CN106397446B - A method of preparing 2- (piperazine -1- base) -8- flutamine ketone - Google Patents
A method of preparing 2- (piperazine -1- base) -8- flutamine ketone Download PDFInfo
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- CN106397446B CN106397446B CN201610790519.3A CN201610790519A CN106397446B CN 106397446 B CN106397446 B CN 106397446B CN 201610790519 A CN201610790519 A CN 201610790519A CN 106397446 B CN106397446 B CN 106397446B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of new method for preparing 2- (piperazine -1- base) -8- flutamine ketone (I).This method for raw material, passes through switch ring and brief two steps synthesis target product (I) of amination with 5- amino isatoic anhydride (II) and 5- fluoro indigo red (III).The advantages that this method has experimental implementation simple, environmental-friendly, and yield high effect is good, therefore it is suitable for industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, are used to prepare 2- (piperazine -1- base) -8- in particular to one kind
The new method of flutamine ketone.
Background technique
Indoleamine 2,3-dioxygenase (indoleamine 2,3-dioxygenase, IDO) is a kind of catalysis tryptophan edge
The rate-limiting enzyme of kynurenine pathway catabolism.The enzyme is it is verified that with tumour, Alzheimer disease, autoimmune disease
Etc. pathogenesis close association, therefore the research of IDO inhibitor have preferable research background.
Couroupitine A (Tryptanthrine) is indole quinazoline Alkaloid, has extensive pharmacological activity and biology living
Property.In terms of bioactivity, couroupitine A has the effects that antibacterial, anti-inflammatory, pre- anti-cancer, antitumor, antimalarial and anti parasitic,
It or a kind of antagonist of novel aromatic compound receptor.In terms of pharmacological action, couroupitine A is extensive and low thin because of its
Cellular toxicity, very rare in medicine resource, research and development new drug has extensive reference.
According to the patent CN103570726 delivered, which is by aoxidizing 5-bromoisatin, and cyclization replaces, remove-insurance
Totally four step synthesising target compound 2- (piperazine -1- base) -8- flutamine ketone, specific synthetic route are as follows for shield:
The reaction overall yield is lower, and third step and the 4th step are to chromatograph to obtain by column, and use heavy metal
Palladium makees catalyst, endangers Environmental security, carries out Large scale processes preparation as the new drug researched and developed, it is clear that be unworkable.
Therefore, it is necessary to redesign new synthetic route, new Research idea is provided for the compound.
Summary of the invention
The object of the present invention is to provide a kind of mild conditions, and reaction is simple, environmental-friendly, are suitble to large-scale production 2- (piperazine
Piperazine -1- base) -8- flutamine ketone method.
The first aspect of the present invention provides a kind of method for preparing 2- (piperazine -1- base) -8- flutamine ketone (I), special
Sign is, comprising steps of
In formula, X=Br, Cl；
(1) it in atent solvent, is reacted with formula (II) compound and formula (III) compound, obtains formula (IV) compound；
(2) it in atent solvent, is reacted with formula (IV) compound and formula (V) compound, obtains formula (I) compound.
In another preferred example, the step (1) carries out in the presence of base catalyst；Preferably, the base catalysis
Agent is selected from the group: triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DMF, DBU, DMAP, 2,6- lutidines,
2,2,6,6- tetramethyl piperazines, piperazine, morpholine, or combinations thereof.
In another preferred example, in the step (1), the atent solvent is selected from the group: tetrahydrofuran, toluene,
Dimethylbenzene, dioxane, acetonitrile, propionitrile, or combinations thereof.
In another preferred example, the reaction temperature of the step (1) is 50~120 DEG C, preferably 70~110 DEG C.
In another preferred example, in the step (1), the formula (II) compound and formula (III) compound rub
You are than being 1:0.5-2, preferably 1:0.8-1.2.
In another preferred example, in the step (1), the molar ratio of the formula (III) compound and base catalyst
For 1:0.5-2, preferably 1:0.8-1.2.
In another preferred example, in the step (2), the reaction carries out in catalyst selected from the group below: carbon
Sour sodium, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine,
DMF, DBU, DMAP, 2,6- lutidines, 2,2,6,6- tetramethyl piperazines, piperazine, morpholine, or combinations thereof；It is preferred that sodium carbonate,
Potassium carbonate, or combinations thereof.
In another preferred example, in the step (2), the atent solvent is selected from the group: water, methanol, and ethyl alcohol is different
Propyl alcohol, the tert-butyl alcohol, tetrahydrofuran, toluene, dimethylbenzene, dioxane, or combinations thereof；It is preferred that water, methanol, ethyl alcohol, or combinations thereof.
In another preferred example, in the step (2), mole of the formula (IV) compound and formula (V) compound
Than for 0.5-2:1, preferably 0.8-1.2:1.
