CN103819478B - 阿拉格列汀中间体2-甲基-吡唑并[1,5-a]嘧啶-6-羧酸的制备方法 - Google Patents
阿拉格列汀中间体2-甲基-吡唑并[1,5-a]嘧啶-6-羧酸的制备方法 Download PDFInfo
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- CN103819478B CN103819478B CN201410109842.0A CN201410109842A CN103819478B CN 103819478 B CN103819478 B CN 103819478B CN 201410109842 A CN201410109842 A CN 201410109842A CN 103819478 B CN103819478 B CN 103819478B
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- reaction
- methyl
- pyrimidine
- pyrazolo
- carboxylic acid
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- YHVGUXFUOSJCFJ-UHFFFAOYSA-N 2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid Chemical compound N1=CC(C(O)=O)=CN2N=C(C)C=C21 YHVGUXFUOSJCFJ-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 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 claims abstract description 40
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- FYTLHYRDGXRYEY-UHFFFAOYSA-N 5-Methyl-3-pyrazolamine Chemical compound CC=1C=C(N)NN=1 FYTLHYRDGXRYEY-UHFFFAOYSA-N 0.000 claims abstract description 24
- 230000007062 hydrolysis Effects 0.000 claims abstract description 24
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006482 condensation reaction Methods 0.000 claims abstract description 22
- 239000007787 solid Substances 0.000 claims abstract description 19
- YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 238000000967 suction filtration Methods 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000011230 binding agent Substances 0.000 claims abstract description 9
- 238000009833 condensation Methods 0.000 claims abstract description 3
- 230000005494 condensation Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 77
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000011259 mixed solution Substances 0.000 claims description 19
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 230000000977 initiatory effect Effects 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- 229940072033 potash Drugs 0.000 claims description 7
- 235000015320 potassium carbonate Nutrition 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 229940043279 diisopropylamine Drugs 0.000 claims description 5
- -1 carrene Chemical compound 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000007791 liquid phase Substances 0.000 abstract description 20
- 238000000034 method Methods 0.000 abstract description 6
- 238000010923 batch production Methods 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 18
- 239000012043 crude product Substances 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 3
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- LDXYBEHACFJIEL-HNNXBMFYSA-N anagliptin Chemical compound C=1N2N=C(C)C=C2N=CC=1C(=O)NCC(C)(C)NCC(=O)N1CCC[C@H]1C#N LDXYBEHACFJIEL-HNNXBMFYSA-N 0.000 description 1
- 229950009977 anagliptin Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 229960002050 hydrofluoric acid Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229950002366 nafoxidine Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- GDASVOXREDJRGF-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-6-carboxylic acid Chemical compound C1=C(C(=O)O)C=NC2=CC=NN21 GDASVOXREDJRGF-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000010792 warming 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
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CN201410109842.0A CN103819478B (zh) | 2014-03-21 | 2014-03-21 | 阿拉格列汀中间体2-甲基-吡唑并[1,5-a]嘧啶-6-羧酸的制备方法 |
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CN201410109842.0A CN103819478B (zh) | 2014-03-21 | 2014-03-21 | 阿拉格列汀中间体2-甲基-吡唑并[1,5-a]嘧啶-6-羧酸的制备方法 |
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CN103819478A CN103819478A (zh) | 2014-05-28 |
CN103819478B true CN103819478B (zh) | 2016-05-04 |
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Families Citing this family (3)
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WO2015152319A1 (ja) * | 2014-04-02 | 2015-10-08 | 株式会社 三和化学研究所 | 5,7-無置換-ピラゾロ[1,5-a]ピリミジン-6-カルボン酸の製造方法 |
CN105315284A (zh) * | 2014-07-23 | 2016-02-10 | 上海医药工业研究院 | 阿拉格列汀中间体的制备方法 |
CN110003218B (zh) * | 2019-03-26 | 2020-07-31 | 杭州瀚康生物医药科技有限公司 | 阿拉格列汀中间体的制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101171256A (zh) * | 2005-03-14 | 2008-04-30 | 葛兰素集团有限公司 | 具有组胺h3受体亲和性的稠合噻唑衍生物 |
CN101535313A (zh) * | 2006-10-30 | 2009-09-16 | 诺瓦提斯公司 | 作为蛋白激酶调节剂的3-氨基羰基取代的稠合的吡唑衍生物 |
WO2014034626A1 (ja) * | 2012-08-28 | 2014-03-06 | 株式会社 三和化学研究所 | N-[2-({2-[(2S)-2-シアノピロリジン-1-イル]-2-オキソエチル}アミノ)-2-メチルプロピル]-2-メチルピラゾロ[1,5-a]ピリミジン-6-カルボキサミドの結晶 |
WO2014034871A1 (ja) * | 2012-08-30 | 2014-03-06 | 株式会社 三和化学研究所 | 脂質異常症の予防又は治療薬 |
CN103626775A (zh) * | 2013-12-02 | 2014-03-12 | 南京华威医药科技开发有限公司 | 具有二嗪结构的dpp-4抑制剂 |
-
2014
- 2014-03-21 CN CN201410109842.0A patent/CN103819478B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101171256A (zh) * | 2005-03-14 | 2008-04-30 | 葛兰素集团有限公司 | 具有组胺h3受体亲和性的稠合噻唑衍生物 |
CN101535313A (zh) * | 2006-10-30 | 2009-09-16 | 诺瓦提斯公司 | 作为蛋白激酶调节剂的3-氨基羰基取代的稠合的吡唑衍生物 |
WO2014034626A1 (ja) * | 2012-08-28 | 2014-03-06 | 株式会社 三和化学研究所 | N-[2-({2-[(2S)-2-シアノピロリジン-1-イル]-2-オキソエチル}アミノ)-2-メチルプロピル]-2-メチルピラゾロ[1,5-a]ピリミジン-6-カルボキサミドの結晶 |
WO2014034871A1 (ja) * | 2012-08-30 | 2014-03-06 | 株式会社 三和化学研究所 | 脂質異常症の予防又は治療薬 |
CN103626775A (zh) * | 2013-12-02 | 2014-03-12 | 南京华威医药科技开发有限公司 | 具有二嗪结构的dpp-4抑制剂 |
Non-Patent Citations (1)
Title |
---|
N-1 SUBSTITUTED ETHYL 4-PYRAZOLECARBOXYLATES - SYNTHESIS AND SPECTROSCOPIC INVESTIGATIONS;HOLZER, W,等;《JOURNAL OF HETEROCYCLIC CHEMISTRY》;19931231;第30卷(第4期);第865-872页,尤其Scheme 1 * |
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