate for an anticancer substance represented by the above formula (I). Another object of the present invention is the above equation (I).^*) Hisage the Pila Roh India lysine derivative represented by the one in which provide. Furthermore, another object of the present invention is to provide a method for producing these pyranoindolizine derivatives. The compound (I) of the present invention generally comprises closing the compound (V) to form the compound (Ia) of the present invention according to, for example, the following reaction formula, and oxidizing the compound (Ia) to form the compound (Ib) of the present invention. Is prepared by obtaining and subjecting compound (Ib) to a de-ketal reaction.<img file="JPH0737460B2_D0006.tif" />That is, ethyl 6-[(acetoxy) methyl] -α-ethyl-1,1-ethylenedioxy-5-oxo-1,2,3,5-tetrahydroindolizine-7-acetate (V) [MC Wanai et al. (MCWani) et al., Journal of Medicinal Chemistry (J.Med.Chem.) 23,554 (1980)] was added to water in an alkaline solvent prepared with lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. After decomposition, the compound of formula (Ia) was treated with an acidic solvent prepared with acetic acid, hydrochloric acid, sulfuric acid, etc. [R = H in formula (I),<img file="JPH0737460B2_D0007.tif" />Can be obtained. The solvent is not particularly limited as long as it is an inert solvent for the reaction, and for example, alcohols such as methanol, dioxane, N, N-dimethylformamide and the like are used. This compound (Ia) is dissolved in a reaction-inactive solvent such as N, N-dimethylformamide, and in the presence of cupric acetate, cupric chloride, etc. or alkali metal alcoholate and trialkyl phosphite. Alternatively, by introducing oxygen gas in the presence of triaryl phosphite, the compound of formula (Ib) having a hydroxyl group [R = OH in formula (I),<img file="JPH0737460B2_D0008.tif" />Can lead to. Further, when the compound of the formula (Ib) is deketalized in an acidic solvent prepared with hydrochloric acid, sulfuric acid or the like, the compound of the (Ic) having a ketone group [R = OH, Q in the formula (I)) = C = O] can be obtained. The compound of formula (Ia) is a known compound 4-ethyl-7,8-dihydro-1H-pyrano [3,4] if de-ketalization is carried out in the same manner as above without introducing a hydroxyl group. -f] Indolizine-3,6,10 (4H) -trion [R = H, Q = C = O in equation (I)] can be derived. In addition, a pyranoindolizine derivative having a steric coordination of S (I)^*) Is preferably produced, for example, by the following method. Method 1: Pyranoindolizine derivative (I^*), Where Q is represented by O = [Compound (I)^*c)] is obtained by reacting the above compound (Ib) with (R)-(+)-α-methylbenzylamine or (S)-(-)-α-methylbenzylamine according to the following formula. It can be produced by separating the compound represented by the formula (VI) or (VII) from the mixture of the diastereomers and treating it with an acid.<img file="JPH0737460B2_D0009.tif" />That is, first, compound (Ib) is mixed with (R)-(+)-α-methylbenzylamine or (S)-(-)-α-methylbenzylamine under a nitrogen stream at a temperature of about 20 to about 200 ° C. The reaction gives compound (VIII) or compound (IX), which is a mixture of two diastereomers. The mixture is then separated according to a conventional method such as fractional crystallization to give diastereomers (VI) or diastereomers (VII). Suitable solvents for crystallization and recrystallization include, for example, dichloromethane, n-hexane, benzene, isopropyl alcohol and the like. This separation of diastereomers can be performed almost completely by one or two recrystallizations, and the recovery rate is also good. When the diastereomer (VI) or diastereomer (VII) thus obtained is treated in an acidic solvent prepared with an acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid, the hydrolysis of the amide and the lactone are performed. Hydrolysis and de-ketalization proceed at once, and the target optically active compound of the present invention (I)^*c) is obtained. Method 2: Pyranoindolizine derivative (I^*), Q<img file="JPH0737460B2_D0010.tif" />Represented by [Compound (I)^*b)] is derived from the compound represented by the formula (X) according to the following reaction formula.