JPH0544958B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel anthracycline derivative, and more specifically, the present invention relates to a novel anthracycline derivative, and more specifically, to The present invention relates to 14-trifluoromethanesulfonyloxydaunomycin and its salts represented by formula (2), a method for producing the same, and a method for producing adriamycin or its salt from the compound of the above formula (). Adriamycin is a substance useful as an antibacterial agent and an antitumor agent that has excellent antibacterial and antitumor effects, and various synthesis methods are known. For example, Japanese Patent Publication No. 47-46597 (U.S. Patent No. 3803124)
14-halodaunomycin obtained by reacting daunomycin with a halogen is reacted with an alkali metal acetate in a polar solvent, and the resulting 14-acetoxydaunomycin is hydrolyzed under alkaline conditions. A method for producing adriamycin is disclosed. However, the above-mentioned method of hydrolyzing 14-acetoxydaunomycin under alkaline conditions has a serious drawback in that the produced adriamycin is unstable to alkali, resulting in decomposition of adriamycin and a decrease in its yield. Therefore, the present inventors conducted intensive research on a method for producing adriamycin that does not have such drawbacks, and as a result, a novel product of the above formula () obtained by reacting 14-halodaunomycin with a metal salt of trifluoromethanesulfonate was obtained. It was discovered that the 14-trifluoromethanesulfonyloxydaunomycin shown above can be hydrolyzed under acidic conditions, and that adriamycin can be produced in high yield, leading to the completion of the present invention. Thus, the present invention provides 14-
The present invention provides trifluoromethanesulfonyloxydaunomycin and its salts as new substances. Examples of salts of the compound of formula () include inorganic acid salts such as hydrochloride, hydrobromide, and hydroiodide, and organic acids such as acetate, trifluoromethanesulfonate, and trifluoroacetate. Salt is an example. The compound of the formula () is represented by the following formula In the formula, X is a halogen atom. It can be produced by reacting 14-halodaunomycin or its salt represented by the following with a trifluoromethanesulfonic acid metal salt. The reaction between the compound () or its salt (e.g., hydrochloride, hydrobromide, etc.) and trifluoromethanesulfonic acid metal salt is usually carried out in a polar organic solvent inert to the reaction, such as dimethylformamide, dimethyl It can be carried out in a solvent such as a sulfoxide, preferably dimethylformamide, at a temperature within the range of about 0°C to about 70°C, preferably at about room temperature. The amount of trifluoromethanesulfonate used for the compound of formula () or its salt is not particularly limited, but is generally in the range of 1 to 5 mol, preferably 2 to 4 mol, per 1 mol of the compound of formula () or salt thereof. It is appropriate to use the amount within. The compound of the formula () used as a starting material in the above reaction is a compound known per se, and can be prepared by various methods known per se, for example,
Publication No. 47-46597 (U.S. Patent No. 3803124),
Japanese Patent Publication No. 54-26529 (U.S. Patent No. 4225589), Japanese Patent Publication No. 13558-1987, Japanese Patent Publication No. 1982-
It can be easily produced by the method described in literature such as No. 59719 (US Pat. No. 4,360,664). Further, as the trifluoromethanesulfonic acid metal salt reacted with the compound of the above formula (), silver salt of trifluoromethanesulfonic acid is most preferable, but in addition, copper salt, tin salt, lithium salt, potassium salt, sodium salt Metal salts such as can also be used. The resulting compound of formula () or a salt thereof can be separated and purified from the reaction mixture by methods known per se, for example, by chromatography, crystallization, precipitation, etc., or can be separated and purified. It can also be directly subjected to the hydrolysis step described below. The thus obtained compound of formula () or its salt can be hydrolyzed under acidic conditions to lead to adriamycin or its salt in high yield. Hydrolysis of a compound of formula () or a salt thereof can be carried out by preparing a compound of formula () in an aqueous medium such as water, an aqueous buffer solution or a mixture of water and a water-miscible organic solvent at about 10°C.
