CN102399229A - N-acylpyrazole derritol, preparation method thereof, and application thereof - Google Patents
N-acylpyrazole derritol, preparation method thereof, and application thereof Download PDFInfo
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- CN102399229A CN102399229A CN2010102735165A CN201010273516A CN102399229A CN 102399229 A CN102399229 A CN 102399229A CN 2010102735165 A CN2010102735165 A CN 2010102735165A CN 201010273516 A CN201010273516 A CN 201010273516A CN 102399229 A CN102399229 A CN 102399229A
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Abstract
The invention discloses N-acylpyrazole derritol with a chemical formula represented by the formula I. In the formula, R is selected from C1-C2 alkyl, C3-C4 straight-chain or branched-chain alkyl, and C6H5; X(CH2)n, X=OH, NH2, NHAc, Cl, Br, or C6H5; and n=1, 2, 3 or 4. The preparation method of N-acylpyrazole derritol comprises steps that: (2R)-5-[7,8-dimethoxy-3,3a,4,9b-tetrahydrobenzopyrano[3,4-c]pyrazole-1-group]-2-(propylene-2-group)-2,3-dihydrobenzopyran-4-phenol and acyl chloride or anhydride are subject to a reaction according to a molar ratio of 1:1, such that N-acylpyrazole derritol is obtained. The invention also provides an application of N-acylpyrazole derritol in the preparations of neuraminidase inhibitors.
Description
Technical field
The present invention relates to N-acyl group pyrazoles derritol.
Background technology
Zhou Zhongzhen etc. have described 2, and the synthetic and desinsection of 3a-dihydro-chromene [4,3-c] pyrazoles-3-ketones derivant and fungicidal activity (organic chemistry, 2009,29:1774).Do not study report about N-acyl group pyrazoles derritol and anti-neuraminic acid enzymic activity thereof.
Summary of the invention
The object of the present invention is to provide the N-acyl group pyrazoles derritol shown in the structural formula I:
Wherein, the R of formula I is selected from: C
1～C
2Alkyl, C
3～C
4The straight or branched alkyl, C
6H
5X (CH
2)
n, X=OH, NH
2, NHAc, Cl, Br, C
6H
5, n=1,2,3 or 4.
The chemical name of N-acyl group pyrazoles derritol is 1-[(R)-4-hydroxyl-2-(propylene-2-yl)-2,3-Dihydrobenzofuranes-5-yl]-7, and 8-dimethoxy-3-acyl group-3a, 4-dihydrobenzopyrans be [3,4-c] pyrazoles also; The numbering of its atom is following:
The present invention also provides the preparation method of N-acyl group pyrazoles derritol; The preparation method who it is characterized in that N-acyl group pyrazoles derritol be (2R)-5-[7,8-dimethoxy-3,3a; 4; 9b-tetrahydro benzo pyrans is [3,4-c] pyrazol-1-yl also]-2-(propylene-2-yl)-2,3-Dihydrobenzofuranes-4-phenol and acyl chlorides or acid anhydrides obtain N-acyl group pyrazoles derritol by 1: 1 molar ratio reaction; The preparation method is undertaken by following reaction formula:
Described N-acyl group pyrazoles derritol has anti-neuraminic acid enzymic activity, is used to prepare anti-neuraminidase agent.
The present invention compared with prior art has following advantage:
1. the present invention designs first and has prepared and has the higher active new compound of anti-neuraminidase---N-acyl group pyrazoles derritol.N-acyl group pyrazoles derritol has anti-preferably neuraminic acid enzymic activity.
2. based on the difference of the activity of hydrogen and phenolic hydroxyl group on the pyrazoles ring,, improve the selectivity of reaction through control reactant rate of charge and feed way.Preparing method's employing (2R)-5-of N-acyl group pyrazoles derritol [7,8-dimethoxy-3,3a, 4,9b-tetrahydro benzo pyrans is [3,4-c] pyrazol-1-yl also]-2-(propylene-2-yl)-2,3-Dihydrobenzofuranes-4-phenol and acyl chlorides or acid anhydrides were by 1: 1 molar ratio reaction.Obtain N-acyl group pyrazoles derritol through control reactant feed ratio and feed way.
3.N-acyl group pyrazoles derritol can be used for preparing neuraminidase inhibitor.
Embodiment
Following examples are intended to explain the present invention rather than to further qualification of the present invention.
