CN109776527A - A kind of synthetic method of 5- bromo-7-azaindole - Google Patents
A kind of synthetic method of 5- bromo-7-azaindole Download PDFInfo
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- CN109776527A CN109776527A CN201910130527.9A CN201910130527A CN109776527A CN 109776527 A CN109776527 A CN 109776527A CN 201910130527 A CN201910130527 A CN 201910130527A CN 109776527 A CN109776527 A CN 109776527A
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Abstract
The present invention provides a kind of synthetic methods of 5- bromo-7-azaindole.The invention belongs to medical chemistries to synthesize field.The present invention, for raw material, reacts to obtain intermediate 3 with bromine, intermediate 3 obtains intermediate 4 under alkali effect, and intermediate 4 reacts to obtain 5- bromo-7-azaindole 1 with 2- amino-pyrroles with 1,1,3,3- tetramethoxy propane 2.Reaction step of the present invention is few, raw material is easy to get, high income, and pollution is small, is easy to amplify production.
Description
Technical field:
Invention is related to a kind of synthetic method of medicine intermediate, specifically, the present invention relates to a kind of 5- is bromo-
The synthetic method of 7- azaindole.
Technical background
ABT-199 (Venetoclax), chemical name 2- [(1H- pyrrolo- [2,3-B] pyridine -5- base) oxygroup] -4- [4-
[[2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkenyl] methyl] piperazine -1- base]-nitrogen-[3- nitro 4- [[(oxinane -
4- yl) methyl] amino] benzsulfamide] methyl benzoate is a kind of experimental B cell lymphoma factor -2 (BCL-2) inhibition
Agent is developed jointly by AbbVie Corp. and Roche Holding Ag.BCL-2 is that one kind can prevent some cells (including lymphocyte) apoptosis
Albumen.ABT-199 is intended to the function of the selective depression BCL-2 factor, restores the communication system of cell, and cancer cell is allowed self to ruin
It goes out, to achieve the effect that treat tumour.It is mainly used for treating chronic lymphocytic leukemia, non-Hodgkin lymphoma, primary lymphedema
Cell lymphoma, diffusivity large B cell lymphoid tumor and Huppert's disease etc..
FDA thinks that this drug has in terms for the treatment of the patients with chronic myelocytic leukemia with 17p deletion mutant
Significant curative effect.There are about a line patients with chronic myelocytic leukemia of 3-10% all to have this gene mutation at present, and is going out
In the chronic leukemia patient of existing drug resistance, this ratio is more up to as many as 50%.So far, FDA is authorized 3 are obtained altogether
A breakthrough therapeutic agent qualification: in April, 2015, FDA authorize Venetoclax single therapy and carry the recurrence that 17p deletes mutation
The breakthrough drug qualification of property/intractable chronic lymphocytic leukemia (CLL)；In January, 2016, FDA authorize Venetoclax
It is prominent that joint anticarcinogen Rituximab (Rituximab, Mabthera) treats recurrent/intractable chronic lymphocytic leukemia
Broken property drug qualification；Shortly after that, FDA authorizes Venetoclax again and controls with demethylation drug (HMAs) drug combination mutability
Treat drug qualification, the past untreated patients with acute myeloid leukemia for standard induction therapies should not to be received.In addition, 2016
At the beginning of 1 month year, FDA authorizes the CLL (including 17p missing CLL) that Venetoclax single therapy has previously received at least one therapy
New Drug Application (NDA) preferential examination qualification.On April 11st, 2016, venetoclax are ratified to list by FDA, slow for treating
Property lymphocytic leukemia, non-Hodgkin lymphoma, small lymphocyte lymthoma, Diffuse large B-cell lymphoma are multiple
The diseases such as myeloma are first and are applied to clinical Bcl-2 inhibitor.
5-bromo-7-azaindoles are a kind of key intermediates for synthesizing Venetoclax, meanwhile, 5- bromo-7-azaindole
It can be used for synthesizing anticancer drug Wei Luofeini (Vemurafenib, kinases potent inhibitor), (cell-signaling pathways inhibit PP121
Agent), the new drugs such as LKB1 (AAK1dualinhibitor).
5- bromo-7-azaindole has caused the research and development interest of scientific worker as important anti-tumor drug intermediate,
Current synthesis 5- bromo-7-azaindole both domestic and external mainly has following methods:
Method 1: patent CN201410596601.3 is in order to fast and convenient synthesis 5- bromo-7-azaindole, with 2- ammonia
Base -3- methyl -5- bromopyridine be raw material, Caro's acid oxidation under generate 2- nitro -3- methyl -5- bromopyridine, then
It is generated under nafoxidine and n,N-Dimethylformamide dimethylacetal (DMF-DMA) effect and obtains intermediate, finally in thunder
Lower reduction cyclization is acted under Buddhist nun's nickel/85% hydrazine hydrate system or other low-valent metals forms 5- bromo-7-azaindole.
