CN105622520A - New intermediate of non-small-cell lung carcinoma treating drug Ceritinib, and preparation method thereof - Google Patents
New intermediate of non-small-cell lung carcinoma treating drug Ceritinib, and preparation method thereof Download PDFInfo
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- CN105622520A CN105622520A CN201410430727.3A CN201410430727A CN105622520A CN 105622520 A CN105622520 A CN 105622520A CN 201410430727 A CN201410430727 A CN 201410430727A CN 105622520 A CN105622520 A CN 105622520A
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- GMLAMRMKROYXNZ-UHFFFAOYSA-N CC(C)S(c(cccc1)c1N)(=O)=O Chemical compound CC(C)S(c(cccc1)c1N)(=O)=O GMLAMRMKROYXNZ-UHFFFAOYSA-N 0.000 description 1
- GBFWDLQEEMHXME-UHFFFAOYSA-N CC(C)S(c(cccc1)c1[N+]([O-])=O)(=O)=O Chemical compound CC(C)S(c(cccc1)c1[N+]([O-])=O)(=O)=O GBFWDLQEEMHXME-UHFFFAOYSA-N 0.000 description 1
- WRFYXBKJHZAUTO-UHFFFAOYSA-N CC(C)Sc1ccccc1[N+]([O-])=O Chemical compound CC(C)Sc1ccccc1[N+]([O-])=O WRFYXBKJHZAUTO-UHFFFAOYSA-N 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N [O-][N+](c(cccc1)c1F)=O Chemical compound [O-][N+](c(cccc1)c1F)=O PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention relates to the field of pharmaceutical chemistry, to a preparation method of a new intermediate of 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidine-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (Ceritinib). According to the present invention, o-fluoronitrobenzene is adopted as a starting raw material, substitution, reduction and condensation are performed to obtain the new intermediate 2-X-5-chloro-N-(2-(isopropyl sulfide)phenyl)pyrimidine-4-amine (X is halogen, p-methyl benzene sulfonyloxy, methyl sulfonyloxy or trifluoromethylsulfonyloxy), the new intermediate can be oxidized to obtain a sulfonyl derivative, and the sulfonyl derivative and 2-isopropoxy-5-methyl-4-(piperidine-4-yl)aniline are subjected to condensation to finally obtain 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidine-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (Ceritinib); and the synthesis method has characteristics of readily available raw materials, high yield, mild reaction, simple operation and low production cost, and is suitable for industrial production.
Description
Technical field
The present invention relates to the chloro-N2-of medical compounds 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2; (color is auspicious for Buddhist nun for 4-diamidogen; and the preparation method of the chloro-N-of key intermediate 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine LDK378).
The auspicious chemistry for Buddhist nun of color is called: the chloro-N2-of 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2,4-diamidogen, chemical constitution is as follows.
Background technology
Color is auspicious for Buddhist nun (Ceritinib, LDK378), is that commodity are called Zykadia by the former one ground of Novartis (Novartis) company little molecule ALK tyrosinase inhibitorTM. In March, 2013, FDA authorizes its " breakthrough medicine " status according to its I phase clinical trial results, obtain FDA approval listing, the treatment of Metastatic Nsclc patient positive for anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK), that fail to respond to any medical treatment for Buddhist nun (Crizotinib) on April 29th, 2014 through gram azoles.
WO2008/073687A1 reports the auspicious synthetic method for Buddhist nun of color, and its synthetic route is as follows:
With compound 1 for initiation material, obtain compound 2 through nitrated. Compound 2 fluorine when cesium carbonate is obtained compound 3 by isopropoxy replacement. Compound 3 and 4-pyridine boronic acid occur Suzuki coupling to obtain compound 4. Compound 4 is reduction nitro and pyridine under platinum dioxide exists; Then Boc protection 5 is gone up. Another side chain is with compound 6, and compound 7 is initiation material, and condensation obtains compound 8. There is Buchward coupling in compound 5 and compound 8, then slough Boc anhydride again, obtain product color auspicious for Buddhist nun under palladium-Xantphos condition.
