CN101838258B - New preparation method of asymmetric synthetic dibenzo dioxy octanone - Google Patents
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Abstract
The invention belongs to the field of pharmaceutical synthesis, and relates to a new asymmetric synthesis preparation method of a dibenzo dioxy octanone compound with a structural formula (I). The compound (I) is a cholesterol transferase inhibitor and can treat cardiovascular system diseases such as a coronary heart disease and the like through selectively increasing high-density lipoprotein cholesterol. Compared with the prior art, the method of the invention adopts the asymmetric synthetic method and a new carbon-carbon coupled technology using triethylborine as an ethyl source, improves the yield of a target product, simplifies the separation and purification difficulty of the product, enables industrialized mass production to be possible and simultaneously lowers the cost, the total yield of the compound I prepared by the method of the invention is 5.46 percent, and the total yield of the product is improved by 3.25 times by being compared with the prior art.
Description
Technical field
This patent belongs to the synthetic field of medicine, relates to the synthesis preparation method that dibenzo dioxy octanone compounds is new.
background technology
Dibenzo dioxy octanone compounds obtains called after Penicillide (11-hydroxyl-3-[(1S)-1-hydroxy-3-methyl butyl by Sassa T. separation from natural product first]-4-methoxyl group-9-methyl-5H, 7H-dibenzo [b, g] [1,5] dioxy octane-5-ketone (Tetrahedron Letter 1974,45,3941-3942).
The Japanese patent WO1994012175 of Taisho Pharmaceutical Co., Ltd in 1994 discloses and sends out filial piety by microorganism, obtains dibenzo dioxy octanone compounds and has the effect that reduces lipid level; Penicillide be take as primer in Beyer Co., Ltd, take cholesterol transferring enzyme as pharmacological model, has carried out the research of the structure activity relationship of system, finds that Compound I has IC
50=15nm, t
1/2(ratplasma) (h)=4.2 outstanding drug effect (the patent WO2004039453 of Beyer Co., Ltd, Bioorganic & MedicinalChemistry Letter, 15 (2005), 3611-3614), be a kind of brand-new cholesterol transferase inhibitor (CETP), can selectivity high density lipoprotein increasing cholesterol, can treat the cardiovascular system diseases such as coronary heart disease.
summary of the invention
The method of asymmetric synthesis that the object of this invention is to provide the compound of a kind of new synthesis type (I).
The prepared Compound I of the inventive method, its total recovery is 5.46%, and the total recovery of the prepared Compound I of prior art (patent CN101066967) is 1.68%, and product total recovery of the present invention has improved 3.25 times than the latter.
The object of the invention is to adopt a kind of new method of asymmetric synthesis to prepare Compound I.Compare with the synthetic method about Compound I adopting in the patent WO2004039453 of Beyer Co., Ltd and CN101066967, it is different with it that the present invention mainly contains Er Ge aspect; First invention, in the preparation process of compound VI II, is characterized in that the amino alcohol that relates to chirality is used as chiral source part; Its scope comprises lower routine compound.By asymmetric synthesis; can directly obtain the compound of required configuration, consuming time thereby before overcoming, use the chirality preparative column purifies and separates that related to of patent is brought, consume wealth; the shortcoming of can not mass-producing amplification quantity producing, in preparation, possessed become medicine may.
Second the present invention, in the preparation process of Compound I I, is characterized in that relating to triethyl-boron as ethyl source; Catalyzer is 2 % by mole of Pd (dppf) Cl
2; Alkali is 2 equivalents, and scope comprises the potassium of carbonic acid, sodium, cesium salt, or cesium acetate.Its yield is 65%, and is better than 40% yield and the upper Still linked reaction (yield is 22%) adopting of WO2004039453 that patent CN101066967 uses Negeish linked reaction.
Be below synthetic route of the present invention:
Wherein the synthetic method of Compound I X adopts the method on patent CN101066967, and the synthetic method of compound VI II adopts J.Am.Chem.Soc., Vol.108,1986,6071 and J.Am.Chem.Soc., Vol.109, the method on 1987,7111; The preparation method of two tertiary amyl zinc adopts J.Am.Chem.Soc., Vol.100, the method on 1978,3359 and J.C.S.Dalton, 1974,2187.
