CN104130301B - The preparation method of a kind of gemcitabine hydrochloride intermediate - Google Patents
The preparation method of a kind of gemcitabine hydrochloride intermediate Download PDFInfo
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- CN104130301B CN104130301B CN201410394643.9A CN201410394643A CN104130301B CN 104130301 B CN104130301 B CN 104130301B CN 201410394643 A CN201410394643 A CN 201410394643A CN 104130301 B CN104130301 B CN 104130301B
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- cytosine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 title abstract description 13
- 229960005144 gemcitabine hydrochloride Drugs 0.000 title abstract description 11
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims abstract description 125
- 229940104302 cytosine Drugs 0.000 claims abstract description 30
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 14
- 239000010703 silicon Substances 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000007787 solid Substances 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- 238000009413 insulation Methods 0.000 claims description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 6
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 238000005352 clarification Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000001514 detection method Methods 0.000 claims description 5
- 230000008034 disappearance Effects 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 abstract description 14
- 239000002904 solvent Substances 0.000 abstract description 6
- 238000003032 molecular docking Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 7
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 6
- 150000002340 glycosyl compounds Chemical class 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 239000004519 grease Substances 0.000 description 4
- 229920001296 polysiloxane Polymers 0.000 description 4
- MNESLHFFAVMPAT-UHFFFAOYSA-N trifluoromethanesulfonate;trimethylazanium Chemical compound C[NH+](C)C.[O-]S(=O)(=O)C(F)(F)F MNESLHFFAVMPAT-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000018199 S phase Effects 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011973 solid acid Substances 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical class N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- -1 fluoro cytidine Chemical compound 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000003930 superacid Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the preparation method of a kind of gemcitabine hydrochloride intermediate; taking cytosine(Cyt) be raw material and hexamethyldisilazane generate after silicon ether protecting group again with 2-deoxidation-2; the docking of the fluoro-D-of 2-bis-red formula-five furanose-3,5-benzhydryl ester-1-methylsulfonic acid ester obtains the finished product after hydrochloric acid aftertreatment. The method technique is simple, and operational condition is convenient, generates required isomer proportion height, and solvent is green, need not harsh reaction conditions, be applicable to suitability for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical field, it is specifically related to the preparation method of a kind of gemcitabine hydrochloride intermediate.
Background technology
Gemcitabine is a kind of two fluoro ucleosides anticarcinogens destroying cellular replication, acts primarily on the tumour cell that DNA synthesizes the phase, i.e. S phase cell, the progress of G1 phase to the S phase can be stoped under certain condition, its chemical name is 2 '-deoxidation-2 ', 2 '-two fluoro cytidine, chemical structural formula is as follows:
The synthetic method of the gemcitabine hydrochloride reported up to now has a lot; the synthetic route of great majority is through an important intermediate ��-1-(2 '-deoxidation-2 '; 2 '-two fluoro-3 '; 5 '-two-O-benzoyl-D-RIBOSE base)-4-aminopyrimidine-2-keto hydrochloride; structural formula such as formula (I) it through deprotection with become salt, taking the form of hydrochloride as the finished product.
Da Buer pharmaceuticals of India Chinese patent 200580049120.X discloses and under trimethylsilyl trifluoromethanesulfonate katalysis with sugar base docks the analogue that generate gemcitabine hydrochloride intermediate (I) as raw material and hexamethyldisilazane generate after cytosine(Cyt) protecting group to replace cytosine(Cyt). It is that raw material generates gemcitabine hydrochloride intermediate (I) this technique with docking with sugar base under trimethylsilyl trifluoromethanesulfonate katalysis after hexamethyldisilazane generation cytosine(Cyt) protecting group that Chinese patent 201210040408.2 also uses cytosine(Cyt); and the consumption of trifluoromethanesulfonic acid trimethylammonium silicone grease and cytosine(Cyt) equivalent are three times amount of glycosyl compound. And the by product trifluoromethanesulfonic acid generated after reacting is the acid that organic acid is the strongest, the sulfuric acid of acidity more than 100%, belongs to super acids. Not only operate and there is certain potential safety hazard, and equipment is existed serious corrodibility. Although Chinese patent 201110334019.6 employs amylene oxide ring to protect two hydroxyls on gemcitabine intermediate sugar base; but it is catalyzer that sugar base have employed tosic acid when docking reaction with cytosine(Cyt); tosic acid residual can cause generating tosylate with the reaction of alcohol reagent below; p-toluenesulfonic esters is genotoxicity impurity; DNA is had potential destructiveness, so technique is avoided using this type of material as far as possible.
