CN1730481A - 5-aza-indole preparation method - Google Patents
5-aza-indole preparation method Download PDFInfo
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- CN1730481A CN1730481A CN 200510060249 CN200510060249A CN1730481A CN 1730481 A CN1730481 A CN 1730481A CN 200510060249 CN200510060249 CN 200510060249 CN 200510060249 A CN200510060249 A CN 200510060249A CN 1730481 A CN1730481 A CN 1730481A
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- Prior art keywords
- azaindole
- dioxane
- preparation
- weight
- nitropyridine
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- SRSKXJVMVSSSHB-UHFFFAOYSA-N 1h-pyrrolo[3,2-c]pyridine Chemical compound N1=CC=C2NC=CC2=C1 SRSKXJVMVSSSHB-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 13
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000852 hydrogen donor Substances 0.000 claims abstract description 11
- -1 nitro radicals Chemical class 0.000 claims abstract description 8
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000007710 freezing Methods 0.000 claims abstract description 3
- 230000008014 freezing Effects 0.000 claims abstract description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 14
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 14
- NAAZAWRQDAEVME-UHFFFAOYSA-N 2-ethenyl-4-nitropyridine Chemical compound [O-][N+](=O)C1=CC=NC(C=C)=C1 NAAZAWRQDAEVME-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 6
- UYAWSMUOLFSNGC-UHFFFAOYSA-N 3-methyl-4-nitropyridine Chemical compound CC1=CN=CC=C1[N+]([O-])=O UYAWSMUOLFSNGC-UHFFFAOYSA-N 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 4
- AYZXEGOJMRKZCV-UHFFFAOYSA-N n-(diethoxymethyl)-n-ethylethanamine Chemical compound CCOC(OCC)N(CC)CC AYZXEGOJMRKZCV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- QDKJWXBGYXJIOS-UHFFFAOYSA-N n-(dimethoxymethyl)-n-ethylethanamine Chemical compound CCN(CC)C(OC)OC QDKJWXBGYXJIOS-UHFFFAOYSA-N 0.000 claims description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 2
- MGWGWNFMUOTEHG-UHFFFAOYSA-N 4-(3,5-dimethylphenyl)-1,3-thiazol-2-amine Chemical compound CC1=CC(C)=CC(C=2N=C(N)SC=2)=C1 MGWGWNFMUOTEHG-UHFFFAOYSA-N 0.000 abstract 1
- 239000007868 Raney catalyst Substances 0.000 abstract 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 abstract 1
- KERWYOBMWAISKN-UHFFFAOYSA-N [N+](=O)[O-].CC=1C=NC=CC1[N+](=O)[O-] Chemical compound [N+](=O)[O-].CC=1C=NC=CC1[N+](=O)[O-] KERWYOBMWAISKN-UHFFFAOYSA-N 0.000 abstract 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 abstract 1
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 229950003988 decil Drugs 0.000 description 5
- 238000009835 boiling Methods 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000013019 agitation Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 235000001018 Hibiscus sabdariffa Nutrition 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 235000005291 Rumex acetosa Nutrition 0.000 description 1
- 240000007001 Rumex acetosella Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 235000003513 sheep sorrel Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The invention provides a process for preparing 5-azaindole comprising the following steps, using 3-methyl-4-nitro pyridine nitrogen dioxide and N,N-dialkyl formamide dialkyl acetal as raw material for reacting 1-2 hrsa at 100-150 deg C, freezing and crystallizing to obtain 3-dialkylaminoacetylene-4-nitropyridine nitrogen dioxide, then deacidizing the nitro radicals into amino radicals with palladium-containing catalyst and hydrogen donor at 0 deg C to room temperature, then using Raney nickel and hydrogen donor as reducer for deoxidization and cyclization at 40-80 deg C.
Description
Technical field
The present invention relates to the preparation method of 5-azaindole.
