- Preparation method and application of ganciclovir
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The invention belongs to the field of medicine synthesis, and discloses a preparation method and application of ganciclovir. According to the preparation method, N-(6-carbonyl-6, 9-dihydro-1H-purine-2-yl) acetamide and 2-hydroxy-1, 3-propylene diacetate are subjected to condensation with chloroformyl chloride at the same time, an obtained intermediate is subjected to hydrolysis, and ganciclovir is obtained. The preparation method of ganciclovir can effectively improve the utilization rate of raw materials, reduce the use cost of the raw materials in the production process, shorten the process flow, and reduce the occurrence of side reactions and the use amount of solvents. The preparation method is suitable for preparing ganciclovir, and the prepared ganciclovir is used for preparing ganciclovir for injection.
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- Preparation method of ganciclovir
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The invention discloses a preparation method of ganciclovir, and belongs to the technical field of medicine synthesis. The method comprises the following steps: condensing 1, 3-diacetyl oxygen-2-(acetoxymethoxyl) propane, 2, 9-diacetylguanine and a catalyst in a microwave reactor to obtain triacetyl ganciclovir; hydrolyzing a coarse triacetyl ganciclovir product in the microwave reactor to obtaina coarse ganciclovir product; and purifying to obtain high-purity ganciclovir. According to the method, the microwave reactor is used, so that the reaction selectivity is high; the raw material diacetylguanine residues are few, so that the conversion rate is high; the shortages of change of rate of post-process isomers are removed; the quality of an obtained intermediate is high; the operation steps are decreased; the cost is reduced; and moreover, the synthesizing quality of ganciclovir is improved; and the production efficiency is high.
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Paragraph 0030; 0032; 0034; 0035; 0036; 0038; 0039; 0040
(2018/09/28)
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- Method for synthesizing acyclovir and ganciclovir by carbon-hydrogen bond activation
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The invention discloses a method for synthesizing acyclovir and ganciclovir by carbon-hydrogen bond activation and belongs to the field of organic synthesis. The method comprises that inexpensive guanine as a raw material undergoes methyl protection on 9th NH, a high-valent iodine reagent and monoacetyl-protected ethylene glycol or 1, 2-isopropylidene-protected glycerol are added into the raw material under catalysis of palladium acetate, the mixture undergo a heating reaction to produce acetyl-protected acyclovir or acetyl-protected ganciclovir, and the acetyl group is removed by an inorganicalkali alcohol solution so that acyclovir and ganciclovir are obtained. The method utilizes cheap and easily available raw materials, prevents use risk and corrosive reagents, has the advantages of short reaction route, simple operation, high atomic economy and high total product yield, provides a novel synthesis route of acyclovir and ganciclovir and has a potential application prospect.
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Paragraph 0032; 0039; 0040; 0041
(2019/01/07)
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- A succinct synthesis of valganciclovir hydrochloride, a cytomegalovirus (CMV) retinitis inhibitor
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A concise and efficient synthesis of valganciclovir hydrochloride 1, a CMV retinitis inhibitor, without involving protection-deprotection sequences, is described. The synthetic utility of (2S)-azido-3-methylbutyric acid, which acts as a masked L-valine equivalent, is demonstrated in the synthesis of 1. ARKAT-USA, Inc.
- Babu, K. Srihari,Srinivas,Madhavi,Babu,Reddy, G. Madhusudhan,Haldar,Rao, P. Narasimha,Krishna,Srinivas,Venkateshwarulu,Reddy, P. Pratap,Anand, R. Vijaya
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experimental part
p. 199 - 208
(2011/05/11)
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- PREPARATION OF VALGANCICLOVIR AND ITS SALTS
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Processes for preparing valganciclovir and pharmaceutically acceptable salts thereof, as well as intermediates for the processes.