Therefore find a kind of security height, that eco-friendly technique prepares gemcitabine hydrochloride formula (I) intermediate is significant.
Summary of the invention
It is desirable to provide security height, an eco-friendly technique prepare gemcitabine hydrochloride formula (I) intermediate.
The present invention is achieved through the following technical solutions:
The preparation method of a kind of formula (I) compound, comprises the following steps:
A) taking cytosine(Cyt) be raw material and hexamethyldisilazane under the katalysis of ammonium sulfate back flow reaction until solution molten clear after steam excessive hexamethyldisilazane and obtain cytosine(Cyt) protecting group, then add solvent be warming up to 70-80 DEG C the solution of cytosine(Cyt) silicon ether protecting group;
B) 2-deoxidation-2, the fluoro-D-of 2-bis-red formula-five furanose-3,5-benzhydryl ester-1-methylsulfonic acid ester be dissolved in solvent stir, then add catalyzer be heated to below solvent boiling point 10 DEG C to 5 DEG C 2-deoxidation-2, the fluoro-D-of 2-bis-red formula-five furanose-3,5-benzhydryl ester-1-methylsulfonic acid ester solution;
Also comprise the following steps c)
Silicon ether protecting group solution in a) is dripped into step b) 2-deoxidation-2; the fluoro-D-of 2-bis-red formula-five furanose-3; 5-benzhydryl ester-1-methylsulfonic acid ester solution; within 2-3 hour, dropwise; then continue to be down to 40-50 DEG C after insulation reaction 2-2.5 hour and take out filter through diatomite, drip in filtrate and precipitate out solid after adding hydrochloric acid and dry to obtain formula (I) compound.
Reaction equation is as follows:
Described step a), step b) solvent is primary isoamyl alcohol or Pentyl alcohol.
The preparation method of described formula (I) compound, step b) described in catalyzer be phospho-wolframic acid or phospho-molybdic acid.
The preparation method of described formula (I) compound; the silicon ether protecting group solution of step a) drips into step b) 2-deoxidation-2; the dripping to add of the fluoro-D-of 2-bis-red formula-five furanose-3,5-benzhydryl ester-1-methylsulfonic acid ester solution keeps step b) solution temperature below boiling point to boiling point 5 DEG C in process.
Adopting phospho-wolframic acid or phospho-molybdic acid to substitute the big trifluoromethanesulfonic acid trimethylammonium silicone grease of toxicity or tosic acid in the present invention, avoid the generation of trifluoromethanesulfonic acid, environment is more friendly; And the liquid trifluoromethanesulfonic acid trimethylammonium silicone grease of solid acid (phospho-wolframic acid or phospho-molybdic acid) replacement avoids the situation that generation smog occurs to decompose in operation owing to liquid acids meets moisture in air, convenient in reinforced process.
Adopt primary isoamyl alcohol or the Pentyl alcohol of low poison; make technique green safety more; cytosine(Cyt) docks with glycosyl compound and belongs to SN2 reaction, and test proves to drip the selection adding and being conducive to intermediate (I) configuration in cytosine(Cyt) protecting group solution to glycosyl compound solution under the high temperature conditions.
Preparation technology's tool of the present invention has the following advantages:
1. adopting solid acid phospho-wolframic acid or phospho-molybdic acid replacement trifluoromethanesulfonic acid trimethylammonium silicone grease or tosic acid to make more convenient to operate, technique is safe green more; And avoid sulphonate class or salt by-product generation.
2. adopt low poison solvent primary isoamyl alcohol or Pentyl alcohol, make technique more meet green chemical concept.
3. adopt lower of hot conditions to add the selection that ensure that intermediate (I) formula configuration in cytosine(Cyt) protecting group solution to glycosyl compound solution.
In the present invention, glycosyl compound refers to the fluoro-D-of 2-deoxidation-2,2-two red formula-five furanose-3,5-benzhydryl ester-1-methylsulfonic acid ester.
