Method for preparing antibiotic carminomycine or its hydrochloride

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing antibiotic carminomycine or its hydrochloride. Method involves glycosylation of carminomycinone with 1,4-di-O-substituted N-acyldaunosamine (2,3,6-trideoxy-3-amino-L-lyxo-hexapyranose) of the formula (3):

wherein R1 means trifluoroacetyl, N-(9H-fluorene-2-ylmethoxy)carbonyl, allyloxycarbonyl; R2 means acetyl, trifluoroacetyl, 4-nitrobenzoyl, allyloxycarbonyl; R3 means trichloroacetamidyl, trialkylsilyl, acetyl, trifluoroacetyl, 4-nitrobenzoyl, allyloxycarbonyl in the presence of trimethylsilyltrifluoromethane sulfonate in mixture of anhydrous aprotonic organic solvents followed by removing blocking groups and isolation of carminomycine as a base or hydrochloride. Glycosyl-donor is used as a mixture of α- and β-isomers or as individual α- or β-isomers. As anhydrous aprotonic organic solvent method involves using mixtures of dioxane with chloroform, methylene chloride, diethyl ether, acetone and tetrahydrofuran. The reaction is carried out in presence of molecular sieves at temperature 10°C, nor above, in atmosphere of dried air or dried inert gas. Removal of protecting groups is carried out in the presence of alkaline metal hydroxides in an aqueous-organic medium: water - methanol, water - dioxane, water - tetrahydrofuran, water - acetone. Method provides increasing yield of carminomycine by 3 times as compared with the prototype.

EFFECT: improved preparing method, enhanced yield.

5 cl, 7 ex

 

The invention relates to pharmaceutical industry and relates to a method of producing antibiotic karminomitsin or its hydrochloride.

Karminomitsin (formula 1, R=R1=R2=N) belongs to the group of anthracycline antibiotics that have been proven as highly effective anti-tumor and anti-leukemia drugs, widely used in the clinics of the Russian Federation and abroad. Antibiotic karminomitsin is original domestic antibiotic, which was first obtained by biosynthesis at the Institute to find antibiotics AMS of the USSR. Karminomitsin successfully passed clinical trials and was approved for use in the USSR and the Russian Federation. Karminomitsin recommended for the following diseases: soft tissue sarcoma (laconically, rhabdomyosarcoma, liposarcoma, and others); retikulosarkoma and lymphosarcoma; breast cancer and chorionepithelioma of uterus; acute myeloblastic and lymphoblastic leukemia. The antibiotic has a wide readings in the treatment of malignant tumors in adults and children, and used as individual drug or in combination with other medicines.

The known method biosynthetic get karminomitsin [A.S. "a Method of obtaining karminomitsin" No. 508076 from 11.11.1975 g, A.S. "a Method of obtaining karminomitsin" No. 543257 from 21.09.1976,]. The disadvantage of this method one is by the presence of concomitant impurities - 13-dihydroartemisinin, the low productivity of the producer strain Actinomadura carminata compared with the productivity of the strains antitumor anthracycline antibiotics group, the complexity of the process of isolation and purification.

A known method of producing karminomitsin chemical synthesis [Cassinelli G., Greiner, A., Masi, P., Suarato A., Bemardi L., Arcamone F.. Preparation and biological evaluation of 4-0-demethyldaunorubicin (carminomycin I) and its 13-dihydro derivative-Journal of Antibiotics, 31, 178-184, 1978]. The hydrolysis of glycosidic bonds of daunorubicin get the aglycone of daunomycin (formula 2, R=CH3) and the monosaccharide - daunosamine (formula 3, R1=R2=R3=H). Daunomycin subjected to a demethylation reaction with AlClCin boiling methylene chloride. Obtained with a yield of 62% of the aglycone carminomycin (formula 2, R=H) glycosylases 2,3,6-trideoxy-3-triptoreline-4-O-TRIFLUOROACETYL-α-L-lxo-hexopyranosyl chloride in the presence of triftoratsetata silver in a mixture of methylene chloride-dimethylformamide. Protected glycoside will unlock n NaOH, getting karminomitsin hydrochloride with a yield of 10% based on daunomycin. One drawback of chemical synthesis is the low yield of 10% based on daunomycin, the need for a pure anomer 2,3,6-trideoxy-3-triptoreline-4-O-TRIFLUOROACETYL-α-L-lyxo-hexopyranosyl chloride and its instability.

