WO1986000073A1 - Process for preparing adriamycine and halide salts thereof - Google Patents
Process for preparing adriamycine and halide salts thereof Download PDFInfo
- Publication number
- WO1986000073A1 WO1986000073A1 PCT/HU1984/000037 HU8400037W WO8600073A1 WO 1986000073 A1 WO1986000073 A1 WO 1986000073A1 HU 8400037 W HU8400037 W HU 8400037W WO 8600073 A1 WO8600073 A1 WO 8600073A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- adriamycine
- alkyl
- daunomycine
- derivative
- solution
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
Definitions
- This invention relates to a new process for preparing adriamycine and halide salts thereof.
- adriamycine is an antitumor antibiotics which is used in the form of a halide for the treatment of tumouroua diseases.
- Adriamycine can be produced directly by fermentation (Belgian Patent Specification Ho. 713,773) or by semisynthetic route from daunomycine (German Patent Specification No. 1,917,874 and US Patent Specification No. 4,012,448).
- Adriamycine can be prepared by a more simple way from daunomycine through the 14-halo derivative of the latter, without changing the structure of the sugar moiety of the molecule (German patent specification No.
- the bromination can directly be carried out by using a solution of bromine in chloroform, while in the course of iodination the amino group of the daunozamine is protected by transforming the latter into an acyl derivative or a Schiff base, thereafter the protecting group is removed and the adriamycine thus obtained is purified by column chromatography.
- the simpliest way for preparing adriamycine from daunomycine by semi-synthetic route appears to be the direct bromination of daunomycine.
- the daunozamine and the side-chain containing 14 carbon atoms can easily be splitted off, thus 14-bromodaunomycinone and other decomposition products without side-chain are formed.
- the bromination reaction results in a rather low, i.e. 58-59 %, yield.
- the yield based on the starting daunomycine is only about 6 to 13 %.
- the present invention is aimed at developing a semi-synthetic process starting from daunomycine which enables to obtain adriamycine by a more simple and more economic way.
- the process of the invention is carried out by reacting daunomycine or a halide salt thereof in an anhydrous organic solvent system in the presence of a solvent suitable for ketal formation, preferably in the presence of an alkyl ortoalkanecarboxylate or alkyl alkanoylate containing 1 to 6 carbon atoms in the alkyl moieties, with bromine, suitably at a temperature of 0 to 20 °C, preferably at 8 °C for 3 to 30 hours, preferably for 5 hours, thereafter transforming the formed 14-bromo derivative to the 14- hydroxy derivative in a manner known per se, optionally acidifying the solution with a haloid acid and recovering the product, optionally after purification.
- a solvent suitable for ketal formation preferably in the presence of an alkyl ortoalkanecarboxylate or alkyl alkanoylate containing 1 to 6 carbon atoms in the alkyl moieties
- bromine suitably at a temperature of 0 to 20 °C,
- the triethyl orthoformate reacts with the enolic form of the 13- keto group of the daunomycine molecule formed due to the bromine being present, thus a ketal is produced which stabilizes the molecule, prohibites the side-reactions and the alkyl group cleavage.
- the solvent suitable for ketal formation e.g. the triethyl orthoformate
- the 11-bromodaunomycine derivative can be achieved in higher yields.
- the 14- bromodaunomycine derivative need not to be recovered as the acetonic solution of 14-bromodaunomycine treated with hydrogen bromide can be directly used in a process where the bromo atom is replaced by a hrdroxyl group. This procedure can be carried out by a ranner well known in the art.
- this process can more preferably be carried out through the 14-formyloxy derivative than by the direct conversion of the bromo atom to hydroxyl group by treating with sodium hydroxyde.
- the hydrolysis of the 14-formyloxy derivative at pH 7.6 to 8.0 assures much more favourable conditions for the adriamycine being less resistant against alkaline agents than acids, than the basic treatment at pH 10.3.