This can be carried out by maintaining the temperature at a temperature of from about room temperature to about 60°C, more preferably from about room temperature to about 50°C. It is generally desirable to maintain the pH of the aqueous medium during hydrolysis under acidic conditions within the range of 2 to 6.5. Therefore, since an aqueous solution of the compound of formula () or a salt thereof usually exhibits acidity within the range of PH2.0 to 2.4, depending on the type of the salt, there is no need to particularly adjust the PH during hydrolysis. However, if necessary, sodium hydroxide, potassium hydroxide, sodium carbonate,
The pH of the aqueous medium can also be adjusted to the above-mentioned preferred range by adding a pH adjuster such as sodium carbonate or sodium phosphate or by using an aqueous buffer solution. Hydrolysis can usually be completed in about 10 to 40 minutes under such conditions, and adriamycin or its salt produced from the reaction mixture after hydrolysis can be separated and purified by methods known per se, such as acid conversion. This can be done by means such as extraction, crystallization, etc. The adriamycin produced can be converted into a salt by treatment with a suitable pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, etc. Next, the present invention will be explained in more detail with reference to Examples. Example 1 (1) Production of 14-trifluoromethanesulfonyloxydaunomycin Add 10 ml of DMF solution of 14-bromodaunomycin hydrochloride (0.500 g, 0.7777 mmol) prepared by the method described in Example 2 of Japanese Patent Publication No. 56-156300 (U.S. Pat. No. 4,360,664) in a cutlet-colored container.
Silver trifluoromethanesulfonate under nitrogen atmosphere
0.5995g, 2.333mmol) was added thereto, and the mixture was stirred at room temperature overnight. Solid (AgBr) precipitated in the reaction mixture
After filtration, the solid was washed with DMF, and the filtrate and washings were combined and concentrated under reduced pressure. Chloroform was added to the concentrated and dried product, stirred vigorously, and ultrasonic waves were applied to disperse and precipitate insoluble matter. The precipitate was filtered, washed with chloroform, and dried to give 0.5600 g (quantitative yield) of 14-trifluoromethanesulfonyloxydaunomycin hydrochloride.Physical and chemical properties of 14-trifluoromethanesulfonyloxydaunomycin hydrochloride Rf value: 0.40 (TLC plate: Merck Art5715 Development system: CHCl ₃ : CH ₃ OH: AcOH=20:6:1) IR ν ^KBr _nax cm ^-1 : 3420 (OH, NH ₂ ), 1715 (C=
O), 1615, 1580 (C=O), 1270, 1265, 1170
(-OSO ₂ CF ₃ ) ¹ H-NMR δppm (DMSO-d ₆ /TMS): 1.17 (3H, d, J = 6.5Hz, H-6') 1.68 (1H, dd, J = 11.8Hz, 3.4Hz , H-2'e) 1.90 (1H, broad t, J = 11.8Hz, H-2'a) 2.09 (1H, dd, J = 13.3Hz, 5.7Hz, H-8a) 2.29 (1H, broad d, J=13.3Hz, H-8e) 2.83 (1H, d, J=18.4Hz, H-10a) 3.07 (1H, d, J=18.4Hz, H-10e) 3.34-3.40 (1H, m, H-3 ') 3.99 (3H, s, O-CH ₃ ) 4.19 (1H, broad q, J=6.5Hz, H-5') 4.94-4.99 (1H, m, H-7) 5.28-5.30 (1H, m, H-1') 5.25 (1H, d, J = 19.8Hz, H-14) 5.33 (1H, d, J = 19.8Hz, H-14) 5.58 (1H, s, OH) 7.65-7.70 (2H, m , H-2, H-3) 7.70-7.78 (2H, broad s, NH ₂ ) 7.92 (1H, d, J=3.7Hz, H-1) ¹³ C-NMR δppm (DMSO-d ₆ ): 20.6 C -6' 32.2 C-2' 35.7 C-10 39.8 C-8' 50.7 C-3' 60.5 OCH ₃ 68.9 C-14 70.2 C-4', C-5' 73.4 C-7 83.1 C-9 103.2 C- 1' 114.5, 114.6 (C-5a, C-11a) 122.9 C-3 123.6 C-1 123.7 C-4a 137.6 C-10a 138.4, 138.8 (C-12a, C-6a) 138.8 CF ₃ J _CF = 320.4Hz 140.1 C-2 158.3 C-11 159.9 C-6 164.7 C-4 190.1, 190.2 (C-5, C-12) 211.1 C-13 (2) Production of adriamycin hydrochloride 14-trifluoromethanesulfonyloxydaunomycin hydrochloride obtained in (1) above (0.200g,
Hydrolysis was carried out by dissolving 0.2797 mmol) in 20 ml of water (PH2.4) and maintaining it at room temperature for 25 hours with stirring. The reaction mixture was diluted with 20 ml of water and extracted twice with chloroform. Add sodium chloride to the aqueous layer to make an approximately 5% aqueous solution.