Embodiment
For making the object, technical solutions and advantages of the present invention clearly understand, below in conjunction with embodiment, the present invention is described in more detail. It is to be understood that these describe just exemplary, and do not really want to limit the scope of the invention. In addition, in the following description, the description to known technology is eliminated, to avoid the concept unnecessarily obscuring the present invention.
In following examples, the fluoro-D-of raw materials used 2-deoxidation-2,2-two red formula-five furanose-3,5-benzhydryl ester-1-methylsulfonic acid ester percentage composition is more than 95%.
Embodiment 1
By cytosine(Cyt) (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), 0.10g ammonium sulfate be placed in 500mL there-necked flask and stir, after reflux to cytosine(Cyt) dissolves clarification completely, continue after insulation reaction 0.5-1h to releasing without ammonia. Then it is cooled to 100 DEG C of concentrating under reduced pressure to go out to remain hexamethyldisilazane and obtain cytosine(Cyt) silicon ether protecting group white solid. Add in 500mL reaction flask 100mL primary isoamyl alcohol stir, be heated to 70-80 DEG C make white solid dissolve after be transferred to insulation dropping funnel in.
2-deoxidation-2 is added in 1L there-necked flask, the fluoro-D-of 2-bis-red formula-five furanose-3, 5-benzhydryl ester-1-methylsulfonic acid ester (45g, 0.1mol), 0.5g phospho-wolframic acid, 100mL primary isoamyl alcohol is heated with stirring to 128-132 DEG C, then drip and add cytosine(Cyt) silicon ether protecting group, 2.5h is warming up to backflow insulation reaction 2h after dropwising, 2-deoxidation-2 is treated in TLC detection, the fluoro-D-of 2-bis-red formula-five furanose-3, stopped reaction after the disappearance of 5-benzhydryl ester-1-methylsulfonic acid ester raw material point, it is cooled to 40-50 DEG C and takes out filter through diatomite, drip in filtrate and add hydrochloric acid soln (200mL, 6M) stirring and crystallizing 2h, produce a large amount of white solid, filter after filter cake is dried and obtain 45.6g white solid, receipts rate 90%.
Embodiment 2
By cytosine(Cyt) (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), 0.10g ammonium sulfate be placed in 500mL there-necked flask and stir, after reflux to cytosine(Cyt) dissolves clarification completely, continue after insulation reaction 0.5-1h to releasing without ammonia. It is cooled to 100 DEG C of concentrating under reduced pressure to go out to remain hexamethyldisilazane and obtain cytosine(Cyt) silicon ether protecting group white solid. Add in 500mL reaction flask 100mL primary isoamyl alcohol stir, be heated to 70-80 DEG C make white solid dissolve after be transferred to insulation dropping funnel in.
2-deoxidation-2 is added in 1L there-necked flask, the fluoro-D-of 2-bis-red formula-five furanose-3, 5-benzhydryl ester-1-methylsulfonic acid ester (45g, 0.1mol), 0.8g phospho-molybdic acid, 100mL primary isoamyl alcohol is heated with stirring to 128-132 DEG C, then drip and add cytosine(Cyt) silicon ether protecting group, 3h is warming up to backflow insulation reaction 2h after dropwising, 2-deoxidation-2 is treated in TLC detection, the fluoro-D-of 2-bis-red formula-five furanose-3, stopped reaction after the disappearance of 5-benzhydryl ester-1-methylsulfonic acid ester raw material point, it is cooled to 40-50 DEG C and takes out filter through diatomite, drip in filtrate and add hydrochloric acid soln (200mL, 6M) stirring and crystallizing 2.5h, produce a large amount of white solid, filter after filter cake is dried and obtain 47.0g white solid, receipts rate 93%.
Embodiment 3
By cytosine(Cyt) (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), 0.10g ammonium sulfate be placed in 500mL there-necked flask and stir, after reflux to cytosine(Cyt) dissolves clarification completely, continue after insulation reaction 0.5-1h to releasing without ammonia. Then it is cooled to 100 DEG C of concentrating under reduced pressure to go out to remain hexamethyldisilazane and obtain cytosine(Cyt) silicon ether protecting group white solid. Add in 500mL reaction flask 100mL Pentyl alcohol stir, be heated to 70-80 DEG C make white solid dissolve after be transferred to insulation dropping funnel in.
