CN102093451A - Method for preparing gemcitabine intermediate - Google Patents
Method for preparing gemcitabine intermediate Download PDFInfo
- Publication number
- CN102093451A CN102093451A CN2009102010365A CN200910201036A CN102093451A CN 102093451 A CN102093451 A CN 102093451A CN 2009102010365 A CN2009102010365 A CN 2009102010365A CN 200910201036 A CN200910201036 A CN 200910201036A CN 102093451 A CN102093451 A CN 102093451A
- Authority
- CN
- China
- Prior art keywords
- compound
- benzoyl
- alkali metal
- sodium
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing an anti-tumor medicament, namely a gemcitabine intermediate 4-amino-1-(2'-deoxygenation-2',2'-difluoro-3,5-bi-O-benzoyl-D-ribofuranose-2-group)-1H-pyrimidine-2-ketone. In the method, 2-deoxygenation-2,2-difluoro-D-ribofuranose-3,5-bi-O-benzoyl-mesylate and trimethyl silicon-protected cytosine which serve as raw materials are reacted with each other in ether, halogenated hydrocarbon and nitrile organic solvents under the action of alkali metal halides to obtain a product, namely the 4-amino-1-(2'-deoxygenation-2',2'-difluoro-3,5-bi-O-benzoyl-D-ribofuranose-2-group)-1H-pyrimidine-2-ketone.
Description
Technical field
The present invention relates to a kind of intermediates preparation of cancer therapy drug gemcitabine.
Background technology
Gemcitabine hydrochloride is a kind of Difluoronucleosides class antimetabolic antitumour drug, and human leukocytes, some mouse solid knurl and the xenotransplantation of people's tumour are had good inhibitory effect.As a kind of Difluoronucleosides class metabolic antagonist anticarcinogen that destroys cellular replication, gemcitabine is the water-soluble analogues of cytosine deoxyriboside, to ribonucleotide reductase is a kind of surrogate of substrate material of inhibition, this kind of enzyme is at DNA in the synthetic and repair process, is vital to the generation of needed deoxynucleotide.Clinically, gemcitabine is particularly useful for treating inoperable late period or transitivity carcinoma of the pancreas and treats local progressivity or the transitivity nonsmall-cell lung cancer
[1]
Gemcitabine hydrochloride, chemistry is by name: 4-amino-1-(2 '-deoxidation-2 ', 2 '-two fluoro-3,5-two-O-benzoyl-D-ribofuranose-2-yl)-1H-pyrimid-2-one hydrochloride, its structural formula is as follows:
In the process of preparation gemcitabine hydrochloride, the formation of nucleosides is that glycosylation is the committed step in the building-up process.1 end group condensation of the corresponding furyl glycosyl derivative of nucleoside base attack forms C-N key nucleosides.The gained nucleosides is again through deprotection, and salify separates, and then obtains gemcitabine hydrochloride.
U.S. Pat 5426183 reports; with 2-deoxidation-2; 2-two fluoro-D-ribose furans-3; 5-two-O-benzoyl-methanesulfonates is a raw material; salt with potassium, barium, caesium and the trialkyl quaternary amine of trifluoromethanesulfonic acid, sulfuric acid, perchloric acid, nitric acid and trifluoroacetic acid is made catalyzer; the protected gemcitabine nucleosides of synthesis of hydroxy; preferred trifluoromethanesulfonic acid sylvite in the document; in acetonitrile, propionitrile, methyl-phenoxide, dioxane, ethylene glycol diethyl ether or its mixed solvent, under 50~100 ℃ of conditions, react; obtaining product, but this type of catalyzer is relatively more expensive.
International monopoly WO2006063105 discloses with Lewis acid and has done the Preparation of Catalyst gemcitabine, and the characteristics of glycosylation are with SnCl in the building-up process
4Or the TMS triflate is catalyzer, and with doubly above (mole) silica-based protection cytosine(Cyt) of 3-20 and 2-deoxidation-2,2-two fluoro-D-ribose furans-3,5-two-O-benzoyl-methanesulfonates react and obtain the gemcitabine that benzoyl is protected.
