CN102558174B - New pyrazolo[4,3-c]pyridine compound and synthesis method thereof - Google Patents
New pyrazolo[4,3-c]pyridine compound and synthesis method thereof Download PDFInfo
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- -1 pyrazolo[4,3-c]pyridine compound Chemical class 0.000 title abstract description 6
- 238000001308 synthesis method Methods 0.000 title abstract 2
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WCXFPLXZZSWROM-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridine Chemical class C1=NC=C2C=NNC2=C1 WCXFPLXZZSWROM-UHFFFAOYSA-N 0.000 claims description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 235000010288 sodium nitrite Nutrition 0.000 claims description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- 230000006196 deacetylation Effects 0.000 claims description 2
- 238000003381 deacetylation reaction Methods 0.000 claims description 2
- 239000012954 diazonium Substances 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 12
- 239000002547 new drug Substances 0.000 abstract description 2
- 206010028980 Neoplasm Diseases 0.000 abstract 2
- 201000010099 disease Diseases 0.000 abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 2
- 208000024827 Alzheimer disease Diseases 0.000 abstract 1
- 208000001132 Osteoporosis Diseases 0.000 abstract 1
- 206010039966 Senile dementia Diseases 0.000 abstract 1
- 230000001272 neurogenic effect Effects 0.000 abstract 1
- 230000001766 physiological effect Effects 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 238000012827 research and development Methods 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002473 indoazoles Chemical class 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical class [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a new pyrazolo[4,3-C]pyridine compound, which is 3-bromo-1H-pyrazolo[4,3-C]pyridine-6-methyl formate. The synthesis method is that: 2-amino-5-methylpyridine is adopted as a starting raw material to produce the target compound pyrazolo[4,3-C]pyridine derivative, which provides good therapeutic effects in prevention and treatment of tumors and cancers, neurogenic diseases, osteoporosis, senile dementia and other diseases. The pyrazolo pyridine compound has wide physiological activity so as to induce the interest of majority of researchers. The synthesized pyrazolo[4,3-C]pyridine compound is a multi-functional group compound, has a wide market prospect and a high application value, and is subjected to high attention in the field of new drug research and development.
Description
Technical field
The present invention relates to pyrazolo [4,3-c] pyridine compounds and their, specifically belong to the invention of the bromo-1H-pyrazolo of a kind of 3-[4,3-c] pyridine-6-methyl-formiate and synthetic method thereof.
Background technology
Pyrazolo [4,3-c] pyridine compounds and their is the class chemical drugs intermediate that show great attention in current new drug development field, compound with Pyrazolopyridine basic structure has very important effect in pharmaceutical research, and the structural diversity of this compounds also provides wide space for they are synthetic.My company relies on Superiority of Scientific Research, with simple method for synthesizing, succeeds in developing, and does parent can further synthesize more complicated derivative with this compound, for studying more widely such compound property, provides condition.
Summary of the invention
The present invention aims to provide a kind of brand-new indazole compounds and synthetic method thereof, and the method is relatively simple, raw material is easy to get.
A kind of brand-new pyrazolo provided by the invention [4,3-c] pyridine compounds and their, is the bromo-1H-pyrazolo of 3-[4,3-c] pyridine-6-methyl-formiate, its structural formula:
A kind of brand-new pyrazolo [4,3-c] pyridine compounds and their provided by the invention and synthetic method thereof, carry out in accordance with the following steps:
(1). 2-amino-5-picoline is carried out to bromine in diazonium with bromine and Sodium Nitrite.
(2). upper bromine product is made to pyridine nitric oxide with m-CPBA oxidation.
(3). oxygenated products is carried out nitrated with the vitriol oil and nitrosonitric acid.
(4). above-mentioned oxygenated products is reduced with iron powder.
(5). by reduzate, with Pd (dppf) Cl
2make catalyzer, methyl alcohol is made solvent, and logical CO inserts carbonyl reaction.
(6). will insert carbonyl product and acetic anhydride amino will be protected, then close ring with Isopentyl nitrite.