Background technology
The 5-azaindole has certain restraining effect to kinases, can be used for treating cardiovascular diseases, inflammation, diseases such as central nervous system confusion and diabetes.U.S. Pat 4625033 discloses the preparation method of 5-azaindole: with 3-methyl-4-nitropyridine oxynitride and N, the dinethylformamide dimethylacetal is a raw material, in 120 ℃, reacted 2～3 hours, distillation makes 3-decil thiazolinyl-4-nitropyridine oxynitride, then in the mixed solvent of ethanol water, by 3-decil thiazolinyl-4-nitropyridine oxynitride, with weight is that 150% Raney's nickel is that catalyzer carries out former dose of hydrogenation, makes the 5-azaindole.The shortcoming of this method is to produce methyl alcohol, and boiling point is low, has reduced temperature of reaction, reacts complete inadequately; Need to use a large amount of Raney's nickel catalysts, and no matter in pressurization still under the condition of normal pressure, all reaction not exclusively.
Summary of the invention
The method for preparing the 5-azaindole that the purpose of this invention is to provide a kind of reaction conditions gentleness, high purity and constant product quality.
The preparation method of 5-azaindole of the present invention in turn includes the following steps:
The first step, with 3-methyl-4-nitropyridine oxynitride and N, N-dialkylformamide dioxane acetal is a raw material, in non-proton property polar solvent, in 100～150 ℃, reacted 1～2 hour, freezing and crystallizing makes 3-dioxane amine vinyl-4-nitropyridine oxynitride, 3-methyl-4-nitropyridine oxynitride and N, the weight ratio of N-dialkylformamide dioxane acetal is 1: 1～1: 2;
In second step,, with hydrogen donor nitroreduction is become amino with palladium-containing catalyst 0 ℃～room temperature;
The 3rd step was a reductive agent with Raney's nickel and hydrogen donor, made the 5-azaindole in 40～80 ℃ of deoxidations, Cheng Huan.
Concrete synthetic route is as follows:
Among the preparation method of the present invention: the said N of the first step, N-dialkylformamide dioxane acetal can be N, dinethylformamide dimethylacetal, N, dinethylformamide diethyl acetal, N, N-diethylformamide dimethylacetal or N, N-diethylformamide diethyl acetal.Non-proton property polar solvent is N, dinethylformamide or N, N-diethylformamide.
Used palladium-containing catalyst is 5～10% palladium charcoal in the reaction of second step, and its consumption is 1～10% of 3-dioxane amine vinyl-4-nitropyridine oxynitride weight.Hydrogen donor is anhydrous formic acid ammonium or hydrazine hydrate, and the consumption of hydrazine hydrate is 20～80% of 3-dioxane amine vinyl-4-nitropyridine oxynitride weight, and the consumption of anhydrous formic acid ammonium is 30～100% of 3-dioxane amine vinyl-4-nitropyridine oxynitride weight.
Used hydrogen donor is anhydrous formic acid ammonium or hydrazine hydrate in the 3rd step, the consumption of hydrazine hydrate is 8～30% of 3-dioxane amine vinyl-4-nitropyridine oxynitride weight, and the consumption of anhydrous formic acid ammonium is 15～40% of 3-dioxane amine vinyl-4-nitropyridine oxynitride weight.
Adopt the beneficial effect of the inventive method to be:
1. the product yield height of the first step gained can reach 95%, and non-proton property polar solvent can be used by recovery set;
2. with palladium carbon and hydrogen donor nitro is catalysed and reduced into amino, gentleness is swift in response;
3. used catalyzer all is easy to reclaim and uses;
4. the 5-azaindole color and luster that makes is good, the purity height.
Embodiment
Below in conjunction with embodiment the present invention is described in further detail.