List of references WO20110/140338; HelveticaChimicaActa; Vol.63; Nb.6; (1980): the synthetic method that 1412-1429 provides compound 7 is as follows:
The former condensation condition grinding the compound 6 and compound 7 provided in patent, is not suitable for iodine. This step condensation reaction uses sodium hydride to make alkali, and along with the increasing of reaction scale, reaction is gradually increased gathering of internal heat effect; After iodine, temperature control is comparatively difficult, it is easy to causing interior temperature too high, product is mixed and disorderly. Needing a large amount of sodium hydride of cancellation that adds water after this step reaction, so operation has certain danger. This step document yield relatively low (60%), when feather weight is amplified, yield only can maintain 40��45%. It is thus desirable to a kind of efficient synthesis, adapt to amplify the demand produced.
Summary of the invention
The preparation method that it is an object of the invention to provide the auspicious synthesis for Buddhist nun (Ceritinib) of new color and intermediate thereof.
It is an object of the invention to provide a kind of chloro-N2-of new 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2; the preparation method of 4-diamidogen and the chloro-N-of intermediate 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine. Through research, the preparation method having invented new easily industrialized 2,5-bis-chloro-N-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, advantage is in that reaction directly prepares this intermediate, operating process simple possible. Specifically; the invention provides a kind of with o-fluoronitrobenzene for initiation material; through intermediate 2; the chloro-N-of 5-bis-(2-(isopropyl thioether) phenyl) pyrimidine-4-amine prepares 2; the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, prepares the auspicious method for Buddhist nun of color further, and this route commercially obtains steady quality initiation material; operating process is simple and convenient, is suitable for industrialized production.
The chloro-N2-of 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2 related in the present invention, 4-diamidogen synthetic route is as follows:
The synthetic route of compound 2-isopropoxy-5-methyl-4-(piperidin-4-yl) anilinechloride is with reference to WO2008/073687A1.
The chloro-N-of compound 2,5-bis-(2-(isopropyl thioether) phenyl) pyrimidine-4-amine is obtained by compound 2-isopropyl thioether aniline and the condensation in the basic conditions of 2,4,5-trichloropyrimidines. This step reaction alkali be: triethylamine, diisopropyl ethyl amine, pyridine, 1,8-diazabicylo 11 carbon-7-alkene, DMAP, alkali and alkaline earth metal ions carbonate, alkali-metal bicarbonate, and alkali and alkaline earth metal ions hydroxyl alkali. The solvent of this step reaction is methanol, ethanol, isopropanol, acetonitrile, DMF, dimethyl sulfoxide, N-Methyl pyrrolidone, acetone. Reaction temperature is 20��120 DEG C.
The chloro-N-of compound 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine is obtained by the oxidation of 2,5-bis-chloro-N-(2-(isopropyl thioether) phenyl) pyrimidine-4-amine. This step reaction oxidant is: peracetic acid, hydrogen peroxide, potassium hydrogen persulfate, sodium hypochlorite, ask chloroperoxybenzoic acid, sodium metaperiodate. Solvent is: acetone, dichloromethane, acetonitrile, methanol, ethanol, isopropanol, oxolane. Reaction temperature is-20��40 DEG C.
The chloro-N2-of compound 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2, the synthetic method of 4-diamidogen is with reference to Yuan Yan company crystal formation patent WO2012/082972A1.
Accompanying drawing explanation
The proton nmr spectra of the chloro-N-of Fig. 1 compound 2,5-bis-(2-(isopropyl thioether) phenyl) pyrimidine-4-amine.
The LCMS spectrogram of the chloro-N-of Fig. 2 compound 2,5-bis-(2-(isopropyl thioether) phenyl) pyrimidine-4-amine.
