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WO2007015265A2 - Fabrication de 6,9-imino ether - Google Patents

Fabrication de 6,9-imino ether Download PDF

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Publication number
WO2007015265A2
WO2007015265A2 PCT/IN2006/000180 IN2006000180W WO2007015265A2 WO 2007015265 A2 WO2007015265 A2 WO 2007015265A2 IN 2006000180 W IN2006000180 W IN 2006000180W WO 2007015265 A2 WO2007015265 A2 WO 2007015265A2
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WO
WIPO (PCT)
Prior art keywords
formula
imino ether
azithromycin dihydrate
water
erythromycin
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/IN2006/000180
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English (en)
Other versions
WO2007015265A3 (fr
Inventor
Mahajan Kiran Madhaorao
Patil Gokul Laxman
Chawan Mangesh Balwant
Hire Chandrabhan Madhav
Ambre Rajesh Viswanath
Randive Sachin Yashwant
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.)
Kopran Research Laboratories Ltd
Original Assignee
Kopran Research Laboratories Ltd
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 Kopran Research Laboratories Ltd filed Critical Kopran Research Laboratories Ltd
Publication of WO2007015265A2 publication Critical patent/WO2007015265A2/fr
Anticipated expiration legal-status Critical
Publication of WO2007015265A3 publication Critical patent/WO2007015265A3/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the invention relates to a process for preparing 6,9-Imino ether of formula I.
  • the invention also relates to a process for preparing Azithromycin dihydrate of Formula V.
  • Azithromycin is a semi-synthetic macrolide antibiotic chemically related to Erythromycin.
  • Azithromycin is a broad-spectrum bactericide and effective against a wide variety of microorganisms, such as Hemophilus influenzae, Streptococcus pneumoniae, Mycoplasma pneumoniae, Staphylococcus aureus, and Mycobacterium avium, and many others.
  • the transformation of Erythromycin A into Azithromycin comprises the conversion of Erythromycin base into its oxime; Beckmann's rearrangement of the Erythromycin oxime into 6,9-Imino ether; hydrogenation of the 6,9-Imino ether to 9-deoxo-9a-aza-9a-homoerythromycin A and further reductive methylation to obtain Azithromycin.
  • Erythromycin Oxime is prepared by treating Erythromycin base with hydroxylamine hydrochloride in methanol in presence of base. Erythromycin Oxime (either in the form of base or salt) is further subjected to Beckmann's rearrangement by treating it with p-Toluene sulfonyl chloride in aqueous acetone to produce 6,9-Imino ether, which is reported in WO 00/26,758, EP 0,503,932, EP 0,137,132 and US 4,328,334.
  • WO 00/27,856 reports the stable hydrate form of 6,9-Imino ether and its process of preparation. During the preparation of Azithromycin dihydrate, 6,9-Imino ether is further hydrogenated to 9-Deoxo-9a-aza- 9a-homoerythromycin A. Use of 6,9-Imino ether in its hydrated form for hydrogenation to 9-Deoxo-9a- aza-9a-homoerythromycin A, may hampers the hydrogenation due to its water content, which results iii reduction of the yield.
  • Reductive methylation of the secondary Amine is carried out to obtain Azithromycin.
  • This process is described in US 4,517,359 and J. chem. Res. 1998, 132, which consists basically of the Escheweiler- Clarke reaction and uses formaldehyde in acetic acid or formaldehyde, and formic acid in carbon tetrachloride or chloroform for methylation.
  • EP 0,879,823 discloses preparation of Azithromycin from 6,9-Imino ether by carrying out the reduction and reductive methylation sequentially with the noble catalyst and hydrogen in the presence of formaldehyde.
  • the preferred catalyst is 5 % rhodium over carbon but platinum, palladium or rhuthenium, can also be used.
  • An object of the invention is to provide simple, efficient and economical alternative to known methods, to prepare 6,9-Imino ether from Erythromycin thiocyante.
  • Another object of the invention is to provide the simple, efficient and economical process for preparing 87 to 96 % pure 6,9-Imino ether from Erythromycin thiocyanate without isolating and purifying Erythromycin base and Erythromycin oxime.
  • Yet another object of the invention is to provide the simple, efficient and economical process for preparation of 6,9-Imino ether where reaction is carried out in biphasic system, where 6,9-Imino ether need not be further purified.
  • Yet another object of the invention is to provide the simple, efficient and economical process for preparation of 6,9-Imino ether where p-toluene sulfonyl chloride is employed in the form of solution in methylene chloride, which avoids decomposition of p-toluene sulfonyl chloride.
  • Yet another object of the invention is to provide the simple, efficient and economical process for preparation of 6,9-Imino ether where triethylamine, which is used in oximation of erythromycin base, is carried forward in the next step of Beckmann's rearrangement and used along with sodium carbonate as base, which increase the rate of the reaction.
  • Yet another object of the present invention is to provide the simple, efficient and economical process for preparation of 6,9-Imnio ether, where organic solvent can be recycled.
  • Yet another object of the present invention is to provide 87 to 96 % pure 6,9-Imino ether.
