CN106146411A - (S) preparation method of-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one - Google Patents
(S) preparation method of-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one Download PDFInfo
- Publication number
- CN106146411A CN106146411A CN201510181775.8A CN201510181775A CN106146411A CN 106146411 A CN106146411 A CN 106146411A CN 201510181775 A CN201510181775 A CN 201510181775A CN 106146411 A CN106146411 A CN 106146411A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- fluoro
- amino
- propyl
- quinazoline
- 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
- 0 CC[C@@]1NC(C2OC(C)(C)C)*2C1=O Chemical compound CC[C@@]1NC(C2OC(C)(C)C)*2C1=O 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the preparation method of one (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one; the method is that the cyclization under the conditions of trim,ethylchlorosilane of formula (V) compound obtains (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3; 4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate, then take off BOC protection through acid and obtain.The synthetic route that the application provides overcomes prior art defect, and often step reaction condition is gentle, and stable reaction, yield are high, is very suitable for the big key intermediate 6 producing Idelalisib of industry.
Description
Technical field
The present invention relates to the preparation method technical field of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one.
Background technology
Idelalisib is PI3K inhibitor to be administered orally by the first selectivity of lucky Leadd B.V research and development, compared with α, β, γ subunit, its can high selectivity act on δ subunit, retardance PI3K δ-Akt signal path also promotes apoptosis, U.S. FDA approval listing is obtained, for recurring the treatment of chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma in July, 2014.Chemistry entitled (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-base amino) propyl group]-3H-quinazoline-4-one.
Its synthetic route of synthetic method that international monopoly WO2005113556A1 discloses a kind of Idelalisib is as follows:
The method is with 2-fluoride-6-nitrobenzoic acid as raw material; elder generation and aniline condensation; react with N-Boc-L-2-aminobutyric acid after obtaining intermediate with thionyl chloride reaction again and obtain bisamide product; obtaining (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one after reduction cyclization, deprotection again, last and 6-bromine purine obtains (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-base amino) propyl group]-3H-quinazoline-4-one (i.e. Idelalisib) through nucleophilic displacement of fluorine.
But the defect of said method is that compound 6 is as the important source material preparing Idelalisib, the most commercially do not have cheap finished industrial product can buy, and in prior art disclosed in international monopoly WO2005113556A1, this step yield preparing compound 4 is relatively low, and need to be obtained by column chromatography, prepare this step of compound 5 also needs to be obtained by column chromatography simultaneously, and obtains being foaming solid, purity is bad, is unfavorable for subsequent operation and industrialized production.Overall yield is low, and atom utilization is the highest.
It is thus desirable to a kind of raw material of exploitation is easy to get, safety, the method that what yield was high prepare Idelalisib intermediate.
Summary of the invention
The object of the invention solves existing above-mentioned technical problem exactly, it is provided that one is suitable to the big production of industry, and the Idelalisib intermediate preparation method that yield is higher than existing method.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
(S) preparation method of-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one; the method is that lower formula V compound cyclization under the conditions of trim,ethylchlorosilane obtains (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3; 4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate, then take off BOC protection through acid and obtain
Further, above-mentioned formula (V) compound is by obtaining with the reaction of formula III compound after the activated carboxylic of formula IV compound is become anhydride again:
The activator of above-mentioned activation formula IV BOC-L-2-aminobutyric acid carboxyl can be chloro-formate class such as isobutyl chlorocarbonate etc., alkali used is organic base such as N-methylmorpholine and triethylamine etc., the anhydride obtained after activation and formula III compound react in former reaction system, i.e. one cooking-pot type reaction.
Further, above-mentioned formula III compound is formula II compound reduction reaction to be obtained:
This reduction reaction can be Pd/C be that catalyst carries out hydro-reduction, it is also possible under the conditions of Zn/ ammonium chloride reduce.
