- A new route to famciclovir via palladium catalysed allylation
-
An efficient route to the acyclic nucleoside analogue famciclovir has been developed based on a palladium(0) catalysed coupling of 2-amino-6- chloropurine and an allylic carbonate sidechain derived from 2,2-dimethyl- 1,3-dioxan-5-one. The reaction proceeds via a highly N-9 regioselective purine allylation step involving a novel palladium mediated N-7 to N-9 rearrangement. (C) 2000 Elsevier Science Ltd.
- Freer, Richard,Geen, Graham R.,Ramsay, Thomas W.,Share, Andrew C.,Slater, Graham R.,Smith, Neil M.
-
-
Read Online
- Method for synthesizing famciclovir by using microchannel reactor
-
The invention discloses a preparation method for synthesizing famciclovir by using a microchannel reactor, which comprises the following steps: mixing and dispersing 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbutyl) purine serving as a raw material and a palladium-carbon catalyst in a solvent, feeding by using a slurry pump, and performing dechlorination reaction with hydrogen in a microchannel continuous flow reactor to obtain reaction liquid, filtering the obtained reaction liquid, respectively inputting the filteringed reaction liquid and an acetic anhydride solution into the microchannel continuous flow reactor by using a diaphragm feeding pump, and carrying out esterification reaction in the microchannel reactor to obtain famciclovir. Compared with the prior art, the method has the advantages that the process safety can be greatly improved by carrying out hydrogenation reaction in the micro-channel continuous flow reactor; as the microchannel continuous flow reactor has the characteristic of high-efficiency mass and heat transfer, the reaction time can be effectively shortened, the use amount of raw materials is reduced, and the discharge of three wastes is reduced; and the route of first hydrogenation and then esterification is adopted, so that hydrolysis of ester bonds during first esterification and then hydrogenation can be effectively avoided, and the product purity is improved.
- -
-
Paragraph 0054-0068
(2021/06/22)
-
- SUBSTITUTED ARYLUREA COMPOUNDS FOR INDUCING APOPTOSIS AND COMPOSITION FOR ANTICANCER COMPRISING THE SAME
-
The present invention relates to a substituted arylurea compound inducing apoptosis and an anticancer composition comprising the same. The present invention relates to a novel compound capable of preventing, treating and alleviating cancer diseases such as prostate cancer, breast cancer, lung cancer, colorectal cancer, and skin cancer by inhibiting apoptosis of cancer cells and inhibiting proliferation of cancer cells.
- -
-
-
- Preparation method of high-purity famciclovir
-
The invention relates to a method for synthesizing famciclovir with very low byproduct content, which comprises the following steps of: reacting a compound 2- [2 (6-chlorine -2-amino -9H-purine-9-yl) ethyl] -1, 3-propylene glycol- diacetate (hereinafter referred to as G4) in a halogen removal reaction in which palladium carbon is used as a catalyst and ammonium formate is used as a hydrogen source to obtain famciclovir. One or more mixed organic or inorganic acids are used to improve the reaction rate of the main reaction and shorten the reaction time to avoid side reactions and impurity generation. According to the method, the conventional synthesis process is improved, the reaction time is greatly shortened, the reaction energy consumption is reduced, the side reaction and the generation of impurities are greatly controlled, and the method has an excellent application value in industrial production.
- -
-
Paragraph 0014-0024
(2021/04/21)
-
- Preparation method of famciclovir
-
The invention relates to a preparation method of famciclovir. The preparation method comprises the following steps of: adopting guanidine nitrate and diethyl malonate as raw materials, carrying out ring-closing reaction under an alkaline condition to obtain 2-amino-4,6-pyrimidinediol, then obtaining 2-amino-4,6-dichloropyrimidine by hydroxyl chlorination, reacting with 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl-1-amine to generate 6-chloro-N(i)4(/i)-(2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl)pyrimidine-2,4-diamine, then reacting with sodium nitrite under the acidic condition to obtain 2-(2-((2-amino-6-chloro-5-nitrosopyrimidin-4-yl)amino)ethyl)propane-1,3-diol, and finally carrying out reduction/dechloridation, ring-closing and esterification reaction to obtain the famciclovir. The preparation method has the beneficial effects that the problems of poor N-alkylation reaction selectivity and need of additional purification of reaction intermediates and the like in the current process are solved.
