CN103980272B - A kind of method of synthesis 5-cyano group-1H-pyrazolo [3,4-b] pyridine - Google Patents
A kind of method of synthesis 5-cyano group-1H-pyrazolo [3,4-b] pyridine Download PDFInfo
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- CN103980272B CN103980272B CN201410155055.XA CN201410155055A CN103980272B CN 103980272 B CN103980272 B CN 103980272B CN 201410155055 A CN201410155055 A CN 201410155055A CN 103980272 B CN103980272 B CN 103980272B
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- AXJHOIDYWSISKB-JTQLQIEISA-N CC(C)N(C(C)C)[C@@H](C)C=C Chemical compound CC(C)N(C(C)C)[C@@H](C)C=C AXJHOIDYWSISKB-JTQLQIEISA-N 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N CC(C)NC(C)C Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 0 CCC1=NC(C2*)C2C(C)=C1 Chemical compound CCC1=NC(C2*)C2C(C)=C1 0.000 description 1
- HRLRAFGTCAPJRK-UHFFFAOYSA-N O=CC(C1)C(F)=NC=C1[U] Chemical compound O=CC(C1)C(F)=NC=C1[U] HRLRAFGTCAPJRK-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a kind of synthesis 5-cyano group-1H-pyrazolo [3,4-b] method of pyridine, the method comprises synthesis LDA, synthetic intermediate one, synthetic intermediate two, synthesis 5-cyano group-1H-pyrazolo [3,4-b] pyridine finished product and subsequent purification process.Beneficial effect of the present invention is: the raw material that this synthetic method uses cheaply is easy to get, and can greatly reduce production cost, and reasonable raw material proportioning, step is brief, and mild condition, safe and reliable, the target product purity obtained is higher, is particularly suitable for suitability for industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to a kind of method of synthesis 5-cyano group-1H-pyrazolo [3,4-b] pyridine.
Background technology
5-cyano group-1H-pyrazolo [3,4-b] pyridine is the crux intermediate of some Therapeutic cancer medicine.In recent years, due to going from bad to worse of living environment, the problems affect such as food sanitation, the rate of falling ill of cancer is more and more higher, therefore increases the pharmaceutical requirements amount of Therapeutic cancer, also more and more payes attention to the research of the key intermediate of Therapeutic cancer medicine.
Current synthesis 5-cyano group-1H-pyrazolo [3,4-b] method of pyridine, synthetic intermediate adopt for the moment ethyl acetate extract concentrated after participate in the next step again, step is comparatively loaded down with trivial details, intermediate one is in instability under concentrated condition of being heated simultaneously, very easily produces impurity; Adopt the directly cyclization in ethanol of intermediate one, anhydrous hydrazine when synthetic intermediate two, and anhydrous hydrazine is a kind of poisonous, inflammable liquid, makes product can not get fine guarantee in transport and the security in producing; And being Material synthesis with intermediate two, target product is not soluble in Conventional solvents, target product is existed and is difficult to shortcomings such as purifying, yield is low, synthesis cost is higher.
Therefore, the technology being badly in need of a kind of improvement solves problems of the prior art.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of method of synthesis 5-cyano group-1H-pyrazolo [3,4-b] pyridine, and the raw material that this synthetic method uses cheaply is easy to get, production cost can be greatly reduced, and step is brief, mild condition, safe and reliable, be particularly suitable for suitability for industrialized production.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
A kind of method of synthesis 5-cyano group-1H-pyrazolo [3,4-b] pyridine, the method comprises the following steps:
A) by Diisopropylamine and n-Butyl Lithium low-temp reaction under the condition of THF solvent and nitrogen protection, obtain LDA, the mol ratio of Diisopropylamine and n-Butyl Lithium is not less than 1.2:1;
B) fluoro-to LDA, 2-5-bromopyridine and ethyl formate are reacted in THF solvent, obtain the THF solution containing intermediate one, the mol ratio of the fluoro-5-bromopyridine of 2-and ethyl formate is 1:1-1:2;
C) the above-mentioned THF solution containing intermediate one and hydrazine hydrate are fully reacted at the temperature of 40-45 DEG C, add dehydrated alcohol band water, then obtain intermediate two through concentrating under reduced pressure, anhydrous diethyl ether making beating process;
D) under the protection of nitrogen, intermediate two and zinc cyanide are stirred in DMF solvent, add 4-triphenylphosphine palladium and react, temperature controls at 75-85 DEG C, react after 9-11 hour and lowers the temperature, filters, extraction, concentrates and obtain solid crude product;
E) by steps d) in gained solid crude product volume ratio be that the methyl alcohol of 1:1 and the making beating of chloroform mixed solution are washed, filter, dried to obtain secondary crude product;
F) the hydrogenchloride alcoholic solvent being 1% by above-mentioned secondary crude product mass concentration carries out recrystallization, obtains 5-cyano group-1H-pyrazolo [3,4-b] the pyridine finished product that purity is more than 98%.
