CN106243010A - A kind of preparation method of 4 nitroindolines - Google Patents
A kind of preparation method of 4 nitroindolines Download PDFInfo
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- CN106243010A CN106243010A CN201610631503.8A CN201610631503A CN106243010A CN 106243010 A CN106243010 A CN 106243010A CN 201610631503 A CN201610631503 A CN 201610631503A CN 106243010 A CN106243010 A CN 106243010A
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- nitroindoline
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- methoxyl group
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
- B01J31/36—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of vanadium, niobium or tantalum
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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Abstract
The invention discloses the preparation method of a kind of 4 nitroindolines, comprise the following steps: 4 methoxyphenyl hydrazine hydrochlorides are carried out nitration reaction and prepares 3 nitro 4 methoxyphenyl hydrazine hydrochlorides, afterwards under catalyst, react with acetaldehyde, preparing 5 methoxyl group 4 nitroindolines, finally removing methoxyl group had both obtained required 4 nitroindolines；Course of reaction is as shown below.The method uses ternary catalyst systems, and reaction conversion ratio is high, and selectivity is strong.Further, needed for this preparation method, reaction condition is gentle, and reaction cost is relatively low, has higher industrial production prospect.
Description
Technical field:
The present invention relates to medicine intermediate field, particularly relate to the preparation method of a kind of 4-nitroindoline.
Background technology:
Benzazole compounds is an important branch in heterocyclic compound, is widely distributed in nature, tool
There is multiple physiologically active, be respectively provided with important effect in fields such as pesticide, medicine, dyestuff and luminescent materials.In terms of pesticide,
Benzazole compounds can be as antibacterial or plant growth regulator etc..In terms of medicine, there is antipyretic-antalgic, fall blood
Pressure, expansion blood vessel, antihistamine and the biological activity such as anticancer.Additionally, the synthesis that indoles are also used as spice or dyestuff is former
Material.The daily biology being applied to people of Benzazole compounds is closely bound up, therefore about the study on the synthesis of Benzazole compounds
Significant.
The synthetic method of 4-nitroindoline has a variety of, such as following several: (1) passes through 2-methyl-3 nitro phenyl ring closed loop
Synthesis 4-nitroindoline；(2) 4-nitroindoline is prepared by meta nitro aniline hydrazone cyclisation hydrolysis the most again；(3) pass through between dinitro
Base benzene derivative prepares 4-nitroindoline.Although these methods have been achieved for the success in terms of laboratory, but all exist
Some defects such as reaction condition is harsher, costly or by-product is more high for raw material so that it is be difficult to large-scale industrial production.
Chinese patent 201010145377.8 discloses the preparation method of a kind of 4-nitroindoline, in flask, by 2-first
Base-3-Nitrobenzol, triethyl orthoformate, oxalic acid add by a certain percentage, after heating reflux reaction certain time, be cooled to 0～
After 10 DEG C, it is slowly added dropwise the ethanol solution of potassium ethoxide, after continuing reaction a period of time at normal temperatures, pours reactant liquor into frozen water
In, a large amount of solid occurs, sucking filtration obtains solid, is 4-nitroindoline.It is high that the method has yield, it is easy to the features such as operation.
But, this preparation method still employs some more dangerous reagent, has higher potential safety hazard.
Summary of the invention:
It is an object of the invention to provide the preparation method of a kind of 4-nitroindoline, the method uses ternary catalyst systems,
Reaction conversion ratio is high, and selectivity is strong.Further, needed for this preparation method, reaction condition is gentle, and reaction cost is relatively low, has higher
Industrial production prospect.
For achieving the above object, the present invention is by the following technical solutions:
The preparation method of a kind of 4-nitroindoline, comprises the following steps:
4-methoxyphenyl hydrazine hydrochloride is carried out nitration reaction and prepares 3-nitro-4-methoxyphenyl hydrazine hydrochloride, exist afterwards
Under catalyst, reacting with acetaldehyde, prepare 5-methoxyl group-4-nitroindoline, finally removing methoxyl group had both obtained required 4-nitro
Indole.
Preferably, the specific operation process of the preparation method of described 4-nitroindoline is:
(1) 4-methoxyphenyl hydrazine hydrochloride is dissolved in concentrated sulphuric acid, is added thereto to concentrated nitric acid, carry out nitration reaction,
Preparation 3-nitro-4-methoxyphenyl hydrazine hydrochloride；
(2) the 3-nitro-4-methoxyphenyl hydrazine hydrochloride of preparation is dissolved in DMF, adds a small amount of concentrated sulphuric acid, and urge
Agent mix homogeneously, add excess acetaldehyde, control temperature at 60-80 DEG C, back flow reaction 90-120min, reaction terminate after, mistake
Filter, prepares 5-methoxyl group-4-nitroindoline；
(3) prepared 5-methoxyl group-4-nitroindoline is dissolved in acetic acid/toluene solution, control temperature at 0-4 DEG C,
Add BBr3After reaction 30min, adding methanol, stopped reaction, after removed under reduced pressure solvent, recrystallization had both obtained required 4-nitro Yin
Diindyl.