<img file="JPH0737460B2_D0011.tif" /><img file="JPH0737460B2_D0012.tif" />(In the formula, X represents a halogen atom and Ts represents a p-toluenesulfonyl group) As shown in the chemical reaction formula, this production method comprises a halogenation reaction, a substitution reaction, an ethylation reaction, a reduction reaction, a transfer reaction via nitroso, and a ring closure reaction. Each reaction will be described below. Halogenation reaction: Ethyl 6-cyano-1,1- (ethylenedioxy) -5-oxo-1,2,3,5-tetrahydroindolidine-7-acetate (X) [Journal of Medicinal Chemistry (J. Med. Chem.) 23,554 (1980)] is treated with a base such as sodium hydride, potassium t-butoxide, etc. in a solvent not involved in the reaction such as 1,2-dimethoxyethane, N, N-dimethylformamide, or a mixed solvent thereof. Then, by adding a halogen such as bromine or chlorine, the compound of the formula (XI) can be produced. The reaction is usually carried out at 0 to 100 ° C, preferably 30 to 80 ° C, for 10 minutes to 15 hours, preferably 20 minutes to 5 hours. Substitution reaction; The compound of formula (XI) is reacted with an alkali metal salt such as sodium or potassium of (R) -N-tosylproline in a solvent such as N, N-dimethylformamide or N, N-dimethylacetamide which is not involved in the reaction. The compound of formula (XII) can be produced by allowing the compound to be produced. The reaction is usually carried out at 20-100 ° C, preferably 50-80 ° C, for 5 minutes-5 hours, preferably 10 minutes-1 hour. Ethylation reaction: The compound of formula (XII) is reacted with a base such as sodium hydride or potassium t-butoxide in a solvent such as N, N-dimethylformamide or 1,2-dimethoxyethane which is not involved in the reaction, and then iodide. The compound of formula (XIII) can be produced by adding an ethyling agent such as ethyl or diethyl sulfate. The reaction is usually carried out at -20 to 50 ° C, preferably 0 to 30 ° C, for 10 minutes to 15 hours, preferably 30 minutes to 5 hours. Reduction reaction: The compound of the formula (XIII) can be produced by reacting the compound of the formula (XIII) in a hydrogen stream in the presence of acetic anhydride using a lanenitkel and, if necessary, irradiating with a tungsten lamp. The reaction is usually carried out at 10-100 ° C, preferably 20-60 ° C, for 10 minutes-8 hours, preferably 30 minutes-5 hours. Rearrangement reaction via nitroso: The compound of formula (XIV) is mixed with a nitroso agent such as sodium nitrite in a mixed solvent of acetic anhydride and acetic acid at 0 to 50 ° C, preferably 0 to 30 ° C for 30 minutes to 15 hours, preferably. The formula (XV) is obtained by reacting for 1 to 5 hours and then heating and stirring the resulting nitroso compound at 50 to 120 ° C, preferably 60 to 90 ° C, for 30 minutes to 12 hours, preferably 1 hour to 5 hours. ) Compound can be produced. Ring closure reaction: The compound of formula (XV) is hydrolyzed with an alkaline aqueous solution such as lithium hydroxide, sodium hydroxide or potassium hydroxide in an alcohol such as ethanol or a solvent not involved in the reaction such as dioxane, and then acetic acid, citric acid or Formula (I) by treatment in an acidic solvent prepared with hydrochloric acid or the like.^*The compound of b) can be produced. Hydrolysis is carried out at 0 to 50 ° C, preferably 20 to 40 ° C, for 5 minutes to 5 hours, preferably 10 minutes to 3 hours, and the reaction in an acidic solvent is 0 to 70 ° C, It is preferably carried out at 10 to 40 ° C. for 1 hour to 72 hours, preferably 12 to 24 hours. De-ketal reaction: The compound (I) is treated in the same manner as the de-ketal reaction of the compound (Ib).^*b) to compound (I^*c) can be manufactured. [Effect of the invention] The compound (I) of the present invention thus obtained is N- (o-aminobenzylidene) -p-toluidine (XVI) or 2-amino-4-methoxypropiophenone (XVII), for example, according to the following reaction formula. ) To camptothecin (V) having an anticancer activity or a camptothecin derivative (II) described in JP-A-58-39683, which is further demethylated to lead to compound (III). Can be done.