Wherein, above-mentioned hydrogenchloride alcoholic solvent is one or more in methanolic hydrogen chloride solvent, hydrogenchloride isopropanol solvent or ethanolic hydrogen chloride solvent.
Each reaction formula of the present invention is as follows:
Synthetic intermediate one:
Synthetic intermediate two:
Synthesis finished product:
Beneficial effect of the present invention is: (1) the method optimizes proportioning raw materials during synthesis LDA, and lower step product foreign matter content is obviously reduced; (2) intermediate one is concentrated after adopting THF solvent extraction participates in the next step directly, both simplifies synthesis step, because of the concentrated generation impurity that is heated, can not improve the purity of product again; (3), during synthetic intermediate two, moisture hydrazine hydrate is first adopted to react, then by ethanol band water law, repeatedly be with water, to make in product moisture reduce and cyclization occurs, and uses the synthetic method of anhydrous hydrazine to compare at present, substantially increase the security of product transporting, in production; (4) volume ratio is after the methyl alcohol of 1:1 and chloroform mixed solution making beating removing specific impurities, then carries out recrystallization with the hydrogenchloride alcoholic solvent that mass concentration is 1%, further increases the purity of product.
Embodiment:
Below in conjunction with embodiment, the present invention is described in further detail.
Embodiment 1
In 50L reactor, logical nitrogen, adds 2380g Diisopropylamine, THF solvent, stirs; Be cooled to-30 DEG C, drip 1983g n-Butyl Lithium, reaction 0.5h; Be cooled to-65 DEG C, drip the mixing solutions of the fluoro-5-bromopyridine of 3110g2-and THF, reaction 2.5h; Drip 1308g ethyl formate, reaction 5min, then drip the mixing solutions of 1630g citric acid and THF; In HPLC, control reaction terminates; At the temperature of 0 DEG C, add 8.7L water, stir 15min; Leave standstill separatory, water layer THF extracts, and merges organic phase, must containing the THF solution of the fluoro-3 aldehyde radical pyridines of the bromo-2-of intermediate one 5-.
In 50L reactor, add the THF solution containing intermediate one obtained above, the stirring of 2.8kg hydrazine hydrate, being warming up to 45 DEG C, controlling to reacting completely in TLC; By reaction solution concentrated by rotary evaporation to pasty state; Add dehydrated alcohol, add the hydrazine hydrate of 0.5 times, be warming up to 80 DEG C of back flow reaction; Add 9L dehydrated alcohol band water twice, reaction end adds gac and stirs 1h, heat filter, and filtrate reduced in volume obtains yellow solid; Solid is added anhydrous diethyl ether making beating, centrifugal, the dry crude product 2.35kg that must contain intermediate two 5-bromo-1H-pyrazolo [3,4-b] pyridine, purity 94%, yield 75%.
Embodiment 2
In 50L reactor, logical nitrogen, adds 2380g Diisopropylamine, THF solvent, stirs; Be cooled to-30 DEG C, drip 1258g n-Butyl Lithium, reaction 0.5h; Be cooled to-65 DEG C, drip the mixing solutions of the fluoro-5-bromopyridine of 3110g2-and THF, reaction 2.5h; Drip 1970g ethyl formate, reaction 5min, then drip the mixing solutions of 1630g citric acid and THF; In HPLC, control reaction terminates; At the temperature of 0 DEG C, add 8.7L water, stir 15min; Leave standstill separatory, water layer THF extracts, and merges organic phase, must containing the THF solution of the fluoro-3 aldehyde radical pyridines of the bromo-2-of intermediate one 5-.
