KR800000335B1 - Process for preparation of daunorubicin derivatives - Google Patents

Abstract

No content.

Description

Method for preparing daunorubicin derivatives

The present invention relates to a process for the preparation of novel daunorubicin derivatives.

The novel daunorubicin derivatives of the present invention are acid addition salts, preferably hydrochloride salts, when the compound of formula I and R ₂ are hydrogen atoms.

In the above formula, R ₁ is a group of the following general formula II, R ₂ is a hydrogen atom or a trichloroacetyl group.

In the formula (i), X ₁ and X ₂ are both oxygen atoms or sulfur atoms, and R ₃ is a C ₁ -C ₄ alkyl group, a phenyl group or a phenyl group substituted with methyl methoxy or methylthio group in the para-position, respectively. Or together form a C ₂ -C ₄ alkylene group, or (ii) _one of X ₁ and X ₂ is an oxygen atom and the other a sulfur atom, and R ₃ together are C ₂ -C ₄ alkylene A group is formed and R ₄ is a hydrogen atom, an alkyl group of C ₁ -C ₄ or a phenyl group.

According to the invention, a compound of formula I wherein R ₂ is a hydrogen atom is prepared by reacting an alkali metal or alkaline earth metal salt of an acid of formula III with a daunorubicin derivative of formula IV or an acid addition salt thereof:

R ₁ -COOH III

Where R ₁ is as defined above

Where T is a -CO- group or a -C (OCH ₃ ) ₂ -group.

In general, hydrochlorides of the daunorubicin derivatives of general formula IV are used and the reaction is carried out in a polar solvent such as ketone (e.g. acetone or methyl isobutyl ketone), alcohol (e.g. methanol or ethanol) or dimethylformamide, Or in a mixture of the above solvents, such as a mixture of acetone and ethanol.

The daunorubicin derivative (form of acid addition salt) of formula IV wherein T is a -C (OCH ₃ ) ₂ -group can be obtained by brominating the acid addition salt of daunorubicin of the following structure (V) in the presence of methanol.

The acid addition salts of the resulting daunorubicin derivatives of the general formula IV can be converted to the free base as desired, essentially by known methods, for example by dissolving this salt in water and adding aqueous sodium bicarbonate solution.

Bromination of compounds of general formula V is generally directed to the action of bromine, phenyltrimethylammonium perbromide, pyridinium perbromide or pyrrolid-2-one hydrobromide at a temperature of 20 ° -50 ° C. in a solvent such as dioxane or methanol. Performed by Bromination may also be carried out by the action of dioxane dibromide prepared separately before the reaction.

Daunorubicin derivatives of formula IV wherein T is a -CO- group can be prepared by deketalisation of the corresponding compounds of formula IV wherein T is a -C (OCH ₃ ) ₂ -group. Deketalization is generally carried out in the presence of hydrochloric acid and in the presence of ketones such as acetone or cyclohexanone.

In order to carry out this deketalization, it is not necessary to separate the compound of formula IV wherein T is a -C (OCH ₃ ) ₂ -group.

Acids of general formula III wherein R ₁ is a group of general formula II and R ₃ and R ₄ are as defined above, and X ₁ and X ₂ are both oxygen atoms or sulfur atoms, X ₁ and X ₂ are oxygen atoms Except for the acid in which R ₃ and R ₄ are alkyl groups of C ₁ -C ₄ , it can be prepared according to the method described in Tetraheadon Vol. 24, 5,293 (1968) by I. Minna Mida et al.

Acids of Formula III wherein R ₁ is a group of formula II wherein X ₁ and X ₂ are oxygen atoms and R ₃ and R ₄ are alkyl groups of C ₁ -C ₄ are respectively Bull. Soc. Ci, described in Chim 732 (1964). G. Vermouth and H. Can be prepared by the method of Max.

R ₁ is a group of formula II wherein both X ₁ and X ₂ are oxygen atoms or _one of X ₁ and X ₂ is an oxygen atom and the other is a sulfur atom and R ₃ together is a C ₂ -C ₄ alkyl An acid of Formula III wherein R ₄ is a hydrogen atom, an alkyl group of C ₁ -C ₄ or a phenyl group is reacted with n-butylester of α-keto acid of Formula VI with a compound of Formula VII, The resulting ester can be prepared by saponification to obtain acid from the ester without affecting other parts of the molecule.

In the above formulas, R ₄ is as defined above, A is an alkylene group of C ₂ -C ₄ , X ₁ and X ₂ are as defined above.

The reaction is generally in an organic solvent such as benzene, where X ₁ and X ₂ are oxygen atoms, at the reflux temperature of the reaction mixture in the presence of para-toluenesulfonic acid, or _one of X ₁ and X ₂ is an oxygen atom and the other In the case of sulfur atoms it is carried out at a temperature of 20-30 ℃ in the presence of boron trifluoride etherate. The reaction for saponifying the resulting ester to acid is carried out, for example, using sodium hydroxide or potassium hydroxide in an aqueous medium, preferably at the reflux temperature of the reaction mixture.

The acid of Formula VI wherein R ₄ is a hydrogen atom is F. second. Wolf and Jay. It may be prepared according to the method described in Weisrad's Org. Synth, Vol. 35, p. 18 (1955).