The technical problem from which retene - the increase in the output of karminomitsin at getting it by chemical synthesis.

The technical problem is solved in that a method of obtaining karminomitsin or its hydrochloride, including glycosylation of carminomycin glycosyl donor 1,4-di-O-substituted-3-N-acylcarnitines in the presence of a catalyst in a mixture of anhydrous aprotic organic solvent, removal of the blocking groups and the allocation of karminomitsin in the form of a base or hydrochloride, as a catalyst used trimethylsilyltrifluoromethane, as glicozidelor used 1,4-di-O-substituted-3-N-acidentaly (2,3,6-trideoxy-3-amino-L-lyxo-hexopyranosyl),

where R1=TRIFLUOROACETYL or N-(9-N-fluoren-2-ylethoxy)carbonyl or allyloxycarbonyl, mainly N-(9-N-fluoren-2-ylethoxy)carbonyl or TRIFLUOROACETYL, R2=acetyl or TRIFLUOROACETYL, or 4-nitrobenzoyl or allyloxycarbonyl, mainly acetyl, R3=trichloroacetamide or trialkylsilyl or acetyl or TRIFLUOROACETYL, or 4-nitrobenzoyl or allyloxycarbonyl, mainly acetyl, as anhydrous aprotic organic solvents used dioxane-methylene chloride or dioxane-chloroform or dioxane-methylene chloride-diethyl ether or dioxane, acetone or dioxane-chloroform the-diethyl ether or dioxane-tetrahydrofuran-methylene chloride, mainly dioxane-methylene chloride, the reaction is carried out in the presence of molecular sieves (mostly 4Å), removal of the blocking groups spend an alkaline agent.

As glycosyl donor, a mixture of α and β or individual isomers α or β isomers. The reaction is carried out at low temperature, mainly not higher than 10°C. the Reaction is carried out in an atmosphere of dried air or dried inert gas. The removal of the protective groups is carried out in the presence of hydroxides of alkali metals in an aqueous-organic medium: water - methanol or water - dioxane or water - tetrahydrofuran or water - acetone.

For protection of 3-amino and 4-O-hydroxyl groups of daunosamine use a combination of blocking groups, stable in slightly acidic environments. The introduction of protective and activating groups were performed by standard techniques used in carbohydrate chemistry [H.M.I.OSBORN, Best Synthetic methods, Carbohydrates, Academic press, 2003; Handbook of Reagents for Organic Synthesis "Activating Agents and Protective Groups", edited by A.J.Pearson, W.J. Roush, JOHN WILEY & SONS, 1999]. A special case in the use of 1,4-di-O-substituted-N-acylcarnitine containing provisions 1-O - 4-O - the same group of the acyl type (formula 3, where R2=R3=acyl group) mainly acetyl, allows us to simplify the synthesis of glycosyl donor. Using these compounds (formula 3, where R2 =R3=acyl group), it is also possible to replace the activating acyl group, R3on the other activating group by selective hydrolysis to hydroxy groups (with preservation of the protective groups R1, R2), with the subsequent introduction of other activating groups (R3) [H.M.I.OSBORN, Best Synthetic methods. Carbohydrates, Academic press, 2003, p.164].

The proposed method allows to increase the output of karminomitsin in 3 times in comparison with the prototype.

AIDS:

Trimethylsilyltrifluoromethane, diethylamin, molecular sieves 4Å, triethylamine, 4-(dimethylamino)pyridine were commercial products of the firm Aldrich (USA). N-(N-Fluoren-2-ylmethoxycarbonyl)succinimide was a commercial product of Merck (Germany).

Thin-layer chromatography was performed on plates of silica gel G60 (Merck) in mixtures of solvents: petroleum ether-ethyl acetate, 1:1 (A); chloroform-methanol-formic acid, 20:1:0.1 (B); chloroform-methanol-25%aqueous ammonia, 7:3:0.01 (); chloroform-methanol-formic acid, 7:1:0.1 (G). For preparative purification used column chromatography on silica gel Merck G60 with a particle size 0.040-0.063 mm.

