CN102285915B - Synthesis method for alkaloid secondary metabolite aspernigerin having anticancer activity - Google Patents
Synthesis method for alkaloid secondary metabolite aspernigerin having anticancer activity Download PDFInfo
- Publication number
- CN102285915B CN102285915B CN201110173852.7A CN201110173852A CN102285915B CN 102285915 B CN102285915 B CN 102285915B CN 201110173852 A CN201110173852 A CN 201110173852A CN 102285915 B CN102285915 B CN 102285915B
- Authority
- CN
- China
- Prior art keywords
- organic solvent
- binding agent
- tetrahydroquinoline
- acid binding
- piperazine
- 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.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
The invention discloses a synthesis method for alkaloid secondary metabolite aspernigerin having anticancer activity, which belongs to the technical field of synthesis of organic compounds. The compound is synthesized by the following steps: dissolving 1,2,3,4-tetra-hydroquinoline in an organic solvent 1, adding chloroacetic chloride, then adding acid binding agent I, keeping the temperature till the reaction is accomplished completely, adding N-chloroacetyl-1,2,3,4-tetrahydroquinol in an organic solvent II, dripping the solution into solvent II solution of piperazine and an acid binding agent II, keeping the temperature till the reaction is accomplished completely, and obtaining N,N'-bis(1,2,3,4-tetra-hydroquinolyl-N-formylmethyl)piperazine, namely aspernigerin. When the synthesis method disclosed by the invention is used, the yield is high, the product purity is high, and the operation method is simple, convenient and easy to implement.
Description
Technical field
The invention belongs to organic compound synthesis technical field, be specifically related to a kind of synthetic method with the alkaloids secondary metabolite Aspernigerin of antitumour activity.
Background technology
The chemical name of Aspernigerin is Aspernigerin, and English name is Aspernigerin; Its structure is compound shown in formula one:
(formula one)
(the Chem.Eur.J.2006 that the auspicious seminar of Tan Ren of Aspernigerin Shi You Nanjing University found first in 2006,12,4393), that their separation from the solid culture extracting solution of Bermuda grass endophyte Aspergillus niger IFB-E003 obtains, its structure is resolved and is confirmed by the analysis of X-single crystal diffraction by multiple spectral method especially MS and NMR, and discovery is the alkaloids secondary metabolite of a skeleton novelty.
Further in vitro cytotoxic effect test is found, Aspernigerin shows stronger cytotoxic activity to people's oral cavity epidermoid carcinoma cell KB, cervical cancer cell Hela, colon cancer cell SW1116, and its IC50 value is respectively 22,46 and 35 μ M.Positive control 5 FU 5 fluorouracil (5-FU) is respectively 14,115 and 42 μ M to the IC50 value of this three strains JEG-3.Therefore, Aspernigerin is potential drug molecule or a lead compound with excellent activity.
Complete synthesis about Aspernigerin, so far, only has the auspicious seminar of Tan Ren to have pertinent literature report (Li Shen, Yong-Hao Ye, Xiao-Ting Wang, Hai-Liang Zhu, Chen Xu, Yong-Cun Song, Hai Li, and Ren-Xiang Tan Chem.Eur.J.2006,12,4393), route is as follows:
The method route is longer, operates comparatively loaded down with trivial detailsly, and yield is lower, is only 47.3%, and product purification difficulty, need to carry out column chromatography purification, and operating process needs acid adjustment alkali frequently, and the three wastes are more.For making Aspernigerin obtain studying more widely and applying, explore a kind of preparation method easy, cheap, that obtain efficiently high purity Aspernigerin and just seem very meaningful.
Summary of the invention
The object of this invention is to provide a kind of synthetic method with the alkaloids secondary metabolite Aspernigerin of antitumour activity.
