CN101643465A - Preparation method of COMT inhibitor 5, 6, 7, 3', 4'-pentamethoxyl isoflavone - Google Patents
Preparation method of COMT inhibitor 5, 6, 7, 3', 4'-pentamethoxyl isoflavone Download PDFInfo
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- CN101643465A CN101643465A CN200910056511A CN200910056511A CN101643465A CN 101643465 A CN101643465 A CN 101643465A CN 200910056511 A CN200910056511 A CN 200910056511A CN 200910056511 A CN200910056511 A CN 200910056511A CN 101643465 A CN101643465 A CN 101643465A
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Abstract
The invention relates to a preparation method for COMT inhibitor 5, 6, 7, 3', 4'-pentamethoxyl isoflavone, comprising the following steps: mixing 3, 4-dimethoxyphenylacetic acid and oxalyl chloride indichloromethane solution to carry out reflux reaction for 2 to 3 h, and cooling to room temperature; adding 3, 4, 5-trimethoxy sodium phenolate to carry out esterification reaction to carry out Friesrearrangement reaction under the catalysis of Lewis acid boron trifluoride ether; and finally carrying out reaction with DMF with the existence of the Lewis acid boron trifluoride ether; and adding methane sulfonyl chloride to promote Vilsmeier-Haack formylation reaction and subsequent cyclization reaction to obtain light yellow crystals 5, 6, 7, 3', 4'-pentamethoxyl isoflavone. The preparation method has simple and easily available raw materials, simple operation, short reaction time, mild reaction condition, environment protection and high yield of 76 %, and is suitable for industrial production.
Description
Technical field
The invention belongs to the preparation field of chemicals, particularly relate to a kind of COMT inhibitor 5,6,7,3 ', 4 '-preparation method of pentamethoxyl isoflavones.
Background technology
Dopamine HCL (DA) is neurotransmitter in the brain of generally acknowledging, its importance shows that the up nerve pathway of DA and the affinity of the somatic movement of regulating human body and cerebration concern, when these DA nervous functions were not normal, the schizophrenia or the dysthymia disorders of dyskinesia Parkinson's disease and mental disorder promptly appearred.Catechol-O-methyltransferase (COMT) is a kind of enzyme that extensively exists in human body, and it methylates on 3 hydroxyls by the catalysis catecholamine and degrades, and is the main metabolic enzyme of biologically active or toxic catecholamine.It and monoamine oxidase-B (MAO-B) acting in conjunction are homovanillic acid (HVA) with the DA metabolism.
Reports such as nineteen eighty-two Gandhi Dasan separate from the root of plant Dalbergia spinosa and obtain 5,6,7,3 ', 4 '-pentamethoxyl isoflavones (1) and analogue (Gandhi Dasan R thereof, Nagarajan NS, Narayanan V, et al.Dalspinin andDalspinosin, two new isoflavones from Dalbergia spinosa roots, Indian J.Chem., 1982,21B:385-386).Report such as Sethi is from the leaf of plant Juniperus macropoda etc. subsequently, separate and obtain 5,6,7,3 ', 4 '-pentamethoxyl isoflavones (1) and analogue (Sethi M.L, Taneja S.C, Dhar K.L, et al.Three isoflavoneglycosides from Juniperus macropoda, Phytochemistry, 1983,22:289-292; Veitch NC, SuttonPSE, Kite GC, et al.Six new isoflavones and a 5-deoxyflavonol glycoside from the leaves ofAteleia herbert-smithii, J.Nat.Prod., 2003,66:210-216).
Chimura etc. have studied isoflavones (1) and analog thereof the restraining effect for the COMT in the suis, find that this quasi-isoflavone may become COMT inhibitor (the Chimura H of the novel excellence of a class, Sawa T, Kumada Y, et al.New isoflavones, inhibiting catechol-O-methyltransferase, produced by Streptomyces, J.Antibiotics, 1975,28:619-626).But, relevant so far 5,6,7,3 ', 4 '-chemical synthesis process of pentamethoxyl isoflavones (1) do not appear in the newspapers as yet.
Summary of the invention
Technical problem to be solved by this invention provides a kind of COMT inhibitor 5,6,7,3 ', 4 '-preparation method of pentamethoxyl isoflavones, this preparation method used raw material is simple and easy to, and is simple to operate, and the reaction times is short, the reaction conditions gentleness, environmentally friendly, productive rate is fit to suitability for industrialized production up to 76%.
