CN109096255A - A kind of refining methd for the imidazole diketone analog derivative that trifluoromethyl replaces - Google Patents
A kind of refining methd for the imidazole diketone analog derivative that trifluoromethyl replaces Download PDFInfo
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- CN109096255A CN109096255A CN201810822579.8A CN201810822579A CN109096255A CN 109096255 A CN109096255 A CN 109096255A CN 201810822579 A CN201810822579 A CN 201810822579A CN 109096255 A CN109096255 A CN 109096255A
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- analog derivative
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention provides a kind of refining methds for the imidazole diketone analog derivative that trifluoromethyl replaces, this method is handled by soda acid and is recrystallized again, recrystallization solvent for use is cyclohexanone-alcohol mixed solvent system, pass through the refining methd, the HPLC purity for the imidazole diketone analog derivative crude product that trifluoromethyl to be refined can be made to replace is promoted from 98% to 99.5% or more, and the refining methd is easy to operate, the period is short, single miscellaneous content is controllable.
Description
Technical field
The invention belongs to field of medicinal chemistry, in particular to the essence for the imidazole diketone analog derivative that a kind of trifluoromethyl replaces
Method processed.
Background technique
Chinese patent CN 2018106587737 reports the imidazole diketone class that trifluoromethyl shown in a kind of formula (I) replaces
Derivative:
The preparation method of its final step as shown in Figure 1,
Above-mentioned reaction is easy to produce an impurity, shown in structure such as following formula (II):
Wherein, R1、R2Selected from H, NO2, one of methoxyl group,
Preferably, the structural formula of formula (I) compound is selected from one of following:
The impurity of compound 1:
Its structure is confirmed by nuclear magnetic resonance spectroscopy and mass spectrum:1H-NMR(400MHz,DMSO-d6)δppm8.02(s,1H),
7.91(d,1H),7.70(d,1H),7.53(d,1H),7.14(s,1H),6.85(d,1H),6.81(d,1H),6.64(s,1H),
3.47(s,3H),1.68(s,3H)；ESI/MS:m/z=466 (M+H)+.According to the post-processing approach reported in patent, gained is produced
Product purity is 98.5%, and the content of impurity shown in formula (II-1) is 0.17%~0.39%.
The impurity of compound 2:
1H-NMR(400MHz,DMSO-d6)δppm8.02(s,1H),7.91(d,1H),7.70(d,1H),7.53(d,1H),
7.14(s,1H),6.83(d,1H),6.79(d,1H),6.58(s,1H),3.47(s,6H),1.68(s,3H)；ESI/MS:m/z
=451 (M+H)+.According to the post-processing approach reported in patent, products obtained therefrom purity is 98.6%, miscellaneous shown in formula (II-2)
The content of matter is 0.15%~0.31%.
The impurity of compound 3:
Its structure is confirmed by nuclear magnetic resonance spectroscopy and mass spectrum:1H-NMR(400MHz,DMSO-d6)δppm8.02(s,1H),
7.91(d,1H),7.70(d,1H),7.53(d,1H),7.14(s,1H),6.75(s,1H),6.71(s,1H),6.52(s,1H),
3.47(s,6H),1.68(s,3H)；ESI/MS:m/z=451 (M+H)+.According to the post-processing approach reported in patent, gained is produced
Product purity is 98.7%, and the content of impurity shown in formula (II-3) is 0.13%~0.29%.
The impurity of compound 4:
Its structure is confirmed by nuclear magnetic resonance spectroscopy and mass spectrum:1H-NMR(400MHz,DMSO-d6)δppm8.02(s,1H),
7.91(d,1H),7.70(d,1H),7.53(d,1H),7.14(s,1H),6.74(s,1H),6.70(s,1H),3.47(s,9H),
1.68(s,3H)；ESI/MS:m/z=481 (M+H)+.According to the post-processing approach reported in patent, products obtained therefrom purity is
98.2%, the content of impurity shown in formula (II-4) is 0.21%~0.34%.
The content of impurity is not met in general drug standard in relation to single requirement of the miscellaneous content lower than 0.1%.Moreover, by
It is excessively high in impurity content, during the quality research of drug, it is necessary to carry out related toxicological experiment to impurity shown in formula (II)
Research, so that the cost and risk of medicament research and development can be greatly increased.
Summary of the invention
The present invention provides a kind of refining methds for the imidazole diketone analog derivative that trifluoromethyl replaces, it is therefore an objective to solve to produce
Product purity is low, the excessively high problem of major impurity formula (II) compounds content.
The purpose of the present invention is what is be achieved by the steps of:
Formula (I) crude compound is added in organic solvent by step 1), is passed through hydrogen chloride gas, and mixing time is 1~
6h, system temperature are 20~55 DEG C；
Step 2) is cooled to room temperature, and water is added, and extraction separates water phase, discards organic phase；
Sodium hydroxide is added to water layer in step 3), and organic solvent extraction is added, separates organic phase；
Step 4) is added to active carbon, 1~5h of heating stirring, filtering, removing active carbon to organic；
Step 5) concentration removes organic solvent, and residue is recrystallized with ethyl alcohol-cyclohexanone mixed solvent system, mistake
Filter, it is dry, obtain the sterling of formula (I).
