CN102285968A - Method for preparing 3-[4-(2,6-dichlorophenyl)-piperidine-1-methylene]-2,5-disubstituted indole - Google Patents
Method for preparing 3-[4-(2,6-dichlorophenyl)-piperidine-1-methylene]-2,5-disubstituted indole Download PDFInfo
- Publication number
- CN102285968A CN102285968A CN2011101886656A CN201110188665A CN102285968A CN 102285968 A CN102285968 A CN 102285968A CN 2011101886656 A CN2011101886656 A CN 2011101886656A CN 201110188665 A CN201110188665 A CN 201110188665A CN 102285968 A CN102285968 A CN 102285968A
- Authority
- CN
- China
- Prior art keywords
- dichlorophenyl
- piperidines
- reaction
- preparation
- solvent
- 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
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The invention belongs to the field of organic chemistry and particularly relates to a method for preparing 3-[4-(2,6-dichlorophenyl)-piperidine-1-methylene]-2,5-disubstituted indole serving as an ORL-1(opioid receptor-like 1) receptor modulator. The 3-[4-(2,6-dichlorophenyl)-piperidine-1-methylene]-2,5-disubstituted indole is obtained by performing a reaction of 2,5-disubstituted indole and 4-(2,6-dichlorophenyl) piperidine under the condition of existence of formaldehyde, a catalyst and a solvent. The solvent is alcohol or tetrahydrofuran. The catalyst is ZnCl2, AlCl3 or SnCl2. The catalyst used in the process of preparing the compound has high catalytic efficiency, is cheap, is easy to obtain and is easy to separate and recycle. Moreover, the low boiling point solvent, i.e. micromolecule alcohol or tetrahydrofuran, which is used in the method, is also easy to separate from the product to be recycled by a distillation mode, and the method is convenient and rapid to use.
Description
Technical field
The invention belongs to organic chemistry filed, be specifically related to a kind of 3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical as the ORL-1 receptor modulators]-2, the preparation method of 5-disubstituted indole.
Background technology
ORL-1 acceptor (lonely opioid receptor) had both claimed to be called the nociceptin acceptor again by the G-protein linked receptor, and reported first was in 1994, and it is distributed widely in the body system, comprises brain and spinal cord etc., has vital role in the transmission of human body pain.Orphanin FQ FQ(nociceptin) inhibited with combining of ORL-1 acceptor to the specific conductivity of synthetic, the voltage-controlled calcium channel of cAMP and potassium.Because orphanin FQ FQ(nociceptin) acquisition is very difficult, in order to prevent, to alleviate and treat by receptor-mediated disease of ORL-1 and indication, as anxiety, dysthymia disorders, neuropathic pain, acute and chronic pain, psychosis, paranoea etc., having nociceptin with orphanin FQ FQ() the small molecules ORL-1 receptor modulators of similar action comes into one's own and develops.
3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2, the 5-disubstituted indole is the micromolecular compound with ORL-1 receptor modulating activities, is disclosed among the U.S. Pat 20070197603A1, its structural formula is:
3-[4-(2, the 6-dichlorophenyl)-and piperidines-1-methylene radical]-2, raw material when the 5-disubstituted indole prepares is 2,5-disubstituted indole and 4-(2, the 6-dichlorophenyl) piperidines, reactions steps is long, process is complicated, the characteristics of reaction preference difference but present intermediate 4-(2, the 6-dichlorophenyl) piperidines exists in the preparation; 2, though the 5-disubstituted indole has more bibliographical information in the preparation, but raw materials used being difficult to obtains from market, also have with polyphosphoric acid catalysis synthetic and report, but document is condensing agent and solvent with the polyphosphoric acid, and raw material must add in batches gradually, on the one hand the reaction conditions fierceness, product can further act on polyphosphoric acid, produces the isomers similar to product inevitably; On the other hand, need after the reaction to remove polyphosphoric acid, can produce a large amount of phosphorus-containing wastewaters with a large amount of water hydrolysis, defective is obvious.
Summary of the invention
The purpose of this invention is to provide a kind of 3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole.
The present invention is by the following technical solutions:
3-[4-(2, the 6-dichlorophenyl)-and piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole, it is characterized in that, by 2,5-disubstituted indole and 4-(2, the 6-dichlorophenyl) piperidines reacts in the presence of formaldehyde, catalyzer and solvent and obtains, described solvent is alcohol or tetrahydrofuran (THF), and described catalyzer is ZnCl
2, AlCl
3Or SnCl
2, reaction formula is:
Described 2, the mol ratio of 5-disubstituted indole and 4-(2, the 6-dichlorophenyl) piperidines is 1:0.2-5, and the consumption of described formaldehyde is 2, and the 1-5 of 5-disubstituted indole molar weight doubly; Described temperature of reaction is 0-100 ℃, and the reaction times is 2-30 hour.
Catalyst consumption is 2, and the 0.1-5 of 5-disubstituted indole molar weight doubly.
The consumption of solvent is 2, and the 5-10 of 5-disubstituted indole quality doubly.
Described alcohol is methyl alcohol or ethanol.
Preparation 3-[4-(2, the 6-dichlorophenyl)-and piperidines-1-methylene radical]-2, the post-treating method of system was after reaction finished during the 5-disubstituted indole: reaction finishes after-filtration, the catalyzer filter cake reclaims, filtrate concentrating reclaimed solvent, resistates washing, dichloromethane extraction concentrate the silicagel column purifying after the organic phase drying.
