CN101066967A - Synthesis process of dibenzo dioxy octanone compound - Google Patents
Synthesis process of dibenzo dioxy octanone compound Download PDFInfo
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Abstract
The present invention belongs to the field of medicine synthesis technology, and is especially dibenzo dioxy octanone compound in the structure as shown and its new synthesis process. The compound is cholesterol transferase inhibitor, and may be used in increasing high density lipoprotein cholesterol selectively to treat coronary heart disease and other cardiovascular system diseases. Compared with available technology, the present invention has the advantages of lowered cost, saving in resource, and greatly raised target product yield.
Description
Technical field
The invention belongs to the synthetic field of medicine, relate to the dibenzo dioxy octanone compounds of formula (I) and new synthesis preparation method.
Background technology
The dibenzo dioxy octanone compounds is separated from natural product by Sassa T. first and obtains, and called after Penicillide (the 11-hydroxyl-3-[(1S)-1-hydroxy-3-methyl butyl]-4-methoxyl group-9-methyl-5H, 7H-dibenzo [b, g] [1,5] dioxy octane-5-ketone (Tetrahedron Letter 1974,15,45,3941-3942).
By the high-throughput screening active ingredients, find that the dibenzo dioxy octanone compounds is a kind of brand-new cholesterol transferase inhibitor (CETP), can selectivity high density lipoprotein increasing cholesterol, can treat cardiovascular system diseases such as coronary heart disease.Beyer Co., Ltd is guide's thing with Penicillide, is pharmacological model with the cholesterol transferring enzyme, has carried out the research of the structure activity relationship of system, finds that Compound I has IC
50(μ M)=0.2, t
1/2(rat plasma) outstanding drug effect (the patent WO2004039453 of Beyer Co., Ltd, Bioorganic ﹠amp (h)=4.2; Medicinal Chemistry Letter, 15 (2005), 3611-3614).
Summary of the invention
The method that the purpose of this invention is to provide a kind of compound of new synthesis type (I).
The prepared Compound I of the inventive method, its total recovery are 1.68%, and the total recovery of the prepared Compound I of prior art (patent WO2004039453) is 0.12%, and product total recovery of the present invention has improved nearly 14 times than the latter.
The synthetic method about Compound I that is adopted in the present invention and the prior art (patent WO2004039453) is compared, possess following characteristics: first, the present invention is from chemical economic angle, before two fragment butt joints, at first carry out chlorination, prepare midbody compound XII, compare with the method that is adopted among the patent WO2004039453, reduced cost; The second, (VI → V), the method that benzyl is taken off in reaction utilization hydrogenation has improved its yield (being 95%), and the iron trichloride that obviously is better than being adopted among the patent WO2004039453 takes off the method (yield is 63%) of benzyl in preparation compound V process in the present invention; The 3rd, the present invention is in preparation intermediate compound III (raceme) process, and utilization Negeish linked reaction has been introduced ethyl on its structure 10-position, and the reaction reagent that is adopted is zinc ethyl (a 1-3 equivalent); Solvent is a nitrogen, nitrogen-dimethyl formamide (DMF); Catalyzer is tri-o-tolyl phosphorus and palladium; Its yield is 40%, is better than the Still linked reaction (yield is 22%) that is adopted among the patent WO2004039453; The 4th, the present invention adopts chemical method for splitting to prepare the isomeric compound IIIS and the IIIR of the absolute configuration of intermediate compound III, wherein, S-isomer IIIS and the further esterification of intermediate feed XVI obtain target compound I, R-isomer IIIR is then further oxidized, use the method (Corey reduction method) of asymmetric reduction to transform the needed S-isomer IIIS of generation again, thereby saved resource, improved the yield of target product.
The inventive method adopts following synthetic route:
Wherein, the synthetic method of starting raw material XV adopts the method that is adopted among the patent WO2004039453, the synthetic method of intermediate feed XI adopts the method that is adopted among the patent US5198463, the synthetic method of compounds X VI adopts Journal of Organic Chemistry, Vol.44, No.19,1979, the method that is adopted among the 2206-2210.
Description of drawings
Fig. 1 is the monomolecular sp figure of target compound (I).
Fig. 2 is the sp figure of target compound (I) hydrogen bond relation.
Fig. 3 is the structure cell sp figure that target compound (I) is piled up.
Fig. 4 is the chiral separation figure of compound d l-III.
Fig. 5 is the chiral separation figure of compound III-S.
Fig. 6 is the chiral separation figure of compound III-R.