- the reaction mixture is preferably extracted with chloroform at pH 3.5 to 4.0 in order to remove the aglycone-type decomposition products.
- the pH of 7.6 to 8.0 required to the hydrolysis is preferably adjusted with a 5 % by weight solution of sodium bicarbonate, the adriamycine base formed is recovered from the reaction mixture by repeated extraction with chloroform.
- the extracts are concentrated, treated with a solution of hydrochloric acid in methanol in order to form adriamycine hydrochloride which is then precipitated from the solution with ether.
- Adriamycine is used in the form of a halide salt for the preparation of medicaments, optionally after purification.
- the purification is carried out in a manner known per se.
- the reaction mixture is poured into a mixture of 230 ml. of diethyl ether and 120 ml. of petrol ether, the product precipitated is filtered off, washed with 3 x 30 ml. of diethyl ether in order to remove impurities. Then it is dissolved in a mixture of 40 ml. of acetone and 40 ml. of 0.25 N aqueous hydrogen bromide and kept at 25 °G for 17 hours. Thereafter a solution of 2.0 g. (29.4 millimoles) of sodium formate in 20 ml. of deionized water is added to the solution and stirred for 43 hours at 25 °C.
- the pH of the reaction mixture is adjusted to 3.7 by adding 1 N hydrochloric acid solution and extracted with 50 ml. of chloroform five times. Then the pH of the aqueous phase is adjusted to 7.6 by adding a. 5 % solution of sodium bicarbonate and the adriamycine base is extracted from the mixture. The extraction is continued until the chloroformic extract is coloured.
- the chloroformic extracts are washed with 5 To of deionized water, calculated for the volume of the extracts, and dried over anhydrous sodium sulphate. After the drying agent is filtered off, the solution is concentrated to a volume of 50 ml.
- the free base is transformed to its hydrochloric salt by treating with a calculated amount of anhydrous hydrochloric acid solution in methanol and the salt is precipitated with 500 ml. of diethyl ether.
- the product precipitated is filtered, washed four times with 30 ml. of diethyl ether and dried in vacuo at room temperature. Yield: 0.61 g, (42.4 % ) of adriamycine hydrochloride.
- the analytical data of the product are listed below.
- the pH of the reaction mixture is adjusted to 3.7 by adding 1 N hydrochloric solution and the mixture is extracted with chloroform five times. Then the pH of the aqueous layer is adjusted to 7.6 by adding a 5 % solution of sodium bicarbonate and the adriamycine base is recovered by extraction. The extraction is continued until the chloroformic extract becomes uncoloured.
- the chloroformic extracts are washed with 5 To of deionized water, calculated for the volume of the extracts, then dried over anhydrous sodium sulphate. After filtering off the drying agent, the solution is concentrated in vacuo to a volume of 25 ml.
- the free base is transformed into its hydrochloric salt by treating with a calculated amount of
- Example 4 0.70 g. (1.24 mmoles) daunomycine hydrochloride are dissolved in a mixture of 10 ml. of anhydrous methyl alcohol, 30 ml. of dioxane and 0.8 ml. (4.35 mmoles) of triethyl orthoacetate. To the mixture thus obtained 0.25 g. (1.58 mmoles) of bromine in 2.7 ml, of anhydrous chloroform are added, the flask is closed and kept at 6 °C for 6 hours.
- the reaction mixture is poured into a mixture of 140 ml. of diethyl ether and 60 ml. of petrol ether, the product precipitated is filtered off, the impurities are removed by washing with 3 x 15 ml. of diethyl ether.
- the product is dissolved in a mixture of 20 ml. of acetone and 20 ml, of 0.25 N aqueous hydrogen bromide and kept at 25 °G for 17 hours. Then a solution of 1.0 g. (l4.7 mmoles) of sodium formate in 10 ml. of deionized water is added to the reaction mixture and the latter stirred at a temperature of 25 °C for 48 hours.