Embodiment 1:
The first step: with 3-methyl-4-nitropyridine oxynitride 46.2 grams (0.3mol), N, N-diethylformamide diethyl acetal 70ml, N, dinethylformamide 20ml drops in the four-hole boiling flask of 1L, slowly is heated to 130 ℃ under agitation condition, reacted 1.5 hours, distillation removes the ethanol that generates in the dereaction, and excessive acetal and solvent N,N-dimethylacetamide are reclaimed in decompression down then.Sorrel resistates boiling dissolve with ethanol, freeze overnight is separated out the solid suction filtration, and drying gets red-purple crystal 3-decil thiazolinyl-4-nitropyridine oxynitride, dries the 59.6g that weighs, yield 95.1%.
Second step: with 3-decil thiazolinyl-4-nitropyridine oxynitride 45g, 10% palladium charcoal 2.7g, ethanol 300ml puts in the 500ml four-hole boiling flask, ice bath is cooled to 15 ℃, begins the hydrazine hydrate of slow Dropwise 35 ml 85%, drips to finish to remove ice bath, insulation is about 1 hour at 30-35 ℃, become green by redness to the reaction solution color, it is standby that suction filtration reclaims palladium carbon, and mother liquor directly carries out next step reaction.
The 3rd step: the 20g Raney's nickel of new system is joined in the reaction solution of second step acquisition, temperature control 30-35 ℃, the hydrazine hydrate of adding 15m185%, reacted 2 hours, and became white by yellow-green colour, be warming up to 60 ℃ with oil bath again up to the foam color that stirs, reacted 4 hours, filter, it is standby that the recovery Raney's nickel is put into distilled water, and mother liquor concentrates to be done, the water recrystallization, suction filtration, oven dry obtains the little yellow crystals 22g of 5-azaindole.Yield 86.7%, m.p.109～110 ℃.
Embodiment 2:
The first step: use 65ml N, the dinethylformamide acetal replaces N, the dinethylformamide acetal, 16ml N, dinethylformamide replaces N, dinethylformamide, slowly be heated to 100 ℃ under agitation condition, all the other get red-purple crystal 3-decil thiazolinyl-4-nitropyridine oxynitride with embodiment 1 the first step, dry the 59.3g that weighs, yield 94.6%.；
Second and third step obtains 5-azaindole 21.8g with embodiment 1.
Embodiment 3:
The first step is with embodiment 1;
Second step: replace hydrazine hydrate with 44g anhydrous formic acid ammonium, mother liquor directly carries out next step reaction;
The 3rd step obtained 5-azaindole 22.3g with embodiment 1
Embodiment 4:
First and second step is with embodiment 1;
The 3rd step: replace hydrazine hydrate with 16g anhydrous formic acid ammonium, all the other obtain little yellow crystals 22.1g with the 3rd step of embodiment 1.
Embodiment 5:
The first step: with embodiment 2;
Second step: replace hydrazine hydrate with 44g anhydrous formic acid ammonium, mother liquor directly carries out next step reaction, and all the other are with 1 second step of embodiment;
The 3rd step: replace hydrazine hydrate with 16g anhydrous formic acid ammonium, all the other obtain little yellow crystals 21.9g with the 3rd step of embodiment 1.
Claims (6)
1.5-the preparation method of azaindole in turn includes the following steps:
The first step, with 3-methyl-4-nitropyridine oxynitride and N, N-dialkylformamide dioxane acetal is a raw material, in non-proton property polar solvent, in 100～150 ℃, reacted 1～2 hour, freezing and crystallizing makes 3-dioxane amine vinyl-4-nitropyridine oxynitride, 3-methyl-4-nitropyridine oxynitride and N, the weight ratio of N-dialkylformamide dioxane acetal is 1: 1～1: 2;
In second step,, with hydrogen donor nitroreduction is become amino with palladium-containing catalyst 0 ℃～room temperature;
The 3rd step was a reductive agent with Raney's nickel and hydrogen donor, made the 5-azaindole in 40～80 ℃ of deoxidations, Cheng Huan.