In 50L reactor, add the THF solution containing intermediate one obtained above, the stirring of 2.8kg hydrazine hydrate, being warming up to 45 DEG C, controlling to reacting completely in TLC; By reaction solution concentrated by rotary evaporation to pasty state; Add dehydrated alcohol, add the hydrazine hydrate of 0.5 times, be warming up to 80 DEG C of back flow reaction; Add 9L dehydrated alcohol band water twice, reaction end adds gac and stirs 1h, heat filter, and filtrate reduced in volume obtains yellow solid; Solid is added anhydrous diethyl ether making beating, centrifugal, the dry crude product 2.48kg that must contain intermediate two 5-bromo-1H-pyrazolo [3,4-b] pyridine, purity 94%, yield 79%.
Embodiment 3
In 50L reactor, logical nitrogen, adds 2380g Diisopropylamine, THF solvent, stirs; Be cooled to-30 DEG C, drip 1161g n-Butyl Lithium, reaction 0.5h; Be cooled to-65 DEG C, drip the mixing solutions of the fluoro-5-bromopyridine of 3110g2-and THF, reaction 2.5h; Drip 2615g ethyl formate, reaction 5min, then drip the solution of citric acid 1630g and THF; In HPLC, control reaction terminates; At the temperature of 0 DEG C, add 8.7L water, stir 15min; Leave standstill separatory, water layer THF extracts, and merges organic phase, must containing the THF solution of the fluoro-3 aldehyde radical pyridines of the bromo-2-of intermediate one 5-.
In 50L reactor, add the THF solution containing intermediate one obtained above, the stirring of 2.8kg hydrazine hydrate, being warming up to 45 DEG C, controlling to reacting completely in TLC; By reaction solution concentrated by rotary evaporation to pasty state; Add dehydrated alcohol, add the hydrazine hydrate of 0.5 times, be warming up to 80 DEG C of back flow reaction; Add 9L dehydrated alcohol band water twice, reaction end adds gac and stirs 1h, heat filter, and filtrate reduced in volume obtains yellow solid; Solid is added anhydrous diethyl ether making beating, centrifugal, the dry crude product 2.51kg that must contain intermediate two 5-bromo-1H-pyrazolo [3,4-b] pyridine, purity 94%, yield 80%.
Embodiment 4
In 20L reaction flask, add 1.25kg intermediate two crude product and DMF under nitrogen protection, be stirred to entirely molten; Add 2 times to the zinc cyanide pressed powder of intermediate two crude product amount, stir 0.5h, finally add 0.1 times to the 4-triphenylphosphine palladium of intermediate two crude product amount, be warming up to 85 DEG C of reaction 10h, control in sampling HPLC, until reaction terminates; Be down to room temperature, filter, filtrate is stirred with frozen water, adds 30LEA extracting twice, concentrates to obtain solid crude product; Solid crude product volume ratio is methyl alcohol and the chloroform mixed solution making beating washing of 1:1, filters, dries, obtain secondary crude product 1.25kg, purity 95%, yield 70%.
Embodiment 5
In 20L reaction flask, add 1.25kg intermediate two crude product and DMF under nitrogen protection, be stirred to entirely molten; Add 3 times to the zinc cyanide pressed powder of intermediate two crude product amount, stir 0.5h, finally add 0.1 times to the 4-triphenylphosphine palladium of intermediate two crude product amount, be warming up to 85 DEG C of reaction 10h, control in sampling HPLC, until reaction terminates; Be down to room temperature, filter, filtrate is stirred with frozen water, adds 30LEA extracting twice, concentrates to obtain solid crude product; Solid crude product volume ratio is methyl alcohol and the chloroform mixed solution making beating washing of 1:1, filters, dries, obtain secondary crude product 1.43kg, purity 95%, yield 80%.
Embodiment 6
In 20L reaction flask, add 1.25kg intermediate two crude product and DMF under nitrogen protection, be stirred to entirely molten; Add 5 times to the zinc cyanide pressed powder of intermediate two crude product amount, stir 0.5h, finally add 0.1 times to the 4-triphenylphosphine palladium of intermediate two crude product amount, be warming up to 85 DEG C of reaction 10h, control in sampling HPLC, until reaction terminates; Be down to room temperature, filter, filtrate is stirred with frozen water, adds 30LEA extracting twice, concentrates to obtain solid crude product; Solid crude product volume ratio is methyl alcohol and the chloroform mixed solution making beating washing of 1:1, filters, dries, obtain secondary crude product 1.47kg, purity 95%, yield 82%.