Acids of the general formula (VI) wherein R ₄ is an alkyl group are known as Al. Ann of Barre. It may be prepared according to the method described in Chim (10), Vol. 9, page 235 (1928).

According to the present invention, the daunorubicin derivative of the general formula (I) in which R ₂ is a trichloroacetyl group is as defined above for R ₁ as a reactive derivative of trifluoro acetic acid such as anhydride or chloride, and R ₂ is a hydrogen atom. Prepared by reacting with a corresponding daunorubicin derivative of the general formula I in phosphorus free base form.

The reaction is generally carried out at a temperature of 20-35 ° C. in a mixture of organic solvents such as a mixture of chloroform and diethyl ether.

The daunorubicin derivatives of formula I prepared by the process described above can be converted by the physical method such as crystallization or chromatography, or by converting the compound in which R ₂ is a hydrogen atom to an acid addition salt and crystallizing the salt and in an alkaline medium. It may optionally be purified by chemical methods such as decomposition thereof.

The daunorubicin derivative of formula I, wherein R ₂ is a hydrogen atom, is essentially known by methods such as reacting a basic compound with an acid in a suitable solvent such as alcohols, ethers, ketones or chlorinated hydrocarbons. Can be converted to acid addition salts. The salt formed is separated by concentrating the solution as necessary and then filtering by precipitation or by pouring off the supernatant.

The novel daunorubicin derivatives of formula I and their acid addition salts thereof have been shown to have excellent antitumor activity with low toxicity and special activity against leukemia L 1,210 and P 388 and breast and lung cancer.

The following examples detail the preparation of the novel daunorubicin derivatives of the present invention.

Example 1

A mixture of 14-bromo daunorubicin 13-dimethylacetal hydrochloride (2.2 g) and dry 2,2-diethoxy-sodium acetate (2.05 g) in acetone (500 cc) is heated under reflux for 3 hours with stirring. The mixture is then left to cool, filtered and concentrated to dryness under reduced pressure (20 mmHg). The residue is taken up in chloroform (100 cc), the solution is washed with saturated aqueous sodium chloride solution (100 cc) and the aqueous phase is extracted with chloroform (100 cc). The organic phase is dried over sodium sulfate. After combining and filtering, 1.085N solution of dry hydrogen chloride in dioxane (2.2cc) was added to the resulting solution. The mixture is concentrated under reduced pressure (20 mmHg) to about 30 cc. Diethyl ether (150 cc) was added and the precipitate was filtered off, washed with ethyl acetate (2 x 50 cc) and washed with diethyl ether (2 x 50 cc). The red solid is dried at 40 ° C. under reduced pressure (0.5 mmHg). Thus, 14- (2,2-diethoxy-acetoxy) daunorubicin hydrochloride (1.44 g) having the following characteristics was obtained.

=+186.4±8°(C=0.515, 메탄올)

= + 186.4 ± 8 ° (C = 0.515, Methanol)

Rf = 0.58 [silica gel; Methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C 55.82, H 5.68, N 1.97, O 31.54, Cl 4.99

Found%: C 54.85, H 6.04, N 1.96, Cl 5.68

2,2-diethoxy-acetic acid is i. It can be prepared by the method described in Tetra Headon Vol. 24, 5,293 (1968) by Minnamida et al. From this, 2,2-diethoxy-sodium acetate is produced by a conventional method.

14-Bromo daunorubicin 13-dimethylacetal hydrochloride can be manufactured by the following method. Daunorubicin hydrochloride (10 g) is dissolved in anhydrous methanol (270 cc) and dioxane (480 cc) is added.

The mixture is heated to 30 ° C. and a solution of bromine (3 g) dissolved in chloroform (25 cc) is added while stirring. After a short period of exothermic reaction, the solution is held at 25 ° -30 ° C. for 2 hours. The reaction mixture is poured into water (2 liters). At this stage the pH is about 3 and under these conditions dimethylacetal is sufficiently stable and can be separated. The mixture is immediately extracted with chloroform (500 cc) followed by (2 x 200 cc), the pH of the aqueous solution is adjusted to 8 by addition of sodium bicarbonate and the solution is extracted four steps with chloroform (2 liters). After drying over sodium sulfate and filtration, the chloroform solution is treated with 4.8 N hydrogen chloride solution (2.06 cc) dissolved in anhydrous dioxane. Chloroform is evaporated under reduced pressure (20 mmHg) at 30 ° C. to give a red solid which is resuspended and washed with diethyl ethyl. This insoluble material is dissolved in chloroform (100 cc) and the solution is filtered to remove a small amount of insoluble material and the filtrate is evaporated at 30 ° C. under reduced pressure (20 mmHg). The residue is washed with diethyl ether and then dried under reduced pressure (0.1 mmHg) to give 14-bromodaunorubicin 13-dimethyl acetal hydrochloride (2.6 g) in the form of a red powder.