The synthetic method of Aspernigerin (Aspernigerin), carry out in accordance with the following steps:
(1) by 1,2,3,4-tetrahydroquinoline is dissolved in organic solvent I, at-10~40 ℃ of temperature, drips chloroacetyl chloride, then add acid binding agent I, insulation is to reacting completely, and aqueous hydrochloric acid washing is 2~3 times for reaction solution, separate organic layer, dry precipitation, then, underpressure distillation obtains N-chloracetyl-1,2,3,4-tetrahydroquinoline;
(2) piperazine is dissolved in organic solvent II, adds acid binding agent II, at 50~150 ℃ of temperature, drip containing N-chloracetyl-1, the solution of the organic solvent II of 2,3,4-tetrahydroquinoline, insulation is to reacting completely, cooling, filters, and desolventizing obtains product crude product, adds organic solvent II I, heating for dissolving, filtered while hot, filtrate decrease temperature crystalline, obtaining white crystal, is end product N, and N '-bis-(1,2,3,4-tetrahydric quinoline group-N-formyl methyl) piperazine.
Described organic solvent I is methylene dichloride, 1,2-ethylene dichloride, chloroform, tetracol phenixin, chlorobenzene, ether, tetrahydrofuran (THF), toluene, benzene, dimethylbenzene or dioxane, preferably methylene dichloride or chloroform.
Described acid binding agent I is triethylamine, Trimethylamine 99, pyridine, DMA or N, N-Diethyl Aniline, preferably triethylamine or DMA.
Described organic solvent II is DMF, N, N-diethylformamide, methyl alcohol, ethanol, toluene, benzene, dimethylbenzene or acetonitrile, preferably DMF or toluene.
Described acid binding agent II is triethylamine, Trimethylamine 99, pyridine, DMA, N, N-Diethyl Aniline, salt of wormwood, sodium carbonate, saleratus or sodium bicarbonate, preferably triethylamine or salt of wormwood.
Described organic solvent II I is the mixed solvent of toluene, benzene, dimethylbenzene, methyl acetate and sherwood oil or the mixed solvent of methyl acetate and normal hexane, preferably toluene.
Step (1) is used 1,2,3, and the mol ratio of 4-tetrahydroquinoline, chloroacetyl chloride and acid binding agent I is: 1: (1~2): (1~2).
Step (2) N-used chloracetyl-1, the mol ratio of 2,3,4-tetrahydroquinoline, piperazine and acid binding agent II is: (2~3): 1: (2~6).
Beneficial effect of the present invention: the synthetic method of Aspernigerin of the present invention, reactions steps is few, simple to operate, and the three wastes are few, and yield is high, and good product purity is raw materials used cheap and easy to get, greatly reduces production cost.Wherein the first step product adopts the mode of distillation to steam, and yield is high, and purity is good, has reduced greatly the purifying difficulty of second step, and easy handling; In second step, adopt the mode of toluene recrystallization to obtain product, yield is high, and purity is good, and easy handling; Institute in steps without severe condition, simple to operate, environmentally friendly, solvent is easy to recovery of applied.
Embodiment
With specific embodiment, the present invention will be further described below.
Embodiment 1
(1) in 500ml there-necked flask, add 26.6g (0.2mol) 1,2,3,4-tetrahydroquinoline and 300mL methylene dichloride, cryosel is bathed and is cooled to-5 ℃~0 ℃.Slowly drip the solution that 25g (0.22mol) chloroacetyl chloride and 100mL methylene dichloride are made into, dropwise, stirring reaction 10 minutes, then slowly drip 21.2g (0.21mol) triethylamine, after dropwising, be incubated in-5 ℃~5 ℃ reactions 5~8 hours, reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After reacting completely, add the aqueous hydrochloric acid of 50mL5%, stir 30 minutes, stratification, separates organic layer, then washs one time with the aqueous hydrochloric acid of 100mL5%, separate organic layer, with anhydrous sodium sulfate drying, filter, solvent is deviate from the first air distillation of filtrate, then, and oil pump underpressure distillation, the cut 38.8g that collects 162 ℃~164 ℃/130Pa, is N-chloracetyl-1,2,3,4-tetrahydroquinoline, yield 92.8%.m/z(%):209[M]+;