Summary of the invention
The invention provides a kind of reaction conditions gentleness, synthesizing gemcitabine intermediate 4-amino-1-(2 '-deoxidation-2 ' low in the pollution of the environment, with low cost, 2 '-two fluoro-3,5-two-O-benzoyl-D-ribofuranose-2-yl)-and the method for 1H-pyrimid-2-one (I), may further comprise the steps:
Compound 2-deoxidation-2,2-two fluoro-D-ribose furans-3, the cytosine(Cyt) (III) of 5-two-O-benzoyl-methanesulfonates (II) and protection are in organic solvent, and by alkali metal halide catalysis, reaction at a certain temperature obtains target compound I.
Wherein, Compound I I is a kind of difluoro carbohydrate derivative, is a kind of of alpha-anomer compound and beta-anomer-compound or their mixture.
Described L is selected from aryl-sulfonyl oxygen, the C of aryl-sulfonyl oxygen, replacement
1-C
4The alkane sulfonyloxy, the alkylsulfonyloxy of replacement is preferably benzene mesyloxy, tolysulfonyl oxygen base, p-nitrophenyl sulfonyloxy, mesyloxy, ethanesulfonyloxy group.
Described R
1, R
2Independently be selected from the aryl formyl radical of replacement respectively, be preferably p-nitrophenyl formyl radical, halogeno-benzene formyl radical, dibenzoyl base or benzoyl.
Wherein, the R of described compound III
3Be selected from C
1-C
7Three alkane silica-based, can be sec.-propyl dimethylsilyl, tertiary butyl dimethylsilyl, TMS, methyl di-isopropyl silylation, tri isopropyl silane base etc.
Wherein, described organic solvent is selected from nitrile, halogenated hydrocarbon, arene, inert solvents such as ethers are preferably acetonitrile, methylene dichloride, 1, one or more of 2-ethylene dichloride, toluene, dimethylbenzene, substituted benzene, methyl-phenoxide, phenyl ether or substituted diphenylamine ether etc.
Wherein, described alkali metal halide is selected from Potassium monofluoride, Sodium Fluoride, sodium-chlor, Repone K, lithium chloride, lithiumbromide, lithium iodide, potassiumiodide, sodium iodide, Sodium Bromide, Potassium Bromide etc.
Wherein, the mol ratio of Compound I I and compound III is 1: 1~1: 30, is preferably 1: 1.5~1: 15;
Wherein, the mol ratio of alkali metal halide and Compound I I is 1: 1~1: 14, is preferably 1: 1~1: 7;
Described temperature of reaction is 50~200 ℃, is preferably 70~100 ℃; Described reaction is generally 5~48h with the TLC endpoint detection, is preferably 10~30h.
The compound III that the present invention relates to is feedstock production by methods known in the art by cytosine(Cyt).
Method of the present invention has been abandoned expensive catalysts, has reduced cost; The reaction conditions gentleness, aftertreatment is simple; What use all is that gentle reagent is convenient to reclaim, and whole process environments close friend is easy and simple to handle, can obtain to higher yields purity and reach product more than 99%, and be the method for suitable suitability for industrialized production.
Embodiment
The preparation of embodiment 1 compound III
Under the nitrogen protection, in 10g cytosine(Cyt) adding 50ml hexamethyldisilazane, and add the 0.01g monoammonium sulfate, temperature rising reflux reaction 4 hours, cooling concentrates, and gets the white solid compound III.
The preparation of embodiment 2 Compound I
N
2Protection; in compound III, add 100ml 1; the 2-ethylene dichloride dissolves it fully, adds NaBr2.6g; Dropwise 5 .7g 2-deoxidation-2; 2-two fluoro-D-ribose furans-3,1 of 5-two-O-benzoyl-methanesulfonates (α: β=2.4: 1), 2-ethylene dichloride (20ml) solution; dripping complete temperature rising reflux reacts to raw material disappearance, TLC detection reaction terminal point.Be cooled to room temperature, drip frozen water 500ml, dropwise the back and continue to stir 30 minutes, suction filtration, filter cake are with 1, and the 2-ethylene dichloride washs.Organic phase concentrates evaporate to dryness and gets target compound 5.6g, yield 92.4%, HPLC purity 97.3% (α: β=1: 1.9).