Accompanying drawing explanation
Fig. 1 is the chiral separation figure of compound dl-VIII.
Fig. 2 is the chiral separation figure of compound VI II-S.
Embodiment
(1) 6-{2-benzyloxy-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrroles-2-oxygen base) methyl] phenoxy group-3-(1 (S)-hydroxyl-3,3 '-dimethylbutyl)-O-Anisic Acid methyl esters synthetic 1
By (-)-3-outer-(74.1 milligrams of dimethylamino iso-borneols, 0.4 mmole) be dissolved in the dry toluene of 50 milliliters, heating and cooling are degassed repeatedly, with argon shield, (4.76 grams of toluene solutions that add two tertiary amyl zinc when 15 spend, 23 mmoles), at this temperature, stir 15 minutes, then be cooled to-78 degree, (10.4 grams of benzaldehyde compound IX, 18.8 mmoles) be dissolved in 10 milliliters of toluene, add in reaction solution, mixture is progressively warming up to 0 degree, continue to stir 6 hours, then saturated ammonium chloride solution is slowly added in reaction solution, by ethyl acetate, extract 3 times, merge organic phase, organic phase water and salt washing, anhydrous magnesium sulfate drying, filter, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (chloroform/ethyl acetate=50:1), obtaining 7.06 grams of (60%) compounds (S)-VIII is faint yellow oily matter, optical purity is more than 99%, [α]
d 20=+22.5 ° of (c=1.0, CHCl
3), it is as follows that we have carried out checking by chirality HPLC: compound (S)-VIII that the compound VI II of the racemization making by the method for patent CN101066967 adds this law to make, at chiral column: Chiralpak AD-H, mobile phase: normal hexane/ethanol=80: 20.Under this separation condition, detection wavelength is 254nm, mixture You Erchuchu peak and ratio 1: 3 respectively when 5 minutes and 7.4 minutes, and the compound that this law makes (S)-VIII is only at 7.29 minutes Chu Chu peaks; Accompanying drawing 1,2 is shown in by concrete analysis collection of illustrative plates.Equally, with compound 1,2, be respectively chiral source part, its result is respectively yield 64%, 66%, and optical purity is 92%, 86%.
1H-NMR(CD
3Cl)：δ：1.01(s，9H)；1.20-1.70(m，8H)；2.02(s，1H)；2.37(s，3H)；3.45(m，1H)；3.86(s，3H)；3.92(s，3H)；4.50(dd，1H)；4.65(m，1H)；4.93(dd，1H)；5.02(s，2H)；5.08(m，1H)；6.38(d，1H)；6.90(s，1H)；7.18-7.35(m，6H)ppm.
13C-NMR(CD
3Cl)：δ：20.4，20.5，25.4，27.1，30.1(3C)，30.5，51.5，52.4，58.6，62.3，63.3，66.5，71.1，114.5，116.9，118.8，121.3，123.6，127.1(2C)，127.6，128.9(2C)，131.0，131.6，131.8，136.7，138.3，?142.3，144.1，151.1，154.2，168.2ppm.
MS(ESI)：m/z＝625.3(M-H)
+
(2) 6-[2-benzyloxy-4-methyl-5-chloro-6-(methylol) phenoxy group]-3-(1 (S)-hydroxyl-3,3 '-dimethylbutyl)-O-Anisic Acid methyl esters
The tosic acid of the compound of 12.5 grams (20mmole) (S)-VIII and 22 milligrams is dissolved in the Virahol and 22ml water of 100ml, and reaction solution refluxes 5 hours.Finish to add water and ethyl acetate after reaction, organic phase is washed with salt, anhydrous magnesium sulfate drying, filter, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (petrol ether/ethyl acetate=12: 1-6: 1), obtaining 8.2 grams of (75%) compound VI I is colorless oil.