Chemical equation of the present invention is as follows:
A kind of COMT inhibitor 5,6,7,3 of the present invention ', 4 '-preparation method of pentamethoxyl isoflavones, comprising:
(1) with 3, the 4-dimethoxyphenylacetic acid mixes with oxalyl chloride 1: 1 in molar ratio～1.5, adds the dichloromethane solution of 2.0mol/L, in 40～60 ℃ of back flow reaction 2～3h, is cooled to room temperature, reclaims solvent, gets brown oil 3,4-dimethoxy phenyllacetyl chloride;
(2) with 3,4-dimethoxy phenyllacetyl chloride and 3,4,5-trimethoxy phenol sodium is 1～1.5: 1 mixing in molar ratio, in tetrahydrofuran (THF), carry out esterification,, be cooled to room temperature in 60～70 ℃ of back flow reaction 2～3h, successively through extraction, washing, drying get white needle-like crystals 3,4-dimethoxyphenylacetic acid 3 ', 4 ', 5 '-the trimethoxy phenyl ester;
(3) 3,4-dimethoxyphenylacetic acids 3 ', 4 ', 5 '-the trimethoxy phenyl ester under the catalysis of Lewis acid boron trifluoride diethyl etherate, in the methylene dichloride of 2.0mol/L, in 40～60 ℃ the Fries rearrangement reaction takes place, reaction times 2～3h, be cooled to room temperature, successively through extraction, washing, dry, silica gel column chromatography, light yellow needle-like crystal hydroxyl deoxybenzoin compound 1-(6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-2-(3 ", 4 " Dimethoxyphenyl) ethyl ketone;
(4) with 1-(6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-2-(3 "; 4 "-Dimethoxyphenyl) ethyl ketone reacts with DMF in the presence of Lewis acid boron trifluoride diethyl etherate, and excessive DMF double as solvent is heated to 50 ℃; add methane sulfonyl chloride simultaneously and promote Vilsmeier-Haack formylation reaction and ring-closure reaction subsequently, behind the 2～3h that refluxes, successively through extraction; washing, dry, silica gel column chromatography; promptly get pale yellow crystals 5,6,7; 3 ', 4 '-the pentamethoxyl isoflavones.
Dichloromethane solution and 3 in the described step (1), the volume mol ratio of 4-dimethoxyphenylacetic acid is 1～1.3mL: 1mmol;
In the described step (2) 3,4,5-trimethoxy phenol sodium are that the mineral oil with 60% (mass percent) sodium hydride is added to 3,4, in the tetrahydrofuran solution of 5-trimethoxy phenol, under argon shield, mix and stir 30min; Wherein, sodium hydride and 3,4, the mol ratio of 5-trimethoxy phenol is 1.5～2.0: 1; 3,4,5-trimethoxy phenol is 1mmol: 1.5～1.8mL with the molecular volume ratio of tetrahydrofuran (THF);
Tetrahydrofuran (THF) and 3 in the described step (2), the volume mol ratio of 4-dimethoxy phenyllacetyl chloride is 1.2～1.5mL: 1mmol;
In the described step (3) 3,4-dimethoxyphenylacetic acid 3 ', 4 ', 5 '-mol ratio of trimethoxy phenyl ester and boron trifluoride diethyl etherate is 1: 12～15; Methylene dichloride and 3,4-dimethoxyphenylacetic acid 3 ', 4 ', 5 '-the volume mol ratio of trimethoxy phenyl ester is 1mL: 1.2～1.5mmol;
1-in the described step (4) (6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-mol ratio of 2-(3 ", 4 " Dimethoxyphenyl) ethyl ketone and boron trifluoride diethyl etherate is 1: 5～6; DMF and 1-(6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-the volume mol ratio of 2-(3 ", 4 " Dimethoxyphenyl) ethyl ketone is 1mL: 1.0～1.2mmol; Methane sulfonyl chloride and 1-(6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-mol ratio of 2-(3 ", 4 " Dimethoxyphenyl) ethyl ketone is 3.5～3.7: 1.
Beneficial effect
The present invention is with 3,4-dimethoxyphenylacetic acid and 3,4,5-trimethoxy phenol is starting raw material, by 4 steps reaction synthesis of natural products 5,6 such as acyl chloride reaction, esterification, Fries rearrangement and Vilsmeier-Haack reactions, 7,3 ', 4 '-the pentamethoxyl isoflavones, used raw material is simple and easy to, and is simple to operate, and the reaction times is short, the reaction conditions gentleness, environmentally friendly, productive rate is fit to suitability for industrialized production up to 76%.