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Page/Page column 51; 52
(2010/04/27)
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- An Improved Total Synthesis of PET HSV-tk Gene Expression Imaging Agent 9-[(3-[18F]Fluoro-1-hydroxy-2-propoxy)methyl]guanine ([ 18F]FHPG)
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An improved total synthesis of [18F]FHPG starting from 1,3-dibenzyloxy-2-propanol and guanine has been developed. [18F]FHPG was prepared by nucleophilic substitution of the appropriate precursor with [18F]KF/ Kryptofix 2.2.2 followed by a quick deprotection reaction and purification with a simplified Silica Sep-Pak solid-phase extraction (SPE) method in 10-15% radiochemical yield, and 70 min synthesis time from end of bombardment (EOB).
- Wang, Ji-Quan,Zheng, Qi-Huang,Fei, Xiangshu,Liu, Xuan,Gardner, Thomas A.,Kao, Chinghai,Raikwar, Sudhanshu P.,Glick-Wilson, Barbara E.,Sullivan, Michael L.,Mock, Bruce H.,Hutchins, Gary D.
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p. 917 - 932
(2007/10/03)
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- A novel approach to the synthesis of the purine anti-viral agent gancyclovir
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The aim of this research is to synthesize gancyclovir, a purine anti-viral drug in large scale via simple intermediates. Reaction of guanine 1 with acetic anhydride followed by the attachment of the 2-O-acetoxymethyl-1,3-di-O-benzyl glycerol 3 as a side chain, subsequently lead to the production of N2acetyl-9-(1,3dibenzyloxy-2-propoxymethyl)guanine 6 and N2, acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine 7 and finally synthesizing gancyclovir 8. Among many pathways to the synthesis of purine derivatives, our four step procedure results in good yield and is proved to be an economic way of large scale synthesis.
- Sariri, Reyhaneh,Khalili, Gholamhosein
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p. 651 - 654
(2007/10/03)
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- Novel radiosynthesis of PET HSV-tk gene reporter probes [ 18F]FHPG and [18F]FHBG employing dual Sep-Pak SPE techniques
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Positron emission tomography (PET) herpes simplex virus thymidine kinase (HSV-tk) gene reporter probes 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy) methyl]guanine ([18F]FHPG) and 9-(4-[18F]fluoro-3- hydroxymethylbutyl)guanine ([18F]FHBG) were prepared by nucleophilic substitution of the appropriate tosylated precursors with [18F]KF/ Kryptofix 2.2.2 followed by a quick deprotection reaction and purification with a simplified dual Silica Sep-Pak solid-phase extraction (SPE) method in 15-30% radiochemical yield.
- Wang, Ji-Quan,Zheng, Qi-Huang,Fei, Xiangshu,Mock, Bruce H.,Hutchins, Gary D.
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p. 3933 - 3938
(2007/10/03)
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- Specific lipid conjugates to nucleoside diphosphates and their use as drugs
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The present invention concerns new phospholipid derivatives of nucleosides of the general formula (I) in which R1represents a straight-chained or branched, saturated or unsaturated aliphatic residue with 9-14 carbon atoms which can optionally be substituted once or several times; R2can represent a straight-chained or branched, saturated or unsaturated aliphatic residue with 8-12 carbon atoms which can optionally be substituted once or several times; m is 2 or 3; A can represent a methylene group or an oxygen; Nuc can be a nucleoside or a residue derived from a nucleoside derivative; and tautomers thereof and their physiologically tolerated salts of inorganic and organic acids and bases as well as pharmaceutical preparations containing these compounds.
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- Effect of mono- and di-acylation on the ocular disposition of ganciclovir: Physicochemical properties, ocular bioreversion, and antiviral activity of short chain ester prodrugs
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A series of short-chain carboxylic mono- and diesters of ganciclovir were synthesized in our laboratory. Physico-chemical properties, i.e., solubility (pH 4.2), partition coefficient in 1-octanol/phosphate buffer (pH 7.4), aqueous stability at various pH values, bioreversion kinetics in various ocular homogenates and effectiveness against various Herpes viruses in vitro were determined. The compounds exhibited a decrease in solubility as the ester length ascended with a corresponding increase in the octanol/buffer partition coefficient values. All of the prodrugs exhibit stability profiles typical of a carboxylic ester with maximum stability at neutral or slight acidic pH (4.07.0). Apparent first-order rate constants associated with prodrug to drug hydrolysis in the ocular homogenates varied depending on the size of the promoiety, lipophilicity of the compound, and the ocular tissue studied. The acetyl and butyryl mono and diesters were screened against various Herpes viruses. The monobutyrate ester of ganciclovir exhibits excellent activity against HSV-2 and VZV and provides a very high selectivity index against most of the viruses studied.
