CN102690225B - New synthetic method of bazedoxifene - Google Patents
New synthetic method of bazedoxifene Download PDFInfo
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- CN102690225B CN102690225B CN201210103696.1A CN201210103696A CN102690225B CN 102690225 B CN102690225 B CN 102690225B CN 201210103696 A CN201210103696 A CN 201210103696A CN 102690225 B CN102690225 B CN 102690225B
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- UCJGJABZCDBEDK-UHFFFAOYSA-N bazedoxifene Chemical compound C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 UCJGJABZCDBEDK-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- 229960000817 bazedoxifene Drugs 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- -1 phenyl aldehyde Chemical class 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 8
- FIIDVVUUWRJXLF-UHFFFAOYSA-N 4-phenylmethoxyaniline Chemical compound C1=CC(N)=CC=C1OCC1=CC=CC=C1 FIIDVVUUWRJXLF-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 238000005576 amination reaction Methods 0.000 claims description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 4
- 239000002585 base Substances 0.000 claims 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 230000002829 reductive effect Effects 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- KUVIRDUPAGKTER-UHFFFAOYSA-N n-phenylmethoxyaniline Chemical compound C=1C=CC=CC=1CONC1=CC=CC=C1 KUVIRDUPAGKTER-UHFFFAOYSA-N 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 5
- 238000010511 deprotection reaction Methods 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 abstract 1
- 230000031709 bromination Effects 0.000 abstract 1
- 238000005893 bromination reaction Methods 0.000 abstract 1
- 238000006268 reductive amination reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000006837 decompression Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 150000002475 indoles Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- KRIJKJMYOVWRSJ-UHFFFAOYSA-N 3-methyl-5-phenylmethoxy-2-(4-phenylmethoxyphenyl)-1h-indole Chemical compound C1=C2C(C)=C(C=3C=CC(OCC=4C=CC=CC=4)=CC=3)NC2=CC=C1OCC1=CC=CC=C1 KRIJKJMYOVWRSJ-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BVJSUAQZOZWCKN-UHFFFAOYSA-N p-hydroxybenzyl alcohol Chemical compound OCC1=CC=C(O)C=C1 BVJSUAQZOZWCKN-UHFFFAOYSA-N 0.000 description 2
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 0 *Oc(cc1)ccc1N Chemical compound *Oc(cc1)ccc1N 0.000 description 1
- SGAJFGXKBQUGMO-UHFFFAOYSA-N CC(C)OCCN1CCCCCC1 Chemical compound CC(C)OCCN1CCCCCC1 SGAJFGXKBQUGMO-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- COFCTUNXRHGCRK-UHFFFAOYSA-N O=Cc(cc1)ccc1OCCN1CCCCCC1 Chemical compound O=Cc(cc1)ccc1OCCN1CCCCCC1 COFCTUNXRHGCRK-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 1
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The invention discloses a new synthetic method of bazedoxifene. Bazedoxifene is prepared by the steps of bromination, substitution, reductive amination, substitution, cyclization, deprotection, and the like of azepane which is selected as a raw material. The synthetic method of the invention has the advantages of mild reaction conditions, simple and convenient operating process, easily obtained reagent, and low cost.
Description
(1) technical field
The invention belongs to technical field of medicine synthesis, particularly, the present invention relates to the synthetic method for the treatment of postmenopausal osteoporosis medicine WAY 140424.
(2) technical background
WAY 140424, English name Bazedoxifene, an indole derivatives, its chemistry 1-(4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-2-(4-hydroxy phenyl)-3-Methyl-1H-indole-5-phenol by name.Its chemical structural formula is as follows:
WAY 140424 is developed by Wyeth at first, is third generation selective estrogen receptor modulators.In April, 2009, commodity were called Conbriza, are used for the treatment of postmenopausal osteoporosis in Italy and Spain's listing.
The WAY 140424 synthetic method of current bibliographical information mainly contains two.
1, EP0802183, JP1998036346, US5998402 is that starting raw material replaces through ethyl bromoacetate with p-Hydroxybenzylalcohol, sulfur oxychloride chloro obtains ethyl 2-(4-(chloromethyl) phenoxy group) acetic ester, ethyl 2-(4-((5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-Methyl-1H-indole-1-base) methyl) phenoxy group) acetic ester is generated again with the reaction of intermediate 5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-Methyl-1H-indole, through bromo, a word used for translation ring in heptan replaces, deprotection obtains WAY 140424.Synthetic route is as follows:
There is following shortcoming in this route:
(1) on indoles N, substitution reaction productive rate is low, and the reagent sodium hydride used not easily is preserved
(2) there is to LAH active agent hidden danger such as preserving safety equally in reduction
(3) during indole synthesis, productive rate is low, only has 50%-60%, and after indoles cyclization, also have four-step reaction, and initial charging capacity is increased, and improves synthesis cost.