=+148°(C=0.4, 메탄올)

= + 148 ° (C = 0.4, Methanol)

Rf = 0.60 [silica gel; Methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

Example 2

A mixture of 14-bromo daunorubicin hydrochloride (2.5 g) and dry 2,2-diethoxy-sodium acetate (8.5 g) in acetone (2,500 cc) is heated under reflux for 3 hours with stirring. The mixture is concentrated to dryness under reduced pressure (20 mmHg). The residue is dissolved in saturated aqueous sodium bicarbonate solution (150 cc) and extracted with chloroform (6 × 150 cc). The extract is dried over sodium sulfate, filtered and then to the filtered solution is added a dry hydrogen chloride 1N solution dissolved in dioxane (3.78 cc). The mixture is concentrated to about 50 cc under reduced pressure. Ethyl acetate (50 cc) is added, the precipitate is filtered off, washed with ethyl acetate (2 x 100 cc) and washed with diethyl ether (4 x 200 cc). The red solid is dried under reduced pressure (0.5 mmHg) at 40 ° C. to obtain 14- (2,2-diethoxy-acetoxy) daunorubicin hydrochloride (2 g). The characteristic of this is the same as the product of Example 1.

14-Bromodaunorubicin hydrochloride can be prepared by the following method:

Daunorubicin hydrochloride (29 g) is dissolved in methanol (540 cc). Dioxane (960 cc) is added and the solution is heated to 30 ° C. A solution of bromine (10 g) (57.2 cc) dissolved in chloroform (100 cc) was added all at once and the mixture was stirred at 30 ° C. for 2 hours. Pour this into water (2000cc) and extract with chloroform (3 × 1000cc).

The organic phase is discarded, the aqueous phase is treated with 5% (W / V) aqueous sodium bicarbonate solution (200 cc) and then extracted with chloroform (4 x 1000 cc). The organic solution is washed with saturated aqueous sodium chloride solution (2 x 1000 cc) and dried over sodium sulfate. This was filtered and acetone (200 cc) was added to the filtrate, followed by 4.8 N dry hydrogen chloride solution in dioxane (5 cc). After 30 minutes, the precipitate obtained was filtered and recrystallized from a mixture of chloroform (100 cc) and methanol (300 cc) to give 14-bromodaunorubicin hydrochloride (12.54 g), which has the following characteristics:

=-97°(C=0.226, 물)

= -97 ° (C = 0.226, water)

Rf = 0,5 [silica gel; Methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

Example 3

A mixture of 14-bromodaunorubicin hydrochloride (3 g) and dry 2,2-dibutoxy-sodium acetate (4.5 g) in acetone (500 cc) is heated under reflux for 2 hours 30 minutes. After cooling, the mixture is filtered over diatom silica and the filtrate is concentrated under reduced pressure (0.5 mmHg) at 40 ° C. to a capacity of about 50 cc. The red precipitate is filtered off, washed with acetone (2 x 15 cc) and dried at 25 ° C under reduced pressure (0.5 mmHg). The precipitate is dissolved in chloroform (10 cc) and treated with 0.83 N dry hydrogen chloride solution dissolved in dioxane (3.3 cc). The clear red solution is concentrated to dryness at 25 ° C. under reduced pressure (20 mmHg).

The resulting red solid is taken up in methanol (5 cc) and diethyl ether (100 cc) is added. The precipitate is filtered off and washed with ethyl acetate (3 x 15 cc) and diethyl ether (15 cc). The red solid was dried under reduced pressure (0.5 mmHg) at 40 ° C. to obtain 14- (2,2-dibutoxy-acetoxy) daunorubicin hydrochloride (1.250 g) having the following properties.

=+155±9°(C=0.416, 메탄올)

= + 155 ± 9 ° (C = 0.416, Methanol)

Rf = 0.64 [silica gel: methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 58.00 H, 6.31 Cl, 4.63 N, 1.83 O, 29.23

Found%: C, 56.36 H, 6.17 Cl, 5.6 N, 2.19

Butyl 2,2-dibutoxy-acetate, the starting material of 2,2-dibutoxy-sodium acetate, is i. It can be produced by the method described in tetrahedron such as Minna Mida, Vol. 24, 5,293 (1968).

Example 4

A mixture of 14-bromo daunorubicin hydrochloride (5 g) and dry 2,2-diphenoxy-sodium acetate in acetone (3,500 cc) is heated under reflux for 1 hour 45 minutes with stirring. After cooling, the reaction mixture is filtered and the solid is washed with acetone (2 x 50 cc).

The filtrate is concentrated at 40 ° C. under reduced pressure. The residue is suspended in methylene chloride (70 cc), filtered and washed with methylene chloride (3 x 20 cc). The resulting red solid was dissolved in chloroform containing 5% by volume methanol (150cc) and the solution was dissolved in 5% (W / V) aqueous sodium bicarbonate solution (2x150cc), saturated aqueous sodium chloride solution (150cc) and distilled water (150cc). Wash with. The organic phase is dried over sodium sulfate, filtered, and concentrated to about 50 cc at 30 ° C. under reduced pressure (20 mmHg). Diethyl ether (300 cc) is added and the precipitate is filtered off and washed with diethyl ethyl (3 x 50 cc). The red solid was dried under reduced pressure (0.5 mmHg) at 40 ° C. to obtain 14- (2,2-diphenoxy-acetoxy) daunorubicin (1.99) having the following properties:

=173.5±17°(C =0.258, 클로로포름)

= 173.5 ± 17 ° (C = 0.258, Chloroform)

Rf = 0.33 [Silica gel: methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 63.97 H, 5.11 N, 1.82 O, 29.10

Found%: C, 63.3. H, 5.1 N, 2.08

Ethyl 2,2-diphenoxy-acetate, the starting material of 2,2-diphenoxy-sodium acetate, is i. It can be manufactured by the method described in tetrahedron 24, 5,293 (1968), such as Minamida.