1H-NMR(CD
3Cl)：δ：1.01(s，9H)；1.50-1.78(m，2H)；2.05(s，1H)；2.38(s，3H)；3.88(s，3H)；3.93(s，3H)；4.79(d，2H)；5.00(s，2H)；5.10(m，1H)；6.38(d，1H)；6.87(s，1H)；7.18-7.35(m，6H)ppm.
(3) 6-[2-benzyloxy-4-methyl-5-chloro-6-(methylol) phenoxy group]-3-(1 (S)-hydroxyl-3,3 '-dimethylbutyl)-O-Anisic Acid
19.1 grams of (35mmole) compound VI I and 41.5 grams of potassium hydroxide are dissolved in 500ml methyl alcohol, reaction solution reflux 9 hours, cool to room temperature, adds methylene dichloride and water, separates organic phase, organic phase is washed with salt, anhydrous magnesium sulfate drying, filters, and organic phase reclaims, residuum can be directly used in next step reaction without carrying out purifying, and obtaining 17.7 grams of (95%) compound VI is colourless crystallization powder.
1H-NMR(d-DMSO)：δ：0.92(s，9H)；1.10-1.50(m，2H)；2.31(s，3H)；3.81(s，3H)；4.39(s，2H)；4.90(m，1H)；5.09(s，2H)；6.10(d，1H)；7.05(d，1H)；7.20-7.26(m，6H)ppm.
(4) 11-benzyloxy-3-(1 (S)-hydroxyl-3,3 '-dimethylbutyl)-chloro-9-of 4-methoxyl group-8-methyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
The dry triethylamine of the compound VI of 11.4 grams (21.7mmole) and 16.3ml is dissolved in the acetonitrile that 200ml is dry, the above-mentioned solution making is added drop-wise to slowly by 16.3 grams of chloro-1-picolines of iodate 2-and is dissolved in the solution that acetonitrile that 600ml is dry is made into when 70 spend, stir lower 9 hours consuming time, after dropwising, further at this temperature, react 8 hours.Then vacuum concentration, add methylene dichloride, organic phase water and salt washing, anhydrous magnesium sulfate drying, filter, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (petrol ether/ethyl acetate=10: 1-3: 1), obtaining 8.84 grams of (80%) compound V is colorless oil.
1H-NMR(CD
3Cl)：δ：1.03(s，9H)；1.50-1.78(m，2H)；2.30(s，3H)；3.99(s，3H)；5.18(m，1H)；5.20(s，2H)；5.45(d，2H)；6.90(d，1H)；6.93(s，1H)；7.32-7.45(m，5H)；7.53(d，1H)ppm.
(5) 11-hydroxyl-3-(1 (S)-hydroxyl-3,3 '-dimethylbutyl)-chloro-9-of 4-methoxyl group-8-methyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
The palladium carbon of the compound V of 13 grams (25.3mmole) and 4.42 milligram 10% is dissolved in the ethanol of 250ml ethyl acetate and 80ml, at the logical hydrogen of normal pressure, point plate tracks to without raw material, filter, filtrate vacuum concentration, gained residuum can be directly used in next step reaction without carrying out purifying, and obtaining 10.1 grams of (95%) compound IV is colourless crystallization powder.
1H-NMR(CD
3Cl)：δ：1.02(s，9H)；1.54(m，1H)；1.59(m，1H)；2.28(s，3H)；3.96(s，3H)；5.14(d，1H)；5.33(dd，1H)；5.49(dd，1H)；6.78(d，1H)；6.93(s，1H)；7.55(d，1H)ppm.
13C-NMR(CD
3Cl)：δ：20.5；30.1(3C)；30.8；52.4；62.3；65.8；66.5；116.9；118.3；118.5；123.3；124.2；131.1；133.7；138.2；142.7；146.0；151.0；154.1；167.8ppm.
