CN110372687A - A kind of Preparation method and use of 4- (4- ethylamino- phenyl) morpholine -3- ketone - Google Patents
A kind of Preparation method and use of 4- (4- ethylamino- phenyl) morpholine -3- ketone Download PDFInfo
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- CN110372687A CN110372687A CN201910507497.9A CN201910507497A CN110372687A CN 110372687 A CN110372687 A CN 110372687A CN 201910507497 A CN201910507497 A CN 201910507497A CN 110372687 A CN110372687 A CN 110372687A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to drug field more particularly to a kind of Preparation method and use of 4- (4- ethylamino- phenyl) morpholine -3- ketone, which includes: to prepare 4- (4- aminophenyl) morpholine -3- ketone and acetaldehyde；The 4- (4- aminophenyl) morpholine -3- ketone and the acetaldehyde are added in reaction dissolvent；Reducing agent is added in the reaction dissolvent to be reacted, 4- (4- ethylamino- phenyl) morpholine -3- ketone is obtained.The preparation method is using 4- (4- aminophenyl) morpholine -3- ketone and acetaldehyde as raw material, under the action of reducing agent, it is reacted in reaction dissolvent, preparation method route is simple, appointed condition is of less demanding, 4- (4- ethylamino- phenyl) morpholine -3- ketone is prepared so as to more easy, safer, the quality for effectively controlling 4- (4- aminophenyl) morpholine -3- ketone is of great significance.
Description
Technical field
The invention belongs to drug fields, and in particular to a kind of preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone and
Purposes.
Background technique
4- (4- ethylamino- phenyl) morpholine -3- ketone is starting material 4- (4- aminophenyl) morpholine -3- ketone of razaxaban
One of impurity, razaxaban is usually with the adjacent benzene of 4- (4- aminophenyl) morpholine -3- ketone and (S)-N- (2,3- glycidyl)
Dicarboximide is raw material, is substituted, is deprotected, being condensed, turning brilliant and etc. and be made, and 4- (4- aminophenyl) morpholine -3- ketone
In 4- (4- ethylamino- phenyl) morpholine -3- ketone and (S)-N- (2,3- glycidyl) phthalimide can occur instead
It answers, generates the impurity of razaxaban as follows:
The presence of impurity not only influences whether the purity of razaxaban, it is also possible to the toxic side effect of non-therapeutic can be brought,
And the preparation method step of 4- (4- ethylamino- phenyl) morpholine -3- ketone is more at present, equipment requirement is higher, it is thus determined that a kind of 4-
The preparation method of (4- ethylamino- phenyl) morpholine -3- ketone has the quality for effectively controlling 4- (4- aminophenyl) morpholine -3- ketone
Significance.
Summary of the invention
The purpose of the present invention is to provide a kind of Preparation method and uses of 4- (4- ethylamino- phenyl) morpholine -3- ketone, can
4- (4- ethylamino- phenyl) morpholine -3- ketone is prepared with more easy, safer, for effectively controlling 4- (4- aminobenzene
Base) quality of morpholine -3- ketone is of great significance.
For achieving the above object, The technical solution adopted by the invention is as follows:
One aspect of the present invention provides a kind of preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone, comprising:
Prepare 4- (4- aminophenyl) morpholine -3- ketone and acetaldehyde；
The 4- (4- aminophenyl) morpholine -3- ketone and the acetaldehyde are added in reaction dissolvent；
Reducing agent is added in the reaction dissolvent to be reacted, 4- (4- ethylamino- phenyl) morpholine -3- ketone is obtained.
In a kind of preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone provided by the invention, with 4- (4- aminobenzene
Base) morpholine -3- ketone and acetaldehyde is that raw material is reacted in reaction dissolvent under the action of reducing agent, preparation method route letter
Single, appointed condition is of less demanding, can be more easy, safer prepare 4- (4- ethylamino- phenyl) morpholine -3- ketone, it is right
It is of great significance in the quality of effectively control 4- (4- aminophenyl) morpholine -3- ketone.
Another aspect of the present invention provides a kind of purposes of 4- (4- ethylamino- phenyl) morpholine -3- ketone, utilizes above-mentioned preparation
The purity of 4- (4- ethylamino- phenyl) morpholine -3- ketone that method obtains is higher, for having in 4- (4- aminophenyl) morpholine -3- ketone
It closes when substance checks as standard reference material.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy spectrogram of 4- (4- ethylamino- phenyl) morpholine -3- ketone made from the embodiment of the present invention 1；
Fig. 2 is the high performance liquid chromatography spectrogram of 4- (4- ethylamino- phenyl) morpholine -3- ketone made from the embodiment of the present invention 1.