  • the ratio of methylene chloride to water used in preparation of 6,9-Imino ether from Erythromycin oxime is 0.41: 1.1 v/v.
  • the preferred ratio of methylene chloride to water used in preparation of 6,9-Imino ether from Erythromycin oxime is 0.46: 1 v/v.
  • the amount of triethylamine added is in the range of 30 to 35 % v/w with respect to Erythromycin thiocyanate.
  • the preferred amount of triethylamine added is 32 % v/w with respect to Erythromycin thiocyanate. According to the present invention there is also provided a process for preparing Azithromycin dihydrate of formula (V);
  • Formula V comprising a) hydrogenating 6,9-Imino ether of formula (I);
  • Formula I obtained according to the invention in the presence of methanol as a solvent, to which 70 % perchloric acid is added to adjust the pH to 5.5 in presence 20 % by wt of Pt/C catalyst with respect to 6,9-Imino ether at temperature in the range of 30°-50° C and pressure in the range of 10-14 kg/cm 2 to achieve atleast 85 % conversion of 6,9-Imino ether to 9-Deoxo-9a-aza-9a-homoerythromycin A of formula (VI);
  • the hydrogenation of 6,9-Imino ether of step (a) is carried out preferably at temperature in the range of 40° -45° C and pressure in the range of 13 to 14 kg/cm 2 .
  • the Azithromycin dihydrate is isolated in step (c) by separating acetone/ lower chain alcohol layer from the methylation of 9-Deoxo-9a-aza-9a-homoerythromycin A mixture, followed by adding water to the acetone / alcohol layer within 12 hour while stirring, further stirring the mixture at 20° C for 12 hours, filtering the Azithromycin dihydrate of formula (V)
  • the alcohol / acetone to water ratio used to isolate Azithromycin dihydrate is atleast 1:2.3 v/v.
  • the Azithromycin dihydrate is purified in step (d) by dissolving Azithromycin dihydrate in a solvent like acetone or lower chain alcohol comprising methanol, ethanol or isopropanol with stirring, adding charcoal to the solution with stirring, filtering the solution to obtain filtrate, adding water to filtrate at 50-55 0 C, cooling aqueous filtrate to room temperature, chilling the aqueous filtrate to 0° to 5° C, filtering Azithromycin dihydrate from the aqueous filtrate, washing the Azithromycin dihydrate with chilled water and drying Azithromycin dihydrate at 65° C.
  • a solvent like acetone or lower chain alcohol comprising methanol, ethanol or isopropanol
  • the alcohol / acetone to water ratio used to purify the Azithromycin dihydrate is at least 1:6 v/v.
  • the invention provides a process for preparing 87-96 % pure 6,9-Imino ether from erythromycin thiocyanate without isolating and purifying Erythromycin base and Erythromycin oxime, thus minimizing steps.
  • the present process for preparing 6,9-Imino ether is carried out in biphasic system (i.e. methylene. chloride and water), p-toluene sulfonic acid formed during the process goes into methylene chloride along with the other impurities formed during the reaction and thus isolated 6,9- Imino ether need not to be further purified.
  • p-toluene sulfonyl chloride is employed in the form of solution in methylene chloride, which avoids decomposition and hence it is not required ii ⁇ excess amount.
  • Triethylamine used in the preparation of Erythromycin oxime is carried forward in the next step of 6,9-Imino ether formation, which can react with hydrochloric acid released during 6,9- Imino ether preparation and triethylamine hydrochloride is formed. This is further neutralized with sodium bicarbonate and triethylamine is again free to react with hydrochloric acid. This increases the rate of reaction and results in good yield.
  • the process for preparing 6,9-Imino ether of the invention is simple, efficient and economical.
  • reaction mixture was further cooled to room temperature and 460 ml of methylene chloride was added to it. pH of the reaction mixture was adjusted to 9.8 to 10.0 by adding ammonia. Organic layer was separated from the reaction mixture and washed the organic layer with water. The organic layer was cooled to 0° to 3 0 C. Chilled Sodium bicarbonate solution (1.24 % w/v) was added to the reaction mixture followed by addition of p-toluene sulfonyl chloride solution (50 gm of p-toluene sulfonyl chloride + 100 ml methylene chloride) at 0° to 3 0 C and then reaction mixture was stirred for 2 hours at the same temperature.
  • p-toluene sulfonyl chloride solution 50 gm of p-toluene sulfonyl chloride + 100 ml methylene chloride
  • the pH of the reaction mixture was adjusted to 5.4 to 5.5 by adding acetic acid. Organic layer was separated from the reaction mixture. The pH of aqueous layer of the reaction mixture was adjusted to 12 to 13 by adding Sodium hydroxide solution at 30° C. 6,9-Imino ether was filtered from the reaction mixture. The 6,9-Imino ether was washed with water and dried at 50° to 6O 0 C. The yield and purity of 6,9-Imino ether was 90% and 95 %.
  • Azithromycin dihydrate was filtered and washed with water. Azithromycin dihydrate was dried at 65° C. The yield and purity of the Azithromycin dihydrate was 87 % and 98 %.
  • Azithromycin dihydrate was filtered from the aqueous filtrate and washed with chilled water (0° to 5° C). Azithromycin dihydrate was dried at 65° C. The yield and purity of Azithromycin dihydrate was 95 % and 100 %.
  • Azithormycin dihydrate was characterized by IR (Refer Figure 2 of the Accompanying drawing).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)