MS(ESI)：m/z＝419.0(M-H)
+
(6) 11-hydroxyl-3-(1 (S)-hydroxyl-3,3 '-dimethylbutyl)-bromo-5 hydrogen of the chloro-9-methyl isophthalic acid of 4-methoxyl group-8-0-, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
The bromo-succinimide of the compound IV of 16 grams (38mmole) and 7.49 grams (42mmole) is dissolved in the ethanol of 500ml, reaction solution stirring at room 2 hours, finish reaction, add ethyl acetate and water, separate organic phase, saturated sodium bisulfite solution salt washing for organic phase, anhydrous magnesium sulfate drying, filters, and organic phase reclaims, residuum can be directly used in next step reaction without carrying out purifying, and obtaining 16.7 grams of (88%) compound III is pistac crystalline powder.
1H-NMR(CD
3Cl)：δ：1.03(s，9H)；1.57-1.61(m，2H)；2.51(s，3H)；3.98(s，3H)；5.18(dd，1H)；5.41(dd，2H)；6.84(s，1H)；6.85(d，1H)；6.95(s，1H)；7.60(d，1H)ppm.
(7) 11-hydroxyl-3-(1 (S)-hydroxyl-3,3 '-dimethylbutyl)-chloro-9-methyl isophthalic acid 0-of 4-methoxyl group-8-ethyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
Under argon shield, by the compound III of 18 grams (36mmole), Pd (dppf) Cl of 35.2 grams of (108mmole) cesium acetates and 540 milligrams (0.72mmole)
2be dissolved in dry tetrahydrofuran (THF), the tetrahydrofuran solution of the triethyl-boron of the 1M of 108ml (108mmole) is added in reaction solution, reflux 4 hours.Reaction solution is cooled to 0 degree, sodium hydroxide with 10% and 30% hydrogen peroxide cancellation reaction, stirring at room after 0.5 hour with dilute hydrochloric acid neutralization, by ethyl acetate, extract 3 times, merge organic phase, organic phase is washed with salt, and anhydrous magnesium sulfate drying filters, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (petrol ether/ethyl acetate=8: 1-1: 1), obtaining 10.5 grams of (65%) Compound I I is colourless crystallization powder.
1H-NMR(CD
3Cl)：δ：1.03(s，9H)；1.15(t，3H)；1.57(m，1H)；1.61(m，1H)；1.93(d，1H)；2.31(s，3H)；2.77(q，2H)；3.99(s，3H)；5.16(m，1H)；5.37(dd，1H)；5.48(dd，1H)；6.26(s，1H)；6.84(d，1H)；6.95(s，1H)；7.59(d，1H)ppm.
13C-NMR(CD
3Cl)：δ：13.3；16.2；20.7，30.1(3C)；30.8；52.4；62.3；65.9；66.6；116.9；118.8；121.3；123.6；131.0；131.6；131.8；138.3；142.3；144.1；151.1；154.2；167.4ppm.
HRMS(MALDI/DHB)：471.1550(M+Na)
+；C
24H
29O
6ClNa
+1
(8) 11-{7 '-methyl bicyclic [2.2.1] heptane-7-methanoyl }-3-[(1s)-hydroxyl-3,3 '-dimethylbutyl]-chloro-9-methyl isophthalic acid the 0-of 4-methoxyl group-8-ethyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
Under argon shield, 10.4 grams of (23.2mmole) Compound I I are dissolved in dry tetrahydrofuran (THF), under 0 degree, add 702 milligrams of (25.2mmole) sodium hydrogen, reaction solution was stirring at room 1 hour.The compounds X VI preparing is dissolved in to dry tetrahydrofuran (THF) and is prepared into solution and adds in above-mentioned reaction solution in room temperature, further stir 5 hours.Finish to add salt solution and ethyl acetate after reaction, organic phase is washed with salt, anhydrous magnesium sulfate drying, filter, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (petrol ether/ethyl acetate=10: 1-6: 1), obtaining 13.4 grams of (99.6%) Compound I is colourless crystallization (petrol ether/ethyl acetate).
1H-NMR(CD
3Cl)：δ：1.03(s，9H)；1.12(t，3H)；1.23-2.08(m，14H)；2.32(s，5H)；2.63(br.，s，2H)；3.98(s，3H)；5.13-5.19(m，1H)；5.21-5.60(br.，s，2H)；6.98(d，1H)；7.59(d，1H)ppm.