Fig. 7 is the HPLC purity check figure of Compound I.
Embodiment
(1) 2-hydroxyl-3-benzyloxy-5-methyl-6-chloro-benzoic acid is synthetic
396 gram (1.52mole) 2-hydroxyl-3-benzyloxy-5-tolyl acids are dissolved in the mixed solution of 2500ml ethanol and 1200ml water, add 301.5 gram (2.27mole) chlorosuccinimides and 340 gram (2.1mole) iron trichlorides, stirring at room 3 hours.Remove ethanol then, add methylene dichloride, water is transferred PH to 1, and organic phase is washed with salt, and anhydrous magnesium sulfate drying filters, and organic phase reclaims, and obtaining 334 gram (75%) compounds X IV is faint yellow needle crystal.
1H-NMR(CD
3OD)：δ：2.30(s，3H)；5.08(s，2H)；6.79(s，1H)；7.37-7.46(m，5H)ppm.
(2) 2-benzyloxy-4-methyl-5-chloro-6-methylolphenol is synthetic
280 gram (0.96mole) compounds X IV are dissolved in the tetrahydrofuran (THF) of doing of 1500ml, are cooled to 0 degree under stirring, add 90 gram (2.3mole) tetrahydrochysene lithium aluminium in batches, further refluxed 1 hour.Slowly successively ethyl acetate and water are joined in the reaction solution, transfer PH to 6 with saturated ammonium chloride, with ethyl acetate extraction 2 times, merge organic phase, salt washing, anhydrous magnesium sulfate drying, filter, organic phase reclaims, recrystallization (petrol ether/ethyl acetate), and obtaining 240 gram (90%) compounds X III is white crystals.
1H-NMR(CD
3Cl)：δ：2.30(s，3H)；4.92(s，2H)；5.08(s，2H)；6.79(s，1H)；7.37-7.46(m，5H)ppm.
(3) methyl 2-benzyloxy-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrroles-2-oxygen base)] phenol synthetic
175 gram (0.63mole) compounds X III and 2 gram tosic acid are dissolved in the methylene dichloride of doing of 600ml, and under 0 degree, with 45ml (0.66mole) 3, the 4-dihydropyrane slowly is added dropwise in the reaction solution, and further stirring reaction is 5 hours.The 2ml triethylamine is added reaction solution, and organic phase is washed with salt, and anhydrous magnesium sulfate drying filters, and organic phase reclaims, recrystallization (sherwood oil/acetone), and obtaining 196 gram (86%) compounds X II is white crystals.
1H-NMR(CD
3Cl)：δ：1.70-1.90(m，6H)；2.30(s，3H)；3.60(m，1H)；3.95(m，1H)；4.92(d，2H)；5.02(d，1H)；5.12(s，2H)；6.79(s，1H)；7.37-7.46(m，5H)ppm.
(4) methyl 6-{2-benzyloxy-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrroles-2-oxygen base)] phenoxy group }-3-aldehyde radical-O-Anisic Acid methyl esters
Under argon shield; with the compounds X I of 30.5 grams (112mmole), the 4-N of the compounds X II of 48 grams (133mmole) and 41.6 grams, N-lutidine are dissolved in the dried acetonitrile of 800ml; add 18 active copper powders of gram and 23 gram cupric oxide, reaction is 12 hours under 80 degree stir.Reaction solution dilutes with methylene dichloride, filters the organic phase vacuum concentration.The separation and purification of residuum silica gel column chromatography, eluent (petrol ether/ethyl acetate=6: 1), obtaining 42 gram (68%) compounds Xs is faint yellow oily thing.
1H-NMR(CD
3Cl)：δ：1.20-1.60(m，6H)；2.30(s，3H)；3.45(m，1H)；3.95(s，3H)；3.98(s，3H)；4.50(d，1H)；4.60(m，1H)；4.93(d，1H)；5.02(s，2H)；6.47(d，1H)；6.92(s，1H)；7.37-7.46(m，5H)；7.73(d，1H)；10.22(s，1H)ppm.