HPLC was carried out on the instrument Shimadzu HPLC LC 10 column Diaspher 18 No. 1914, eluent: n H3PO4- MeCN, pH 2.6, gradient of acetonitrile from 10% to 90%, flow rate 1.1 ml/min Check was conducted on the wavelength of the s 254 nm, at a temperature of 20°C.

Optical rotation [α]Dstudied at the polarimeter "Perkin - Elmer-241".

Example 1.

Karminomitsin hydrochloride.

Carminomycin (0.500 g, 1.30 mmol) was dissolved in a mixture of dry methylene chloride - dry dioxane (4:1, 375 ml)was added 1,4-di-O-acetyl-3-N-(9-N-fluoren-2-ylethoxy)carbonintensity (α:β=4:1) (0.706 g, 1.56 mmol) and molecular sieves (10 g). The solution was stirring his in a stream of argon, was cooled to -10°and there was added dropwise a solution of trimethylsilyltrifluoromethane (0.35 ml, 1.95 mmol) in dry methylene chloride (10 ml). The reaction mixture was stirred at a temperature of not higher than 10°C for 40 min, then was poured into a saturated solution of NaHCO3(150 ml). The organic layer was separated, washed with water until rn, dried and evaporated. The residue was dissolved in dioxane (20 ml), was added 0.2 n NaOH (20 ml). The reaction mixture was stirred for 3 hours at 4°C in an atmosphere of argon, then was acidified to pH 5 n HCl. The reaction mixture was diluted with H2O and was extracted with chloroform aglycone (5×70 ml), then the pH value of the aqueous fraction was brought to 7.5 with 5%solution of K2CO3and was extracted with chloroform base karminomitsin (4×50 ml). The organic fraction was evaporated to a minimum volume. The solution was acidified to pH 3.5 n solution of HCl in dry Meon was added ether (30 ml). Fallen sieges which it was filtered and dried.

Yield 250 mg (35%, based on carminomycin), Rf(G) 0.22, Rt16.20.

TPL185-187°C (decomposition)

1H-NMR (Py-d5): 7.835 (d, 1H, 7.33 Hz, H-1); 7.62 (t, 1H, 7.81 Hz, H-2); 7.325 (d, 1H, 8.30 Hz, H-3); 5.82 (s, 1H, W˜7 Hz, H-1'); 5.35 (m, 1H, H-7); 4.70 (q, 1H, 6.65 Hz, H-5'); 4..50 (s, 1H, W˜7 Hz, H-4'); 4.39 (m, 1H, H-3'); 3.60d, 3.42d (2H, 17 Hz, H-10), 2.75 (m, 1H, H-2'); 2.75 (m, 2H, 2H-8); 2.57 (s, 3H, 3H-14); 2.80m, 2.45dd, (2H, Jgem 14 Hz, 4.3Hz, 2H, H-2'); 1.43(d, 3H, 6.65 Hz, 3H-6')

λmax236, 256, 293, 464, 478, 492, 512, 525 nm (in ethanol)

[α]D+289° (0.15 Meon)

Sample karminomitsin hydrochloride by its physical-chemical (TPL, Rf, Rtand [α]D) and spectral characteristics (UV-, NMR-spectra) does not differ from the standard sample obtained by biosynthesis pilot plant GU NIINA them. Grause RAMS.

Example 2.

Karminomitsin hydrochloride.

Carminomycin (0.520 g, 1.35 mmol) was dissolved in a mixture of dry methylene chloride - dry dioxane (4:1, 600 ml)was added 1,4-di-O-acetyl-3-N-cryptorchidectomy (α:β=1:2) (0.531 g, 1.62 mmol) and molecular sieves (12 g). The solution mixture was stirred in a stream of argon, was cooled to -10°and there was added dropwise a solution of trimethylsilyltrifluoromethane (0.24 ml, 1.35 mmol) in dry methylene chloride (10 ml). The reaction mixture was stirred at a temperature of not higher than 10°C for 40 min, then was poured into a saturated solution of NaHCO3(150 ml). Organic is Loy separated, washed with water to pH 6, dried and evaporated. The residue was dissolved in a mixture of dioxane - Meon (30 ml, 2:1), cooled to 4°and was added 0.4 n NaOH (10 ml). The reaction mixture was stirred for 30 hours at 4°With an argon atmosphere, and then acidified to pH 5 n HCl. The reaction mixture was diluted with H2O and was extracted with chloroform (2×40 ml). The pH value of the aqueous fraction was brought to 7.5 with 5%solution of K2CO3and was extracted with chloroform (4×30 ml). The organic fractions were combined, dried and evaporated to a minimum volume. The solution was acidified to pH 3.5 n solution of HCl in dry Meon was added ether (30 ml). The precipitation was filtered and dried.