1H?NMR(300MHz,CDCl3)δ1.88~1.97(m,2H,CH2CH2CH2),2.71~2.75(t,2H,ArCH2),3.71~3.75(t,2H,NCH2),4.55(s,2H,CH2Cl)。
(2) in 500ml there-necked flask, add 8.6g (0.1mol) piperazine, 42g (0.3mol) Anhydrous potassium carbonate and 100mLDMF, stir, heating and thermal insulation is between 80 ℃~100 ℃.Drip 44g (0.21mol) N-chloracetyl-1, the solution that 2,3,4-tetrahydroquinoline and 50mLDMF are made into, after dropwising, is incubated in 80 ℃~100 ℃ reactions 4~6 hours, and reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After reacting completely, be cooled to room temperature, suction filtration, remove solid salts substances, the underpressure distillation of filtrate water pump, steams DMF, residue adds 50mL toluene, and reflux makes to dissolve completely for 10 minutes, then suction filtration while hot, further remove solid salts substances, filtrate is placed, and is naturally down to room temperature, and process has a large amount of crystal to separate out, room temperature continues to place about 2 hours, makes crystallization complete.Then, suction filtration is also used 20ml toluene wash 1~2 time, dries, and obtains white crystal 37.5g, for N, N '-bis-(1,2,3,4-tetrahydric quinoline group-N-formyl methyl) piperazine (Aspernigerin), yield 86.6%, it is >=99% that HPLC analyzes normalizing content.m/z(%):432[M]+;
1H?NMR(300MHz,CDCl3)δ1.85~1.89(m,4H,CH2CH2CH2),2.37(Brs,8H,pip-H),2.67~2.72(t,4H,ArCH2),3.24(s,4H,COCH2),3.67~3.71(t,2H,NCH2),7.03~7.17(m,6H,Ar-H),7.56(Brs,2H,
)。
Embodiment 2
(1) in 500ml there-necked flask, add 26.6g (0.2mol) 1,2,3,4-tetrahydroquinoline and 300mL methylene dichloride, cryosel is bathed and is cooled to-5 ℃~0 ℃.Slowly drip the solution that 25g (0.22mol) chloroacetyl chloride and 100mL methylene dichloride are made into, dropwise, stirring reaction 10 minutes, then slowly drip 21.2g (0.21mol) triethylamine, after dropwising, be incubated in-5 ℃~5 ℃ reactions 5~8 hours, reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After reacting completely, add the aqueous hydrochloric acid of 50mL5%, stir 30 minutes, stratification, separates organic layer, then washs one time with the aqueous hydrochloric acid of 100mL5%, separate organic layer, with anhydrous sodium sulfate drying, filter, solvent is deviate from the first air distillation of filtrate, then, and oil pump underpressure distillation, the cut 38.6g that collects 162 ℃~164 ℃/130Pa, is N-chloracetyl-1,2,3,4-tetrahydroquinoline, yield 92.3%.
(2) in 500ml there-necked flask, add 8.6g (0.1mol) piperazine, 21.2g (0.21mol) triethylamine and 100mL toluene, stir reflux.At 50 ℃~80 ℃ temperature, drip 44g (0.21mol) N-chloracetyl-1, the solution that 2,3,4-tetrahydroquinoline and 100mL toluene are made into, after dropwising, back flow reaction 4~6 hours, reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After reacting completely, steam about toluene 150mL, reaction solution, then suction filtration while hot, removes solid salts substances, and filtrate is placed, and naturally is down to room temperature, and process has a large amount of crystal to separate out, and room temperature continues placement about 2 hours, makes crystallization complete.Then, suction filtration is also used 20ml toluene wash 1~2 time, dries, and obtains white crystal 38.6g, for N, N '-bis-(1,2,3,4-tetrahydric quinoline group-N-formyl methyl) piperazine (Aspernigerin), yield 89.2%, it is >=99% that HPLC analyzes normalizing content.
