S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof

S-type 2-substituted hydroxy-2-pyridyl butyrate compound and its preparation method

Field of invention

The invention relates to an S-type 2-substituted hydroxy-2-pyridyl butyrate compound and its preparation method. In detail, the present invention relates to an S-type 2-substituted hydroxy-2-pyridylbutyrate compound, which is used as an intermediate for the preparation of canptothecin derivatives with anti-tumor activity. And it relates to a method for preparing the compound with high yield and high stereoselectivity.

Prior art

The method for preparing camptothecin derivatives with anti-tumor activity according to Friedland reaction (Friedlaender ieaction) is right (see, EP-A-540099, EP-A-296597, JP-A-6-87746kick, WO90/03169, EP-A-418099), among which Japanese studies have found that it is used as an important intermediate for the preparation of 4-hydroxypyranopyridine compounds of the formula [VIII]S type,<chemistry general="n"><img file="TW464652B_D0001.tif" /></chemistry>

In addition, for example, in EP-A-220601, the following formula [XXI]S type 2-[(R)-H-methanesulfonyl-prolineoxy]-2-pyridyl butyrate compound was reported The preparation,<chemistry general="n"><img file="TW464652B_D0002.tif" /></chemistry>It is brominated at the 2-position of the 2-inoxidinyl acetate compound of the following formula [XX],<chemistry general="n"><img file="TW464652B_D0003.tif" /></chemistry>The resultant is reacted with (R)-N-methanesulfonylproline and then ethylated at the 2-position of the reaction product. Furthermore, a camptothecin derivative was prepared from this compound via S-type 4-hydroxypyranoindoxinium compound [VIII].

However, according to this method, the desired S-type 2-[(R)-N-toluenesulfonylprolineoxy]-2-indoxidinylbutyrate compound [XXI] is only better than that obtained at the same time The diastereomers with absolute configuration "R" at the 2-position are 2.6~4.6 times larger (44~64% de), and are recrystallized by fractional distillation [see Organic Synthetic Chemistry] , Volume 49, No. 11, pages 1013-1020, 1991], the S-type compound was isolated from it with a low yield of 56%.

Summary of the invention

The present invention provides S-type 2-substituted hydroxy-2-inoxidinyl butyrate compounds, which are used as intermediates for preparing camptothecin derivatives with high yield and high stereoselectivity.

Detailed description of the invention

According to the present invention, the following formula [II]S type 2-substituted hydroxy-2-inoxidinyl butyrate compound is prepared,<chemistry general="n"><img file="TW464652B_D0004.tif" /></chemistry>Let the following formula [III] 2-halo-2-indoxidinyl acetate compound,<chemistry general="n"><img file="TW464652B_D0005.tif" /></chemistry>(In the formula, X is a halogen atom, R¹And n²Is a lower alkyl group, and E is an enzyme residue), reacts with the following formula [IV] R type nitrogen-containing fused heterocyclic carboxylic acid compound or its salt,<chemistry general="n"><img file="TW464652B_D0006.tif" /></chemistry>[In the formula, R^oThe residue of a nitrogen-containing fused heterocyclic carboxylic acid with absolute configuration "R" is obtained by removing the carboxyl group from the carboxyl group of the carboxylic acid compound (in the formula, the nitrogen atom contained in the residue is protected)], Obtain the following formula [I] 2-substituted hydroxy-2-indoxidinyl acetate tyrosine compound,<chemistry general="n"><img file="TW464652B_D0007.tif" /></chemistry>(In the formula, the definition of the symbol is as described above), and then, the obtained compound [I] is ethylated at the 2-position.

The method of the present invention is characterized in that the 2-substituted hydroxy-2-inoxridinyl acetate compound [I] is steriially obstructive in the acetal part. bulky), and has an optically active nitrogen-fused heterocyclic steric barrier substituent at the 2-position, and it is ethylated at the 2-position with high yield and high stereoselectivity. High selectivity, for example, 9 times or higher (80%de or higher) compared with non-like isomers with absolute configuration "R" at the 2-position to obtain the desired S-type 2-substituted hydroxyl group- 2-pyridyl butyrate compound [II]. In particular, if in compound [I], the substituent R^oThe "Y" group in the group is 4-nitrosylsulfonyl or 4-diphenylsulfonyl, and the higher three-dimensional selection is 20 times (90%de) or 15.2 times (88%de) respectively. , And higher separation rate. Respectively 75% or 76%, to obtain the desired compound.

The R-type nitrogen-condensed heterocyclic carboxylic acid compound [IV] in the present invention refers to a carbon atom that has a carboxyl group connected to a nitrogen-containing condensed heterocyclic ring (the nitrogen atom of the compound is protected) and is connected to the carboxyl group Compounds with absolute configuration "R", this nitrogen fused heterocycle inclusion: stupid fused nitrogen-containing heterocycle, for example, tetrahydroiso ring, tetrahydro ring, dihydro ring, or ring.

The nitrogen-containing fused heterocyclic carboxylic acid compound with absolute configuration "R", a suitable example is the compound of the following formula [XIX],<chemistry general="n"><img file="TW464652B_D0008.tif" /></chemistry>(In the formula, n is 0 to 1, and Y is substituted or unsubstituted arylenesulfonyl or lower alkylsulfonyl).

The above compound [XIX] (in the formula, n is 1) refers to H-substituted 1,2,3,4-tetrahydro-3-yl phosphonium carboxylic acid, and the compound [XIX] (in the formula, n is 0) Refers to N-substituted 2-carboxylic acids. Substitution on the nitrogen atom of the above compound [XIX] The group "Y" includes: benzenesulfonyl, naphthalenesulfonyl or biphenylsulfonyl (optionally selected from nitro, lower alkyl, lower alkoxy, cycloalkyl, halogen atom, or phenenyl Substituted with one group), or lower alkylsulfonyl, for example, benzenesulfonyl, toluenesulfonyl, 2,4,6-trimethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4- Chlorobenzenesulfonyl, 4-methoxybenzenesulfonyl, 4-cyclohexylsulfonyl, 4-(3-phenyl)benzenesulfonyl, 2-naphthalenesulfonyl, 4-biphenylsulfonyl Acetyl, methylsulfonyl, and ethylsulfonyl.

Among the above, the preferred compound is that the substituent "Y" on the nitrogen atom in the formula is toluenesulfonyl, 2-naphthalenesulfonyl, 2,4,6-tritosylsulfonyl, 4-biphenylsulfonyl A compound in which a 4-nitrobenzenesulfonyl group or a 4-nitrobenzenesulfonyl group and n is 1 [XIX], and in the formula, the substituent "Y" on the nitrogen atom is a toluenesulfonyl group, and a compound in which n is 0 [XIX] . Particularly preferred compounds are compounds in the formula wherein the substituent "Y" on the nitrogen atom is 4-biphenylsulfonyl or 4-nitrophenylsulfonyl, and n is 1 compound [XIX].

R¹And R²It is a lower alkyl group, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl; X is a halogen atom, such as chlorine, bromine, and iodine. E includes: any conventional ester residues, such as lower alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, or isobutyl. Among them, the base is R¹And R²Is a methyl group, X is a chlorine atom or a bromine atom, and E is a methyl group or an ethyl group.

The reaction between 2-halogen-2-pyridyl acetate compound [III] and R-type nitrogen-containing fused heterocyclic carboxylic acid compound [IV] or its salt is carried out in a suitable solvent.

The salt of the R-type nitrogen-containing fused heterocyclic carboxylic acid compound [IV] includes: alkali metal (for example, potassium salt, sodium ), alkaline earth metal salt (for example, magnesium , calcium ).

The reaction of 2-halogen-2-pyridyl acetate compound [III] and R-type nitrogen-containing fused heterocyclic carboxylic acid compound [IV] or its is preferable to the presence or absence of acid remover Proceed under. Suitable examples of acid removers are inorganic bases, such as alkali metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), alkali metal amides (e.g., lithium amine, sodium amine, potassium amine), and alkali metal carbonates. Salt (e.g., sodium carbonate, potassium carbonate), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide); and Organic bases, such as alkali metal alkoxides (e.g., sodium ethoxide, potassium tert-butoxide), alkali metal alkyl amides (e.g., lithium diisopropylamide), trialkylamines (e.g., triethylamine) , Trimethylamine), N,N-dialkylaniline (eg, N,N-dimethylaniline), 1,8-azobicyclo[5.4.0]undec-7-ene.

The solvent used in this reaction includes: any conventional solvent that does not affect the reaction. Suitable examples are amide-type solvents (e.g., dimethylformamide, dimethylacetamide), and amide solvents (e.g., tetrahydro) Methane, dimethyl ether, dioxane). The reaction is usually carried out at a temperature of 20 to 100°C (preferably 50 to 70°C).

The subsequent 2-ethylation reaction of the 2-substituted hydroxy-2-pyridyl acetate compound [I] is carried out in a suitable solvent in the presence of an acid removing agent.