Example 5

A mixture of 14-bromodaunorubicin hydrochloride (6 g) and dry 2,2-bis- (4-methoxy phenoxy) -sodium acetate (12.1 g) in acetone (1,500 cc) was heated under reflux for 2 hours 30 minutes. Heat during. The mixture is filtered over diatom silica gel while hot and the filtrate is concentrated to dryness at 40 ° C. under reduced pressure (20 mmHg). The resulting red paste was dissolved in chloroform (300 cc), and the resulting solution was washed with saturated aqueous sodium bicarbonate solution (50 cc), then washed with water (2 x 50 cc), dried over sodium sulfate, filtered, and reduced pressure (20 mmHg). ) And concentrated to dryness at 40 ° C. The obtained red solid is dissolved in chloroform (15 cc), and the solution is poured into the top of a column (height 500 cm diameter 30 mm) containing silica gel (100 g) in chloroform.

Eluate with chloroform (2,100 cc) containing 2-5% (volume) of methanol (concentration gradient), and the eluate is collected in 70 cc aliquots. The aliquots 16-28 were combined and concentrated to dryness at 40 ° C under reduced pressure (20 mmHg). The red solid is dissolved in chloroform (10 cc), diethyl ether (100 cc) is added, the precipitate is filtered off, washed with diethyl ether (2 x 10 cc), and dried under reduced pressure (0.5 mmHg) at 40 ° C. 14- [2,2-bis (4-methoxy phenoxy-acetoxy] daunorubicin (0.65 g) having the following properties is obtained:

Rf = 0.6 [silica gel: methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 62.24 H, 5.22 N, 1.69 O, 30,85

Found%: C, 62.25 H, 5.15 N, 1.0

Methyl 2,2-bis (4-methoxyphenoxy) -acetate is i. It can be prepared by the method as described below applying the method described in the tetrahedron 24, 5,293 (1968), such as Minamida, from 2,2-bis (4-methoxyphenoxy) by a conventional method Prepare sodium acetate:

Sodium (5.4 g) is dissolved in anhydrous ethanol (160 cc). 4-methoxy phenol (29.2 g) dissolved in anhydrous ethanol (20 cc) is added. The mixture is stirred at ambient temperature for 1 hour, then ethyl 2,2-dichloro-acetate (20 g) dissolved in anhydrous ethanol (20 cc) is added and the mixture is heated at reflux for 20 hours. Ethanol was built at 40 ° C. under reduced pressure (20 mmHg) and the residue was taken up in diethyl ether (100 cc). The organic phase is washed with 0.1 N sodium hydroxide solution (100 cc) and washed with water (2 x 100 cc) and dried over sodium sulfate. Filtration and concentrated to dryness at 40 ° C. under reduced pressure (20 mmHg) yielded ethyl 2,2-bis (4-ethoxyphenoxy) -acetate (30 g) in oil form.

Example 6

A mixture of 14-bromodaunorubicin hydrochloride (5 g) and dry 2,2-diethylthio acetate (6.25 g) in acetone (3,500 cc) is heated under reflux for 2 hours with stirring. After cooling, the reaction mixture is filtered and the solid is washed with acetone (2 x 50 cc). The filtrate is concentrated at 40 ° C. under reduced pressure (20 mmHg). The residue is suspended in methylene chloride (100 cc), filtered and washed with methylene chloride (3 x 30 cc). The resulting red solid was dissolved in chloroform (150cc) containing 5% by volume methanol, and the solution was dissolved in 5% (W / V) aqueous sodium bicarbonate solution (2x150cc), saturated aqueous sodium chloride solution (150cc) and distilled water (150cc). Wash with. The organic phase is dried over sodium sulphate and filtered and concentrated to 30 cc at 30 ° C. under reduced pressure (20 mmHg). Diethyl ether (300 cc) was added and the precipitate was filtered off and washed with diethyl ether (3 x 50 cc). The red solid was dried under reduced pressure (0.5 mmHg) at 40 ° C. to obtain 14- (2,2-diethylthio-acetoxy) daunorubicin (2 g) having the following properties:

=+170±9° (C=0.398, 클로로포름)

= + 170 ± 9 ° (C = 0.398, Chloroform)

Rf = 0.32 [Silica gel: methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 56.16 H, 5.57 N, 1.98 O, 27.20 S, 9.09

Found%: C, 56.40 H, 5.65 N, 2.06 S, 8.89

Ethyl 2,2-diethylthio-acetate is i. It can be prepared by the method described in tetrahedron No. 24, 5,293 (1968) by Minnamida et al., From which a 2,2-diethylthio-sodium acetate is produced by a conventional method.