In another preferred example, in the step (2), the molar ratio of the formula (V) compound and base catalyst is
2:0.5-2 preferably 2:0.8-1.2.
In another preferred example, the step (2) reaction temperature is 50~110 DEG C, preferably 60~100 DEG C.
In another preferred example, the step (2) carries out under neutral or basic conditions.
The second aspect of the present invention provides a kind of method for preparing 2- (piperazine -1- base) -8- flutamine ketone (I), described
Method comprising steps of
(2) it in atent solvent, is reacted with formula (IV) compound and formula (V) compound, obtains formula (I) compound.
In another preferred example, in the step (2), the reaction carries out in catalyst selected from the group below: carbon
Sour sodium, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine,
DMF, DBU, DMAP, 2,6- lutidines, 2,2,6,6- tetramethyl piperazines, piperazine, morpholine, or combinations thereof；It is preferred that sodium carbonate,
Potassium carbonate, or combinations thereof.
In another preferred example, in the step (2), the atent solvent is selected from the group: water, methanol, and ethyl alcohol is different
Propyl alcohol, the tert-butyl alcohol, tetrahydrofuran, toluene, dimethylbenzene, dioxane, or combinations thereof；It is preferred that water, methanol, ethyl alcohol, or combinations thereof.
In another preferred example, the step (1) reaction temperature is 50~110 DEG C, preferably 60~100 DEG C.
In another preferred example, the formula (IV) compound is prepared by the following method:
(1) it in atent solvent, is reacted with formula (II) compound and formula (III), obtains formula (IV) compound.
In another preferred example, the step (1) carries out in the presence of base catalyst, it is preferable that the base catalysis
Agent is selected from the group: triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DMF, DBU, DMAP, 2,6- lutidines,
2,2,6,6- tetramethyl piperazines, piperazine, morpholine, or combinations thereof；And in the step (1), the atent solvent is selected from down
Group: tetrahydrofuran, toluene, dimethylbenzene, dioxane, acetonitrile, propionitrile, or combinations thereof.
In another preferred example, the reaction temperature of the step (1) is 50~120 DEG C, preferably 70~110 DEG C.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
This project group on the basis of research has a clear understanding of couroupitine A biosynthetic process, close at bio-mimetic syntheses route by exploitation
At 2- (piperazine -1- base) -8- flutamine ketone.This method high, at low cost, environmentally protective, easy to operate, reaction condition with yield
The features such as mild, therefore it is able to carry out industrialization new drug development.
2- (piperazine -1- base) -8- flutamine ketone and its preparation
2- (piperazine -1- base) -8- flutamine ketone is a kind of compound with IDO enzyme inhibition activity, can be used for having
The disease of the pathological characteristics for the tryptophan metabolic pathway that IDO is mediated, can be used as the IDO inhibitor of high activity, for having
The disease of the pathological characteristics for the tryptophan metabolic pathway that IDO is mediated, including tumour, cancer, Alzheimer disease, autoimmunity
The treatment of the major diseases such as property disease, cataract, mental handicape, depression, anxiety disorder and AIDS, as very rare
Medicine resource, the potentiality with good research and development new drug.Its specific structural formula are as follows:
However, the method for preparing 2- (piperazine -1- base) -8- flutamine ketone in the prior art needs to urge using heavy metal palladium
Agent, and need to purify using column chromatography scheme, therefore be not suitable for industrialized production.In this regard, being prepared the present invention provides a kind of
The new method of 2- (piperazine -1- base) -8- flutamine ketone (I).This method is with 5- amino isatoic anhydride (II) and 5- fluoro indigo red (III)
Have experimental implementation simple, environmental-friendly, yield by switch ring and brief two steps synthesis target product (I) of amination for raw material
The advantages that high effect is good, therefore it is suitable for industrialized production.
The preparation of 2- (piperazine -1- base) -8- flutamine ketone
The present invention provides a kind of 2- (piperazine -1- base) -8- flutamine ketone to prepare variation route.This method has synthesis road
The short novelty of line, environmental-friendly, the advantages that income is good, high efficiency.The method includes the following steps:
Wherein, X is Cl or Br；
(1), the preparation of 2- amino base -8- flutamine ketone (IV)
5- amino isatoic anhydride (II) and 5- fluoro indigo red (III) are distributed in suitable solvent, no catalyst or addition are closed
Suitable base catalyst completes reaction at a proper temperature, obtains 2- amino -8- flutamine ketone (IV).
In preferred embodiment, the step (1) carries out in the presence of a catalyst,
Wherein: suitable solvent is tetrahydrofuran, toluene, dimethylbenzene, dioxane, acetonitrile, propionitrile, preferably toluene, two
Toluene；Suitable catalyst of triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DMF, DBU, DMAP, 2,6- diformazans
Yl pyridines, 2,2,6,6- tetramethyl piperazines, piperazine, morpholine, preferably triethylamine, diisopropyl ethyl amine；Divide at a temperature of suitable
It criticizes and is added, reaction temperature is 50~120 DEG C, preferably 70~110 DEG C.