The proton nmr spectra of the chloro-N-of Fig. 3 compound 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine.
The chloro-N2-of Fig. 4 compound 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2, the proton nmr spectra of 4-diamidogen
Specific embodiments
Embodiment is used for illustrating the present invention, but should not be construed as limitation of the present invention.
Embodiment 1,2-isopropyl thioether Nitrobenzol preparation
1.4kg2-fluoronitrobenzene, 0.77kg isopropyl mercaptan, 1.55kg potassium carbonate being added 8kgN, in dinethylformamide, is warming up to 80��90 DEG C and reacts 24 hours, HPLC monitors reaction and completes. It is cooled to 20��25 DEG C, is filtered to remove insoluble matter. Filtrate being added in the purified water of 76kg0��5 DEG C being stirred vigorously, temperature control 5��10 DEG C adjusts pH=6��7. Add 15kg petroleum ether: ethyl acetate=2: the mixed extractant solvent of 1 twice. Merging extraction phase, concentrating under reduced pressure removes petroleum ether, to cumulative volume about 10L, directly throws next step.
Embodiment 2,2-isopropyl thioether aniline preparation
Adding 400g egression Z activated carbon one step up in gained ethyl acetate solution, 30��40 DEG C are stirred 15��16 hours. Being filtered to remove activated carbon, 2kg ethyl acetate washes twice. 140g10%Pd/C is added in ethyl acetate solution, 30��40 DEG C, 1.6atm catalytic hydrogenation, within about 19��20 hours, react, HPLC monitors reaction. Filtration of catalyst, concentrating under reduced pressure is dry obtains 1.9kg red oil.
The preparation of the chloro-N-of embodiment 3,2,5-bis-(2-(isopropyl thioether) phenyl) pyrimidine-4-amine
By previous step 1.9kg crude product, 1.9kg2,4,5-trichloropyrimidines, 2.4kg diisopropyl ethyl amine adds in 20kg isopropanol, is warming up to back flow reaction. HPLC monitors reaction end, to raw material 2-isopropyl thioether aniline content lower than 6%. It is cooled to 40��55 DEG C of concentrating under reduced pressure dry reaction liquid, adds 20kg ethyl acetate and carry secretly once. Adding 20kg ethyl acetate, 20kg purified water washes twice. Concentrating under reduced pressure dry ethyl acetate phase, adds 10kg dehydrated alcohol in dark oil thing, 20��25 DEG C of stirred crystallization 4 hours, 0��5 DEG C of stirred crystallization 16 hours. Filter, 1kg absolute ethanol washing 1 time. 40 DEG C of vacuum dryings obtain 2.65kg white powder solid.1HNMR:(CDCl3, 400MHz) and ��: 9.29 (s, 1H), 8.67-8.44 (d, J=7.6Hz, 1H), 8.23 (s, 1H), 7.60-7.58 (dd, J1=7.6Hz, J2=1.2Hz, 1H), 7.48-7.44 (t, J=8.8Hz, 1H), 7.13��7.08 (t, J=7.6Hz, 1H), 3.19-3.12 (m, 1H), 1.28 (s, 3H), 1.26 (s, 3H).
