CN102796068A - Method for synthetizing (R)-(plus)-pinocembrin and (S)-(minus)-pinocembrin - Google Patents
Method for synthetizing (R)-(plus)-pinocembrin and (S)-(minus)-pinocembrin Download PDFInfo
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- CN102796068A CN102796068A CN2011101381577A CN201110138157A CN102796068A CN 102796068 A CN102796068 A CN 102796068A CN 2011101381577 A CN2011101381577 A CN 2011101381577A CN 201110138157 A CN201110138157 A CN 201110138157A CN 102796068 A CN102796068 A CN 102796068A
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- IAFBOKYTDSDNHV-AWEZNQCLSA-N COc1cc(OC)c(C(C[C@@H](c2ccccc2)O2)=O)c2c1 Chemical compound COc1cc(OC)c(C(C[C@@H](c2ccccc2)O2)=O)c2c1 IAFBOKYTDSDNHV-AWEZNQCLSA-N 0.000 description 1
- URFCJEUYXNAHFI-ZDUSSCGKSA-N Oc1cc(O[C@@H](CC2=O)c3ccccc3)c2c(O)c1 Chemical compound Oc1cc(O[C@@H](CC2=O)c3ccccc3)c2c(O)c1 URFCJEUYXNAHFI-ZDUSSCGKSA-N 0.000 description 1
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Abstract
The invention relates to a method for synthetizing (R)-(plus)-pinocembrin and (S)-(minus)-pinocembrin, phloroglucinol and (S)-3-hydroxyl-3 ethyl phenylpropiolate are taken as raw materials, the hydroxyl of the phloroglucinol is protected by methyl or methoxy methyl and Weinreb amine ((S)-3-(tert-butyl dimethyl silyl)-N-methoxy-N-methyl-3-phenyl acrylic amide) which is protected by silyl carry out Weinreb reaction under the organic alkali condition, so (S)-1-[2, 4-dimethoxy-6-(methoxy-methyl)-phenyl]-3-phenyl-3-(tert-butyl dimethyl silyl)-propyl-1-ketone is obtained, the methoxy-methyl is removed under the acid condition, intramolecular Mitsunobu cyclization is carried out, and finally, the (R)-(plus)-pinocembrin is obtained after removing the methyl. According to the same method, (R)-3-hydroxyl-3 ethyl phenylpropiolate is taken as the raw material, so the (S)-(minus)-pinocembrin can be obtained.
Description
Technical field
The present invention relates to treat the chemicals field of cardiovascular and cerebrovascular diseases, be specifically related to a kind of (R)-(+)-Nuo Sailin with the effect of treatment cardiovascular and cerebrovascular diseases is reached (S)-(-)-a Nuo Sailin synthetic method.
Background technology
Nuo Sailin (pinocembrin) chemical name is 2,3-dihydro-5,7-dihydroxyl-2-phenyl-4H-1-chromene-4-ketone (2,3-Dihydro-5,7-dihydroxy-2-phenyl-4H-1-benzopyran-4-one).Nuo Sailin separates to obtain a kind of flavanone compound from propolis, contains a chiral centre in its chemical structure, and natural promise plug body structure that stands in great numbers is the S configuration, specific optical rotation [α] D
15For-45.3 (c, 0.9, acetone is solvent).In addition, in nut pine (Pinus cembra), eucalyptus (Eucalyptus sieberi), red raising plants such as (Alnussieboldiana), also isolate this compound, but content is all very low.Development product is complete synthesis racemic modification at present.Nuo Sailin has multiple biological activity; As treat cardiovascular and cerebrovascular diseases; Antibiotic, protozoacide, antimutagenic, anti-oxidant, the testosterone 5 suppresses active, Transglucosylase suppresses active, suppress mastocyte and (Du Guanhua etc., CN1695608 such as neutrophil leucocyte secretion activity, anti-tumor activity and local anaesthesia activity; Guang, H.M., Du G.H.; European Journal of Pharmacology, 542 (1-3), 77-832006..Brown Matthew J.et.al.Electronic Journal of Environmental; Agriculturaland Food Chemistry; 5 (2), 1265-1277,2006).Research well afoot with a Nuo Sailin uses as medicine has very big potentiality to be exploited.