Next, chloroform:methanol (4:1) was added, and the aqueous layer was diluted with a saturated aqueous sodium bicarbonate solution.
The pH was set to 7.4. The aqueous layer was extracted four times with chloroform:methanol (4:1), and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing the solvent, 0.1074 g (yield: 70.7%) of adriamycin (educt) was obtained. This adriamycin (free form) was dissolved in 10 ml of chloroform:methanol (10:1),
1N-HCl (in CH ₃ OH, f = 1.013) (1.2 equivalents,
Add 0.234ml (0.2377mmol). When the reaction solution was concentrated, a precipitate was formed. This precipitate was filtered, and the filtered product was washed with chloroform:methanol (10:1), further washed with chloroform, and dried to yield 0.1023 g of adriamycin hydrochloride.
(HPLC relative purity: 94:1%, total yield from 14-bromodaunomycin hydrochloride: 63.1%) was obtained. Physical and chemical properties of Adriamycin hydrochloride Melting point: 203-205℃ (decomposition) [α] ^D ₂₄ : +250.8 (c=0.096, CH ₃ OH) λmax (CH ₃ OH) nm: 531, 495, 480 IR ν ^KBr _nax : 3370 (-OH, _NH2 ), 1725 (C=O), 1610, 1580 (C=O) NMR δppm (DMSO- _d6 /TMS): 1.16 (3H, d, J=6Hz, H-6 ') 1.67-1・99 (2H, m, H-2') 1.99-2.21 (2H, m, H-8) 2.80-3.00 (2H, m, H-10) 3.55-3.70 (1H, m, H -4') 3.99 (3H, s, -OCH ₃ ) 4.08-4.17 (1H, m, H-5') 4.60 (2H, s, H-14) 4.89 (1H, m, H-7) 5.28 (1H , m, H-1') 5.50 (1H, s, 9-OH) 7.52-7.70 (2H, m, H-2, H-3) 7.80 (1H, d, J=3Hz, H-1) 7.92- 8.12 (2H, m, NH ₂ ) 13.25 (1H, broad s, Ar-OH) 14.08 (1H, s, Ar-OH) Example 2 Production of Adriamycin hydrochloride without isolating 14-trifluoromethanesulfonyloxydaunomycin A 5 ml DMF solution of 14-bromodaunomycin hydrochloride (1.00 g, 1.555 mmol) prepared by the method described in Example 2 of Japanese Patent Publication No. 56-156300 (U.S. Pat. No. 4,360,664) in a colored container was added with nitrogen. Silver trifluoromethanesulfonate (0.751 g, 2.923 mmol) was added under atmosphere, and the mixture was stirred at room temperature overnight. Solid (AgBr) precipitated in the reaction mixture
After filtration, the solid was washed with DMF and the filtrate and washings were combined. 40 ml of water was added to this DMF solution, and the pH was adjusted to 6.0 to 6.5 with 1N-NaOH, followed by hydrolysis for 0.5 hours. The reaction mixture was diluted with water and diluted with 1N HCl.
After setting the pH to 3.5, it was washed twice with chloroform.
