CN1765895A - Nolatrexed hydrochloride synthesis process - Google Patents
Nolatrexed hydrochloride synthesis process Download PDFInfo
- Publication number
- CN1765895A CN1765895A CN 200510084232 CN200510084232A CN1765895A CN 1765895 A CN1765895 A CN 1765895A CN 200510084232 CN200510084232 CN 200510084232 CN 200510084232 A CN200510084232 A CN 200510084232A CN 1765895 A CN1765895 A CN 1765895A
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- Prior art keywords
- methyl
- bromo
- bromine
- dihydro
- compound
- 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.)
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 10
- XHWRWCSCBDLOLM-UHFFFAOYSA-N nolatrexed Chemical compound CC1=CC=C2NC(N)=NC(=O)C2=C1SC1=CC=NC=C1 XHWRWCSCBDLOLM-UHFFFAOYSA-N 0.000 title description 9
- 229950000891 nolatrexed Drugs 0.000 title description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 239000001117 sulphuric acid Substances 0.000 claims abstract description 5
- 235000011149 sulphuric acid Nutrition 0.000 claims abstract description 5
- FHTDDANQIMVWKZ-UHFFFAOYSA-N 1h-pyridine-4-thione Chemical compound SC1=CC=NC=C1 FHTDDANQIMVWKZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- 238000010992 reflux Methods 0.000 claims abstract description 3
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- PJKVJJYMWOCLIJ-UHFFFAOYSA-N 2-amino-6-methyl-5-pyridin-4-ylsulfanyl-1h-quinazolin-4-one;hydron;dichloride Chemical compound Cl.Cl.CC1=CC=C2NC(N)=NC(=O)C2=C1SC1=CC=NC=C1 PJKVJJYMWOCLIJ-UHFFFAOYSA-N 0.000 claims description 9
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims description 6
- VAJCSPZKMVQIAP-UHFFFAOYSA-N 5-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1 VAJCSPZKMVQIAP-UHFFFAOYSA-N 0.000 claims description 5
- -1 added highly basic Chemical compound 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 150000001879 copper Chemical class 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000006237 Beckmann rearrangement reaction Methods 0.000 claims 1
- DKAVQCARZCYRIS-UHFFFAOYSA-N 4-bromo-5-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1Br DKAVQCARZCYRIS-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003472 neutralizing effect Effects 0.000 abstract 2
- DESUDZIADGQZIJ-UHFFFAOYSA-N 6-amino-2-bromo-3-methylbenzoic acid Chemical compound CC1=CC=C(N)C(C(O)=O)=C1Br DESUDZIADGQZIJ-UHFFFAOYSA-N 0.000 abstract 1
- 239000012670 alkaline solution Substances 0.000 abstract 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 abstract 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- 102000005497 Thymidylate Synthase Human genes 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- RYTLGWCJESCDMY-UHFFFAOYSA-N carbamimidoyl chloride Chemical compound NC(Cl)=N RYTLGWCJESCDMY-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Images
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- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2005100842320A CN1303080C (en) | 2005-07-18 | 2005-07-18 | Nolatrexed hydrochloride synthesis process |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2005100842320A CN1303080C (en) | 2005-07-18 | 2005-07-18 | Nolatrexed hydrochloride synthesis process |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1765895A true CN1765895A (en) | 2006-05-03 |
CN1303080C CN1303080C (en) | 2007-03-07 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2005100842320A Expired - Fee Related CN1303080C (en) | 2005-07-18 | 2005-07-18 | Nolatrexed hydrochloride synthesis process |
Country Status (1)
Country | Link |
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CN (1) | CN1303080C (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104140416A (en) * | 2013-05-10 | 2014-11-12 | 北京康辰药业有限公司 | Crystal form of nolatrexed hydrochloride, and preparation method and application thereof |
CN104177335A (en) * | 2013-05-27 | 2014-12-03 | 北京康辰药业有限公司 | Nolatrexed dihydrochloride crystal form III and preparation method and application thereof |
CN104177334A (en) * | 2013-05-27 | 2014-12-03 | 北京康辰药业有限公司 | Nolatrexed dihydrochloride crystal form II and preparation method and application thereof |
CN105092752B (en) * | 2014-05-20 | 2017-03-01 | 北京康辰药业股份有限公司 | A kind of with liquid chromatography separation nolatrexed dihydrochloride and the method about material |
CN109380304A (en) * | 2018-11-28 | 2019-02-26 | 吉林大学 | A kind of oxide-based nanomaterial of anti-plant decay disease, preparation method and applications |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5430148A (en) * | 1992-03-31 | 1995-07-04 | Agouron Pharmaceuticals, Inc. | Antiproliferative quinazolines |
