- Method for synthesizing famciclovir by using microchannel reactor
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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.
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Paragraph 0032-0053
(2021/06/22)
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- A new method to synthesize famciclovir
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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
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p. 2803 - 2808
(2011/04/17)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF PURINE DERIVATIVE
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The present invention provides an improved process for the preparation of purine derivative of Formula I.
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Page/Page column 11-12
(2008/12/06)
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- AN IMPROVED PROCESS FOR PREPARING PURINE DERIVATIVE
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A process for the preparation of famciclovir a compound of Formula (I) and its intermediates.
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Page/Page column 16-17
(2009/01/23)
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- Preparation of famciclovir and other purine derivatives
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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.
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Page/Page column 4; 5
(2008/06/13)
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- Regioselective functionalization of guanine: Simple and practical synthesis of 7- and 9-alkylated guanines starting from guanosine
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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
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p. 2026 - 2034
(2007/10/03)
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- PROCESS FOR THE PREPARATION OF FAMCICLOVIR
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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.
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- Purine derivatives having cyclopropane ring
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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:
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Example II-6
(2008/06/13)
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- Purine derivatives having cyclopropane ring
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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.
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- A direct approach to the synthesis of famciclovir and penciclovir
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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
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p. 981 - 994
(2007/10/03)
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- Process for preparing purine derivatives and intermediates thereof
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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).
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- Derivatives of purine
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Antivirally active compounds of the formula STR1 wherein R1 is hydrogen or hydroxymethyl; R2 is hydrogen, hydroxy or hydroxymethyl; R3 is hydrogen; or R1 and R3 together constitute an additional carbon-carbon bond; with the proviso that when R1 is hydrogen then R2 is hydroxy or hydroxymethyl, that when R1 is hydroxymethyl then R2 is hydrogen and that when R2 is hydroxy then R1 is hydrogen; and physiologically acceptable salts; geometric or optical isomers thereof; processes for preparation of said compounds, pharmaceutical preparations containing the compounds, methods for treatment of virus infections and medical use of the compounds.
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- Prodrugs of the Selective Antiherpesvirus Agent 9-guanine (BRL 39123) with Improved Gastrointestinal Absorption Properties
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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
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p. 1738 - 1743
(2007/10/02)
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- Synthesis and Antiviral Activity of 9-purines
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Alkylation of 2-amino-6-chloropurine with 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxane (5) provided 2-amino-6-chloro-9-purine (6) in high yield.This aminochloropurine 6 readily converted to the antiviral acyclonucleoside 9-guanine (1) and to its 6-chloro (10), 6-thio (11), 6-alkoxy (12-17), 6-amino (20), and 6-deoxy (21) purine analogues.The guanine derivative 1 was converted to its xanthine analogue 9.Similarly, alkylation of 6-chloropurine with 5 provided a route to 8, the hypoxanthine analogue of 1.Of these 9-substituted purines, the guanine derivative 1 showed the highest activity against herpes simplex virus types 1 and 2 in cell cultures, and in some tests it was more active than acyclovir, with no evidence of toxicity for the cells.A series of monoesters (30-33) and diesters (24-27, 29) of 1 were prepared, and some of these also showed antiherpes virus activity in cell cultures, the most active ester being the dihexanoate 27.
- Harnden, Michael R.,Jarvest, Richard L.,Bacon, Teresa H.,Boyd, Malcolm R.
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p. 1636 - 1642
(2007/10/02)
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