Described 2, the preparation process of 5-disubstituted indole is: by mol ratio be 1:0.2-5 the 4-substituted phenylhydrazines with replace ethyl ketone and in organic solvent, under the catalysis of acid, react and obtain, temperature of reaction is 50-150 ℃, the reaction times is 2-30 hour, reaction formula is:
In described organic solvent nail benzene, chlorobenzene or the dimethylbenzene one or more mix, and the consumption of organic solvent is 5-10 a times of 4-substituted phenylhydrazines quality; Described acid is polyphosphoric acid, and the consumption of acid is 1-20 a times of 4-substituted phenylhydrazines quality.
Preparation 2, the post-treating method of system was after reaction finished during the 5-disubstituted indole: reaction is cooled to 80-90 ℃ after finishing, and leaves standstill, and polyphosphoric acid PPA is recyclable in lower floor; Upper strata solvent layer washing, drying, negative pressure remove solvent, concentrated recrystallization obtains 2, the 5-disubstituted indole
Described 4-(2, the 6-dichlorophenyl) piperidines
3Preparation process be: at first by 2, hydrochloride, vitriol or the acetate of 6-dichlorobenzene boric acid and tetrabromo pyridine or tetrabromo pyridine generates 4-(2 by linked reaction in solvent in the presence of transition-metal catalyst and alkali, the 6-dichlorophenyl) pyridine, 4-(2, the 6-dichlorophenyl) pyridine is in the presence of catalyzer, in the solvent, obtain 4-(2 by catalytic hydrogenation again under the hydrogen atmosphere, the 6-dichlorophenyl) piperidines, reaction formula is:
During described linked reaction, 2, the mol ratio of hydrochloride, vitriol or the acetate of 6-dichlorobenzene boric acid and tetrabromo pyridine or tetrabromo pyridine is 1:0.5-5, and the temperature of linked reaction is 50-180 ℃, and the time is 3-30 hour; Described transition-metal catalyst is PdCl
2, Pd[P (Ph
3)]
4, Pd (OAc)
2In one or more, catalyst consumption is 2, the 0.01-0.2 of 6-dichlorobenzene boric acid molar weight doubly; Described alkali is Na
2CO
3, K
2CO
3, Cs
2CO
3Or NEt
3, the consumption of alkali is 2, the 0.5-3 of 6-dichlorobenzene boric acid molar weight is doubly; Described solvent refers to one or more among water, toluene, DMF or the NMP, and the consumption of solvent is 2, and the 5-10 of 6-dichlorobenzene boric acid quality doubly.
During described catalytic hydrogenation, the pressure of hydrogen is 3-50psi, and solvent is an acetic acid, and catalyzer is PtO
2, temperature of reaction is 0-150 ℃, the reaction times is 5-30 hour; The consumption of solvent be 4-(2, the 6-dichlorophenyl) pyridine quality 5-10 doubly, catalyst consumption be 4-(2, the 6-dichlorophenyl) pyridine molar weight 0.01-0.5 doubly.
The post-treating method of system was after reaction finished during preparation 4-(2, the 6-dichlorophenyl) pyridine: reaction finishes back cooling filtration, and filtrate washing, dichloromethane extraction concentrate the silicagel column purifying after the organic phase drying.
The post-treating method of system was after reaction finished during preparation 4-(2, the 6-dichlorophenyl) piperidines: reaction finishes after-filtration, and the platinum oxide filter cake reclaims, and filtrate concentrates, the silicagel column purifying.
The present invention is at preparation 3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2, during the 5-disubstituted indole, with ZnCl
2, AlCl
3Or SnCl
2Be catalyzer, wherein preferred ZnCl
2Be solvent with alcohols or tetrahydrofuran (THF) simultaneously, by 2,5-disubstituted indole and 4-(2, the 6-dichlorophenyl) piperidines obtains the purpose product easily by Mannich reaction in the presence of formaldehyde, catalyst system therefor catalytic efficiency height, cheap and easy to get and separate easily recovery when The compounds of this invention prepares, used low boiling point solvent small molecule alcohol or the tetrahydrofuran (THF) of the present invention also is easy to reclaim by distillatory mode and product separation in addition, and be convenient and swift.
The present invention is at preparation intermediate 2, during the 5-disubstituted indole, selecting suitable organic solvent (one or more in toluene, chlorobenzene or the dimethylbenzene mix) and suitable excessive polyphosphoric acid for use is catalyst system, and reaction raw materials once drops into, after reactant generates product, be dissolved in organic solvent at once, and surplus stock continues to transform, and has avoided product to be subjected to the further conversion of the influence of polyphosphoric acid to by product, therefore prepares 2, the specificity of 5-disubstituted indole is good, the product yield height; Simultaneously, because polyphosphoric acid is insoluble to selected organic solvent, product separation can separate by standing demix, and polyphosphoric acid can recycle, and has avoided the waste of polyphosphoric acid and the generation of synthetic wastewater.
The present invention is when preparation intermediate 4-(2, the 6-dichlorophenyl) piperidines, and selected raw material is simple and easy to, and two-step reaction obtains, and particularly in catalytic hydrogenation step, is solvent and PtO with acetic acid
2Be the catalyst system of catalyzer, have catalytic hydrogenation specificity preferably, avoided production of by-products, reduced separating difficulty, improved product purity.
The present invention has designed new preparation method, adopts new catalyst system, and with 2,5-disubstituted indole and 4-(2, the 6-dichlorophenyl) piperidines is a raw material, with ZnCl
2, AlCl
3Or SnCl
2Be catalyzer, wherein preferred ZnCl
2, in the presence of formaldehyde and simple reaction solvent, obtain purpose product 3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical easily by Mannich reaction by substituted indole and 4-(2, the 6-dichlorophenyl) piperidines] and-2, the 5-disubstituted indole; Related intermediate 2,5-disubstituted indole and 4-(2, the 6-dichlorophenyl) piperidines also can be synthesized into from simple, the raw material that is easy to get respectively; Preparation method of the present invention has that raw material is cheap and easy to get, reaction yield is high, convenient post-treatment, catalyzer and solvent are easy to characteristics such as recycling, product purity height, is fit to scale production.