(4) impurity of a word used for translation ring in heptan modification reaction generation is wayward, and in the end a few step carries out the difficulty that modification directly can increase finished product purifying.
2, EP1025077, WO9919293 is that starting raw material replaces through 1-(2-chloroethyl) a word used for translation ring in heptan with p-Hydroxybenzaldehyde, sodium borohydride reduction, sulfur oxychloride chloro obtains 1-(2-(4-(chloromethyl) phenoxy group) ethyl) a word used for translation ring in heptan, react with intermediate 5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-Methyl-1H-indole again and generate 1-(4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-Methyl-1H-indole, last deprotection obtains WAY 140424.Synthetic route is as follows:
This route carries out the shortcoming that a word used for translation ring in heptan is modified after solving previous routes, but still there is following deficiency:
(1), during the sodium borohydride reduction of phenyl aldehyde reacts, the sodium borohydride equivalents of use is high, and cancellation needs the plenty of time and produces a large amount of flammable explosive hydrogen, there is potential safety hazard
(2) on indoles N, substitution reaction productive rate is low, and the reagent sodium hydride used not easily is preserved
Above two kinds of methods all use intermediate 5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-Methyl-1H-indole, and its syntheti c route is as follows
This reaction yield only has 50%-60% should not be placed on route first half.
(3) summary of the invention
The present invention improves on the route basis that forefathers provide, and object there are provided a kind of new synthetic method, and overall yield is high, easy and simple to handle, and synthesis cost is low.
In order to reach above-mentioned requirements, the present invention adopts a word used for translation ring in heptan (1) for raw material is through 1, 2-ethylene dibromide (2) replaces afterwards and p-Hydroxybenzaldehyde (3) is obtained by reacting intermediate 4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenyl aldehyde (4), intermediate (4) and 4-(benzyloxy) aniline (5) reduction amination generate key intermediate N-(4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-4-(benzyloxy) aniline (6), intermediate (6) and 1-(4-(benzyloxy) phenyl)-2-monobromethane-1-ketone (7) cyclization generate 1-(4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-Methyl-1H-indole (8), intermediate (8) deprotection obtains finished product WAY 140424.Without any bibliographical information before this route, concrete synthetic route is as follows:
The beneficial effect of present method is:
(1) adopt glycol dibromide to replace chlorine, add the activity of substitution reaction
(2) intermediate (4) and (5) reduction amination generate intermediate (6), and reaction conditions is gentle, and productive rate is high, and purifying is convenient
(3) adopt intermediate (6) and (7) cyclization, shorten reactions steps, improve overall conversion.
(4) route is avoided using sodium hydride, the inflammable and explosive active agent such as Lithium Aluminium Hydride
(5) there is no bibliographical information before this method, there is novelty, the protection of Yuan Yan house journal can be got around.
(4) embodiment
Below by specific embodiment, this invention is further described.
