CN102367236A - Synthesizing technology of donepezil hydrochloride - Google Patents
Synthesizing technology of donepezil hydrochloride Download PDFInfo
- Publication number
- CN102367236A CN102367236A CN2011103914631A CN201110391463A CN102367236A CN 102367236 A CN102367236 A CN 102367236A CN 2011103914631 A CN2011103914631 A CN 2011103914631A CN 201110391463 A CN201110391463 A CN 201110391463A CN 102367236 A CN102367236 A CN 102367236A
- Authority
- CN
- China
- Prior art keywords
- solution
- dimethoxy
- donepezil hydrochloride
- indone
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Abstract
The invention relates to the synthesis of donepezil hydrochloride. According to a published patent CN100436416 which relates to a synthesizing technology of donepezil hydrochloride, diethyl malonate is adopted as an initial material, and 5 steps of condensation, reduction, substitution, ring-closing, and decarboxylation are adopted, such that donepezil hydrochloride is obtained. The steps are complicated, and the total yield is not high. The invention aims at providing a donepezil hydrochloride synthesizing technology employing 5,6-dimethoxy-2-(4-pyridyl)methylene-indan-1-one as an initial material. The technical scheme of the invention comprises steps that: the raw material is processed through hydrogenation, cooling, and filtration; a solvent glacial acetic acid is removed by reduced-pressure distillation; the obtained solution is processed through neutralization and extraction; a filtrate is condensed, and is dissolved in dichloromethane; the mixture is stirred, and triethylamine and benzyl chloride are dropped into the solution; the solution is cooled, the filtrate is condensed, and the obtained material is dissolved in methanol; a methanol solution of hydrogen chloride is dropped into the solution, such that a salt is formed; and the solution is cooled, crystallized, filtered, and dried, such that donepezil hydrochloride is obtained. The synthesizing technology provided by the invention is advantaged in short synthetic route and improved total yield. With the technology, the donepezil hydrochloride content is higher than 99%. The technology is suitable for industrialized productions.
Description
Technical field
The present invention relates to a kind of synthesis technique of medicine E 2020, refer to that specially 6-dimethoxy-2-(4-pyridyl) methylene radical-1-indone is a starting raw material synthetic hydrochloric acid E2020 with 5.
Background technology
E 2020 (Donepezil Hydrochloride) chemical name (±) 2; 3-dihydro-5,6-dimethoxy-2{ [(1-phenmethyl)-4-piperidyl] methyl }-1H-indenes-1 keto hydrochloride, be the anti-acetylcholinesterase suppressor factor; Anti-acetylcholinesterase activity with intensive and highly selective; And persistent, safe by Eisai Co., Ltd's exploitation, is second medicine that is used to treat alzheimer's disease of U.S. food and drugs administration approved.Domestic approved import, commodity are called " aricept ", are used to treat the treatment of slight or moderate DAT symptom.At present, the synthetic route of preparation E 2020 is a lot, and according to relevant bibliographical information, its synthetic route has following several kinds:
Method 1:
Method 2:
Method 3:
Wherein aforesaid method 1 is the synthetic route of bibliographical information; Starting raw material is 5, and 6-dimethoxy triketohydrindene hydrate, 4-pyridylaldehyde obtain E2020 through condensation, benzylization, hydro-reduction; But its total recovery is lower, uses platinum dioxide also to cause production cost higher as catalyzer.
Method 2,3 all has report already at home, and method 2 needs low temperature, and production unit is had relatively high expectations.Method 3 synthesis steps are longer, and overall yield is not high.
Disclosed patent (CN100436416) " E 2020 synthesis technique " is starting raw material with the ethyl malonate, makes E 2020 through five steps reactions such as condensation, reduction, replacement, pass ring decarboxylations at last, and step is more, and total recovery is not high.
Summary of the invention
The objective of the invention is to develop a kind of synthesis technique of medicine E 2020, a kind of with 5,6-dimethoxy-2-(4-pyridyl) methylene radical-the 1-indone is a starting raw material; Synthetic route is short; Reduce cost, improve the production technique performance, chemical reaction condition is gentle; Improve total recovery, be suitable for suitability for industrialized production.