The ethylating agent is preferably ethyl halide (e.g., ethyl iodide, ethyl bromide), and more preferably ethyl iodide. The acid remover is the same as the acid remover used in the reaction of the above-mentioned 2-halo-2-pyridyl acetate compound [III] and the R-type nitrogen-containing fused heterocyclic carboxylic acid compound [IV] or its salt , The most preferred acid remover is sodium hydride.

The solvents used in this reaction include: any conventional solvents that do not affect the reaction. Suitable examples are amide-type solvents (e.g., dimethylformamide, dimethylacetamide), and sulfide solvents (e.g., dimethylacetamide). ), ether solvents (e.g., tetrahydrofuran , Dioxane, dimethyl ether), aromatic hydrocarbon solvents (for example, toluene, xylene, benzene, chlorobenzene), or their mixtures. The particularly preferred solvent is a mixture of dimethylacetamide and toluene. The reaction is usually carried out at a temperature of -10 to 50°C (particularly preferably at room temperature).

The desired compound [II] is obtained in a crude form and can be easily purified by recrystallization to obtain a highly purified compound [II].

The obtained S-type 2-substituted hydroxy-2-pyridylbutyrate compound [II] undergoes a catalytic reduction reaction to reduce its cyano group, and then undergoes an alkylation reaction to obtain the following formula [V]S-type 2 -Substituted hydroxy-2-(6-substituted aminomethylpyridinyl)butyrate compound,<chemistry general="n"><img file="TW464652B_D0009.tif" /></chemistry>(In the formula, R³Is a lower alkane group, and the definitions of other symbols are as above), the resultant undergoes nitrosation reaction and rearrangement to obtain the following formula [VI] S type 2-substituted hydroxy-2-(6-substituted hydroxymethyl) (pyridyl)butyrate compound,<chemistry general="n"><img file="TW464652B_D0010.tif" /></chemistry>(In the formula, the definition of the symbol is as above). Then, the compound [VI] undergoes an intramolecular cyclization reaction, after or at the same time as the cyclization reaction, its acetal group is converted to a ketone group to obtain the following formula [VII] S type 4-substituted hydroxypyranopyridine compound<chemistry general="n"><img file="TW464652B_D0011.tif" /></chemistry>(In the formula, the definition of the symbol is as above).

The above compound [VII] and the following formula [XIV] o-aniline compound<chemistry general="n"><img file="TW464652B_D0012.tif" /></chemistry>(In the formula, R⁵~R⁹Each of the groups is a hydrogen atom or any protected substituent), the Friedlander reaction is carried out together in a conventional manner to obtain a camptothecin compound with a substituent on the 20-hydroxyl group of the following formula [XV],<chemistry general="n"><img file="TW464652B_D0013.tif" /></chemistry>(In the formula, the definition of the symbol is as above), this compound [XV] is removed R⁰Base, and if R⁵~R⁹The group is protected, the protecting group is removed, and converted into its arbitrarily, to obtain the following formula [XVI] camptothecin compound or its ,<chemistry general="n"><img file="TW464652B_D0014.tif" /></chemistry>(In the formula, R⁵¹~R⁹¹Each group is a hydrogen atom or an unprotected substituent).

In addition, if the S-type 2-substituted hydroxy-2-(6-substituted hydroxymethylpyridinyl)butyrate compound [VI] undergoes the above intramolecular cyclization reaction, the compound of the following formula is prepared,<chemistry general="n"><img file="TW464652B_D0015.tif" /></chemistry>(In the formula, the definition of the symbol is as above).

Camptothecin compound [XVI] or its salt can also be prepared according to a method including the following steps:

(a-1) S-type 4-substituted hydroxypyranoxidine compound [VII] is removed R^oBase, or

(a-2) The S type 2-substituted hydroxy-2-(6-substituted hydroxymethyl pyridyl) butyrate compound [VI] is subjected to an ester hydrolysis reaction to obtain the following formula [IX] S type 2 -Hydroxy-2-(6-hydroxymethylpyridinyl)butyric acid compound,<chemistry general="n"><img file="TW464652B_D0016.tif" /></chemistry>(In the formula, the definition of the symbol is as described above), the compound [IX] is subjected to an intramolecular cyclization reaction, after or at the same time as the cyclization reaction, its acetal group is converted to a ketone group, and the product is optionally converted into its nucleus , To obtain the following formula [VIII]S type 4-hydroxypyranoxidine compound or its salt,<chemistry general="n"><img file="TW464652B_D0017.tif" /></chemistry>

(b) The compound [VIII] and the o-aniline compound [XIV] are subjected to the Friedland reaction together in a conventional manner to obtain the camptothecin compound of the following formula [XVII],<chemistry general="n"><img file="TW464652B_D0018.tif" /></chemistry>(In the formula, the definition of the symbol is as above),

(c) Make this compound [XVII] remove R⁵~R⁹The protecting group of the group (if the group contains a protecting group), and

(d) Randomly transform this product into its .

Alternatively, the camptothecin compound [XVI] or its salt can be prepared according to a method including the following steps:

(i) The S type 2-substituted hydroxy-2-(6-substituted hydroxymethyl dolidinyl) butyrate compound [VI] is subjected to an ester hydrolysis reaction to obtain S type 2-hydroxy-2-(6 -Hydroxymethyl(pyridyl)butyric acid compound [IX] or its ,

(ii) Subjecting this compound [IX] to an intramolecular cyclization reaction, and arbitrarily transforming this product into its nucleus, to obtain the following formula [X]S-type 4-hydroxypyranopyridine compound or its , <chemistry general="n"><img file="TW464652B_D0019.tif" /></chemistry>(In the formula, the definition of the symbol is as above),

(iii) reacting compound [X] with the following formula [XI] lower alkanecarboxylic acid or its reactive derivative,<chemistry general="n"><img file="TW464652B_D0020.tif" /></chemistry>(In the formula, R⁴Is a lower alkanoyl group) to obtain the following formula [XII]S type 4-alkanooxypyranopyridine compound,<chemistry general="n"><img file="TW464652B_D0021.tif" /></chemistry>(In the formula, the definition of the symbol is as above),

(iv) Converting the acetal group of the compound [XII] into a ketone group to obtain the following formula [XIII]S type 4-alkyloxypyranoxidium compound,<chemistry general="n"><img file="TW464652B_D0022.tif" /></chemistry>(In the formula, the definition of the symbol is as above),

(v) The compound [XIII] and the o-aniline compound [XIV] are subjected to Friedland reaction in a conventional manner to obtain the following formula [XVIII] in 20- Camptothecin compounds with substituents on the hydroxyl group,<chemistry general="n"><img file="TW464652B_D0023.tif" /></chemistry>(In the formula, the definition of the symbol is as above),

(vi) Make this compound [XVIII] remove R⁴Base, then remove R⁵~R⁸The protecting group of the group (if these groups contain a protecting group), and,

(vii) arbitrarily transform this product into its .

In the above compounds, R⁵~R⁹The base includes: in known camptothecin derivatives (see, for example, EP-A-540099, EP-A-296597, JP-A-6-228141, WO 90/03169, EP-A-418099 ) And any substituents in camptothecin derivatives disclosed in European Patent Publication Nos. 757049 and 781781, such as the following groups:

(a) in R⁵~R⁹Group, adjacent two groups are joined to form a linear or branched alkylene group with 2 to 6 carbon atoms, or the adjacent two groups are hydrogen atoms, and one of the residues is -Q_q-AlK_p-R¹⁰, And the other two groups of the residue are hydrogen atoms, substituted or unsubstituted lower alkyl groups, or base atoms,

(b) in R⁵~R⁹Group, adjacent two groups are joined to form a straight or branched alkylene group with 2 to 6 carbon atoms, and any carbon atom in the alkylene group is a group of the following formula: -Q_q-AlK_p-R¹⁰Replace, and R⁵~R⁹The remaining three groups of the group are hydrogen atoms, substituted or unsubstituted lower alkyl groups, or halogen atoms,

In the above (a) and (b), one or two methylene groups in the alkylene group can be replaced by -O-, -S- or -NH-,

Q is -O- or -NH-,

AlK is a straight or branched chain alkylene group with 1 to 6 carbon atoms that can be arbitrarily inserted into oxygen atoms,

R¹⁰Is a protected amine group, a protected lower alkylamino group, a protected hexahydro group, or a protected hydroxyl group,

When p and q are both 0 or 1, or when p is 1, q is 0.

R⁵¹~R⁹¹For R⁵~R⁹The base derived by removing the protecting group, in detail, such as R⁵~R⁹In the defined base, R¹⁰The base is the base formed after removing the protecting group, that is, R¹⁰The group is an amino group, a lower alkylamino group, a hexahydro group, or a hydroxyl group.