It is preferred that step 1 used in solvent be isoamyl acetate；The mass ratio of formula (I) crude compound and isoamyl acetate
For 1:5~20；Mixing time is 2~5h, and system temperature is 20~45 DEG C.
It is preferred that step 3 used in the mass ratio of sodium hydroxide and formula (I) crude compound be 0.55~5:1.
It is preferred that step 4 used in the mass ratio of active carbon and (I) compound be 0.1~3:1, mixing time is 2~3h,
Heating temperature is 40~60 DEG C.
It is preferred that step 5 used in formula (I) crude compound: ethyl alcohol: the mass ratio of cyclohexanone be 1:10~20:2~10.
Operation of the present invention is simple, the period is short, product purity is high, single miscellaneous content is controllable.
Detailed description of the invention
Fig. 1 is the preparation flow figure for the imidazole diketone analog derivative that trifluoromethyl replaces.
Specific embodiment
Embodiment 1
The purification of compound 1:
(E) -1- (3- (3- methoxyl group -4- nitrobenzophenone) acryloyl group) -5- methyl -3- (5- (morpholinyl) pyrazine -2-
Base) -5- (trifluoromethyl) imidazolidine -2-1,4- diketone
Crude product by 3.0g content for 98.5% compound 1 is added in 43ml isoamyl acetate, and stirring and dissolving is passed through
Dry hydrogen chloride gas stirs 2.5h, and it is 40 DEG C that heating, which keeps system temperature, and the water of 30g × 2 is added and is extracted, water phase is separated,
Organic phase discards.3g sodium hydroxide is added to water phase, stirs 0.5h, the isoamyl acetate of 30ml × 2 is added, extraction merges organic
1.5g active carbon is added in phase in organic phase, is heated to 40 DEG C, stirs 2h, is cooled to room temperature, is filtered to remove active carbon, filtrate
Concentration, residue are crystallized with the mixed solvent of ethyl alcohol+cyclohexanone (30g+10g), are filtered, dry, obtain 2.5g (E) -1-
(3- (3- methoxyl group -4- nitrobenzophenone) acryloyl group) -5- methyl -3- (5- (morpholinyl) pyrazine -2- base) -5- (fluoroform
Base) imidazolidine -2-1,4- diketone sterling.Content 99.51%, the content 0.04% of formula (II-1) compound, other are single miscellaneous equal
Less than 0.1%.
Embodiment 2
The purification of compound 2:
(E) -1- (3- (3,4- Dimethoxyphenyl) acryloyl group) -5- methyl -3- (5- (morpholinyl) pyrazine -2-
Base) -5- (trifluoromethyl) imidazolidine -2,4- diketone
Crude product by 3.0g content for 98.6% compound 2 is added in 48ml isoamyl acetate, and stirring and dissolving is passed through
Dry hydrogen chloride gas stirs 2.5h, and it is 45 DEG C that heating, which keeps system temperature, and the water of 30g × 2 is added and is extracted, water phase is separated,
Organic phase discards.2.8g sodium hydroxide is added to water phase, stirs 0.5h, the isoamyl acetate of 30ml × 2 is added, extraction is associated with
1.3g active carbon is added in machine phase in organic phase, is heated to 40 DEG C, stirs 2h, is cooled to room temperature, is filtered to remove active carbon, filters
Liquid concentration, residue are crystallized with the mixed solvent of ethyl alcohol+cyclohexanone (32g+21g), are filtered, dry, obtain 2.3g (E)-
1- (3- (3,4- Dimethoxyphenyl) acryloyl group) -5- methyl -3- (5- (morpholinyl) pyrazine -2- base) -5- (fluoroform
Base) imidazolidine -2,4- diketone sterling.Content 99.54%, the content 0.02% of formula (II-2) compound, other are single miscellaneous small
In 0.1%.
Embodiment 3
The purification of compound 3:
(E) -1- (3- (3,5- Dimethoxyphenyl) acryloyl group) -5- methyl -3- (5- (morpholinyl) pyrazine -2-
Base) -5- (trifluoromethyl) imidazolidine -2,4- diketone
Crude product by 3.0g content for 98.7% compound 3 is added in 43ml isoamyl acetate, and stirring and dissolving is passed through
Dry hydrogen chloride gas stirs 3h, and it is 45 DEG C that heating, which keeps system temperature, and the water of 30g × 2 is added and is extracted, separates water phase, has
Machine mutually discards.3g sodium hydroxide is added to water phase, stirs 0.5h, the isoamyl acetate of 30ml × 2 is added, extraction merges organic phase,
1.6g active carbon is added in organic phase, is heated to 40 DEG C, stirs 2h, is cooled to room temperature, is filtered to remove active carbon, filtrate is dense
Contracting, residue are crystallized with the mixed solvent of ethyl alcohol+cyclohexanone (36g+20g), are filtered, dry, obtain 2.1g (E) -1- (3-
(3,5- Dimethoxyphenyl) acryloyl group) -5- methyl -3- (5- (morpholinyl) pyrazine -2- base) -5- (trifluoromethyl) imidazoles
The sterling of alkane -2,4- diketone.Content 99.61%, the content 0.03% of formula (II-3) compound, other single miscellaneous respectively less than 0.1%.