Technical solution of the present invention: with 5,6-dimethoxy-2-(4-pyridyl) methylene radical-the 1-indone is a starting raw material, through hydro-reduction, the synthetic E2020 of condensation two-step reaction, obtains E 2020 behind the salify, and its synthetic route is:
Synthesis process flow diagram of the present invention is seen Fig. 1.
Reactions step is:
(1) with original raw material 5,6-dimethoxy-2-(pyridin-4-yl) methyl methylene radical-1-indone is dissolved in Glacial acetic acid min. 99.5, is catalyzer with 10% palladium charcoal (Pd-C), feeds hydrogen in 70~80 ℃; 0.35MPa pressurize reaction 1~3 hour is cooled to 28~32 ℃, filters; Get hydrogenation liquid, pressure reducing and steaming solvent Glacial acetic acid min. 99.5, reaction product (2; 3-dihydro-5,6-dimethoxy-2-(4-piperidyl) methyl isophthalic acid-indone, and partial impurities; But because contain impurity, the processing below also needing), adding 5%~15% (add-on is controlled with pH value) NaHCO3 aqueous solution, to be neutralized to the pH value be 7; Divide extraction three to four times with methylene dichloride, organic layer is removed sodium sulfate with anhydrous sodium sulfate drying 20~30 hours, and filtrating concentrates, and gets 2,3-dihydro-5,6-dimethoxy-2-(4-piperidyl) methyl isophthalic acid-indone (II).
(2) compound I I is dissolved in methylene dichloride, stirs, drip triethylamine after 32~36 ℃ of dissolvings, continue to stir, drip Benzyl Chloride or cylite; The temperature of keeping 32~36 ℃ continues reaction 3~5 hours, is cooled to 20~25 ℃, suction filtration, and filter residue discards, and filtrating concentrates; Enriched material is used dissolve with methanol, drips 10% methyl alcohol hydrogen chloride solution salify, and 0~4 ℃ of crystallisation by cooling filters, and uses the methanol wash filter cake; 55~60 ℃ of dryings get the E 2020 bullion, and bullion is used anhydrous alcohol solution, adds activated carbon decolorizing, removes by filter gac; Behind 0~4 ℃ of cooling recrystallization, filter, solid gets E 2020 (I) with 55~60 ℃ of oven dry.
The feed ratio (mol ratio) of each step reaction of the present invention is:
5,6-dimethoxy-2-(pyridin-4-yl) methyl methylene radical-1-indone: hydrogen=1: (3~5)
Compound I I: Benzyl Chloride: 10% methyl alcohol hydrogen chloride solution=1: (3~5): (1~2)
In above-mentioned feed ratio scope, the reaction yield of each step is higher, can arrive more than 60%.
In the above-mentioned technology, under situation about not particularly pointing out, then all refer at normal temperatures and pressures, refer to pure substance.
Advantage of the present invention and effect:
1, with 5,6-dimethoxy-2-(4-pyridyl) methylene radical-the 1-indone is a starting raw material, and salify after first hydrogenation, the condensation uses palladium carbon as catalyzer, and it is higher to reach yield; Because adopting catalyzer is palladium carbon, so the low purpose of production cost is suitable for suitability for industrialized production.
2, through experiment, from E 2020 assay HPLC collection of illustrative plates, learn that content can reach more than 99%.
Description of drawings
Fig. 1 is the E 2020 synthesis process flow diagram; Fig. 2 is an E 2020 assay HPLC collection of illustrative plates.