Embodiment
Embodiment 1
1,
The preparation of 2-(2-thienyl)-indoles
(10.8g, 0.1mol) (63.0g 0.5mol) puts in three mouthfuls of reaction flasks that fill the 150mL chlorobenzene, adds polyphosphoric acid (PPA) 11g again, is heated to 150 with the 2-acetyl thiophene with phenylhydrazine
oC reaction 2 hours cools to 80 ℃, leaves standstill.Pour out the upper strata chlorobenzene layer, the PPA of lower floor is recyclable.Chlorobenzene layer washing, NaHCO
3The aqueous solution is neutralized to neutrality, drying, and negative pressure removes the solvent chlorobenzene, and recrystallization gets product 2-(2-thienyl)-indoles 15.9g, yield 80%.The nuclear magnetic resonance data of 2-(2-thienyl)-indoles is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.12(s,?1H);?7.53(d,?1H);?7.3(d,?1H);?7.18(m,?2H);?7.12(dd,?1H);?7.06(m,?2H);?6.65(s,?1H)。
Dichlorophenyl)-preparation of pyridine
2, and 6-dichlorobenzene boric acid (1.9g, 0.01mol), the 4-bromopyridine hydrochloride (9.7g, 0.05mol), four triphenyl phosphorus palladium Pd (PPh
3)
4(116mg, 0.1mmol) and yellow soda ash (2.7g 0.025mol) adds 30 mL toluene and water (V is arranged
Toluene: V
WaterIn=3:1) the reaction flask, under protection of nitrogen gas, be heated to 180 ℃ of reactions 3 hours.Reaction mixture cooling after-filtration, filtrate water is washed, dichloromethane extraction, concentrates after the organic phase drying, and the silicagel column purifying gets 4-(2, the 6-dichlorophenyl) pyridine 1.5g, yield 67%.The nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl) pyridine is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.66(d,?2H);?7.35(d,?2H);?7.21(dd,?1H);?7.14(d,?2H)。
Dichlorophenyl)-preparation of piperidines
(9.0g is 0.04mol) with platinum oxide PtO with 4-(2, the 6-dichlorophenyl)-pyridine
2(0.09g 0.4mmol) throws in the reaction flask that fills 200mL acetic acid, reaction system reaction 30 hours under 15 ℃, hydrogen pressure at 50psi.Reaction mixture filters, platinum oxide PtO
2Filter cake is recyclable.Filtrate concentrates, and the residuum after concentrating gets product 4-(2, the 6-dichlorophenyl)-piperidines 8.1g, yield 88% through the silicagel column purifying.The nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl)-piperidines is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?7.32(br.,?2H);?7.11(dd,?1H);?3.82(m,?1H);?3.63(d,?2H);?3.1(m,?2H);?2.93(m,?2H);?2.73(s,?1H);?1.84(d,?2H)。
Dichlorophenyl)-piperidines-1-methylene radical]-preparation of 2-(2-thiophene)-1-hydrogen-indoles
4-(2, the 6-dichlorophenyl)-piperidines (17.3g, 0.075mol), aluminum chloride (1.0g, 7.5mmol), formaldehyde (11.3g, 0.375mol) and 2-(2-thienyl)-indoles (75.0g 0.375mol) puts into and fills in the 100mL alcoholic acid reaction flask, and reaction mixture is 100
oC stirring reaction 2 hours.Reaction mixture filters then, and the aluminum chloride filter cake reclaims and uses; Filtrate concentrating reclaimed ethanol, and resistates washes with water, dichloromethane extraction.Concentrate after the organic phase drying, the silicagel column purifying obtains product 3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2-(2-thiophene)-1-hydrogen-indoles 26.5g, yield 80%.3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-nuclear magnetic resonance data of 2-(2-thiophene)-1-hydrogen-indoles is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.79(s,1H);?7.67(d,?1H);?7.47(m,?2H);?7.39-7.17(m,?6H);?7.05(dd,?1H);?4.71(s,?2H);?3.54(d,?2H);?3.45(m,?1H);?3.03(m,?2H);?2.63(m,?2H);?1.61(d,?2H)。
Embodiment 2
1,
The preparation of 2-(2-thienyl)-indoles
(54.0g, 0.5mol) (12.6g 0.1mol) puts in three mouthfuls of reaction flasks that fill the 150mL chlorobenzene, adds polyphosphoric acid (PPA) 250g again, is heated to 60 with the 2-acetyl thiophene with phenylhydrazine
oC reaction 30 hours is left standstill.Pour out the upper strata chlorobenzene layer, the PPA of lower floor is recyclable.Chlorobenzene layer washing, NaHCO
3The aqueous solution is neutralized to neutrality, drying, and negative pressure removes solvent chlorobenzene and excess raw material, and recrystallization gets product 2-(2-thienyl)-indoles 11g, yield 55%.The nuclear magnetic resonance data of 2-(2-thienyl)-indoles is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.12(s,?1H);?7.53(d,?1H);?7.3(d,?1H);?7.18(m,?2H);?7.12(dd,?1H);?7.06(m,?2H);?6.65(s,?1H)。
Dichlorophenyl)-preparation of pyridine
2, and 6-dichlorobenzene boric acid (9.6g, 0.05mol), the 4-bromopyridine hydrochloride (1.9g, 0.01mol), four triphenyl phosphorus palladium Pd (PPh
3)
4(2.3g, 2mmol) and salt of wormwood (2.8g 0.02mol) adds 30 mL toluene and water (V is arranged
Toluene: V
WaterIn=3:1) the reaction flask, under protection of nitrogen gas, be heated to 50 ℃ of reactions 30 hours.Reaction mixture cooling after-filtration, filtrate water is washed, dichloromethane extraction, concentrates after the organic phase drying, and the silicagel column purifying gets 4-(2, the 6-dichlorophenyl) pyridine 0.8g, yield 36%.The nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl) pyridine is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.66(d,?2H);?7.35(d,?2H);?7.21(dd,?1H);?7.14(d,?2H)。