Further, above-mentioned formula II compound be formula I compound is first become amide after obtain with aniline reaction the most in the basic conditions:
Acylating agent used by the reaction of this step can be oxalyl chloride, thionyl chloride etc., and solvent used during reaction is oneself alkyl chloride hydro carbons such as dichloromethane etc. of knowing of those skilled in the art, afterwards with aniline reaction selected by solvent can be cyclic ethers class such as Isosorbide-5-Nitrae-dioxane etc..Reaction temperature can select optimal temperature range according to solvent used, those skilled in the art.The alkali that can use includes such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
Beneficial effects of the present invention: when studying the preparation method of Idelalisib, present inventor has been found surprisingly that a kind of new synthetic route is to prepare intermediate (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one, this new synthetic route overcomes prior art defect, often step reaction condition is gentle, stable reaction, yield are high, are very suitable for the big key intermediate 6 producing Idelalisib of industry.
Detailed description of the invention
The preparation of embodiment 1-2:2-fluoro-6-nitro-N-phenyl-Benzoylamide formula II
By 2-fluoride-6-nitrobenzoic acid (18.5g), DMF (1ml) and dichloromethane (100ml) mix and blend, the dropping dichloromethane solution (60ml) containing oxalyl chloride (19g), reaction 2 hour is stirred at room temperature, is concentrated to give orange solids serosity.Above-mentioned serosity is dissolved in containing in anhydrous dioxanes (16ml), and it is slowly dropped at 6 DEG C containing aniline (9ml) and sodium bicarbonate (16.8g) in the mixing suspension of dioxanes (40) and water (40), after finishing, half an hour is stirred at room temperature, adds water (250ml), have solid to produce, solid is collected by filtration, wash with water, obtain title compound 2-fluoro-6-nitro-N-phenyl-Benzoylamide 25.6g, yield 98.4%.1H NMR(400MHz,CDCl3) δ 8.01 (d, J=8.2Hz, 1H), 7.70-7.60 (m, 4H), 7.41 (t, J=7.8Hz, 2H), 7.23 (t, J=7.4Hz, 1H) .ESI-MS (m/z): 261 [M+H]+
By 2-fluoride-6-nitrobenzoic acid (18.5g), DMF (1ml) and dichloromethane (100ml) mix and blend, the dropping dichloromethane solution (60ml) containing oxalyl chloride (19g), reaction 2 hour is stirred at room temperature, is concentrated to give orange solids serosity.Above-mentioned serosity is dissolved in containing in anhydrous THF (16ml), and it is slowly dropped at 6 DEG C containing aniline (9ml) and sodium bicarbonate (16.8g) in the mixing suspension of THF (40ml) and water (40ml), after finishing, half an hour is stirred at room temperature, adds water (250ml), have solid to produce, solid is collected by filtration, wash with water, obtain title compound 2-fluoro-6-nitro-N-phenyl-Benzoylamide 24.6g, yield 94.6%.
The preparation of embodiment 3-4:2-amino-6-fluoro-N-phenyl-benzamide formula III
2-amino-6-fluoro-N-phenyl-benzamide (13g), Pd/C (1g) and ethyl acetate (100ml) are blended in 50 DEG C of hydrogenations four hours, filter, it is concentrated to dryness and obtains title compound 2-amino-6-fluoro-N-phenyl-benzamide 11.1g, yield 96.5%.1H NMR(400MHz,CDCl3) δ 8.33 (d, J=15.5Hz, 1H), 7.61 (d, J=7.6Hz, 2H), 7.43 7.35 (m, 2H), 7.21 7.12 (m, 2H), 6.51 (d, J=8.3Hz, 1H), 6.43 (ddd, J=13.0,8.1,1.0Hz, 1H), 5.97 (s, 2H) .ESI-MS (m/z): 231 [M+H]+
2-amino-6-fluoro-N-phenyl-benzamide (13g), Pd/C (0.8g) and ethyl acetate (100ml) are blended in 50 DEG C of hydrogenations six hours, filter, it is concentrated to dryness and obtains title compound 2-amino-6-fluoro-N-phenyl-benzamide 10.5g, yield 91.3%.
