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
- Publication number
- 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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- CN
- China
- Prior art keywords
- cyt
- cytosine
- white solid
- fluoro
- deoxidation
- Prior art date
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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
-
- 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
Landscapes
- 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
Description
Claims (1)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410394643.9A CN104130301B (en) | 2014-08-13 | 2014-08-13 | The preparation method of a kind of gemcitabine hydrochloride intermediate |
CN201610142166.6A CN105693797A (en) | 2014-08-13 | 2014-08-13 | Preparation method of intermediate of anticancer drug gemcitabine |
CN201610142159.6A CN105693795A (en) | 2014-08-13 | 2014-08-13 | Preparation method of difluoro nucleoside anticancer drugs capable of destroying cell replication |
CN201610142160.9A CN105693796A (en) | 2014-08-13 | 2014-08-13 | Preparation method of anticancer drug capable of destroying cell replication |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410394643.9A CN104130301B (en) | 2014-08-13 | 2014-08-13 | The preparation method of a kind of gemcitabine hydrochloride intermediate |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610142166.6A Division CN105693797A (en) | 2014-08-13 | 2014-08-13 | Preparation method of intermediate of anticancer drug gemcitabine |
CN201610142160.9A Division CN105693796A (en) | 2014-08-13 | 2014-08-13 | Preparation method of anticancer drug capable of destroying cell replication |
CN201610142159.6A Division CN105693795A (en) | 2014-08-13 | 2014-08-13 | Preparation method of difluoro nucleoside anticancer drugs capable of destroying cell replication |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104130301A CN104130301A (en) | 2014-11-05 |
CN104130301B true CN104130301B (en) | 2016-06-01 |
Family
ID=51803192
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410394643.9A Active CN104130301B (en) | 2014-08-13 | 2014-08-13 | The preparation method of a kind of gemcitabine hydrochloride intermediate |
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 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
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 |
Country Status (1)
Country | Link |
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CN (3) | CN104130301B (en) |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006063105A1 (en) * | 2004-12-08 | 2006-06-15 | Sicor Inc. | 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 |
-
2014
- 2014-08-13 CN CN201410394643.9A patent/CN104130301B/en active Active
- 2014-08-13 CN CN201610142159.6A patent/CN105693795A/en not_active Withdrawn
- 2014-08-13 CN CN201610142166.6A patent/CN105693797A/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
CN105693797A (en) | 2016-06-22 |
CN104130301A (en) | 2014-11-05 |
CN105693795A (en) | 2016-06-22 |
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C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C41 | Transfer of patent application or patent right or utility model | ||
CB03 | Change of inventor or designer information |
Inventor after: Lun Junjie Inventor after: Sun Zongli Inventor before: Chen Xin |
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COR | Change of bibliographic data | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20160504 Address after: 262400 Changle County People's Hospital, 278 Limin street, Changle County, Shandong, Weifang Applicant after: Lun Junjie Address before: 34-1 modern escape city, Jiefang East Road, Lixia District, Ji'nan City, Shandong province 250014 Applicant before: Chen Xin |
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C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right |
Effective date of registration: 20170802 Address after: Ding Yan Zhen Ding new road in Rugao city of Jiangsu province Nantong City, No. 30, 226500 Patentee after: Rugao Tianji hospital Address before: 262400 Changle County People's Hospital, 278 Limin street, Changle County, Shandong, Weifang Patentee before: Lun Junjie |
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TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20191118 Address after: 314100 Building 9, Guantang Road, Huimin street, Jiashan County, Jiaxing City, Zhejiang Province Patentee after: Jiashan Zhengfeng Electronic Factory Address before: 226500 No. 30 Dingxin Middle Road, Dingyan Town, Rugao City, Nantong City, Jiangsu Province Patentee before: Rugao Tianji hospital |