- the identifying data of the end product are the same as indicated in Example 1.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP50256584A JPS61502956A (en) | 1984-06-14 | 1984-06-14 | Method for preparing adriamycin and its halide salts |
PCT/HU1984/000037 WO1986000073A1 (en) | 1984-06-14 | 1984-06-14 | Process for preparing adriamycine and halide salts thereof |
EP19840902361 EP0183691A1 (en) | 1984-06-14 | 1984-06-14 | Process for preparing adriamycine and halide salts thereof |
DK059486A DK157082C (en) | 1984-06-14 | 1986-02-06 | PROCEDURE FOR THE PREPARATION OF ADRIAMYCINE AND ITS HALOGENEAL SALTS |
FI860683A FI860683A0 (en) | 1984-06-14 | 1986-02-14 | FOERFARANDE FOER FRAMSTAELLNING AV ADRIAMYCIN OCH HALIDSALTER DAERAV. |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/HU1984/000037 WO1986000073A1 (en) | 1984-06-14 | 1984-06-14 | Process for preparing adriamycine and halide salts thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1986000073A1 true WO1986000073A1 (en) | 1986-01-03 |
Family
ID=10980572
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/HU1984/000037 WO1986000073A1 (en) | 1984-06-14 | 1984-06-14 | Process for preparing adriamycine and halide salts thereof |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0183691A1 (en) |
JP (1) | JPS61502956A (en) |
DK (1) | DK157082C (en) |
FI (1) | FI860683A0 (en) |
WO (1) | WO1986000073A1 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0358161A2 (en) * | 1988-09-06 | 1990-03-14 | Sanraku Incorporated | Novel anthracycline derivatives and process for production thereof |
EP0363604A2 (en) * | 1988-10-11 | 1990-04-18 | Sicor Societa' Italiana Corticosteroidi S.P.A. | Improved process for the conversion of daunorubicin into doxorubicin |
US5026691A (en) * | 1987-03-30 | 1991-06-25 | The Upjohn Company | Combination of minoxidil and an antiinflammatory agent for treating patterned alopecia |
US7388083B2 (en) | 2005-03-07 | 2008-06-17 | Solux Corporation | Epimerization of 4′-C bond and modification of 14-CH3-(CO)-fragment in anthracyclin antibiotics |
ITMI20090784A1 (en) * | 2009-05-08 | 2010-11-09 | Antibioticos Spa | PROCEDURE FOR THE PREPARATION OF 14-BROMO DAUNOMICINA |
ITMI20100007A1 (en) * | 2010-01-08 | 2011-07-09 | Antibioticos Spa | PROCESS FOR THE PREPARATION OF DOXORUBICINE |
US8357785B2 (en) | 2008-01-08 | 2013-01-22 | Solux Corporation | Method of aralkylation of 4′-hydroxyl group of anthracylins |
US8802830B2 (en) | 2005-12-20 | 2014-08-12 | Solux Corporation | Synthesis of epirubicin from 13-dihydrodaunorubicine |
US9035032B2 (en) | 2005-12-13 | 2015-05-19 | Solux Corporation | Method for preparing 4-demethyldaunorubicin |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT848009E (en) | 1996-12-16 | 2000-11-30 | Pharmachemie Bv | PROCESS FOR THE PREPARATION OF EPIRUBICIN OR ITS SALTS OF ADDITION OF ACID FROM DAUNORUBICIN |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT283597B (en) * | 1968-04-12 | 1970-08-10 | Farmaceutici Italia | Process for the preparation of adriamycin and adriamycinone |
DE2652391A1 (en) * | 1975-11-18 | 1977-05-26 | Farmaceutici Italia | DAUNOSAMINYLANTHRACYCLINONE, METHOD OF MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