Yield 230 mg (31%, based on carminomycin), Rf(G) 0.22, Rt16.201.

Sample karminomitsin hydrochloride by its physical-chemical (TPL, Rf, Rtand [α]D) and spectral characteristics (UV-, NMR-spectra) does not differ from the standard sample obtained by biosynthesis pilot plant GU NIINA them. Grause RAMS.

Example 3.

Karminomitsin hydrochloride.

The synthesis is carried out analogously to the previous example, on the basis of 100 mg (0.26 mmol) of carminomycin, 102 mg (0.31 mmol, 1.2 EQ) of 1,4-di-O-acetyl-N-cryptorchidectomy (clean α-anomer according to 'H NMR), 56.5 μl trimethylsilyltrifluoromethane. The output hydrochlori is and karminomitsin - 38 mg (28%, based on carminomycin).

Sample karminomitsin hydrochloride by its physical-chemical (TPL, Rf, Rtand [α]D) and spectral characteristics (UV-, NMR-spectra) does not differ from the standard sample obtained by biosynthesis pilot plant GU NIINA them. Grause RAMS.

Example 4.

1,4-Di-O-acetyl-3-N-(9-N-fluoren-2-ylethoxy)carbonintensity (α:β=4:1)

Daunosamine hydrochloride (1.00 g, 5.45 mmol) was dissolved in a mixture of dioxane - water (14 ml, 1:1)was added Et3N to pH 8, portions was added dry N-(N-fluoren-2-ylmethoxycarbonyl)succinimide (2.20 g, 6.54 mmol), maintaining the pH 8 by addition of Et3N. the Reaction mixture was stirred for 20 hours, was added 30 ml of water, partially dioxane was evaporated. The precipitation was filtered and dried. The residue was dissolved in ethyl acetate and was added petroleum ether. The precipitation was filtered, evaporated with pyridine and used in the next stage without additional purification. 3-N-(9-N-Fluoren-2-ylethoxy)carbonintensity [˜2 g, Rf=0.75 (In)] was dissolved in dry pyridine (20 ml) was added acetic anhydride (1.03 ml, 10.9 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (30 mg). The reaction mixture was stirred for 20 hours, was added 1 ml of methanol was stirred for 1 hour and evaporated to dryness. The residue was dissolved in whom dilacerate and added petroleum ether. The precipitation was filtered and dried. Yield 1.97 g (80% based on daunosamine). The ratio of anomers α:β=4:1 has been determined using the1H-NMR spectroscopy. Rfα ≈Rfβ=0.68 (B).

Example 5.

1,4-Di-O-acetyl-3-N-cryptorchidectomy (α:β=1:2), and individual αand β-isomers.

Daunosamine hydrochloride (4) (1.26 g, 6.87 mmol) was dissolved in dry Meon (20 ml)was added Et3N (2.87 ml, 2.6 mmol) and ethyl ether triperoxonane acid (1.63 ml, 13.73 mmol).

The reaction mixture was stirred for 3 h, then evaporated. The residue was dissolved in hot acetone (40 ml), precipitated precipitate was filtered. The solution was evaporated, the residue was re-evaporated from dry pyridine and used without further purification in the next stage. 3-N-Cryptorchidectomy (1.42 g, Rf0.70, In) was dissolved in absolute pyridine (30 ml), was added AU2(1.8 ml) and a catalytic amount of 4-(dimethylamino)pyridine (20 mg). The reaction mixture was stirred for 48 h, then was cooled to 0°and added Meon (1 ml). The reaction mixture was stirred for 1 h, then evaporated. The residue was shared by flash chromatography on silica gel, petroleum ether - ethyl acetate, using a gradient of ethyl acetate from 20% to 50%. Identified three fractions: α-anomer mixture of anomers (α+β) and β-anomer. For each f the shares solvent was removed, to the residue was added ether (40 ml), precipitated precipitate was filtered and dried. Output: α-anomer 164 mg Rf(A) 0.62, [α]D20-92.8°; a mixture of anomers (α+β) 1.23 g; β-anomer 430 mg, Rf(A) 0.53, [α]D20-50.4°. The total yield (α+β) 1.82 g (81% per daunosamine).

