- Penciclovir crystal form and preparation method thereof
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The invention provides a penciclovir crystal form and a preparation method thereof. In the X-ray powder diffraction of the crystal form, characteristic peaks exist at 2theta diffraction angles of 7.526 +/- 0.2 degrees, 20.399 +/- 0.2 degrees, 22.001 +/- 0.2 degrees, 23.250 +/- 0.2 degrees, 27.991 +/- 0.2 degrees and 33.898 +/- 0.2 degrees. Compared with the prior art, the penciclovir crystal formis smaller in particle size, higher in purity and better in stability, and particularly, the stability of the penciclovir crystal form is remarkably improved under the illumination condition. Moreover, the preparation method disclosed by the invention is high in yield, simple in purification, simple and convenient to operate and suitable for industrial production.
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Paragraph 0034-0043
(2020/07/24)
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- Preparation method of penciclovir
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The invention discloses a preparation method of penciclovir. An existing synthetic route mainly has the following defects that the N-7 site by-products need to be removed through column chromatography, a large amount of three wastes are generated, and the yield of N-9 site products is not high. According to the technical scheme adopted by the invention, the preparation method comprises the following steps: carrying out alkylation on 2-amino-6-chloropurine and triethyl bromopropane under an alkaline condition to introduce an N-9 site side chain, carrying out decarboxylation and transesterification in a methanol solution of sodium methoxide to generate the 2-amino-6-chloro-9-(3,3-dimethoxycarbonyl-1-propyl)purine; then reducing the 2-amino-6-chloro-9-(3,3-dimethoxycarbonyl-1-propyl)purine togenerate 2-amino-6-chloro-9-(3-hydroxymethyl-4-hydroxy-1-butyl)purine with sodium borohydride; and finally, directly hydrolyzing under acidic conditions to obtain penciclovir. According to the method, the target product is obtained by directly hydrolyzing the reduction product, ester group protection and deprotection are not needed, and the method has the advantages of few reaction steps, good product quality, simplicity and convenience in operation, suitability for industrial production and the like.
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Paragraph 0041; 0048-0049
(2020/02/14)
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- Synthesis and anti-HSV activity of tricyclic penciclovir and hydroxybutylguanine derivatives
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A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against her
- Mohammed, Anber F.,Andrei, Graciela,Hayallah, Alaa M.,Abdel-Moty, Samia G.,Snoeck, Robert,Simons, Claire
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p. 1023 - 1033
(2019/02/09)
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- Practical syntheses of penciclovir and famciclovir from N2-acetyl-7-benzylguanine
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We have established practical methods for the synthesis of penciclovir (PCV) and famciclovir (FCV) from readily available guanosine via N2-acetyl-7-benzylguanine. The alkylation of N2-acetyl-7-benzylguanine proceeded selectively at the N9 position to give the desired alkylated product in good yield in salt form. After conventional catalytic hydrogenolysis of the benzyl group and hydrolysis of the resulting acetate, pure PCV was obtained without the need for chromatography. As a side chain precursor, the mesylate was selected rather than a halide since the corresponding halides gave several impurities under the same reaction conditions. Two procedures for the synthesis of FCV from PCV and a derivative are also reported.
- Torii, Takayoshi,Shiragami, Hiroshi,Yamashita, Keizo,Suzuki, Yumiko,Hijiya, Toyoto,Kashiwagi, Tatsuki,Izawa, Kunisuke
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p. 5709 - 5716
(2007/10/03)
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- Improved industrial syntheses of penciclovir and famciclovir using N2-acetyl-7-benzylguanine and a cyclic side chain precursor
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We have established practical synthetic methods for penciclovir (PCV, 1) and famciclovir (FCV, 2) from N2-acetyl-7-benzylguanine (NAc7BnG, 3) and 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (4)-the latter being a more easily prepared cyclic precursor
- Torii, Takayoshi,Yamashita, Keizo,Kojima, Mitsuhiko,Suzuki, Yumiko,Hijiya, Toyoto,Izawa, Kunisuke
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p. 625 - 634
(2008/02/08)
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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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- An Improved Total Synthesis of PET HSV-tk Gene Reporter Probe 9-(4-[ 18F]Fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG)
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An improved total synthesis of [18F]FHBG starting from triethyl-1,1,2-ethanetricarboxylate and 2-amino-6-chloropurine is reported. [18F]FHBG 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 20-25% radiochemical yield.