R⁵¹~R⁹¹The best combination method of the base is as follows:

(i)R⁷¹Is 3-aminopropoxy, R⁵¹Is ethyl, and R⁶¹, R⁸¹And R⁹¹Each is a hydrogen atom,

(ii) R⁵¹Is hexahydromethyl, R⁶¹And R⁹¹Each is a hydrogen atom, and R⁷¹And R⁸¹Combine to form ethylenedioxy group,

(iii) R⁵¹Is aminomethyl, R⁷¹And R⁸¹Combine to form ethylenedioxy group, and R⁶¹And R⁹¹Each is a hydrogen atom,

(iv) R⁵¹For the amine group, R⁷¹And R⁸¹Combine to form methylenedioxy group, and R⁶¹And R⁹¹Each is a hydrogen atom,

(v)R⁶¹Is an amine group, and R⁵¹, R⁷¹, R⁸¹And R⁹¹Each is a hydrogen atom,

(vi)R⁵¹And R⁶¹Join to form trimethylene substituted by amino group, R⁷¹Is methyl, R⁸¹Is a fluorine atom, and R⁹¹Is a hydrogen atom,

(vii)R⁵¹And R⁶¹Join to form trimethylene group, R⁷¹Is 3-aminopropoxy, R⁸¹And R⁹¹Each is a hydrogen atom,

(viii)R⁷¹Is 3-aminopropoxy, and R⁵¹, R⁶¹, R⁸¹And R⁹¹Each is a hydrogen atom.

S-type 4-hydroxypyranoindoxidine compound [VIII], S-type 2-hydroxy-2-(6-hydroxymethylimidinyl) butyric acid compound [IX] or S-type 4-hydroxypyrano The indole pyridine compound [X] contains: alkali metal (e.g., sodium, lithium), and the camptothecin compound [XVI] contains: a salt formed with inorganic acid (e.g., acid salt, sulfate salt) ) Or formed with organic acids (e.g., oxalic acid salt, toluene sulfonic acid salt).

In the above-mentioned preparation method of camptothecin compound, the reduction and alkylation reaction of the S-type 2-substituted hydroxy-2-indolidinylbutyrate compound [II] is carried out in a suitable solvent. The reduction reaction is usually carried out with a catalyst (such as Raney nickel) in a hydrogen atmosphere and a room temperature of 60°C. The alkylation reaction is usually carried out at room temperature to 60°C using a conventional alkanoating agent (e.g., lower alkanoic acid, lower alkane halides, lower alkane carboxylic acid anhydride). Solvents used in these reactions include: lower alkane carboxylic acid anhydride (e.g., acetic anhydride), lower alkane carboxylic acid (e.g., acetic acid), or a mixture thereof. If the lower alkanoic acid anhydride, lower alkanoic acid, or a mixture thereof is used in the reduction reaction, it can also be used as an alkylation agent. In this case, the reduction reaction and the alkylation reaction can be carried out in a single step.

The nitrosation reaction and rearrangement reaction of S-type 2-substituted hydroxy-2-(6-substituted aminomethylpyridyl) butyrate compound [V] can be found in the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry) , Volume 23, pages 554 to 560 (1980) disclosed similar methods, carried out in a suitable solvent. The nitrosation reaction is carried out at 0°C under acidic conditions with conventional nitrosating agents (eg, sodium nitrite, potassium nitrite). The solvent used in this reaction includes: lower alkane carboxylic acid anhydride (eg, acetic anhydride), lower alkane carboxylic acid (eg, acetic acid), or a mixture thereof.

The subsequent rearrangement reaction is carried out by heating the product obtained from the above nitrosation reaction at a temperature of 60 to 70°C. The solvents used for rearrangement and application include: halogenated hydrocarbons (e.g., tetrachloride dish, chloroform, dichloromethane), ester solvents (e.g. ethyl acetate), non-aromatic hydrocarbon solvents (e.g., n-hexane), aromatics Group hydrocarbon solvents (e.g., toluene).

The ester hydrolysis reaction of S-type 2-substituted hydroxy-2-(6-substituted hydroxymethylpyridinyl)butyrate compound [VI] can be performed according to the conventional method of ester hydrolysis, and it is suitable in the presence of alkali In solvent.

The alkali used for ester hydrolysis includes: inorganic bases, such as alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (eg, calcium hydroxide), ammonium hydroxide, alkali metals Carbonate (e.g., sodium carbonate, potassium carbonate), alkali metal bicarbonate (e.g., sodium bicarbonate); organic bases, such as alkali metal alkoxide (e.g., sodium ethoxide, sodium methoxide), alkali metal phenolate ( For example, sodium phenate), mono-, di- or tri-lower alkylamines (e.g., methylamine, ethylamine, N,N-dimethyl-1,3-propanediamine, trimethylamine, triethylamine) . Solvents include alcohol solvents (e.g., methanol, ethanol, propanol, isopropanol, butanol), sulfite solvents (e.g., dimethyl sulfoxide), halogenated hydrocarbon solvents (e.g., dichloromethane), ether solvents (e.g., Tetrahydrofuran), or a mixture of organic solvent and water. If the base is liquid, it can also be used as a solvent. The reaction is preferably carried out at 0 to 50°C, more preferably at room temperature.

If S-type 2-substituted hydroxy-2-(6-substituted hydroxymethylpyridyl) butyrate compound [VI] or S-type 2-hydroxy-2-(6-hydroxymethylpyridyl) ) Intramolecular cyclization reaction of butyric acid compound [IX] or its salt, and conversion of acetal group to ketone The radical conversion reaction is carried out at the same time, and it can be carried out by treating the compound in a single step with a suitable acid. Acids include: inorganic acids (e.g., acid, sulfuric acid), organic acids (e.g., trifluoroacetic acid), and mixtures of these acids and water. This acid can also be used as a solvent.

On the other hand, if the S type 2-substituted hydroxy-2-(6-substituted hydroxymethylridinyl) butyrate compound [VI] or the S type 2-hydroxy-2-(6-hydroxymethyl The intramolecular cyclization reaction of the (pyridyl)butyric acid compound [IX] or its halo is carried out first, and then the conversion reaction of the acetal group to the ketone group is carried out. The compound is treated with a weak acid (e.g., acetic acid, citric acid), and then the resultant is treated with the same strong acid used in the single-step reaction described above. For example, if the S-type 2-hydroxy-2-(6-hydroxymethylpyridinyl)butyric acid compound [IX] or its salt is treated with a weak acid, the S-type 4-hydroxypyranopyridine compound [X ], treated with strong acid to convert it into S-type 4-hydroxypyranopyridine compound [VIII].

The reaction of S type 4-hydroxypyranopyridine compound [X] or its with lower alkanoic acid [XI] or its reactive derivative can be carried out in the presence of a base.

Lower alkane carboxylic acid [XI] includes: for example, acetic acid, and its reactive derivatives include: acid anhydride (e.g., acetic anhydride), acyl halide (e.g., acetyl chloride), active ester (e.g., p-nitrobenzene ester). The base includes: alkali metal hydride (e.g., sodium hydride, potassium hydride), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate), pyridine, And 4-N,N-dimethylaminopyridine. The reaction is usually carried out at 0 to 50°C, preferably at room temperature.

S-type 4-substituted hydroxypyranopyridine compound [XII] acetal group The subsequent conversion reaction into the ketone group is carried out by treating the compound with a suitable acid. This acid can be S-type 2-substituted hydroxy-2-(6-substituted hydroxymethylpyridyl)butyric acid compound [VI] or S-type 2-hydroxy-2-(6-hydroxymethyl The same acid used in the intramolecular cyclization reaction of the pyridyl) butyric acid compound [IX] or its salt, and the conversion reaction of the acetal group to the ketone group in a single step.

S-type 4-substituted hydroxypyranopyridine compound [VII], S-type 4-hydroxypyranopyridine compound [VIII] or its halogen, or S-type 4-substituted hydroxypyrano The reaction of the pyridine compound [XIII] with the o-aniline compound [XIV] can be based on the known Friedland reaction [see, Organic Reactions, Volume 28, pages 37~202, John Wiley The parent company (John Wiley &amp; Sons, Inc.), New York (1982)].

4-substituted hydroxypyranopyridine compound [VII] and 4-alkanooxypyranopyridine compound [XIII] are better than S-type 4-hydroxypyranopyridine compound [VIII] or It is more stable and will not affect the decomposition of o-aniline compounds [XIV] during the Friedel-Lander reaction, thereby reducing undesirable impurities and by-products. Therefore, these compounds can help with a small amount of The o-aniline compound [XIV] is reacted with simple post-reaction treatments such as purification to obtain the desired camptothecin compound [XVI] or its salt in a high yield.

Furthermore, the molecular weight of the 4-alkanooxypyranopyridine compound [XIII] is much smaller than that of the 4-substituted hydroxypyranopyridine compound [VII], therefore, it can be smaller and smaller The reaction vessel performs the Friedland reaction.

Remove R⁵~R⁹The protective group contained in the base can be carried out according to the conventional method suitable for the contained protective group. For example, if the amine protecting group is benzyloxycarbonyl, it can be In the presence of palladium-carbon in a suitable solvent (e.g., tetrahydrofuran, methanol) to remove by catalytic reduction reaction, and if the amine protecting group is the tertiary butoxycarbonyl group, it can be removed by acid (e.g., silic acid, trifluoroacetic acid) Treat it in a suitable solvent (eg, tetrahydrofuran, methanol, dioxane, dichloromethane) and remove it.