US5340148A (en) * | 1993-11-03 | 1994-08-23 | Trw Vehicle Safety Systems Inc. | Air bag inflator with composite stored gas container |
CN1335307A (en) * | 2000-07-20 | 2002-02-13 | 中国人民解放军第一军医大学 | Synthesis process of 2-amino quinbolone compounds |
-
2005
- 2005-07-18 CN CNB2005100842320A patent/CN1303080C/en not_active Expired - Fee Related
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104140416A (en) * | 2013-05-10 | 2014-11-12 | 北京康辰药业有限公司 | Crystal form of nolatrexed hydrochloride, and preparation method and application thereof |
CN104140416B (en) * | 2013-05-10 | 2016-08-10 | 北京康辰药业股份有限公司 | A kind of nolatrexed dihydrochloride crystal formation and preparation method and application |
CN104177335A (en) * | 2013-05-27 | 2014-12-03 | 北京康辰药业有限公司 | Nolatrexed dihydrochloride crystal form III and preparation method and application thereof |
CN104177334A (en) * | 2013-05-27 | 2014-12-03 | 北京康辰药业有限公司 | Nolatrexed dihydrochloride crystal form II and preparation method and application thereof |
CN106831715A (en) * | 2013-05-27 | 2017-06-13 | 北京康辰药业股份有限公司 | A kind of nolatrexed dihydrochloride crystal formation II and preparation method and application |
CN106892899A (en) * | 2013-05-27 | 2017-06-27 | 北京康辰药业股份有限公司 | A kind of nolatrexed dihydrochloride crystal formation III and preparation method and application |
CN105092752B (en) * | 2014-05-20 | 2017-03-01 | 北京康辰药业股份有限公司 | A kind of with liquid chromatography separation nolatrexed dihydrochloride and the method about material |
CN109380304A (en) * | 2018-11-28 | 2019-02-26 | 吉林大学 | A kind of oxide-based nanomaterial of anti-plant decay disease, preparation method and applications |
CN109380304B (en) * | 2018-11-28 | 2020-12-01 | 吉林大学 | Oxide nano material for resisting plant rot disease, preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN1303080C (en) | 2007-03-07 |
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Legal Events
Date | Code | Title | Description |
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C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C56 | Change in the name or address of the patentee |
Owner name: KANGCHEN PHARMACEUTICAL COMPANY LIMITED Free format text: FORMER NAME OR ADDRESS: KANGCHEN MEDICINE DEVELOPMENT CO., LTD. |
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CP03 | Change of name, title or address |
Address after: A, building seven, building nine, Wah Wah Street, 3rd Street, Beijing, Haidian District Patentee after: Konruns Pharmaceutical Co.,Ltd. Address before: A, building seven, building nine, Wah Wah Street, 3rd Street, Beijing, Haidian District Patentee before: Konruns Pharmaceutical Co.,Ltd. |
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PE01 | Entry into force of the registration of the contract for pledge of patent right |
Effective date of registration: 20090520 Pledge (preservation): Pledge |
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PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20100612 Granted publication date: 20070307 Pledgee: Beijing industrial development Cci Capital Ltd. Pledgor: Konruns Pharmaceutical Co.,Ltd. Registration number: 2009110000548 |
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ASS | Succession or assignment of patent right |
Owner name: BEIJING KONRUNS PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: KANGCHEN PHARMACEUTICAL CO., LTD. Effective date: 20120328 |
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C41 | Transfer of patent application or patent right or utility model | ||
COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 100085 HAIDIAN, BEIJING TO: 101500 MIYUN, BEIJING |
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TR01 | Transfer of patent right |
Effective date of registration: 20120328 Address after: 101500 Miyun Economic Development Zone, Beijing, No. 11 South Road Patentee after: BEIJING KONRUNS PHARMACEUTICAL Co.,Ltd. Address before: 100085, A, building seven, building nine, Wah Wah Street, 3rd Street, Beijing, Haidian District Patentee before: Konruns Pharmaceutical Co.,Ltd. |
|
CP01 | Change in the name or title of a patent holder |
Address after: 101500 Miyun Economic Development Zone, Beijing, No. 11 South Road Patentee after: BEIJING KONRUNS PHARMACEUTICAL Co.,Ltd. Address before: 101500 Miyun Economic Development Zone, Beijing, No. 11 South Road Patentee before: BEIJING KONRUNS PHARMACEUTICAL Co.,Ltd. |
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CP01 | Change in the name or title of a patent holder | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070307 Termination date: 20210718 |