The preparation of embodiment 1N-acetyl pyrazole derritol
0.01mol (2R)-and 5-[7,8-dimethoxy-3,3a; 4,9b-tetrahydro benzo pyrans is [3,4-c] pyrazol-1-yl also]-2-(propylene-2-yl)-2; 3-Dihydrobenzofuranes-4-phenol, 20mL methylene dichloride, 1.5g pyridine; 25 ℃ add the 0.01mol Acetyl Chloride 98Min.s, reaction 15min, reaction solution through revolve steam thick product; Ethyl alcohol recrystallization, N-acetyl pyrazole derritol, yield 54.4%, m.p.210～214 ℃,
1H NMR (CDCl
3, 400MHz) δ: 1.75,1.78 (2 * s, 3H, CH
3), 2.37 (s, 3H, COCH
3), 2.99 (m, 1H, 3 '-H), 3.33 (m, 1H, 3 '-H), 3.66 (s, 3H, 8-OCH
3), 3.79 (s, 3H, 7-OCH
3), 3.94 (d, J=12Hz, 1H, 4-H), 4.82 (d, J=10Hz, 1H, 3a-H), 4.90～4.93 (m, 2H ,=CH
2, 9b-H), 5.06～5.10 (m, 2H ,=CH
2, 4-H), 5.26 (q, J=7.6Hz, 1H, 2 '-H), 6.46 (s, 1H, 6-H), 6.49 (d, J=8.4Hz, 1H, 7 '-H), 6.81 (s, 1H, 9-H), 7.49 (d, J=8.4Hz, 1H, 6 '-H).
The preparation of embodiment 2N-propionyl group pyrazoles derritol
0.01mol (2R)-and 5-[7,8-dimethoxy-3,3a; 4,9b-tetrahydro benzo pyrans is [3,4-c] pyrazol-1-yl also]-2-(propylene-2-yl)-2; 3-Dihydrobenzofuranes-4-phenol, 20mL methylene dichloride, 1.5g pyridine; 25 ℃ add the 0.01mol propionyl chlorides, reaction 35min, reaction solution through revolve steam thick product; Ethyl alcohol recrystallization, N-propionyl group pyrazoles derritol, yield 36.6%, m.p.205～208 ℃,
1H NMR (CDCl
3, 400MHz) δ: 1.21 (t, J=7.2Hz, 3H, CH
3), 1.74,1.77 (2 * s, 3H, CH
3), 2.71 (q, J=7.2Hz, 2H, COCH
2), 3.01 (m, 1H, 3 '-H), 3.32 (m, 1H, 3 '-H), 3.65 (s, 3H, 8-OCH
3), 3.79 (s, 3H, 7-OCH
3), 3.95 (dd, J=2.4Hz, J=12Hz, 1H, 4-H), 4.81 (d, J=10.4Hz, 1H, 3a-H), 4.89,4.93 (2 * s, 1H, 9b-H), 4.93 (s, 1H ,=CH
2), 5.09 (s, 1H ,=CH
2), 5.09 (dd, J=2.4Hz, J=12Hz, 1H, 4-H), 5.26 (t, J=8.8Hz, 1H, 2 '-H), 6.46 (s, 1H, 6-H), 6.49 (d, J=8.0Hz, 1H, 7 '-H), 6.81 (s, 1H, 9-H), 7.49 (d, J=8.0Hz, 1H, 6 '-H).
The preparation of embodiment 3N-isobutyryl pyrazoles derritol
0.01mol (2R)-5-[7,8-dimethoxy-3,3a, 4,9b-tetrahydro benzo pyrans is [3,4-c] pyrazol-1-yl also]-2-(propylene-2-yl)-2,3-Dihydrobenzofuranes-4-phenol, the 20mL methylene dichloride, the 1.5g pyridine, 25 ℃ add 0.01mol isobutyryl chloride (CH
3)
2CHCOCl, reaction 35min, reaction solution through revolve steam thick product; Ethyl alcohol recrystallization, N-isobutyryl pyrazoles derritol, yield 62.6%, m.p.185～203 ℃,
1H NMR (CDCl
3, 400MHz) δ: 1.19 (d, J=7.2Hz, 3H, CH
3), 1.26 (d, J=7.2Hz, 3H, CH
3), 1.75,1.78 (2 * s, 3H, CH
3), 2.99 (m, 1H, 3 '-H), 3.23 (m, 1H, COCH), 3.34 (m, 1H, 3 '-H), 3.66 (s, 3H, 8-OCH
3), 3.79 (s, 3H, 7-OCH
3), 3.94 (dd, J=2.4Hz, J=12Hz, 1H, 4-H), 4.82 (dd, J=2.4Hz, J=10.4Hz, 1H, 3a-H), 4.88～4.93 (m, 2H, 9b-H ,=CH
2), 5.02～5.09 (m, 2H ,=CH
2, 4-H), 5.09 (s, 1H ,=CH
2), 5.27 (q, J=8.0Hz, 1H, 2 '-H), 6.46 (s, 1H, 6-H), 6.49 (d, J=8.4Hz, 1H, 7 '-H), 6.82 (s, 1H, 9-H), 7.49 (d, J=8.4Hz, 1H, 6 '-H).