Embodiment
Embodiment 1
2,3-dihydro-5, the preparation of 6-dimethoxy-2-(4-piperidyl) methyl isophthalic acid-indone (II):
In the hydrogenation still of 1L, add 10g (0.035mol) and replace indone, 300ml Glacial acetic acid min. 99.5,1g10% palladium charcoal; In 75 ℃ of feeding hydrogen, 0.35MPa pressurize reaction 1 hour is cooled to 30 ℃, filters out the palladium charcoal; Hydride ,-0.08MPa, 95 ℃ boil off the solvent Glacial acetic acid min. 99.5, reaction product adds 10% sodium bicarbonate aqueous solution, and to be neutralized to the pH value be 7; Add the 200ml methylene dichloride and divide three extractions, organic layer is removed sodium sulfate with 20g anhydrous sodium sulfate drying 24 hours; Filtrating concentrates, and gets yellow oil (II) 8.5g, yield 84%.The feed ratio (mol ratio) of reaction is above: 5; 6-dimethoxy-2-(pyridin-4-yl) methyl methylene radical-1-indone: hydrogen=1: (3~5); Any number between the ratio hydrogen here=(3~5) are meant 3~5 is as 3.1,1.3,3.5,3.6,3.9,4.0,4.1,4.3,4.4,4.5,4.6,4.8,4.9 etc.
Embodiment 2
2,3-dihydro-5, the preparation of 6-dimethoxy-2-(4-piperidyl) methyl isophthalic acid-indone (II):
In the hydrogenation still of 1L, add 10g (0.035mol) and replace indone, 300ml Glacial acetic acid min. 99.5,1g10% palladium charcoal; In 75 ℃ of feeding hydrogen, 0.35MPa pressurize reaction 2 hours is cooled to 30 ℃, filters out the palladium charcoal; Hydride ,-0.08MPa, 95 ℃ boil off the solvent Glacial acetic acid min. 99.5, reaction product adds 10% sodium bicarbonate aqueous solution, and to be neutralized to the pH value be 7; Add the 200ml methylene dichloride and divide four extractions, organic layer is removed sodium sulfate with 20g anhydrous sodium sulfate drying 20 hours; Filtrating concentrates, and gets yellow oil (II) 7.8g, yield 77%.The feed ratio (mol ratio) of reaction is above: 5; 6-dimethoxy-2-(pyridin-4-yl) methyl methylene radical-1-indone: hydrogen=1: (3~5); Any number between the ratio hydrogen here=(3~5) are meant 3~5 is as 3.2,3.5,3.7,3.8,4.0,4.2,4.3,4.4,4.5,4.7,4.8,4.9 etc.
Embodiment 3
The preparation of E 2020 (I):
In exsiccant 1L there-necked flask, add 30g (0.104mol) hydrogenate, 500ml methylene dichloride, stir, drip triethylamine 45ml (0.325mol) after 35 ℃ of dissolvings, continue to stir 10 minutes, drip 40ml (0.345mol) Benzyl Chloride at 35 ℃; Keep 35 ℃ and continue reaction 4 hours, be cooled to 20~25 ℃, suction filtration, filter residue discards; Filtrating concentrates, and enriched material is used the 300ml dissolve with methanol, drips 10% methyl alcohol hydrogen chloride solution salify, 4 ℃ of crystallisation by cooling; Filter, with 50ml methanol wash filter cake, 58~60 ℃ of dryings get E 2020 bullion 24g; Bullion is used the 50ml anhydrous alcohol solution, adds the 1g activated carbon decolorizing, removes by filter gac, behind 4 ℃ of cooling recrystallizations; Filter, solid gets E 2020 (I) 15g, yield 61% with 58~60 ℃ of oven dry.The feed ratio (mol ratio) of reaction is above: compound I I: Benzyl Chloride: 10% methyl alcohol hydrogen chloride solution=1: (3~5): (1~2).In like manner, any number between (3~5) of Benzyl Chloride are meant 3~5 is as 3.2,3.5,3.7,3.8,4.0,4.2,4.3,4.4,4.5,4.7,4.8,4.9 etc.; Any number between (1~2) of 10% methyl alcohol hydrogen chloride solution is meant 1~2 is as 1.1,1.3,1.5,1.6,1.8,1.9 etc.
