[go: up one dir, main page]

WO1986000073A1 - Procede de preparation d'adriamycine et ses sels d'halogenure - Google Patents

Procede de preparation d'adriamycine et ses sels d'halogenure Download PDF

Info

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
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.)
Ceased
Application number
PCT/HU1984/000037
Other languages
English (en)
Inventor
János BÁLINT
Szabolcs BORBÉLY
Zsuzsanna Emri
József FAZEKAS
György TÓTH
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
Priority to JP59502565A priority Critical patent/JPS61502956A/ja
Priority to FI860683A priority patent/FI860683A0/fi
Priority to PCT/HU1984/000037 priority patent/WO1986000073A1/fr
Priority to EP84902361A priority patent/EP0183691A1/fr
Publication of WO1986000073A1 publication Critical patent/WO1986000073A1/fr
Priority to DK059486A priority patent/DK157082C/da
Anticipated expiration legal-status Critical
Ceased 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)

Abstract

Les sels d'halogénure d'adriamycine sont utiles comme antibiotiques antitumoraux. L'adriamycine et ses sels d'halogénure sont préparés, en obtenant des rendements élevés, à partir de la daunomycine ou ses sels d'halogénure en faisant réagir la daunomycine ou un sel d'halogénure de celle-ci avec du brome dans un système de solvant organique anhydre en présence d'un solvant approprié à la formation d'un cétal, en transformant le dérivé 14-bromo en un dérivé 14-hydroxy d'une manière connue en soi, éventuellement en acidifiant la solution avec un acide haloïde et en récupérant le produit éventuellement après purification.
PCT/HU1984/000037 1984-06-14 1984-06-14 Procede de preparation d'adriamycine et ses sels d'halogenure Ceased WO1986000073A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP59502565A JPS61502956A (ja) 1984-06-14 1984-06-14 アドリアマイシン及びそのハロゲン化塩の調整法
FI860683A FI860683A0 (fi) 1984-06-14 1984-06-14 Foerfarande foer framstaellning av adriamycin och halidsalter daerav.
PCT/HU1984/000037 WO1986000073A1 (fr) 1984-06-14 1984-06-14 Procede de preparation d'adriamycine et ses sels d'halogenure
EP84902361A EP0183691A1 (fr) 1984-06-14 1984-06-14 Procede de preparation d'adriamycine et ses sels d'halogenure
DK059486A DK157082C (da) 1984-06-14 1986-02-06 Fremgangsmaade til fremstilling af adriamycin og halogenidsalte deraf

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/HU1984/000037 WO1986000073A1 (fr) 1984-06-14 1984-06-14 Procede de preparation d'adriamycine et ses sels d'halogenure

Publications (1)

Publication Number Publication Date
WO1986000073A1 true WO1986000073A1 (fr) 1986-01-03

Family

ID=10980572

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1984/000037 Ceased WO1986000073A1 (fr) 1984-06-14 1984-06-14 Procede de preparation d'adriamycine et ses sels d'halogenure

Country Status (5)

Country Link
EP (1) EP0183691A1 (fr)
JP (1) JPS61502956A (fr)
DK (1) DK157082C (fr)
FI (1) FI860683A0 (fr)
WO (1) WO1986000073A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0358161A3 (fr) * 1988-09-06 1990-07-11 Sanraku Incorporated Dérivés d'anthracyclines et procédé pour leur production
EP0363604A3 (fr) * 1988-10-11 1990-07-25 Sicor Societa' Italiana Corticosteroidi S.P.A. Procédé de conversion de la daunorubicine en doxorubicine
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 (it) * 2009-05-08 2010-11-09 Antibioticos Spa Procedimento per la preparazione di 14-bromo daunomicina
ITMI20100007A1 (it) * 2010-01-08 2011-07-09 Antibioticos Spa Processo per la preparazione di doxorubicina
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69609845T2 (de) 1996-12-16 2000-12-21 Pharmachemie B.V., Haarlem Verfahren zur Herstellung von Epirubicin oder Zusatzsalzen davon, von Daunorubicin

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT283597B (de) * 1968-04-12 1970-08-10 Farmaceutici Italia Verfahren zur Herstellung von Adriamycin und Adriamycinon
DE2652391A1 (de) * 1975-11-18 1977-05-26 Farmaceutici Italia Daunosaminylanthracyclinone, verfahren zur herstellung und arzneimittel, die diese verbindungen enthalten
AT358736B (de) * 1976-12-22 1980-09-25 Erba Farmitalia Verfahren zur herstellung von neuen antitumorglycosiden
EP0039060A1 (fr) * 1980-04-26 1981-11-04 Zaidanhojin Biseibutsu Kagaku Kenkyukai Méthode pour la préparation de dérivés d'anthracycline