There is a chiral carbon in promise plug standing forest, have pair of optical enantiomorph (R)-Nuo Sailin with (S)-Nuo Sailin.Naturally occurring being (S)-Nuo Sailin, and content is less in plant, can't obtain on a large scale; And the bioactivity research of (R)-Nuo Sailin is reported seldom.Therefore, for (R)-Nuo Sailin carry out study on the synthesis, and a Nuo Sailin of two kinds of configurations is carried out the comparative studies of pharmacologically active, and instructs drug development research and application in the future with this, have important practical value.
Bibliographical information (Wu Song etc., CN 101429186) with racemic Nuo Sailin through fractionation obtain (R)-Nuo Sailin with (S)-Nuo Sailin, this method is to separate the isomer of R and S configuration with silica gel column chromatography, because of the two R
fDiffer less, so extensive synthetic acquiring a certain degree of difficulty, concrete route is following:
Synthesizing of K.J.Hodgetts report (S)-(-) pinostrobin, route is (Tetrahedron 2005,61,6860) as follows:
At present, about R-(+)-Nuo Sailin with (S)-(-)-Nuo Sailin complete synthesis do not see bibliographical information as yet.
Summary of the invention
The technical problem that the present invention will solve provide a kind of new synthetic (R)-(+)-Nuo Sailin with (S)-(-)-a Nuo Sailin synthetic method.
The present invention is on the reference basis of above-mentioned document; According to synthetic (R)-(+) of a following route-Nuo Sailin: with Phloroglucinol with (S)-3-hydroxyl-3-phenylpropionic acid ethyl ester is a raw material; Hydroxyl is protected through the methyl or methoxy methyl in the Phloroglucinol; Under the organic bases condition, carry out the Weinreb reaction and obtain (S)-1-[2 with the Weinreb amine of protecting through siloyl group ((S)-3-(tertiary butyl dimethylsilyl oxygen)-N-methoxyl group-N-methyl-3-Phenylpropionamide); 4-dimethoxy-6-(methoxy methoxy base)-phenyl]-3-phenyl-3-(tertiary butyl dimethylsilyl) oxygen-propyl group-1-ketone; Carry out intramolecularly Mitsunobu cyclization after under acidic conditions, sloughing methoxymethyl, last demethylating obtains (R)-(+)-Nuo Sailin.Concrete route is following:
Wherein, the synthetic of midbody 10 also can be synthesized with reference to literature method of the prior art; Compound 10 is demethylating preparation (R)-(+)-Nuo Sailin (1) under the demethylation reagent effect:
Preferred demethylation reagent is selected from aluminum chloride, boron tribromide, boron trichloride, Iodotrimethylsilane or Hydrogen bromide; Preferred demethylation reagent is selected from Iodotrimethylsilane.
Temperature of reaction is-80 a ℃-solvent refluxing temperature, preferred-50 ℃-120 ℃;
Reaction times is 1h-24h, preferred 4-12h;
Be reflected in the organic solvent and carry out, solvent is toluene, benzene, acetonitrile, trichloromethane, methylene dichloride or Glacial acetic acid min. 99.5.
By same method, adopting (R)-3-hydroxyl-3 phenylpropionic acid ethyl ester is raw material, then can be obtained (S)-(-)-Nuo Sailin.
Compound 10 ' is demethylating preparation ((S)-(-)-Nuo Sailin (1 ') under the demethylation reagent effect.
The present invention provides a kind of (R)-(+)-Nuo Sailin with (S)-(-)-total synthesis method of a Nuo Sailin, can be used for obtaining the medicine of single configuration.
Description of drawings
Accompanying drawing 2 is the optical purity color atlas of compound 1.
Embodiment
Through following embodiment, will still it will be appreciated by persons skilled in the art that the present invention is not limited only to these embodiment to further explain of the present invention.The fusing point appearance: the YRT-3 of Precision Instrument Factory, Tianjin Univ. fusing point appearance is measured, and TM is not proofreaied and correct;
1H NMR spectrum is measured with Varian Mercury-300 nmr spectrometer, adopts DMSO-d
6And CDCl
3Make solvent, in be designated as TMS; Mass spectrum uses the AutoSpecUltima-TOF mass spectrograph to measure, and adopts fast atom bombardment(FAB) ionize mode, and optically-active is measured with PE Model 343 polarimeters.