<img file="JPH0737460B2_D0013.tif" />That is, the compound (Ic) of the present invention obtained by treating the compound (Ib) of the present invention in an acidic solvent prepared with an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid is used in a reaction called a free drender reaction. Under the above conditions, condensation with a compound of formula (XVI) or formula (XVII) can lead to natural camptothecin (IV) or a derivative thereof (II), which is further demethylated to give compound (III). Be done. Condensation can be carried out, for example, by heating under reflux with a Dane Stark apparatus in the presence of p-toluenesulfonic acid or the like in a solvent inert to the reaction such as toluene or benzene. Further, the demethylation reaction can be carried out, for example, by heating and refluxing in the presence of aluminum chloride, aluminum bromide or the like or in a hydrobromic acid solution in a solvent inert to the reaction such as toluene or benzene. The formula (I) is used as a starting material for producing camptothecin and the like.^*) Pyranoid lysine derivatives are used, and the natural camptothecin (IV) shown in the following formula is used.^*) And natural camptothecin derivatives (II)^*) And (III^*) Is obtained, and a better effect is expected.<img file="JPH0737460B2_D0014.tif" /><img file="JPH0737460B2_D0015.tif" />[Example] Next, the present invention will be described in more detail with reference to Examples and Reference Examples. Example 1 4-Ethyl-6,6- (ethylenedioxy) -7,8-dihydro-1H-pyrano [3,4-f] Indolizine-3,10 (4H) -dione (Ia): Ethyl 6-[(acetoxy) methyl] -α-ethyl-1,1- (ethylenedioxy) -5-oxo-1,2,3,5-tetrahydroindridin-7-acetic acid (V) 759 mg in methanol Dissolve in 15 ml, add 5 ml of water and then 420 mg of lithium hydroxide (monohydrate), and stir at room temperature for 2 hours. After distilling off methanol, about 10 ml of ice water and then 1.5 ml of acetic acid are added to the residue, and the mixture is stirred at room temperature for 22 hours. Extract with dichloromethane, wash with water and dry with anhydrous Glauber's salt. The solvent is distilled off and the residue is recrystallized from dichloromethane and n-hexane to obtain 535 mg of the title compound as colorless crystals. Melting point: 130 ~ 131 ° C NMR (CDCl₃Medium) δ: 1.01 (3H, t, J = 7Hz, CH₃-), 1.95 (2H, m, -CH₂CH₃), 2.37 (2H, t, J = 7Hz, C₇-H), 3.43 (1H, t, J = 6Hz, C₄-H), 4.12 (6H, m, -O-CH₂CH₂-O- and C₈-H), 5.27 (2H, ABq, J = 17Hz, C₁-H), 6.11 (1H, s, C₅-H)<img file="JPH0737460B2_D0016.tif" />Elemental analysis C₁₅H₁₇NO₅Against Calculated C, 61.85; H, 5.88; N, 4.81 Measured value C, 61.71; H, 5.85; N, 4.79 Example 2 4-Ethyl-6,6- (ethylenedioxy) -7,8-dihydro-4-hydroxy-1H-pyrano [3,4-f] Indolizine-3,10 (4H) -dione (Ib): 300 mg of compound (Ia), 352 mg of cupric acetate and 50 μl of 50% dimethylamine obtained in Example 1 are dissolved in 15 ml of N, N-dimethylformamide, and the mixture is stirred at room temperature for 1 hour while introducing oxygen gas. After distilling off the solvent, the residue is dissolved in dichloromethane and washed with water. The organic layer is dried over anhydrous Glauber's salt, the solvent is distilled off, and the residue is applied to a column kutomato graphie using silica gel (7 g) as a carrier. The yellow oil obtained from the benzene: ethyl acetate = 1: 1 fraction is recrystallized from dichloromethane and n-hexane to give 135 mg of the colorless needle-like title compound. Melting point: 180 ~ 181 ° C NMR (CDCl₃Medium) δ: 0.96 (3H, t, J = 7Hz, CH₃), 1.77 (2H, q, J = 7Hz, CH₃CH₂-), 2.38 (2H, t, J = 7Hz, C₇-H), 4.12 (6H, m, -OCH₂CH₂-O- and C₈-H), 5.30 (2H, ABq, J = 16Hz, C₁-H), 6.53 (1H, s, C₅-H)<img file="JPH0737460B2_D0017.tif" />Elemental analysis C₁₅H₁₇NO₆Against Calculated C, 58.63; H, 5.58; N, 4.56 Measured value C, 58.56; H, 5.57; N, 4.56 Example 3 4-Ethyl-6,6- (ethylenedioxy) -7,8-dihydro-4-hydroxy-1H-pyrano [3,4-f] Indolizine-3,10 (4H) -dione (Ib): 9.96 g of compound (Ia) obtained in Example 1 is dissolved in 200 ml of N, N-dimethylformamide, 5.01 g of potassium tert-butoxide is added at -40 ° C, and the mixture is stirred for 20 minutes. Add 21 ml of triethyl phosphate and stir for 2 hours and 30 minutes while introducing oxygen gas. Further, 6 ml of concentrated hydrochloric acid was added to adjust the pH to 1, and the mixture was stirred for 20 minutes, and then 2.5 ml of concentrated ammonia water was added to adjust the pH to 8. The solvent is distilled off, the