Example 6.

Carminomycin.

To a solution of daunomycin (2.50 g, 6.28 mmol) in dry dichloroethane (300 ml) was added AlCl3(2.51 g, 18.84 mmol). The reaction mixture is boiled for 1.5 h, then was added a fresh portion of AlCl3(2.51 g, 18.84 mmol) and boiled for 1.5 h, the procedure was repeated once more (just added 8 g of AlCl3), then poured the reaction mixture into water (400 ml), acidified water fraction 4n HCl to pH 3. Separated water layer and heated it to a boil. The precipitation was filtered, washed with water, dried. The organic fraction was dried, partially evaporated and left to crystallize first at room temperature for 4 hours and then at 4°C for 20 hours. The precipitation was filtered, combined with the precipitate from the aqueous fraction and dried to constant weight. Yield 2.05 g (85%), Rf(A) 0.37, Rf(B) 0.47.

Example 7.

Karminomitsin hydrochloride.

Carminomycin (2.60 g, 6.77 mmol) was dissolved in a mixture of dry methylene chloride - dry dioxane (4:1, 1.8 l), EXT is ulali 1,4-di-O-acetyl-3-N-cryptorchidectomy (α :β=1:2) (2.655 g, 8.12 mmol) and molecular sieves (50 g). The solution mixture was stirred in a stream of argon, was cooled to -10°and there was added dropwise a solution of trimethylsilyltrifluoromethane (1.20 ml, 6.75 mmol) in dry methylene chloride (20 ml). The reaction mixture was stirred at a temperature of not higher than 10°C for 40 min, then was poured into a saturated solution of NaHCO3(700 ml). The organic layer was separated, washed with water to pH 6, dried and evaporated. The residue was dissolved in a mixture of dioxane - Meon (150 ml, 2:1), cooled to 4°and was added 0.4 n NaOH (50 ml). The reaction mixture was stirred for 30 hours at 4°With an argon atmosphere, and then acidified to pH 5 n HCl. The reaction mixture was diluted with H3O and was extracted with chloroform (3×100 ml). The pH value of the aqueous fraction was brought to 7.5 with 5%solution of K2CO3and was extracted with chloroform (4×100 ml). The organic fractions were combined, dried and evaporated to a minimum volume. The solution was acidified to pH 3.5 n solution of HCl in dry Meon was added ether (100 ml). The precipitation was filtered and dried.

Yield 1.23 g (33%, based on carminomycin), Rf(G) 0.22, Rt16.203.

Sample karminomitsin hydrochloride by its physical-chemical (TPL, Rf, Rtand [α]D) and spectral characteristics (UV-, NMR-spectra) is not different from standard is th sample, obtained by biosynthesis pilot plant GU NIINA them. Grause RAMS.

The method of producing antibiotic karminomitsin or its hydrochloride

R1=TRIFLUOROACETYL, N-(9-N-fluoren-2-ylethoxy)carbonyl, allyloxycarbonyl; R2=acetyl, TRIFLUOROACETYL, 4-nitrobenzoyl, allyloxycarbonyl; R3=trichloroacetamide, trialkylsilyl, acetyl, TRIFLUOROACETYL, 4-nitrobenzoyl, allyloxycarbonyl.

