- Synthesis and in vitro cytotoxic activity on human anaplastic thyroid cancer cells of lipoamino acid conjugates of gemcitabine
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Lipophilic derivatives of the antitumor drug gemcitabine (GEM) with the potential for improving drug loading in lipid-based colloidal carriers, like liposomes or lipid nanoparticles, are described. GEM free base was conjugated to lipoamino acids bearing an alkyl side chain of different length, by either a carbodiimide-assisted or an ethylchloroformiate-assisted coupling reaction, to obtain N4-acyl GEM derivatives. These compounds retained the same in vitro cell growth inhibitory activity of the parent drug against two lines of human anaplastic thyroid cancer cells. Stability studies suggested that the observed activity was due mainly to intact derivatives and not to released GEM. Accordingly, these amphiphilic derivatives can be proposed in a further step for the encapsulation in liposomes or lipid nanocarriers, to achieve as a final goal an improvement of the pharmacokinetics and therapeutic activity of GEM.
- Pignatello, Rosario,Vicari, Luisa,Pistara, Venerando,Musumeci, Teresa,Gulisano, Massimo,Puglisi, Giovanni
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Read Online
- An improved preparation process for gemcitabine
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An improved, cost-effective, and convenient process, using cinnamoyl as hydroxyl protective group and tosyl as the leaving group for gemcitabine (1) is described. The overall yield obtained from this newly developed process is around 10%, including two st
- Jiang, Xiangrui,Li, Jianfeng,Zhang, Rongxia,Zhu, Yi,Shen, Jingshan
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Read Online
- Stereoselective N-glycosylation with N4-acyl cytosines and efficient synthesis of gemcitabine
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Through systematical comparison of various N4-protected cytosine derivatives in the glycosylation step of gemcitabine synthesis, highly beta-stereoselective and high yielding TBAI catalyzed N-glycosylation was achieved with N4-Bz cytosine and anomeric mixture of 2,2‘-difluororibose mesylate donor. The subsequent global deprotection gave gemcitabine efficiently. Meanwhile, the anomeric chloride intermediate and fluoride-displaced side products of this N-glycosylation were identified, too. This new glycosylation method reveals the importance of N4-protection in the stereoselective preparation of pyrimidine nucleoside, also provides a potential alternative to current industrial process to gemcitabine.
- Liu, Tongchao,Tang, Jiadeng,Liang, Jianpeng,Chen, Yabin,Wang, Xiaowen,Shen, Jingkang,Zhao, Dongmei,Xiong, Bing,Cen, Jun-Da,Chen, Yue-Lei
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p. 1203 - 1213
(2019/01/29)
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- Preparation method of cytidine
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The invention provides a preparation method of cytidine 1, which comprises the following steps: (1) carrying out a condensation reaction on a compound 6 and a compound 7 in the presence of stannic chloride to generate a compound 8; (2) removing an alpha-isomer and other reaction impurities in the compound 8 to obtain the beta-isomer compound 8; and (3) carrying out a deprotection reaction on the beta-isomer compound 8 in the presence of an alcohol solvent, and then carrying out a salt forming reaction with hydrochloric acid to obtain a compound 1. The nucleoside compound 8 can be obtained withhigh beta-stereoselectivity starting from a cheap raw material 7 with a mixed anomeric carbon configuration, especially the raw material 7a, and a slightly excessive basic group 6, especially the basic group 6a; the trace alpha-compound 8 isomer impurities can be removed from the nucleoside compound 8 through a simple pulping method; and subsequently, deprotection and salifying reactions for beta-compound 8 have high yield, so that the method can reduce the production cost of the compound 1.
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Paragraph 0123-0128
(2019/12/10)
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- Drug delivery devices with drug-permeable component and methods
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Implantable drug delivery devices include a housing having a closed drug reservoir lumen bounded by a first wall structure and a hydrophilic second wall structure, and a drug contained in the drug reservoir lumen, wherein the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug. Methods of providing controlled release of drug to a patient include deploying a drug delivery device in the patient releasing a drug from the drug reservoir lumen via diffusion through the second wall structure.
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- Novel preparation method for gemcitabine hydrochloride
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The invention discloses a preparation method for gemcitabine hydrochloride. The preparation method comprises the steps: carrying out condensation, cracking and addition on D-mannitol serving as an initial raw material, and protecting hydroxyl by TESC1 to prepare an intermediate; and after carrying out condensation on the intermediate and cytosine under the catalysis of chiral phosphoric acid, carrying out salification to prepare gemcitabine hydrochloride. The preparation method has the advantages that the reaction steps are reduced, and the cost is reduced. Due to the use of the chiral phosphoric acid, the proportion of a required beta structure is greatly increased, the ratio of beta to alpha can reach 9:1, and the yield is increased. The chiral phosphoric acid belongs to an organic acidand is recyclable, little to environment pollution and particularly suitable for industrial production of gemcitabine hydrochloride.