- -
-
Paragraph 0037-0042
(2019/03/28)
-
- PROCESS FOR PREPARING PURINE DERIVATIVE
-
A process for the preparation of famciclovir a compound of Formula (I) and its intermediates.
- -
-
Page/Page column 8
(2010/06/16)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF PURINE DERIVATIVE
-
The present invention provides an improved process for the preparation of purine derivative of Formula I.
- -
-
Page/Page column 12; 13; 13-14
(2008/12/06)
-
- A new method to synthesize famciclovir
-
A new and efficient method has been reported for the synthesis of 2-amino-9-[4-acetoxy-3-(acetoxymethyl)butyl-1-yl]purine(famciclovir)starting from guanine. The route involves chlorination of guanine, optimized Mitsunobu reaction, coupling with diethyl malonate, hydrogenation, reduction and esterification,and the overall yield is about 29%. This method does not require any form of chromatographic purification to give pure famciclovir, and it is an industrially viable manufacturing process for this drug. The Japan Institute of Heterocyclic Chemistry.
- Luo, Lei,Chen, Guorong,Li, Yuanchao
-
experimental part
p. 2803 - 2808
(2011/04/17)
-
- AN IMPROVED PROCESS FOR PREPARING PURINE DERIVATIVE
-
A process for the preparation of famciclovir a compound of Formula (I) and its intermediates.
- -
-
Page/Page column 17-18
(2009/01/23)
-
- A process for the manufacture of famciclovir using phase-transfer catalysts
-
The invention relates to a process for the preparation of Famciclovir, which comprises the preparation of a compound of formula (II) wherein X is a halogen atom by reaction of a compound of formula (III) with a compound of formula (VII) wherein L is a leaving group, in the presence of a catalytic amount of a quaternary ammonium salt, followed by hydrogenation of compound (II) to Famciclovir.
- -
-
Page/Page column 5
(2008/06/13)
-
- Preparation of famciclovir and other purine derivatives
-
Purine derivatives, substituted at the 9-position, are prepared from a chloro substituted purine starting material, first making an alkyl substitution at the 9-position, then forming the desired esterified side chain, reducing this and hydrogenating the resultant diol prior to addition of alkyl carbonyl groups.
- -
-
Page/Page column 4; 5
(2008/06/13)
-
- PROCESS FOR PREPARING FAMCICLOVIR
-
The invention provides a process for making famciclovir, comprising reacting 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-amino-6-chloropurine (Cl-FMC) with a palladium on charcoal catalyst in water and ammonium formate. The invention also provides methods of treating viral diseases by administering the famciclovir prepared according to the above process.
- -
-
Page/Page column 6-8
(2008/06/13)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF PURINES
-
The present invention relates to a process for the preparation of Purines. More particularly it relates to the preparation of Purines of formula (1) wherein X is hydrogen, thioaryl; R1 and R2 are hydrogen or acetyl.
- -
-
Page/Page column 5-6
(2008/06/13)
-
- Regioselective functionalization of guanine: Simple and practical synthesis of 7- and 9-alkylated guanines starting from guanosine
-
Reaction of N2-acetyl-9- and/or -7-benzylated guanines 8 and 12 with selected alkylating agents in 1-methyl-2-pyrrolidone at 120°C yielded the guaninium salts 9 and 13. The salts were consequently transformed by phase transfer hydrogenation into N7- and N9-isomers 10 and 14, respectively, in a highly regioselective manner. A convenient deoxygenation of both derivatives, achieved via the corresponding O6-arenesulfonates, into 2-aminopurine potential prodrugs was also established.