Example 7

A mixture of 14-bromodaunorubicin hydrochloride (5 g) and dry 2,2-diphenylthio-sodium acetate (9.2 g) in acetone (3,500 cc) is heated under reflux for 2 hours with stirring. The reaction mixture is filtered while hot and the solid is washed with acetone (2 x 50 cc). The filtrate is concentrated to dryness at 40 ° C. under reduced pressure (20 mmHg), the residue is suspended in methylene chloride (100 cc), filtered and washed with methylene chloride (3 × 20 cc). Dissolve the resulting red solid in chloroform (300cc) containing 10% by volume methanol: The resulting solution was dissolved in 5% (W / V) aqueous sodium bicarbonate solution (2 x 150cc), saturated aqueous sodium chloride solution (150cc) and distilled water ( 150 cc). The organic phase is dried over sodium sulphate and filtered and concentrated to 30 cc at 30 ° C. under reduced pressure (20 mmHg). Diethyl ether (300 cc) was added and the precipitate was filtered off and washed with diethyl ether (3 x 50 cc). The red solid was dried under reduced pressure (0.5 mmHg) at 40 ° C. to obtain 14- (2,2-diphenylthio-acetoxy) daunorubicin (2.45 g) having the following characteristics.

=+156±12°(C=0.331, 클로로포름)

= + 156 ± 12 ° (C = 0.331, Chloroform)

Rf = 0.36 [Silica gel: methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 61.41 H, 4.90 N, 1.75 O, 23.93 S, 8.00

Found%: C, 61.15 H, 4.99 N, 1.54 S, 8.93

Ethyl 2,2-diphenylthio-acetate is a child. It can be prepared according to the method described in Tetra Headon Vol. 5,293 (1968) by Minnamida et al., From which a 2,2-diphenylthio-sodium acetate is prepared by a conventional method.

Example 8

A mixture of 14-bromodaunorubicin hydrochloride (5.2 g) and dry 1,3-dioxolane-2-carboxylic acid sodium (5.2 g) in acetone (2,500 cc) is heated under reflux for 24 hours with stirring. After cooling the reaction mixture is filtered. The amorphous red product obtained by concentrating and drying a filtrate at 40 degreeC under reduced pressure (20 mmHg) is taken in reflux methylene chloride (300 cc). The resulting red solution is cooled to 0 ° C., the precipitate obtained is filtered off and washed with methylene chloride (2 × 25 cc). This gives a red solid (1.93 g), which is dissolved in the breaking methanol (50 cc). A small amount of insoluble material is filtered off and the methanol solution is cooled to 0 ° C. The red precipitate is filtered off and washed with cold methanol (2 x 5 cc). The red solid was dried under reduced pressure (0.5 mmHg) at 40 ° C. to form a salt of 1,3-dioxolane-carboxylic acid having the following properties: 14-[(1,3-dioxolan-2-yl) Carbonyloxy] daunorubicin (0.74 g).

=+108±11° [(C=0.3 : 클로로포름 : 메탄올부피로 8 : 2)]

= + 108 ± 11 ° [(C = 0.3: Chloroform: Methanol Volume 8: 2)]

Rf = 0.58 silica gel .. [methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 55.19 H, 5.16 N, 1.84 O, 37.81

Found%: C, 55.0 H, 5.2 N, 1.8

Ethyl 1,3-dioxolane-2-carboxylate is child. According to the method described in Tetrahedron Vol. 24, 5,293 (1968) by Minna Mida et al., It can be prepared by the operation as described below. From this compound, 1,3-dioxolane-2- Sodium carboxylate can be prepared.

A mixture of ethyl 2,2-diethoxy-acetate (96 g), ethylene glycol (40 g) and boron trifluoride etherate (50 g) in cyclohexane (300 cc) is heated under reflux for 4 days with stirring. After cooling, the mixture is poured onto 200 g of crushed ice) and neutralized with solid sodium bicarbonate. The mixture is extracted with diethyl ether (3 x 250 cc) and the ether phase is washed with water (2 x 100 cc) and dried over sodium sulfate. Concentrate and dry at 30 degreeC under reduced pressure (20 mmHg). Distillation at a pressure of 35 mm Hg yields an oil (40 g) which is distilled at 101-104 ° C. and contains 15% ethyl 2,2-diethoxy-acetate. The oil thus produced is reacted again for two days under the same conditions. After the same treatment, ethyl 1,3-dioxolane-2-carboxylate (18.5 g: boiling point 95 DEG C / 35 mmHg) is obtained.