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Paragraph 0008; 0019
(2018/04/21)
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- Industrial preparation process for key intermediate sulfonated saccharide of Gemcitabine
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The invention relates to a preparation method for a compound represented by a formula (I) shown in the description, i.e., a key intermediate sulfonated saccharide of Gemcitabine. The final product is prepared through subjecting a compound represented by a formula (II) shown in the description to sodium borohydride reduction, hydroxyl protection and resolution. The method is simple in process, high in yield and high in product purity and has no need of harsh reaction conditions, thereby being very suitable for industrial production.
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- A gemcitabine hydrochloride method for the preparation of
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The invention relates to a preparation method of gemcitabine hydrochloride, and the preparation method is a new process method and comprises the following steps: firstly preparing 3',5' and N-protected cytidine by using cytidine as a raw material, oxidizing to obtain 2'-keto-cytidine intermediate, and then preparing gemcitabine through catalystic deoxidation bi-fluorination by using a novel efficient deoxidation fluorination reagent. Compared with the widely used method for preparing gemcitabine by coupling fluorinated deoxyribose and cytosine base at present, the possibility of generating an alpha isomer is completely eliminated; the possibility of generating the alpha isomer is eliminated since the reaction of cytosine base configuration is not involved, the product can be easily purified, the purification process is greatly simplified, an efficient and practical new process method is provided for preparing the gemcitabine, and high industrial application value is realized.
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Paragraph 0071-0074
(2017/03/25)
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- PROCESS FOR THE PREPARATION OF GEMCITABINE HYDROCHLORIDE
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The present invention relates to an improved as well as an industrially viable process for the preparation of 2'-deoxy-2',2'-difluorocytidine and its pharmaceutical acceptable acid salts thereof in high purity and acceptable yield by using a simple and inexpensive process. The process involves reacting an alpha anomer enriched 2'-deoxy-2',2'-difluorocarbohydrate with silylated nucleobase derivatives via the SN2 displacement of an anomeric sulfonyloxy group in an inert solvent to produce 2',2'-difluoro-2'-deoxycytidine-3',5'-dibenzoate in about a 5:1 β/α anomeric ratio, and a process for selectively isolating β-2',2'-difluoro-2'-deoxycytidine-3',5'- dibenzoate from the 5:1 β/α anomeric mixture. The pure β-2',2'-difluoro-2'- deoxycytidine-3',5'-dibenzoate is then converted to the corresponding nucleoside utilizing ammonium hydroxide in a polar and preferably protic solvent to obtain β- 2'-deoxy-2',2'-difluorocytidine, which is thereafter converted to gemcitabine hydrochloride that is effective against non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer. The present invention relates to an improved and convenient method for preparing antineoplastic nucleosides, more particularly, a process for preparing gemcitabine hydrochloride, represented by the formula I below, which exhibits good antitumor activity. (I)
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- PROCESS FOR THE PREPARATION OF GEMCITABINE HYDROCHLORIDE
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Disclosed is the preparation of 2-deoxy-D-erythro-2,2-difluoro-ribofuranose-3,5-dibenzoate: a known intermediate for the preparation of Gemcitabine, by means of a reduction process; further disclosed is the purification of Gemcitabine by chromatography and the purification of Gemcitabine hydrochloride by crystallization techniques from ternary solvent mixtures. The main advantage of the invention is providing Gemcitabine hydrochloride with purity in conformity with the Pharmacopoeia requirements, as well as a process particularly convenient from the industrial point of view.
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Page/Page column 4
(2010/05/13)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF GEMCITABINE AND ITS INTERMEDIATES USING NOVEL PROTECTING GROUPS AND ION EXCHANGE RESINS
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An improved process for preparing gemcitabine or salts thereof, comprising the following steps, dissolved 2-Deoxy-2,2- difluoro-D-ribofuranose-3,5-dibenzoate in an organic solvent and allowed to cool to 0 to 10 degree centigrade temperature, stirred for a period of 1 to 2 hours to this triethylamine is added for a period of 2 to 10 minutes, an indigenous protecting compound added under constant stirring, solvents were distilled off, and to the residual volume IN HCL is added until to form a clear solution adjusted the PH of about 2, further to this an ethyl acetate was added followed by washing the organic phase using NaHCo3, water and brine solution, the organic phase was dried over MgSo4, concentrated the above reaction mixture under reduced pressure to obtain a crude 2-deoxy-2,2-difluoro-D- riboufuranose-3,5-dibenzoate-l-arylateas an oil phase, above product is dissolved in dry methanol under constant stirring using Ion exhange resin for a period of 15 to 25 hours at 30 to 45 degree centigrade temperature, which gives pure gemcitabine hydrochloride.