- Kalayanov, Genadiy,Jaksa, Suzana,Scarcia, Tommaso,Kobe, Joze
-
p. 2026 - 2034
(2007/10/03)
-
- PROCESS FOR THE PREPARATION OF FAMCICLOVIR
-
The invention provides processes for making famciclovir with low levels of undesirable by-products. The present invention discloses a process comprises reacting a compound of formula I (acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo [4,5-b]pyridin-3-yl)-butyl ester) in the presence of a palladium on charcoal catalyst in a C1-C6 alkyl acetate and ammonium formate. The present invention further discloses a process comprises reacting a compound of formula I (acetic acid 2-- acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b]pyridin-3-yl)-butyl ester) in the presence of a palladium on charcoal catalyst in a mixture of a C1-C6 alkyl acetate, a C1-C4 alcohol and ammonium formate.
- -
-
-
- A PROCESS FOR THE PREPARATION OF 2-ACETOXYMETHYL-4 HALO-BUT-1-YL ACETATES
-
A process for the preparation of 2- acetoxymethyl-4-halo-but-l-yl acetates (I) in which X is chlorine or bromine, which are useful intermediates for the preparation of antiviral medicaments such as Penciclovir and Famciclovir, comprising the opening of 3-hydroxymethyl-tetrahydrofuran (V) in the presence of an acylating agent and a Lewis acid selected from magnesium bromide and samarium triiodide.
- -
-
-
- PROCESS FOR PREPARING 9-[4-ACETOXY-3-(ACETOXYMETHYL)BUT-1-YL]-2-AMINOPURINE
-
Disclosed is a process for preparing 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine (called Famciclovir), a drug of purine derivatives having antiviral activity. This process comprises reacting 2-aminopurine with 2-acetoxymethyl-4-bromobut-1-yl-acetate in the presence of thallium (I) ethoxide to give the desired compound. According to this process, the desired compound can be prepared in very high selectivity and purity under mild reaction conditions.
- -
-
-
- Process for the production of purine derivatives and intermediates therefor
-
A process for preparing purine derivatives, such as famiciclovir and penciclovir, by reacting, in the presence of a palladium (0) catalyst and a ligand, a compound of the formula with a compound of the formula wherein X is H, OH or halo; Y is a leaving group; and R1and R2are selected independently from C1-12alkyl, aryl, C1-12alkylaryl, C1-12alkylsilyl, arylsilyl and C1-12alkyldiarylsilyl or are joined together to form a moiety of the formula wherein R3and R4are selected independently from H, C1-12alkyl and aryl.
- -
-
-
- Process for the production of purine derivatives
-
The invention provides a method of rearranging a compound of formula (I), wherein R and R′ are selected independently from hydrogen and C1-12alkyl; and R1and R2are selected independently from hydrogen, hydroxy, halo, C1-12alkyl- or aryl carbonate, amino, mono- or di-C1-12alkylamino, C1-12alkyl or arylamido, C1-12alkyl- or arylcarbonyl, C1-12alkyl- or arylcarboxy, C1-12alkyl- or arylcarbamoyl, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, aryl, heteroaryl, C1-12alkoxy, aryloxy, azido, C1-12alkyl- or arylthio, C1-12alkyl- or arylsulfonyl, C1-12alkyl- or arylsilyl, C1-12alkyl- or arylphosphoryl, and phosphato; to form a compound of formula (II), wherein R, R′, R1and R2are as defined for formula (I); said method comprising treating the compound of formula (I) with a palladium (0) catalyst and a (diphenylphosphino)nC1-6alkane, wherein n is an integer of 1-6. The invention also provides methods of R making penciclovir and famciclovir using this rearrangement reaction.
- -
-
-
- Purine derivatives having cyclopropane ring
-
The present invention is directed to a process for preparing a cyclopropane ring-cleaved purine derivative represented by the following formula: comprising hydrogenating a purine derivative having a cyclopropane ring represented by the following formula:
- -
-
Example II-5
(2008/06/13)
-
- Regioselective alkylation of guanines using 2-acetoxytetrahydrofurans
-
Reaction of silylated guanine derivatives with 2-acetoxy-4-benzoyloxymethyltetrahydrofuran in DMF or NMP resulted in selective N-9 alkylation. This was used as the basis for a regioselective synthesis of the anti-viral agents famciclovir and penciclovir.