The preparation of embodiment 4,2,5-bis-chloro-N-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine
Chloro-for 2.60kg2,5-bis-N-(2-(isopropyl thioether) phenyl) pyrimidine-4-amine is added in 19kg dichloromethane, stir molten clear after, be cooled to 0��5 DEG C. The 42kg dichloromethane solution of dropping 3.3kg metachloroperbenzoic acid, controls dropping process temperature lower than 10 DEG C, controls 10��15 DEG C of stirring reactions of temperature 3��4 hours after dropwising, and HPLC monitors reaction end. After having reacted, it is cooled to-10 DEG C��-5 DEG C and stirs 2 hours, be filtered to remove insoluble matter. In filtrate, add 34kg isopropanol, the dichloromethane concentrating under reduced pressure in this mixed solution is removed, obtains the aqueous isopropanol of product, 20��25 DEG C of stirred crystallization 15��16 hours, filter, 1kg washed with isopropyl alcohol 3 times. 45 DEG C of vacuum dryings 20 hours. Obtain the chloro-N-of product 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine 2.55kg white powder.1HNMR:(CDCl3, 400MHz) and ��: 10.06 (s, 1H), 8.63-8.61 (d, J=0.8Hz, 1H), 8.29 (s, 1H), 7.93-7.90 (d, J=0.8Hz, 1H), 7.75��7.70 (t, J=0.8Hz, 1H), 7.34��7.30 (t, J=0.8Hz, 1H), 3.24-3.17 (m, 1H), 1.32 (s, 3H), 1.30 (s, 3H).
The chloro-N2-of embodiment 5,5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2, the preparation of 4-diamidogen [color is auspicious for Buddhist nun]
By 2.50kg2; the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine and 2.50kg2-isopropoxy-5-methyl-4-(piperidin-4-yl) anilinechloride add in 30kg isopropanol; it is warming up to back flow reaction 24 hours; HPLC monitors reaction end; judge that reaction completes to the chloro-N-of raw material 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine content lower than 4.0. It is cooled to 20��25C stirred crystallization 12��14 hours, filters, 1kg washed with isopropyl alcohol 3 times. 45 DEG C of vacuum dryings obtain the chloro-N2-of 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2,4-diamine hydrochloride 3.75kg for 24 hours. By chloro-for 3.75kg5-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2; 4-diamine hydrochloride adds in 40kg purified water; temperature control 10��15 DEG C dropping 40% sodium hydrate aqueous solution regulates pH to 6.5��7.0; stir 2 hours; filtering, 10kg purified water is washed 4 times. 40 DEG C of vacuum dryings obtain the chloro-N2-of 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2,4-diamidogen 3.07kg white powder for 24 hours.1HNMR(DMSO-d6, 400MHz) and ��: 8.47-8.45 (d, J=8.4Hz, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.85-7.82 (dd, J1=8.0Hz, J2=0.8Hz, 1H), 7.63-7.59 (t, J=7.2Hz, 1H), 7.51 (s, 1H), 7.36-7.32 (t, J=7.6Hz, 1H), 6.82 (s, 1H), 4.57-4.51 (m, 2H), 3.51-3.45 (m, 1H), 3.06-3.03 (d, J=12.0Hz, 2H), 2.75-2.69 (m, 1H), 2.65-2.59 (m, 2H), 2.12 (s, 3H), 1.62-1.46 (m, 4H), 1.23-1.22 (d, J=6.0Hz, 6H), 1.17-1.15 (d, J=6.8Hz, 6H).
Claims (11)
1. a treatment auspicious new intermediate for Buddhist nun (Ceritinib) of non-small cell lung cancer drug color (compound of formula I), wherein X is selected from halogen, to Methyl benzenesulfonyl oxygen base, sulfonyloxy methyl oxygen base, and trimethyl fluoride sulfonyl oxygen base.
2. the preparation method of compound I according to claim 1, comprises the steps:
A 2-isopropyl thioether aniline is added in appropriate solvent mix with substituted pyrimidines, alkali by ();
B gained solution is heated to proper temperature reaction by ();
C reactant liquor concentration is done by (), then water-washing desalting obtains product with suitable polar solvent crystallize.
3. preparation method according to claim 2, the alkali of its reaction is: triethylamine, diisopropyl ethyl amine, pyridine, 1,8-diazabicylo 11 carbon-7-alkene, DMAP, alkali and alkaline earth metal ions carbonate, alkali-metal bicarbonate, and alkali and alkaline earth metal ions hydroxyl alkali.