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Page/Page column 8-9
(2010/04/06)
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- Novel and Highly Stereoselective Process for Preparing Gemcitabine and Intermediates Thereof
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The present invention provides a novel and highly stereoselective process for preparing gemcitabine, which is suitable for industrial production, wherein, it includes the following reactions. Additionally, the invention discloses the key intermediates. The definition for the groups of G1, G2, G3, G4, and G5 are described in the specification.
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Page/Page column 9
(2010/08/03)
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- Process for the preparation of gemcitabine chlorohydrate
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Disclosed is the preparation of 2-deoxy-D-erythro-2,2-difluororibofuranose-3,5-dibenzoate: a known intermediate for the preparation of Gemcitabine, by means of a reduction process; further disclosed is the purification of Gemcitabine by chromatography and the purification of Gemcitabine hydrochloride by crystallization techniques from ternary solvent mixtures. The main advantage of the invention is providing Gemcitabine hydrochloride with purity in conformity with the Pharmacopoeia requirements, as well as a process particularly convenient from the industrial point of view.
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Page/Page column 8-9
(2010/05/13)
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- Manufacturing Process of 2' ,2' - Difluoronucleoside and Intermediate
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The present invention relates to more improved process for preparing 2′-deoxy-2′,2′-difluoronucleoside and its intermediate. The present invention provide a process for preparing an erythro enantiomer in greater than 98% purity, comprising forming a lactone ring by hydrolyzing ethyl (3RS)-2,2-difluoro-3-hydroxy-3-(2,2-dimethyloxolan-4-yl)propionate is hydrolyzed in the presence of hydrolysis reagents selected from acetic acid or chloroacetic acid, water and a mixture of organic solvents selected from the group comprising acetonilrile, dioxane, tetrahydrofuran or toluene, introducing a substituted benzoyl protecting group at the 3-position and 5-position, and recrys- tallizing said erythro enantiomer. Further, the present invention provides a process for selectively preparing, in greater than 99% purity, a beta-anomer 2′-deoxy-2′,2′-difluoronucleoside at the 3′-position and 5′-position that are protected by a substituted benzoyl in a 2:3 alpha/beta anomeric ratio.
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Page/Page column 7
(2009/12/04)
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- PROCESS AND INTERMEDIATES OF 2,2' DIFLUORONUCLEOSIDES
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The present invention provides novel 1-trihaloacetimido-2-deoxy-2,2'-difluoro-3,5-di-O-protected ribose intermediates. The compounds are useful in the preparation of 2'-deoxy-2,2'-difluoro-beta nucleosides and more particularly 2'-deoxy-2,2'-difluoro-beta cytidine and other beta anomer nucleosides and its salts having antiviral and anticancer activity
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Page/Page column 15-16
(2008/06/13)
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- GEMCITABINE PRODUCTION PROCESS
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Provided is a process for preparing gemcitabine or a salt thereof, which preferably includes selectively precipitating the β-anomer of a 3′,5′-di-O-protected-N4-trimethylsilyl-2′-deoxy-2′,2′-difluorocytidine, removing the protecting groups to produce gemcitabine, and, optionally, converting the gemcitabine into a salt. Preferably, the 3′ and 5′ protecting groups are the same or different, and at least one of the 3′ and 5′ protecting groups is cinnamoyl, naphthoyl, naphthylmethylcarbonyl, 2-methylbenzylcarbonyl, 4-methylbenzylcarbonyl or 9-fluorenylmethyloxycarbonyl. Also provided are methods for enriching the β-anomer from an anomeric mixture of a 3′,5′-di-O-protected-N4-trimethylsilyl-2′-deoxy-2′,2′-difluorocytidine, e.g., a N4-trimethylsilyl-2′-deoxy-2′,2′-difluoro-cytidine-3′,5′-diester, e.g., 3′,5′-dicinnamoyl-N4-trimethylsilyl-2′-deoxy-2′,2′-difluorocytidine, using a slurrying process, and methods for converting the β-anomer-enriched product into gemcitabine or a salt thereof.