Specific embodiment
In order to which technical problems, technical solutions and advantageous effects to be solved by the present invention are more clearly understood, below in conjunction with
Embodiment, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only used to explain
The present invention is not intended to limit the present invention.
On the one hand, the embodiment of the invention provides a kind of preparation methods of 4- (4- ethylamino- phenyl) morpholine -3- ketone, including
Following steps:
Step S10 prepares 4- (4- aminophenyl) morpholine -3- ketone and acetaldehyde；
The 4- (4- aminophenyl) morpholine -3- ketone and the acetaldehyde are added in reaction dissolvent step S20；
Step S30 is added reducing agent in the reaction dissolvent and is reacted, obtains 4- (4- ethylamino- phenyl) morpholine -3-
Ketone.
In a kind of preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone provided in an embodiment of the present invention, with 4- (4- ammonia
Base phenyl) morpholine -3- ketone and acetaldehyde is that raw material is reacted in reaction dissolvent under the action of reducing agent, preparation method road
Line is simple, and appointed condition is of less demanding, can be more easy, safer prepare 4- (4- ethylamino- phenyl) morpholine -3-
Ketone, the quality for effectively controlling 4- (4- aminophenyl) morpholine -3- ketone are of great significance.
Further, in step slo, the molar ratio of the acetaldehyde and the 4- (4- aminophenyl) morpholine -3- ketone is 1
~6, for example, the molar ratio of acetaldehyde and 4- (4- aminophenyl) morpholine -3- ketone can be 1,1.5,2,4,6 etc..In the present embodiment
The molar ratio for controlling acetaldehyde and 4- (4- aminophenyl) morpholine -3- ketone is 1~6, it is ensured that reaction is normally carried out, while can be with
Avoid one of substance inventory too small or excessive.Preferably, the acetaldehyde and the 4- (4- aminophenyl) morpholine -3- ketone
Molar ratio be 3~5, such as the molar ratio of acetaldehyde and 4- (4- aminophenyl) morpholine -3- ketone can be 3,3.5,4.5,5 etc.,
Under this molar ratio, the yield of obtained 4- (4- ethylamino- phenyl) morpholine -3- ketone is higher.
Further, in step S20, the reaction dissolvent includes anhydrous methanol, dehydrated alcohol or tetrahydrofuran.It is anhydrous
Methanol, dehydrated alcohol and tetrahydrofuran have preferable dissolubility to reaction raw materials 4- (4- aminophenyl) morpholine -3- ketone and acetaldehyde,
It can make the progress of rapid reaction.
Further, in step S20, when reaction dissolvent includes anhydrous methanol, anhydrous methanol and 4- (4- aminobenzene
Base) morpholine -3- ketone mass ratio be 10~20, for example, the quality of anhydrous methanol and the 4- (4- aminophenyl) morpholine -3- ketone
Than that can be 10,11,15,17,19,20.When the amount that anhydrous methanol is added is less, dissolution of raw material may be made incomplete, from
And the yield of 4- (4- ethylamino- phenyl) morpholine -3- ketone is caused to reduce；When the amount of addition anhydrous methanol is excessive, so that 4- (4- ammonia
Base phenyl) morpholine -3- ketone and acetaldehyde concentration it is too low, to reduce reaction rate, the present embodiment controls anhydrous methanol and 4- (4-
Aminophenyl) morpholine -3- ketone mass ratio be 10~20, neither will cause the waste of raw material, and can guarantee rapid reaction
It carries out.Preferably, the mass ratio of anhydrous methanol and 4- (4- aminophenyl) morpholine -3- ketone is 12~14, for example, anhydrous methanol with
The mass ratio of 4- (4- aminophenyl) morpholine -3- ketone can be 12,12.5,13,13.5,14, can guarantee 4- (4- second at this time
Aminocarbonyl phenyl) morpholine -3- ketone yield while so that reaction be more rapidly performed by.