4. preparation method according to claim 2, the solvent of its reaction is methanol, ethanol, isopropanol, acetonitrile, DMF, dimethyl sulfoxide, N-Methyl pyrrolidone and acetone.
5. preparation method according to claim 2, the reaction temperature of its reaction is 20��120 DEG C, it is preferable that temperature 80��120 DEG C.
6. compound according to claim 1, it is characterised in that the preferred chlorine atom of X.
7. a preparation method for the compound of Formula II, its preparation process is as follows:
A 2,5-bis-chloro-N-(2-(isopropyl thioether) phenyl) pyrimidine-4-amine solvent in appropriate solvent, is cooled to suitable temperature by ();
B () adds suitable oxidant, oxidation reaction;
(c) by crude reaction with suitable solvent crystallization;
8. preparation method according to claim 7, its suitable reaction temperature is-20��50 DEG C, it is preferable that 0��5 DEG C.
9. preparation method according to claim 7, its suitable oxidant is: peracetic acid, hydrogen peroxide, potassium hydrogen persulfate, sodium hypochlorite, metachloroperbenzoic acid, sodium metaperiodate, oxidant equivalent is 2.0��5.0 equivalents, the preferred metachloroperbenzoic acid of oxidant.
10. preparation method according to claim 7, its suitable reaction dissolvent is: acetone, dichloromethane, acetonitrile, methanol, ethanol, isopropanol, oxolane, the preferred dichloromethane of reaction dissolvent.
11. preparation method according to claim 7, its suitable recrystallisation solvent is ethanol, acetone, isopropanol, methyl tertiary butyl ether(MTBE), diisopropyl ether, the preferred isopropanol of recrystallisation solvent.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602483A (en) * | 2016-07-12 | 2018-01-19 | 上海博璞诺科技发展有限公司 | Ceritinib intermediate and preparation method thereof |
| CN108689993A (en) * | 2018-06-22 | 2018-10-23 | 苏州市贝克生物科技有限公司 | The preparation method of Ceritinib |
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| CN102459236A (en) * | 2009-05-27 | 2012-05-16 | 雅培制药有限公司 | Pyrimidine inhibitors of kinase activity |
| WO2014071832A1 (en) * | 2012-11-06 | 2014-05-15 | Shanghai Fochon Pharmaceutical Co Ltd | Alk kinase inhibitors |
| CN104109149A (en) * | 2013-04-22 | 2014-10-22 | 苏州泽璟生物制药有限公司 | Deuterated diamino pyrimidine compound and pharmaceutical composition containing same |
| CN105242921A (en) * | 2015-09-23 | 2016-01-13 | 国网上海市电力公司 | Compatibile UI developing device and application therefor |
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2014
- 2014-08-25 CN CN201410430727.3A patent/CN105622520A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102459236A (en) * | 2009-05-27 | 2012-05-16 | 雅培制药有限公司 | Pyrimidine inhibitors of kinase activity |
| WO2014071832A1 (en) * | 2012-11-06 | 2014-05-15 | Shanghai Fochon Pharmaceutical Co Ltd | Alk kinase inhibitors |
| CN104109149A (en) * | 2013-04-22 | 2014-10-22 | 苏州泽璟生物制药有限公司 | Deuterated diamino pyrimidine compound and pharmaceutical composition containing same |
| CN105242921A (en) * | 2015-09-23 | 2016-01-13 | 国网上海市电力公司 | Compatibile UI developing device and application therefor |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602483A (en) * | 2016-07-12 | 2018-01-19 | 上海博璞诺科技发展有限公司 | Ceritinib intermediate and preparation method thereof |
| CN107602483B (en) * | 2016-07-12 | 2020-04-03 | 上海博璞诺科技发展有限公司 | Ceritinib intermediate and preparation method thereof |
| CN108689993A (en) * | 2018-06-22 | 2018-10-23 | 苏州市贝克生物科技有限公司 | The preparation method of Ceritinib |
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Application publication date: 20160601 |