2. press the preparation method of the described 5-azaindole of claim 1, it is characterized in that said N, N-dialkylformamide dioxane acetal is N, dinethylformamide dimethylacetal, N, dinethylformamide diethyl acetal, N, N-diethylformamide dimethylacetal or N, N-diethylformamide diethyl acetal.
3. by the preparation method of the described 5-azaindole of claim 1, it is characterized in that said non-proton property polar solvent is N, dinethylformamide or N, N-diethylformamide.
4. by the preparation method of the described 5-azaindole of claim 1, it is characterized in that palladium-containing catalyst is 5～10% palladium charcoal, its consumption is 1～10% of 3-dioxane amine vinyl-4-nitropyridine oxynitride weight.
5. press the preparation method of the described 5-azaindole of claim 1, it is characterized in that step 2) reaction in used hydrogen donor be anhydrous formic acid ammonium or hydrazine hydrate, the consumption of hydrazine hydrate is 20～80% of 3-dioxane amine vinyl-4-nitropyridine oxynitride weight, and the consumption of anhydrous formic acid ammonium is 30～100% of 3-dioxane amine vinyl-4-nitropyridine oxynitride weight.
6. press the preparation method of the described 5-azaindole of claim 1, it is characterized in that used hydrogen donor is anhydrous formic acid ammonium or hydrazine hydrate in the step 3) reaction, the consumption of hydrazine hydrate is 8～30% of 3-dioxane amine vinyl-4-nitropyridine oxynitride weight, and the consumption of anhydrous formic acid ammonium is 15～40% of 3-dioxane amine vinyl-4-nitropyridine oxynitride weight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100602492A CN1321118C (en) | 2005-08-02 | 2005-08-02 | 5-aza-indole preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100602492A CN1321118C (en) | 2005-08-02 | 2005-08-02 | 5-aza-indole preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1730481A true CN1730481A (en) | 2006-02-08 |
| CN1321118C CN1321118C (en) | 2007-06-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100602492A Expired - Fee Related CN1321118C (en) | 2005-08-02 | 2005-08-02 | 5-aza-indole preparation method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891678A (en) * | 2010-07-15 | 2010-11-24 | 上海大学 | 4-(N,N-dimethyl) aminopyridine derivate and synthesis method thereof |
| CN105646489A (en) * | 2016-03-23 | 2016-06-08 | 叶芳 | 7-azaindole and preparation method thereof |
| CN105646486A (en) * | 2016-03-01 | 2016-06-08 | 苏州艾缇克药物化学有限公司 | Synthesizing method of 5-azaindole |
| CN106279157A (en) * | 2016-08-02 | 2017-01-04 | 叶芳 | A kind of preparation method of 5 azaindoles |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2564836B1 (en) * | 1984-05-25 | 1986-09-26 | Sanofi Sa | PROCESS FOR THE PREPARATION OF AZA-5 INDOLE AND COMPOUND OBTAINED BY THIS PROCESS |
-
2005
- 2005-08-02 CN CNB2005100602492A patent/CN1321118C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891678A (en) * | 2010-07-15 | 2010-11-24 | 上海大学 | 4-(N,N-dimethyl) aminopyridine derivate and synthesis method thereof |
| CN101891678B (en) * | 2010-07-15 | 2012-06-20 | 上海大学 | 4-(N,N-dimethyl) aminopyridine derivate and synthesis method thereof |
| CN105646486A (en) * | 2016-03-01 | 2016-06-08 | 苏州艾缇克药物化学有限公司 | Synthesizing method of 5-azaindole |
| CN105646489A (en) * | 2016-03-23 | 2016-06-08 | 叶芳 | 7-azaindole and preparation method thereof |
| CN106279157A (en) * | 2016-08-02 | 2017-01-04 | 叶芳 | A kind of preparation method of 5 azaindoles |
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| Publication number | Publication date |
|---|---|
| CN1321118C (en) | 2007-06-13 |
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