After adding methanol to the aqueous layer and adding a saturated aqueous sodium hydrogen carbonate solution until the pH of the aqueous layer reached 8 to 9,
Extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. Concentrate the solvent and add 1N HCl (in CH ₃ OH, f=1.013)
Add 1.005ml, then add chloroform,
Adriamycin hydrochloride was precipitated. The precipitate was filtered, and the filtrate was diluted with chloroform:methanol (10:
After washing with 1) and drying, 0.632 g of adriamycin hydrochloride (HPLC relative purity: 94.7%, yield from 14-bromodaunomycin hydrochloride: 70.1%) was obtained. The physical and chemical properties of this product were consistent with those obtained in Example 1. Example 3 Differences between alkaline hydrolysis of 14-bromodaunomycin, alkaline hydrolysis of 14-acetoxydaunomycin, and acid hydrolysis of 14-trifluoromethanesulfonyloxydaunomycin [Method] Adriamycin is reported to be sensitive to alkali [ Literature: F.ARCAMONE, “To pics
in Antibiotic Chemistry volume 2”ed.by P.
G. SAMMES, ELLIS HORWOOD LIMITED
(1978), p172). The alkaline hydrolysis method described in Japanese Patent Publication No. 47-46597 (U.S. Pat. No. 3,803,124) includes hydrolysis of 14-bromodaunomycin using sodium phosphate and hydrolysis of 14-acetoxydaunomycin using aqueous sodium bicarbonate. I did the disassembly. On the other hand, as acid hydrolysis of 14-trifluoromethanesulfonyloxydaunomycin, water and
The reaction was carried out using a 0.05M phosphate buffer solution (PH6.0). The production of decomposition products of both methods was detected using a TLC scanner, and their superiority was compared. [Reaction conditions] (1) Alkaline hydrolysis method 1-a Hydrolysis of 14-bromodaunomycin with sodium phosphate 14-bromodaunomycin hydrochloride 0.1g 0.5M-Na ₃ PO ₄ Water 10ml Acetone 10ml Adjust to PH11 1- b Hydrolysis of 14-acetoxydaunomycin with aqueous sodium bicarbonate 14-acetoxydaunomycin 0.01g Acetone/CH ₃ OH (2:1) 5ml 5% NaHCO ₃ aqueous solution 1ml Water 3ml (2) Acid hydrolysis of 14-trifluoromethanesulfonyloxydaunomycin 2-1 Hydrolysis with _H2O 14-trifluoromethanesulfonyloxydaunomycin hydrochloride 0.2g _H2O 20ml PH2.4 2-2 Hydrolysis with 0.05M phosphate buffer solution (PH6.0) 14-trifluoromethanesulfonyloxy Daunomycin hydrochloride 0.2g 0.05M/PBS (PH6.0) 20ml PH4.2 [TLC conditions] TLC plate: Merck Art 5715 Developing system: CHCl ₃ :CH ₃ OH:CH ₃ COOH=20:
4:1 TLC scanner: Shimadzu TLC scanner CS-
930 Wavelength: 495nm [Results] Shown in the table below.

[Table] Comparative Example 1 An attempt was made to produce adriamycin hydrochloride according to Example 1 of US Pat. No. 3,803,124. 14-bromodaunomycin was prepared according to the method described in Example 1 of US Pat. No. 3,803,124, but the yield was 18.3%, so 14-bromodaunomycin was prepared by the method described in Example 2 of US Pat. No. 4,360,664. - Bromodaunomycin hydrochloride (1.0g, 1.555mmol)
70 ml of distilled water was added to 150 ml of methanol solution.
Under a nitrogen atmosphere, 0.1N-NaOH was added at 20°C until the pH reached 10.3, and hydrolysis was carried out at the same pH for 20 minutes.
Add 130 ml of distilled water to the reaction solution and dilute with chloroform.
