CN102399229B - 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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- CN102399229B CN102399229B CN 201010273516 CN201010273516A CN102399229B CN 102399229 B CN102399229 B CN 102399229B CN 201010273516 CN201010273516 CN 201010273516 CN 201010273516 A CN201010273516 A CN 201010273516A CN 102399229 B CN102399229 B CN 102399229B
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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 and its preparation method and application.
Background technology
Zhou Zhongzhen etc. described the synthetic and desinsection of 2,3a-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]-7,8-dimethoxy-3-acyl group-3a, 4-dihydrobenzopyrans be [3,4-c] pyrazoles also; The numbering of its atom is as follows:
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 is (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 chemical equation:
Described N-acyl group pyrazoles derritol has anti-neuraminic acid enzymic activity, for the preparation of anti-neuraminidase agent.
The present invention compared with prior art has following advantage:
1. the present invention designs first and has prepared the new compound with higher anti-neuraminic acid enzymic activity---N-acyl group pyrazoles derritol.N-acyl group pyrazoles derritol has anti-neuraminic acid enzymic activity preferably.
2. according to the difference of the activity of hydrogen and phenolic hydroxyl group on the pyrazoles ring, by control reactant feed ratio and feed way, improve the selectivity of reaction.The preparation method of N-acyl group pyrazoles derritol adopts (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 were by 1: 1 molar ratio reaction.Obtain N-acyl group pyrazoles derritol by 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 illustrate the present invention rather than limitation of the invention further.
The preparation of embodiment 1N-acetyl pyrazole derritol
0.01mol (2R)-5-[7,8-dimethoxy-3,3a, 4,9b-tetrahydro benzo pyrans also [3,4-c] pyrazol-1-yl]-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 gets N-acetyl pyrazole derritol, yield 54.4%, and 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 pyrazoles derritol
0.01mol (2R)-5-[7,8-dimethoxy-3,3a, 4,9b-tetrahydro benzo pyrans also [3,4-c] pyrazol-1-yl]-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 gets N-propionyl pyrazoles derritol, yield 36.6%, and 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)-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, 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 gets N-isobutyryl pyrazoles derritol, yield 62.6%, and 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)-5-[7,8-dimethoxy-3,3a, 4,9b-tetrahydro benzo pyrans also [3,4-c] pyrazol-1-yl]-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)-5-[7,8-dimethoxy-3,3a, 4,9b-tetrahydro benzo pyrans also [3,4-c] pyrazol-1-yl]-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 gets N-(4-chlorobutyryl) pyrazoles derritol, yield 67.3%, and 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 makes N-(glycyl) pyrazoles derritol through the ammonia solution.
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 produces under the neuraminidase effect 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.Be under the parameter condition of 450nm at excitation wavelength 360nm and emission wavelength, measure 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 inhibiting rate of NA activity.
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 :-(CH
2)
nX, X=Cl, Br, n=1,2,3 or 4.
2. the preparation method of the described 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 described N-acyl group of claim 1 pyrazoles derritol in the preparation neuraminidase inhibitor.
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| US4452988A (en) * | 1982-12-06 | 1984-06-05 | Sterling Drug Inc. | 1-Ethenyl-6-(4-phenyl)-3,4,9,9a-tetrahydro-9a-methyl-6H-naptho[2,3-c]pyrazoles |
| CN1069272A (en) * | 1991-08-02 | 1993-02-24 | 布茨公司 | The method for preparing benzo pyrrole or thiapyran and pyrazoles |
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2010
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452988A (en) * | 1982-12-06 | 1984-06-05 | Sterling Drug Inc. | 1-Ethenyl-6-(4-phenyl)-3,4,9,9a-tetrahydro-9a-methyl-6H-naptho[2,3-c]pyrazoles |
| CN1069272A (en) * | 1991-08-02 | 1993-02-24 | 布茨公司 | The method for preparing benzo pyrrole or thiapyran and pyrazoles |
Non-Patent Citations (3)
| Title |
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| Ivanka Kostova,等.Preparation and Stereochemical Characterization of Some N-Acyl-[1]benzopyrano[3,4-clpyrazole Derivatives from Rotenoids.《Monatshefte fuer Chemie》.1989,第120卷(第12期),第1107-1112页,尤其是第1110页结构式. * |
| IvankaKostova，等.PreparationandStereochemicalCharacterizationofSomeN-Acyl-[1]benzopyrano[3 4-clpyrazole Derivatives from Rotenoids.《Monatshefte fuer Chemie》.1989 |
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