Embodiment 1: the synthesis the first step of intermediate 4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenyl aldehyde (4): the synthesis of intermediate 1-(2-bromotrifluoromethane) a word used for translation ring in heptan (2)
In 2L there-necked flask, add a word used for translation ring in heptan (1) 100g, glycol dibromide (2) 246.2g, and salt of wormwood 208.9g, finally add acetonitrile 1.25L, treats allly to mix post-heating 100 degree reaction.After TLC detection reaction terminates, reaction solution is cooled to room temperature, crosses and filter salt of wormwood, filtrate decompression is removed organic solvent, steam residual 800mL methylene dichloride to dissolve, wash with water 2-3 time, after anhydrous sodium sulfate drying, decompression removing methylene dichloride obtains oily 185.5g, productive rate 89.1%
Second step: the synthesis of intermediate 4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenyl aldehyde (4)
In 2L there-necked flask, add 1-(2-bromotrifluoromethane) a word used for translation ring in heptan (2) 100g, p-Hydroxybenzaldehyde (3) 77.02g, and salt of wormwood 100.57g, finally add acetonitrile 1.0L, treats allly to mix post-heating 50 degree reaction.After TLC detection reaction terminates, reaction solution is cooled to room temperature, crosses and filter salt of wormwood, filtrate decompression is removed organic solvent, steam residual 800mL methylene dichloride to dissolve, with washing with water 2-3 time, after anhydrous sodium sulfate drying, decompression removing methylene dichloride obtains product 111.5g, productive rate 93.0%
Embodiment 2: the synthesis of intermediate N (4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-4-(benzyloxy) aniline (6)
4-(benzyloxy) aniline (5) 50.0g is added in 1L there-necked flask, 4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenyl aldehyde (4) 74.4g, use 500mL dissolve with ethanol, reaction system ice-water bath is cooled to 0-5 degree, slowly add sodium triacetoxy borohydride 106.3g in batches, add rear reaction solution and be warming up to 35 degree, stirring reaction.TLC detection reaction terminates rear reaction solution and is cooled to 0-5 degree, slowly adds water 200mL wherein, and add stirring two lab scale, layering, abandons aqueous phase, and organic phase obtains product 85.5g through purification by silica gel column chromatography, productive rate 79.2% after concentrating and doing
The synthesis of embodiment 3:1-(4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-Methyl-1H-indole (8)
N-(4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-4-(benzyloxy) aniline (6) 5.0g is added in 25mL single port bottle, 1-(4-(benzyloxy) phenyl)-2-monobromethane-1-ketone (7) 9.2g, and triethylamine 2.9g, with 4mLN, dinethylformamide dissolves, stir lower heating 120 degree reaction, TLC detection reaction terminates rear reaction solution and is cooled to 0-5 degree, pour in 20mL water, after being extracted with ethyl acetate, in methyl alcohol, recrystallization obtains solid 10.3g, productive rate 55.0%.
Embodiment 4: the synthesis of WAY 140424
1-(4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-Methyl-1H-indole (8) 5.0g is added in 100mL single port bottle, dissolve with 38mL Glacial acetic acid, add palladium carbon 500mg, react under hydrogen, after TLC detection reaction terminates, suction filtration removing palladium carbon, filtrate decompression is except desolventizing, the crude product obtained obtains WAY 140424 1.6g through silica gel column chromatography, productive rate 44.4%
Claims (1)
1. a synthetic method for WAY 140424, its step is as follows:
The synthesis of intermediate N (4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-4-(benzyloxy) aniline as shown in chemical formula 6 is obtained with reduction amination by intermediate 4-(2-(a word used for translation ring in the heptan-1-base) oxyethyl group) phenyl aldehyde such as shown in chemical formula 4 and the 4-as shown in chemical formula 5 (benzyloxy) aniline; Reductive agent used is sodium triacetoxy borohydride or sodium borohydride; Temperature of reaction is 35 degree; Reaction solvent is ethanol, methyl alcohol, methylene dichloride, tetrahydrofuran (THF) or toluene; 4-(benzyloxy) aniline as shown in chemical formula 5 and the mol ratio of reductive agent are 1: 2;
N-(4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-4-(benzyloxy) aniline in the synthesis of intermediate 1-(4-(2-(a word used for translation ring in heptan-1-base) oxyethyl group) phenmethyl)-5-(benzyloxy)-2-(4-(benzyloxy) the phenyl)-3-Methyl-1H-indole as shown in chemical formula 8 as shown in chemical formula 6 is 1: 2.5 with the mol ratio of 1-(4-(benzyloxy) the phenyl)-2-monobromethane-1-ketone as shown in chemical formula 7; Alkali used is triethylamine; Solvent for use is DMF, N,N-dimethylacetamide or dimethyl sulfoxide (DMSO); Temperature of reaction is 120 degree.
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| CN104774170A (en) * | 2014-01-14 | 2015-07-15 | 江苏柯菲平医药股份有限公司 | Separation preparation method of bazedoxifene acetate impurity A |
| CN103739540B (en) * | 2014-01-20 | 2016-05-04 | 华润赛科药业有限责任公司 | A kind of preparation method of bazedoxifene acetate intermediate |
| CN103772261B (en) * | 2014-03-04 | 2015-02-18 | 苏州立新制药有限公司 | Preparation method of bazedoxifene |
| CN103864666B (en) * | 2014-03-04 | 2016-04-06 | 苏州明锐医药科技有限公司 | WAY 140424 intermediate and preparation method thereof |
| CN103864665B (en) * | 2014-03-04 | 2016-03-02 | 苏州特瑞药业有限公司 | The preparation method of bazedoxifene acetate |
| WO2023284782A1 (en) * | 2021-07-14 | 2023-01-19 | 复旦大学 | Method for screening compound for treating or preventing mhtt-related neurodegenerative diseases, target protein, and compound |
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