(7). will close ring product salt of wormwood and methyl alcohol deacetylate.
(8). by bromine on bromine for deacetylation product.
Reaction equation:
In this highway route design, have three emphasis, first bromination one step can obtain good positioning product before closing ring; It two is to insert carbonyl reaction, obtains methyl-formiate, can further be transformed to other substituting groups; It three is that Guan Huanyi step is used the effect of Sodium Nitrite more far short of what is expected than this design.
Accompanying drawing explanation
Fig. 1 is the HNMR collection of illustrative plates of the bromo-1H-pyrazolo of 3-[4,3c] pyridine-6-methyl-formiate.
Embodiment
One. 60 grams of 2-amino-5-picolines are added in 600 milliliters of HBr solution in batches, and system is cooled to-20 ℃, drips bromine, drips and finishes, insulation reaction 1h; Drip again the aqueous solution of Sodium Nitrite, insulated and stirred 2h.React complete, regulate PH to 10, ethyl acetate extraction, organic phase is dry, concentrates to obtain yellow liquid A75g, productive rate 78.58%.TLC information (PE: EA=10: 1): raw material Rf=0.05, product Rf=0.60.
Two. 32 grams of A are dissolved in chloroform, then add m-CPBA, room temperature is complete to raw material reaction.System is concentrated, and column chromatography obtains 37 grams of yellow oily B, productive rate 100%.TLC information (PE: EA=10: 1): raw material Rf=0.6, product Rf=0.05.
Three. 37 grams of B are slowly dropped in the vitriol oil of 80 milliliters, 80 milliliters and 140 milliliters nitrosonitric acid nitration mixture of the cooling lower dropping of ice bath, then be warming up to 100 ℃ complete to raw material reaction.System is slowly poured in 1L frozen water, then regulated PH to 9 with concentrated sodium hydroxide, suction filtration obtains yellow solid C34 gram, productive rate 74.15%.TLC information (DCM: MeOH=20: 1): raw material Rf=0.3, product Rf=0.8.
1H-NMR(DMSO-d6；400MHZ)：8.38(S，1H)；7.78(d，1H，8.0Hz)；7.11(d，1H，8.0Hz)；2.24(S，3H)。
Four. 20 grams of C and 20 grams of iron powders are added in the mixed solution of 60 milliliters of THF, MeOH and water, under room temperature, add 20 grams of ammonium chlorides, then it are complete to be warming up to back flow reaction.System is cooling, suction filtration, ethyl acetate extraction, organic phase is dry, concentrated 15.3 grams of yellow solid D, the productive rate 95.3% of obtaining.TLC information (PE: EA=2: 1): raw material Rf=0.65, product Rf=0.6.1H-NMR(CDCl3；400MHZ)：8.41(S，1H)；8.31(S，1H)；2.59(S，3H)。
Five. by 8 grams of dppfPdCl
2join in 1 liter of methanol solution of 100 grams of D, 100 milliliters of triethylamines carbon monoxide displacement 3 times for reaction, logical carbon monoxide pressure P=0.5MPa, T=80 ℃ of reaction.React complete, system suction filtration filtrate was concentrated to post and obtain 80 grams of faint yellow solid E, productive rate 90.04%.TLC information PE:EA=2: 1): raw material Rf=0.6, product Rf=0.1.1H-NMR(CDCl3；400MHZ)：7.84(S，1H)；6.70(S，1H)；4.22(S，2H)；2.06(S，3H)。
Six. 80 grams of E are joined in 1 liter of chloroform, system is cooled to 0 ℃, add 135 grams of potassium acetates and 340 grams of diacetyl oxides, back flow reaction is spent the night.-6 and 124 grams of Isopentyl nitrites of 25.4 grams of 18-hats are added in system, back flow reaction is spent the night again.React complete, system is joined in saturated sodium bicarbonate solution and regulates PH to 9, organic phase is dry, the concentrated brown solid F90 gram, productive rate 85.29% of obtaining.TLC information (DCM: MeOH=15: 1): raw material Rf=0.4, product Rf=0.85.