The preparation of embodiment 4N-chloracetyl pyrazoles derritol
0.01mol (2R)-and 5-[7,8-dimethoxy-3,3a; 4,9b-tetrahydro benzo pyrans is [3,4-c] pyrazol-1-yl also]-2-(propylene-2-yl)-2; 3-Dihydrobenzofuranes-4-phenol, 20mL methylene dichloride, 1.5g pyridine; 25 ℃ add the 0.01mol chloroacetyl chlorides, reaction 35min, reaction solution through revolve steam thick product; Ethyl alcohol recrystallization gets N-chloracetyl pyrazoles derritol, yield 29.1%, and m.p.206～208 ℃,
1H NMR (CDCl
3, 400MHz) δ: 1.78 (s, 3H, CH
3), 3.01 (m, 1H, 3 '-H), 3.32 (m, 1H, 3 '-H), 3.66 (s, 3H, 8-OCH
3), 3.79 (s, 3H, 7-OCH
3), 3.95 (dd, J=2.0Hz, J=12Hz, 1H, 4-H), 4.43 (s, 2H, COCH
2), 4.86 (d, J=10.4Hz, 1H, 3a-H), 4.92～4.96 (m, 2H, 9b-H ,=CH
2), 5.10 (s, 1H ,=CH
2), 5.10 (dd, J=12Hz,, J=2Hz, 1H, 4-H), 5.27 (t, J=8.8Hz, 1H, 2 '-H), 6.46 (s, 1H, 6-H), 6.51 (d, J=8.4Hz, 1H, 7 '-H), 6.79 (s, 1H, 9-H), 7.50 (d, J=8.4Hz, 1H, 6 '-H).
The preparation of embodiment 5N-(4-chlorobutyryl) pyrazoles derritol
0.01mol (2R)-and 5-[7,8-dimethoxy-3,3a; 4,9b-tetrahydro benzo pyrans is [3,4-c] pyrazol-1-yl also]-2-(propylene-2-yl)-2; 3-Dihydrobenzofuranes-4-phenol, 20mL methylene dichloride, 1.5g pyridine; 25 ℃ add 0.01mol 4-chlorobutanoylchlorides, reaction 25min, reaction solution through revolve steam thick product; Ethyl alcohol recrystallization, N-(4-chlorobutyryl) pyrazoles derritol, yield 67.3%, m.p.160～165 ℃,
1H NMR (CDCl
3, 400MHz) δ: 1.75～1.78 (2 * s, 3H, CH
3), 2.20 (m, 2H, CH
2), 2.89 (t, J=7.6Hz, 2H, COCH
2), 3.01 (m, 1H, 3 '-H), 3.34 (m, 1H, 3 '-H), 3.64 (s, 3H, 8-OCH
3), 3.66 (t, J=8Hz, 2H, CH
2Cl), 3.79 (s, 3H, 7-OCH
3), 3.95 (d, J=12Hz, 1H, 4-H), 4.81 (dd, J=1.6Hz, J=10.4Hz, 1H, 3a-H), 4.91～4.93 (m, 2H, 9b-H ,=CH
2), 5.07～5.09 (m, 2H ,=CH
2, 4-H), 5.26 (q, J=8Hz, 1H, 2 '-H), 6.46 (s, 1H, 6-H), 6.50 (d, J=8.4Hz, 1H, 7 '-H), 6.80 (s, 1H, 9-H), 7.49 (d, J=8.4Hz, 1H, 6 '-H).
