CN107118215A - 一种治疗乳腺癌药物瑞博西尼中间体的制备方法 - Google Patents
一种治疗乳腺癌药物瑞博西尼中间体的制备方法 Download PDFInfo
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- CN107118215A CN107118215A CN201710314267.1A CN201710314267A CN107118215A CN 107118215 A CN107118215 A CN 107118215A CN 201710314267 A CN201710314267 A CN 201710314267A CN 107118215 A CN107118215 A CN 107118215A
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- chloro
- pyrimidine
- pyrroles
- cyclopenta
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000000543 intermediate Substances 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims description 7
- 206010006187 Breast cancer Diseases 0.000 title claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 title claims description 5
- 229940079593 drug Drugs 0.000 title claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 52
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 24
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000002696 manganese Chemical class 0.000 claims abstract description 16
- NMPVEAUIHMEAQP-UHFFFAOYSA-N 2-Bromoacetaldehyde Chemical class BrCC=O NMPVEAUIHMEAQP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 235000019270 ammonium chloride Nutrition 0.000 claims abstract description 12
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims abstract description 9
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 9
- 230000003647 oxidation Effects 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 22
- -1 N, N- dimethyl-aminomethyl Chemical group 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical class NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 239000011572 manganese Substances 0.000 claims description 7
- 150000003230 pyrimidines Chemical class 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 5
- 239000012286 potassium permanganate Substances 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 2
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 239000011565 manganese chloride Substances 0.000 claims description 2
- MIVBAHRSNUNMPP-UHFFFAOYSA-N manganese(II) nitrate Inorganic materials [Mn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MIVBAHRSNUNMPP-UHFFFAOYSA-N 0.000 claims description 2
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical group [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000357 manganese(II) sulfate Inorganic materials 0.000 claims description 2
- 206010011224 Cough Diseases 0.000 claims 1
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical compound [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 11
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 239000010970 precious metal Substances 0.000 abstract description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 4
- 229910052801 chlorine Inorganic materials 0.000 abstract 4
- 239000000460 chlorine Substances 0.000 abstract 4
- 150000003233 pyrroles Chemical class 0.000 abstract 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 238000010606 normalization Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 3
- BFYREAQTFGYRAU-UHFFFAOYSA-N CN(C)CC1=NC=CC=N1 Chemical compound CN(C)CC1=NC=CC=N1 BFYREAQTFGYRAU-UHFFFAOYSA-N 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000003863 metallic catalyst Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical class ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 description 1
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical class OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229950003687 ribociclib Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Description
Claims (8)
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CN201710314267.1A CN107118215B (zh) | 2017-05-06 | 2017-05-06 | 一种治疗乳腺癌药物瑞博西尼中间体的制备方法 |
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CN201710314267.1A CN107118215B (zh) | 2017-05-06 | 2017-05-06 | 一种治疗乳腺癌药物瑞博西尼中间体的制备方法 |
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CN107118215A true CN107118215A (zh) | 2017-09-01 |
CN107118215B CN107118215B (zh) | 2019-04-05 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110016024A (zh) * | 2018-01-09 | 2019-07-16 | 南京药石科技股份有限公司 | 一种合成cdk4/6双重抑制剂的关键中间体及其制备方法和应用 |
CN111100128A (zh) * | 2018-10-26 | 2020-05-05 | 广安凯特制药有限公司 | 一种瑞博西尼中间产品的合成方法及其中间体化合物 |
US10723739B2 (en) | 2018-05-14 | 2020-07-28 | Apotex Inc. | Processes for the preparation of Ribociclib and intermediates thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010020675A1 (en) * | 2008-08-22 | 2010-02-25 | Novartis Ag | Pyrrolopyrimidine compounds as cdk inhibitors |
CN106478641A (zh) * | 2016-10-09 | 2017-03-08 | 杭州科巢生物科技有限公司 | 瑞博西尼中间体的新合成方法 |
-
2017
- 2017-05-06 CN CN201710314267.1A patent/CN107118215B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010020675A1 (en) * | 2008-08-22 | 2010-02-25 | Novartis Ag | Pyrrolopyrimidine compounds as cdk inhibitors |
CN106478641A (zh) * | 2016-10-09 | 2017-03-08 | 杭州科巢生物科技有限公司 | 瑞博西尼中间体的新合成方法 |
Non-Patent Citations (1)
Title |
---|
ALEEM GANGJEE ET AL: "Novel 2-amino-4-oxo-5-arylthio-substituted-pyrrolo[2,3-d]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110016024A (zh) * | 2018-01-09 | 2019-07-16 | 南京药石科技股份有限公司 | 一种合成cdk4/6双重抑制剂的关键中间体及其制备方法和应用 |
US10723739B2 (en) | 2018-05-14 | 2020-07-28 | Apotex Inc. | Processes for the preparation of Ribociclib and intermediates thereof |
CN111100128A (zh) * | 2018-10-26 | 2020-05-05 | 广安凯特制药有限公司 | 一种瑞博西尼中间产品的合成方法及其中间体化合物 |
CN111100128B (zh) * | 2018-10-26 | 2022-09-06 | 广安凯特制药有限公司 | 一种瑞博西尼中间产品的合成方法及其中间体化合物 |
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Effective date of registration: 20231229 Address after: Room 303-9, Building 10, No. 2168 Chenhang Road, Minhang District, Shanghai, 201114 Patentee after: Lingyao Biotechnology (Shanghai) Co.,Ltd. Address before: Room E268, 2nd Floor, Building No. 3, 2118 Guanghua Road, Minhang District, Shanghai, 201100 Patentee before: Shanghai Yaoda Biotechnology Co.,Ltd. |
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