EP0183691A1 - Process for preparing adriamycine and halide salts thereof - Google Patents

Process for preparing adriamycine and halide salts thereof

Info

Publication number
EP0183691A1
EP0183691A1 EP19840902361 EP84902361A EP0183691A1 EP 0183691 A1 EP0183691 A1 EP 0183691A1 EP 19840902361 EP19840902361 EP 19840902361 EP 84902361 A EP84902361 A EP 84902361A EP 0183691 A1 EP0183691 A1 EP 0183691A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
adriamycine
derivative
solution
daunomycine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19840902361
Other languages
German (de)
English (en)
French (fr)
Inventor
János BALINT
Szabolcs Borbely
Zsuzsanna Emri
József FAZEKAS
György TOTH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Works PLC
Original Assignee
Biogal Gyogyszergyar Rt
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biogal Gyogyszergyar Rt filed Critical Biogal Gyogyszergyar Rt
Publication of EP0183691A1 publication Critical patent/EP0183691A1/en
Withdrawn legal-status Critical Current

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.

Landscapes

  • 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)
EP19840902361 1984-06-14 1984-06-14 Process for preparing adriamycine and halide salts thereof Withdrawn EP0183691A1 (en)

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
EP0183691A1 true EP0183691A1 (en) 1986-06-11

Family

ID=10980572

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19840902361 Withdrawn EP0183691A1 (en) 1984-06-14 1984-06-14 Process for preparing adriamycine and halide salts thereof

Country Status (5)

Country Link
EP (1) EP0183691A1 (da)
JP (1) JPS61502956A (da)
DK (1) DK157082C (da)
FI (1) FI860683A (da)
WO (1) WO1986000073A1 (da)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0848009A1 (en) 1996-12-16 1998-06-17 Pharmachemie B.V. A process for preparing epirubicin or acid addition salts thereof from daunorubicin

Families Citing this family (9)

* Cited by examiner, † Cited by third party
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
US4997922A (en) * 1988-09-06 1991-03-05 Sanraku Incorporated Anthracycline derivatives
IT1230505B (it) * 1988-10-11 1991-10-25 Sicor Spa Procedimento per la conversione della daunorubicina in doxorubicina.
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
EP1976858B1 (en) 2005-12-13 2016-01-06 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
IT1398273B1 (it) * 2009-05-08 2013-02-22 Antibioticos Spa Procedimento per la preparazione di 14-bromo daunomicina
IT1397234B1 (it) * 2010-01-08 2013-01-04 Antibioticos Spa Processo per la preparazione di doxorubicina.

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL145536B (nl) * 1968-04-12 1975-04-15 Farmaceutici Italia Werkwijze voor de bereiding van een nieuw antibioticum of zijn aglycon.
GB1511680A (en) * 1975-11-18 1978-05-24 Farmaceutici Italia Daunosaminyl anthracyclinones
AT358736B (de) * 1976-12-22 1980-09-25 Erba Farmitalia Verfahren zur herstellung von neuen antitumorglycosiden
JPS56156300A (en) * 1980-04-26 1981-12-02 Microbial Chem Res Found Novel preparative method of anthracyclin derivative

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8600073A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0848009A1 (en) 1996-12-16 1998-06-17 Pharmachemie B.V. A process for preparing epirubicin or acid addition salts thereof from daunorubicin

Also Published As

Publication number Publication date
DK157082B (da) 1989-11-06
DK157082C (da) 1990-04-09
JPS61502956A (ja) 1986-12-18
FI860683A0 (fi) 1986-02-14
DK59486D0 (da) 1986-02-06
WO1986000073A1 (en) 1986-01-03
FI860683A (fi) 1986-02-14
DK59486A (da) 1986-02-06

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Inventor name: EMRI, ZSUZSANNA

Inventor name: TOTH, GYOERGY

Inventor name: FAZEKAS, JOZSEF

Inventor name: BALINT, JANOS

Inventor name: BORBELY, SZABOLCS