Seven. 90 grams of F are dissolved in 700 ml methanol, then add 70 grams of salt of wormwood, room temperature reaction.System is concentrated, adds water, ethyl acetate extraction, and organic phase is dry, concentrates post and obtains white solid G30 gram, productive rate 41.24%.TLC information (DCM: MeOH=15: 1): raw material Rf=0.85, product Rf=0.4.1H-NMR(DMSO-d6；400MHZ)：13.87(S，1H)；9.21(S，1H)；8.48(S，1H)；8.24(S，1H)；3.92(S，3H)。
Eight. 10 grams of F are added in 100 ml waters, under room temperature, drip bromine.React complete, in system, add saturated sodium thiosulfate solution, suction filtration obtains white solid H11.47 gram, productive rate 79.36%.TLC information (DCM: MeOH=15: 1): raw material Rf=0.4, product Rf=0.6.1H-NMR(DMSO-d6；400MHZ)：14.27(S，1H)；9.06(S，1H)；8.26(d，1H)；3.96(S，3H)。
Claims (1)
1. the synthetic method of a pyrazolo [4,3-c] pyridine compounds, is characterized in that: products therefrom is the bromo-1H-pyrazolo of 3-[4,3-c] pyridine 6-methyl-formiate, and structural formula is:
Comprise the steps:
(1) 2-amino-5-picoline is carried out to bromine in diazonium with bromine and Sodium Nitrite;
(2) upper bromine product is made to pyridine nitric oxide with m-CPBA oxidation;
(3) oxygenated products is carried out nitrated with the vitriol oil and nitrosonitric acid;
(4) above-mentioned oxygenated products is reduced with iron powder;
(5) by reduzate, with Pd (dppf) Cl
2make catalyzer, methyl alcohol is made solvent, and logical CO inserts carbon reaction;
(6) will insert carbonyl product and acetic anhydride amino will be protected, then close ring with Isopentyl nitrite;
(7) will close ring product salt of wormwood and methyl alcohol deacetylate;
(8) by bromine on bromine for deacetylation product.
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| CN104230811B (en) * | 2014-07-30 | 2016-09-28 | 斯芬克司药物研发（天津）股份有限公司 | A kind of pyrazolopyridines compound and preparation method thereof |
| CN109336810A (en) * | 2018-11-02 | 2019-02-15 | 浙江星月药物科技股份有限公司 | A kind of preparation method of haloperidid class nitrogen oxides |
| CN110343103A (en) * | 2019-07-04 | 2019-10-18 | 深圳市格物致欣化学技术有限公司 | Pyrazolo-pyridines and preparation method thereof |
| CN110872212A (en) * | 2019-12-12 | 2020-03-10 | 大连中汇达科学仪器有限公司 | Preparation method of 2-bromo-4-fluoro-6-methylphenol |
| CN113912533B (en) * | 2021-11-23 | 2023-06-20 | 西安凯立新材料股份有限公司 | Method for preparing 3, 6-dichloropicolinic acid |
| CN114751855B (en) * | 2022-05-23 | 2024-05-07 | 上海皓鸿生物医药科技有限公司 | Preparation method of 2-bromo-4-amino-5-methylpyridine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1099033A (en) * | 1992-10-22 | 1995-02-22 | 赫彻斯特-柔斯尔药物有限公司 | Pyrazolo [4,3-c] pyridine, their preparation method and as the purposes of serotonin reuptake inhibitors |
| WO2010106333A1 (en) * | 2009-03-19 | 2010-09-23 | Medical Research Council Technology | Compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1099033A (en) * | 1992-10-22 | 1995-02-22 | 赫彻斯特-柔斯尔药物有限公司 | Pyrazolo [4,3-c] pyridine, their preparation method and as the purposes of serotonin reuptake inhibitors |
| WO2010106333A1 (en) * | 2009-03-19 | 2010-09-23 | Medical Research Council Technology | Compounds |
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