CN102250090A - 一种米诺膦酸中间体的制备方法 - Google Patents
一种米诺膦酸中间体的制备方法 Download PDFInfo
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- CN102250090A CN102250090A CN 201110145991 CN201110145991A CN102250090A CN 102250090 A CN102250090 A CN 102250090A CN 201110145991 CN201110145991 CN 201110145991 CN 201110145991 A CN201110145991 A CN 201110145991A CN 102250090 A CN102250090 A CN 102250090A
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- Prior art keywords
- imidazo
- pyridin
- iii
- preparing
- sodium
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- 238000000034 method Methods 0.000 title claims abstract description 24
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 title abstract description 9
- 229950011129 minodronic acid Drugs 0.000 title abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 6
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 3
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 3
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 7
- ZVBVKRNOISRONE-UHFFFAOYSA-N 2-imidazo[1,2-a]pyridin-3-ylacetic acid Chemical compound C1=CC=CN2C(CC(=O)O)=CN=C21 ZVBVKRNOISRONE-UHFFFAOYSA-N 0.000 abstract description 3
- APYSHMNJHJRIDR-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine Chemical compound C1=CC=CN2C(Br)=CN=C21 APYSHMNJHJRIDR-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 7
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 125000001246 bromo group Chemical class Br* 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- -1 azepine aryl diphosphonate derivative Chemical class 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 0 *C(*)(Cc1cnc2[n]1cccc2)O Chemical compound *C(*)(Cc1cnc2[n]1cccc2)O 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- SFCNXCZZKZRJLZ-UHFFFAOYSA-N CCOC(Cc1cnc2[n]1cccc2)=O Chemical compound CCOC(Cc1cnc2[n]1cccc2)=O SFCNXCZZKZRJLZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- SSVFMICWXDVRQN-UHFFFAOYSA-N ethanol;sodium Chemical compound [Na].CCO SSVFMICWXDVRQN-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims (8)
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CN 201110145991 CN102250090B (zh) | 2011-06-01 | 2011-06-01 | 一种米诺膦酸中间体的制备方法 |
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CN 201110145991 CN102250090B (zh) | 2011-06-01 | 2011-06-01 | 一种米诺膦酸中间体的制备方法 |
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CN102250090A true CN102250090A (zh) | 2011-11-23 |
CN102250090B CN102250090B (zh) | 2013-01-16 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103342639A (zh) * | 2013-07-25 | 2013-10-09 | 南通瑞点化工科技有限公司 | 一种合成2-苯基羧酸酯的方法 |
CN110964010A (zh) * | 2019-11-29 | 2020-04-07 | 上海应用技术大学 | 一种米诺磷酸中间体的制备方法 |
CN112390794A (zh) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | 一种米诺膦酸关键中间体的制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007023504A1 (en) * | 2005-08-24 | 2007-03-01 | Elder Pharmaceuticals Ltd | Process for the preparation of imidazopyridines |
CN101812062A (zh) * | 2010-03-31 | 2010-08-25 | 北京京卫信康医药科技发展有限公司 | 一种新的米诺膦酸重要中间体的制备方法 |
-
2011
- 2011-06-01 CN CN 201110145991 patent/CN102250090B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007023504A1 (en) * | 2005-08-24 | 2007-03-01 | Elder Pharmaceuticals Ltd | Process for the preparation of imidazopyridines |
CN101812062A (zh) * | 2010-03-31 | 2010-08-25 | 北京京卫信康医药科技发展有限公司 | 一种新的米诺膦酸重要中间体的制备方法 |
Non-Patent Citations (2)
Title |
---|
《Bioconjugate Chem.》 20070828 Valentino Laquintana 等 N-Benzyl-2-(6,8-dichloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N-(6-(7-nitrobenzo[c][1,2,5]oxadiazol-4-ylamino)hexyl)acetamide as a New Fluorescent Probe for Peripheral Benzodiazepine Receptor and Microglial Cell Visualization 第1397-1407页 1-8 第18卷, 第5期 * |
《中国医药工业杂志》 20041231 皮士卿 等 米诺膦酸二钠的合成 第193-194页 1-8 第35卷, 第4期 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103342639A (zh) * | 2013-07-25 | 2013-10-09 | 南通瑞点化工科技有限公司 | 一种合成2-苯基羧酸酯的方法 |
CN112390794A (zh) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | 一种米诺膦酸关键中间体的制备方法 |
CN112390794B (zh) * | 2019-08-19 | 2023-05-26 | 鲁南制药集团股份有限公司 | 一种米诺膦酸关键中间体的制备方法 |
CN110964010A (zh) * | 2019-11-29 | 2020-04-07 | 上海应用技术大学 | 一种米诺磷酸中间体的制备方法 |
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CN102250090B (zh) | 2013-01-16 |
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Owner name: HEFEI YIGONG MEDICINE CO., LTD. Effective date: 20120627 Owner name: GUANGDONG WINNERWAY GROUP PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: HEFEI YIGONG MEDICINE CO., LTD. Effective date: 20120627 |
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Inventor after: He Guangwei Inventor after: Huang Jinwei Inventor after: Li Feng Inventor after: Luo Sitong Inventor after: Liu Weizhong Inventor after: Duan Junchang Inventor after: Wang Yinhu Inventor after: Liu Wei Inventor before: He Guangwei Inventor before: Li Feng Inventor before: Wang Yinhu |
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Free format text: CORRECT: ADDRESS; FROM: 230088 HEFEI, ANHUI PROVINCE TO: 523109 DONGGUAN, GUANGDONG PROVINCE Free format text: CORRECT: INVENTOR; FROM: HE GUANGWEI LI FENG WANG YINHU TO: HE GUANGWEI HUANG JINWEI LI FENG LUO SITONG LIU WEIZHONG DUAN JUNCHANG WANG YINHU LIU WEI |
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Address after: 523109 Zhangcun Industrial Zone, Dongcheng District, Dongguan City, Guangdong Province Co-patentee after: Hefei Medical and Pharmaceutical Co., Ltd. Patentee after: Guangdong Winnerway Group Pharmaceutical Co., Ltd. Address before: 523109 Zhangcun Industrial Zone, Dongcheng District, Dongguan City, Guangdong Province Co-patentee before: Hefei Yigong Medicine Co., Ltd. Patentee before: Guangdong Winnerway Group Pharmaceutical Co., Ltd. |
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Effective date of registration: 20211028 Address after: 523109 Dongguan Zhangcun Industrial Zone, Dongguan City, Guangdong Province Patentee after: GUANGDONG WINNERWAY (Group) PHARMACEUTICAL Co.,Ltd. Address before: 523109 Zhangcun Industrial Zone, Dongcheng District, Dongguan City, Guangdong Province Patentee before: GUANGDONG WINNERWAY (Group) PHARMACEUTICAL Co.,Ltd. Patentee before: HEFEI INDUSTRIAL PHARMACEUTICAL INSTITUTE Co.,Ltd. |