A single configuration Nuo Sailin optical purity is with high effective liquid chromatography for measuring among the embodiment, and concrete parameter is following:
Agilent 1260 performance liquid; Chiralcel OD-H chromatographic column, 5 μ m, 150mm * 4.6mm ID; Moving phase: ethanol: normal hexane (contain at 30: 70 0.1% trifluoroacetic acid); Flow velocity: 1mL/min; Column temperature: 25 ℃; Detect wavelength: 290nm.
Accompanying drawing 2 is the optical purity color atlas of compound 1.
Embodiment
The preparation of embodiment 1 (S)-3-hydroxy-n-methoxyl group-N-methyl-3-Phenylpropionamide (3)
With N, O-dimethyl hydroxylamine hydrochloride 66.9g (0.672mol) is dissolved among the anhydrous THF of 1200mL, and-78 ℃ drip 840mL n-BuLi (1.6molL down
-1, 0.134mol), drip and finish stirring at room 15min; Be cooled to-78 ℃ again, drip THF (300mL) solution of compound (2) 43.4g (0.224mol), drip and finish, continue reaction 2h; With saturated ammonium chloride solution cancellation reaction, ethyl acetate extraction, anhydrous sodium sulfate drying; Evaporate to dryness gets colourless oily mater (S)-3-(tertiary butyl dimethylsilyl oxygen)-N-methoxyl group-N-methyl-3-Phenylpropionamide (3) 43.0g, yield 93% through silica gel column chromatography.
1H?NMR(CDCl
3)δ(ppm)：2.81(m，2H)，3.20(s，3H)，3.62(s，3H)，4.26(s，1H)，5.15(d，1H，J＝2.5and?9.2Hz，)，7.26-7.42(m，5H)。
The preparation of embodiment 2 (S)-3-(tertiary butyl dimethylsilyl oxygen)-N-methoxyl group-N-methyl-3-Phenylpropionamide (4)
(20.9g 100mmol) with the dissolving of 500mL methylene dichloride, adds imidazoles 13.6g (200mmol) with compound (3); TERT-BUTYL DIMETHYL CHLORO SILANE 16.5g (110mmol), stirred overnight at room temperature pours in the saturated ammonium chloride solution; With dichloromethane extraction, combining extraction liquid, anhydrous sodium sulfate drying; Evaporate to dryness gets colourless oily mater (S)-3-(tertiary butyl dimethylsilyl oxygen)-N-methoxyl group-N-methyl-3-Phenylpropionamide (4) 28.7g, yield 89% through silica gel column chromatography.
1H?NMR(CDCl
3)δ(ppm)：-0.13(s，3H)，0.10(s，3H)，0.84(s，9H)，2.47(dd，1H，J＝3.5，14.5Hz)，3.02-3.07(brs，1H)，3.18(s，3H)，3.64(s，3H)，5.26(dd，1H，J＝3.5，9.0Hz)，7.24-7.39(m，5H)。
FAB-MS?341.2(M+NH
4 +，100％)；
Embodiment 33, the preparation of 5-syringol (6)
Phloroglucinol 126.0g (1mol) is dissolved in the 1000mL anhydrous methanol, slowly drips vitriol oil 126.0g under the vigorous stirring, drip and finish heating reflux reaction 24h; Be cooled to room temperature, with remaining methyl alcohol evaporate to dryness, massive laundering is to neutral; Ethyl acetate extraction, anhydrous sodium sulfate drying, evaporate to dryness; Get colourless oily mater 3 through silica gel column chromatography, 5-syringol (6) 101.0g, yield 65.6%.
1H?NMR(CDCl
3)δ(ppm)：3.74(s，6H)，5.53(brs，1H)，6.03(d，2H，J＝2.0Hz)，6.08(t，1H，J＝2.0Hz)。
Embodiment 41, the preparation of 3-dimethoxy-5-(methoxy methoxy base) benzene (7)
Compound (6) 100g (0.65mol) is dissolved among the 2500mL DMF, adds K
2C0
3179.4g (0.13mmol), drip chloromethyl methyl ether 64.4g (0.8mmol) under the vigorous stirring, drip and finish stirred overnight at room temperature.Reaction solution is poured in the 2500mL saturated ammonium chloride solution into ethyl acetate extraction, combining extraction liquid; Successively with water, 2N sodium hydroxide solution, saturated common salt water washing; Anhydrous sodium sulfate drying, evaporate to dryness gets colourless oily mater 1; 3-dimethoxy-5-(methoxy methoxy base) benzene (7) 91.0g, yield 90.9%.