Further, in step s 30, the reducing agent includes sodium triacetoxy borohydride, sodium cyanoborohydride, first
Sour ammonium and palladium carbon, hydrogen and palladium carbon, sodium borohydride or zinc borohydride.Wherein, sodium triacetoxy borohydride is a kind of selectivity
, relatively mild go back original reagent, and only one hydride ion in sodium triacetoxy borohydride, so as to more tight
The dosage of the control sodium triacetoxy borohydride of lattice；Sodium cyanoborohydride is dissolved in methanol, tetrahydrofuran, is that one kind is mild also
Former agent；Ammonium formate and palladium carbon are similar as the principle of reducing agent to hydrogen and palladium carbon as reducing agent, ammonium formate and hydrogen conduct
Hydrogen donor, palladium carbon capture hydrogen and activate to be reacted；Under sodium borohydride normal temperature and pressure stablize, be most common reducing agent it
One, operation processing is easy, and has stronger selective reduction；Zinc borohydride is dissolved in tetrahydrofuran, is that one kind is mild also
Former agent.Above-mentioned reducing agent is selected in the present embodiment with can making rapid reaction, leniently carry out.
Further, in step s 30, the sodium triacetoxy borohydride and the 4- (4- aminophenyl) morpholine-
The molar ratio of 3- ketone is 0.5~5, for example, the molar ratio of sodium triacetoxy borohydride and 4- (4- aminophenyl) morpholine -3- ketone
It can be 0.5,1,3,3.5,4,5.When the amount of sodium triacetoxy borohydride is very few, the reaction raw materials 4- when reaction was completed
(4- aminophenyl) morpholine -3- ketone and acetaldehyde might have residue, to reduce the production of 4- (4- ethylamino- phenyl) morpholine -3- ketone
Rate；When the amount of sodium triacetoxy borohydride is excessive, it may appear that after the completion of reaction, still there is more triacetoxy borohydride
Sodium hydride is remaining, to cause the waste of reducing agent.Sodium triacetoxy borohydride and 4- (4- ammonia are controlled in the embodiment of the present invention
Base phenyl) molar ratio range of morpholine -3- ketone is 0.5~5, it is ensured that and reaction is normally carried out, and avoids any one participation
The substance of reaction causes to waste because inventory is excessive.Preferably, the sodium triacetoxy borohydride and the 4- (4- are controlled
Aminophenyl) molar ratio of morpholine -3- ketone is 1.5~2.5, for example, sodium triacetoxy borohydride and 4- (4- aminophenyl)
The molar ratio of morpholine -3- ketone can be 1.5,1.7,2,2.3,2.5 etc., under this molar ratio, finally obtained 4- (4- ethylamino-
Phenyl) morpholine -3- ketone yield it is higher.
Further, step S30 includes:
The reducing agent is added in the reaction dissolvent and is reacted by step S31；
Step S32 adjusts the pH to 7~8 of the reaction dissolvent；
Step S33, is extracted using organic solvent；
Organic solvent extracted is evaporated by step S34, obtains the 4- (4- ethylamino- phenyl) morpholine -3- ketone.
The pH value for adjusting reaction dissolvent using sodium hydroxide solution in step s 32, for destroying excessive reducing agent, because
4- (4- ethylamino- phenyl) morpholine -3- ketone is weak base, therefore pH value is adjusted to 7~8, is then concentrated under reduced pressure, and is improved anti-
The concentration of each substance in solvent is answered, so that effect of extracting is preferable when step S33 is extracted using organic solvent, by concentration
After more 4- (4- ethylamino- phenyl) morpholine -3- ketone is transferred in organic solvent, wherein organic solvent can be dichloro
After being evaporated organic solvent extracted, 4- (4- ethylamino- phenyl) morpholine -3- ketone is can be obtained in methane.
Further, step S34 includes:
It is evaporated organic solvent extracted to obtain solid；
By the solid column chromatographic purifying, obtaining white solid is the 4- (4- ethylamino- phenyl) morpholine -3- ketone.
Not only contain 4- (4- ethamine in the organic solvent obtained after step S33 is extracted using organic solvent
Base phenyl) morpholine -3- ketone, therefore obtained after organic solvent is evaporated as 4- (4- ethylamino- phenyl) morpholine -3- ketone crude product, wherein
There can be impurity, to need obtained 4- (4- ethylamino- phenyl) morpholine -3- ketone crude product carrying out column chromatographic purifying, because of 4-
Each component is different with distribution coefficient in mobile phase in stationary phase in (4- ethylamino- phenyl) morpholine -3- ketone crude product, through repeatedly anti-
Subdivision matches the higher 4- of available concentration (4- ethylamino- phenyl) morpholine -3- ketone white solid.
A kind of preferred steps of the preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone of the embodiment of the present invention are as follows:
Step S1 prepares 4- (4- aminophenyl) morpholine -3- ketone and acetaldehyde, wherein acetaldehyde and 4- (4- aminophenyl)
The molar ratio of quinoline -3- ketone is 1.5~2.5.