Preferably, described catalyst is the mixture of zinc chloride, copper acetate and Columbium pentachloride..
Preferably, described catalyst be zinc chloride, copper acetate and Columbium pentachloride. mol ratio be the mixture of 6:2:1.
Preferably, described 4-methoxyphenyl hydrazine hydrochloride is 1:(1.2-1.5 with the mol ratio of concentrated nitric acid).
Preferably, described 3-nitro-4-methoxyphenyl hydrazine hydrochloride is 1:(0.02-with the mass ratio that feeds intake of catalyst
0.04)。
Preferably, described 5-methoxyl group-4-nitroindoline, BBr3And the mol ratio of methanol is 1:(2-3): (0.5-
0.8)。
Wherein, material is that those skilled in the art can infer according to prior art with the mass ratio of solvent,
This is no longer described in detail.
The invention have the advantages that, use novel composite catalyst, the effective selection improving substitution reaction
Property so that product purity is high, and productivity is high.Secondly, needed for course of reaction, condition is the gentleest, simple to operate, and energy waste is less.
In a word, the method running cost is low, and production efficiency is high, has good industrialization large-scale production prospect.
Detailed description of the invention:
In order to be better understood from the present invention, below by embodiment, the present invention is further described, and embodiment is served only for solving
Release the present invention, the present invention will not be constituted any restriction.
Embodiment 1
(1) 100mmol 4-methoxyphenyl hydrazine hydrochloride is dissolved in concentrated sulphuric acid, is added thereto to the dense nitre of 150mmol
Acid, carries out nitration reaction, prepares 3-nitro-4-methoxyphenyl hydrazine hydrochloride；
(2) the 10g 3-nitro-4-methoxyphenyl hydrazine hydrochloride of preparation is dissolved in DMF, adds a small amount of concentrated sulphuric acid, with
And 0.2g catalyst mix homogeneously, add excess acetaldehyde, control temperature at 70 DEG C, back flow reaction 90min, reaction terminate after,
Filter, prepare 5-methoxyl group-4-nitroindoline；
(3) prepared 10mmol 5-methoxyl group-4-nitroindoline is dissolved in acetic acid/toluene solution, controls temperature and exist
0-4 DEG C, add the BBr of 30mmol3After reaction 30min, add 7mmol methanol, stopped reaction, after removed under reduced pressure solvent, heavily tie
Crystalline substance had both obtained required 4-nitroindoline.
Embodiment 2
(1) 100mmol 4-methoxyphenyl hydrazine hydrochloride is dissolved in concentrated sulphuric acid, is added thereto to the dense nitre of 130mmol
Acid, carries out nitration reaction, prepares 3-nitro-4-methoxyphenyl hydrazine hydrochloride；
(2) the 10g 3-nitro-4-methoxyphenyl hydrazine hydrochloride of preparation is dissolved in DMF, adds a small amount of concentrated sulphuric acid, with
And 0.4g catalyst mix homogeneously, add excess acetaldehyde, control temperature at 60 DEG C, back flow reaction 90min, reaction terminate after,
Filter, prepare 5-methoxyl group-4-nitroindoline；
(3) prepared 10mmol 5-methoxyl group-4-nitroindoline is dissolved in acetic acid/toluene solution, controls temperature and exist
0-4 DEG C, add the BBr of 20mmol3After reaction 30min, add 5mmol methanol, stopped reaction, after removed under reduced pressure solvent, heavily tie
Crystalline substance had both obtained required 4-nitroindoline.
Embodiment 3
(1) 100mmol 4-methoxyphenyl hydrazine hydrochloride is dissolved in concentrated sulphuric acid, is added thereto to the dense nitre of 140mmol
Acid, carries out nitration reaction, prepares 3-nitro-4-methoxyphenyl hydrazine hydrochloride；
(2) the 10g 3-nitro-4-methoxyphenyl hydrazine hydrochloride of preparation is dissolved in DMF, adds a small amount of concentrated sulphuric acid, with
And 0.3g catalyst mix homogeneously, add excess acetaldehyde, control temperature at 70 DEG C, back flow reaction 100min, reaction terminate after,
Filter, prepare 5-methoxyl group-4-nitroindoline；
(3) prepared 10mmol 5-methoxyl group-4-nitroindoline is dissolved in acetic acid/toluene solution, controls temperature and exist
0-4 DEG C, add the BBr of 30mmol3After reaction 30min, add 7mmol methanol, stopped reaction, after removed under reduced pressure solvent, heavily tie
Crystalline substance had both obtained required 4-nitroindoline.