Example 9

A mixture of rust-14-bromodaunorubicin hydrochloride (4 g) and dry 1,3-dithiolane-2-carboxylic acid sodium (3.84 g) in acetone (4,000 cc) is heated under reflux for 4 hours with stirring. The mixture is concentrated to dryness under reduced pressure (20 mmHg) and the residue is taken up in chloroform (300 cc) and the solution is washed successively with water (100 cc) and 0.01 N hydrochloric acid (100 cc). The aqueous acid solution was adjusted to pH 8.2 with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform (3 × 100 cc). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure (20 mmHg), the resulting product was dissolved in methylene chloride (10 cc), and the solution was dissolved in methylene chloride in a column containing silica gel (125 g) (2.4 cm in diameter). Height 40 cm) on top. Elution was successively carried out with methylene chloride (1,000 cc) and methylene chloride (2,000 cc) containing 3-10% by volume methanol (concentrate), and the eluate was collected in 125 cc aliquots. The aliquots 17-24 are combined and concentrated to dryness under reduced pressure (20 mmHg). The product is dissolved in a mixture of chloroform and methanol (by volume 98: 2, 100 cc), the solution is cooled to 0 ° C. and a 1.085 N solution in which dry hydrogen chloride is dissolved in dioxane (2.76 cc) is added. The mixture is filtered and the red solid precipitate is dried at 40 ° C. under reduced pressure (0.5 mmHg). 14-[(1,3-dithiolan-2-yl) carbonyloxy] daunorubicin hydrochloride (1.25 g) having the following properties is obtained.

=-136.6±7.5°(C=0.505, 물)

= -136.6 ± 7.5 ° (C = 0.505, water)

Rf = 0.29 [Silica gel: methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 52.28 H, 4.81 Cl, 4.98 N, 1.97 O, 26.96 S, 9.60

Found%: C, 51.4 H, 5.2 Cl, 5.1 N, 1.76 8.7

1,3-dithiolane-2-carboxysilane sodium is prepared by conventional methods from 1,3-dithiolane-carboxylic acid, the latter compound being i. It can be manufactured by the method described in tetrahedron No. 24, 5,293 (1968) by Minnamida et al.

Example 10

A mixture of 14-bromodaunorubicin hydrochloride (5 g) and dry 1,3-dithiolane-2-carboxylic acid sodium (5.8 g) in acetone (150 cc) is heated under reflux for 6 hours with stirring. After cooling, the reaction mixture is filtered. On the other hand, the precipitate is washed with a mixture of water and acetone (1: 1,4 × 50 cc by volume), then with distilled water (50 cc) and dried in air to give a red powder (2.57 g). On the other hand, the filtrate is concentrated to dryness at 40 ° C. under reduced pressure (20 mmHg). The resulting solid is suspended in chloroform (200 cc), and the precipitate is filtered and washed with chloroform (50 cc), methanol (50 cc), ethyl acetate (50 cc) and diethyl ether (50 cc). The red solid is dried at 20 ° C. under reduced pressure (0.5 mmHg). This gave a red powder (3.28 g), which appeared to be the same as the precipitate previously separated on thin layer chromatography on silica gel [solvent: methylene chloride: methanol: formic acid: water (volume 88: 15: 2: 1)]. .

A more pure second solid is suspended in methanol (100 cc) and the resulting clear red solution is treated with diethyl ether (250 cc) by treatment of dry hydrogen chloride with 1.06 N solution dissolved in dioxane (4.5 cc).

The resulting precipitate is filtered off and washed with ethyl acetate (2 x 50 cc) and diethyl ether (50 cc). The red solid was dried under reduced pressure (0.5 mmHg) at 40 ° C. to obtain 14-[(1,3-dithia-2-yl) carbonyloxy] daunorubicin hydrochloride (2.4 g) having the following properties.

=+226.4±3.5° (C=0.5,메탄올)

= + 226.4 ± 3.5 ° (C = 0.5, methanol)

Rf = 0.44 [silica gel, methylene chloride: ethanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 52.92 H, 5.00 Cl, 4.88 N, 1.93 O, 26.44 S, 8.85

Found%: C, 52.39 H, 5.25 Cl, 5.16 N, 1.92 8.86

1,3-dithiane-2-carboxylic acid is i. Sodium 1,3-dithiane-2-carboxylic acid can be prepared according to the method described in Tetrahedron 24, 5,293 (1968) by Minnamida et al.

Example 11

A mixture of 14-bromodaunorubicin hydrochloride (6 g) dissolved in acetone (3,000 cc) and dry 1,3-oxathiola-2-sodium carboxylate (6 g) is heated under reflux for 24 hours with stirring. After cooling the reaction mixture is filtered. The filtrate is concentrated to dryness at 40 ° C. under reduced pressure (20 mmHg). The red amorphous product is taken up in ice water (150 cc) and extracted with chloroform (2 x 150 cc). The aqueous phase is adjusted to pH 8 with 5% (W / V) aqueous sodium bicarbonate solution, extracted with chloroform (3 x 100 cc), dried over sodium sulfate, concentrated under reduced pressure (20 mmHg) and concentrated at 20 ° C. to dryness.

Red powder (3.5 g) is obtained, this solid is dissolved in chloroform (15 cc), and the solution is poured into a column (3.25 cm in diameter and 25 cm in height) containing silica gel (100 g) in chloroform. Eluate with chloroform (1,500 cc) containing 6 vol% methanol and collect the eluate in 150 cc aliquots. The first 10 aliquots are combined and concentrated to dryness at 40 ° C. under reduced pressure (20 mmHg). The resulting solid is dissolved in chloroform (150 cc) and the solution is poured into a column containing silica gel (60 g) (diameter 2 sheets, height 40 cm). Eluate with chloroform (1800 cc) containing 5 volume% methanol to collect the eluate in 100 cc aliquots. The aliquots 11-18 were combined and concentrated-dried at 40 ° C. under reduced pressure (20 mmHg). The resulting product is dissolved in chloroform (20 cc) and 0.32N solution in which dry hydrogen chloride is dissolved in dioxane (1.3 cc) is added. Diethyl ether (20 cc) was added, the resulting red solid was separated by filtration, washed with diethyl ether (2 x 10 cc), and dried under reduced pressure (1 mmHg) at 40 deg.