Extracted twice. After washing the organic layer with saturated saline,
It was dried with anhydrous sodium sulfate. Concentrate the solvent
1.86 ml of 0.6N HCl (in CH ₃ OH, f=0.967) was added, followed by a further 70 ml of ether to precipitate adriamycin hydrochloride. The precipitate was filtered, and the filtered product was washed with 60 ml of ether and dried to obtain 0.6766 g of adriamycin hydrochloride (HPLC relative purity: 58
%) obtained. Attempts were made to crystallize the obtained adriamycin hydrochloride from propanol-methanol, chloroform-methanol, or methylene chloride-methanol solvents as described in Example 1 of the above-mentioned US patent, but the purity was low. Crystallization failed, and the purity of the obtained adriamycin hydrochloride could not be improved. Comparative Example 2 As in Comparative Example 1 above, when Example 1 of U.S. Pat. No. 3,803,124 was repeated as it was, it was not possible to obtain highly pure Adriamycin hydrochloride, so the operating conditions were changed slightly as follows. An attempt was made to produce adriamycin hydrochloride by making a change. 14-bromodaunomycin was prepared according to the method described in Example 1 of U.S. Pat. No. 3,803,124, but the yield was 18.3%, so 14-bromodaunomycin was prepared according to the method described in Example 2 of U.S. Pat.
Bromodaunomycin (1.0 g, 1.555 mmol) was dissolved in 200 ml of distilled water. Under a nitrogen atmosphere, add 0.1N-NaOH at 20℃ until the pH reaches 10.3.
Hydrolyzed for 20 minutes. 150 ml of methanol was added to the reaction solution, and the mixture was extracted five times with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing the solvent, the residue was dissolved in chloroform:methanol (10:1) and diluted with 0.6N-
3.01 ml of HCl (in CH ₃ OH, f=0.967) was added, concentrated, and precipitated by standing at low temperature. When the precipitate was filtered, washed with chloroform and dried, 0.2152 g of adriamycin hydrochloride (HPLC relative purity: 94.1
%, yield: 23.9%) was obtained. Comparative Example 3 According to the method described in Example 2 of US Pat. No. 3,803,124, an attempt was made to produce adriamycin hydrochloride via 14-acetoxydaunomycin. 14-bromodaunomycin was prepared according to the method described in Example 1 of US Pat. No. 3,803,124, but the yield was 18.3%, so 14-bromodaunomycin was prepared according to the method described in Example 2 of US Pat. No. 4,360,664.
- Bromodaunomycin hydrochloride 0.6g
(0.933 mmol) was suspended in 200 mmol of anhydrous acetone, 1.8 g of molten potassium acetate was added, and the mixture was heated under reflux for 45 minutes. After filtering off insoluble matter, the filtrate was concentrated to dryness under reduced pressure. After dissolving the residue in chloroform, add ether and filter the precipitate to remove the solid matter.
0.429g was obtained. This was applied to a silica gel column (Merck Art7734, methylene chloride: methanol:
Water = 100:20:2) to obtain 0.247 g of 14-acetoxydaunomycin. 0.1 g of 14-acetoxydaunomycin was dissolved in 30 ml of acetone:methanol (2:1), 10 ml of a 5% aqueous sodium bicarbonate solution was added, and the mixture was stirred for 3 hours. The reaction solution was diluted with water and then extracted with chloroform. The extract was quenched with a saturated NaCl aqueous solution and then dehydrated with anhydrous Na ₂ SO ₄ .
Concentrate under reduced pressure, add 0.6N hydrochloric acid methanol,
Furthermore, 3 times the amount of ether was added, and the precipitate was filtered to obtain 57.4 mg of adriamycin hydrochloride (HPLC
Relative purity: 72.4%, total yield from 14-Br-DM form: 18.9%).

Claims (1)

[Claims] 1 formula 14-trifluoromethanesulfonyloxydaunomycin and its salts. 2 formulas A formula characterized by reacting 14-halodaunomycin or its salt represented by the formula, wherein X is a halogen atom, with a trifluoromethanesulfonic acid metal salt. A method for producing 14-trifluoromethanesulfonyloxydaunomycin or a salt thereof. 3 formulas 1. A method for producing adriamycin or a salt thereof, which comprises hydrolyzing 14-trifluoromethanesulfonyloxydaunomycin or a salt thereof under acidic conditions, and optionally converting the product into a salt.