Embodiment 5-6:(S)-2-{ [the fluoro-2-of 3-[(phenyl amino) carbonyl] phenyl] amino-1-ethyl } preparation of-isobutyl carbamate formula (V)
nullBy BOC-L-2-aminobutyric acid (20.3g)、N-methylmorpholine (11.2g) is dissolved in anhydrous THF (120ml)，The dropping anhydrous THF (40ml) solution containing isobutyl chlorocarbonate (13.7g) at-15 DEG C，Drip and finish，Stir 1 hour under the conditions of-15 DEG C，Anhydrous THF (40ml) solution of dropping fluoro-N-phenyl-benzamide Han 2-amino-6-(11.5g) again，Drip and finish，React half an hour at this temperature，It is slowly increased to room temperature，React 1 hour，Filter out solid，Filtrate is warming up to back flow reaction 3.5 hours，Concentration of reaction solution，Add ethyl acetate (150ml) and water (200ml)，Separatory，Aqueous layer with ethyl acetate (100ml × 2) extracts，Merge organic layer，Washing，Saturated common salt is washed，It is dried，Filter，It is concentrated to give crude product 19.2g，It is recrystallized to give title compound (S)-2-{ [the fluoro-2-of 3-[(phenyl amino) carbonyl] phenyl] amino-1-ethyl with isopropanol (70ml) }-isobutyl carbamate 17.1g，Yield 82.4%.1H NMR(400MHz,CDCl3) δ 11.72 (s, 1H), 8.55 (d, J=8.5Hz, 1H), 8.37 (d, J=14.5Hz, 1H), 7.64 (d, J=7.8Hz, 2H), 7.51 7.45 (m, 1H), 7.41 (t, J=7.9Hz, 2H), 7.23 (t, J=7.4Hz, 1H), 6.93 (dd, J=12.3,8.4Hz, 1H), 5.11 (s, 1H), 4.28 (s, 1H), 2.07 1.97 (m, 1H), 1.83 1.73 (m, 1H), 1.45 (s, 9H), 1.03 (t, J=7.4Hz, 3H) .ESI-MS (m/z): 416 [M+H]+
nullBy BOC-L-2-aminobutyric acid (20.3g)、N-methylmorpholine (11.2g) is dissolved in anhydrous THF (120ml)，The dropping anhydrous THF (40ml) solution containing isobutyl chlorocarbonate (13.7g) at-15 DEG C，Drip and finish，Stir 1 hour under the conditions of-15 DEG C，Anhydrous THF (40ml) solution of dropping fluoro-N-phenyl-benzamide Han 2-amino-6-(11.5g) again，Drip and finish，React half an hour at this temperature，It is slowly increased to room temperature，React 1 hour，Filtrate is warming up to back flow reaction 3.5 hours，Concentration of reaction solution，Add ethyl acetate (150ml) and water (200ml)，Separatory，Aqueous layer with ethyl acetate (100ml × 2) extracts，Merge organic layer，Washing，Saturated common salt is washed，It is dried，Filter，It is concentrated to give crude product 19.2g，It is recrystallized to give title compound (S)-2-{ [the fluoro-2-of 3-[(phenyl amino) carbonyl] phenyl] amino-1-ethyl with isopropanol (70ml) }-isobutyl carbamate 14.9g，Yield 71.8%.
Embodiment 7-8:(S) preparation of [1-(5-fluorin-4-oxygen generation-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate
By (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3, 4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate (8.3g), trim,ethylchlorosilane (40ml), triethylamine (150ml) is blended in acetonitrile (500ml) vexed tank under nitrogen-sealed and reacts 48 hours, filter, it is concentrated to dryness, add ethyl acetate (500ml), successively with saturated sodium carbonate solution (150ml), water (150ml), saturated aqueous common salt (150ml) is washed, it is dried, filter, it is concentrated to give title compound (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3, 4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate 7.2g, yield 90.6%.1H NMR(400MHz,CDCl3) δ 7.71 (td, J=8.2,5.4Hz, 1H), 7.65 7.49 (m, 4H), 7.38 (d, J=6.5Hz, 1H), 7.29 (d, J=7.6Hz, 1H), 7.13 (dd, J=10.4,8.2Hz, 1H), 5.43 (s, 1H), 4.43 (s, 1H), 1.67 1.49 (m, 2H), 1.44 (s, 9H), 0.79 (t, J=7.4Hz, 3H) .ESI-MS (m/z): 398 [M+H]+
By (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate (8.3g), trim,ethylchlorosilane (40ml), triethylamine (150ml) be blended in nitrogen in acetonitrile (500ml) and react 48 hours, and thin layer chromatography is displayed without reaction.