- Dias, Clapton S.,Anand, Banmeet S.,Mitra, Ashim K.
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p. 660 - 668
(2007/10/03)
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- Azetidinone derivatives for the treatment of HCMV infections
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A compound of formula 1: wherein Y is S or O; R1is C1-6alkyl; (C0-6alkyl)aryl; (C0-6alkyl)Het; or R1is an amino acid analog or dipeptide analog of the formula: wherein R2is H, C1-10alkyl; or an amide or ester group; A is C6-10aryl, Het or CH—R3wherein R3is C1-6alkyl or (C0-4alkyl)aryl; and Z is H, C1-6alkyl, or an acyl; R4is hydrogen, lower alkyl, methoxy, ethoxy, or benzyloxy; and R5is alkyl, cycloalkyl, carboxyl group; an aryl; Het or Het(lower alkyl); or R4and R5together with the nitrogen atom to which they are attached form a nitrogen containing ring optionally substituted with phenyl or C(O)OCH2-phenyl, said phenyl ring optionally mono- or di-substituted with among others C(O)OR7wherein R7is lower alkyl or phenyl(lower alkyl); or a therapeutically acceptable acid addition salt thereof which compounds are useful in the treatment of HCMV infections.
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- A facile synthesis of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (ganciclovir) from guanosine
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The potent and selective antiviral drug ganciclovir (6) has been synthesized in two steps via transpurination of fully acetylated guanosine (1) in the presence of 1,3-diacetoxy-2-(acetoxymethoxy)propane (2), followed by deacetylation in aqueous ammonia. The transpurination reaction also provides valuable side products, tetra-O-acetyl-β-D-ribofuranose (5) and the 7-regioisomer of triacetylganciclovir (4); the latter product can be converted to the desired 9-isomer in a thermal 7 ? 9 isomerization.
- Boryski, Jerzy,Golankiewicz, Bozenna
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p. 625 - 628
(2007/10/03)
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- Nucleoside analogue phosphates for topical use
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Compositions for topical use in herpes virus infections comprising anti-herpes nucleoside analogue phosphate esters, such as acyclovir monophosphate, acyclovir diphosphate, and acyclovir triphosphate which show increased activity against native strains of herpes virus as well as against resistant strains, particularly thymidine kinase negative strains of virus. Also disclosed are methods for treatment of herpes infections with nucleoside phosphates. Anti-herpes nucleoside analogues phosphate esters include the phosphoramidates and phosphothiorates, as well as polyphosphates comprising C and S bridging atoms.
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- Process for producing acyclic nucleosides and process for separating purine nucleosides
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Herein is disclosed a novel and industrially advantageous process for synthesizing acyclic nucleosides such as acyclovir and ganciclovir from ribonucleosides, which process comprises adding an acid catalyst and an acid anhydride to a solution of a ribonucleoside such as guanosine and an ester derivative of an acyclic sugar, and heating the mixture, whereby a transglycosilation reaction takes place between the ribose moiety of the ribonucleoside and the ester derivative of the acyclic sugar. Herein is also disclosed an industrially favorable method for the separation of 9-substituted purine nucleosides which are important intermediates for the synthesis of acyclic nucleosides such as acyclovir, ganciclovir, and the like from ribonucleosides, which method comprises crystallizing only the 9-isomer from a solution or suspension containing both a 9-substituted purine nucleoside and a 7-substituted purine nucleoside by cooling the solution or/and by adding a crystallizing solvent thereto.
