122111-02-8Relevant academic research and scientific papers
High-selectivity synthesis method for gemcitabine intermediate
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Paragraph 0057-0058, (2021/01/29)
The invention discloses a high-selectivity synthesis method for a gemcitabine intermediate. The high-selectivity synthesis method specifically comprises the following process: Step 1, synthesis of T1;Step2, synthesis of T2, to be specific, 550kg of hydrogen peroxide is dropwise added into the T1, and a reaction is controlled to produce the T2; Step3, synthesis of T3, to be specific, sodium acetate trihydrate or sodium carbonate is added into a reaction kettle, the PH value is adjusted with glacial acetic acid, a 10%-15% sodium hypochlorite aqueous solution is dropwise added, and a reaction iscontrolled to produce the T3; Step 4, synthesis of T4; Step 5, synthesis of T5; Step 6, synthesis of T6; Step 7, synthesis of T7; Step 8, synthesis of T8; and Step9, T8 configuration transformation.The high-selectivity synthetic method for the gemcitabine intermediate can reduce the production cost, and meanwhile, can also increase the yield of the gemcitabine intermediate.
Method for synthesizing 2- deoxy -2,2- difluoropentanoic acid -1- ketone -3,5- dibenzoin (by machine translation)
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Paragraph 0058-0061, (2020/03/09)
The invention takes 2,2 - dimethyl - 4444444H-1, 3-dioxane - 4 4-one and difluorobromoacetic acid as the reaction raw material, without having a specific chiral configuration, to selectively synthesize a specific configuration cyclization product, under the action of a monovalent copper salt and a chiral ligand . reaction is simpler, and Reformatsky environment-friendly, is avoided under slightly acidic condition by hydrolysis, of, the cyclization product of the cyclization product. The preparation ;NaBH, reduces side reactions. 4 - I2 The reduction system can selectively reduce the carboxylic acid without reducing the reduction effect, of the lactone by . and has the 2 -deoxy - 2222,dibenzofuran sugar - 1 1-ketone - 3333,5-dibenzoin synthesis route, is simple, environment-friendly, total yield . for industrial production, can be effectively reduced. (by machine translation)
Method for preparing Gemcitabine intermediate from chiral catalyst
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Paragraph 0031; 0036; 0037; 0042; 0043; 0048, (2019/05/28)
The invention relates to a method for preparing a Gemcitabine intermediate from a chiral catalyst, and belongs to the technical field of synthesis of medical intermediates. In order to solve the problem that the existing reaction is poor in stereoselectivity, the invention provides the method for preparing the Gemcitabine intermediate from the chiral catalyst; the method comprises the following steps: performing a condensation reaction on R-glyceraldehyde acetonide and difluoro halogenated ethyl acetate in an inert organic solvent under the combined catalytic action of active zinc powder and delta-amino alcohol ligands to obtain a corresponding intermediate; performing deprotection and lactonization treatment on the intermediate and performing a reaction on the intermediate and benzoyl chloride in the presence of an acid-binding agent to obtain the corresponding Gemcitabine intermediate. A product obtained with the method provided by the invention has an ee value being as high as 98% or above, the content of an erythro form product is high, and the obtained product does not need to be refined and can be directly used for next reaction.
Thiophene-expanded guanosine analogues of Gemcitabine
Chen, Zhe,Ku, Therese C.,Seley-Radtke, Katherine L.
, p. 4274 - 4276 (2020/12/14)
The chemotherapeutic drug Gemcitabine, 2′,2′-difluoro-2′-deoxycytidine, has long been the standard of care for a number of cancers. Gemcitabine's chemotherapeutic properties stem from its 2′,2′-difluoro-2′-deoxyribose sugar, which mimics the natural nucleoside, but also disrupts nucleic acid synthesis, leading to cell death. As a result, numerous analogues have been prepared to further explore the biological implications for this structural modification. In that regard, a thieno-expanded guanosine analogue was of interest due to biological activity previously observed for the tricyclic heterobase scaffold. Several analogues were prepared, including the McGuigan ProTide, however the parent nucleoside exhibited the best chemotherapeutic activity, specifically against breast cancer cell lines (89.53% growth inhibition).
PREPARATION OF GEMCITABINE AND INTERMEDIATES THEREOF
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Page/Page column 13, (2010/05/14)
The present patent application relates to a process for the preparation gemcitabine or a salt thereof. More particularly it relates to preparation of 3,5- dihydroxy protected -2-deoxy-2,2-difluoro -1-oxoribose, an intermediate used in the preparation of gemcitabine and its salts by using cyclohexylidene or cyclopentylidene protecting group, with high yield and purity.