Dichlorophenyl)-preparation of piperidines
(9.0g is 0.04mol) with platinum oxide PtO with 4-(2, the 6-dichlorophenyl)-pyridine
2(4.5g 20mmol) throws in the reaction flask that fills 200mL acetic acid, reaction system reaction 5 hours under 150 ℃, hydrogen pressure at 30psi.Reaction mixture filters, platinum oxide PtO
2Filter cake is recyclable.Filtrate concentrates, and the residuum after concentrating gets product 4-(2, the 6-dichlorophenyl)-piperidines 6.5g, yield 71% through the silicagel column purifying.The nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl)-piperidines is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?7.32(br.,?2H);?7.11(dd,?1H);?3.82(m,?1H);?3.63(d,?2H);?3.1(m,?2H);?2.93(m,?2H);?2.73(s,?1H);?1.84(d,?2H)。
Dichlorophenyl)-piperidines-1-methylene radical]-preparation of 2-(2-thiophene)-1-hydrogen-indoles
4-(2, the 6-dichlorophenyl)-piperidines (86g, 0.375mol), tindichloride (71g, 0.375mol), formaldehyde (11.3g, 0.375mol) and 2-(2-thiophene)-indoles (15.0g 0.075mol) puts into and fills in the 100mL alcoholic acid reaction flask, and reaction mixture is 5
oC stirring reaction 30 hours.Reaction mixture filters then, and the tindichloride filter cake reclaims and uses; Filtrate concentrating reclaimed ethanol, and resistates washes with water, dichloromethane extraction.Concentrate after the organic phase drying, the silicagel column purifying obtains product 3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2-(2-thiophene)-1-hydrogen-indoles 21.3g, yield 64%.3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-nuclear magnetic resonance data of 2-(2-thiophene)-1-hydrogen-indoles is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.79(s,1H);?7.67(d,?1H);?7.47(m,?2H);?7.39-7.17(m,?6H);?7.05(dd,?1H);?4.71(s,?2H);?3.54(d,?2H);?3.45(m,?1H);?3.03(m,?2H);?2.63(m,?2H);?1.61(d,?2H)。
Embodiment 3
1,
The preparation of 2-(2-thienyl)-indoles
(10.8g, 0.1mol) (12.6g 0.1mol) puts in three mouthfuls of reaction flasks that fill the 150mL chlorobenzene, adds polyphosphoric acid (PPA) 20g again, is heated to 135 with the 2-acetyl thiophene with phenylhydrazine
oC refluxed 10 hours, cooled to 90 ℃, left standstill.Pour out the upper strata chlorobenzene layer, the PPA of lower floor is recyclable.Chlorobenzene layer washing, NaHCO
3The aqueous solution is neutralized to neutrality, drying, and negative pressure removes the solvent chlorobenzene, and recrystallization gets product 2-(2-thienyl)-indoles 17g, yield 85%, and the nuclear magnetic resonance data of 2-(2-thienyl)-indoles is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.12(s,?1H);?7.53(d,?1H);?7.3(d,?1H);?7.18(m,?2H);?7.12(dd,?1H);?7.06(m,?2H);?6.65(s,?1H)。
Dichlorophenyl)-preparation of pyridine
2, and 6-dichlorobenzene boric acid (1.9g, 0.01mol), the 4-bromopyridine hydrochloride (1.8g, 0.009mol), four triphenyl phosphorus palladium Pd (PPh
3)
4(1.2g, 1mmol) and cesium carbonate (3.3g 0.01mol) adds 30 mL toluene and water (V is arranged
Toluene: V
WaterIn=3:1) the reaction flask, under protection of nitrogen gas, be heated to 100 ℃ of reactions 9 hours.Reaction mixture cooling after-filtration, filtrate water is washed, dichloromethane extraction, concentrates after the organic phase drying, and the silicagel column purifying gets 4-(2, the 6-dichlorophenyl) pyridine 1.8g, yield 89%, the nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl) pyridine is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.66(d,?2H);?7.35(d,?2H);?7.21(dd,?1H);?7.14(d,?2H)。
Dichlorophenyl)-preparation of piperidines
(9.0g is 0.04mol) with platinum oxide PtO with 4-(2, the 6-dichlorophenyl)-pyridine
2(1.80g 8mmol) throws in the reaction flask that fills 200mL acetic acid, reaction system reaction 8 hours under 50 ℃, hydrogen pressure at 50psi.Reaction mixture filters, platinum oxide PtO
2Filter cake is recyclable.Filtrate concentrates, and the residuum after concentrating gets product 4-(2, the 6-dichlorophenyl)-piperidines 6.9g through the silicagel column purifying, yield 75%, and the nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl)-piperidines is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?7.32(br.,?2H);?7.11(dd,?1H);?3.82(m,?1H);?3.63(d,?2H);?3.1(m,?2H);?2.93(m,?2H);?2.73(s,?1H);?1.84(d,?2H)。
Dichlorophenyl)-piperidines-1-methylene radical]-preparation of 2-(2-thiophene)-1-hydrogen-indoles
4-(2, the 6-dichlorophenyl)-piperidines (17.3g, 0.075mol), zinc chloride (15.0g, 0.11mol), formaldehyde (2.3g, 0.075mol) and 2-(2-thiophene)-indoles (15.0g, 0.075mol) put in the reaction flask that fills 100mL methyl alcohol, reaction mixture is stirring reaction 6 hours at room temperature.Reaction mixture filters then, and the zinc chloride filter cake reclaims and uses; Filtrate concentrating reclaimed methyl alcohol, and resistates washes with water, dichloromethane extraction.Concentrate after the organic phase drying, the silicagel column purifying obtains product 3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2-(2-thiophene)-1-hydrogen-indoles 28.0g, yield 85%.3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-nuclear magnetic resonance data of 2-(2-thiophene)-1-hydrogen-indoles is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.79(s,1H);?7.67(d,?1H);?7.47(m,?2H);?7.39-7.17(m,?6H);?7.05(dd,?1H);?4.71(s,?2H);?3.54(d,?2H);?3.45(m,?1H);?3.03(m,?2H);?2.63(m,?2H);?1.61(d,?2H)。