residue is dissolved in dichloromethane, and the mixture is washed with water. After drying the organic layer with anhydrous sodium sulfate, the solvent is distilled off, n-hexane is added to the residue, and the mixture is stirred. The insoluble material is removed and recrystallized from dichloromethane and n-hexane to obtain 8.10 g of the colorless needle-shaped title compound. The melting points, NMR and IR of this substance were in agreement with those of the compound obtained in Example 2. Example 4 4-Ethyl-7,8-dihydro-4-hydroxy-1H-pyrano [3,4-f] indolizine-3,6,10 (4H) -trione (Ic): 500 mg of the compound (Ib) obtained in Example 2 is dissolved in 15 ml of acetone, 1 ml of 2N sulfuric acid is added, and the mixture is stirred at room temperature for 5 hours. After distilling off acetone, the residue is dissolved in diclomethane and washed with water. After drying the organic layer with anhydrous Glauber's salt, the solvent is distilled off. The residue is recrystallized from ether to give 260 mg of the title compound in pale yellow granularity. Melting point: 193 ~ 195 ° C (decomposition) NMR (CDCl₃Medium) δ: 0.96 (3H, t, J = 7Hz, CH₃), 1.80 (2H, q, J = 7Hz, CH₃CH₂-), 2.93 (2H, t, J = 7Hz, C₇-H), 4.30 (2H, t, J = 7Hz, C₈-H), 5.37 (2H, ABq, J = 17Hz, C₁-H), 7.16 (1H, s, C₅-H)<img file="JPH0737460B2_D0018.tif" />Elemental analysis C₁₃H₁₃NO₅Against Calculated C, 59.31; H, 4.98; N, 5.32 Measured value C, 59.19; H, 5.15; N, 5.19 Example 5 (1) (S) -α-Ethyl-1,1- (Ethylenedioxy) -α-Hydroxy-6- (Hydroxymethyl) -N-[(R) -1-phenylethyl] -5-oxo-1, 2,3,5-tetrahydroindolizine-7-acetamide (VI): 3 g of the compound (Ib) obtained in Example 2 is added to 5.9 g of (R)-(+)-α-methylbenzylamine, and the mixture is stirred at 80 ° C for 20 hours under a nitrogen gas stream. After completion of the reaction, add 200 ml of dichloromethane, wash with 10% citric acid and water in this order, dry with anhydrous Glauber's salt, and distill off the solvent. The residue is purified by column chromatography on silica gel (100 g) to give 3 g of a colorless oil from the flow of chloroform-methanol (98: 2). This is crystallized with dichloromethane and n-hexane to obtain 2.7 g of colorless crystals. Further, the crystals are dissolved in benzene when heated and left overnight. The precipitate is removed by excess and the mother liquor is concentrated to dryness to obtain 1.35 g of a colorless foam. This was crystallized with dichloromethane and n-hexane, and recrystallization was repeated twice with dichloromethane-n-hexane to obtain 1.25 g of the title compound as colorless scaly crystals. Melting point: 119 ~ 120 ° C NMR (CDCl₃Medium) δ: 0.99 (3H, t, J = 7Hz, CH₃CH₂), 1.52 (3H, d, J = 7Hz, CH₃CH-), 2.30 (2H, t, J = 7Hz, C₂-H), 4.04 (6H, m, -O- (CH)₂)₂-O-, C₃-H), 4.68 (2H, ABq, J = 12.5Hz, CH₂OH), 5.07 (1H, m, CHCH₃), 6.60 (1H, s, C₈-H), 7.29 (5H, s, Ph)<img file="JPH0737460B2_D0019.tif" />Elemental analysis C₂₃H₂₈N₂O₄ 3 / 4H₂Against O Calculated C, 62.50; H, 6.73; N, 6.34 Measured value C, 62.49; H, 6.45; N, 6.25 (2) (S) -4-Ethyl-7,8-dihydro-4-hydroxy-1H-pyrano [3,4-f] Indolizine-3,6,10 (4H) -trione (I)^*c): 815 mg of compound (VI) obtained in (1) was dissolved in 15 ml of dimethoxyethane, and 2N-H was dissolved therein.₂SO₄Add 5 ml. The solution is heated and stirred under a nitrogen gas stream for 20 hours. After completion of the reaction, 150 ml of dichloromethane was added, and after washing with water, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was crystallized with ethanol and petroleum ether to obtain 315 mg of the title compound as colorless needle-like crystals. Melting point: 176 ~ 177 ° C (decomposition) Specific rotation: [α]_D+ 120.57 ° (C = 0.622, chloroform) NMR (CDCl₃Medium) δ: 0.98 (3H, t, J = 7Hz, CH₃CH₂), 1.82 (2H, ABq, J = 7Hz, CH₃CH₂-), 2.96 (2H, t, J = 7Hz, C₇-H), 3.71 (1H, s, OH), 4.35 (2H, t, J = 7Hz, C₈-H), 5.46 (2H, ABq, J = 17Hz, C₁-H), 7.23 (1H, s, C₅-H)<img file="JPH0737460B2_D0020.tif" />Elemental analysis: C₁₃H₁₃NO₅Against Calculated C, 59.31; H, 4.98; N, 5.32 Measured value C, 59.18; H, 5.03; N, 5.28 Example 6 (1) (S) -α-Ethyl-1,1- (Ethylenedioxy) -α-Hydroxy-6- (Hydroxymethyl) -N-[(S) -1-phenylethyl] -5-oxo-1, 2,3,5-tetrahydroindolizine-7-acetamide (VII): 1 g of the compound (Ib) obtained in Example 2 is added to 3 ml