Description of drawings
Fig. 1 is 5,6,7,3 ', 4 '-molecular structural formula of pentamethoxyl isoflavones
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
Synthesizing of (1) 3,4-dimethoxy phenyllacetyl chloride 2
(5.8mL 11.6mmol) is added drop-wise to 3 under argon shield, 4-dimethoxyphenylacetic acid (1.53g with oxalyl chloride; 7.8mmol) methylene dichloride (2.0mol/L; 10mL) in the solution, dropwise heating and make reaction mixture, be cooled to room temperature in 40～60 ℃ of backflow 2h.Decompression removes down and desolvates and excessive oxalyl chloride, gets product 3,4-dimethoxy phenyllacetyl chloride 2, brown oil 1.67g, yield 100%.Product is directly used in next step reaction.
(2) 3,4-dimethoxyphenylacetic acids 3 ', 4 ', 5 '-trimethoxy phenyl ester 3 synthetic
With sodium hydride (be scattered in the mineral oil, content 60%, 0.42g 10.5mmol) is added to 3,4, (1.20g in tetrahydrofuran (THF) 6.5mmol) (10mL) solution, stirs 30min with reaction mixture to 5-trimethoxy phenol under argon shield.(heating makes reaction mixture in 60～70 ℃ of backflow 2h, is cooled to room temperature for 1.67g, tetrahydrofuran (THF) 7.8mmol) (10mL) solution to the compound 2 that wherein adds step (1) preparation.Reaction mixture is handled with saturated sodium carbonate solution (30mL), used methylene dichloride (30mL * 3) extraction then, merge organic phase, with the saturated common salt water washing, with anhydrous sodium sulfate drying, steaming desolventizes can be quantitatively (based on 3,4,5-trimethoxy phenol), obtain product 3,4-dimethoxyphenylacetic acid 3 ', 4 ', 5 '-trimethoxy phenyl ester 3, white, needle-shaped crystals 2.36g; M.p.126.8 ℃.
1H NMR (CDCl
3, 300MHz) δ 3.79 (s, 2H, CH
2), 3.81 (s, 9H, OCH
3), 3.90 (s, 3H, OCH
3), 6.31 (s, 2H, 2 '-and 6 '-H), 6.85-6.94 (m, 3H, 2-, 5-and 6-H);
13C NMR (CDCl
3, 75.5MHz) δ 40.7 (CH
2), 55.8 (OCH
3* 2), 56.0 (OCH
3* 2), 60.8 (OCH
3), 98.9 (2 '-and 6 '-C), and 111.2 (5-C), 112.4 (2-C), 121.5 (6-C), 125.6 (1-C), 135.7 (4 '-C), 146.7,148.3,153.4 (3 '-and 5 '-C), 170.3 (C=O); Mass spectrum (EI, 70eV) m/z 363 (M
++ 1), 335,303,289,261,215,185,153,151; Ultimate analysis C
19H
22O
7(362.37) theoretical value C 62.97, and H 6.12; Measured value C 63.07, H 6.14.
(3) 1-(6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-2-(3 ", 4 " Dimethoxyphenyl) ethyl ketone 4 synthetic
With syringe with boron trifluoride diethyl etherate (5.0mL, 5.6g (1.04g is 2.87mmol) in the solution of the new methylene dichloride (2mL) that steams 39.5mmol) to join the compound 3 of step (2) preparation, under argon atmospher with reaction mixture in 40～60 ℃ of reflux 2h, be cooled to room temperature.Reaction mixture is handled with 10% sodium carbonate solution (150mL), used ether (20mL * 3) extraction then.Water is acidified to pH=1 with concentrated hydrochloric acid, uses methylene dichloride (20mL * 4) extraction then.Merge organic phase, with the saturated common salt water washing, with anhydrous sodium sulfate drying.Steaming desolventizes, and the brown resistates that obtains carries out silica gel column chromatography, product 1-(6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-2-(3 ", 4 " Dimethoxyphenyl) ethyl ketone 4, light yellow needle crystal 0.90g, yield 87%; M.p.86.4 ℃.
1H NMR (CDCl
3, 300MHz) δ 3.78 (s, 3H, OCH
3), 3.87 (s, 6H, OCH
3), 3.89 (s, 3H, OCH
3), 4.00 (s, 3H, OCH
3), 4.32 (s, 2H, CH
2), 6.25 (s, 1H, 5 '-H), and 6.78-6.87 (m, 3H, 2 ", 5 " and 6 "-H);
13CNMR (CDCl
3, 75.5MHz) δ 49.0 (CH
2), 55.8 (OCH
3), 55.9 (OCH
3), 56.1 (OCH
3), 61.1 (OCH
3), 61.3 (OCH
3), 96.2 (5 '-C), 108.1 (1 '-C), 111.2 (5 " C), 113.0 (2 " C), 121.8 (6 " C), 127.6 (3 " C), 134.7 (1-C), 147.9,148.8,155.0,160.2,203.4 (C=O).