(5) methyl 6-{2-benzyloxy-4-methyl-5-chloro-6-[(tetrahydrochysene-2H-pyrroles-2-oxygen base)] phenoxy group }-3-(1-hydroxyl-3,3 '-dimethylbutyl)-O-Anisic Acid methyl esters
3.46 gram magnesium powder is suspended from the dried ether of 10ml, with the 1-bromo-2 of 16.7ml, the 2-dimethylpropane is dissolved in the dried ether of 32ml, stirring, is added drop-wise under the room temperature in the above-mentioned solution, further reacts 12 hours; The above-mentioned Grignard reagent for preparing slowly is added drop-wise to 28 gram (51mmole) compounds Xs is dissolved in the solution of the dried tetrahydrofuran (THF) of 207ml under-78 degree, dropwise, further stirred 2 hours.Slowly add saturated ammonium chloride solution in the reaction solution then, with ethyl acetate extraction 3 times, merge organic phase, organic phase water and salt washing, anhydrous magnesium sulfate drying filters, organic phase reclaims, the separation and purification of residuum silica gel column chromatography, eluent (chloroform/ethyl acetate=50: 1), obtaining 21 gram (65%) Compound I X is faint yellow oily thing.
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.
(6) 6-[2-benzyloxy-4-methyl-5-chloro-6-(methylol) phenoxy group]-3-(1-hydroxyl-3,3 '-dimethylbutyl)-O-Anisic Acid methyl esters
The Compound I X of 25 grams (40mmole) and 44 milligrams tosic acid are dissolved in the Virahol and 44ml water of 170ml, and reaction solution refluxed 5 hours.Finish to add water and ethyl acetate after the 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, (petrol ether/ethyl acetate=12: 1-6: 1), obtain 16.3 gram (75%) compound VIII is colorless oil to eluent.
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.
(7) 6-[2-benzyloxy-4-methyl-5-chloro-6-(methylol) phenoxy group]-3-(1-hydroxyl-3,3 '-dimethylbutyl)-O-Anisic Acid
38.2 gram (70mmole) compound VIII and 83.7 gram potassium hydroxide are dissolved in the 900ml methyl alcohol, reaction solution reflux 9 hours, cool to room temperature adds methylene dichloride and water, tells organic phase, organic phase is washed with salt, anhydrous magnesium sulfate drying filters, and organic phase reclaims, residuum need not to carry out purifying can be directly used in next step reaction, and obtaining 35.3 gram (95%) compound VI I is the 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.
(8) 11-benzyloxy-3-(1-hydroxyl-3,3 '-dimethylbutyl)-4-methoxyl group-8-chloro-9-methyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
The compound VI I of 34.3 grams (65mmole) and the exsiccant triethylamine of 48.8ml are dissolved in the 600ml exsiccant acetonitrile, the above-mentioned solution that makes is added drop-wise to when 70 spend slowly by 49 gram iodate 2-chloro-1-picolines is dissolved in the solution that 1600ml exsiccant acetonitrile is made into, stirred 9 hours consuming time down, after dropwising, further under this temperature, reacted 8 hours.Vacuum concentration adds methylene dichloride then, organic phase water and salt washing, anhydrous magnesium sulfate drying filters, and organic phase reclaims, the separation and purification of residuum silica gel column chromatography, (petrol ether/ethyl acetate=10: 1-3: 1), obtain 26.5 gram (80%) compound VI is colorless oil to eluent.
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.
(9) 11-hydroxyl-3-(1-hydroxyl-3,3 '-dimethylbutyl)-4-methoxyl group-8-chloro-9-methyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
The compound VI of 39 grams (76mmole) and 13.26 milligram 10% palladium carbon are dissolved in the ethanol of 720ml ethyl acetate and 240ml, at the logical hydrogen of normal pressure, the point plate tracks to no raw material, filter, the filtrate vacuum concentration, the gained residuum need not to carry out purifying can be directly used in next step reaction, and obtaining 30.3 gram (95%) compound V is the 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)
+
(10) 11-hydroxyl-3-(1-hydroxyl-3,3 '-dimethylbutyl)-4-methoxyl group-8-chloro-9-methyl isophthalic acid 0-bromo-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
The compound V of 32 grams (76mmole) and the bromo-succinimide of 14.98 grams (84mmole) are dissolved in the ethanol of 1000ml, reaction solution stirring at room 2 hours, finish reaction, add ethyl acetate and water, tell organic phase, organic phase is washed with saturated sodium bisulfite solution salt, anhydrous magnesium sulfate drying filters, and organic phase reclaims, residuum need not to carry out purifying can be directly used in next step reaction, and obtaining 33.3 gram (88%) compound IV is the 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.