Embodiment 4
1, the preparation of 5-bromo-2-ethyl formate indoles
(9.4g, 0.05mol) (5.8g 0.05mol) puts in three mouthfuls of reaction flasks that fill the 150mL chlorobenzene, adds polyphosphoric acid (PPA) 20g again, is heated to 135 with 2-carbonyl propionic acid ethyl ester with the 4-bromophenyl-hydrazine
oAfter the C back flow reaction 6 hours, cool to 85 ℃, leave standstill.Pour out the upper strata chlorobenzene layer, (PPA) is recyclable for lower floor's polyphosphoric acid.Chlorobenzene layer washing, NaHCO
3The aqueous solution is neutralized to neutrality, drying, vacuum removal solvent chlorobenzene.Recrystallization gets product 5-bromo-2-ethyl formate indoles 12g, yield 90%.The nuclear magnetic resonance data of 5-bromo-2-ethyl formate indoles is as follows:
1H?NMR?(400MHz,?CDCl3)?δ:?9.1(br.s,?1H);?7.8(s,?1H);?7.7(m,?1H);?7.2(m,?1H);?7.1(s,?1H);?4.4(q,?2H);?1.4(t,?3H)。
Dichlorophenyl)-preparation of pyridine
2, and 6-dichlorobenzene boric acid (1.9g, 0.01mol), the 4-bromopyridine hydrochloride (9.7g, 0.05mol), four triphenyl phosphorus palladium Pd (PPh
3)
4(116mg, 0.1mmol) and triethylamine (2.5g 0.025mol) adds 30 mL toluene and water (V is arranged
Toluene: V
WaterIn=3:1) the reaction flask, under protection of nitrogen gas, be heated to 60 ℃ of reactions 25 hours.Reaction mixture cooling after-filtration, filtrate water is washed, dichloromethane extraction, concentrates after the organic phase drying, and the silicagel column purifying gets 4-(2, the 6-dichlorophenyl) pyridine 1.5g, yield 67%.The nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl) pyridine is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.66(d,?2H);?7.35(d,?2H);?7.21(dd,?1H);?7.14(d,?2H)。
Dichlorophenyl)-preparation of piperidines
(9.0g is 0.04mol) with platinum oxide PtO with 4-(2, the 6-dichlorophenyl)-pyridine
2(0.09g 0.4mmol) throws in the reaction flask that fills 200mL acetic acid, reaction system reaction 30 hours under 20 ℃, hydrogen pressure at 50psi.Reaction mixture filters, platinum oxide PtO
2Filter cake is recyclable.Filtrate concentrates, and the residuum after concentrating gets product 4-(2, the 6-dichlorophenyl)-piperidines 7.9g, yield 86% through the silicagel column purifying.The nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl)-piperidines is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?7.32(br.,?2H);?7.11(dd,?1H);?3.82(m,?1H);?3.63(d,?2H);?3.1(m,?2H);?2.93(m,?2H);?2.73(s,?1H);?1.84(d,?2H)。
Bromo-3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-preparation of 2-ethyl formate-1-hydrogen-indoles
4-(2, the 6-dichlorophenyl)-piperidines (17.3g, 0.075mol), zinc chloride (15.0g, 0.11mol), formaldehyde (2.3g, 0.075mol) and 5-bromo-2-ethyl formate indoles (20.1g, 0.075mol) put in the reaction flask that fills the 100mL tetrahydrofuran (THF), reaction mixture is stirring reaction 6 hours at room temperature.Reaction mixture filters then, and the zinc chloride filter cake reclaims and uses; Filtrate concentrating reclaimed tetrahydrofuran (THF), and resistates washes with water, dichloromethane extraction.Concentrate after the organic phase drying, the silicagel column purifying obtains product 5-bromo-3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2-ethyl formate-1-hydrogen-indoles 31g, yield 81%.5-bromo-3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2-ethyl formate-1-hydrogen-indole nucleus MR data is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.9(s,1H);?7.80(d,?1H);?7.51(s,?1H);?7.28-7.0(m,4H);?4.21(s,?2H);?4.3(q,2H)；3.52(d,?2H);?3.43(m,?1H);?3.01(m,?2H);?2.62(m,?2H);?1.63(d,?2H)；1.3(t，3H)。
Embodiment 5
The preparation of 5-chloro-2-ethyl formate indoles
(7.1g, 0.05mol) (5.8g 0.05mol) puts in three mouthfuls of reaction flasks that fill the 150mL chlorobenzene, adds polyphosphoric acid (PPA) 20g again, is heated to 110 with 2-carbonyl propionic acid ethyl ester with the 4-chlorophenyl hydrazine
oAfter the C back flow reaction 15 hours, cool to 80 ℃, leave standstill.Pour out the upper strata chlorobenzene layer, (PPA) is recyclable for lower floor's polyphosphoric acid.Chlorobenzene layer washing, NaHCO
3The aqueous solution is neutralized to neutrality, drying, vacuum removal solvent chlorobenzene.Recrystallization gets product 5-chloro-2-ethyl formate indoles 10g, yield 89%.The nuclear magnetic resonance data of 5-chloro-2-ethyl formate indoles is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?9.0(br.s,?1H);?7.7(s,?1H);?7.6(m,?1H);?7.2(m,?1H);?7.1(s,?1H);?4.3(q,?2H);?1.3(t,?3H)。
Dichlorophenyl)-preparation of pyridine
2, and 6-dichlorobenzene boric acid (1.9g, 0.01mol), the 4-bromopyridine hydrochloride (9.7g, 0.05mol), four triphenyl phosphorus palladium Pd (PPh