(4) 5,6,7,3 ', 4 '-pentamethoxyl isoflavones 1 synthetic
((724mg is 2.0mmol) in the solution of dry DMF (2mL) 12.0mmol) to be added drop-wise to the compound 4 of step (3) preparation under argon atmospher for 1.52mL, 1.70g with boron trifluoride diethyl etherate.With add after the mixture heating up to 50 ℃ methane sulfonyl chloride (0.544mL, 805mg, 7.0mmol), backflow 2h.Reaction mixture is cooled to room temperature, handles, use ether (20mL * 3) extraction then with 10% sodium carbonate solution (150mL).Water is acidified to pH=1 with concentrated hydrochloric acid, uses methylene dichloride (20mL * 4) extraction then, merges organic phase, with the saturated common salt water washing, with anhydrous sodium sulfate drying, steaming desolventizes, the brown resistates that obtains carries out silica gel column chromatography, get product 5,6,7,3 ', 4 '-pentamethoxyl isoflavones 1, light yellow crystallization 0.90g, yield 87%; M.p.185 ℃.
1H NMR (CDCl
3, 300MHz) δ 3.90 (s, 3H, OCH
3), 3.92 (s, 6H, OCH
3), 3.95 (s, 3H, OCH
3), 3.96 (s, 3H, OCH
3), 6.69 (s, 1H, 8-H), 6.92 (d, 1H, J=8.3Hz, 5 '-H), 7.00 (dd, 1H, J=8.3 and 1.9Hz, 6 '-H), 7.19 (d, 1H, J=1.9Hz, 2 '-H), 7.83 (s, 1H, 2-H);
13C NMR (CDCl
3, 75.5MHz) δ 55.8 (OCH
3* 2), 56.1 (OCH
3), 61.4 (OCH
3), 62.0 (OCH
3), 96.0 (8-C), 111.0 (5 '-C), 112.6 (2 '-C), 113.4 (10-C), 121.1 (6 '-C), 124.6 (1 '-C), 125.3 (3-C), 140.4 (6-C), 148.6 (3 '-C), 148.9 (4 '-C), 150.6 (2-C), 152.9 (5-C), 154.4 (9-C), 157.6 (7-C), 175.0 (C=O); Ultimate analysis C
20H
20O
7(372.37) theoretical value C 64.51, and H 5.41; Measured value C 64.32, H 5.42.
Claims (6)
- A COMT inhibitor 5,6,7,3 ', 4 '-preparation method of pentamethoxyl isoflavones, comprising:(1) with 3, the 4-dimethoxyphenylacetic acid mixes with oxalyl chloride 1: 1 in molar ratio～1.5, adds the dichloromethane solution of 2.0mol/L, in 40～60 ℃ of back flow reaction 2～3h, is cooled to room temperature, reclaims solvent, gets brown oil 3,4-dimethoxy phenyllacetyl chloride;(2) with 3,4-dimethoxy phenyllacetyl chloride and 3,4,5-trimethoxy phenol sodium is 1～1.5: 1 mixing in molar ratio, in tetrahydrofuran (THF), carry out esterification,, be cooled to room temperature in 60～70 ℃ of back flow reaction 2～3h, successively through extraction, washing, drying get white needle-like crystals 3,4-dimethoxyphenylacetic acid 3 ', 4 ', 5 '-the trimethoxy phenyl ester;(3) 3,4-dimethoxyphenylacetic acids 3 ', 4 ', 5 '-the trimethoxy phenyl ester under the catalysis of Lewis acid boron trifluoride diethyl etherate, in the methylene dichloride of 2.0mol/L, in 40～60 ℃ the Fries rearrangement reaction takes place, reaction times 2～3h, be cooled to room temperature, successively through extraction, washing, dry, silica gel column chromatography, light yellow needle-like crystal hydroxyl deoxybenzoin compound 1-(6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-2-(3 ", 4 " Dimethoxyphenyl) ethyl ketone;(4) with 1-(6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-2-(3 "; 4 "-Dimethoxyphenyl) ethyl ketone reacts with DMF in the presence of Lewis acid boron trifluoride diethyl etherate, and excessive DMF double as solvent is heated to 50 ℃; add methane sulfonyl chloride simultaneously and promote Vilsmeier-Haack formylation reaction and ring-closure reaction subsequently, behind the 2～3h that refluxes, successively through extraction; washing, dry, silica gel column chromatography; promptly get pale yellow crystals 5,6,7; 3 ', 4 '-the pentamethoxyl isoflavones.