Process control: the detection reaction of taking a sample at any time process situation, method is following:
TLC method: developping agent: methyl alcohol-ETHYLE ACETATE-ammoniacal liquor (1: 4: 0.05); Carrier: silica GF254; Rf
1=0.46Rf
11=0.68;
Quality control: outward appearance: off-white color meal; Fusing point: 220~225 ℃; Content: greater than 99% (performance liquid chromatography, area normalization method).(see figure 2)
Chromatographic condition: chromatographic column: octadecylsilane chemically bonded silica post; Moving phase: the phosphoric acid buffer (4: 1) of acetonitrile-pH value 6.6; Detect wavelength: 268nm.
1HNMR(300MHz,CDCl
3)δ:1.256(1.530)(sm,2H,CH
2),1.831~1.856(1.880~2.075)(mm,4H,CH
2),1.856~1.880(m,1H,CH),2.617~2.721(d,1H,CH
2),2.671~2.761(3.269~3.301)(mm,2H,CH
2),3.483(2.721~2.761)(mt,4H,NH
2),3.893(s,3H,OCH
3),3.963(s,3H,OCH
3),4.199(s,2H,PhCH
2),6.851(s,1H,ArH),7.110(s,1H,ArH),7.309~7.456(m,3H,PhH),7.642~7.672(m,2H,PhH),12.20(s,1H,NH)。
IR(KBr):3426.09,3006.48,2960.00,2924.01,2836.77,2461.61,2406.73,1697.96,1604.48,1589.20,1499.63,1453.43,1313.06,1265.40,1111.41,1071.64,748.66,702.44cm
-1。
Embodiment 4
The preparation of E 2020 (I):
In exsiccant 1L there-necked flask, add 30g (0.104mol) hydrogenate, 500ml methylene dichloride, stir, drip triethylamine 45ml (0.325mol) after 32 ℃ of dissolvings, continue to stir 10 minutes, at 32 ℃ of Dropwise 5 4ml (0.345mol) cylite; Keep 32 ℃ and continue reaction 5 hours, be cooled to 20~25 ℃, suction filtration, filter residue discards; Filtrating concentrates, and enriched material is used the 300ml dissolve with methanol, drips 10% methyl alcohol hydrogen chloride solution salify, 0 ℃ of crystallisation by cooling; Filter, with 50ml methanol wash filter cake, 58~60 ℃ of dryings get E 2020 bullion 24g; Bullion is used the 50ml anhydrous alcohol solution, adds the 1g activated carbon decolorizing, removes by filter gac, behind 0 ℃ of cooling recrystallization; Filter, solid gets E 2020 (I) 14.4g, yield 60% with 58~60 ℃ of oven dry.
The feed ratio (mol ratio) of reaction is above: compound I I: Benzyl Chloride: 10% methyl alcohol hydrogen chloride solution=1: (3~5): (1~2).In like manner, any number between (3~5) of Benzyl Chloride are meant 3~5 is as 3.1,3.3,3.4,3.5,3.7,3.8,4.0,4.2,4.3,4.4,4.5,4.7,4.8,4.9 etc.; Any number between (1~2) of 10% methyl alcohol hydrogen chloride solution is meant 1~2 is as 1.1,1.2,1.3,1.4,1.5,1.6,1.7,1.8,1.9 etc.