Remove R from S-type 4-substituted hydroxypyranopyridine compound [VII] or camptothecin compound with 20-substituted hydroxy group [XV]^oIn the case of residues, it can be carried out by the conventional ester hydrolysis method in a suitable solvent in the presence of a base. The base and solvent are the same bases and solvents used in the ester hydrolysis of S-type 2-substituted hydroxy-2-(6-substituted hydroxymethyl pyridylbutyrate compound [VI]. This reaction can be carried out in cold , Room temperature, or under heating.

In addition, the camptothecin compound with 20-alkylated hydroxyl group [XVIII] removes R⁴The group is based on the ester hydrolysis of S-type 2-substituted hydroxy-2-(6-substituted and methylridinyl) butyrate compound [VI], or from S-type 4-substituted hydroxypyrano Pyridine compound [VII] or camptothecin compound with 20-substituted hydroxyl group [XV] remove R^oThe same way for residues.

The o-aniline compound [XIV] used in the above condensation reaction can be prepared according to the method shown in the following reaction diagram-1,<chemistry general="n"><img file="TW464652B_D0024.tif" /></chemistry>(In the formula, the definition of the symbol is as above).

That is, the hydroxyl compound [XXII] is treated with an oxidizing agent (for example, activated manganese dioxide, pyridine dichromate) to obtain the ketone compound [XXIII], and then in a suitable solvent in the presence of a suitable catalyst (for example, palladium-carbon) Catalytic reduction reaction is carried out to obtain the desired o-aniline compound [XIV]. Furthermore, if in R⁵~R⁹The protective group is removed by catalytic reduction reaction, and the product can be introduced into the protective group to obtain o-aniline compound [XIV]. In addition, where R⁵For the preparation of the o-aniline compound [XIV] which is a lower alkyl group, R⁵The hydroxyl compound [XXII], which is a lower alkenyl group, is treated with an oxidizing agent, followed by catalysis and reaction.

Furthermore, where R⁵~R⁹For the preparation of hydroxyl compounds [XXII] with protected amine groups, protected lower alkylamino groups, protected hexahydro groups, or protected hydroxyl groups, the protective group can also be introduced according to conventional methods. To Guwei It is formed from the corresponding compound of the protected group.

The 2-halo-2-pyridyl acetate compound [III] used in the present invention is novel and can be prepared according to the method shown in the following reaction diagram-2.<chemistry general="n"><img file="TW464652B_D0025.tif" /></chemistry>(In the formula, the definition of the symbol is as above).

That is, the pyridine compound [XXIV] reacts with 1,3-(propanediol compound [XXV] in the presence of acid (e.g., p-toluenesulfonic acid) or Lewis acid (e.g., trimethylsilyl chloride) pyridylmethane compound [XXVI], this compound [XXVI] is a carboxylic acid diester [XXVII], in the presence of a base (such as sodium hydride, potassium tert-butoxide) in a suitable solvent (such as toluene, Treatment in tetrahydrofuran) to obtain 2-pyridyl acetate compound [XXVIII], and halogenation according to the conventional method to obtain the desired 2-halo-2-pyridyl acetate compound [ III].

In the R-type nitrogen-containing fused heterocyclic carboxylic acid compound [IV] or its , the nitrogen-containing fused heterocyclic carboxylic acid compound [XIX] or its salt is novel, and can make the following formula [XXIX]N- Substituted nitrogen-containing fused heterocyclic carboxylic acid compound or its ,<chemistry general="n"><img file="TW464652B_D0026.tif" /></chemistry>(In the formula, the definition of the symbol is as above), and the following formula [XXX] sulfonic acid or its reactive derivative or its salt,<chemistry general="n"><img file="TW464652B_D0027.tif" /></chemistry>(In the formula, the symbols are defined as above), according to the conventional sulfonamide formation reaction, for example, the nitrogen-containing fused heterocyclic carboxylic acid compound [XXIX] and the halide of the sulfonic acid [XXX] (eg, chloride) , It is prepared by phase reaction in the presence of alkali (eg, alkali metal hydroxide).

In this text and in the scope of the patent application, the term "S type" refers to 2-substituted hydroxy-2-pyridylbutyrate compound [II], 2-substituted hydroxy-2-(6-substituted amine) Methylpyridyl)butyrate compound [V], 2-substituted hydroxy-2-(6-substituted hydroxymethylpyridyl)butyrate compound [VI] or 2-hydroxy-2- (6-Hydroxymethylpyridyl)butyric acid compound [IX] or its absolute configuration at the 2-position, or 4-substituted hydroxypyranopyridine compound [VII], 4-hydroxy pyranopyridine compound [VIII] or its halo, 4-hydroxyl pyranopyridine compound [X] or its halogen, 4-alkanooxypyranopyridine compound [XII], or 4-alkanohydropyranopyridine compound [XIII] of 4 The absolute configuration at the position; and the absolute configuration at the 2 position of the 2-[(R)-N-toluenesulfonylprolineoxy]-2-indolidylbutyrate compound [XXI], All are "S" configuration.

In this text and in the scope of the patent application, the term "lower alkyl" refers to a straight or branched alkyl group with 1 to 6 carbon atoms, and "lower alkanoyl" and "lower alkanoic acid" respectively refer to containing 1 Alkyl and alkanoic acids with straight chain and branched chain up to 7 carbon atoms. The term "alkylene" refers to a straight or branched alkylene group containing 1 to 10 carbon atoms.

Example

The following examples and reference examples describe the present invention in detail, but the scope of the present invention is not limited thereby.

<u style="single">Example 1</u>

(1) 2-Bromo-2-(6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro- 7-indolidinyl) ethyl acetate (22.21 g), (3R)-N-(4-biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isocarboxylic acid ( 24.70g) and potassium carbonate (5.11g) in dimethylformamide (220ml) were stirred at 60°C for 70 minutes. The reaction mixture was extracted with ethyl acetate, and the resulting extract was washed with a saturated aqueous solution and dehydrated over sodium sulfate. After the solvent was removed by vacuum carbonyl distillation, the residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 10:16:1) to obtain 2-[[(3R)-N -(4-Biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isoxolinyl]carbonyloxy]-2-[6-cyano-1,1-(2,2 -Dimethyltrimethylenedioxy)-5-oxo-1,2,3, 5-Tetrahydro-7-pyridyl] ethyl acetate (35.41 g) as a colorless powder. Yield: 92%<chemistry general="n"><img file="TW464652B_D0028.tif" /></chemistry>IR (Nujol, cm-1): 2220, 1750, 1665, 1615 MS (m/z): 738 (MH⁺)<img file="TW464652B_D0029.tif" />

(2) 2-[[3R)-N-(4-Biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isoxolinyl]carbonyloxy]-2-[6- Cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-imidinyl) ethyl acetate (33.63 G) was dissolved in anhydrous dimethylacetamide-toluene (1:1) (330 ml), and a 60% oil dispersion of sodium hydride (2.21 g) (1.2 equivalents) was added, and the mixture was stirred at room temperature for 75 minutes. To this mixture, ethyl iodide (36.5 ml) (10 equivalents) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate, and the resulting extract was washed with aqueous citric acid and saturated aqueous solution, dehydrated with sodium sulfate-magnesium sulfate, and then treated with activated carbon (5 g). Solvent After removal by vacuum distillation, the residue (35.69 g) [2S compound and 2R compound non-mirror stereoselectivity = 15.2: 1.0 (88%de), is based on the integrated value of NMR spectrum δ: 6.71 and 6.46 The calculated ratio] was dissolved in acetone (60 ml), the mixture was stirred at room temperature, hexane (76 ml) was added in portions, and the seed crystals of the desired diastereomer were also added. The precipitated crystals were collected by filtration and washed with acetone-hexane (60:76) (about 100 ml) to obtain (2S-2-[[(3R)-N-(4-biphenylsulfonyl)-1, 2,3,4-Tetrahydro-3-iso]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxy Substitute 1,2,3,5-tetrahydro-7-pyridyl]butyric acid ethyl ester (26.64 g), colorless crystals. Yield: 76%<chemistry general="n"><img file="TW464652B_D0030.tif" /></chemistry>Melting point: &gt;82°C (gradual decomposition) [α]D²⁶: -43.3° (c=1.02, chloroform) IR (paraffin oil, cm^-¹): 2220, 1755, 1660, 1615 MS (m/z): 766 (MH⁺)<img file="TW464652B_D0031.tif" /><img file="TW464652B_D0032.tif" />

(3)(2S)-[[(3R)-N-(4-Biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isoxolinyl]carbonyloxy]-2- [6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-ridinyl]butyric acid Ethyl ester (23.71g) and Raney nickel (W-4) (49g) were dissolved in acetic anhydride-acetic acid (460ml-190ml), and the mixture was stirred at 50-60°C under hydrogen atmosphere. After the reaction was completed, the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol=100:170:160:1) to obtain ( 2S)-2-[[(3R)-N-(4-Biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isoyl]carbonyloxy]-2-[6 -[(Acetylamino)methyl]-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7- Pyridinyl] ethyl butyrate (22.10 g.), a light yellow powder. Yield: 87%<chemistry general="n"><img file="TW464652B_D0033.tif" /></chemistry>[α]_D²⁶:-14.9°(c=1.01, chloroform) IR (paraffin oil, cm^-^l): 3405, 3295, 1750, 1660 MS(m/z): 812(MH⁺)<img file="TW464652B_D0034.tif" /><img file="TW464652B_D0035.tif" />