2-deoxidation-2 is added in 1L there-necked flask, the fluoro-D-of 2-bis-red formula-five furanose-3, 5-benzhydryl ester-1-methylsulfonic acid ester (45g, 0.1mol), 1.0g phospho-molybdic acid, 100mL Pentyl alcohol is heated with stirring to 128-137 DEG C, then drip and add cytosine(Cyt) silicon ether protecting group, 2h is warming up to backflow insulation reaction 3h after dropwising, 2-deoxidation-2 is treated in TLC detection, the fluoro-D-of 2-bis-red formula-five furanose-3, stopped reaction after the disappearance of 5-benzhydryl ester-1-methylsulfonic acid ester raw material point, it is cooled to 40-50 DEG C and takes out filter through diatomite, drip in filtrate and add hydrochloric acid soln (200mL, 6M) stirring and crystallizing 2.5h, produce a large amount of white solid, filter after filter cake is dried and obtain 48.2g white solid, receipts rate 95%.
Embodiment 4
By cytosine(Cyt) (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), 0.10g ammonium sulfate be placed in 500mL there-necked flask and stir, after reflux to cytosine(Cyt) dissolves clarification completely, continue after insulation reaction 0.5-1h to releasing without ammonia. Then it is cooled to 100 DEG C of concentrating under reduced pressure to go out to remain hexamethyldisilazane and obtain cytosine(Cyt) silicon ether protecting group white solid. Add in 500mL reaction flask 100mL amylalcohol stir, be heated to 70-80 DEG C make white solid dissolve after be transferred to insulation dropping funnel in.
2-deoxidation-2 is added in 1L there-necked flask, the fluoro-D-of 2-bis-red formula-five furanose-3, 5-benzhydryl ester-1-methylsulfonic acid ester (45g, 0.1mol), 1.2g phospho-wolframic acid, 100mL amylalcohol is heated with stirring to 132-137 DEG C, then drip and add cytosine(Cyt) silicon ether protecting group, 3h is warming up to backflow insulation reaction 2.5h after dropwising, 2-deoxidation-2 is treated in TLC detection, the fluoro-D-of 2-bis-red formula-five furanose-3, stopped reaction after the disappearance of 5-benzhydryl ester-1-methylsulfonic acid ester raw material point, it is cooled to 40-50 DEG C and takes out filter through diatomite, drip in filtrate and add hydrochloric acid soln (200mL, 6M) stirring and crystallizing 2.5h, produce a large amount of white solid, filter after filter cake is dried and obtain 47.5g white solid, receipts rate 94%.
With reference to European Pharmacopoeia 8.0 2230-2231 page gemcitabine hydrochloride product inspection method, adopt HPLC to detect sample in embodiment 1-4 and detect. The results are shown in following table:
Remarks: above data adopt area percentage method to calculate gained, and maximum list is mixed as cytosine(Cyt).
HPLC result statistics shows, adopts technique of the present invention to prepare gemcitabine hydrochloride intermediate purity higher, reaches more than 99%, and maximum list is mixed cytosine(Cyt) less than 0.15%, can remove after in the later stage, deprotection becomes salt.
Although having described embodiments of the present invention in detail, it should be appreciated that, when without departing from the spirit and scope of the present invention, it is possible to embodiments of the present invention are made various change, replacement and change.