- Geen, Graham R.,Kincey, Peter M.,Spoors, P. Grant
-
p. 1781 - 1784
(2007/10/03)
-
- Azetidinone derivatives for the treatment of HCMV infections
-
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.
- -
-
-
- Purine derivatives having cyclopropane ring
-
A purine derivative having a cyclopropane ring represented by the formula (I): wherein A is -CH2- group or -CO- group; X1 is hydrogen atom, a halogen atom, an alkoxy group having 1 to 10 carbon atoms, or hydroxyl group; each of X2, X3, and X4 is independently hydrogen atom or a halogen atom; R1 is hydrogen atom, a halogen atom, or a protected or unprotected amino group; and each of R2 and R3 is independently hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 7 carbon atoms, a substituted or unsubstituted aralkyl group, having 7 to 11 carbon atoms, or a substituted or unsubstituted acyl group having 1 to 7 carbon atoms, with proviso that in a case where A is -CO- group, neither R2 nor R3 is a substituted or unsubstituted acyl group having 1 to 7 carbon atoms, and each of X3 and X4 is independently a halogen atom, and a process for preparing the same.
- -
-
-
- Convenient syntheses of 9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine (penciclovir) and 9-[4-acetoxy-3-(acetoxymethyl)butyl]-2-amino-9h-purine (famciclovir)
-
Guanine 11 was converted, in a one pot reaction, into 2-amino-6-[(4- chlorophenyl)sulfanyl]purine 9a in 88% isolated yield. 4-Acetoxy-3- (acetoxymethyl)butanol 123 was prepared from 2-chloroethanol in five steps and in 46% overall yield. The mesylate ester of compound 23 reacted with 9a in the presence of potassium carbonate with a high degree of regioselectivity (89%) to give the N-9 alkylated product 26 which was isolated in 80% yield. Acidic hydrolysis of the latter compound 26 gave penciclovir 4 in virtually quantitative yield. Penciclovir 4 and famciclovir 5 were prepared from 2- amino-6-[(4-chlorophenyl)sulfanyl]purine 9a in four and five steps, respectively, by procedures involving initial alkylation with 1,2- dibromoethane. The overall yields obtained were 65 and ca. 60%, respectively.
- Brand, Briony,Reese, Colin B.,Song, Quanlai,Visintin, Cristina
-
p. 5239 - 5252
(2007/10/03)
-
- A direct approach to the synthesis of famciclovir and penciclovir
-
Reaction of 2-amino-6-chloropurine with triethyl 3-bromopropane-1,1,1- tricarboxylate followed by decarbethoxylation/transsesterification of the unpurified product was the key sequence in sythesising both the anti- herpesvirus agent penciclovir and its form famciclovir in three isolated steps.
- Choudary, Bernadette M.,Geen, Graham R.,Kincey, Peter M.,Parratt, Martin J.,Dales, J. Robert M.,Johnson, Graham P.,O'Donnell, Steven,Tudor, David W.,Woods, Neil
-
p. 981 - 994
(2007/10/03)
-
- Regiospecific Michael Additions with 2-Aminopurines
-
N-9 alkylated materials are the sole products obtained from extended reaction of 2-aminopurines (potential guanine precursors) with Michael acceptors.This was used as the basis for a highly regioselective synthesis of famciclovir, the oral form of the anti-herpesvirus agent penciclovir. Key Words: Michael addition; 2-aminopurines; regiospecific; famciclovir; penciclovir.
- Geen, Graham R.,Kincey, Peter M.,Choudary, Bernadette M.