Embodiment 3
(1) in 500ml there-necked flask, add 26.6g (0.2mol) 1,2,3,4-tetrahydroquinoline and 300mL methylene dichloride, cryosel is bathed and is cooled to-5 ℃~0 ℃.Slowly drip the solution that 25g (0.22mol) chloroacetyl chloride and 100mL methylene dichloride are made into, dropwise, stirring reaction 10 minutes, then slowly drip 25.5g (0.21mol) N, N-dimethylbenzene aniline, after dropwising, be incubated in-5 ℃~5 ℃ reactions 5~8 hours, reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After reacting completely, add the aqueous hydrochloric acid of 50mL5%, stir 30 minutes, stratification, separates organic layer, then washs one time with the aqueous hydrochloric acid of 100mL5%, separate organic layer, with anhydrous sodium sulfate drying, filter, solvent is deviate from the first air distillation of filtrate, then, and oil pump underpressure distillation, the cut 39.0g that collects 162 ℃~164 ℃/130Pa, is N-chloracetyl-1,2,3,4-tetrahydroquinoline, yield 93%.
(2) in 500ml there-necked flask, add 8.6g (0.1mol) piperazine, 25.5g (0.21mol) N, N-dimethylbenzene aniline and 100mL toluene, stir reflux.At 100 ℃~150 ℃ temperature, drip 44g (0.21mol) N-chloracetyl-1, the solution that 2,3,4-tetrahydroquinoline and 100mL toluene are made into, after dropwising, back flow reaction 4~6 hours, reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After reacting completely, steam about toluene 150mL, reaction solution, then suction filtration while hot, removes solid salts substances, and filtrate is placed, and naturally is down to room temperature, and process has a large amount of crystal to separate out, and room temperature continues placement about 2 hours, makes crystallization complete.Then, suction filtration is also used 20ml toluene wash 1~2 time, dries, and obtains white crystal 38.2g, for N, N '-bis-(1,2,3,4-tetrahydric quinoline group-N-formyl methyl) piperazine (Aspernigerin), yield 88.3%, it is >=99% that HPLC analyzes normalizing content.
Embodiment 4
(1) in 500ml there-necked flask, add 26.6g (0.2mol) 1,2,3,4-tetrahydroquinoline and 300mL methylene dichloride, cryosel is bathed and is cooled to-5 ℃~0 ℃.Slowly drip the solution that 25g (0.22mol) chloroacetyl chloride and 100mL chloroform are made into, dropwise, stirring reaction 10 minutes, then slowly drip 25.5g (0.21mol) N, N-dimethylbenzene aniline, after dropwising, be incubated in-5 ℃~5 ℃ reactions 5~8 hours, reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After reacting completely, add the aqueous hydrochloric acid of 50mL5%, stir 30 minutes, stratification, separates organic layer, then washs one time with the aqueous hydrochloric acid of 100mL5%, separate organic layer, with anhydrous sodium sulfate drying, filter, solvent is deviate from the first air distillation of filtrate, then, and oil pump underpressure distillation, the cut 38.3g that collects 162 ℃~164 ℃/130Pa, is N-chloracetyl-1,2,3,4-tetrahydroquinoline, yield 91.3%.
(2) in 500ml there-necked flask, add 8.6g (0.1mol) piperazine, 42g (0.3mol) Anhydrous potassium carbonate and 100mL dehydrated alcohol, stir reflux.At 80 ℃~100 ℃ temperature, drip 44g (0.21mol) N-chloracetyl-1, the solution that 2,3,4-tetrahydroquinoline and 50mL dehydrated alcohol are made into, after dropwising, back flow reaction 4~6 hours, reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After reacting completely, steam about toluene 150mL, reaction solution, then suction filtration while hot, removes solid salts substances, and filtrate is placed, and naturally is down to room temperature, and process has a large amount of crystal to separate out, and room temperature continues placement about 2 hours, makes crystallization complete.Then, suction filtration is also used 20ml toluene wash 1~2 time, dries, and obtains white crystal 28.6g, for N, N '-bis-(1,2,3,4-tetrahydric quinoline group-N-formyl methyl) piperazine (Aspernigerin), yield 66.1%, it is 97.6% that HPLC analyzes normalizing content.
