EP1565469A1 - Verfahren zur synthese von ganciclovir - Google Patents

Verfahren zur synthese von ganciclovir

Info

Publication number
EP1565469A1
EP1565469A1 EP02785726A EP02785726A EP1565469A1 EP 1565469 A1 EP1565469 A1 EP 1565469A1 EP 02785726 A EP02785726 A EP 02785726A EP 02785726 A EP02785726 A EP 02785726A EP 1565469 A1 EP1565469 A1 EP 1565469A1
Authority
EP
European Patent Office
Prior art keywords
solvent
formula
isomer
mixtures
methanol
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Withdrawn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
EP02785726A
Other languages
English (en)
French (fr)
Inventor
Jayachandra Suresh Babu
Purna Chandra Ray
Yatendra Kumar
Chandra Has Khanduri
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.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy 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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Priority claimed from PCT/IB2002/004897 external-priority patent/WO2004048380A1/en
Publication of EP1565469A1 publication Critical patent/EP1565469A1/de
Withdrawn legal-status Critical Current

Links

Definitions

  • the present invention relates to an industrial useful process for the synthesis of antiviral compound, ganciclovir.
  • Ganciclovir is chemically, 9-(1 ,3-dihydroxy-2-propoxymethyl) guanine and has the structural formula I
  • N-9 substituted guanine compounds involve the direct alkylation of appropriately substituted 2- aminopurines e.g. guanine derivatives.
  • the major drawback in this process is that it always results in a mixture of N-9 and N-7 alkylation products. Since alkylation of guanine derivatives like diacetyl / monoacetyl guanine is a thermodynamically controlled reaction, N-7 isomer is always formed. However, the N-9 isomer being thermodynamically more stable is produced as the major product. The unwanted N-7 isomer is difficult to separate from the desired N-9 isomer and is generally purified by costly and tedious processes requiring chromatographic separation and are highly undesirable on a commercial scale.
  • U.S. Patent No. 5,821 ,367 describes a regiospecific process which comprises reacting protected guanine derivative with an alkylating agent selected from 2-oxa-1 ,4-butanediol diacetate, 1-4-diacetoxy- 3-acetoxymethyl-2-oxa-butane, and 1 ,4-dibenzyloxy-3-acetoxymethyl-2- oxabutane in the absence of solvent or any acid catalyst to obtain the penultimate intermediates which are then converted to acylic nucleosides (acyclovir and ganciclovir).
  • U.S. Patent No. 6,043,364 teaches a process for the conversion of N-7 isomer to N-9 isomer by heating a suspension of the N-7 isomer in an alkylating agent.
  • the crystallization procedure of the present invention is very simple and produces the N-9 isomer having more than 95% purity which can directly be used for the preparation of ganciclovir.
  • the present process is cost effective and obviates the need for chromatographic separation.
  • the N-7 isomer so separated is recycled in the next batch of alkylation. It has been observed that the recycling of the N-7 isomer during alkylation enhances the formation of N-9 isomer and decreases the formation of N-7 isomer in the subsequent batches. This recycling of the side product improves the overall yield of the N-9 isomer and consequently the desired product i.e. ganciclovir.
  • the present invention provides a process which does not require discarding the unwanted N-7 isomer or an additional step of conversion of the N-
  • the present invention provides a process for the separation of N-7 and N-9 isomers of structural formulae II and III, respectively,
  • FORMULA III which comprises dissolving a mixture comprising the N-7 and N-9 isomers in an organic solvent, or a mixture of organic solvents, and isolating the N-7 and N-9 isomers from a solution thereof.
  • N-7 and N-9 isomers are structural formulae II and III.
  • solubilities one of them being consistently more soluble than the other.
  • the levels of solubility vary according to the solvent, and so a solvent system will desirably be chosen which allows a practical recovery of the two isomers that is present prior to the separation.
  • the solvent system from which the isomers may be separated will desirably be selected from alcoholic solvents, which include lower alkanols, water-immiscible solvents, or a mixture thereof.
  • the N-7 isomer of structural formula II will preferably be separated from the solvent system which has at least one lower alkanol.
  • the lower alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms, for example, methanol, ethanol, n- propyl alcohol, isopropyl alcohol, isobutanol, n-butanol, tertiary butanol, or mixtures thereof. Most preferred being methanol, ethanol, or isopropyl alcohol.
  • the N-9 isomer of structural formula III will preferably be separated from a solvent system which in addition to alcoholic solvents may contain water- immiscible solvents which include aromatic hydrocarbons such as benzene, toluene, or xylene, and chlorinated hydrocarbons such as chloroform, dichloromethane, or 1 ,2-dichloroethane.
  • alcoholic solvents may contain water- immiscible solvents which include aromatic hydrocarbons such as benzene, toluene, or xylene, and chlorinated hydrocarbons such as chloroform, dichloromethane, or 1 ,2-dichloroethane.
  • the concentration of the filtrate containing the N-9 isomer is adjusted by evaporation of the solvent or by dilution.
  • the separation may comprise the last stage or stages of a reaction in which the mixture of N-7 and N-9 isomers is formed.
  • the reaction in which ganciclovir of the structural formula I, is formed will preferably be an alkylation reaction carried out in the manner described in US Patent No. 4,355,032 which is incorporated herein by reference.
  • the solution containing the mixture of N-7 and N-9 isomers may be heated for dissolution, or it may be cooled to separate out the product or the slurry may further be cooled prior to filtration.
  • N-7 isomer of structural formula II so separated is used in the next batch of alkylation. Accordingly, a mixture of diacetyl guanine of Formula IV
  • N-7 N 2 -acetyl-7(1 ,3-diacetoxy-2- propoxymethyl) guanine
  • the N-7 isomer N 2 -acetyl-7(1 ,3-diacetoxy-2- propoxymethyl) guanine
  • the solvent is removed under vacuum to yield a dark oil from which N-7 and N-9 isomers are separated in accordance with the process of the present invention and N-7 isomer is again recycled.
  • the N-9 isomer so obtained after separation is hydrolyzed to yield ganciclovir by the methods known in the literature (J.E. Martin et. al., J. Med. Chem., 1983, 26, 759-61).
  • a mixture of diacetyl guanine (25g, 0.106mole), 2-acetoxymethoxy-1 ,3- diacetoxy propane (40. Og, 0.161 mole), p-toluene sulfonic acid monohydrate (0.5g) in N,N-dimethylformamide (75ml) is heated at 95°C to 100°C under continuous stirring for 42 hours. After completion of the reaction, the solvents are removed under vacuum yielding a dark brown syrup.
  • the syrup is dissolved by heating in methanol (400ml). The solution is cooled to 0°C, stirred for 1 hour at 0 to 5°C. The crystalline product is filtered and washed with methanol (50ml) to yield N 2 -acetyl-7-(1 ,3-diacetoxy-2- propoxymethyl) guanine (54.1g). Solvent is removed completely from the filtrate and methanol (100ml) and toluene (800ml) were added to the residue and the mixture is heated to 60°C and then cooled to 5°C and stirred for 30 minutes.