Method 2: patent CN201210025316.7 provides a kind of preparation method of 5- bromo-7-azaindole, with 7- azepine
Indoles is raw material, mainly includes step: 7- azaindole is reacted with sodium hydrogensulfite generates dihydro -7- azaindole -2- sulfonic acid
Sodium salt；Dihydro -7- azaindole -2- sulfonate sodium occurs bromo-reaction and generates dihydro -5- bromo-7-azaindole -2- sodium sulfonate
Salt；Dihydro -5- bromo-7-azaindole -2- sulfonate sodium takes off sodium sulfonate under alkaline condition and generates 5- bromo-7-azaindole.
Method 3: patent CN201610114529.5 is using 7- azaindole as raw material, hydrogenated protection, bromine bromination, chromium oxygen
Fluidized dehydrogenation and etc. synthesis 5- bromo-7-azaindole.
Method 4:CN201610020068.5 discloses a kind of synthesis technology of 5- bromo-7-azaindole, step are as follows: by 7-
Azaindole, Raney's nickel, ethyl alcohol stir and are filled with hydrogen reaction；Reaction filtering, filter cake ethanol washing, merging filtrate, concentration
It is dry, obtain 7- azaindole quinoline crude product；The crude product is mixed with p-methyl benzenesulfonic acid, methylene chloride, bromine is added dropwise and is stirred；It will reaction
Liquid is washed with sodium thiosulfate, and organic phase is dry with anhydrous sodium sulfate, is concentrated to give 5- bromo-7-azaindole quinoline product；By the product
It is dissolved in toluene, manganese dioxide, heating reflux reaction is added；Reaction solution is filtered, filter cake is washed with methylene chloride, merge organic phase,
It is dry, it is concentrated to give 5- bromo-7-azaindole crude product, crystallizes to obtain finished product with PE/EA mixed solution.
Method 5:CN201610569355.1 is related to a kind of production technology of 5- bromo-7-azaindole, with 7- azaindole
For raw material, it is anti-to include the following steps: that catalytic hydrogenation occurs under the action of palladium catalyst loaded mesoporous carbon for (1) 7- azaindole
It answers, generates dihydro -7- azaindole；(2) under the action of hydrogen bromide and hydrogen peroxide bromo occurs for the dihydro -7- azaindole
Reaction generates dihydro -5- bromo-7-azaindole, wherein the molar ratio of dihydro -7- azaindole, hydrogen bromide and hydrogen peroxide
For 1:10~30:1~2, the temperature of bromo-reaction is 20~30 degrees Celsius；(3) dihydro -5- bromo-7-azaindole described in exists
Manganese dioxide/glacial acetic acid effect is lower to occur the oxidative dehydrogenation generation 5- bromo-7-azaindole.
Method 6:CN201711390143.8 discloses a kind of synthetic method of 5- bromo-7-azaindole, including following step
It is rapid: 2- diazanyl -5- bromopyridine is dissolved in solvent, the concentrated sulfuric acid is added and is uniformly mixed, being heated to temperature is 70-90 DEG C,
Catalyst is added, acetaldehyde, back flow reaction 3-4h is added under stirring condition, reaction terminates, is cooled to room temperature, is filtered, and will filter
Liquid is evaporated under reduced pressure, and 5- bromo-7-azaindole is made in recrystallization.
Method 7:CN201711458438.4 is related to a kind of synthetic method of 5- bromo-7-azaindole, with 7- azaindole
For raw material, low pressure liquid-phase hydrogenatin destroys indoles five-membered ring conjugation, through in oxybromination, the crucial medicine of nonmetallic oxidative dehydrogenation preparation
Mesosome 5- bromo-7-azaindole.
Other reports are also: using 2-aminopyridine as raw material, forming by bromination, coupling, cyclization.With 7- azaindole
For raw material, through bromination, cancellation, reduction, oxidation and etc. synthesis 5- bromo-7-azaindole etc..
The synthesis of these 5- bromo-7-azaindoles is reported or needs complex process, seriously polluted；Reaction condition
Harshness, industrial cost is high, and industrial efficiency is lower.During deprotection, using metal catalytic, it is easy to cause metal residual super
Mark, this is very unfavorable for the production of medical product.
Summary of the invention
The invention discloses a kind of synthetic methods of 5- bromo-7-azaindole, and the present invention is with 1,1,3,3- tetramethoxy third
Alkane 2 is raw material, reacts to obtain intermediate 3 with bromine, intermediate 3 obtains intermediate 4, intermediate 4 and 2- amino under alkali effect
Pyrroles reacts to obtain 5- bromo-7-azaindole 1, synthetic route are as follows:
1. solvent used is selected from water in a preferred embodiment, in the step (1)；Reaction temperature used
Degree is room temperature；Acid used is selected from hydrochloric acid.
2. solvent used is selected from water in a preferred embodiment, in the step (2)；Reaction temperature used
Degree is 4 DEG C；What alkali was selected is sodium hydroxide.
3. solvent used is selected from ethyl alcohol in a preferred embodiment, in the step (3)；Reaction used
Temperature is reflux temperature；What acid was selected is the mixed liquor of acetic acid and hydrobromic acid.