Process for Preparing Gemcitabine and Associated Intermediates
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Page/Page column 13, (2008/06/13)
The present invention provides processes for preparing novel chemical substances that are useful as intermediates in the preparation of gemcitabine and processes for preparing gemcitabine therewith. Exemplary intermediates include mixtures of D-erythro and D-threo (3R- and 3S-) isomers of 3-(hydroxy)-2,2-difluoro-3-(2,2-dimethyldioxolan-4-yl)propionic acid salts. Also provided is a novel process for selectively isolating the D-erythro and D-threo isomers of the said salts in purities of at least about 95%, and processes of using them for preparing nucleoside analogs such as, e.g., gemcitabine and intermediates and analogs thereof.
AN IMPROVED ONE POT PROCESS FOR MAKING KEY INTERMEDIATE FOR GEMCITABINE HCL
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Page/Page column 13; 15-16, (2010/11/27)
An improved one pot process for preparing 2-deoxy-D-erythro-2,2-difluoro-pentafuranose-1-ulose-3,5-dibenzoate of Formula (I) comprising hydrolysis of (erythro:threo) alkyl-3-dioxalan-4-yl-2,2-difluoro-3-hydroxy propionate of Formula (III) where alkyl group is having C1-C4 number of carbon atoms using a mild acid and selectively isolating 2-deoxy-D-erythro-2,2-difluoro-pentafuranose-1-ulose-3,5-dibenzoate from the mixture of erythro and threo enantiomers using ethyl acetate, ethylene dichloride and diisopropyl ether as solvents with improved yield and purity.
AN IMPROVED PROCESS FOR THE MANUFACTURE OF HIGH PURE GEMCITABINE HYDROCHLORIDE
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Page/Page column 7; 13; 15, (2010/02/14)
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.
Structure-activity relationships of 2'-deoxy-2',2'-difluoro-L-erythro- pentofuranosyl nucleosides
Kotra, Lakshmi P.,Xiang, Yuejun,Gary Newton,Schinazi, Raymond F.,Cheng, Yung-C.,Chu, Chung K.
, p. 3635 - 3644 (2007/10/03)
Following the recent discoveries that some L-nucleosides are more or equal potent than their D-counterparts, we synthesized 2'-deoxy-2',2'- difluoro-L-erythro-pentofuranosyl nucleosides as potential antiviral agents. The target compounds were synthesized via the key intermediates 7a or 7b from L-gulono γ-lactone. Compound 2 was oxidatively cleaved and coupled with ethyl bromodifluoroacetate in the presence of activated zinc under Reformatsky conditions to obtain a diastereomeric mixture of 4(R) and 4(S), in a 4:1 ratio. The major 4(R) isomer was cyclized and treated appropriately to obtain the mesylate 8a or 8b, which was condensed with various silyl- protected pyrimidines. Condensation of the alcohol 7a or 7b with 6- chloropurine under Mitsunobu conditions afforded the 6-chloropurine analogs 53a or 53b and 54a or 54b. Further treatment of the compounds 53a, 54a and 53b, 54b afforded the inosine and adenine derivatives 57-60, respectively. The condensation of 2-amino-6-chloropurine with compound 8a and subsequent treatment with 2-mercaptoethanol/sodium methoxide afforded the guanine analogs 63 and 64. All of the synthesized nucleosides 31-52, 57-60, 63, and 64 were evaluated for antiviral activity and for cellular toxicity. Adenine derivative 57 showed a moderate activity against HIV-1 in PBM cells (3.4 μM). None of the other compounds showed any significant activities against HIV-1, HBV, HSV-1, HSV-2, and toxicity in Veto, CEM, and PBM cell lines up to 100 μM. The X-ray structure of the 5-iodocytosine analog showed a 2'- exo/3'-endo conformation for the carbohydrate moiety, which is different from those of the biologically active compounds (-)-FTC and L-FMAU.
Stereospecific synthesis of 2-deoxy-2,2-difluororibonolactone and its use in the preparation of 2'-deoxy-2',2'-difluoro-β-D-ribofuranosyl pyrimidine nucleosides: The key role of selective crystallization
Chou,Heath,Patterson,Poteet,Lakin,Hunt
, p. 565 - 570 (2007/10/02)
A stereospecific synthesis of 2'-deoxy-2',2'-difluorocytidine (gemcitabine), a potential anticancer agent, is described. The stereoselectivity was accomplished via two diastereoselective crystallizations, i.e. the crystallization of the key intermediate, difluororibonolactone 2a, and the crystallization of the hydrochloride salt of gemcitabine 16b from the anomeric mixture. Because of the availability of 2a in large quantities, other 2'-deoxy-2',2'-difluoropyrimidine nucleosides such as 2'-deoxy-2',2'-difluorouridine (19) were synthesized for structure-activity relationship studies.