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- Regiospecific process for synthesis of acyclic nucleosides
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This invention relates to an improved regiospecific process for the synthesis of acyclic nucleosides such as, acyclovir and ganciclovir, anti-viral compounds especially effective against herpes virus, and intermediates thereof starting from dyacylguanine and an alkylating agent, selected from 2-oxa-1,4-butanediol diacetate (OBDDA), 1,4-diacetoxy-3-acetoxymethyl-2-oxa-butane, 1,4-dibenzyloxy-3-acetoxymethyl-2-oxabutane. The reaction is carried out in the absence of an acid catalyst and a solvent.
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- An improved regiospecific process for synthesis of acyclic nucleosides
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This invention relates to an improved regiospecific process for the synthesis of acyclic nucleosides such as, acyclovir and ganciclovir, anti-viral compounds especially effective against herpes virus, and intermediates thereof starting from diacylguanine and appropriate addendum, selected from 2-oxa-1,4-butanediol diacetate (OBDDA), 1,4-diacetoxy-3-acetoxymethyl-2-oxa-butane, 1,4-dibenzyloxy-3-acetoxymethyl-2-oxabutane.
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- Syntheses of acyclic guanine nucleosides
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A method is provided for the synthesis of synthesis of acyclic purine nucleosides, particularly 9-(2-hydroxyethoxymethyl)-guanine (acyclovir) and 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine ("DHPG") where the N2,N9 -diprotected guanine is reacted with CH3 C(O)OCH2 O(CH2)2)OC(O)CH3 or diacetoxypropane, respectively, in the presence of a mixture of an acid and acetic anhydride, or in the presence of an acid, where the acid can be phosphoric acid or polyphosphoric acid.
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- Preparation of N-9 substituted guanine compounds
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The invention relates to efficient and selective processes for the synthesis of the antiviral N-9 substituted guanine compounds acyclovir and ganciclovir.
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- Transglycosilation process for producing acyclic nucleosides
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Herein is disclosed a novel and industrially advantageous process for synthesizing acyclic nucleosides such as acyclovir and ganciclovir from ribonucleosides, which process comprises adding an acid catalyst and an acid anhydride to a solution of a ribonucleoside such as guanosine and an ester derivative of an acyclic sugar, and heating the mixture, whereby a transglycosilation reaction takes place between the ribose moiety of the ribonucleoside and the ester derivative of the acyclic sugar.
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- Substituted 9-(1 or 3-monoacyloxy or 1,3-diacyloxy-2-propoxymethyl) purines as antiviral agent
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Compounds useful as antiviral agents are defined by the following formula: STR1 and the pharmaceutically acceptable acid addition salts thereof wherein R1 is hydrogen or --C(O)R7 wherein R7 is hydrogen, alkyl of one to nineteen carbon atoms, hydroxyalkyl of one to eight carbon atoms, alkoxyalkyl of two to nine carbon atoms, alkenyl of two to nineteen carbon atoms, phenyl, 1-adamantyl or 2-carboxyethyl and the pharmaceutically acceptable alkali metal salts thereof; R2 is --C(O)R7 wherein R7 is as defined above; R3 is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms, azido, NR9 R10 wherein R9 and R10 are independently hydrogen or lower alkyl of one to six carbon atoms or --NHC(O)R8 wherein R8 is hydrogen, alkyl of one to nineteen carbon atoms or 1-adamantyl; and (a) R6 is hydrogen, halo, lower alkoxy of one to six carbon atoms, azido, thio, lower alkylthio of one to six carbon atoms, --NR9 R10 wherein R9 and R10 are as defined above or --NHC(O)R8 wherein R8 is as defined above and R4 together with R5 is a bond; or (b) R5 together with R6 is a keto group and R4 is hydrogen.
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- Anti-viral guanine compounds
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9-(1,3-Dihydroxy-2-propoxymethyl)guanine and 9-(2,3-dihydroxy-1-propoxymethyl)guanine have been found to have potent anti-viral activity against herpes viruses. These compounds, their acyl derivatives, their phosphate derivatives and their pharmaceutically acceptable salts, pharmaceutical formulations containing these compounds, the treatment of DNA viral or herpes viral infections with these compounds, method of preparing these compounds, and novel intermediates useful in their preparation are all disclosed. The compounds may be prepared by reaction of the appropriate acetoxymethyl ether with diacetylguanine, followed by deprotection. The acetoxymethyl ethers may be obtained by reaction of glycerol formal with acetic anhydride in the presence of a catalyst.