(4)(2S)-2-[[(3R)-H-(4-biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isoxanyl]carbonyloxy]- 2-[6-[(Acetamino)methyl](1,1-(2,2-Dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro Ethyl -7-pyridyl]butyrate (30.16g) is dissolved in acetic anhydride-acetic acid (450ml-150ml), and subpound sodium (13.18g) is added to it under ice-cold sweetness. The mixture is placed on ice- Stir on a water bath for 4 hours. The reaction mixture was poured onto chloroform (1.5 liters), and the insoluble matter was removed by filtration. The filtrate was evaporated to dryness under reduced pressure, and the residue was mixed with ethyl acetate (900 ml). Stir for 13 hours at 60°C. The reaction mixture was diluted with ethyl acetate (700 ml), the mixture was washed with water and solution, dehydrated with sodium sulfonate, and then treated with activated carbon. After the solvent was removed by distillation under reduced pressure, the residue remained The product was crystallized from ethyl acetate-hexene to obtain (2S)-2-[[(3R)-N((4-biphenylsulfonyl)-1,2,3,4-tetrahydro-3- Iso-(Hydroxy)carbonyloxy]-2-[6-Acetyloxyshenyl-1,1-(2,2-bishenyltrimethylenedioxy)-5-oxo-1,2,3 ,5-Tetrahydro-7-pyridyl]butyric acid ethyl ester (16.77 g), colorless prisms. Yield: 55%<chemistry general="n"><img file="TW464652B_D0036.tif" /></chemistry>Melting point: 145-148°C[α]D²⁷:-9.6°(c=1.0, chloroform) IR (paraffin oil, cm^-¹): 1755, 1659, 1614 MS(m/z): 813(MH⁺)<img file="TW464652B_D0037.tif" />

(5)(2S)-2-[[(3R)-N-(4-Biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isoxolinyl]carbonyloxy]- 2-[6-Acetyloxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7- Ethyl pyridyl]butyrate (1.457 g) was dissolved in 80% trifluoroacetic acid aqueous solution (15 ml) under ice-cold , and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, the residue was extracted with chloroform, the resulting extract was washed with water, and dehydrated with magnesium sulfate. The extract was distilled under reduced pressure to remove the solvent to obtain (4S)-7,8-dihydro-4-ethyl-4-[[(3R)-N-(4-biphenylsulfonyl)-1,2 ,3,4-Tetrahydro-3-isoxolinyl]carbonyloxy]-1H-pyrano[3,4-f]dolidine-3,6,10(4H)-trione (1.145 g ), is a colorless foam. Yield: 100%<chemistry general="n"><img file="TW464652B_D0038.tif" /></chemistry><img file="TW464652B_D0039.tif" />

(6)(4S)-7,8-dihydro-4-ethyl-4-[((3R)-N-(4-biphenylsulfonyl)-1,2,3,4-tetrahydro- 3-Isoxolinyl]carbonyloxy]-1H-pyrano[3,4-f]inoxidine-3,6,10(4H)-trione (1.145g) and 1-[5'- (3"-(tert-butoxycarbonylamine propoxy)-2'-aminophenyl]propan-1-one (867 mg) was dissolved in acetic acid (15 ml), and the mixture was stirred at 60°C for 47 hours. The reaction mixture After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: ammoniaform: ethyl acetate: 2:11:1), and then recrystallized from ethyl acetate-hexane to precipitate. Obtain (20S)-7-ethyl-10-[3-(tertiary butoxycarbonylamino )Propoxy]-20-0-[[(3R)-N-(4-Biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isoyl]carbonyl]Camptotheca Alkali (1,11 g), colorless crystals. Yield: 67% Melting point: 213-216°C 1R (paraffin oil, cm^-¹): 3407, 1763, 1753, 1709, 1669, 1614 MS(m/z): 925(MH⁺)<img file="TW464652B_D0040.tif" />

(7)(20S)-7-ethyl-10-[3-(tertiary butoxycarbonylamino)propoxy]-20-0-[[(3R)-N-(4-biphenylsulfonyl Yl)-1,2,3,4-tetrahydro-3-isoxolinyl]carbonyl]camptothecin (991mg) dissolved in water-methanol (6ml-30ml), and added with hydrogen under ice-cold Lithium monohydrate (180 mg) into it, mix<chemistry general="n"><img file="TW464652B_D0041.tif" /></chemistry>The material was stirred at room temperature for 22 hours and then at 50°C for 4 hours. The reaction mixture was concentrated under reduced pressure, chloroform (20 mL) and acetone (4 mL) were added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with chloroform and water, the chloroform layer was washed with water and a saturated aqueous solution, and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (20S)-7-ethyl-10-[3-(tertiary butoxycarbonylamino)propoxy]camptothecin.<chemistry general="n"><img file="TW464652B_D0042.tif" /></chemistry>

(8) The obtained (20S)-7-ethyl-10-[3-(tert-butoxycarbonylamino)propoxy]camptothecin is dissolved in water-ethanol (5ml-15ml), add 6.6 Nacid-ethanol (5ml), the mixture was stirred at room temperature for 23 hours. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate and water. The ethyl acetate layer was extracted with water again, and the water layer was combined and evacuated to dryness under reduced pressure. The residue was crystallized from isopropanol-water to obtain (20S)-7-ethyl-10-(3-aminopropoxy)camptothecin (240 mg) as light yellow needle crystals. Yield: 44% (total of (7) and (8) above)<chemistry general="n"><img file="TW464652B_D0043.tif" /></chemistry>Melting point: &gt;218°C(decomposition)[α]D²⁵:+9.8°(c=10, water) MS(m/z): 450(M-Cl⁺)IR (paraffin oil, cm-¹)：3450, 3370, 1745, 1660 <img file="TW464652B_D0044.tif" />

<u style="single">Example 2</u>

(1) (4S)-7,8-dihydro-4-ethyl-4-[[(3R)-N-(4-biphenylsulfonyl)-1 obtained from Example 1-(5) , 2,3,4-Tetrahydro-3-isoyl]carbonyloxy]-1H-pyrano[3,4-f]pyridine-3,6,10(4H)-trione, Treated in the same manner as described in Example 1-(7) to obtain (4S)-7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano[3,4-f]pyridine -3,6,10(4H)-Triketone<chemistry general="n"><img file="TW464652B_D0045.tif" /></chemistry>

(2) (4S)-7,8-Dihydro-4-ethyl-4-hydroxy-1H-pyrano[3,4-f]pyridine-3,6,10(4H)-trione , Processed in the same manner as described in Examples 1-(6) and 1-(8) to obtain (20S)-7-ethyl-10-[3-aminopropoxy]camptothecin phosphonic acid as a yellow powder .<chemistry general="n"><img file="TW464652B_D0046.tif" /></chemistry>

<u style="single">Example 3</u>

(1) 2-Bromo-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro- 7-pyridyl]ethyl acetate (1.28g), (3R)-N-(4-Nitrobenzenesulfonyl)-1,2,3,4-tetrahydro-3-isoxolincarboxylic acid (1.63g) and potassium carbonate (357mg) in dimethylform Amide (15 mL) was mixed, and the mixture was stirred at 70°C for 20 minutes. The reaction mixture was treated in the same manner as described in Example 1-(1) to obtain 2-[[(3R)-N-(4-nitrobenzenesulfonyl)-1,2,3,4-tetrahydro-3- Isoxolinyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5- Tetrahydro-7-pyridyl] ethyl acetate (2.10 g) as a colorless powder. Yield rate: 99%<chemistry general="n"><img file="TW464652B_D0047.tif" /></chemistry>IR (paraffin oil, cm^-^l): 2225, 1750, 1665, 1615 MS (m/z): 707 (MH⁺)<img file="TW464652B_D0048.tif" />

(2) 2-[[(3R)-N-(4-Nitrobenzenesulfonyl)-1,2,3,4-tetrahydro-3-isoyl]carbonyloxy]-2-[6 -Cyano-1,1-(2,2-Dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-imidinyl)ethyl acetate ( 25.09 G) was dissolved in anhydrous dimethylacetamide-methyl (1:1) (240ml), the mixture was mixed with sodium hydride (1680mg) (1.2eq) 60% oil dispersion and ethyl iodide (54.58g) ) (10 equivalents). The reaction was carried out in the same manner as described in Example 1-(2). The extract was washed with aqueous citric acid and saturated aqueous solution, and dehydrated by magnesium sulfate. After the solvent was removed by distillation under reduced pressure, the residue was formed into a powder from ethyl acetate-ether to obtain 2-[[(3R)-N-(4-nitrobenzenesulfonyl)-1,2,3,4-tetra Hydroxy-3-isoxolinyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2, Ethyl 3,5-tetrahydro-7-pyridinyl]butyrate (mixture of non-mirror stereoisomers) (22.04 g) as a colorless powder. The non-mirror stereoselectivity of the 2S compound and the 2R compound = 20.0: 1.0 (90% de), and calculated from the ratio of the integrated value of the NMR spectrum waveδ: 6.85 and 6.41. This colorless powder was recrystallized from isopropanol to obtain a pure product (19.32 g) as colorless crystals. Yield: 75%<chemistry general="n"><img file="TW464652B_D0049.tif" /></chemistry>Melting point: 181-182°C[α]_D²⁶:-128.39°(c=0.5, chloroform) IR (paraffin oil, cm^-¹): 2217, 1755, 1665, 1615 MS (m/z): 735 (MH⁺)<img file="TW464652B_D0050.tif" /><img file="TW464652B_D0051.tif" />