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT283597B (de) * 1968-04-12 1970-08-10 Farmaceutici Italia Verfahren zur Herstellung von Adriamycin und Adriamycinon
DE2652391A1 (de) * 1975-11-18 1977-05-26 Farmaceutici Italia Daunosaminylanthracyclinone, verfahren zur herstellung und arzneimittel, die diese verbindungen enthalten
AT358736B (de) * 1976-12-22 1980-09-25 Erba Farmitalia Verfahren zur herstellung von neuen antitumorglycosiden
EP0039060A1 (fr) * 1980-04-26 1981-11-04 Zaidanhojin Biseibutsu Kagaku Kenkyukai Méthode pour la préparation de dérivés d'anthracycline

Cited By (10)

* 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
EP0358161A3 (fr) * 1988-09-06 1990-07-11 Sanraku Incorporated Dérivés d'anthracyclines et procédé pour leur production
US4997922A (en) * 1988-09-06 1991-03-05 Sanraku Incorporated Anthracycline derivatives
EP0363604A3 (fr) * 1988-10-11 1990-07-25 Sicor Societa' Italiana Corticosteroidi S.P.A. Procédé de conversion de la daunorubicine en doxorubicine
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 (it) * 2009-05-08 2010-11-09 Antibioticos Spa Procedimento per la preparazione di 14-bromo daunomicina
ITMI20100007A1 (it) * 2010-01-08 2011-07-09 Antibioticos Spa Processo per la preparazione di doxorubicina

Also Published As

Publication number Publication date
DK59486D0 (da) 1986-02-06
FI860683L (fi) 1986-02-14
DK157082C (da) 1990-04-09
EP0183691A1 (fr) 1986-06-11
DK59486A (da) 1986-02-06
FI860683A7 (fi) 1986-02-14
JPS61502956A (ja) 1986-12-18
FI860683A0 (fi) 1986-02-14
DK157082B (da) 1989-11-06

Similar Documents

Publication Publication Date Title
JP2751385B2 (ja) エリスロマイシンａオキシム及びその塩の製造方法
JPH08208681A (ja) スクロース誘導体の製造法
JPH0212478B2 (fr)
WO1986000073A1 (fr) Procede de preparation d'adriamycine et ses sels d'halogenure
JP3983803B2 (ja) アンスラサイクリン系抗生物質の製造法
IE46165B1 (en) Daunomycinone derivatives
EP0678501B1 (fr) Procédé pour la préparation de N-chloroacétylglutamine
JP2843592B2 (ja) Ｌ−リボース誘導体
EP0053919B1 (fr) Dérivé de céphamycine C et sa préparation
US5220002A (en) Deacetylcolchicine derivatives
KR950013771B1 (ko) 14-클로로다우노마이신의 제조방법과 (2"r)-4'-o-테트라하이드로피란일아드리아마이신의 제조방법
EP0483754B1 (fr) Procédé pour la préparation de 6-(3-diméthylaminopropionyl)forskolin
CN114349631B (zh) 4-甲氧基巴豆酸的制备方法及其应用
JP3134010B2 (ja) デスアラニンベナノマイシンａ誘導体およびそれらの製造法
KR850001961B1 (ko) 3"-아실화 매크롤라이드 항생물질의 제조방법
NO860500L (no) Fremgangsmaate for fremstilling av adriamycin og halogenidsalter derav.
JP2894366B2 (ja) デアセチルコルヒチンの製造方法
KR930001165B1 (ko) 4'-데옥시독소루비신의 제조방법
JP2579678B2 (ja) アントラサイクリン誘導体及びその製法
KR850000528B1 (ko) 안트라사이클린유도체의 신제조법
CN120965785A (zh) L-甘露糖的制备方法
US5463040A (en) Method of preparing etoposide
JPH0481599B2 (fr)
JP3398176B2 (ja) セファロスポリンプロドラッグエステルの７−アミノ−３−メトキシメチルセフ−３−エム−４−カルボン酸への分解法
WO1981000409A1 (fr) Composes intermediaires pour la preparation de derives de la morphine

Legal Events

Date Code Title Description
AK Designated states

Designated state(s): AU DK FI JP NO RO SU US

Kind code of ref document: A1

Designated state(s): AU DK FI JP NO RO SU US

AL Designated countries for regional patents

Designated state(s): AT BE CH DE FR GB LU NL SE

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 1984902361

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 860683

Country of ref document: FI

WWP Wipo information: published in national office

Ref document number: 1984902361

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1984902361

Country of ref document: EP