3)
4(116mg, 0.1mmol) and yellow soda ash (2.7g 0.025mol) adds 30 mL toluene and water (V is arranged
Toluene: V
WaterIn=3:1) the reaction flask, under protection of nitrogen gas, be heated to 170 ℃ of reactions 4 hours.Reaction mixture cooling after-filtration, filtrate water is washed, dichloromethane extraction, concentrates after the organic phase drying, and the silicagel column purifying gets 4-(2, the 6-dichlorophenyl) pyridine 1.5g, yield 67%.The nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl) pyridine is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.66(d,?2H);?7.35(d,?2H);?7.21(dd,?1H);?7.14(d,?2H)。
Dichlorophenyl)-preparation of piperidines
(9.0g is 0.04mol) with platinum oxide PtO with 4-(2, the 6-dichlorophenyl)-pyridine
2(0.09g 0.4mmol) throws in the reaction flask that fills 200mL acetic acid, reaction system reaction 6 hours under 140 ℃, hydrogen pressure at 50psi.Reaction mixture filters, platinum oxide PtO
2Filter cake is recyclable.Filtrate concentrates, and the residuum after concentrating gets product 4-(2, the 6-dichlorophenyl)-piperidines 7.5g, yield 82% through the silicagel column purifying.The nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl)-piperidines is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?7.32(br.,?2H);?7.11(dd,?1H);?3.82(m,?1H);?3.63(d,?2H);?3.1(m,?2H);?2.93(m,?2H);?2.73(s,?1H);?1.84(d,?2H)。
The 5-chloro-
3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2-Ethyl formate
The preparation of-1-hydrogen-indoles
4-(2, the 6-dichlorophenyl)-piperidines (17.3g, 0.075mol), zinc chloride (15.0g, 0.11mol), formaldehyde (2.3g, 0.075mol) and 5-chloro-2-ethyl formate indoles (17.0g, 0.075mol) put into and fill in the 100mL alcoholic acid reaction flask, reaction mixture is stirring reaction 6 hours at room temperature.Reaction mixture filters then, and the zinc chloride filter cake reclaims and uses; Filtrate concentrating reclaimed ethanol, and resistates washes with water, dichloromethane extraction.Concentrate after the organic phase drying, the silicagel column purifying obtains product 5-chloro-3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2-ethyl formate-1-hydrogen-indoles 28g, yield 80%.5-chloro-3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2-ethyl formate-1-hydrogen-indole nucleus MR data is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?9.0(s,1H);?7.70(d,?1H);?7.41(s,?1H);?7.2-6.9(m,4H);?4.20(s,?2H);?4.29(q,2H)；3.51(d,?2H);?3.42(m,?1H);?3.00(m,?2H);?2.61(m,?2H);?1.62(d,?2H)；1.3(t，3H)。
Embodiment 6
The preparation of 5-fluoro-2-ethyl formate indoles
(6.3g, 0.05mol) (5.8g 0.05mol) puts in three mouthfuls of reaction flasks that fill the 150mL chlorobenzene, adds polyphosphoric acid (PPA) 20g again, is heated to 50 with 2-carbonyl propionic acid ethyl ester with 4-fluorobenzene hydrazine
oAfter the C back flow reaction 30 hours, leave standstill.Pour out the upper strata chlorobenzene layer, (PPA) is recyclable for lower floor's polyphosphoric acid.Chlorobenzene layer washing, NaHCO
3The aqueous solution is neutralized to neutrality, drying, vacuum removal solvent chlorobenzene.Recrystallization gets product 5-fluoro-2-ethyl formate indoles 9.3g, yield 90%.5-fluoro-2-ethyl formate indole nucleus MR data is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?9.0(br.s,?1H);?7.5(s,?1H);?7.3(m,?1H);?7.2(s,?1H);?7.1(m,?1H);?4.4(q,?2H);?1.4(t,?3H)。
Dichlorophenyl)-preparation of pyridine
2, and 6-dichlorobenzene boric acid (1.9g, 0.01mol), the 4-bromopyridine hydrochloride (9.7g, 0.05mol), four triphenyl phosphorus palladium Pd (PPh
3)
4(116mg, 0.1mmol) and yellow soda ash (2.7g 0.025mol) adds 30 mL toluene and water (V is arranged
Toluene: V
WaterIn=3:1) the reaction flask, under protection of nitrogen gas, be heated to 110 ℃ of reactions 10 hours.Reaction mixture cooling after-filtration, filtrate water is washed, dichloromethane extraction, concentrates after the organic phase drying, and the silicagel column purifying gets 4-(2, the 6-dichlorophenyl) pyridine 1.5g, yield 67%.The nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl) pyridine is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?8.66(d,?2H);?7.35(d,?2H);?7.21(dd,?1H);?7.14(d,?2H)。
Dichlorophenyl)-preparation of piperidines
(9.0g is 0.04mol) with platinum oxide PtO with 4-(2, the 6-dichlorophenyl)-pyridine
2(0.09g 0.4mmol) throws in the reaction flask that fills 200mL acetic acid, reaction system reaction 10 hours under 100 ℃, hydrogen pressure at 50psi.Reaction mixture filters, platinum oxide PtO
2Filter cake is recyclable.Filtrate concentrates, and the residuum after concentrating gets product 4-(2, the 6-dichlorophenyl)-piperidines 7.7g, yield 84% through the silicagel column purifying.The nuclear magnetic resonance data of 4-(2, the 6-dichlorophenyl)-piperidines is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?7.32(br.,?2H);?7.11(dd,?1H);?3.82(m,?1H);?3.63(d,?2H);?3.1(m,?2H);?2.93(m,?2H);?2.73(s,?1H);?1.84(d,?2H)。
5-
Fluoro-3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-preparation of 2-ethyl formate-1-hydrogen-indoles