of (S)-(-)-α-methylbenzylamine, and the mixture is stirred at 100 ° C for 18 hours under a nitrogen gas stream. After completion of the reaction, 150 ml of dichloromethane is added, the mixture is washed with 10% citric acid and water in this order, dried over anhydrous Glauber's salt, and the solvent is distilled off. The residue is purified by column chromatography on silica gel (30 g) to give 1 g of a colorless oil from the flow of chloroform-methanol (98: 2). This is crystallized with dichloromethane and n-hexane and taken to obtain 900 mg of colorless crystals. The obtained crystals are dissolved in benzene when heated and left overnight. Precipitated crystals were removed to obtain 460 mg of colorless needle-shaped crystals, which were further recrystallized using dichloromethane and n-hexane to obtain 380 mg of the title compound of colorless needle-shaped crystals. Melting point: 115 ~ 116 ° C NMR (CDCl₃Medium) δ: 0.88 (3H, t, J = 7Hz, CH₃CH₂-), 1.50 (3H, d, J = 7Hz, CH₃CH-), 2.32 (2H, t, J = 7Hz, C₂-H)), 4.10 (6H, m, -O- (CH)₂)₂-O, C₃-H), 4.88 (2H, ABq, J = 12.6Hz, CH₂OH), 5.10 (1H, m, CHCH₃), 6.67 (1H, s, C₈-H), 7.32 (5H, s, Ph)<img file="JPH0737460B2_D0021.tif" />Elemental analysis C₂₃H₂₈N₂O₄ 1 / 4H₂Against O Calculated C, 63.80; H, 6.63; N, 6.47 Measured value C, 63.51; H, 6.69; N, 6.45 (2) (S) -4-Ethyl-7,8-dihydro-4-hydroxy-1H-pyrano [3,4-f] Indolizine-3,6,10 (4H) -trione (I)^*c): 300 mg of the compound (VII) obtained in (1) is dissolved in an 80% trifluoracetic acid solution, and stirring is continued for 2 hours at room temperature under a nitrogen gas stream. The reaction solution is concentrated to dryness, and the obtained residue is purified by column chromatography using silica gel (10 g) to obtain a colorless oil from a chloroform-methanol (98: 2) stream. This was crystallized with ethanol and petroleum ether to obtain 170 mg of the title compound as colorless needle-shaped crystals. Specific rotation: [α]_D+ 121.42 ° (C = 0.532, chloroform) The melting points, NMR, and IR of this substance were completely in agreement with those of the compound obtained in Example 5 (2). Example 7 (1) Ethyl α-Brom-6-cyano-1,1- (ethylenedioxy) -5-oxo-1,2,3,5-tetrahydroindolidine-7-acetate (XI): Dissolve 3.04 g of compound (X) in 60 ml of 1,2-dimethoxyethane, add 440 mg of 60% NaH to this, stir at 80 ° C for 10 minutes, return the reaction solution to room temperature, add 0.77 ml of bromine, and stir for 2 hours. To do. After distilling off the reaction solution, the residue was dissolved in chloroform, and 10% citric acid and 10% Na were dissolved.₂S₂O₃, Wash in the order of water, dry with anhydrous sodium sulfate, and concentrate. The residue was solidified with chloroform-ether and taken to give 3.72 g of the title compound. Melting point: 161 ~ 163 ° C (decomposition) NMR (CDCl₃Medium) δ: 1.32 (3H, t, J = 7Hz, -CH₂CH₃), 2.42 (2H, t, J = 7Hz, C₂-H), 4.16 (4H, s, -O- (CH)₂)₂-O-), 4.0 ~ 4.5 (4H, m, C₃-H, -CH₂CH₃), 5.55 (1H, s, -CHBr-), 6.60 (1H, s, C₈-H)<img file="JPH0737460B2_D0022.tif" />Elemental analysis C₁₅H₁₅N₂O₅Against Br Calculated value (%) C, 47.02; H, 3.95; N, 7.31 Measured value (%) C, 43.97; H, 3.87; N, 7.34 (2) Ethyl 6-cyano-1,1- (ethylenedioxy) -α-[(R) -1- (p-toluenesulfonyl) pyrrolidine-2-ylcarbonyloxy] -5-oxo-1,2, 3,5-Tetrahydroindolizine-7-acetate (XII): 14.37 g of (R) -N-tosylproline was dissolved in 50 ml of N, N-dimethylformamide, and anhydrous Na₂CO₃Add 1.91g. Add 9.35 g of compound (XI) obtained in (1) under a nitrogen stream and stir at 70 ° C for 1 hour. After distilling off the reaction solution, the residue was dissolved in chloroform, and water was added to 5% LVDS.₃, Sequentially washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was placed on a silica gel column and developed with a mixed solution of toluene-ethyl acetate (2: 1) to concentrate and dry the fraction containing the desired product to obtain 13.0 g of the title compound. NMR (CDCl₃Medium) δ: 1.28,1.30 (each 1.5H, each t, each J = 7Hz, -CH₂CH₃), 1.5 ~ 2.6 (6H, m, C₂-H, -CH₂CH₂-), 2.43 (3H, s, -CH₃), 3.0 ~ 3.8 (2H, m, -CH₂-), 3.8 ~ 4.6 (9H, m, -O- (CH)₂)₂-O-, -CH₂CH₃, C₃-H,<img file="JPH0737460B2_D0023.tif" />6.18,6.29 (each 0.5H, each s), 6.61,6.64 (each 0.5H, each s, C₈-H), 7.31 (2H, d, J = 9Hz, Ph), 7.72 (2H, d, J = 9Hz, Ph)<img