(2), the preparation of 2- (piperazine -1- base) -8- flutamine ketone (I)
2- amido -8- flutamine ketone (IV) and two (2- halogenated ethyl) amine hydrochlorates (V) are mixed with suitable solvent, then
Suitable base catalyst is added, completes reaction at a proper temperature, obtains compound 2- (piperazine -1- through processing appropriate
Base) -8- flutamine ketone (I).
Wherein: suitable solvent is water, methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran, toluene, dimethylbenzene, dioxy
Six rings, preferably water, methanol, ethyl alcohol.Most preferred solvent is the mixed solvent of water and ethyl alcohol, more preferably water: ethyl alcohol=1:
0.5-2, the preferably solvent of 1:0.8-1.2.
Catalyst appropriate be sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, two
Diisopropylethylamine, N-methylmorpholine, DMF, DBU, DMAP, 2,6- lutidines, 2,2,6,6- tetramethyl piperazines, piperazine,
Morpholine, preferably sodium carbonate, potassium carbonate；Be added portionwise at a temperature of suitable, reaction temperature be 50~110 DEG C, preferably 60~100
℃。
The feature that the features described above or embodiment that the present invention mentions are mentioned can be in any combination.Disclosed in this case specification
All features can be used in combination with any composition form, each feature disclosed in specification, can by it is any provide it is identical,
The alternative characteristics of impartial or similar purpose replace.Therefore except there is special instruction, revealed feature is only impartial or similar spy
The general example of sign.
The invention has the beneficial effects that:
(1) the present invention provides a kind of novel IDO inhibitor preparation methods, and the method total recovery is high, and uncomfortable
It is environmental-friendly with heavy metal catalyst, it is suitble to industrialization large-scale production.
(2) compared to known method, inventive substrate (II) yield when reacting with 5- fluoro indigo red is greatly promoted, and then leads
Preparation method total recovery is caused to be promoted.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Embodiment 1.
(1), the preparation of 2- amino -8- flutamine ketone (IV)
5- amino isatoic anhydride (II) (22.6g, 127.2mmol) is added in the three-neck flask of 250ml, 5- fluoro indigo red
(III) (20g, 121.1mmol), triethylamine (12.3g, 121.1mmol) and toluene (200ml) are placed in oil bath after stirring 15min
In be heated to 100 DEG C, be stirred to react 2h, TLC detection, reaction is completed.It is cooled to room temperature, filters, washed with a small amount of toluene, dries,
Obtain product 2- amino -8- flutamine ketone (IV) 32.5g, yield 95.3%.
(2), the preparation of 2- (piperazine -1- base) -8- flutamine ketone (I)
2- amido -8- flutamine ketone (IV) (10g, 35.6mmol), two (2- chloroethyl) amine hydrochlorates (V) (6.7g,
It 37.3mmol) is dissolved in ethanol/water (1:1,100mL) mixed solution, adds sodium carbonate (7.55g, 71.2mmol), heat back
2h, TLC detection are flowed, reaction is completed, filtered, and a small amount of ethanol/water (1:1) washing, drying obtains compound 2- (piperazine -1- base) -
8- flutamine ketone (I) 11.7g, yield 93.9%.
Embodiment 2.
(1), the preparation of 2- amino -8- flutamine ketone (IV)
5- amino isatoic anhydride (II) (22.6g, 127.2mmol) is added in the three-neck flask of 250ml, 5- fluoro indigo red
(III) (20g, 121.1mmol) and toluene (200ml) are placed in oil bath after stirring 15min and are heated to 100 DEG C, be stirred to react
2h, TLC detection, reaction are completed.It is cooled to room temperature, filters, washed with a small amount of toluene, dries, obtain product 2- amino -8- flutamine ketone
(IV) 21.6g, yield 63.4%.