4-(2, the 6-dichlorophenyl)-piperidines (17.3g, 0.075mol), zinc chloride (15.0g, 0.11mol), formaldehyde (2.3g, 0.075mol) and 5-fluoro-2-ethyl formate indoles (16.0g, 0.075mol) put in the reaction flask that fills the 100mL tetrahydrofuran (THF), reaction mixture is stirring reaction 6 hours at room temperature.Reaction mixture filters then, and the zinc chloride filter cake reclaims and uses; Filtrate concentrating reclaimed tetrahydrofuran (THF), and resistates washes with water, dichloromethane extraction.Concentrate after the organic phase drying, the silicagel column purifying obtains product 5-fluoro-3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2-ethyl formate-1-hydrogen-indoles 27g, yield 80%.5-fluoro-3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2-ethyl formate-1-hydrogen-indole nucleus MR data is as follows:
1H?NMR?(400MHz,?CDCl
3)?δ:?9.1(s,1H);?7.40(d,?1H);?7.21(s,?1H);?7.1-6.9(m,4H);?4.22(s,?2H);?4.3(q,2H)；3.52(d,?2H);?3.44(m,?1H);?3.10(m,?2H);?2.63(m,?2H);?1.64(d,?2H)；1.3(t，3H)。
Claims (10)
1.3-[4-(2, the 6-dichlorophenyl)-and piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole, it is characterized in that, by 2,5-disubstituted indole and 4-(2, the 6-dichlorophenyl) piperidines reacts in the presence of formaldehyde, catalyzer and solvent and obtains, described solvent is alcohol or tetrahydrofuran (THF), and described catalyzer is ZnCl
2, AlCl
3Or SnCl
2, reaction formula is:
2. 3-[4-(2 as claimed in claim 1, the 6-dichlorophenyl)-and piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole, it is characterized in that, described 2, the mol ratio of 5-disubstituted indole and 4-(2, the 6-dichlorophenyl) piperidines is 1:0.2-5, the consumption of described formaldehyde is 2, and the 1-5 of 5-disubstituted indole molar weight doubly; Described temperature of reaction is 0-100 ℃, and the reaction times is 2-30 hour.
3. 3-[4-as claimed in claim 1 or 2 (2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole is characterized in that, and catalyst consumption is 2, and the 0.1-5 of 5-disubstituted indole molar weight is doubly.
4. 3-[4-as claimed in claim 3 (2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole is characterized in that, and the consumption of solvent is 2, and the 5-10 of 5-disubstituted indole quality is doubly.
5. 3-[4-as claimed in claim 1 (2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole is characterized in that, described alcohol is methyl alcohol or ethanol.
6. 3-[4-(2 as claimed in claim 1, the 6-dichlorophenyl)-and piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole, it is characterized in that, described 2, the preparation process of 5-disubstituted indole is: by mol ratio be 1:0.2-5 the 4-substituted phenylhydrazines with replace ethyl ketone and in organic solvent, under the catalysis of acid, react and obtain, temperature of reaction is 50-150 ℃, reaction times is 2-30 hour, and reaction formula is:
7. 3-[4-(2 as claimed in claim 6, the 6-dichlorophenyl)-and piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole, it is characterized in that, in described organic solvent nail benzene, chlorobenzene or the dimethylbenzene one or more mix, and the consumption of organic solvent is 5-10 a times of 4-substituted phenylhydrazines quality; Described acid is polyphosphoric acid, and the consumption of acid is 1-20 a times of 4-substituted phenylhydrazines quality.
8. 3-[4-as claimed in claim 1 (2, the 6-dichlorophenyl)-piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole is characterized in that, described 4-(2, the 6-dichlorophenyl) piperidines
3Preparation process be: at first by 2, hydrochloride, vitriol or the acetate of 6-dichlorobenzene boric acid and tetrabromo pyridine or tetrabromo pyridine generates 4-(2 by linked reaction in solvent in the presence of transition-metal catalyst and alkali, the 6-dichlorophenyl) pyridine, 4-(2, the 6-dichlorophenyl) pyridine is in the presence of catalyzer, in the solvent, obtain 4-(2 by catalytic hydrogenation again under the hydrogen atmosphere, the 6-dichlorophenyl) piperidines, reaction formula is:
, wherein HNu is HCl, H
2SO
4Or HAc.
9. 3-[4-(2 as claimed in claim 8, the 6-dichlorophenyl)-and piperidines-1-methylene radical]-2, the preparation method of 5-disubstituted indole, it is characterized in that, during described linked reaction, 2, the mol ratio of hydrochloride, vitriol or the acetate of 6-dichlorobenzene boric acid and tetrabromo pyridine or tetrabromo pyridine is 1:0.5-5, the temperature of linked reaction is 50-180 ℃, and the time is 3-30 hour; Described transition-metal catalyst is PdCl
2, Pd[P (Ph
3)]
4, Pd (OAc)
2In one or more, catalyst consumption is 2, the 0.01-0.2 of 6-dichlorobenzene boric acid molar weight doubly; Described alkali is Na
2CO
3, K
2CO
3, Cs
2CO
3Or NEt
3, the consumption of alkali is 2, the 0.5-3 of 6-dichlorobenzene boric acid molar weight is doubly; Described solvent refers to one or more among water, toluene, DMF or the NMP, and the consumption of solvent is 2, and the 5-10 of 6-dichlorobenzene boric acid quality doubly.