-
p. 4609 - 4612
(2007/10/02)
-
- Process for preparing purine derivatives and intermediates thereof
-
A process for preparing pharmaceutically active compounds of formula (A): STR1 wherein X is hydrogen, hydroxy, chloro, C1-6 alkoxy or phenyl C1-6 alkoxy; and Ra and Rb are hydrogen, or acyl or phosphate derivatives thereof, which process comprises the preparation of an intermediate of formula (I): STR2 wherein R1 is C1-6 alkyl, or phenyl C1-6 alkyl in which the phenyl group is optionally substituted; R2 is hydrogen, hydroxy, chlorine, C1-6 alkoxy, phenyl C1-6 alkoxy or amino; and R3 is halogen, C1-6 alkylthio, C1-6 alkylsulphonyl, azido, an amino group or a protected amino group, via the reaction of a compound of formula (II): STR3 wherein R2 and R3 are as defined for formula (I) with: (a) a compound of formula (III): STR4 wherein R4 and R5 are independently hydrogen, C1-6 alkyl, or phenyl, or R4 and R5 together are C5-7 cycloalkyl; or (b), a compound of formula (V): STR5 wherein L is a leaving group and R1 is as defined for formula (I), and thereafter converting the resulting intermediates to a compound of formula (I) and converting a compound of formula (I) to a compound of formula (A).
- -
-
-
- Process for the preparation of purine derivatives
-
A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof: STR1 which process comprises reacting a compound of formula (II): STR2 wherein the amino group is optionally protected, Y is iodo, optionally substituted benzylthio or (phenacylmethyl)thio, with a compound of formula (III): STR3 wherein Q is a leaving group, Rx and Ry are protected hydroxymethyl or acyloxymethyl, or group(s) convertible to hydroxymethyl or acyloxymethyl; and Rz is hydrogen or a group convertible thereto; and thereafter converting Y to X is hydroxy by means of hydrolysis, or to X is hydrogen by means of reduction; converting Rx and Ry when other than hydroxymethyl or acyloxymethyl, to hydroxymethyl or acyloxymethyl, optionally converting Rx /Ry hydroxymethyl to acyloxymethyl or vice versa, deprotecting the 2-amino group where necessary and converting Rz, (when other than hydrogen) to hydrogen; and optionally forming a pharmaceutically acceptable salt thereof.
- -
-
-
- Prodrugs of the Selective Antiherpesvirus Agent 9-guanine (BRL 39123) with Improved Gastrointestinal Absorption Properties
-
Potential oral prodrugs of the antiherpesvirus acyclonucleoside 9-guanine (1, BRL 39123) have been synthesized and evaluated for bioavailability of 1 in the blood of mice.Reduction of 9--2-amino-6-chloropurine (13) using ammonium formate and 10percent palladium on carbon afforded the 2-aminopurine 14, which was hydrolyzed to the monoacetate 15 and to 2-amino-9-purine (5).The 2-aminopurine 5 was subsequently converted to additional monoester (17, 21-23) and diester (16, 24) derivatives and to its di-O-isopropylidene derivative 18.Both 5 and its esters (14-17, 21, 22) and also 18 were well absorbed after oral administration and converted efficiently to 1, the diacetyl (14) and dipropionyl (16) esters providing concentrations of 1 in the blood that were more than 15-fold higher than those observed after dosing either 1 or its esters (25-27).Some 6-alkoxy-9-purines (8-10), the preparation of which has been reported previously, also showed improved absorption properties, but their conversion to 1 was less efficient than for the 2-aminopurine derivatives.On the basis of these results and subsequent experiments involving determination of rates of convertion to 1 in the presence of rat and human tissue preparations, 9--2-aminopurine (14, BRL 42810) was identified as the preferred prodrug of 1.Oral bioavailability studies in healthy human subjects confirmed 14 as an effective prodrug, and this compound is now being evaluated in clinical trials.
- Harnden, Michael R.,Jarvest, Richard L.,Boyd, Malcolm R.,Sutton, David,Hodge, R. Anthony Vere
-
p. 1738 - 1743
(2007/10/02)
-