14-[(1,3-oxathiolan-2-yl) carbonyloxy] daunorubicin hydrochloride (0.765 g) having the following properties is obtained.

=+217±12° (C=0.2, 메탄올)

= + 217 ± 12 ° (C = 0.2, Methanol)

Rf = 0.37 [silica gel: methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 53.49 H, 4.92 Cl, 5.09 N, 2.01 O, 29.88 S 4.61

Found%: C, 53.10 H, 4.7 Cl, 4.85 N, 1.70 4.59

n-butyl 1,3-oxathiolane-2-carboxylate can be prepared by reacting as described below, from which the sodium 1,3-oxathiolane-2-carboxylic acid is prepared by conventional methods.

A mixture of n-butyl glyoxylate (32 g) mercaptoethanol (22 g) and boron trifluoride etherate (36 cc) dissolved in benzene (300 cc) is stirred at ambient temperature for 16 hours. The mixture is poured onto crushed ice (300 g), neutralized with solid sodium bicarbonate and extracted with diethyl ether (4 x 200 cc). The ether phase is washed with distilled water (300 cc), dried over sodium sulfate and filtered. Concentrate and dry at 30 degreeC under reduced pressure (20 mmHg). Obtaining liquid (35 g) and distilling yields oil (20 g, boiling point 83 ° C./0.3 mmHg). This oil is poured into a column containing silica gel (300 g) (3.5 cm in diameter and 60 cm in height) in petroleum ethyl (distillation range 40-60 ° C.). Elution with petroleum ether (distillation range 40-60 ° C: 1,000cc), followed by continuous elution with petroleum ether (distillation range 40-60 ° C) (2,000cc) containing 5% by volume of ethyl acetate Collect into aliquots. The liquids 3 and 4 were combined and concentrated to dryness at 30 ° C. under reduced pressure (20 mmHg) to obtain n-butyl.1,3-oxathiolane-2-carboxylate (13 g).

n-butyl glyoxylate is f. second. Wolf and Jay. It can be prepared according to the method described in Wiserad's organic synthesis volume 35, page 18 (1955).

Example 12

A mixture of 14-bromo daunorubicin hydrochloride (1.78 g) and 2,2-diethoxy-propionate sodium (2.55 g) dissolved in acetone (400 cc) and ethanol (40 cc) is heated under reflux for 6 hours with stirring. The reaction mixture is ice cooled and concentrated to dryness at 40 ° C. under filtration and reduced pressure (20 mmHg). The residue was dissolved in chloroform (100 cc), the solution was filtered, washed with buffered aqueous solution (150 cc) [prepared from 0.1 M aqueous potassium phosphate solution (500 cc) and 0.1 N sodium hydroxide solution (291 cc)] at pH 7. The buffer solution is extracted with chloroform (2 × 100 cc), three chloroform solutions are combined, washed with saturated aqueous sodium chloride solution (100 cc), and the saturated aqueous solution is extracted with chloroform (50 cc). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness at 30 ° C. under reduced pressure (20 mmHg). The residue is dissolved in chloroform (15 cc) and the solution is poured into a column (3 cm in diameter and 36 cm in height) containing silica gel (120 g) in chloroform. The eluate is collected in 100 cc aliquots by continuously eluting with chloroform (150 cc) and chloroform (2,250 cc) (concentrate) containing 5-10 volume% methanol. The aliquots 17-27 were combined and concentrated to dryness at 30 ° C. under reduced pressure (20 mmHg). The obtained product is dissolved in chloroform (50 cc). 1.06N dry hydrogen chloride solution dissolved in dioxane (2cc) was added, and the resulting red solid was filtered off and dried at 40 ° C under reduced pressure (0.5 mmHg). Thus, 14- (2,2-diethoxypropanoyloxy) daunorubicin hydrochloride (1.46 g) having the following characteristics is obtained.

=+191.2±5°(C=0.3, 메탄올)

= + 191.2 ± 5 ° (C = 0.3, methanol)

Rf = 0.48 [Silica gel, methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 56.39 H, 5.85 Cl, 4.90 N, 1.93 O, 30.93

Found%: C, 55.96 H, 5.85 Cl, 5.01 N, 1.91

Sodium 2,2-diethyl-propionate can be obtained by conventional methods from ethyl 2,2-diethoxy-propionate.

Ethyl-2,2-diethoxy-propionate is ci. G. Vermouth and Age. It may be prepared according to the method described in Max Bull. Soc. Chim France 732 (1964).