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Page/Page column 7-8
(2008/12/04)
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- A NOVEL AND HIGHLY STEREOSELECTIVE PROCESS FOR PREPARING GEMCITABINE AND INTERMEDIATES THEREOF
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The present invention provides a novel and highly stereoselective process for preparing gemcitabine, which is suitable for industrial production, wherein, it includes the following reactions. Additionally, the invention discloses the key intermediates. The definition for the groups of G1, G2, G3, G4, and G5 are described in the specification.
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Page/Page column 26
(2009/01/20)
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- AN IMPROVED PROCESS FOR PREPARATION OF GEMCITABINE HYDROCHLORIDE.
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A process for isolating ?-anomer enriched Gemcitabine hydrochloride by converting Gemcitabine base into Gemcitabine hydrochloride followed by its purification using solvents from the series of water soluble ethers like 1,4-dioxane or Monoglyme.
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Page/Page column 10-11
(2010/11/27)
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- Method for the Preparation of 2'-Deoxy-2',2'-Difluorocytidine
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This invention relates to an improved method for stereoselectively preparing 2￠￥-deoxy-2￠￥,2￠￥-difluorocytidine of formula (I), which comprises the steps of reacting a 1-halo ribofuranose compound of formula (III) with a nucleobase of formula (IV) in a solvent to obtain a nucleoside of formula (II) with removing the silyl halide of formula (V) produced during the reaction; and deprotecting the nucleoside of formula (II) to obtain 2￠￥-deoxy-2￠￥,2￠￥-difluorocytidine of formula (I).
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Page/Page column 10
(2008/06/13)
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- A MANUFACTURING PROCESS OF 2',2'-DIFLUORONUCLEOSIDE AND INTERMEDIATE
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The present invention relates to more improved process for preparing 2'-deoxy-2',2'-difluoronucleoside and its intermediate. The present invention provide a process for preparing an erythro enantiomer in greater than 98% purity, comprising forming a lactone ring by hydrolyzing ethyl (3RS )-2,2-difluoro-3-hydroxy-3-(2,2-dimethyloxolan-4-yl)propionate is hydrolyzed in the presence of hydrolysis reagents selected from acetic acid or chloroacetic acid, water and a mixture of organic solvents selected from the group comprising acetonitrile, dioxane, tetrahydrofuran or toluene, in? troducing a substituted benzoyl protecting group at the 3-position and 5-position, and recrys- tallizing said erythro enantiomer. Further, the present invention provides a process for selectively preparing, in greater than 99% purity, a beta-anomer 2'-deoxy-2',2'-difluoronucleoside at the 3'-position and 5'-position that are protected by a substituted benzoyl in a 2:3 alpha/beta anomeric ratio.
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Page/Page column 13-14
(2010/11/27)
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- A PROCESS FOR THE PREPARATION OF GEMCITABINE USING NOVEL INTERMEDIATES
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The present invention provides a commercially viable process for preparing gemcitabine and its pharmaceutically acceptable acid addition salts thereof in high yield and purity using novel intermediates.
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Page/Page column 9
(2010/11/25)
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- PURIFICATION OF A DIFLUORONUCLEOSIDE ANOMER USING AQUEOUS ACID SOLUTION
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A process for purifying a crude α- or a crude β-anomer of a 2,2'-difluoronucleoside, or a derivative thereof, which process includes: providing: an organic or inorganic acid; an amount of crude α- or β-anomer of a 2,2'-difluoronucleoside or a derivative thereof; and water; forming an aqueous solution of the crude α- or crude β-anomer in the water; adding a sufficient amount of the acid to the aqueous solution such that the pH of the resulting solution does not exceed a predetermined value; collecting a precipitate; and optionally subjecting the precipitate to one or more washing steps.
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Page/Page column 9
(2008/06/13)
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- PREPARATION OF GEMCITABINE
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A process for preparation of gemcitabine hydrochloride and purification thereof.
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Page/Page column 22-23
(2008/06/13)
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- METHOD FOR THE PREPARATION OF 2#-DEOXY-2#,2#-DIFLUOROCYTIDINE
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This invention relates to an improved method for stereoselectively preparing 2′-deoxy-2′,2′-difluorocytidine of formula (I), which comprises the steps of reacting a 1-halo ribofuranose compound of formula (III) with a nucleobase of formula (IV) in a solvent to obtain a nucleoside of formula (II) with removing the silyl halide of formula (V) produced during the reaction; and deprotecting the nucleoside of formula (II) to obtain 2′-deoxy-2′,2′-difluorocytidine of formula (I).