10. 3-[4-(2, the 6-dichlorophenyl)-piperidines-1-methylene radical as claimed in claim 8 or 9]-2, the preparation method of 5-disubstituted indole is characterized in that, and during described catalytic hydrogenation, the pressure of hydrogen is 3-50psi, and solvent is an acetic acid, and catalyzer is PtO
2, temperature of reaction is 0-150 ℃, the reaction times is 5-30 hour; The consumption of solvent be 4-(2, the 6-dichlorophenyl) pyridine quality 5-10 doubly, catalyst consumption be 4-(2, the 6-dichlorophenyl) pyridine molar weight 0.01-0.5 doubly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101886656A CN102285968A (en) | 2011-07-07 | 2011-07-07 | Method for preparing 3-[4-(2,6-dichlorophenyl)-piperidine-1-methylene]-2,5-disubstituted indole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101886656A CN102285968A (en) | 2011-07-07 | 2011-07-07 | Method for preparing 3-[4-(2,6-dichlorophenyl)-piperidine-1-methylene]-2,5-disubstituted indole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102285968A true CN102285968A (en) | 2011-12-21 |
Family
ID=45332744
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011101886656A Pending CN102285968A (en) | 2011-07-07 | 2011-07-07 | Method for preparing 3-[4-(2,6-dichlorophenyl)-piperidine-1-methylene]-2,5-disubstituted indole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102285968A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1626515A (en) * | 2003-12-10 | 2005-06-15 | 上海化学试剂研究所 | Method for preparing nitro indole-2-carboxylic acid |
| US20070197603A1 (en) * | 2003-07-04 | 2007-08-23 | Alessandra Consonni | Substituted indole ligands for the orl-1 receptor |
-
2011
- 2011-07-07 CN CN2011101886656A patent/CN102285968A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070197603A1 (en) * | 2003-07-04 | 2007-08-23 | Alessandra Consonni | Substituted indole ligands for the orl-1 receptor |
| CN1626515A (en) * | 2003-12-10 | 2005-06-15 | 上海化学试剂研究所 | Method for preparing nitro indole-2-carboxylic acid |
Non-Patent Citations (3)
| Title |
|---|
| LEI ZHANG ET AL.: "1-[(1-Methyl-1H-imidazol-2-yl)methyl]-4- phenylpiperidines as mGluR2 Positive Allosteric Modulators for the Treatment of Psychosis", 《J. MED. CHEM.》, vol. 54, 2 March 2011 (2011-03-02), pages 1724 - 1739 * |
| MEI-LIN GO ET AL.: "Amino Derivatives of Indole As Potent Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase", 《J. MED. CHEM.》, vol. 53, 9 January 2010 (2010-01-09), pages 6838 - 6850 * |
| 冯流星 等: "吲哚-2 -羧酸的合成工艺研究", 《化学与粘合》, no. 4, 31 December 2003 (2003-12-31), pages 196 - 197 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1918282A1 (en) | Method for preparing medetomidine and its salts | |
| CN103570580B (en) | Preparation method of high-purity iopromide | |
| CN101891649A (en) | Novel 3-cyano methyl benzoate preparing method | |
| KR20160094945A (en) | Process for large scale production of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1h-indole dimesylate monohydrate | |
| CN101462974A (en) | Process for synthesizing 5-aminovaleric acid hydrochloride | |
| CN104262264A (en) | New preparation technique of urapidil hydrochloride | |
| CN102417445A (en) | Method for synthesizing succinic acid from maleic acid | |
| CN107778234A (en) | A kind of preparation method of neuromuscular blocking agent intermediate | |
| CN109879788B (en) | Method for preparing N-substituted indole derivative | |
| CN101638406B (en) | 1,3-Dihydrobenzo[C]furan-2-one preparing method | |
| CN102285968A (en) | Method for preparing 3-[4-(2,6-dichlorophenyl)-piperidine-1-methylene]-2,5-disubstituted indole | |
| CN103804232A (en) | 1-cyan-1-(7-methoxyl-3, 4-dihdyro-1-naphthyl) methanol ester compound and preparation method thereof | |
| CN115697968B (en) | Preparation method of (S) -2-amino-3- (4- (2, 3-dimethylpyridine-4-yl) phenylpropionic acid methyl ester and salt thereof | |
| CN102030707A (en) | Method for preparing Blonanserin intermediate | |
| CN101704788B (en) | Improved preparation process of 2-Butyl-1,3-diazapira[4,4]nonane-1-en-4-one | |
| CN114539251A (en) | Pyrido [2,3-d ] pyrimidine derivative and preparation method and application thereof | |
| CN107325055A (en) | A kind of synthetic method of olaparib compound | |
| CN102399235A (en) | Synthesis method of 2-amino-5-pyrimidine pinacol borate | |
| CN102786543A (en) | Preparation methods for imidazole[1,2-a]pyridine-6-boric acid pinacol ester and derivatives thereof | |
| CN104411687A (en) | A process for the preparation of solifenacin or a salt thereof | |
| CN102775391B (en) | Method for preparing migraine resistant medicine Almotriptan | |
| CN104860888B (en) | The synthetic method of Alcaftadine intermediate and Alcaftadine | |
| CN109665953A (en) | A method of preparing styrax class compound | |
| CN102516088B (en) | Combination of triphenylamine compound with strong fluorescence | |
| CN105061434B (en) | A kind of preparation method of Sitagliptin phosphate |
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 |
Application publication date: 20111221 |
|
| WD01 | Invention patent application deemed withdrawn after publication |