The preparation of embodiment 3 Compound I
N
2Protection; in by the compound III of embodiment 1 gained, add the 100ml methylene dichloride; it is dissolved fully; add KBr 4.5g; Dropwise 5 .7g 2-deoxidation-2,2-two fluoro-D-ribose furans-3, methylene dichloride (20ml) solution of 5-two-O-benzoyl-methanesulfonates compound (Compound I I) (α: β=3: 1); drip complete temperature rising reflux to raw material and disappear TLC detection reaction terminal point.Be cooled to room temperature, drip frozen water 500ml, dropwise the back and continue to stir suction filtration, filter cake washed with dichloromethane 30 minutes.Organic phase is dense do target compound 5.7g, yield 93.2%, HPLC purity 96.6% (α: β=1: 2.3).
The preparation of embodiment 4 Compound I
N
2Protection adds the 80ml acetonitrile in by the compound III of embodiment 1 gained, it is dissolved fully; add NaI 3.8g, Dropwise 5 .7g 2-deoxidation-2,2-two fluoro-D-ribose furans-3; acetonitrile (20ml) solution of 5-two-O-benzoyl-methanesulfonates compound (Compound I I) (α: β=3: 1); drip complete temperature rising reflux and react to the raw material disappearance, TLC detection reaction terminal point is cooled to room temperature; drip frozen water 500ml; dropwising the back continues to stir the acetonitrile drip washing of suction filtration, filter cake 30 minutes.Organic phase is dense do target compound 5.7g, yield 93.6%, HPLC purity 96.9% (α: β=1: 2.3).
Claims (10)
1. method for preparing the gemcitabine intermediate may further comprise the steps:
Compound 2-deoxidation-2; 2-two fluoro-D-ribose furans-3; the cytosine(Cyt) (III) of 5-two-O-benzoyl-methanesulfonates (II) and protection is in organic solvent; by alkali metal halide catalysis; reaction at a certain temperature obtains target compound 4-amino-1-(2 '-deoxidation-2 '; 2 '-two fluoro-3,5-two-O-benzoyl-D-ribofuranose-2-yl)-1H-pyrimid-2-one (I)
2. according to claim 1, substituting group L is selected from aryl-sulfonyl oxygen, the C of aryl-sulfonyl oxygen, replacement
1-C
4The alkane sulfonyloxy, the alkylsulfonyloxy of replacement is preferably benzene mesyloxy, tolysulfonyl oxygen base, p-nitrophenyl sulfonyloxy, mesyloxy, ethanesulfonyloxy group.
3. substituent R according to claim 1,
1, R
2Independently be selected from the aryl formyl radical of replacement respectively, be preferably p-nitrophenyl formyl radical, halogeno-benzene formyl radical, dibenzoyl base or benzoyl.
4. substituent R according to claim 1,
3Be selected from C
1-C
7Three alkane silica-based, as sec.-propyl dimethylsilyl, tertiary butyl dimethylsilyl, TMS, methyl di-isopropyl silylation, tri isopropyl silane base etc.
5. according to claim 1, organic solvent is selected from inert solvents such as nitrile, halogenated hydrocarbon, arene, ethers, be preferably acetonitrile, 1, one or more in 2-methylene dichloride, toluene, dimethylbenzene, substituted benzene, methyl-phenoxide, phenyl ether or the substituted diphenylamine ether.
6. according to claim 1, alkali metal halide is selected from Potassium monofluoride, Sodium Fluoride, sodium-chlor, Repone K, lithium chloride, lithiumbromide, lithium iodide, potassiumiodide, sodium iodide, Sodium Bromide, Potassium Bromide etc.
7. according to claim 1, the mol ratio of Compound I I and compound III is 1: 1~1: 30, is preferably 1: 1.5~1: 15.
8. according to claim 1, the mol ratio of alkali metal halide and Compound I I is 1: 1~1: 14, is preferably 1: 1~1: 7.
9. according to claim 1, temperature of reaction is 50~200 ℃, is preferably 70~100 ℃.