Claims (2)
1. the synthesis technique of an E 2020; It is characterized in that: with 5,6-dimethoxy-2-(4-pyridyl) methylene radical-the 1-indone is a starting raw material, through over hydrogenation, the synthetic E2020 of condensation two-step reaction; Obtain E 2020 behind the salify, its synthetic route is:
Reactions step is:
(1) with original raw material 5,6-dimethoxy-2-(pyridin-4-yl) methyl methylene radical-1-indone is dissolved in Glacial acetic acid min. 99.5, is catalyzer with 10% palladium charcoal (Pd-C), feeds hydrogen in 70~80 ℃; 0.35MPa pressurize reaction 1~3 hour is cooled to 28~32 ℃, filters; Get hydrogenation liquid, pressure reducing and steaming solvent Glacial acetic acid min. 99.5, reaction product (2; 3-dihydro-5,6-dimethoxy-2-(4-piperidyl) methyl isophthalic acid-indone, and partial impurities; But because contain impurity, the processing below also needing), adding 5%~15% (add-on is controlled with pH value) NaHCO3 aqueous solution, to be neutralized to the pH value be 7; Divide extraction three to four times with methylene dichloride, organic layer is removed sodium sulfate with anhydrous sodium sulfate drying 20~30 hours, and filtrating concentrates, and gets 2,3-dihydro-5,6-dimethoxy-2-(4-piperidyl) methyl isophthalic acid-indone (II);
(2) compound I I is dissolved in methylene dichloride, stirs, drip triethylamine after 32~36 ℃ of dissolvings, continue to stir, drip Benzyl Chloride or cylite; The temperature of keeping 32~36 ℃ continues reaction 3~5 hours, is cooled to 20~25 ℃, suction filtration, and filter residue discards, and filtrating concentrates; Enriched material is used dissolve with methanol, drips 10% methyl alcohol hydrogen chloride solution salify, and 0~4 ℃ of crystallisation by cooling filters, and uses the methanol wash filter cake; 55~60 ℃ of dryings get the E 2020 bullion, and bullion is used anhydrous alcohol solution, adds activated carbon decolorizing, removes by filter gac; Behind 0~4 ℃ of cooling recrystallization, filter, solid gets E 2020 (I) with 55~60 ℃ of oven dry.
2. the synthesis technique of a kind of E 2020 according to claim 1 is characterized in that: the feed ratio (mol ratio) of above-mentioned each step reaction is:
5,6-dimethoxy-2-(pyridin-4-yl) methyl methylene radical-1-indone: hydrogen=1: (3~5),
Compound I I: Benzyl Chloride: 10% methyl alcohol hydrogen chloride solution=1: (3~5): (1~2).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2011103914631A CN102367236A (en) | 2011-11-30 | 2011-11-30 | Synthesizing technology of donepezil hydrochloride |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2011103914631A CN102367236A (en) | 2011-11-30 | 2011-11-30 | Synthesizing technology of donepezil hydrochloride |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102367236A true CN102367236A (en) | 2012-03-07 |
Family
ID=45759832
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2011103914631A Pending CN102367236A (en) | 2011-11-30 | 2011-11-30 | Synthesizing technology of donepezil hydrochloride |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102367236A (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102702078A (en) * | 2012-05-29 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for preparing donepezil hydrochloride |
CN104402802A (en) * | 2014-12-02 | 2015-03-11 | 千辉药业(安徽)有限责任公司 | Method for preparing troxipide |
CN104892489A (en) * | 2015-06-08 | 2015-09-09 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of donepezil hydrochloride impurities |
CN107121509A (en) * | 2017-04-25 | 2017-09-01 | 四川升和药业股份有限公司 | A kind of method of quality control of donepezil hydrochloride orally disintegrating tablet |
CN108047131A (en) * | 2017-12-08 | 2018-05-18 | 重庆植恩药业有限公司 | Doneppezil Hydrochloride impurity and its preparation method and application |
CN110183375A (en) * | 2018-12-31 | 2019-08-30 | 山东诚汇双达药业有限公司 | A kind of preparation method of high-purity hydrochloric acid donepezil intermediate |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040158070A1 (en) * | 2003-02-12 | 2004-08-12 | Tarur Venkatasubramanian Radhakrishnan | Process for the preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanon)-2-yl) methyl piperidine hydrochloride (Donepezil HCI) |