1HNMR(CDCl
3)δ(ppm)：3.47(s，3H)，3.76(s，6H)，5.14(s，2H)，6.14(s，1H)，6.23(s，2H)。
The preparation of embodiment 5 (S)-1-[2,4-dimethoxy-6-(methoxy methoxy base)-phenyl]-3-phenyl-3-(tertiary butyl dimethylsilyl) oxygen-propyl group-1-ketone (8)
Under the argon shield, compound (7) 23.76g (120mmol) benzene is dissolved in the 1000mL toluene, drips 230mL tert-butyl lithium (1.3molL down in-78 ℃
-1, 300mmol), drip and finish, continue to stir 15min; Slowly be warming up to 0 ℃ then, be cooled to-78 ℃ after continuing to stir 1h, drip toluene (200mL) solution of compound (4) 12.32g (380mmol), drip and finish; Rise to stirring at room 2h, slowly drip saturated ammonium chloride solution cancellation reaction, ethyl acetate extraction, combining extraction liquid; Successively with water, saturated common salt water washing, anhydrous sodium sulfate drying, evaporate to dryness; Get colourless oily mater (S)-1-[2,4-dimethoxy-6-(methoxy methoxy base)-phenyl]-3-phenyl-3-(tertiary butyl dimethylsilyl) oxygen-propyl group-1-ketone (8) 8.97g, yield 65% through silica gel column chromatography.
1H?NMR(CDCl
3)δ(ppm)：-0.13(s，3H)，0.08(s，3H)，0.86(s，9H)，3.02(dd，1H，J＝4.5，17.5Hz)，3.30(dd，1H，J＝7.5，17.5Hz)，3.39(s，3H)，3.69(s，3H)，3.77(s，3H)，5.03(s，2H)，5.38(dd，1H，J＝4.5，7.5Hz)，6.09(s，1H)，6.29(s，1H)，7.20(t，1H，J＝8.0Hz)，7.27(t，2H，J＝7.5Hz)，7.35(d，2H，J＝8.0Hz)；
13C?NMR(75MHz，CDCl3，δppm)：200.71，162.13，158.14，155.99，145.29，127.93，126.90，126.10，114.43，94.55，93.07，92.06，70.45，56.15，55.87，55.55，55.38，25.75，18.07，-4.74，-5.13；
The preparation of embodiment 6 (S)-3-hydroxyl-1-(2-hydroxyl-4,6-dimethoxy-phenyl)-3-phenyl propyl-1-ketone (9)
Compound (8) 6.9g (15mmol) with THF (270mL) and water (30mL) dissolving, is added the 570mg tosic acid, 55 ℃ of reaction 12h; Reaction solution is poured in the saturated sodium bicarbonate solution into ethyl acetate extraction, combining extraction liquid; With water and saturated common salt water washing, anhydrous sodium sulfate drying, evaporate to dryness; Get white solid (S)-3-hydroxyl-1-(2-hydroxyl-4,6-dimethoxy-phenyl)-3-phenyl propyl-1-ketone (9) 3.57g, yield 79% through silica gel column chromatography.
1H?NMR(CDCl
3)δ(ppm)：3.33-3.51(m，3H)，3.77(s，3H)，3.81(s，3H)，5.27(dd，1H，J＝4.0，9.0Hz)，5.90(s，1H)，6.07(s，1H)，7.28(t，1H，J＝8.0Hz)，7.27(t，2H，J＝8.0Hz)，7.35(d，2H，J＝7.5Hz)。
FAB-MS?303.1(M+H
+，15％)
Embodiment 7 (R)-5, the preparation of 7-dimethoxy-2-chromene-4-ketone (10)
With triphenylphosphine (3.93g, 15mmol), diethylazodicarboxylate (2.64mg; 15mmol) with 90mL THF dissolving, 0 ℃ is stirred 15min down, drips THF (90mL) solution of compound (9) 3.02g (10mmol); Drip Bi Jixu and stir 1h, reaction solution is revolved dried, get white solid (R)-5 through silica gel column chromatography; 7-dimethoxy-2-chromene-4-ketone (10) 2.3g, yield 81%.