Embodiment 9:(S) preparation of-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one
By (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3, 4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate (7.94g) is dissolved in dichloromethane (40ml) and trifluoroacetic acid (40ml), it is stirred at room temperature 2 hours, it is concentrated to dryness, dichloromethane (100ml) and 10% potassium carbonate (100ml) solution distribute, separatory, water layer extracts with dichloromethane (50ml × 2) again, merge organic layer, washing, saturated common salt is washed, it is dried, filter, it is concentrated to give title compound (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one 5.1g, yield 85.8%.1H NMR(400MHz,CDCl3) δ 7.70 (td, J=8.2,5.4Hz, 1H), 7.63 7.50 (m, 4H), 7.29 (dd, J=12.9,5.9Hz, 2H), 7.12 (dd, J=10.2,8.4Hz, 1H), 3.55 3.41 (m, 1H), 1.88 1.76 (m, 1H), 1.60 1.47 (m, 1H), 0.81 (t, J=9.6Hz, 3H) .ESI-MS (m/z): 298 [M+H]+ 。
Claims (9)
1. the preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one, the method is by lower formula V
Compound cyclization under the conditions of trim,ethylchlorosilane obtains (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3,4-dihydro-quinoline azoles
Quinoline-2-base)-propyl group]-isobutyl carbamate, then take off BOC protection through acid and obtain
2. the preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one as claimed in claim 1,
It is characterized in that: formula (V) compound is by being become by the activated carboxylic of formula IV compound after anhydride and formula III again
Compound reaction obtains:
3. the preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one as claimed in claim 2,
It is characterized in that: the activator of activation formula IV BOC-L-2-aminobutyric acid carboxyl is isobutyl chlorocarbonate.
4. the preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one as claimed in claim 2,
It is characterized in that: formula (V) compound is obtained by a cooking-pot type reaction.
5. the preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one as claimed in claim 2,
It is characterized in that: above-mentioned formula III compound is formula II compound reduction reaction to be obtained
6. the preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one as claimed in claim 5, its
Be characterised by: reduction reaction be Pd/C be catalyst carry out hydro-reduction or under the conditions of Zn/ ammonium chloride reduce.
7. the preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one as claimed in claim 5, its
Be characterised by: formula II compound be formula I compound is first become amide after obtain with aniline reaction the most in the basic conditions
Arrive
8. the preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one as claimed in claim 7, its
It is characterised by: the acylating agent used by reaction is oxalyl chloride or thionyl chloride.
9. the preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one as claimed in claim 7, its
It is characterised by: the alkali of use includes sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510181775.8A CN106146411A (en) | 2015-04-16 | 2015-04-16 | (S) preparation method of-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510181775.8A CN106146411A (en) | 2015-04-16 | 2015-04-16 | (S) preparation method of-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106146411A true CN106146411A (en) | 2016-11-23 |
Family
ID=58057486
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510181775.8A Pending CN106146411A (en) | 2015-04-16 | 2015-04-16 | (S) preparation method of-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106146411A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503430A (en) * | 2018-12-29 | 2019-03-22 | 浙江东亚药业股份有限公司 | A kind of neighbour's fluorine neighbour's imido grpup benzoic acid Intermediate compound and its preparation method and application |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005113556A1 (en) * | 2004-05-13 | 2005-12-01 | Icos Corporation | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta |
| WO2013082540A1 (en) * | 2011-12-02 | 2013-06-06 | Gilead Calistoga Llc | Compositions and methods of treating a proliferative disease with a quinazolinone derivative |