1. The method of producing karminomitsin or its hydrochloride, including glycosylation of carminomycin glycosyl donor 1-,4-O-,3-N-triple-substituted by daunosamine in the presence of a catalyst in a mixture of anhydrous aprotic organic solvent, removal of the blocking groups and the allocation of karminomitsin in the form of a base or hydrochloride, characterized in that the catalyst used trimethylsilyltrifluoromethane, as glycosyl donor use of 1,4-di-O-substituted-3-N-acidentaly (2,3,6-trideoxy-3-amino-L-lyxo-hexopyranosyl),

where R1- TRIFLUOROACETYL, N-(9-N-fluoren-2-ylethoxy)carbonyl, allyloxycarbonyl,

R2- acetyl, TRIFLUOROACETYL, 4-nitrobenzoyl, allyloxycarbonyl,

R3- trichloroacetamide, trialkylsilyl, acetyl, TRIFLUOROACETYL, 4-nitrobenzoyl, allyloxycarbonyl,

as an anhydrous aprotic organic solvents used dioxane-methylene chloride, dioxane-chloroform, dioxane-methylene chloride-diethyl ether, dioxane, acetone, dioxane-chloroform-diethyl ether, dioxane-tetrahydrofuran-methylene chloride, the reaction is carried out in the presence of molecular sieves, the removal of the blocking groups spend an alkaline agent.

2. The method according to claim 1, characterized in that glycosyl-donor used in the form of a mixture of αand β-isomers or in the form of an individual αor β-isomers.

3. The method according to claim 1, characterized in that the reaction is carried out at a temperature of not higher than 10°C.

4. The method according to claim 1, characterized in that the reaction is carried out in an atmosphere of dried air or dried inert gas.

5. The method according to claim 1, characterized in that the removal of the protective groups is carried out in the presence of hydroxides of alkali metals in an aqueous-organic medium: water - methanol, water - dioxane, water - tetrahydrofuran, water - acetone.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to tetracyclic antibiotic anthraquinone derivatives having anticancer activity.

EFFECT: tetracyclic antibiotic anthraquinone derivatives described in the present invention have the same or higher activity than current medicinal agents such as doxorubicin, daunorubicin or similar, in a cellular level, and at the same time have better tolerance than doxorubicin and daunorubicin for animal organism.

15 cl, 54 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of synthesising salt of 4-demethoxydaunorubicine, which has chemical structure of formula (I): where An- represents anion, which can be used in treatment of acute myeloid leukosis. At the first stage of claimed method hydrochloride salt of daunorubicine is converted into 3'-protected daunorubicine (3'-prot.-daunorubicine) of formula (III) by bringing in contact with azide-forming reagent or in 3'-prot.-daunorubicine of formula (IV) by bringing in contact with trifluoroacetylating reagent. At the second stage demethylation of 3'-prot.-daunorubicine of formula (III) or (IV) by contact with "mild" Lewis acid in water-free solvent results in obtaining 4-demethyl-3'-prot.-daunorubicine of formula (V) or (VI) respectively, whose further trifluoromethanesulphonylation by bringing in contact with trifluoromethanesulphonylating reagent results in 4-O-trifluoromethanesulphonyl-3'-(prot.daunorubicine) of formula (VII) or (VIII) respectively, 4-T1-3'-protective daunorubicine. Reduction of compound of formula (VII) or (VIII) by bringing in contact with reducing agent results in obtaining 4-demethoxy-3'-prot.-daunorubicine of formula (IX) or (X) respectively, 3'-protective-4-demethoxydaunorubicine, and the following removal of protective group 3'-prot. from 4-demethoxy-3'-prot.- daunorubicine of formula (IX) or formula (X), at which compound of formula (IX) is brought in contact with azide-reducing reagent, with compound (X) being brought in contact with alkali solution, results in obtaining 4-demethoxydaunorubicine. In contact of the latter with acid of formula H+An- salt of 4-demethoxydaunorubicine is obtained.

EFFECT: claimed method makes it possible to obtain target product with high output.

12 cl, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel crystalline form of 4'-epidaunorubicine hydrochloride, process for the production thereof and use for the production of anthracyclines. The proposed form of crystalline 4'-epidaunorubicin hydrochloride is stable and readily soluble, with the powder X-ray diffraction pattern as follows (diffraction angle 2θ): 5,13, 7,64, 12,18, 16,77, 19,86, 21,82, 22,58, 23,03.

EFFECT: advantageous process for producing crystalline form by comprising crystallising 4′-epidaunorubicin hydrochloride in a solvent system including C1 and C2 halogenated solvents, C1-C5 alcohols, wherein one of C1-C5 alcohols is selected to provide lower solubility to 4′-epidaunorubicin hydrochloride than the other C1-C5 alcohol.

18 cl, 2 dwg, 4 tbl, 7 ex

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