1H?NMR(CDCl
3)δ(ppm)：2.79(dd，1H，J＝3.0，16.5Hz)，3.01(dd，1H，J＝13.0，16.5Hz)，3.81(s，3H)，3.88(s，3H)，5.40(dd，1H，J＝3.0，13.0Hz)，6.09(d，1H，J＝2.0Hz)，6.15(d，1H，J＝2.0Hz)，7.38-7.46(m，5H)。
FAB-MS?285.0(M+H
+，100％)；
Optical purity is 100%.
The preparation of embodiment 8 (R)-(+)-Nuo Sailin (1)
Compound (10) 2.84g (10mmol) is dissolved in the anhydrous CHCl of 100mL
3In, add 4.0g (40mmol) Iodotrimethylsilane, 50 ℃ of lucifuge reaction 24h; Add the shrend reaction of going out, with chloroform extraction, successively with water and saturated common salt water washing; Anhydrous sodium sulfate drying gets white solid (R)-(+)-Nuo Sailin (1) 0.82g, yield 32% through silica gel column chromatography.
1HNMR(CDCl
3)δ：12.12(s，1H)，10.81(s，1H)，7.516-7.374(m，5H)，5.91(s，1H)，5.88(s，1H)，5.60(dd，1H，J＝3.2Hz，J＝12.8Hz)，3.29(dd，1H，J＝12.8Hz，J＝17.4Hz)，2.80(1H，dd，J＝3.2Hz，J＝17.2Hz)。
13C?NMR(75MHz，DMSO，δppm)：195.95，166.72，163.52，162.72，138.70，128.55，126.61，101.81，95.94，78.39
FAB-MS?257.1(M+H
+，100％)
Optical purity is 98.6%.
Claims (6)
1. the preparation method of (R)-(+)-Nuo Sailin is characterized in that, comprises the steps:
Compound 10 is demethylating preparation (R)-(+)-Nuo Sailin (1) under the demethylation reagent effect.
2. the preparation method of (S)-(-)-Nuo Sailin is characterized in that, comprises the steps:
Compound 10 ' is demethylating preparation ((S)-(-)-Nuo Sailin (1 ') under the demethylation reagent effect.
3. according to each preparation method in the claim 1 and 2, it is characterized in that described demethylation reagent is selected from aluminum chloride, boron tribromide, boron trichloride, Iodotrimethylsilane or Hydrogen bromide.
4. according to each preparation method in the claim 1 and 2, it is characterized in that temperature of reaction is-80 a ℃-solvent refluxing temperature.
5. according to each preparation method in the claim 1 and 2, it is characterized in that the reaction times is 1h-24h.
6. method according to claim 2 is characterized in that, the reaction organic solvent is selected from toluene, benzene, acetonitrile, trichloromethane, methylene dichloride, Glacial acetic acid min. 99.5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111630041A (en) * | 2017-11-21 | 2020-09-04 | 奥萨特有限公司 | Synthesis of morin and morin derivative |
-
2011
- 2011-05-26 CN CN2011101381577A patent/CN102796068A/en active Pending
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| CHAVI YENJAI, ET AL.: "Structural Modification of 5,7-Dimethoxyflavone from Kaempferia parviflora and Biological Activities", 《ARCH. PHARM. RES.》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111630041A (en) * | 2017-11-21 | 2020-09-04 | 奥萨特有限公司 | Synthesis of morin and morin derivative |
| JP2021504459A (en) * | 2017-11-21 | 2021-02-15 | オーサテック ゲーエムベーハーＯｒｓａｔｅｃ Ｇｍｂｈ | Synthesis of morin and morin derivatives |
| CN111630041B (en) * | 2017-11-21 | 2023-08-15 | 奥萨特有限公司 | Synthesis of morin and morin derivatives |
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Application publication date: 20121128 |