| WO2014106800A2 (en) * | 2013-01-04 | 2014-07-10 | Aurigene Discovery Technologies Limited | Substituted 2-amino pyrimidine derivatives as kinase inhibitors |
| CN104130261A (en) * | 2014-08-04 | 2014-11-05 | 山东康美乐医药科技有限公司 | Idelalisib synthetic method |
| WO2015042077A1 (en) * | 2013-09-22 | 2015-03-26 | Calitor Sciences, Llc | Substituted aminopyrimidine compounds and methods of use |
-
2015
- 2015-04-16 CN CN201510181775.8A patent/CN106146411A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005113556A1 (en) * | 2004-05-13 | 2005-12-01 | Icos Corporation | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta |
| WO2013082540A1 (en) * | 2011-12-02 | 2013-06-06 | Gilead Calistoga Llc | Compositions and methods of treating a proliferative disease with a quinazolinone derivative |
| WO2014106800A2 (en) * | 2013-01-04 | 2014-07-10 | Aurigene Discovery Technologies Limited | Substituted 2-amino pyrimidine derivatives as kinase inhibitors |
| WO2015042077A1 (en) * | 2013-09-22 | 2015-03-26 | Calitor Sciences, Llc | Substituted aminopyrimidine compounds and methods of use |
| CN104130261A (en) * | 2014-08-04 | 2014-11-05 | 山东康美乐医药科技有限公司 | Idelalisib synthetic method |
Non-Patent Citations (5)
| Title |
|---|
| BU K.O.ET AL.: "Synthesis of N-heteropolycyclic Compounds Including Quinazolinone Skeleton Using Friedel–crafts Alkylation", 《SYNTHETIC COMMUNICATIONS》 * |
| 史宝萍 等: "三甲基氯硅烷的性质及其应用研究进展", 《化工时刊》 * |
| 王福安 等主编: "《生物大分子的内化》", 30 June 1995, 科学出版社 * |
| 邢其毅 等: "《基础有机化学（下册）第3版》", 30 June 2005, 高等教育出版社 * |
| 高爱红 等: "N,O-双三甲基硅基乙酰胺的合成进展", 《山东化工》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503430A (en) * | 2018-12-29 | 2019-03-22 | 浙江东亚药业股份有限公司 | A kind of neighbour's fluorine neighbour's imido grpup benzoic acid Intermediate compound and its preparation method and application |
| CN109503430B (en) * | 2018-12-29 | 2021-01-29 | 浙江东亚药业股份有限公司 | O-fluoro-o-imine benzoic acid intermediate compound and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6392436B2 (en) | Process for the preparation of substituted 5-fluoro-1H-pyrazolopyridines | |
| CN108699063B (en) | Synthesis process of luccotinib | |
| JP5801011B2 (en) | Method for producing optically active diamine derivative | |
| WO2016026380A1 (en) | Method for preparing idelalisib | |
| CA3210320A1 (en) | Synthesis of a bruton's tyrosine kinase inhibitor | |
| CN107176955A (en) | A kind of Ba Rui replaces the preparation method of Buddhist nun | |
| CN107235958A (en) | A kind of synthetic method for preparing PARP inhibitor Niraparib | |
| CN110088111A (en) | (S) -2- ((2- ((S) -4- (difluoromethyl) -2- oxo oxazolidine -3- base) -5,6- dihydrobenzo [f] imidazo [1,2-d] [1,4] oxygen azatropylidene -9- base) amino) and propionamide preparation method | |
| JP5791825B2 (en) | Method for synthesizing 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-formamidine hydrochloride | |
| CN108707141A (en) | The preparation method of avanaphil | |
| CN106146411A (en) | (S) preparation method of-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one | |
| CN106146352A (en) | Idelalisib intermediate and preparation method thereof | |
| CN102260213B (en) | Method for preparing tolvaptan | |
| CN107286078A (en) | A kind of method for preparing piperazine Ma Selin and its tartrate | |
| CN106831768A (en) | A kind of synthetic method of 2,6 dichloropyridines [3,4 B] pyrazine | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN106588921B (en) | A kind of synthetic method of the methyl formate of 7 azaindole 3 | |
| CN100357294C (en) | Novel crystal of 7- 2-(2-aminothiazole-4-yl)-2-hydroxyiminoa cetamido-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) and method for preparation thereof | |
| CN104910068B (en) | A kind of synthetic method of the tosilate of 2 cyano group isonicotinic acid hydrazide 1.5 | |
| CN102408353A (en) | Preparation method of candesartan intermediate | |
| CN105777743A (en) | Preparation method and application of pyrazolo[3, 4-b]pyridine compound intermediate | |
| JP2021504458A (en) | Method for producing salicylamide acetate | |
| CN104592222A (en) | Preparation method for antiplatelet medicine AZD6482 | |
| CN104163798A (en) | Synthesis method of 3-amino-8-trifluoromethyl quinoline | |
| TWI845992B (en) | A method for preparing a hepatitis B virus nucleocapsid 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: 20161123 |