Abstract

Procédé de fabrication de 6,9-imino éther à partir de thiocyanate d'érythromycine sans isolement d'une base d'érythromycine et d'un oxime d'érythromicine, dans lequel un réagencement Beckmann d'oxime d'érythromycine a lieu avec un système de solvant biphasique comprenant du chlorure de méthylène et de l'eau en présence de triéthylamine et de bicarbonate de soude, le but étant d'obtenir un 6,9-Imino éther pur à 87-96 %. Le 6,9-imino éther est ensuite hydrogéné en 9-déoxo-9a-aza-9a-homoérythromycine, puis soumis à une méthylation réductive pour obtenir un dihydrate d'azithromicine.
PCT/IN2006/000180 2005-05-24 2006-05-24 Fabrication de 6,9-imino ether Ceased WO2007015265A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN627/MUM/2005 2005-05-24
IN627MU2005 2005-05-24

Publications (2)

Publication Number Publication Date
WO2007015265A2 true WO2007015265A2 (fr) 2007-02-08
WO2007015265A3 WO2007015265A3 (fr) 2007-12-06

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WO (1) WO2007015265A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009023191A3 (fr) * 2007-08-09 2009-04-23 Teva Pharma Procédé amélioré de préparation de la clarithromycine
WO2009156938A3 (fr) * 2008-06-24 2010-12-02 Alembic Limited Procédé économique pour préparer de l'éther 6,9-imino
US8106111B2 (en) 2009-05-15 2012-01-31 Eastman Chemical Company Antimicrobial effect of cycloaliphatic diol antimicrobial agents in coating compositions
CN105481913A (zh) * 2014-09-19 2016-04-13 宁夏启元药业有限公司 一种合成阿奇霉素的方法
CN106083954A (zh) * 2016-06-22 2016-11-09 连云港笃翔化工有限公司 一种红霉素6,9亚胺醚化合物的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2696608B2 (ja) * 1993-05-19 1998-01-14 ファイザー・インク． アジスロマイシンの中間物質
WO2001049697A1 (fr) * 2000-01-04 2001-07-12 Teva Pharmaceutical Industries Ltd. Procede de preparation d'azithromycine dihydratee
ES2242668T3 (es) * 2000-03-15 2005-11-16 Hanmi Pharm. Co., Ltd. Metodo para obtener claritromicina en cristales de forma ii.
ES2179756B1 (es) * 2000-11-30 2004-10-01 Ercros Industrial, S.A. Procedimiento de obtencion de azaeritromicina.

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009023191A3 (fr) * 2007-08-09 2009-04-23 Teva Pharma Procédé amélioré de préparation de la clarithromycine
WO2009156938A3 (fr) * 2008-06-24 2010-12-02 Alembic Limited Procédé économique pour préparer de l'éther 6,9-imino
US8106111B2 (en) 2009-05-15 2012-01-31 Eastman Chemical Company Antimicrobial effect of cycloaliphatic diol antimicrobial agents in coating compositions
CN105481913A (zh) * 2014-09-19 2016-04-13 宁夏启元药业有限公司 一种合成阿奇霉素的方法
CN105481913B (zh) * 2014-09-19 2019-01-08 宁夏启元药业有限公司 一种合成阿奇霉素的方法
CN106083954A (zh) * 2016-06-22 2016-11-09 连云港笃翔化工有限公司 一种红霉素6,9亚胺醚化合物的制备方法
CN106083954B (zh) * 2016-06-22 2018-12-11 连云港笃翔化工有限公司 一种红霉素6,9亚胺醚化合物的制备方法

Also Published As

Publication number Publication date
WO2007015265A3 (fr) 2007-12-06

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