13C-NMR(CD
3Cl)：δ：13.5；16.3；17.3；21.6；27.9(2C)；29.4；29.7；30.1(3C)；30.8；42.2(2C)；52.3；58.8；62.8；65.8；66.6；117.8；119.2；123.0；130.9；131.1；131.3；138.2；138.3；139.4；147.7；151.4；154.2；167.2；175.2ppm.
MS-ESI：607.2(M
++Na)，567.3(M
+-OH).
MP：177-179℃.
[α]
D 20＝+2.6°(c＝1.0，CHCl
3)
6-{2-benzyloxy-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrroles-2-oxygen base) methyl] phenoxy group-3-(1 (S)-hydroxyl-3,3 '-dimethylbutyl)-O-Anisic Acid methyl esters synthetic 1
Under argon shield, by (1S, 2S ')-phenyl-(106.8 milligrams of (1-benzyl tetrahydro pyrroles)-1-methyl alcohol, 0.4 mmole), (10.4 grams of benzaldehyde compound IX, 18.8 mmoles) be dissolved in the dry hexanaphthene of 100 milliliters, reflux 0.5 hour, then be cooled to 0 degree, (4.76 grams of cyclohexane solutions that add two tertiary amyl zinc, 23 mmoles), at this temperature, stir 24 hours, saturated ammonium chloride solution is slowly added to cancellation reaction in reaction solution, by ethyl acetate, extract 3 times, merge organic phase, organic phase water and salt washing, anhydrous magnesium sulfate drying, filter, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (chloroform/ethyl acetate=50: 1), obtaining 5.88 grams of (50%) compounds (S)-VIII is yellow oil, optical purity is 96%, equally, with compound 4,6, be respectively chiral source part, its result is respectively yield 58%, 46%, and optical purity is 95%, 82%.
Claims (1)
1. the preparation method of structural formula (I) compound,
It is characterized in that synthetic route is as follows:
In preparing compound VIII process, with two tertiary amyl zinc, be alkyl source, consumption is at 1-2 equivalent; With the amino alcohol part of 2 % by mole of chiralitys, it is chiral source; Solvent is toluene, hexanaphthene; Reaction times is 1-24 hour; Range of reaction temperature is at 0-80 degree; Prepare the compound VIII of required configuration;
In preparation Compound I I process, used Suzuki-Miyaura reaction, reaction reagent is triethyl-boron, 1-3 equivalent; Solvent is tetrahydrofuran (THF) or DMF; Catalyzer is 2 % by mole of Pd (dppf) Cl
2; Alkali is the potassium of the carbonic acid of 2 equivalents, sodium, cesium salt, or cesium acetate; Temperature of reaction is 20-120 degree; Reaction times is 1-10 hour;
Described amino alcohol is following compounds:
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101066967A (en) * | 2006-12-12 | 2007-11-07 | 复旦大学 | Synthesis process of dibenzo dioxy octanone compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101066967A (en) * | 2006-12-12 | 2007-11-07 | 复旦大学 | Synthesis process of dibenzo dioxy octanone compound |
Non-Patent Citations (5)
| Title |
|---|
| Bing Wang et al..Direct B-alkyl Suzuki-Miyaura cross-coupling of trialkylboranes with aryl bromides in the presence of unmasked acidic or basic functions and base-labile protections under mild non-aqueous conditions.《Adv. Synth. Catal.》.2009,第351卷415-422. * |
| David Brückner et al..Dibenzodioxocinones-A new class of CETP inhibitors.《Bioorganic & Medicinal Chemistry Letters》.2005,第15卷3611-3614. |
| David Brückner et al..Dibenzodioxocinones-A new class of CETP inhibitors.《Bioorganic & * |
| M. Kitamura et al..Catalytic Asymmetric Induction. Highly Enantioselective Addition of Dialkylzincs to Aldehydes.《J. Am. Chem. Soc.》.1986,第108卷6071-6072. * |
| Medicinal Chemistry Letters》.2005,第15卷3611-3614. * |
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