Claims (1)
1. a preparation method for formula (I) compound,, it is characterized in that, step is as follows:
(1) 22.2g cytosine(Cyt), 84mL hexamethyldisilazane, 0.10g ammonium sulfate are placed in 500mL there-necked flask and stir, after reflux to cytosine(Cyt) dissolves clarification completely, to releasing without ammonia after continuing insulation reaction 0.5-1h; Then it is cooled to 100 DEG C of concentrating under reduced pressure to go out to remain hexamethyldisilazane, obtains cytosine(Cyt) silicon ether protecting group white solid; Add in 500mL reaction flask 100mL primary isoamyl alcohol stir, be heated to 70-80 DEG C make white solid dissolve after be transferred to insulation dropping funnel in;
(2) in 1L there-necked flask, 45g2-deoxidation-2 is added, the fluoro-D-of 2-bis-red formula-five furanose-3, 5-benzhydryl ester-1-methylsulfonic acid ester, 0.5g phospho-wolframic acid, 100mL primary isoamyl alcohol is heated with stirring to 128-132 DEG C, then drip and add cytosine(Cyt) silicon ether protecting group, 2.5h is warming up to backflow insulation reaction 2h after dropwising, 2-deoxidation-2 is treated in TLC detection, the fluoro-D-of 2-bis-red formula-five furanose-3, stopped reaction after the disappearance of 5-benzhydryl ester-1-methylsulfonic acid ester raw material point, it is cooled to 40-50 DEG C and takes out filter through diatomite, drip in filtrate and add 200mL, the hydrochloric acid soln stirring and crystallizing 2h of 6M, produce a large amount of white solid, filter after filter cake is dried and obtain 45.6g white solid, receipts rate 90%.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610142159.6A CN105693795A (en) | 2014-08-13 | 2014-08-13 | Preparation method of difluoro nucleoside anticancer drugs capable of destroying cell replication |
| CN201610142166.6A CN105693797A (en) | 2014-08-13 | 2014-08-13 | Preparation method of intermediate of anticancer drug gemcitabine |
| CN201410394643.9A CN104130301B (en) | 2014-08-13 | 2014-08-13 | The preparation method of a kind of gemcitabine hydrochloride intermediate |
| CN201610142160.9A CN105693796A (en) | 2014-08-13 | 2014-08-13 | Preparation method of anticancer drug capable of destroying cell replication |
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| CN201410394643.9A CN104130301B (en) | 2014-08-13 | 2014-08-13 | The preparation method of a kind of gemcitabine hydrochloride intermediate |
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| CN201610142166.6A Division CN105693797A (en) | 2014-08-13 | 2014-08-13 | Preparation method of intermediate of anticancer drug gemcitabine |
| CN201610142159.6A Division CN105693795A (en) | 2014-08-13 | 2014-08-13 | Preparation method of difluoro nucleoside anticancer drugs capable of destroying cell replication |
| CN201610142160.9A Division CN105693796A (en) | 2014-08-13 | 2014-08-13 | Preparation method of anticancer drug capable of destroying cell replication |
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| CN104130301A CN104130301A (en) | 2014-11-05 |
| CN104130301B true CN104130301B (en) | 2016-06-01 |
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| CN201610142166.6A Withdrawn CN105693797A (en) | 2014-08-13 | 2014-08-13 | Preparation method of intermediate of anticancer drug gemcitabine |
| CN201410394643.9A Active CN104130301B (en) | 2014-08-13 | 2014-08-13 | The preparation method of a kind of gemcitabine hydrochloride intermediate |
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| CN201610142159.6A Withdrawn CN105693795A (en) | 2014-08-13 | 2014-08-13 | Preparation method of difluoro nucleoside anticancer drugs capable of destroying cell replication |
| CN201610142166.6A Withdrawn CN105693797A (en) | 2014-08-13 | 2014-08-13 | Preparation method of intermediate of anticancer drug gemcitabine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101076535A (en) * | 2004-12-08 | 2007-11-21 | 西科尔公司 | Difluoronucleosides and process for preparation thereof |
| US8168766B2 (en) * | 2008-08-29 | 2012-05-01 | ScnioPharm Taiwan Ltd. | Process of making 2-deoxy-2,2-difluoro-D-ribofuranosyl nucleosides and intermediates therefor |
| CN101628927B (en) * | 2009-08-07 | 2012-10-10 | 卡硼瑞（北京）科技有限公司 | Method for three-dimensionally selectively preparing Beta-gemcitabine hydrochloride by using 1, 3, 5-3-O-benzoyl-Alpha-D-ribofuranose as raw materials |
| CN101717420B (en) * | 2009-11-12 | 2011-03-30 | 浙江先锋化工科技有限公司 | Novel method for synthesizing uridine |
| CN102093451A (en) * | 2009-12-12 | 2011-06-15 | 上海华理生物医药有限公司 | Method for preparing gemcitabine intermediate |
| CN102050857B (en) * | 2010-12-08 | 2012-05-02 | 浙江先锋科技有限公司 | Method for synthesizing 5-methyluridine |
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| CN105693795A (en) | 2016-06-22 |
| CN105693797A (en) | 2016-06-22 |
| CN104130301A (en) | 2014-11-05 |
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