file="JPH0737460B2_D0024.tif" />Elemental analysis C₂₇H₂₉N₃O₉S 3 / 4H₂Against O Calculated value (%) C, 55.42; H, 5.25; N, 7.18 Measured value (%) C, 55.44; H, 4.99; N, 7.30 (3) Ethyl (S) -6-cyano-α-Ethyl-1,1- (ethylenedioxy) -α-[(R) -1- (p-toluenesulfonyl) pyrrolidine-2-ylcarbonyloxy]- 5-oxo-1,2,3,5-tetrahydroindolidin-7-acetate (XIII): Dissolve 3.50 g of compound (XII) obtained in (2) in 28 ml of anhydrous N, N-dimethylformamide, add 248 mg of 60% NaH, stir at room temperature for 1 hour, add 5 ml of ethyl iodide, and stir at room temperature for 3 hours. .. After distilling off the reaction solution, the residue is dissolved in chloroform, washed successively with 10% citric acid and water, dried over anhydrous sodium sulfate, and concentrated. The residue is subjected to silica gel column chromatography and developed with a mixed solution of benzene-ethyl acetate (3: 1) to concentrate the fraction containing the desired product. The residue was crystallized from 2-propanol to give 2.07 g of the title compound. Melting point: 75-80 ° C NMR (CDCl₃Medium) δ: 0.90 (3H, t, J = 7Hz, -CH₂CH₃), 1.31 (3H, t, J = 7Hz, -CH₂CH₃), 1.5 ~ 2.5 (4H, m,-(CH)₂)₂-), 2.43 (3H, s, -CH₃), 2.1 ~ 2.8 (4H, m, C₂-H, -CH₂CH₃), 3.0 ~ 3.8 (2H, m, -CH₂-), 3.8 ~ 4.6 (9H, m, -O- (CH)₂)₂-O-,<img file="JPH0737460B2_D0025.tif" />-CH₂-× 2), 6.61 (1H, s, C₈-H), 7.32 (2H, d, J = 8Hz, Ph), 7.18 (2H, d, J = 8Hz, Ph)<img file="JPH0737460B2_D0026.tif" />Elemental analysis C₂₉H₃₃N₃O₉Against S Calculated value (%) C, 58.09; H, 5.55; N, 7.01 Measured value (%) C, 57.98; H, 5.67; N, 7.02 (4) Ethyl (S) -6- (acetylaminomethyl) -α-ethyl-1,1- (ethylenedioxy) -α-[(R) -1- (p-toluenesulfonyl) pyrrolidine-2-yl Carbonyloxy] -5-oxo-1,2,3,5-tetrahydroindolidin-7-acetate (XIV): 2.00 g of the compound (XIII) obtained in (3) is added to a mixed solvent of 20 ml of acetic acid containing 6 g of Ranenitsukel and 50 ml of acetic anhydride, and reduction is carried out in a hydrogen stream for 2 hours under irradiation with a tungsten lamp. The residue obtained by removing and concentrating the lanenicelle is subjected to silica gel column chromatography. The mixture was developed with a mixed solution of chloroform-methanol (50: 1), and the fraction containing the desired product was concentrated to dryness to obtain 2.15 g of the title compound as amorphus. NMR (CDCl₃Medium) δ: 0.89 (3H, t, J = 7Hz, -CH₂CH₃), 1.29 (3H, t, J = 7Hz, -CH₂CH₃), 1.95 (3H, s, -COCH₃), 2.24 (3H, s, -CH₃), 1.5 ~ 2.8 (8H, m, C₂-H,-(CH₂)₂-,-CH₂CH₃), 3.0 ~ 3.8 (2H, m, -CH₂-), 3.8 ~ 5.0 (11H, m, -O- (CH)₂)₂-O-, -CH₂CH₃,-CH₂NH-, C₃-H,<img file="JPH0737460B2_D0027.tif" />6.78 (1H, s, C₈-H), 7.0 ~ 7.5 (1H, bro s, -NH-), 7.39 (2H, d, J = 7Hz, Ph), 7.84 (2H, d, J = 7Hz, Ph)<img file="JPH0737460B2_D0028.tif" />Elemental analysis C₃₁H₃₉N₃O₁₀S 1 1 / 4H₂Against O Calculated value (%) C, 55.72; H, 6.26; N, 6.29 Measured value (%) C, 55.59; H, 5.75; N, 6.39 (5) Ethyl (S) -6- (acetoxymethyl) -α-ethyl-1,1- (ethylenedioxy) -α-[(R) -1- (p-toluenesulfonyl) pyrrolidine-2-ylcarbonyl Oxy] -5-oxo-1,2,3,5-tetrahydroindolidin-7-acetate (XV): 1.98 g of the compound (XIV) obtained in (4) was dissolved in a mixed solution of 26 ml of acetic anhydride and 8 ml of acetic acid, and NaNO under ice cooling.₂Add 1.1 g and stir at the same temperature for 5 hours. After distilling off the reaction solution, 120 ml of carbon tetrachloride is added to the residue, and the mixture is heated under reflux for 5 hours. After cooling, water, 5% LVDS₃, Sequentially washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (70: 1), and the fraction containing the desired product was concentrated to dryness to obtain 1.46 g of the title compound as amorphus. NMR (CDCl₃Medium) δ: 0.89 (3H, t, J = 7Hz, -CH₂CH₃), 1.23 (3H, t, J = 7Hz, -CH₂CH₃), 2.04 (3H, s, -COCH₃), 1.5 ~ 2.8 (8H, m, C₂-H, -CH₂CH₃,-(CH₂)₂-), 2.43 (3H, s, -CH₃), 3.0 ~ 4.0 (2H, m, -CH₂-), 3.9 ~ 4.6 (9H, m, C₃-H, -CH₂CH₃, -O- (CH₂)₂-O-,<img file="JPH0737460B2_D0029.tif" />5.24 (2H, s, -CH₂O-), 6.76 (1H, s, C₈-H), 7.29 (2H, d, J = 8Hz, Ph), 7.75 (2H, d, J = 8Hz, Ph)<img file="JPH0737460B2_D0030.tif" />Elemental analysis C₃₁H₃₈N₂O₁₁S 1 / 2H₂Against O Calculated value (%) C, 56.78; H, 5.99; N, 4.27 Measured value (%) C, 56.60; H, 5.82; N, 4.19 (6) (S) -4-Tetyl-6,6- (ethylenedioxy) -7,8-dihydro-4-hydroxy-1H-pyrano [3,4-f] Indolizine-3,10 (4H) -Zeon (I^*b): Dissolve 324 mg of the compound (XV) obtained in (5) in a mixed solution of 6 ml of ethanol and 3 ml of water, add 72 mg of lithium hydroxide monohydrate under ice-cooling, and stir for 1 hour. After distilling off ethanol, a small amount of ice, 2 ml of acetic acid and 1 ml of dichloromethane are sequentially added, and the mixture is stirred at room temperature for 20 hours. Extracted with dichloromethane, water, 5% LVDS₃After washing with water, dry with anhydrous sodium sulfate and concentrate. The residue is subjected to silica gel column chromatography and developed with a mixed solution of chloroform-methanol (50: 1) to concentrate the fraction containing the desired product. The obtained oil was recrystallized from dichloromethane and n-hexane to give 138 mg of the title compound as needle-like crystals. Melting point: 170 ~ 171 ° C Specific rotation: [α]_D+ 109.7 ° (C 0.76, CHCl₃) NMR (CDCl₃Medium) δ: 0.97 (3H, t, J = 7Hz, -CH₂CH₈), 1.80 (2H, q, J = 7Hz, -CH₂CH₃), 2.42 (2H, dd, J = 7Hz, 6Hz, -CH₂-), 3.6 ~ 4.5 (6H, m, -O- (CH)₂)₂-O-, -CH₂-), 5.17, 5.57 (2H, ABq, J = 16Hz, -CH₂-), 6.58 (1H, s, C₅-H)<img file="JPH0737460B2_D0031.tif" />Elemental analysis C₁₅H₁₇NO₆ 1 / 2H₂Against O Calculated value (%) C, 56.96; H, 5.74; N, 4.43 Measured value (%) C, 56.82; H, 5.53; N, 4.53 Example 8 (S) -7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano [3,4-f] indolizine-3,6,10 (4H) -trione (I)^*c): The compound of the present invention obtained in (6) of Example 7 (I)^*b) Dissolve 120 mg in 80% trifluoroacetic acid and continue stirring for 1.5 hours at room temperature under a nitrogen gas stream. The reaction mixture was concentrated, dichloromethane was added to the residue, and 5% LVDS was added.₃After washing with water, dry with anhydrous sodium sulfate and concentrate. The residue was crystallized with ethanol and petroleum ether to give 81 mg of the title compound as colorless needles. Melting point: 172 ~ 174 ° C (decomposition) Specific rotation: [α]_D+ 117.6 ° (C 0.56, chloroform) NMR (CDCl₃Medium) δ: 0.98 (3H, t, J = 7Hz, -CH₂CH₃), 1.82 (2H, q, J = 7Hz, -CH₂CH₃), 2.96 (2H, t, J = 7Hz, C₇-H), 3.75 (1H, s, -OH), 4.35 (2H, t, J = 7Hz, C₈-H), 5.24,5.63 (2H, ABq, J = 17Hz, C₁-H), 7.23 (1H, s, C₅-H)<img file="JPH0737460B2_D0032.tif" />Elemental analysis C₁₃H₁₃NO₅ 1 / 4H₂Against O Calculated value (%) C, 58.32; H, 5.08; N, 5.23 Measured value (%) C, 58.15; H, 4.89; N, 5.27 Reference example 1 7-Ethyl-10-Methoxycamptothecin (II): 200 mg of the compound (Ic) obtained in Example 4, 150 mg of 2-amino-5-methoxypropiophenone and 5 mg of p-toluenesulfonic acid were dissolved in 25 ml of toluene, and the mixture was heated under reflux for about 4.5 hours with a Dane-Stark apparatus. To do. After cooling, the precipitate is removed, washed with acetone, and recrystallized from chloroform-methanol to obtain 290 mg of the title compound as pale yellow crystals. Melting point: 265 ~ 269 ° C (decomposition) NMR (DMSO-d₆Medium) δ: 0.88 (3H, t, J = 7Hz, CH₃CH₂-C₂₀), 1.34 (3H, t, J = 7Hz, CH₃CH₂-C₇), 3.97 (3H, s, CH₃O), 5.30 (2H, s, C₅-H or C₁₇-H), 5.42 (2H, s, C₁₇-H or C₅-H), 6.45 (1H, s, OH), 7.26 (1H, s, C₁₄-H), 7.50 (2H, m, C₉-H and C₁₁-H), 8.09 (1H, d, J = 8Hz, C₁₂-H)<img file="JPH0737460B2_D0033.tif" />Elemental analysis C₂₃H₂₂N₂O₅ 1 / 2H₂Against O Calculated C, 66.50; H, 5.58; N, 6.74 Measured value C, 66.70; H, 5.41; N, 6.79 Reference example 2 7-Ethyl-10-Hydroxycamptothecin (III): 400 mg of compound (II) obtained in Reference Example 1 is dissolved in 80 ml of toluene, 500 mg of aluminum chloride is added, and the mixture is heated under reflux for 6 hours. After cooling, ice water is added, and the precipitate is removed and washed with water. Recrystallization from ethanol gives 280 mg of the title compound in pale yellow. Melting point: 268 ~ 271 ° C (decomposition) NMR (DMSO-d₆Medium) δ: 0.89 (3H, t, J = 7Hz, CH₃CH₂-C₂₀), 1.32 (3H, t, J = 7Hz, CH₃CH₂-C₇), 1.88 (2H, ABq, J = 7Hz, CH₃CH₂-C₂₀), 5.27 (2H, s, C₅-H or C₁₇-H), 5.41 (2H, s, C₅-H or C₁₇-H), 6.44 (1H, br, s, OH), 7.27 (1H, s, C₁₄-H), 7.42 (2H, m, C₉-H and C₁₁-H), 8.01 (1H, d, J = 10Hz, C₁₂-H)<img file="JPH0737460B2_D0034.tif" />Elemental analysis C₂₂H₂₀N₂O₅ 2H₂Against O Calculated C, 61.68; H, 5.65; N, 6.54 Measured value C, 61.58; H, 