Example 13

A mixture of 14-bromodaunorubicin hydrochloride (5 g) dissolved in acetone (2,300 cc) and dry 2-phenyl-1,3-dithiolane-2-carboxylic acid sodium (5 g) is heated under reflux for 18 hours while stirring. . The reaction mixture is filtered when hot and the filtrate is concentrated to dryness at 40 ° C. under reduced pressure (20 mmHg). Varnish was taken in methylene chloride (500 cc). The organic solution was washed with 5% (W / V) sodium bicarbonate aqueous solution (2 x 100 cc) and distilled water (250 cc), dried over sodium sulfate-filtered, concentrated to dryness at 40 DEG C under reduced pressure (20 mmHg). The obtained solid is dissolved in chloroform (15 cc) and the solution is poured into a column (2.5 cm in diameter) containing silica gel (100 g) in chloroform. The eluate is collected in 100 cc aliquots by eluting with chloroform (4,000 cc) containing chloroform (2,000 cc) and 1-5 volume% methanol (concentrate). The aliquots 41-55 were combined and concentrated to dryness at 40 ° C under reduced pressure (20 mmHg). The obtained product is dissolved in chloroform (30 cc). 0.91 N dry hydrogen chloride solution dissolved in dioxane (3.5 cc) is added. The resulting red precipitate was filtered and dried under reduced pressure (0.5 mmHg) at 40 ° C. to give 14-[(2-phenyl-1,3-dithiolan-2-yl) carbonyloxy] daunorubicin having the following characteristics: Hydrochloride (2.23 g) is obtained.

=+209±9°(C=0.4 메탄올)

= + 209 ± 9 ° (C = 0.4 Methanol)

Rf = 0.35 [Silica gel, methylene chloride: methanol: formic acid: water (by volume 88: 15: 2: 1)]

analysis

Calculated%: C, 56.38 H, 4.86 Cl, 4.50 N, 1.78 O, 24.35 S, 8.13

Found%: C, 56.68 H, 5.2 Cl, 4.62 N, 1.80 7.82

Sodium 2-phenyl-1,2-dithiolane-2-carboxylic acid can be prepared from an ethyl 2-phenyl-1,3-dithiolane-2-carboxylate-conventional method.

Ethyl 2-phenyl-1,3-dithiolane-2-carboxylate is a child. It can be prepared according to the method described in the tetrahedron 24, 5,293 (1968) to Minnamata et al.

Example 14

14- (2,2-diethoxy-acetoxy) daunorubicin hydrochloride (3.8 g) is dissolved in distilled water (150 cc). The solution was adjusted to pH 8 with aqueous sodium bicarbonate solution and then extracted with chloroform.

The extract is dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg). 14- (2,2-diethoxy-acetoxy) daunorubicin (2.5 g) was obtained and dissolved in chloroform (162 cc). Diethyl ether (65 cc) is added.

The temperature of the mixture rises to 32 ° C. Anhydrous trifluoroacetic acid (3.85cc) is added all at once. The mixture is stirred for 5 minutes, washed with water (3 × 250 cc), dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg).

The resulting product is dissolved in chloroform (10 cc) and the solution is poured into the top of a column (3 cm in diameter, 36 cm in height) containing silica gel (120 g) in chloroform. After eluting with chloroform (500cc), eluting with chloroform (4,000cc) (concentrate) containing 1-10% by volume of ethyl acetate in succession, the eluate was collected in 100cc aliquots. Combine aliquots 16-45 and concentrate to dryness under reduced pressure (20 mmHg). The obtained product is dissolved in chloroform (10 cc) and petroleum ether (boiling point 40-65 ° C .: 20 cc) is added to precipitate. The red solid was filtered off, washed with petroleum ether, and dried under reduced pressure (0.5mmHg) at 40 ° C to have 14- (2,2-diethoxy-acetoxy) -N-trifluoroacetyldaunoru having the following characteristics: Obtain bicine (0.9 g).

=233.7±9° (C =0.385, 클로로포름)

= 233.7 ± 9 ° (C = 0.385, Chloroform)

Rf = 0.57 [silica gel, methylene chloride: methanol (93: 7 in capacity)]

analysis

Calculated%: C, 54.62 H, 4.98 F, 1.82 N, 7.40 O, 31.18

Found%: C, 54.3 H, 4.95 F, 1.8 N, 6.9

Claims (1)

The alkali metal salt or alkaline earth metal salt of the acid of formula III is then reacted with the daunorubicin derivative of formula IV or acid molar salt thereof, and the resulting daunorubicin derivative of formula I ′ is optionally reacted with trifluoroacetic acid. A process for preparing the following daunorubicin derivatives of general formula I and acid addition salts thereof, wherein said reacting with a derivative yields a corresponding daunorubicin derivative of general formula I wherein R ₂ is trifluoro acetyl.

Wherein R ₁ is a group of formula II, R ₂ is a hydrogen atom or a trifluoro acetyl group, T is a -CO- group or a -C (CH ₃ ) ₂ -group,

Wherein (i) X ₁ and X ₂ are both oxygen atoms or sulfur atoms, and R ₃ is a C ₁ -C ₄ alkyl group phenyl group or a phenyl group substituted at the para-position with methyl, methoxy or methylthio group Or together form a C ₂ -C ₄ alkylene group, or (ii) _one of X ₁ and X ₂ is an oxygen atom and the other a sulfur atom, and R ₃ together represent a C ₂ -C ₄ alkylene group And R ₄ is a hydrogen atom, a C ₁ -C ₄ alkyl group or a phenyl group.