Embodiment 7
Get 535g bis-crude products, add the methanolic hydrogen chloride solvent that 15.5L mass concentration is 1%, be heated to backflow, stir entirely molten after, add 160g gac, backflow 1h, heat filtering, the filter cake hot methanol washing of 2L70 DEG C, collects merging filtrate, be concentrated into half-dried, add 1.5L ether stirring to pulp, filter, dry 5h, to weight, obtains the finished product of 482g containing 5-cyano group-1H-pyrazolo [3,4-b] pyridine, purity 98.5%, yield 90%.
Embodiment 8
Get 519g bis-crude products, add the hydrogenchloride isopropanol solvent that 14.5L mass concentration is 1%, be heated to backflow, stir entirely molten after, add 160g gac, backflow 1h, heat filtering, the hot washed with isopropyl alcohol of filter cake 2L70 DEG C, collects merging filtrate, be concentrated into half-dried, add 1.5L ether stirring to pulp, filter, dry 5h, to weight, obtains the finished product of 478g containing 5-cyano group-1H-pyrazolo [3,4-b] pyridine, purity 98.5%, yield 92%.
Embodiment 9
Get 563g bis-crude products, add the ethanolic hydrogen chloride solvent that 16L mass concentration is 1%, be heated to backflow, stir entirely molten after, add 160g gac, backflow 1h, heat filtering, the filter cake hot ethanol washing of 2L70 DEG C, collects merging filtrate, be concentrated into half-dried, add 1.5L ether stirring to pulp, filter, dry 5h, to weight, obtains the finished product of 535g containing 5-cyano group-1H-pyrazolo [3,4-b] pyridine, purity 98.4%, yield 95%.
Claims (1)
1. the method for synthesis 5-cyano group-1H-pyrazolo [3, a 4-b] pyridine, it is characterized in that, the method comprises the following steps:
A) by Diisopropylamine and n-Butyl Lithium low-temp reaction under the condition of THF solvent and nitrogen protection, obtain LDA, the mol ratio of Diisopropylamine and n-Butyl Lithium is not less than 1.2:1;
B) fluoro-to LDA, 2-5-bromopyridine and ethyl formate are reacted in THF solvent, obtain the THF solution containing intermediate one, the mol ratio of the fluoro-5-bromopyridine of 2-and ethyl formate is 1:1-1:2;
C) the above-mentioned THF solution containing intermediate one and hydrazine hydrate are fully reacted at the temperature of 40-45 DEG C, add dehydrated alcohol band water, then obtain intermediate two through concentrating under reduced pressure, anhydrous diethyl ether making beating process;
D) under the protection of nitrogen, intermediate two and zinc cyanide are stirred in DMF solvent, add 4-triphenylphosphine palladium and react, temperature controls at 75-85 DEG C, react after 9-11 hour and lowers the temperature, filters, extraction, concentrates and obtain solid crude product;
E) by steps d) in gained solid crude product volume ratio be that the methyl alcohol of 1:1 and the making beating of chloroform mixed solution are washed, filter, dried to obtain secondary crude product;
F) the hydrogenchloride alcoholic solvent being 1% by above-mentioned secondary crude product mass concentration carries out recrystallization, obtains 5-cyano group-1H-pyrazolo [3,4-b] the pyridine finished product that purity is more than 98%; Wherein, described hydrogenchloride alcoholic solvent is one or more in methanolic hydrogen chloride solvent, hydrogenchloride isopropanol solvent or ethanolic hydrogen chloride solvent.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015124A2 (en) * | 2004-07-27 | 2006-02-09 | Sgx Pharmaceuticals, Inc. | Fused ring heterocycle kinase modulators |
| CN101389626A (en) * | 2004-07-27 | 2009-03-18 | Sgx药物公司 | Fused ring heterocycle kinase modulators |
| CN102821607A (en) * | 2009-12-21 | 2012-12-12 | 萨穆梅德有限公司 | 1H-pyrazolo[3,4-.Beta.]pyridines and therapeutic uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015124A2 (en) * | 2004-07-27 | 2006-02-09 | Sgx Pharmaceuticals, Inc. | Fused ring heterocycle kinase modulators |
| CN101389626A (en) * | 2004-07-27 | 2009-03-18 | Sgx药物公司 | Fused ring heterocycle kinase modulators |
| CN102821607A (en) * | 2009-12-21 | 2012-12-12 | 萨穆梅德有限公司 | 1H-pyrazolo[3,4-.Beta.]pyridines and therapeutic uses thereof |
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