4- (4- aminophenyl) morpholine -3- ketone and acetaldehyde are added in anhydrous methanol step S2, wherein anhydrous methanol with
The mass ratio of 4- (4- aminophenyl) morpholine -3- ketone is 12~14.
Step S3 is added sodium triacetoxy borohydride in anhydrous methanol and is reacted, wherein triacetoxy borohydride hydrogen
The molar ratio for changing sodium and 4- (4- aminophenyl) morpholine -3- ketone is 1.5~2.5, adjusts pH to 7~8；It is carried out using methylene chloride
Extraction, is evaporated methylene chloride extracted to obtain solid, and by solid column chromatographic purifying, obtaining white solid is 4- (4- ethamine
Base phenyl) morpholine -3- ketone.
On the other hand, the embodiment of the invention provides a kind of purposes of 4- (4- ethylamino- phenyl) morpholine -3- ketone, in utilization
The purity for stating 4- (4- ethylamino- phenyl) morpholine -3- ketone that preparation method obtains is higher, in 4- (4- aminophenyl) morpholine -
As standard reference material when 3- ketone Related substances separation.
The present invention successively carried out test of many times, now lifts A partial experiment result as reference, carries out to invention further
Detailed description, is described in detail combined with specific embodiments below.
Embodiment 1
Step S1, prepares 5.00g 4- (4- aminophenyl) morpholine -3- ketone (26.01mmol) and 40% acetaldehyde of 7.3mL is molten
Liquid (52.02mmol).
50mL is added without water beetle in ready 4- (4- aminophenyl) morpholine -3- ketone and 40% acetaldehyde solution by step S2
In alcohol, it is stirred at room temperature.
11.00g sodium triacetoxy borohydride (52.02mmol) is added portionwise in anhydrous methanol and carries out instead by step S3
It answers, finishes, be stirred overnight at room temperature；PH to 7~8 is adjusted with the sodium hydroxide solution of 2mol/L, is concentrated under reduced pressure, residue utilization two
Chloromethanes is extracted, and is washed to organic phase extracted, is evaporated to obtain solid；By solid column chromatographic purifying, obtain white
Color solid 4.01g, yield 70%.
Obtained white solid product is identified using nuclear magnetic resonance chemical analyser:
Nuclear magnetic resonance chemical analyser: Bruker500MHz AVANCEIII HD；
The nucleus magnetic hydrogen spectrum spectrogram of white solid product as shown in Figure 1,
1H-NMR(DMSO-d6) δ 1.137~1.165 (t, 3H), 3.009~3.034 (q, 2H), 3.585~3.605 (t,
2H), 3.909~3.929 (t, 2H), 4.130 (s, 2H), 6.527~6.545 (d, 2H), 7.007~7.024 (d, 2H).
Spectrum analysis is as follows:
Therefore it can determine that above-mentioned white solid product is 4- (4- ethylamino- phenyl) morpholine -3- ketone.
The purity detecting of 4- (4- ethylamino- phenyl) morpholine -3- ketone:
It is appropriate accurately to weigh 4- (4- ethylamino- phenyl) morpholine -3- ketone, add methanol to dissolve and dilute be made in every 1mL containing about
The solution of 1mg, as test solution, according to Chinese Pharmacopoeia four 0512 high performance liquid chromatographies of general rule of version in 2015 to for examination
Product solution is measured, and is filler with bonding phenyl Bio-sil microballoon stationary phase；Using water as mobile phase A, acetonitrile is flowing
Phase B, according to the form below carry out gradient elution；Flow velocity is 0.6mL per minute；Column temperature is 35 DEG C；Detection wavelength is 210nm, 240nm；Into
Sample amount is that the high performance liquid chromatography spectrogram of 10 μ l, 4- (4- ethylamino- phenyl) morpholine -3- ketone is as shown in Figure 2.
The peak result integrated to high performance liquid chromatography spectrogram shown in Fig. 2 is as shown in the table:
As seen from the above table, the appearance time of 4- (4- ethylamino- phenyl) morpholine -3- ketone is 21.701 minutes, and purity is
98.33%.
Embodiment 2
Step S1, prepares 5.00g 4- (4- aminophenyl) morpholine -3- ketone (26.01mmol) and 40% acetaldehyde of 3.7mL is molten
Liquid (26.01mmol).
The anhydrous second of 50mL is added in ready 4- (4- aminophenyl) morpholine -3- ketone and 40% acetaldehyde solution by step S2
In alcohol, it is stirred at room temperature.