The preparation of embodiment 6N-(glycolyl) pyrazoles derritol
N-chloracetyl pyrazoles derritol makes N-(glycolyl) pyrazoles derritol through hydrolysis.
The preparation
of embodiment 7N-(glycyl) pyrazoles derritol
N-chloracetyl pyrazoles derritol is separated through ammonia and is made N-(glycyl) pyrazoles derritol.
Embodiment 8N-acyl group pyrazoles derritol resisiting influenza virus neuraminic acid enzymic activity
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, and the meta-bolites that under the neuraminidase effect, produces excites down in the 360nm irradiation, can produce 450nm fluorescence, and the variation of fluorescence intensity can be reacted the neuraminic acid enzymic activity delicately.Enzyme is all from A/PR/8/34 (H1N1) virus stain.
2. experimental technique
In the enzyme reaction system, the refreshing NA of finite concentration testing compound and influenza virus is suspended in (pH6.5) in the reaction buffer, add fluorogenic substrate MUNANA and start reaction system, 37 ℃ hatch 40 minutes after, add the reaction terminating liquid termination reaction.At excitation wavelength 360nm and emission wavelength is under the parameter condition of 450nm, measures fluorescence intensity level.The fluorescence intensity of reaction system can reflect the activity of enzyme.According to the reduction of fluorescence intensity can the computerized compound to the active inhibiting rate of NA.
3. test sample: dihydrobenzopyrans and pyrazole derivatives.
4. active result
Preferred compound: N-chloracetyl pyrazoles derritol
The result shows that the inhibition activity to neuraminidase when preferred compound N-chloracetyl pyrazoles derritol detectable level in reactive system is 40 μ g/mL is 46.40%.N-acyl group pyrazoles derritol has the activity of inhibition to neuraminidase, can be applicable to prepare neuraminidase inhibitor.
Claims (3)
1. the N-acyl group pyrazoles derritol shown in the chemical structural formula I:
Wherein, the R of formula I is selected from: C
1～C
2Alkyl, C
3～C
4The straight or branched alkyl, C
6H
5X (CH
2)
n, X=OH, NH
2, NHAc, Cl, Br, C
6H
5, n=1,2,3 or 4.
2. the preparation method of the said N-acyl group of claim 1 pyrazoles derritol; It is characterized in that (2R)-5-[7,8-dimethoxy-3,3a; 4; 9b-tetrahydro benzo pyrans is [3,4-c] pyrazol-1-yl also]-2-(propylene-2-yl)-2,3-Dihydrobenzofuranes-4-phenol and acyl chlorides or acid anhydrides obtain N-acyl group pyrazoles derritol by 1: 1 molar ratio reaction; The preparation method is undertaken by following reaction formula:
Wherein, the definition of R according to claim 1.
3. the application of the said N-acyl group of claim 1 pyrazoles derritol in the preparation neuraminidase inhibitor.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702212A (en) * | 2012-06-14 | 2012-10-03 | 湖南大学 | N-(2-subtituted acyl) pyrazol derritol and application thereof as medicament |
| CN105111221A (en) * | 2015-09-28 | 2015-12-02 | 湖南大学 | Furochroman-6-oxime derivative and preparation method and application thereof |
| CN105198866A (en) * | 2015-06-01 | 2015-12-30 | 宁波工程学院 | Cyclopropyl derris hydrazide and application thereof to preparation of neuraminidase inhibitor |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702212A (en) * | 2012-06-14 | 2012-10-03 | 湖南大学 | N-(2-subtituted acyl) pyrazol derritol and application thereof as medicament |
| CN102702212B (en) * | 2012-06-14 | 2014-02-05 | 湖南大学 | N-(2-subtituted acyl) pyrazol derritol and application thereof as medicament |
| CN105198866A (en) * | 2015-06-01 | 2015-12-30 | 宁波工程学院 | Cyclopropyl derris hydrazide and application thereof to preparation of neuraminidase inhibitor |
| CN105198866B (en) * | 2015-06-01 | 2018-03-16 | 宁波工程学院 | Ring the third trifoliate jewelvine hydrazides and its application as neuraminidase inhibitor |
| CN105111221A (en) * | 2015-09-28 | 2015-12-02 | 湖南大学 | Furochroman-6-oxime derivative and preparation method and application thereof |
| CN105111221B (en) * | 2015-09-28 | 2017-09-22 | 湖南大学 | Furans and the 9 oxime derivate of chroman 6 and preparation method and application |
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