4. of the invention be characterized by: providing a kind of synthetic method of completely new 5- bromo-7-azaindole.
5. advantage of the invention is: reaction step of the present invention is few, raw material is easy to get, high income, and pollution is small, is easy to be put
Mass production.
The present invention is further described by the following embodiment, it should be understood by those skilled in the art that example
It is served only for explaining the present invention, be not intended to limit the scope of the present invention.
Specific embodiment Solution Embodiments: the synthesis of 5- bromo-7-azaindole
1. the synthesis of intermediate 3
100g compound 1 is added in the water of 96ml, under 0 degree, is slowly added dropwise to the hydrochloric acid of 5.4ml and the liquid of 105.6g
Bromine is stirred overnight at room temperature, and water is spun off under 45 degree, and filtering, solid is washed several times with PE:EA, dried, and obtains 50g intermediate 3.
2. the synthesis of intermediate 4
16.8g NaOH is added in the water of 400ml, then is slowly added into 60g intermediate 3, spins off water under decompression, until
There is solid precipitation, add the cold acetone of 1L, be stirred overnight under 4 degree, filters, solid is washed 2 times with the cold acetone of 500ml, with oil
Solid is drawn and is done by pump, obtains 68g intermediate 4.
The synthesis of 3.5- bromo-7-azaindole 1
55g intermediate 3 and 26g2- amino-pyrroles are added in the ethyl alcohol of 300ml, then are slowly added dropwise to 100ml30%
Hydrobromic acid acetic acid, be heated to reflux, cooling, filtering, solid is respectively washed 3 times with the ether of ethyl alcohol sum, dried, and obtains 53.9g chemical combination
Object, yield 85.5%.
The present invention is not limited to examples detailed above.The above description is only an embodiment of the present invention, is not intended to limit the invention, all
Within the spirit and principles in the present invention, any modification, equivalent replacement, improvement and so on should be included in guarantor of the invention
Within the scope of shield.
Claims (5)
- The synthetic method of 1.5- bromo-7-azaindole, with the present invention with 1,1,3,3- tetramethoxy propane 2 for raw material, with bromine Reaction obtains intermediate 3, and intermediate 3 obtains intermediate 4 under alkali effect, and intermediate 4 reacts to obtain 5- with 2- amino-pyrroles bromo- 7- azaindole 1, synthetic route are as follows:
- 2. the synthetic method of 5- bromo-7-azaindole according to claim 1, the synthetic method include the following steps:(1) it reacts to obtain intermediate 3 with bromine for raw material with 1,1,3,3- tetramethoxy propane 2；(2) intermediate 3 obtains intermediate 4 under alkali effect.(3) intermediate 4 reacts to obtain 5- bromo-7-azaindole 1 with 2- amino-pyrroles.
- 3. the synthetic method of 5- bromo-7-azaindole according to claim 2, it is characterised in that: in the step (1) Solvent used is selected from water, methanol, ethyl alcohol, normal propyl alcohol, isopropanol, ethyl acetate, tetrahydrofuran, methylene chloride, toluene, neighbour two Toluene, paraxylene, meta-xylene, N, N- diethylformamide, N, the mixing of one or more of N- diethyl acetamide Object；Reaction temperature used is the reflux temperature of 0 DEG C~solvent；Vinegar acid used, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, to first The mixture of one or more of benzene sulfonic acid.
- 4. the synthetic method of 5- bromo-7-azaindole according to claim 2, it is characterised in that: in the step (2) In, alkali used be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, sodium bicarbonate, pyridine, The mixture of one or more of triisopropylamine, saleratus；Solvent used be selected from water, methanol, ethyl alcohol, normal propyl alcohol, Isopropanol, ethyl acetate, tetrahydrofuran, methyl tertiary butyl ether(MTBE), methylene chloride, toluene, ortho-xylene, paraxylene, diformazan Benzene, N, N- diethylformamide, N, the mixture of one or more of N- diethyl acetamide；Reaction temperature used is 0 DEG C~reflux temperature of solvent.
- 5. the synthetic method of 5- bromo-7-azaindole according to claim 2, it is characterised in that: in the step (3) In, acid used is selected from acetic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, the mixing of one or more of p-methyl benzenesulfonic acid Object；Solvent used be selected from water, methanol, ethyl alcohol, normal propyl alcohol, isopropanol, ethyl acetate, tetrahydrofuran, methyl tertiary butyl ether(MTBE), two Chloromethanes, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- diethylformamide, N, in N- diethyl acetamide One or more of mixtures；Reaction temperature used is the reflux temperature of 0 DEG C~solvent.
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Cited By (2)
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| CN115521307A (en) * | 2022-09-30 | 2022-12-27 | 甘肃皓天医药科技有限责任公司 | Preparation method of 5-halogenated-7-azaindole |
| CN115894192A (en) * | 2022-12-05 | 2023-04-04 | 苏州诚和医药化学有限公司 | Synthesis method and application of 2-bromomalondialdehyde and 2-bromomalondialdehyde |
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