27.50g sodium triacetoxy borohydride (130.05mmol) is added portionwise in dehydrated alcohol and carries out instead by step S3
It answers, finishes, be stirred overnight at room temperature；PH to 7~8 is adjusted with the sodium hydroxide solution of 2mol/L, is concentrated under reduced pressure, residue utilization two
Chloromethanes is extracted, and is washed to organic phase extracted, is evaporated to obtain solid；By solid column chromatographic purifying, obtain
3.43g white solid 4- (4- ethylamino- phenyl) morpholine -3- ketone, yield 60%.
Embodiment 3
Step S1, prepares 5.00g 4- (4- aminophenyl) morpholine -3- ketone (26.01mmol) and 22.2mL40% acetaldehyde is molten
Liquid (156.06mmol).
100mL tetrahydro furan is added in ready 4- (4- aminophenyl) morpholine -3- ketone and 40% acetaldehyde solution by step S2
In muttering, it is stirred at room temperature.
2.75g sodium triacetoxy borohydride (13.00mmol) is added portionwise in anhydrous methanol and carries out instead by step S3
It answers, finishes, be stirred overnight at room temperature；PH to 7~8 is adjusted with the sodium hydroxide solution of 2mol/L, is concentrated under reduced pressure, residue utilization two
Chloromethanes is extracted, and is washed to organic phase extracted, is evaporated to obtain solid；By solid column chromatographic purifying, obtain white
Color solid 2.85g, yield 50%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (10)
1. a kind of preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone characterized by comprising
Prepare 4- (4- aminophenyl) morpholine -3- ketone and acetaldehyde；
The 4- (4- aminophenyl) morpholine -3- ketone and the acetaldehyde are added in reaction dissolvent；
Reducing agent is added in the reaction dissolvent to be reacted, 4- (4- ethylamino- phenyl) morpholine -3- ketone is obtained.
2. the preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone as described in claim 1, which is characterized in that described to go back
Former agent includes sodium triacetoxy borohydride, sodium cyanoborohydride, ammonium formate and palladium carbon, hydrogen and palladium carbon, sodium borohydride or boron
Zinc hydride.
3. the preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone as claimed in claim 2, which is characterized in that when described
When reducing agent includes sodium triacetoxy borohydride, the sodium triacetoxy borohydride and the 4- (4- aminophenyl)
The molar ratio of quinoline -3- ketone is 0.5~5.
4. the preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone as claimed in claim 3, which is characterized in that described three
The molar ratio of acetoxyl group sodium borohydride and the 4- (4- aminophenyl) morpholine -3- ketone is 1.5~2.5.
5. the preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone as described in claim 1, which is characterized in that described anti-
Answering solvent includes anhydrous methanol, dehydrated alcohol or tetrahydrofuran.
6. the preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone as described in claim 1, which is characterized in that the second
The molar ratio of aldehyde and the 4- (4- aminophenyl) morpholine -3- ketone is 1~6.
7. the preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone as claimed in claim 6, which is characterized in that the second
The molar ratio of aldehyde and the 4- (4- aminophenyl) morpholine -3- ketone is 1.5~2.5.
8. the preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone as described in any one of claims 1 to 7, feature exist
In the reducing agent that is added in the reaction dissolvent is reacted, and obtaining 4- (4- ethylamino- phenyl) morpholine -3- ketone includes:
The reducing agent is added in the reaction dissolvent to be reacted；
Adjust the pH to 7~8 of the reaction dissolvent；
It is extracted using organic solvent；
Organic solvent extracted is evaporated, the 4- (4- ethylamino- phenyl) morpholine -3- ketone is obtained.
9. the preparation method of 4- (4- ethylamino- phenyl) morpholine -3- ketone as claimed in claim 8, which is characterized in that described to incite somebody to action
Organic solvent extracted is evaporated, and is obtained the 4- (4- ethylamino- phenyl) morpholine -3- ketone and is included:
It is evaporated organic solvent extracted to obtain solid；
By the solid column chromatographic purifying, obtaining white solid is the 4- (4- ethylamino- phenyl) morpholine -3- ketone.
10. a kind of purposes of 4- as described in any one of claims 1 to 9 (4- ethylamino- phenyl) morpholine -3- ketone, the 4-
(4- ethylamino- phenyl) morpholine -3- ketone is used in 4- (4- aminophenyl) morpholine -3- ketone Related substances separation as standard pair
According to product.
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