(2), the preparation of 2- (piperazine -1- base) -8- flutamine ketone (I)
2- amido -8- flutamine ketone (IV) (10g, 35.6mmol), two (2- chloroethyl) amine hydrochlorates (V) (6.7g,
It 37.3mmol) is dissolved in ethanol/water (1:1,100mL) mixed solution, adds potassium carbonate (10g, 71.2mmol), be heated to reflux
2h, TLC detection, reaction are completed, and are filtered, and a small amount of ethanol/water (1:1) washing, drying obtains compound 2- (piperazine -1- base) -8-
Flutamine ketone (I) 12.02g, yield 96.4%.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (16)
1. a kind of method for preparing 2- (piperazine -1- base) -8- flutamine ketone (I), which is characterized in that comprising steps of
In formula, X=Br, Cl；
(1) it in atent solvent, is reacted with formula (II) compound and formula (III), obtains formula (IV) compound；
The step (1) carries out in the presence of optional base catalyst, and the base catalyst is selected from the group: triethylamine, pyrrole
Pyridine, diisopropyl ethyl amine, N-methylmorpholine, DMF, DBU, DMAP, 2,6- lutidines, 2,2,6,6- tetramethyl piperazines,
Piperazine, morpholine, or combinations thereof；
The molar ratio of formula (II) compound and formula (III) compound is 1:0.5-2；
The molar ratio of formula (III) compound and base catalyst is 1:0.5-2；
(2) it in ethanol/water solvent, is reacted with formula (IV) compound and formula (V) compound, obtains formula (I) compound；Wherein,
Water: ethyl alcohol=1:0.8-1.2；
In the step (2), the reaction carries out in catalyst selected from the group below: sodium carbonate, potassium carbonate, bicarbonate
Sodium, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DMF, DBU, DMAP, 2,6-
Lutidines, 2,2,6,6- tetramethyl piperazines, piperazine, morpholine, or combinations thereof；
The molar ratio of formula (IV) compound and formula (V) compound is 0.5-2:1；
The molar ratio of formula (V) compound and base catalyst is 2:0.5-2.
2. the method as described in claim 1, which is characterized in that in the step (1), the formula (II) compound and formula
(III) molar ratio of compound is 1:0.8-1.2.
3. the method as described in claim 1, which is characterized in that the base catalyst is triethylamine.
4. the method as described in claim 1, which is characterized in that in the step (1), the formula (III) compound and
The molar ratio of base catalyst is 1:0.8-1.2.
5. the method as described in claim 1, which is characterized in that in the step (2), the reaction is selected from the group below
It is carried out in catalyst: sodium carbonate, potassium carbonate, or combinations thereof.
6. the method as described in claim 1, which is characterized in that in the step (2), the formula (IV) compound and formula
(V) molar ratio of compound is 0.8-1.2:1.
7. the method as described in claim 1, which is characterized in that in the step (2), the formula (V) compound and alkali
The molar ratio of catalyst is 2:0.8-1.2.
8. a kind of method for preparing 2- (piperazine -1- base) -8- flutamine ketone (I), which is characterized in that comprising steps of
(2) it in ethanol/water solvent, is reacted with formula (IV) compound and formula (V) compound, obtains formula (I) compound；Wherein,
Water: ethyl alcohol=1:0.8-1.2；
In formula, X=Br, Cl；
In the step (2), the reaction carries out in catalyst selected from the group below: sodium carbonate, potassium carbonate, bicarbonate
Sodium, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DMF, DBU, DMAP, 2,6-
Lutidines, 2,2,6,6- tetramethyl piperazines, piperazine, morpholine, or combinations thereof；
The molar ratio of formula (IV) compound and formula (V) compound is 0.5-2:1；
The molar ratio of formula (V) compound and base catalyst is 2:0.5-2.
9. method according to claim 8, which is characterized in that step (2) reaction temperature is 50~110 DEG C.
10. method according to claim 8, which is characterized in that in the step (2), the reaction is being selected from the group
Catalyst in carry out: sodium carbonate, potassium carbonate, or combinations thereof.
11. method according to claim 8, which is characterized in that in the step (2), the formula (IV) compound and
The molar ratio of formula (V) compound is 0.8-1.2:1.
12. method according to claim 8, which is characterized in that in the step (2), the formula (V) compound and alkali
The molar ratio of catalyst is 2:0.8-1.2.
13. method according to claim 8, which is characterized in that described formula (IV) compound is to be prepared by the following method
:
(1) it in atent solvent, is reacted with formula (II) compound and formula (III), obtains formula (IV) compound；
The step (1) carries out in the presence of base catalyst, and the base catalyst is selected from the group: triethylamine, pyridine, two is different
Ethylamine, N-methylmorpholine, DMF, DBU, DMAP, 2,6- lutidines, 2,2,6,6- tetramethyl piperazines, piperazine,
Quinoline, or combinations thereof；
The molar ratio of formula (II) compound and formula (III) compound is 1:0.5-2；
The molar ratio of formula (III) compound and base catalyst is 1:0.5-2.
14. method as claimed in claim 13, which is characterized in that in the step (1), the formula (II) compound and
The molar ratio of formula (III) compound is 1:0.8-1.2.
15. method as claimed in claim 13, which is characterized in that the base catalyst is triethylamine.
16. method as claimed in claim 13, which is characterized in that in the step (1), the atent solvent is selected from down
Group: tetrahydrofuran, toluene, dimethylbenzene, dioxane, acetonitrile, propionitrile, or combinations thereof.
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