(3) The compound obtained from the above (2), as described in Example 1-(3)-(8) or Example 1-(3)-(5)-(7)-(6) and (8) Treated in the same way to obtain (20S)-7-ethyl-10-(3-aminopropoxy)camptothecin carboxylate.<chemistry general="n"><img file="TW464652B_D0052.tif" /></chemistry>

<u style="single">Example 4</u>

(1) 2-Bromo-2-(6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro -7-pyridinyl]ethyl acetate (363 mg), (3R)-N-(4-biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isoxolincarboxylic acid (472 mg) and potassium carbonate (95 mg) were mixed in dimethylformamide (4 ml), and the mixture was stirred at 70°C for 40 minutes. The reaction mixture was treated in the same manner as described in Example 1-(1) to obtain 2-[[(3R)-N-(4-biphenylsulfonyl)-1,2,3,4-tetrahydro-3- Isoxolinyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5- Tetrahydro-7-pyridyl] ethyl acetate (579 mg) as a colorless powder. Yield=94%<chemistry general="n"><img file="TW464652B_D0053.tif" /></chemistry>IR (paraffin oil, cm^-¹): 2225, 1750, 1665, 1615 MS (m/z): 766 (MH⁺)<img file="TW464652B_D0054.tif" />

(2) 2-[[(3R)-N-(4-Biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isoyl]carbonyloxy]-2-[6 -Cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-imidinyl)ethyl acetate ( 564 mg) was dissolved in anhydrous dimethylformamide (5 ml), and the mixture was mixed with a 60% oil dispersion of sodium hydride (35 mg) (1.2 equivalents) and ethyl iodide (1150 mg) (10 equivalents). The reaction was carried out in the same manner as described in Example 1-(2) to obtain 2-[[(3R)-N-(4-biphenylsulfonyl)-1,2,3,4-tetrahydro-3-iso Linyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro Ethyl -7-pyridinyl]butyrate (non-mirror stereo mixture) (522 mg), as a colorless powder. The non-mirror stereoselectivity of the 2S compound and the 2R compound = 10.8:1.0 (83%de), which is calculated from the ratio of the integrated value of the NHR spectrum 6:6.67 and 6.43.<chemistry general="n"><img file="TW464652B_D0055.tif" /></chemistry>IR (paraffin oil, cm^-¹): 2220, 1750, 1660, 1615 MS (m/z): 794 (MH⁺)<img file="TW464652B_D0056.tif" />

(3) The compound obtained from the above (2), as described in Example 1-(3)-(8) or Example 1-(3)-(5), (7), (6) and (8) Treated in the same way to obtain (20S)-7-ethyl-10-(3-aminopropoxy)camptothecin acid salt.<chemistry general="n"><img file="TW464652B_D0057.tif" /></chemistry>

<u style="single">Example 5</u>

(1) (2S)-2-[[(3R)-M-(4-Biphenylsulfonyl)-1,2,3,4-tetrahydro-3- obtained from Example 1-(4) Isoyl]carbonyloxy]-2-[6-acetoxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3 ,5-Tetrahydro-7-dolidinyl]butyric acid ethyl ester (1.00g) dissolved in water-methanol-tetrahydrofuran (5ml+20ml+5ml), and lithium hydroxide monohydrate ( 265 mg), the mixture was stirred at room temperature for 1 hour to obtain (2S)-2-hydroxy-2-[6-hydroxymethyl-1,1-(2,2-dimethyltrimethylenedioxy) Lithium -5-oxo-1,2,3,5-tetrahydro-7-pyridinyl]butyrate.<chemistry general="n"><img file="TW464652B_D0058.tif" /></chemistry>

(2) (2S)-2-hydroxy-2-[6-hydroxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1 obtained from the above, Lithium 2,3,5-tetrahydro-7-pyridyl]butyrate was dissolved in chloroform (20 mL) and acetic acid (4 mL). The mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture. Extract 3 times with chloroform. The extract was washed with saturated aqueous solution, dried over sodium sulfate, and distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent, chloroform) and recrystallized from ethyl acetate to obtain (4S)-7,8-dihydro-4-ethyl-6,6-(2, 2-Dimethyltrimethylenedioxy)-4-hydroxy-1H-pyrano[3,4-f]pyridine-3,10-dione (276 mg), as colorless needles. Yield: 64% (total of (1) and (2) above)<chemistry general="n"><img file="TW464652B_D0059.tif" /></chemistry>Melting point: 208-210°C [α]D27: +88.2°(c=0,99, chloroform) IR (paraffin oil, cm^-¹): 3340, 2924, 1744 MS(m/z): 350(MH⁺)<img file="TW464652B_D0060.tif" />

(3)(4S)-7,8-Dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-hydroxy-1H^-pyrano[3,4-f]pyridine-3,10-dione, treated in the same manner as described in Example 1-(5) to obtain (4S)-7,8-dihydro-4-ethyl 4-hydroxy-1H-pyrano[3,4-f]inoxidine-3,6,10(4H)-trione<chemistry general="n"><img file="TW464652B_D0061.tif" /></chemistry>

(4)(4S)-7,8-Dihydro-4-ethyl-4-hydroxy-1H-pyrano[3,4-f]dolidine-3,6,10(4H)-trione , Processed in the same manner as described in Example 1-(6) and (8) to obtain (20S)-7-ethyl-10-[3-(aminopropoxy)-camptothecin acid .<chemistry general="n"><img file="TW464652B_D0062.tif" /></chemistry>

<u style="single">Example 6</u>

(1) (2S)-2-hydroxy-2-[6-hydroxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5 obtained from Example 5-(1) -Oxo -1,2,3,5 -tetrahydro-7-pyridyl]butyrate, treated in the same manner as described in Example 1-(5) to obtain (4S)-7,8-two Hydrogen-4-ethyl-4-hydroxy-1H-pyrano[3,4-f]pyridine-3,6,10(4H)-trione.<chemistry general="n"><img file="TW464652B_D0063.tif" /></chemistry>

(2)(4S)-7,8-Dihydro-4-ethyl-4-hydroxy-1H-pyrano[3,4-f]pyridine-3,6,10(4H)-trione , Processed in the same manner as described in Example 1-(6) and (8) to obtain (20S)-7-ethyl-10-[3-(aminopropoxy)-camptothecin acid .<chemistry general="n"><img file="TW464652B_D0064.tif" /></chemistry>

<u style="single">Example 7</u>

(1) (4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-obtained from Example 5-(2) Hydroxy-1H-pyrano[3,4-f]pyridine-3,10-dione (50mg), dissolved in acetic anhydride (1ml), add pyridine (1ml) and 4 -N,N-dimethylaminopyridine (4 mg) was added thereto, and the mixture was stirred at room temperature for 23 hours. The reaction mixture is diluted with chloroform and mixed The compound was washed with aqueous citric acid, water and saturated aqueous solution, and dried over sodium sulfate. After the solvent was removed by distillation under reduced pressure, the residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 40:1) to obtain (4S)-7,8-dihydro-4-ethyl-6 ,6-(2,2-Dimethyltrimethylenedioxy)-4-acetoxy-1H-pyrano[3,4-f]dolidine-3,10-dione (56 mg ), is a colorless crystal. Yield rate: 99%<chemistry general="n"><img file="TW464652B_D0065.tif" /></chemistry>Melting point: 185-188°CIR (paraffin oil, cm^-¹): 2922, 2852, 1743, 1671, 1613 MS(m/z): 392(MH⁺)<img file="TW464652B_D0066.tif" />

(2) (4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-acetoxy-1H-pyrano [3,4-f]pyridine-3,10-dione, processed in the same manner as described in Example 1-(5) to obtain (4S)-7,8-dihydro-4-ethyl-4 -Acetyloxy-1H-pyrano[3,4-f]pyridine-3,6,10(4H)-trione, colorless crystals.<chemistry general="n"><img file="TW464652B_D0067.tif" /></chemistry>Melting point: 197-203°CIR (paraffin oil, cm^-¹): 1742, 1732, 1661, 1610 ESI-MS (0.02M ammonium acetate/methanol, m/z): 323 (MNH₄⁺)<img file="TW464652B_D0068.tif" />

