CN103193762B - 苯甲酸阿格列汀的制备方法 - Google Patents
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- CN103193762B CN103193762B CN201310105789.2A CN201310105789A CN103193762B CN 103193762 B CN103193762 B CN 103193762B CN 201310105789 A CN201310105789 A CN 201310105789A CN 103193762 B CN103193762 B CN 103193762B
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- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- PKUFNWPSFCOSLU-UHFFFAOYSA-N 6-chloro-1h-pyrimidine-2,4-dione Chemical compound ClC1=CC(=O)NC(=O)N1 PKUFNWPSFCOSLU-UHFFFAOYSA-N 0.000 claims abstract description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000047 product Substances 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 239000007787 solid Substances 0.000 claims description 45
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- 238000003756 stirring Methods 0.000 claims description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 27
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 12
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 12
- 238000007605 air drying Methods 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 11
- 235000015320 potassium carbonate Nutrition 0.000 claims description 11
- 238000000967 suction filtration Methods 0.000 claims description 11
- QGXNHCXKWFNKCG-UHFFFAOYSA-N 2-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC=C1C#N QGXNHCXKWFNKCG-UHFFFAOYSA-N 0.000 claims description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 10
- 229940059936 lithium bromide Drugs 0.000 claims description 10
- 239000012312 sodium hydride Substances 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
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- WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl n-[(3r)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 claims description 6
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- BXHWWPNRUOHACS-MRVPVSSYSA-N tert-butyl (3r)-1-aminopiperidine-3-carboxylate Chemical class CC(C)(C)OC(=O)[C@@H]1CCCN(N)C1 BXHWWPNRUOHACS-MRVPVSSYSA-N 0.000 abstract description 2
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- UTDVHCQTKWTQEA-UHFFFAOYSA-N 1-(2-aminoacetyl)-n-(4-methyl-2-oxochromen-7-yl)pyrrolidine-2-carboxamide Chemical compound C1=CC=2C(C)=CC(=O)OC=2C=C1NC(=O)C1CCCN1C(=O)CN UTDVHCQTKWTQEA-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
物料 | 投料量(kg) | 质量比 |
SM001 | 3.5 | 1 |
SM002 | 4.37 | 1.25 |
60%NaH | 1.05 | 0.3 |
LiBr | 1.85 | 0.53 |
溶剂 | DMF/DMSO/水 | / |
物料 | 投料量(kg) | 质量比 |
S100801 | 1.9 | 1 |
碘甲烷 | 2.35 | 1.23 |
LiBr | 0.51 | 0.27 |
60%NaH | 0.35 | 0.18 |
溶剂 | DMF/四氢呋喃/水 | / |
物料 | 投料量(kg) | 质量比 |
S100802 | 1.8 | 1 |
SM003 | 1.48 | 0.82 |
碳酸钾 | 1.8 | 1 |
溶剂 | DMF/二氯甲烷/乙酸乙酯 | / |
物料 | 投料量(kg) | 质量比 |
S100803 | 2.75 | 1 |
三氟乙酸 | 5.6L | / |
溶剂 | 二氯甲烷/乙酸乙酯 | / |
物料 | 投料量(kg) | 质量比 |
S100804 | 1.15 | 1 |
苯甲酸 | 415g | 0.36 |
溶剂 | 四氢呋喃 | / |
酶原 | IC50值(nmol/L) |
阿格列汀 | 西他列汀 | 维格列汀 | |
DPP-4 | 6.9±1.5 | 12.1±0.8 | 23.8±1.6 |
DPP-2 | >100000 | >50000 | >100000 |
DPP-8 | >100000 | 19000±2000 | 1400±200 |
DPP-9 | >100000 | 62000±4000 | 81.5±8.1 |
PREP | >100000 | >100000 | >50000 |
FAP/seprase | >100000 | >100000 | 73000±8000 |
类胰蛋白酶 | >390000 | >400000 | >200000 |
Claims (4)
Priority Applications (1)
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CN201310105789.2A CN103193762B (zh) | 2013-03-29 | 2013-03-29 | 苯甲酸阿格列汀的制备方法 |
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CN201310105789.2A CN103193762B (zh) | 2013-03-29 | 2013-03-29 | 苯甲酸阿格列汀的制备方法 |
Publications (2)
Publication Number | Publication Date |
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CN103193762A CN103193762A (zh) | 2013-07-10 |
CN103193762B true CN103193762B (zh) | 2015-07-29 |
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CN201310105789.2A Active CN103193762B (zh) | 2013-03-29 | 2013-03-29 | 苯甲酸阿格列汀的制备方法 |
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CN (1) | CN103193762B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104109147B (zh) * | 2014-06-21 | 2016-10-05 | 安徽省逸欣铭医药科技有限公司 | 羟基脒基苯类衍生物及其制备方法和医药用途 |
CN105315256B (zh) * | 2014-07-07 | 2018-02-06 | 广州朗圣药业有限公司 | 一种适合工业化的高纯度琥珀酸曲格列汀的制备方法 |
CN106632242A (zh) * | 2017-02-14 | 2017-05-10 | 杭州百诚医药科技股份有限公司 | 一种高纯度苯甲酸阿格列汀的制备后处理方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102361557A (zh) * | 2009-03-26 | 2012-02-22 | Mapi医药公司 | 制备阿格列汀的方法 |
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