Embodiment 4
(1) 100mmol 4-methoxyphenyl hydrazine hydrochloride is dissolved in concentrated sulphuric acid, is added thereto to the dense nitre of 150mmol
Acid, carries out nitration reaction, prepares 3-nitro-4-methoxyphenyl hydrazine hydrochloride；
(2) the 10g 3-nitro-4-methoxyphenyl hydrazine hydrochloride of preparation is dissolved in DMF, adds a small amount of concentrated sulphuric acid, with
And 0.3g catalyst mix homogeneously, add excess acetaldehyde, control temperature at 80 DEG C, back flow reaction 120min, reaction terminate after,
Filter, prepare 5-methoxyl group-4-nitroindoline；
(3) prepared 10mmol 5-methoxyl group-4-nitroindoline is dissolved in acetic acid/toluene solution, controls temperature and exist
0-4 DEG C, add the BBr of 20mmol3After reaction 30min, add 8mmol methanol, stopped reaction, after removed under reduced pressure solvent, heavily tie
Crystalline substance had both obtained required 4-nitroindoline.
Claims (7)
1. the preparation method of a 4-nitroindoline, it is characterised in that comprise the following steps:
4-methoxyphenyl hydrazine hydrochloride is carried out nitration reaction and prepares 3-nitro-4-methoxyphenyl hydrazine hydrochloride, afterwards in catalysis
Under agent catalysis, reacting with acetaldehyde, prepare 5-methoxyl group-4-nitroindoline, finally removing methoxyl group had both obtained required 4-nitroindoline.
The preparation method of 4-nitroindoline the most according to claim 1, it is characterised in that: the preparation of described 4-nitroindoline
The specific operation process of method is:
(1) 4-methoxyphenyl hydrazine hydrochloride is dissolved in concentrated sulphuric acid, is added thereto to concentrated nitric acid, carry out nitration reaction, preparation
3-nitro-4-methoxyphenyl hydrazine hydrochloride；
(2) the 3-nitro-4-methoxyphenyl hydrazine hydrochloride of preparation is dissolved in DMF, adds a small amount of concentrated sulphuric acid, and catalyst
Mix homogeneously, add excess acetaldehyde, control temperature at 60-80 DEG C, back flow reaction 90-120min, reaction terminate after, filter,
Prepare 5-methoxyl group-4-nitroindoline；
(3) being dissolved in acetic acid/toluene solution by prepared 5-methoxyl group-4-nitroindoline, control temperature, at 0-4 DEG C, adds
BBr3After reaction 30min, adding methanol, stopped reaction, after removed under reduced pressure solvent, recrystallization had both obtained required 4-nitroindoline.
The preparation method of 4-nitroindoline the most according to claim 1, it is characterised in that: described catalyst be zinc chloride,
Copper acetate and the mixture of Columbium pentachloride..
The preparation method of 4-nitroindoline the most according to claim 1, it is characterised in that: described catalyst be zinc chloride,
Copper acetate and Columbium pentachloride. mol ratio are the mixture of 6:2:1.
The preparation method of 4-nitroindoline the most according to claim 1, it is characterised in that: described 4-methoxyl group phenyl hydrazine hydrochloride
Salt is 1:(1.2-1.5 with the mol ratio of concentrated nitric acid).
The preparation method of 4-nitroindoline the most according to claim 1, it is characterised in that: described 3-nitro-4-methoxyl group
Hydrazinobenzene hydrochloride salt is 1:(0.02-0.04 with the mass ratio that feeds intake of catalyst).
The preparation method of 4-nitroindoline the most according to claim 1, it is characterised in that: described 5-methoxyl group-4-nitro
Indole, BBr3And the mol ratio of methanol is 1:(2-3): (0.5-0.8).
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610631503.8A CN106243010A (en) | 2016-08-02 | 2016-08-02 | A kind of preparation method of 4 nitroindolines |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107954917A (en) * | 2017-11-03 | 2018-04-24 | 苏州艾缇克药物化学有限公司 | A kind of preparation method of 4- oxyindoles |
| CN108084076A (en) * | 2017-12-21 | 2018-05-29 | 苏州艾缇克药物化学有限公司 | A kind of synthetic method of 5- bromo-7-azaindoles |
-
2016
- 2016-08-02 CN CN201610631503.8A patent/CN106243010A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107954917A (en) * | 2017-11-03 | 2018-04-24 | 苏州艾缇克药物化学有限公司 | A kind of preparation method of 4- oxyindoles |
| CN108084076A (en) * | 2017-12-21 | 2018-05-29 | 苏州艾缇克药物化学有限公司 | A kind of synthetic method of 5- bromo-7-azaindoles |
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