AT358736B (en) * | 1976-12-22 | 1980-09-25 | Erba Farmitalia | METHOD FOR PRODUCING NEW ANTITUM ORGLYCOSIDES |
EP0039060A1 (en) * | 1980-04-26 | 1981-11-04 | Zaidanhojin Biseibutsu Kagaku Kenkyukai | A new method for preparation of anthracycline derivatives |
-
1984
- 1984-06-14 JP JP50256584A patent/JPS61502956A/en active Pending
- 1984-06-14 EP EP19840902361 patent/EP0183691A1/en not_active Withdrawn
- 1984-06-14 WO PCT/HU1984/000037 patent/WO1986000073A1/en not_active Application Discontinuation
-
1986
- 1986-02-06 DK DK059486A patent/DK157082C/en not_active IP Right Cessation
- 1986-02-14 FI FI860683A patent/FI860683A0/en not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT283597B (en) * | 1968-04-12 | 1970-08-10 | Farmaceutici Italia | Process for the preparation of adriamycin and adriamycinone |
DE2652391A1 (en) * | 1975-11-18 | 1977-05-26 | Farmaceutici Italia | DAUNOSAMINYLANTHRACYCLINONE, METHOD OF MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
AT358736B (en) * | 1976-12-22 | 1980-09-25 | Erba Farmitalia | METHOD FOR PRODUCING NEW ANTITUM ORGLYCOSIDES |
EP0039060A1 (en) * | 1980-04-26 | 1981-11-04 | Zaidanhojin Biseibutsu Kagaku Kenkyukai | A new method for preparation of anthracycline derivatives |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5026691A (en) * | 1987-03-30 | 1991-06-25 | The Upjohn Company | Combination of minoxidil and an antiinflammatory agent for treating patterned alopecia |
EP0358161A2 (en) * | 1988-09-06 | 1990-03-14 | Sanraku Incorporated | Novel anthracycline derivatives and process for production thereof |
EP0358161A3 (en) * | 1988-09-06 | 1990-07-11 | Sanraku Incorporated | Novel anthracycline derivatives and process for production thereof |
US4997922A (en) * | 1988-09-06 | 1991-03-05 | Sanraku Incorporated | Anthracycline derivatives |
EP0363604A2 (en) * | 1988-10-11 | 1990-04-18 | Sicor Societa' Italiana Corticosteroidi S.P.A. | Improved process for the conversion of daunorubicin into doxorubicin |
EP0363604A3 (en) * | 1988-10-11 | 1990-07-25 | Sicor Societa' Italiana Corticosteroidi S.P.A. | Improved process for the conversion of daunorubicin into doxorubicin |
US7388083B2 (en) | 2005-03-07 | 2008-06-17 | Solux Corporation | Epimerization of 4′-C bond and modification of 14-CH3-(CO)-fragment in anthracyclin antibiotics |
US9035032B2 (en) | 2005-12-13 | 2015-05-19 | Solux Corporation | Method for preparing 4-demethyldaunorubicin |
US8802830B2 (en) | 2005-12-20 | 2014-08-12 | Solux Corporation | Synthesis of epirubicin from 13-dihydrodaunorubicine |
US8357785B2 (en) | 2008-01-08 | 2013-01-22 | Solux Corporation | Method of aralkylation of 4′-hydroxyl group of anthracylins |
ITMI20090784A1 (en) * | 2009-05-08 | 2010-11-09 | Antibioticos Spa | PROCEDURE FOR THE PREPARATION OF 14-BROMO DAUNOMICINA |
ITMI20100007A1 (en) * | 2010-01-08 | 2011-07-09 | Antibioticos Spa | PROCESS FOR THE PREPARATION OF DOXORUBICINE |
Also Published As
Publication number | Publication date |
---|---|
JPS61502956A (en) | 1986-12-18 |
FI860683A (en) | 1986-02-14 |
FI860683A0 (en) | 1986-02-14 |
DK59486D0 (en) | 1986-02-06 |
DK59486A (en) | 1986-02-06 |
DK157082C (en) | 1990-04-09 |
EP0183691A1 (en) | 1986-06-11 |
DK157082B (en) | 1989-11-06 |
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