(11) 11-hydroxyl-3-(1-hydroxyl-3,3 '-dimethylbutyl)-4-methoxyl group-8-chloro-9-methyl isophthalic acid 0-ethyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
Under argon shield; compound IV with 18 grams (36mmole); 532 milligrams tri-o-tolyl phosphorus and 172 milligrams palladium are dissolved in the exsiccant tetrahydrofuran (THF); toluene solution with the zinc ethyl of the 1M of 112ml under 95 degree adds in the reaction solution, further reaction 3 hours under this temperature.With saturated ammonium chloride solution cancellation reaction, water ethyl acetate extraction 2 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, (petrol ether/ethyl acetate=8: 1-1: 1), obtain 6.4 gram (39.7%) compound d l-III is the colourless crystallization powder to eluent.
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
(12) 11-hydroxyl-3-[(1s)-hydroxyl-3,3 '-dimethylbutyl]-4-methoxyl group-8-chloro-9-methyl isophthalic acid 0-ethyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
Compound d l-III is carried out chiral separation, and the separation and purification condition is as follows: chiral column: Chiralpak AD-H; Mobile phase: normal hexane/ethanol=80: 20.
Under this separation condition, the composition of collecting at 5.13-5.90 minute is IIIR, and the composition of collecting at 7.81-8.84 minute is IIIS.The concrete analysis collection of illustrative plates is seen accompanying drawing 4,5,6.
(13) 11-{7 '-methyl bicyclic [2.2.1] heptane-7-methanoyl }-3-[(1s)-and hydroxyl-3,3 '-dimethylbutyl-4-methoxyl group-8-chloro-9-methyl isophthalic acid 0-ethyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
Under argon shield, 5.2 gram (11.6mmole) compound III S are dissolved in the exsiccant tetrahydrofuran (THF), under 0 degree, add 351 milligrams of (14.6mmole) sodium hydrogen, reaction solution was stirring at room 1 hour.The compounds X VI for preparing is dissolved in the exsiccant tetrahydrofuran (THF) is prepared into solution and adds in the above-mentioned reaction solution, further stirred 5 hours in room temperature.Finish to add salt solution and ethyl acetate after the 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, (petrol ether/ethyl acetate=10: 1-6: 1), obtain 6.7 gram (99.6%) Compound I is colourless crystallization (petrol ether/ethyl acetate) to eluent.
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＝+2.626°(c＝1.0，CHCl
3)
The HPLC purity check is seen accompanying drawing 7.
The X diffraction of Compound I is measured
Cultivated for 2 weeks in the petrol ether/ethyl acetate mixed solvent, crystallographic system is an oblique system, and crystallographic dimension is 0.497mm * 0.436mm * 0.158mm, spacer is P2 (1), and brilliant bag parameter is a=14.7275 (18) , b=7.3221 (9) , c=15.0743 (18) , V=1601.5 (3)
3, Z=2, D
Calc=1.213mg/cm
3, λ=0.71073 , μ=0.164mm
-1, F (000)=624, it is 8856 that T=293 (2) K. collection diffraction is counted, and independent diffraction counts 5761, and optimization method is based on F
2, the complete matrix method of least squares, the diffraction zone is-30≤h≤30 ,-30≤k≤30 ,-12≤k≤12, last modified value R (4 σ
F) be 0.0672, R (al1) is that 0.1022 GOF (all) is 0.915.Be surrounded by two molecules at a crystalline substance, have identical configuration, link to each other with different hydrogen bonds to each other.
(1) 11-hydroxyl-3-(3,3 '-dimethyl butyrate acyl group)-4-methoxyl group-8-chloro-9-methyl isophthalic acid 0-ethyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
With the compound III R of 3.68 grams (8.2mmole), the aluminum oxide of the chromic acid pyridine hydrochloride of 3.05 grams (17mmole) and 1.74 grams (17mmole) is dissolved in the methylene dichloride of 15ml, and reaction solution at room temperature further stirred 5 hours.Filter, organic phase is washed with salt, and anhydrous magnesium sulfate drying filters, and organic phase reclaims, the separation and purification of residuum silica gel column chromatography, and eluent (petrol ether/ethyl acetate=12: 1), obtaining 3.1 gram (85%) Compound I I is the colourless crystallization powder.
1H-NMR(CD
3Cl)：δ：1.03(s，9H)；1.15(t，3H)；2.32(s，3H)；2.80(q，2H)；2.90(s，2H)；3.97(s，3H)；5.44(s，2H)；6.26(m，1H)；6.86(d，1H)；7.60(d，1H)ppm.