10. according to claim 1, the reaction times is 5~48h, is preferably 10~30h.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2009102010365A CN102093451A (en) | 2009-12-12 | 2009-12-12 | Method for preparing gemcitabine intermediate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2009102010365A CN102093451A (en) | 2009-12-12 | 2009-12-12 | Method for preparing gemcitabine intermediate |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102093451A true CN102093451A (en) | 2011-06-15 |
Family
ID=44126738
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2009102010365A Pending CN102093451A (en) | 2009-12-12 | 2009-12-12 | Method for preparing gemcitabine intermediate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102093451A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104130301A (en) * | 2014-08-13 | 2014-11-05 | 陈欣 | Preparation method of gemcitabine hydrochloride intermediate |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4965374A (en) * | 1987-08-28 | 1990-10-23 | Eli Lilly And Company | Process for and intermediates of 2',2'-difluoronucleosides |
CN1085560A (en) * | 1992-06-22 | 1994-04-20 | 伊莱利利公司 | Stereoselective glycosylation process |
WO2006092808A1 (en) * | 2005-03-04 | 2006-09-08 | Dabur Pharma Limited | Intermediate and process for preparing of beta- anomer enriched 21deoxy, 21 ,21-difluoro-d-ribofuranosyl nucleosides |
-
2009
- 2009-12-12 CN CN2009102010365A patent/CN102093451A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4965374A (en) * | 1987-08-28 | 1990-10-23 | Eli Lilly And Company | Process for and intermediates of 2',2'-difluoronucleosides |
CN1085560A (en) * | 1992-06-22 | 1994-04-20 | 伊莱利利公司 | Stereoselective glycosylation process |
WO2006092808A1 (en) * | 2005-03-04 | 2006-09-08 | Dabur Pharma Limited | Intermediate and process for preparing of beta- anomer enriched 21deoxy, 21 ,21-difluoro-d-ribofuranosyl nucleosides |
Non-Patent Citations (2)
Title |
---|
姚其正: "《核苷化学合成》", 30 June 2005, 化学工业出版社 * |
王英华,等: "盐酸吉西他滨的合成", 《中国医药工业杂志》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104130301A (en) * | 2014-08-13 | 2014-11-05 | 陈欣 | Preparation method of gemcitabine hydrochloride intermediate |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2703560C (en) | Method of producing 2-deoxy-5-azacytidine (decitabine) | |
US7038038B2 (en) | Synthesis of 5-azacytidine | |
CA2701856C (en) | Method of producing nucleosides | |
NO179675B (en) | Pyrimidine nucleoside derivatives and pharmaceutical compositions containing them | |
KR102226164B1 (en) | Method for preparing nucleoside phosphoramidate prodrug and intermediate thereof | |
EP2933250B1 (en) | Phenyl c-glucoside derivative containing deoxyglucose structure, preparation method and use thereof | |
CN1086519A (en) | Stereoselective anion glycosylation process | |
EA011558B1 (en) | Intermediate compound and process for preparing of beta-anomer enriched 2-deoxy-2,2-difluoro-d-ribofuranosyl nucleosides | |
US11414451B2 (en) | Floxuridine synthesis | |
CA2577449C (en) | Method for the preparation of 2'-deoxy-2',2'-difluorocytidine | |
CN102093451A (en) | Method for preparing gemcitabine intermediate | |
CN102127136A (en) | Method for preparing important intermediate of cytidine and analogues thereof | |
CN104387426A (en) | Method for regioselective synthesis of 6-O-acryloylsaccharide derivatives | |
CN101987858B (en) | New method for preparing decitabine beta-configuration intermediate | |
US3642771A (en) | 5-benzyl - (2'-desoxyribosyl) uracil compounds compositions containing same and process of making and using same | |
CN106317147B (en) | nucleoside compound and preparation method thereof | |
CN113880901B (en) | Synthesis method of (1 beta, 2 alpha, 4 beta) halogenated nucleoside compound | |
KR101241321B1 (en) | Improved preparation method of Decitabine | |
JP2009256335A (en) | Preparation method of ribonucleic acid having alkyl protective group at position 2' | |
CN102424697B (en) | 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound and preparation method thereof | |
CN110143889B (en) | Synthetic method of 3- [ (dimethylamino) methyl ] -5-methyl-2-hexanone | |
WO2016097989A1 (en) | Process for the preparation of gemcitabine hydrochloride | |
CN117343119A (en) | Preparation method of alkylated nucleoside, nucleotide, oligonucleotide and analogues thereof | |
WO2011090052A1 (en) | Phosphorylation reagent | |
NZ736697A (en) | Synthesis of polycyclic-carbamoylpyridone compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110615 |