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP02785726A 2002-11-22 2002-11-22 Verfahren zur synthese von ganciclovir Withdrawn EP1565469A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2002/004897 WO2004048380A1 (en) 2002-11-22 2002-11-22 Process for the synthesis of ganciclovir

Publications (1)

Publication Number Publication Date
EP1565469A1 true EP1565469A1 (de) 2005-08-24

Family

ID=34362299

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02785726A Withdrawn EP1565469A1 (de) 2002-11-22 2002-11-22 Verfahren zur synthese von ganciclovir

Country Status (2)

Country Link
EP (1) EP1565469A1 (de)
AU (1) AU2002351016A1 (de)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004048380A1 *

Also Published As

Publication number Publication date
AU2002351016A1 (en) 2004-06-18

Similar Documents

Publication Publication Date Title
US9340518B2 (en) Process for the preparation of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropdxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one and intermediate used in said process
US7078524B2 (en) Process for the synthesis of ganciclovir
US7786304B2 (en) Process for the preparation of eszopiclone
EP0704445B1 (de) Herstellung N-9-substituierter Guanin-Verbindungen
JPH0570443A (ja) ２−（２’，４’−ジヒドロキシフエニル）−４，６−ジアリール−ｓ−トリアジンの製造方法
EP1883639B1 (de) Herstellung von famciclovir und anderen purinderivaten
ES2527721T3 (es) Procedimiento para la preparación de abacavir
US20050176956A1 (en) Process for the preparation of ganciclovir intermediate n2-acetyl-9-(1,3-diacetoxy-2-propoxymethyl) guanine
US5648489A (en) Syntheses of acyclic guanine nucleosides
EP1565469A1 (de) Verfahren zur synthese von ganciclovir
US7064205B2 (en) Process for preparing 1-methoxymethyl-5,5-diphenylbarbituric acid
US20060142574A1 (en) Process for the preparation of ganciclovir
US5821367A (en) Regiospecific process for synthesis of acyclic nucleosides
EP0806425B1 (de) Verbessertes regiospezifisches Verfahren zur Herstellung von azyklische Nucleosiden
EP1857458A1 (de) Verfahren zur Herstellung von Abacavir
EP0564006A2 (de) Purinderivate und Verfahren zu ihrer Herstellung
EP0461407B1 (de) Verbessertes Verfahren zur Herstellung von 2-Amino(2,3,5-tri-O-benzyl-beta-d-arabinofuranosyl)adenin
EP0709385A1 (de) Herstellung von Acyclovir
CA1300142C (en) Process for the preparation of 3-[(4-bromo-2- fluorophenyl)methyl]-3,4-dihydro-4-oxo-1- phthalazine-acetic acid
JP3084577B2 (ja) 光学活性なアトロラクチン酸の製造方法および製造の中間体
EP0258117A1 (de) Verfahren zur Herstellung von 2,4-Diamino-5-benzyl-pyrimidinen
NL8300536A (nl) Optisch actief alfa-azido-p-hydroxyfenylazijnzuur en zijn zouten alsmede de bereiding daarvan.
US20040122260A1 (en) Process for preparing 2-nitro-4'-fluorobenzophenone
PL157854B1 (en) Method for preparation of the guanine derivatives
ПРОИЗВОДНИ DEVELOPMENT OF AN OPTIMIZED SYNTHETIC APPROACH FOR SYNTHESIS OF CAFFEINE-8-THIOGLYCOLIC ACID AND ITS ESTER DERIVATIVES

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050622

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060107