(2) 11-hydroxyl-3-[(1s)-hydroxyl-3,3 '-dimethylbutyl]-4-methoxyl group-8-chloro-9-methyl isophthalic acid 0-ethyl-5 hydrogen, 7 hydrogen-dibenzo [b, g], [1,5] dioxy octane-5-ketone
The borine tetrahydrofuran solution of the 1M of 207 milligrams of phenylbenzene ((R)-pyrroline-2-yl) methyl alcohol and 8ml is dissolved in the 30ml exsiccant tetrahydrofuran (THF), reaction solution reflux 0.5 hour, cool to room temperature, the Compound I I of 2.3 grams (5mmole) is added in the reaction solution, further stirred 4 hours, the water cancellation, ethyl acetate extraction, 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, (petrol ether/ethyl acetate=8: 1-3: 1), the mixture that obtains 2.18 gram (95%) compound III R and IIIS is the colourless crystallization powder to eluent.Wherein the content of compound III S is 75.537%, and the content of compound III R is 24.463%; Ee:50.4%.
Claims (6)
1, the synthetic method that has the dibenzo dioxy octanone compound of active structures formula (I),
It is characterized in that synthetic route is as follows:
In the described synthetic route, the chlorinating agent that preparation compounds X IV adopts is a chlorosuccinimide, and consumption is the 1-3 equivalent, and solvent is an ethanol/water, and ratio is 0-100%, and the reaction times is 1-5 hour, and temperature of reaction is the 0-80 degree;
The reaction solvent that the preparation compound VIII adopts is a Virahol;
In the preparation compound V process, the method that reaction adopts hydrogenation to take off benzyl, solvent adopts ethanol/ethyl acetate, and ratio is 30-90%, and the catalysis of palladium carbon is catalyzer;
In the preparation compound III process, adopt the Negeish reaction, reaction reagent is a zinc ethyl, and 1-3 equivalent, solvent are tetrahydrofuran (THF) or nitrogen, nitrogen-dimethyl formamide; Catalyzer is the tri-o-tolyl phosphine, palladium; Temperature of reaction is the 20-120 degree; Reaction times is 1-10 hour.
2, by the described synthetic method of claim 1, it is characterized in that midbody compound XII, the XIII or the XIV that wherein make, relate to the compound of a fragment such as general formula A intermediate,
3, by the described synthetic method of claim 1, it is characterized in that midbody compound X, the IX, VIII or the VII that wherein make relating to the compounds of two fragments butt joint backs as the Formula B intermediate,
4, by the described synthetic method of claim 1, it is characterized in that described intermediate VI is the compound with following structure,
5, by the described synthetic method of claim 1, it is characterized in that the compound III chiral separation that relates to, the chiral separation condition is a column type: Chiralpak AD-H, mobile phase: normal hexane/ethanol=80: 20; Under this separation condition, the composition that compound III was collected at 5.13-5.90 minute is IIIR, and the composition of collecting at 7.81-8.84 minute is IIIS.
6, by the described synthetic method of claim 1, it is characterized in that the Compound I I that relates to adopts the method for asymmetric reduction, the chiral environment that utilization phenylbenzene ((R)-pyrroline-2-yl) methyl alcohol and borine tetrahydrofuran solution form is carried out asymmetric reduction to Compound I I, obtain compound III, yield is 95%, (ee:50.4%).
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101298448B (en) * | 2008-06-27 | 2011-01-05 | 扬州慧清医药科技开发有限公司 | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl ] phenol |
| CN101298447B (en) * | 2008-06-27 | 2011-05-25 | 扬州慧清医药科技开发有限公司 | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5- chloro-6-[( tetrahydro-2H-pyrrole-2-oxyl)methyl] phenol |
| CN101838258B (en) * | 2009-03-14 | 2014-01-15 | 扬州中惠制药有限公司 | New preparation method of asymmetric synthetic dibenzo dioxy octanone |
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2006
- 2006-12-12 CN CN2006101195286A patent/CN101066967B/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101298448B (en) * | 2008-06-27 | 2011-01-05 | 扬州慧清医药科技开发有限公司 | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl ] phenol |
| CN101298447B (en) * | 2008-06-27 | 2011-05-25 | 扬州慧清医药科技开发有限公司 | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5- chloro-6-[( tetrahydro-2H-pyrrole-2-oxyl)methyl] phenol |
| CN101838258B (en) * | 2009-03-14 | 2014-01-15 | 扬州中惠制药有限公司 | New preparation method of asymmetric synthetic dibenzo dioxy octanone |
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| CN101066967B (en) | 2010-11-10 |
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