(3)(4S)-7,8-Dihydro-4-ethyl-4-acetoxy-1H-pyrano[3,4-f]pyridine-3,6,10(4H) -Triketone, treated in the same manner as described in Example 1-(6) to obtain (20S)-20-O-acetyl-7-ethyl-10-[3-(tertiary butoxycarbonylamino) Propoxy]camptothecin is a colorless powder.<chemistry general="n"><img file="TW464652B_D0069.tif" /></chemistry>Melting point: 173-176°CIR (paraffin oil, cm^-¹): 3370, 1765, 1749, 1696, 1657 ESI-MS (m/z): 592 (MH⁺)<img file="TW464652B_D0070.tif" /><img file="TW464652B_D0071.tif" />

(4) (20S)-20-0-acetyl-7-ethyl-10-[3-(tertiary butoxycarbonylamino)propoxy]camptothecin, according to Example 1-(7) Treated in the same manner as described in (8) to obtain (20S)-7-ethyl-10-(3-aminopropoxy)camptothecinacid<chemistry general="n"><img file="TW464652B_D0072.tif" /></chemistry>

<u style="single">Examples 8~12</u>

(1) The corresponding starting compounds were processed in the same manner as described in Example 1-(1) and (2) to prepare the compounds shown in Table 1 below.<tables><img file="TW464652B_D0073.tif" /></tables>

Example 8(1): X=Cl

<img file="TW464652B_D0074.tif" />

Example 9(1): X=CH₃

<img file="TW464652B_D0075.tif" />

Example 10(1): X=OCH₃

<img file="TW464652B_D0076.tif" />

Example 11(1): X=cyclohexyl

<img file="TW464652B_D0077.tif" />

Example 12(1): X=3-phenyl

<img file="TW464652B_D0078.tif" />

(2) The compound obtained from the above (1), as described in Example 1-(3)-(8) or Example 1-(3)-(5), (7), (6) and (8) Treated in the same way to obtain (20S)-7-ethyl-10-(3-aminopropoxy)camptothecin hydrochloride .

<u style="single">Examples 13~16</u>

(1) The corresponding starting compound was processed in the same manner as described in Example 1-(1) and (2) to prepare the compound shown in Table 2 below.<tables><img file="TW464652B_D0079.tif" /></tables>

Example 15 (1)<img file="TW464652B_D0080.tif" />

(2) The compound obtained from the above (1), as described in Example 1-(3)-(8) or Example 1-(3)-(5), (7), (6) and (8) Treated in the same way to obtain (20S)-7-ethyl-10-(3-aminopropoxy)camptothecin acid.

<u style="single">Examples 17~23</u>

The corresponding starting compound, according to the same method as described in Example 1, 2, 5 or 7. The following: The compound shown in 3 was prepared.<tables><img file="TW464652B_D0081.tif" /></tables>

<u style="single">Example 24</u>

(1) Containing 2-chloro-2-(6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetra Hydrogen-7-dolidinyl) ethyl acetate (34.11 g), (3R)-N-(4-biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isocarboxy A mixture of acid (42.33g) and potassium carbonate (8.67g) in dimethylformamide (350ml) was stirred at 60°C for 45 minutes. After the reaction mixture was ice-cooled, it was diluted with ethyl acetate (200 ml), and saturated sodium bicarbonate water was added. Solution (300 mL), and add water (500 mL) to it. The mixture was extracted with ethyl acetate, the obtained extract was washed, dehydrated, treated with activated carbon and filtered, and the solvent was removed by distillation to obtain 2-[[(3R)-N-(4-biphenylsulfonyl) -1,2,3,4-Tetrahydro-3-isoyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy) -5-oxo-1,2,3,5-tetrahydro-7-dolidinyl] ethyl acetate (66.20 g), a pale yellow foam. IR (paraffin oil, cm^-¹): 2220, 1750, 1665, 1615 MS(m/z): 738(MH⁺)<img file="TW464652B_D0082.tif" />

(2) 2-[[(3R)-N-(4-Biphenylsulfonyl)-1,2,3.4-tetrahydro-3-isoyl]carbonyloxy] obtained from (1) above -2-[6-cyano-1,1-(2_,2-Dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-pyridyl)ethyl acetate, according to Example 1-(2)-(8 ) Treated in the same manner as described above, to obtain (20S)-7-ethyl-10-(3-aminopropoxy) sericholine acid salt.

<u style="single">Reference example 1</u>

(1) 6-cyano-7-methyl-1,5-dioxo-1,2,3,5-tetrahydroxidine (1,0g), 2,2-dimethyl-1 ,3-propanediol (6.64g) and p-toluenesulfonic acid (15ml) were mixed in dichloroethane (25ml), and the resulting mixture was set in a Dean-Start dehydrator. The reflux device was heated for 17 hours under reflux. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous solution, and dried over magnesium sulfate. After the solvent was removed by distillation under reduced pressure, the residue was purified by silica gel column chromatography (eluent: aminoform: methanol: 50:1) and recrystallized from methanol to obtain 6-cyano-7-methyl -1,1-(2,2-Dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindoxidine (1.05g) is a colorless needle crystal. Yield: 72% Melting point: 225-226°C<img file="TW464652B_D0083.tif" />

(2) 6-cyano-7-methyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindoxidine (14,43 g) was mixed in dry toluene (300 ml), a 60% oil dispersion of sodium hydride (9.26 g, 4.4 equivalents) was added, and the mixture was stirred at 80°C for 2 hours. To this reaction mixture, diethyl carbonate (24.85 g, 4 equivalents) and ethanol (0.97 g, 0.4 equivalents) were added, and the mixture was reacted at 80°C for 3 hours. While the reaction mixture was cooled in an ice bath, 50% acetic acid (80 ml) was added to it. The mixture was extracted with chloroform, and the resulting extract was washed with an aqueous solution of Heheyuan and dried over magnesium sulfate. After the solvent was removed by distillation under reduced pressure, the residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate: 4:1) and recrystallized from ethyl acetate-ether. Obtain 2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-pyridyl ] Ethyl acetate (14.63 g), as colorless needle crystals. Yield: 80% Melting point: 150-151°C IR (paraffin oil, cm^-¹): 2220, 1725, 1650, 1610 MS(m/z): 347(MH⁺)<img file="TW464652B_D0084.tif" />

(3) 2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7- (Pyridinyl] ethyl acetate (14.60 g) was added to a 60% oil dispersion containing sodium hydride (2.02 g, 1.2 equivalents) in anhydrous tetrahydrofuran (240 ml) suspension, and the mixture was stirred at room temperature for 3 hours . To this reaction mixture, bromine (8.76 g, 1.3 equivalents) was added, the mixture was stirred at room temperature for 2 hours, and ice water was added. The mixture was extracted with chloroform, and the obtained extract was washed with aqueous sodium thiosulfate and saturated aqueous solution, and dehydrated with magnesium sulfate. After the solvent was removed by distillation under reduced pressure, the residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 4:1) and recrystallized from ethyl acetate-ether to obtain 2-bromo- 2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-pyridyl] Ethyl acetate (15.66 g) is colorless needle crystals. Yield: 87% Melting point: 117-119°C IR (paraffin oil, cm^-¹): 2217, 1725, 1650, 1610 MS(m/z): 427(MH⁺)<img file="TW464652B_D0085.tif" />

<u style="single">Reference example 2</u>

(1) 6-cyano-7-methyl-1,5-dioxo-1,2,3,5-tetrahydropyridine (5.93g), 2,2-diethyl-1,3 -Propanediol (49.97g) and p-toluenesulfonic acid (180ml) are mixed in dichloroethane (150ml), and this mixture is heated under reflux in a reflux device equipped with a Dean-Stark dehydrator 22 hours. The reaction mixture was treated in the same manner as described in reference 1-(1), and recrystallized from methanol to obtain 6-cyano-7-methyl-1,1-(2,2-diethyltrimethylenedioxy) )-5-oxo-1,2,3,5-tetrahydropyridine (6.67g), colorless needle crystals. Yield: 70% Melting point: 197-198°C IR (paraffin oil, cm^-¹): 2219, 1655, 1610 MS(m/z): 303(MH⁺)<img file="TW464652B_D0086.tif" />

(2) Repeat the procedure of Reference Example 1-(2)^'Order, but use 6-cyano-7-methyl-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro Pyridine (4.75 g), anhydrous toluene (80 ml), sodium hydride (2,76 g, 4.4 equivalents) 60% oil dispersion, diethyl carbonate (7.42 g, 4 equivalents) and ethanol (0.37 ml, 0.4 equivalents) ), the product was recrystallized from ethyl acetate-ether to obtain 2-[6-cyano-1,1-(2,2-diethyltrimethylene^'Dioxy)-5-yl-1,2,3,5-tetrahydro-7inoxridinyl]ethyl acetate (3.71 g), as colorless needles. Yield: 63% Melting point: 127-129°C IR (paraffin oil, cm^-^l): 2220, 1745, 1660, 1605 MS(m/z): 375(MH⁺)<img file="TW464652B_D0087.tif" />