5.36; N, 6.19 Reference example 3 (20S)-(+)-Camptothecin (IV)^*): The compound obtained in Example 8 (I)^*c) The reaction solution obtained by adding 450 mg and 430 mg of N- (o-aminobenzylidene) -p-toluidine (XVI) in 100 ml of toluene is heated and stirred for 30 minutes using a Dane Stark apparatus, and then p-toluenesulfone. Add 5 mg of acid and continue heating and stirring for another 2.5 hours. After cooling the reaction solution, precipitated crystals were removed, washed with acetone and then dried to obtain 500 mg of the title compound as a yellow crystalline powder. Melting point: 265 ~ 266 ° C (decomposition) Specific rotation: [α]_D+ 41.96 ° (C = 0.51, Chloroform: Methanol = 8: 2) NMR (DMSO-d₆Medium) δ: 0.90 (3H, t, J = 7.5Hz, CH₃CH₂), 1.89 (2H, q, J = 7.5Hz, CH₃CH₂), 5.32 (2H, s, CH₂-N or CH₂O), 5.45 (2H, s, CH₂O or CH₂N-), 6.54 (1H, s, OH), 7.40 (1H, s, C₄-H), 7.60 ~ 8.30 (4H, m, Ar.), 8.74 (1H, s, C₇-H)<img file="JPH0737460B2_D0035.tif" />Elemental analysis C₂₀H₁₆N₂O₄Against Calculated value (%) C, 68.96; H, 4.63; N, 8.04 Measured value (%) C, 68.81; H, 4.85; N, 7.95 Example 4 (20S) -7-Ethyl-10-Methoxycamptothecin (II)^*): The compound obtained in Example 8 (I)^*c) Add 1 g and 750 mg of 2-amino-5-methoxypropiophenone (XVII) to 150 ml of toluene, heat and stir the resulting solution for 1 hour using a Dane Stark device, and then add 10 mg of p-toluenesulfonic acid. Continue heating and stirring for another 25 hours. The reaction mixture was cooled, precipitated crystals were removed, the mixture was thoroughly washed with acetone, and then dried to obtain 1.45 g of the title compound as yellowish-white needle-like crystals. Melting point: 258 ~ 261 ° C (decomposition) Specific rotation: [α]_D+ 39.50 ° (C = 0.324, chloroform: methanol = 8: 2) NMR (DMSO-d₆Medium) δ: 0.83 (3H, t, J = 7Hz, CH₃CH₂), 1.28 (3H, t, J = 7Hz, CH₃CH₂), 1.82 (2H, q, J = 7Hz, CH₃CH₂), 3.93 (3H, s, CH₃O), 5.24 (2H, s, CH₂N or CH₂O), 5.36 (2H, s, CH₂O or CH₂N), 6.39 (1H, s, OH), 7.23 (1H, s, C₄-H), 7.36 ~ 7.60 (2H, m, C₁₁-H, C₁₂-H), 8.01 (1H, d, J = 10Hz, C₉-H) Elemental analysis C₂₃H₂₂N₂O₅Against Calculated value (%) C, 67.96; H, 5.46; N, 6.89 Measured value (%) C, 67.82; H, 5.35; N, 6.84 Reference example 5 (20S) -7-Ethyl-10-Hydroxycamptothecin (III)^*): Compound obtained in Reference Example 4 (II^*) Add 500 mg to 10 ml of 47% HBr solution and heat under reflux for 2.5 hours under a nitrogen gas stream. After completion of the reaction, acetone is added to the residue obtained by concentrating and drying the reaction solution, and the mixture is pulverized and collected. The obtained yellow powder was recrystallized from methanol and chloroform to obtain 430 mg of yellowish white acicular crystals. Melting point: 232 ~ 245 ° C (decomposition) Specific rotation: [α]_D+ 30.13 ° (C = 0.292, chloroform: methanol = 8: 2) NMR (DMSO-d₆Medium) δ: 0.89 (3H, t, J = 7Hz, CH₃CH₂), 1.32 (3H, t, J = 7Hz, CH₃CH₂), 1.87 (2H, q, J = 7Hz, CH₃CH₂), 5.27 (2H, s, CH₂O or CH₂N), 5.41 (2H, s, CH₂N or CH₂O), 6.43 (1H, s, OH), 7.28 (1H, s, C₁₄-H), 7.30 ~ 7.50 (2H, m, C₁₁-H, C₁₂-H), 8.02 (1H, d, J = 10Hz, C₉-H) Elemental analysis C₂₂H₂₀N₂O₅ H₂Against O Calculated value (%) C, 64.38; H, 5.40; N, 6.82 Measured value (%) C, 64.38; H, 5.31; N, 6.62 Reference example 6 (±)-Camptothecin: The reaction solution obtained by adding 250 mg of the compound (Ic) and 240 mg of N- (o-aminobenzylidene) -p-toluidine (XVI) obtained in Example 4 to 20 ml of toluene was heated for 30 minutes using a Dane Stark apparatus. After stirring, add 3 mg of p-toluenesulfonic acid and continue heating and stirring for another 2.5 hours. After cooling the reaction solution, precipitated crystals were removed, and the yellow powder obtained by washing with acetone and then drying was recrystallized from acetonitrile and methanol to obtain 230 mg of the title compound as a yellow crystalline powder. Melting point 265 ~ 272 ° C (decomposition) NMR (DMSO-d₆Medium) δ: 0.90 (3H, t, J = 7Hz, CH₃CH₂), 1.90 (2H, q, J = 7.5Hz, CH₃CH₂), 5.32 (2H, s, CH₂-N or CH₂O), 5.44 (2H, s, CH₂-N or CH₂O), 7.40 (1H, s, C₄-H), 7.60 ~ 8.40 (4H, m, Ar), 8.74 (1H, s, C₇-H)<img file="JPH0737460B2_D0036.tif" />Elemental analysis C₂₀H₁₆N₂O₄Against Calculated value (%) C, 68.96; H, 4.63; N, 8.04 Measured value (%) C, 68.81; H, 4.61; N, 7.98