- Zheng, Qi-Huang,Wang, Ji-Quan,Liu, Xuan,Fei, Xiangshu,Mock, Bruce H.,Glick-Wilson, Barbara E.,Sullivan, Michael L.,Raikwar, Sudhanshu P.,Gardner, Thomas A.,Kao, Chinghai,Hutchins, Gary D.
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p. 689 - 704
(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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- Selective and Practical Synthesis of Penciclovir
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A selective and practical method has been developed for the synthesis of penciclovir (1) in gram quantities involving a highly N9 selective alykylation of 2-amino-6-chloropurine (9) with 2-(2-phenyl-1,3-dioxane-5-yl)ethanol (12) as a key step.
- Toyokuni, Tatsushi,Walsh, Joseph C.,Namavari, Mohammad,Shinde, Shirin S.,Moore, Jennifer R.,Barrio, Jorge R.,Satyamurthy, Nagichettiar
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p. 3897 - 3905
(2007/10/03)
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- Regioselective alkylation of guanines using 2-acetoxytetrahydrofurans
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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
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p. 1781 - 1784
(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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- Convenient syntheses of 9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine (penciclovir) and 9-[4-acetoxy-3-(acetoxymethyl)butyl]-2-amino-9h-purine (famciclovir)
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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
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p. 5239 - 5252
(2007/10/03)
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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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- Influence of remote structure upon regioselectivity in the N-alkylation of 2-amino-6-chloropurine: Application to the synthesis of penciclovir
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Reaction of 2-amino-6-chloropurine with trans-2-alkyl-5-iodoethyl-1,3- dioxanes under basic conditions afforded N-9 and N-7 alkylated products, the product ratio obtained being dependent on the size of the 2-alkyl group. This allowed a highly regioselective key step in the synthesis of the anti-herpes agent penciclovir.
- Choudary,Geen,Grinter,MacBeath,Parratt
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p. 979 - 996
(2007/10/02)
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- Carba-acyclonucleoside antiherpetic agents
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Ganciclovir 2 and 2'-carba-ganciclovir 5a are anti-viral agents differing structurally only in the replacement of an oxygen by a methylene group and yet expressing their biological properties along mechanistically independent pathways. Methoxy, hydroxy an
- Hannah,Tolman,Karkas,Liou,Perry,Field
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p. 1261 - 1271
(2007/10/02)
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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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- Phosphate derivatives of substituted butyl guanines, antiviral compositions containing them, and methods of treating viral infections with them
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Phosphate derivatives of substituted butyl guanines which have antiviral activity against DNA viruses, such as herpes viruses and HTLV-III.
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- GUANINE DERIVATIVE
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Antivirally active compounds of the formula STR1 wherein A is STR2 wherein m is 1 or 2, n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1, R a ' is (CH 2) p OH, NHCONH 2 or COR a ", R a " is hydrogen, hydroxy or amino, p is 1 to 4, R b ' and R b " are independently selected from hydrogen or (CH 2) p OH, with the proviso that at least one of R b ' or R b " is hydrogen; or R b ' and R b " together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt, geometric or optical isomer thereof; pharmaceutical preparations containing the compounds and methods for treatment of virus infections.
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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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- AN IMPROVED SYNTHESIS OF THE ANTIVIRAL ACYCLONUCLEOSIDE 9-(4-HYDROXY-3-HYDROXYMETHYLBUT-1-YL)GUANINE
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Alkylation of 2-amino-6-chloropurine with 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxan (7) and subsequent acid hydrolysis provides an improved procedure for synthesis of the antiviral acyclonucleoside 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (3).
- Harnden, M.R.,Jarvest, R.L.
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p. 4265 - 4268
(2007/10/02)
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