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Page/Page column 21-22
(2008/06/13)
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- METHOD FOR THE PREPARATION OF 2'-DEOXY-2',2'-DIFLUOROCYTIDINE
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This invention relates to an improved method for stereoselectively preparing 2￠￥-deoxy-2￠￥,2￠￥-difluorocytidine of formula (I), which comprises the steps of reacting a 1-halo ribofuranose compound of formula (III) with a nucleobase of formula (IV) in a solvent to obtain a nucleoside of formula (II) with removing the silyl halide of formula (V) produced during the reaction; and deprotecting the nucleoside of formula (II) to obtain 2￠￥-deoxy-2￠￥,2￠￥-difluorocytidine of formula (I).
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Page/Page column 24
(2008/06/13)
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- INTERMEDIATE AND PROCESS FOR PREPARING OF BETA- ANOMER ENRICHED 21DEOXY, 21 ,21-DIFLUORO-D-RIBOFURANOSYL NUCLEOSIDES
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A highly stereoselective, simple and economical glycosylation process for preparation of β-anomer enriched 21-deoxy-21,21-D-ribofuranosyl difluoronucleosides of formula (II), and physiologically acceptable slats thereof, in particular, the β- enriched anomer of gemcitabine hydrochloride of formula (lib) in purity of >99% is provided through utilization of a novel trichloroacetimidate of formula (I).
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Page/Page column 42
(2010/11/23)
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- Method for preparation of 2'-deoxy-2', 2'-difluoro-beta-cytidine or pharmaceutically acceptable salts thereof by using 1,6-anhydro-beta-D-glucose as raw material
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The present invention provides a method for preparation of 2′-deoxy-2′,2′-difluoro-β-cytidine or pharmaceutically acceptable salt thereof, comprising starting from 1,6-anhydro-β-D-glucose as raw material, oxidizing, and fluorinating to obtain 2-deoxy-2,2-difluoro-D-ribofuranose as intermediate. The 2′-deoxy-2′,2′-difluoro-β-cytidine was finally prepared from the intermediate of 2-deoxy-2,2-difluoro-D-ribofuranose. The method is simple in operation and has a high yield. The method can effectively be used in large-scale production.
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Page/Page column 6
(2010/02/15)
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- SYNTHESIS OF 2-DEOXY-2, 2-DI FLUORO-D-RIBO FURANOSE-3, 5 DI(4-METHY/4-NITRO-CHLORO)BENZOATE AND ITS CONVERSION TO GEMCITABINE HYDROCHLORIDE THEREOF
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The invention describes the synthesis of hereto unreported 2-deoxy-2,2-difluoro-D-ribofuranose-3,5-di-(aroyl) derivative of formula-Vb, where in R=;CH3,CI,NO2 and its conversion to Gemcitabine HCl of formula-I, an anti cancer product.
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Page/Page column 9; 18-20
(2008/06/13)
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- AN IMPROVED PROCESS FOR THE MANUFACTURE OF HIGH PURE GEMCITABINE HYDROCHLORIDE
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A process for the preparation of Gemcitabine hydrochloride of formula (I) of extra high purity by the reaction of (R) -2,3-0-isopropylidene glyceraldehyde of formula (II) with ethyl bromo difluoroacetate of formula (III) followed by hydrolytic cyclization of the product of formula (IV) converting the product into a dibenzoyl derivative of formula (V) of high purity reducing the product of formula (V) and converting the resultant lactol into a mesylate of formula (VI) followed by coupling the mesylate of formula (VI) with bis-silyl acetyl cytosine of formula (X) and subsequently deblocking and purifying.
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Page/Page column 18-20
(2010/02/14)
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- Selective protection of 2',2'-difluorodeoxycytidine (gemcitabine)
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Gemcitabine (1) is a promising new anticancer agent used in pancreatic cancer. Improvement in the selective targeting of compound 1 and other cytotoxic agents to solid tumors may be enhanced by conjugation to ligands that target peripheral benzodiazepine receptors (PBRs) located on mitochondria and known to be overexpressed in human brain tumors. Development of such chemical conjugates requires selective protection on 4-NH2, 3'-OH, and 5'-OH of compound 1. All three monoprotected and three diprotected gemcitabine derivatives (2 to 7) were synthesized in good yield by employing a single commonly used protecting reagent, di-tert-butyl dicarbonate, under different conditions. Consequently, the three mono-ligand-gemcitabine conjugates coupled at 4-NH2, 3'-OH, and 5'-OH respectively (14 to 16) were synthesized in high yield using the PBR ligand PK11195. This selective protection/deprotection strategy offers a relatively straightforward means to modify other nucleosides.
- Guo, Zhi-Wei,Gallo, James M.
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p. 8319 - 8322
(2007/10/03)
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