- 2. a kind of COMT inhibitor 5,6,7 according to claim 1,3 ', 4 '-preparation method of pentamethoxyl isoflavones, it is characterized in that: the dichloromethane solution and 3 in the described step (1), the volume mol ratio of 4-dimethoxyphenylacetic acid is 1～1.3mL: 1mmol.
- 3. a kind of COMT inhibitor 5 according to claim 1,6,7,3 ', 4 '-preparation method of pentamethoxyl isoflavones, it is characterized in that: 3,4 in the described step (2), 5-trimethoxy phenol sodium are that the mineral oil with 60% (mass percent) sodium hydride is added to 3,4, in the tetrahydrofuran solution of 5-trimethoxy phenol, under argon shield, mix stirring 30min and make; Wherein, sodium hydride and 3,4, the mol ratio of 5-trimethoxy phenol is 1.5～2.0: 1; 3,4,5-trimethoxy phenol is 1mmol: 1.5～1.8mL with the molecular volume ratio of tetrahydrofuran (THF).
- 4. a kind of COMT inhibitor 5,6,7 according to claim 1,3 ', 4 '-preparation method of pentamethoxyl isoflavones, it is characterized in that: the tetrahydrofuran (THF) and 3 in the described step (2), the volume mol ratio of 4-dimethoxy phenyllacetyl chloride is 1.2～1.5mL: 1mmol.
- 5. a kind of COMT inhibitor 5,6,7 according to claim 1,3 ', 4 '-preparation method of pentamethoxyl isoflavones, it is characterized in that: 3 in the described step (3), 4-dimethoxyphenylacetic acid 3 ', 4 ', 5 '-mol ratio of trimethoxy phenyl ester and boron trifluoride diethyl etherate is 1: 12～15; Methylene dichloride and 3,4-dimethoxyphenylacetic acid 3 ', 4 ', 5 '-the volume mol ratio of trimethoxy phenyl ester is 1mL: 1.2～1.5mmol.
- 6. a kind of COMT inhibitor 5 according to claim 1,6,7,3 ', 4 '-preparation method of pentamethoxyl isoflavones, it is characterized in that: the 1-in the described step (4) (6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-mol ratio of 2-(3 ", 4 " Dimethoxyphenyl) ethyl ketone and boron trifluoride diethyl etherate is 1: 5～6; DMF and 1-(6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-the volume mol ratio of 2-(3 ", 4 " Dimethoxyphenyl) ethyl ketone is 1mL: 1.0～1.2mmol; Methane sulfonyl chloride and 1-(6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxyphenyl)-mol ratio of 2-(3 ", 4 " Dimethoxyphenyl) ethyl ketone is 3.5～3.7: 1.
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| CN103242281A (en) * | 2013-05-28 | 2013-08-14 | 东华大学 | 3'-hydroxy-4',5,6,7-tetramethoxy isoflavanone and preparation method thereof |
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| US9458128B2 (en) | 2012-05-24 | 2016-10-04 | Orion Corporation | Catechol O-methyltransferase activity inhibiting compounds |
| CN107722034A (en) * | 2017-11-06 | 2018-02-23 | 长沙爱扬医药科技有限公司 | A kind of method that absinthin is extracted from smelly red spirit grass |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US9458128B2 (en) | 2012-05-24 | 2016-10-04 | Orion Corporation | Catechol O-methyltransferase activity inhibiting compounds |
| CN103242281A (en) * | 2013-05-28 | 2013-08-14 | 东华大学 | 3'-hydroxy-4',5,6,7-tetramethoxy isoflavanone and preparation method thereof |
| CN103919765A (en) * | 2014-04-24 | 2014-07-16 | 无锡艾德美特生物科技有限公司 | Application of hispidulin in preparing catechol drug synergist and pharmaceutical composition containing hispidulin |
| CN103919765B (en) * | 2014-04-24 | 2016-06-15 | 无锡艾德美特生物科技有限公司 | Dinatin application in preparation catechol medicament synergistic agent and comprise the pharmaceutical composition of dinatin |
| CN107722034A (en) * | 2017-11-06 | 2018-02-23 | 长沙爱扬医药科技有限公司 | A kind of method that absinthin is extracted from smelly red spirit grass |
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