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- EFFICIENT SYNTHESIS OF 1,2-seco AND 1,2-seco 2-nor PYRIMIDINE AND PURINE NUCLEOSIDES.
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Unprotected sylilated purines and pyrimidines (adenine, guanine, cytosine, thymine) reacted with acetoxymethyl ether (acyclic sugar analogues) under solid PTC conditions, using KI and dibenzo-18-crown-6 in benzene-acetonitrile(1:1, v/v) to give regiospecifically the corresponding N-9 purine and N-1 pyrimidine acyclic nucleosides in fairly good yields.
- Azymah, Muhammad,Chavis, Claude,Lucas, Marc,Imbach, Jean-Louis
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p. 6165 - 6168
(2007/10/02)
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- SYNTHESIS OF 9-((1,3-DIHYDROXY-2-PROPOXY)METHYL)GUANINE (DHPG) VIA CONDENSATION OF N2,9-DIACETYLGUANINE WITH A SULFINYLMETHYL ETHER
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The condensation of N2,9-diacetylguanine (8) with methylsulfinylmethyl ether 7 gave DHPG precursor 9.
- McGee, Danny P. C.,Martin, John C.,Verheyden, Julien P. H.
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p. 1651 - 1660
(2007/10/02)
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- Anhydrous crystalline 9-(1,3-dihydroxy-2-propoxymethyl)guanine
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Novel anhydrous crystalline 9-(1,3-dihydroxy-2-propoxymethyl)guanine useful as an antiviral agent.
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- Process for preparing guanine derivatives
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1-Monophosphate esters, 1,3-bisphosphate esters and cyclic phosphate esters of 9-(1,3-dihydroxy-2-propoxymethyl)guanine are useful as antiviral agents.
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- Process for preparing 2,6-substituted-9-(1,3-dihydroxy-2-propoxymethyl)-purines and certain derivatives
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Process and novel intermediates for preparing 9-(1,3-dihydroxy-2-propoxymethyl)guanine and 2,6-diamino-9-(1,3-dihydroxy-2-propoxymethyl)purine and certain esters thereof. The present process and intermediates reduce the number of reaction steps to prepare these compounds as compared to prior processes. The products are useful as antiviral agents.
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- Antiviral triazine compounds
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Compounds to general formula STR1 in which R and R' are hydrogen or benzyl and X represents a purine on pyrimidine base group selected from isoguanine, guanine, cytosine, 5-fluorouracil, S-methyl uracil (thymine) and chloroguanine, exhibit anti-viral properties.
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- 9-(1,3-Dihydroxy-2-propoxymethyl)guanine as antiviral agent
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The compound 9-(1,3-dihydroxy-2-propoxymethyl)guanine and the pharmaceutically acceptable salts thereof are useful as antiviral agents.
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- 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine: A new potent and selective antiherpes agent
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The synthesis of a new acyclic analogue of deoxyguanosine, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, 1) is described starting from epichlorohydrin via condensation of 2-O-(acetoxymethyl)-1,3-di-O-benzylglycerol (5) with N2,9-diacetylguanine (6). In vitro studies indicate that DHPG is a potent and broad-acting (herpes simplex virus types 1 and 2, cytomegalovirus, and Epstein-Barr virus) antiherpetic agent. In vivo studies indicate its lack of toxicity [LD50 (mice) = 1-2 g/kg, ip] and its superiority over acyclovir [oral ED50 = 7 (mg/kg)/day vs. 550 (mg/kg)/day in HSV-2 infected mice].
- Martin,Dvorak,Smee,Matthews,Verheyden
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p. 759 - 761
(2007/10/02)
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- 9-(1,3-Dihydroxy-2-propoxymethyl)guanine as antiviral agent
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The compound 9-(1,3-dihydroxy-2-propoxymethyl)guanine and the pharmaceutically acceptable salts thereof are useful as antiviral agents.
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