Embodiment 5
(1) in 500ml there-necked flask, add 26.6g (0.2mol) 1,2,3,4-tetrahydroquinoline and 300mL methylene dichloride, regulate temperature to 15 ℃~20 ℃.Slowly drip the solution that 25g (0.22mol) chloroacetyl chloride and 100mL chloroform are made into, dropwise, stirring reaction 10 minutes, then slowly drip 25.5g (0.21mol) N, N-dimethylbenzene aniline, after dropwising, be incubated in-5 ℃~5 ℃ reactions 5~8 hours, reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After reacting completely, add the aqueous hydrochloric acid of 50mL5%, stir 30 minutes, stratification, separates organic layer, then washs one time with the aqueous hydrochloric acid of 100mL5%, separate organic layer, with anhydrous sodium sulfate drying, filter, solvent is deviate from the first air distillation of filtrate, then, and oil pump underpressure distillation, the cut 37.3g that collects 162 ℃~164 ℃/130Pa, is N-chloracetyl-1,2,3,4-tetrahydroquinoline, yield 90.3%.
(2) in 500ml there-necked flask, add 8.6g (0.1mol) piperazine, 42g (0.3mol) Anhydrous potassium carbonate and 100mL dehydrated alcohol, stir reflux.At 80 ℃~100 ℃ temperature, drip 44g (0.21mol) N-chloracetyl-1, the solution that 2,3,4-tetrahydroquinoline and 50mL dehydrated alcohol are made into, after dropwising, back flow reaction 4~6 hours, reaction end is determined in the monitoring of thin layer silica gel chromatosheet.After reacting completely, steam about toluene 150mL, reaction solution, then suction filtration while hot, removes solid salts substances, and filtrate is placed, and naturally is down to room temperature, and process has a large amount of crystal to separate out, and room temperature continues placement about 2 hours, makes crystallization complete.Then, suction filtration is also used 20ml toluene wash 1~2 time, dries, and obtains white crystal 26.6g, for N, N '-bis-(1,2,3,4-tetrahydric quinoline group-N-formyl methyl) piperazine (Aspernigerin), yield 60.1%, it is 90.6% that HPLC analyzes normalizing content.
Claims (1)
1.N, the synthetic method of N '-bis-(1,2,3,4-tetrahydric quinoline group-N-formyl methyl) piperazine, is characterized in that, carries out in accordance with the following steps:
(1) by 1,2,3,4-tetrahydroquinoline is dissolved in organic solvent I, at-10~40 ℃ of temperature, drips chloroacetyl chloride, then add acid binding agent I, insulation is to reacting completely, and aqueous hydrochloric acid washing is 2~3 times for reaction solution, separate organic layer, dry precipitation, then, underpressure distillation obtains N-chloracetyl-1,2,3,4-tetrahydroquinoline;
(2) piperazine is dissolved in organic solvent II, adds acid binding agent II, at 50~150 ℃ of temperature, drip containing N-chloracetyl-1, the solution of the organic solvent II of 2,3,4-tetrahydroquinoline, insulation is to reacting completely, cooling, filters, and desolventizing obtains product crude product, adds organic solvent III, heating for dissolving, filtered while hot, filtrate decrease temperature crystalline, obtaining white crystal, is end product N, and N '-bis-(1,2,3,4-tetrahydric quinoline group-N-formyl methyl) piperazine;
Described organic solvent I is methylene dichloride, 1,2-ethylene dichloride, chloroform, tetracol phenixin, chlorobenzene, ether, tetrahydrofuran (THF), toluene, benzene, dimethylbenzene or dioxane;
Described acid binding agent I is triethylamine, Trimethylamine 99, pyridine, DMA or N, N-Diethyl Aniline;
Described organic solvent II is DMF or toluene;
Described acid binding agent II is triethylamine, Trimethylamine 99, pyridine, DMA, N, N-Diethyl Aniline, salt of wormwood, sodium carbonate, saleratus or sodium bicarbonate;
Described organic solvent III is toluene;
Step (1) is used 1,2,3, and the mol ratio of 4-tetrahydroquinoline, chloroacetyl chloride and acid binding agent I is: 1:(1~2): (1~2);