Embodiment 4
The purification of compound 4:
(E) -5- methyl -3- (5- (morpholinyl) pyrazine -2- base) -5- (trifluoromethyl) -1- (3- (3,4,5- trimethoxy
Base phenyl) acryloyl group) imidazolidine -2-1,4- diketone
Crude product by 3.0g content for 98.2% compound 4 is added in 53ml isoamyl acetate, and stirring and dissolving is passed through
Dry hydrogen chloride gas stirs 3h, and it is 40 DEG C that heating, which keeps system temperature, and the water of 30g × 2 is added and is extracted, separates water phase, has
Machine mutually discards.3g sodium hydroxide is added to water phase, stirs 0.5h, the isoamyl acetate of 30ml × 2 is added, extraction merges organic phase,
1.3g active carbon is added in organic phase, is heated to 40 DEG C, stirs 2h, is cooled to room temperature, is filtered to remove active carbon, filtrate is dense
Contracting, residue are crystallized with the mixed solvent of ethyl alcohol+cyclohexanone (45g+30g), are filtered, dry, obtain 1.9g (E) -5- first
Base -3- (5- (morpholinyl) pyrazine -2- base) -5- (trifluoromethyl) -1- (3- (3,4,5- trimethoxyphenyl) acryloyl group)
The sterling of imidazolidine -2-1,4- diketone.Content 99.65%, the content 0.01% of formula (II-4) compound, other lists are miscellaneous to be respectively less than
0.1%.
Claims (6)
1. the refining methd for the imidazole diketone analog derivative that trifluoromethyl shown in a kind of formula (I) replaces,
It is characterized in that, impurity content shown in formula (II) is reduced,
Wherein, R1、R2Selected from H, NO2, one of methoxyl group,
Purification step are as follows:
Formula (I) crude compound is added in organic solvent by step 1), is passed through hydrogen chloride gas, stirs 2~8h, system temperature
It is 20~60 DEG C；
Step 2) is cooled to 5~10 DEG C, and water is added, and stirring extracts liquid separation, separates water phase, discard organic phase；
Sodium hydroxide is added to water layer in step 3), and organic solvent extraction is added, separates organic phase；
Step 4) is added to active carbon, 1~5h of heating stirring, filtering, removing active carbon to organic；
Step 5) concentration removes organic solvent, and residue is recrystallized with cyclohexanone-alcohol mixed solvent system, filters, and does
It is dry, obtain the sterling of formula (I).
2. the refining methd for the imidazole diketone analog derivative that a kind of trifluoromethyl according to claim 1 replaces, feature
It is, the structural formula of formula (I) compound is selected from one of following:
3. the refining methd for the imidazole diketone analog derivative that a kind of trifluoromethyl according to claim 1 replaces, feature
It is, the organic solvent in step 1 is esters solvent, and mixing time is 1~6h, and system temperature is 20~55 DEG C.
4. the refining methd for the imidazole diketone analog derivative that a kind of trifluoromethyl according to claim 1 replaces, feature
It is, the mass ratio of the sodium hydroxide being added in step 3 and formula (I) compound is 0.3~8:1.
5. the refining methd for the imidazole diketone analog derivative that a kind of trifluoromethyl according to claim 1 replaces, feature
It is, the mass ratio of the active carbon being added in step 4 and formula (I) compound is 0.05~4:1.
6. the refining methd for the imidazole diketone analog derivative that a kind of trifluoromethyl according to claim 1 replaces, feature
It is, ethyl alcohol, the cyclohexanone mass ratio being added in step 5 are 1~25:2~14.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810822579.8A CN109096255A (en) | 2018-07-24 | 2018-07-24 | A kind of refining methd for the imidazole diketone analog derivative that trifluoromethyl replaces |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810822579.8A CN109096255A (en) | 2018-07-24 | 2018-07-24 | A kind of refining methd for the imidazole diketone analog derivative that trifluoromethyl replaces |
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| CN109096255A true CN109096255A (en) | 2018-12-28 |
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| CN201810822579.8A Withdrawn CN109096255A (en) | 2018-07-24 | 2018-07-24 | A kind of refining methd for the imidazole diketone analog derivative that trifluoromethyl replaces |
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| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20181228 |
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| WW01 | Invention patent application withdrawn after publication |