(3) 2-[6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3_'5-Tetrahydro-7-pyridyl] ethyl acetate (3.52 g) was added to a suspension of a 60% oil dispersion containing sodium hydride (451 mg, 1.2 equivalents) in anhydrous tetrahydrofuran (60 ml) The mixture was treated at room temperature for 3 hours. Bromine (1.95 g, 1.3 equivalents) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was treated in the same manner as described in Reference Example 1-(3) and recrystallized from ethyl acetate-ether. Obtain 2-bromo-2-[6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7 -pyridyl] ethyl acetate (2.45 g), colorless needle crystals. Yield: 58% Melting point: 106-108°C IR (paraffin oil, cm^-¹): 2220, 1735, 1660, 1610 MS(m/z): 455(MH⁺)<img file="TW464652B_D0088.tif" />

<u style="single">Reference example 3</u>

Sodium hydroxide (13.6 g) was dissolved in water (300 ml), (3R)-1,2,3,4-tetrahydro-3-isocarboxylic acid (30.0 g) was suspended in it, and tetrahydrofuran (120 Ml). 4-Biphenylsulfonyl chloride (42.9 g) was added to the resulting solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was made acidic with 10% sodium acid under ice cooling, diluted with water, and then extracted twice with ethyl acetate. The extract is washed with water and saturated aqueous solution, dehydrated with sodium sulfate, and then treated with activated carbon. The insoluble matter was removed from the extract by filtration, and the solvent was removed by distillation under reduced pressure. The residue was recrystallized and precipitated from ethyl acetate-hexane to obtain (3R)-N-(4-biphenylsulfonyl)-1,2,3,4-tetrahydro-3-isocarboxylic acid ( 36.5 g), colorless crystals. Yield rate: 55% Melting point: 195-202°C[α]D²⁹:+8.02°(c=1.08, dimethylformamide) IR (paraffin oil, cm^-¹): 3300, 2924, 1743, 1456 MS(m/z): 394(MH⁺)<img file="TW464652B_D0089.tif" />

<u style="single">Reference example 4</u>

(3R)-1,2,3,4-tetrahydro-3-isocarboxylic acid (5.32g) and sodium hydroxide (2.40g) are added to the mixture of dichloromethane-water (200ml-200ml) In the solution, a solution containing 4-nitrobenzenesulfonyl chloride (6.62 g) in dichloromethane (100 ml) was added dropwise for 30 minutes under ice cooling. The mixture was stirred under ice cooling for 3 hours, and sodium hydroxide (1.20 g) and a solution of 4-nitrobenzenesulfonyl chloride (3.32 g) in dichloromethane (60 ml) were added sequentially. The mixture was stirred under ice cold for 2 hours and then at room temperature for 17 hours. The reaction mixture was diluted with chloroform and 10% acid to collect. The chloroform layer was washed with water and then washed with a saturated saline solution, dehydrated with sodium sulfate, and then treated with activated carbon. The insoluble matter was removed from the chloroform layer by filtration, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent, chloroform) and recrystallized from ethyl acetate-hexane to obtain (3R)-N-(4-nitrobenzenesulfonyl)-1,2 ,3,4-Tetrahydro-3-isocarboxylic acid (4.01g), as colorless crystals. Yield: 37% Melting point: 140°C [α]D²⁵:+27.2°(c=0.5, ethanol) IR (paraffin oil, cm^-¹): 3316, 1743, 1531, 1169 MS(m/z): 361(MH⁺)<img file="TW464652B_D0090.tif" />

<u style="single">Reference example 5</u>

Add triethylamine (13.94g) under argon atmosphere at -4°C to contain 2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy-5-oxo-1, 2,3,5-Tetrahydro-7-pyridyl]ethyl acetate (43.41g) was added to a suspension of tetrahydrofuran (600ml) at -4 to -3°C for 5 minutes Trimethylsilyl chloride (14.41g). The mixture was stirred at the same temperature for 55 minutes, and N-chlorobutanediimide (17.00g) was added dropwise to tetrahydrofuran (400ml) at -4 to 4°C for 7 minutes. Suspension. The reaction mixture was stirred at a temperature of 0°C to 4°C for 4.5 hours, water (1 liter) was added at 0°C, and the mixture was extracted with ethyl acetate. The resulting extract was washed, dehydrated, treated with activated carbon, and filtered. Then the solvent was distilled off. The residue was recrystallized from ethyl acetate-isopropyl ether to obtain 2-chloro-2-[6-cyano-1,1-(2,2-dimethyltrimethylene) (Oxy)-5-oxo-1,2,3,5-tetrahydro-7-pyridyl] ethyl acetate (40.28 g), colorless needle crystals. Yield: 84%, melting point: 153-155 °C<img file="TW464652B_D0091.tif" /><img file="TW464652B_D0092.tif" />

<u style="single">Reference example 6</u>

(1) 3-Aminopropanol (6.0 g) was dissolved in dichloromethane (50 ml), and di-tert-butyl dicarbonate (18.3 g) was added dropwise with stirring under ice cooling. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and then purified by silica gel column chromatography to obtain 3-tert-butoxycarbonylaminopropanol (13.98 g) as a colorless oil. Yield: 99.9%<img file="TW464652B_D0093.tif" />

(2) 3-Tertiary butoxycarbonylaminopropanol (10.0g) was dissolved in dichloromethane (100ml), stirred under ice-cold condition, and added triethylamine (8.66g) and toluenesulfonyl chloride (16.3g) . The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, the residue was dissolved in water-ethyl acetate, the organic layer was separated, washed with a saturated aqueous solution, dehydrated with sodium sulfate, and then the solvent was removed by distillation. The residue was purified by silica gel column chromatography to obtain 3-tert-butoxycarbonyl toluenesulfonate Aminopropyl ester (15.37 g) is a pale yellow oil. Yield: 82% IR (pure), ν_m_a_xcm^-¹:3400, 3340, 1700, 1600 MS(m/z): 352(M+Na⁺)<img file="TW464652B_D0094.tif" />

(3) 5-Hydroxy-2-nitrobenzaldehyde (6.0 g) was dissolved in anhydrous tetrahydrofuran (90 ml), and vinyl magnesium bromide (2.3 equivalents) was added dropwise with stirring at -78°C. The temperature of the reaction mixture gradually increased. After the reaction was completed, 1N acid was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was separated, washed with saturated aqueous solution, dehydrated with sodium sulfate, and then the solvent was removed by distillation. The residue was purified by silica gel column chromatography to obtain 1-(5'-hydroxy-2'-nitrophenyl)-2-propen-1-ol (5.09 g) as a yellow-brown powder. Yield: 73% Melting point: 126-130°C IR (paraffin oil), ν_m_a_xcm^-^l:3440, 1600MS(m/z):195(M⁺)<img file="TW464652B_D0095.tif" />

(4) 1-(5'-Hydroxy-2'-nitrophenyl)-2-propen-1-ol (2.0g) To anhydrous dimethylformamide (100 ml), add sodium iodide (1 equivalent), potassium carbonate and toluene sulfonic acid 3-butoxycarbonyl propyl ester (1.5 equivalent). The mixture was stirred at 50°C for 6 hours, and ethyl acetate was added. The mixture was washed with saturated aqueous solution and dehydrated with sodium sulfate. After the solvent is removed by distillation, the residue is purified by silica gel column chromatography to obtain 1-[5,-(3''-tertiary butoxycarbonylamine propoxy)-2-'nitrophenyl]-2 -Propylene-1-ol (3,53 g), in the form of light brown caramel. Yield: 98% IR (pure), ν_m_a_xcm^-¹:3400,1690,1680 MS(m/z): 375(M+Na⁺)<img file="TW464652B_D0096.tif" />

(5) 1-(5'-(3''-tert-butoxycarbonylamine propoxy)-2'-nitrophenyl)-2-propen-1-ol (9.66g) dissolved in chloroform (300ml ), add active manganese dioxide (7.2 g) to it, and heat the mixture under reflux. After the reaction was completed, celite was used to filter to remove inorganic substances, the filtrate was concentrated, and ethyl acetate was added. After the organic layer was separated, it was washed with a saturated aqueous solution and dehydrated with sodium sulfate. After the solvent was removed by distillation, the residue was purified by silica gel column chromatography to obtain 1-[5'-(3''-tertiary butoxycarbonylamine propoxy)-2'-nitrophenyl]-2 -Propylene-1-one (6.01 g), yellow crystals. Melting point: 65-71°C Yield: 63% IR (pure), ν_m_a_xcm^-¹:3350,1700 MS(m/z): 351(M+H⁺)<img file="TW464652B_D0097.tif" />

(6) 1-[5'-(3''-Terbutoxycarbonylaminopropoxy)-2'-nitrophenyl)-2-propen-1-one (325mg) dissolved in ethanol (15ml ), 10% palladium-carbon (40 mg) was added, and the mixture was stirred for 1.5 hours under hydrogen atmosphere. After removing the catalyst by filtration, the filtrate is concentrated and purified by silica gel column chromatography to obtain 1-[5'-(3''-tert-butoxycarbonylamine propoxy)-2'-aminophenyl] Propan-1-one (248 mg) is a yellow powder. Melting point: 112-115°C Yield: 83% IR (paraffin oil), ν_m_a_xcm^-^l：3450,3400,3340,1700,1650<img file="TW464652B_D0098.tif" />