WO2005003092A1 (en) * | 2003-07-01 | 2005-01-13 | Hetero Drugs Limited | Preparation of intermediates for acetyl cholinesterase inhibitors |
CN101341122A (en) * | 2005-12-20 | 2009-01-07 | 吉瑞工厂 | Novel process for production of highly pure polymorph (I) donepezil hydrochloride |
CN102060750A (en) * | 2009-11-16 | 2011-05-18 | 天津必佳药业集团有限公司 | Method for preparing donepezil hydrochloride |
-
2011
- 2011-11-30 CN CN2011103914631A patent/CN102367236A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040158070A1 (en) * | 2003-02-12 | 2004-08-12 | Tarur Venkatasubramanian Radhakrishnan | Process for the preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanon)-2-yl) methyl piperidine hydrochloride (Donepezil HCI) |
WO2005003092A1 (en) * | 2003-07-01 | 2005-01-13 | Hetero Drugs Limited | Preparation of intermediates for acetyl cholinesterase inhibitors |
CN101341122A (en) * | 2005-12-20 | 2009-01-07 | 吉瑞工厂 | Novel process for production of highly pure polymorph (I) donepezil hydrochloride |
CN102060750A (en) * | 2009-11-16 | 2011-05-18 | 天津必佳药业集团有限公司 | Method for preparing donepezil hydrochloride |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102702078A (en) * | 2012-05-29 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for preparing donepezil hydrochloride |
CN104402802A (en) * | 2014-12-02 | 2015-03-11 | 千辉药业(安徽)有限责任公司 | Method for preparing troxipide |
CN104892489A (en) * | 2015-06-08 | 2015-09-09 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of donepezil hydrochloride impurities |
CN107121509A (en) * | 2017-04-25 | 2017-09-01 | 四川升和药业股份有限公司 | A kind of method of quality control of donepezil hydrochloride orally disintegrating tablet |
CN108047131A (en) * | 2017-12-08 | 2018-05-18 | 重庆植恩药业有限公司 | Doneppezil Hydrochloride impurity and its preparation method and application |
CN110183375A (en) * | 2018-12-31 | 2019-08-30 | 山东诚汇双达药业有限公司 | A kind of preparation method of high-purity hydrochloric acid donepezil intermediate |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102367236A (en) | Synthesizing technology of donepezil hydrochloride | |
CN104860926B (en) | A kind of preparation method of Vonoprazan fumarate | |
CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
CN106349245A (en) | Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities | |
CN106928236A (en) | A kind of synthesis technique of Rui Boxini | |
CN104356111B (en) | A kind of method for preparing dabigatran etcxilate mesylate hydrolysis impurity | |
CN102432530A (en) | Method for preparing high-purity gimeracil | |
CN102911160A (en) | Method for preparing and purifying dabigatran etexilate intermediate | |
CN108047125A (en) | The preparation method of one kind (2R, 4R) -4- methyl piperidine -2- Ethyl formate compounds | |
CN103509025A (en) | Preparation method of epinastine hydrochloride and intermediate thereof | |
CN102964307B (en) | Dabigatran etexilate related substance and preparation method thereof | |
CN102351790A (en) | Method for synthesizing 7-bromo-6-chloro-4-quinazolinone | |
WO2015111085A2 (en) | Processes for the preparation of eltrombopag and pharmaceutically acceptable salts, solvates and intermediates thereof | |
CN105440014B (en) | A kind of preparation method of lenalidomide | |
CN105461688A (en) | Synthesis method of benzimidazole compound K | |
CN103193699B (en) | Novel method for preparing prucalopride intermediate | |
CN102977077A (en) | Method for preparing dabigatran etexilate intermediate | |
CN104803846B (en) | The method for preparing bis- [4- (6- acryloyl-oxy hexyl) phenyl] hexamethylene -1,4- dicarboxylic esters | |
CN110713471B (en) | Synthetic method of trimetazidine hydrochloride | |
KR101001646B1 (en) | Method of preparing r-+-lansoprazole and intermediate used therein | |
CN102911173A (en) | Synthetic method of 5,6,7,8-tetrahydro-2H-pyridino-[4,3-c]pyridazine-3-ketone | |
CN105669539B (en) | A kind of preparation process of 2- amino -3- fluorine pyridines | |
CN105001129B (en) | A kind of refined Crystallization method of probucol in high yield | |
CN104945398B (en) | A kind of moxifloxacin impurity E preparation method | |
CN107686439A (en) | A kind of preparation method of the key intermediate of ALK inhibitor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120307 |