Step (2) N-used chloracetyl-1, the mol ratio of 2,3,4-tetrahydroquinoline, piperazine and acid binding agent II is: (2~3): 1:(2~6).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110173852.7A CN102285915B (en) | 2011-06-24 | 2011-06-24 | Synthesis method for alkaloid secondary metabolite aspernigerin having anticancer activity |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110173852.7A CN102285915B (en) | 2011-06-24 | 2011-06-24 | Synthesis method for alkaloid secondary metabolite aspernigerin having anticancer activity |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102285915A CN102285915A (en) | 2011-12-21 |
CN102285915B true CN102285915B (en) | 2014-04-02 |
Family
ID=45332694
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201110173852.7A Expired - Fee Related CN102285915B (en) | 2011-06-24 | 2011-06-24 | Synthesis method for alkaloid secondary metabolite aspernigerin having anticancer activity |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102285915B (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8916550B2 (en) * | 2005-05-09 | 2014-12-23 | Hydra Biosciences, Inc. | Compounds for modulating TRPV3 function |
-
2011
- 2011-06-24 CN CN201110173852.7A patent/CN102285915B/en not_active Expired - Fee Related
Non-Patent Citations (4)
Title |
---|
Li Shen et al.Structure and Total Synthesis of Aspernigerin: A Novel Cytotoxic Endophyte Metabolite.《Chem.Eur.J.》.2006,第12卷4393-4396. |
Structure and Total Synthesis of Aspernigerin: A Novel Cytotoxic Endophyte Metabolite;Li Shen et al;《Chem.Eur.J.》;20061231;第12卷;4393-4396 * |
四氢异喹啉衍生物的合成及其抑制血小板聚集作用;王志远等;《中国医药工业杂志》;20051231;第36卷(第5期);261-263 * |
王志远等.四氢异喹啉衍生物的合成及其抑制血小板聚集作用.《中国医药工业杂志》.2005,第36卷(第5期),261-263. |
Also Published As
Publication number | Publication date |
---|---|
CN102285915A (en) | 2011-12-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102020633B (en) | Method for preparing 1-(3,5- dichloropyridine-2-yl)-pyrazolecarboxamide compounds | |
CN103044479B (en) | The synthetic method of bactericide of silthiopham | |
CN103435575A (en) | Preparation method of 1-(3-(3-(4-chlorphenyl) propoxy) propyl) piperidine hydrochloride | |
CN102351778A (en) | Preparation method of arbidol hydrochloride | |
CN104447620B (en) | 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group] preparation method of-piperidine hydrochlorate | |
US9278939B2 (en) | Methods for preparation of (4,6-dihalo-pyrimidin-5-yl)-acetaldehydes | |
CN104860872A (en) | Bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate synthesis method | |
CN101704796B (en) | Preparation method of 3-morpholone | |
CN101475539A (en) | Refining method for preparing high-purity oteracil potassium | |
CN103980120A (en) | Synthesis method of D,L-danshensu isopropyl ester | |
CN102285915B (en) | Synthesis method for alkaloid secondary metabolite aspernigerin having anticancer activity | |
CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
CN102030707A (en) | Method for preparing Blonanserin intermediate | |
CN105461617A (en) | Preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine | |
CN109988108A (en) | A kind of rich preparation method for Buddhist nun of card | |
CN105061253A (en) | Preparation method of bromine-containing azide | |
CN101863836B (en) | Method for preparing 5,5-diphenyl-2-thiohydantoin | |
JPWO2015012271A1 (en) | Method for producing heterocyclic compound | |
CN104447567B (en) | A kind of preparation method of 1 substituted benzimidazole derivant | |
CN104592109A (en) | Method for preparing 8-bromoquinoline derivative | |
CN105418507A (en) | Preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine | |
CN109400507A (en) | The synthesis of Ailamode intermediate impurities | |
CN103755657A (en) | Preparation method of rivaroxaban intermediate | |
CN103539781B (en) | A kind of synthetic method of WNT signal pathway inhibitor | |
CN108752339B (en) | A kind of synthetic method of quindoline and its derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140402 Termination date: 20150624 |
|
EXPY | Termination of patent right or utility model |