CN104496981A - 2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound and preparation method thereof - Google Patents
2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound and preparation method thereof Download PDFInfo
- Publication number
- CN104496981A CN104496981A CN201410853893.4A CN201410853893A CN104496981A CN 104496981 A CN104496981 A CN 104496981A CN 201410853893 A CN201410853893 A CN 201410853893A CN 104496981 A CN104496981 A CN 104496981A
- Authority
- CN
- China
- Prior art keywords
- quinine
- dithienyl
- base ester
- preparation
- oxyacetic acid
- 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.)
- Granted
Links
- 0 C(C1)C2CC*1CC2 Chemical compound C(C1)C2CC*1CC2 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a 2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound and a preparation method thereof. The structure of the compound is shown in the specification. The preparation method comprises the following steps: performing reflux reaction to methyl chlorooxoacetate, quinuclidinol and a base in a solvent, and separating and purifying to obtain a substance A; adding 1/10-3/10 2-bromothiophene and magnesium powder, adding iodine to initiate reaction, then dropwise adding 2-bromothiophene, stirring at room temperature for 30min-1h after the dropwise addition is finished, then adding the substance A, stirring and reacting for 30min at room temperature, then stirring and reflux-reacting for 4-8h, to obtain the 2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound. According to the 2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound and the preparation method thereof, the reaction operations are simple, the yield is high, the price is low, the reaction route is short, three wastes are fewer, and the industrial production is easy.
Description
Technical field
The invention belongs to the anti-chronic lung disease medicine M nachr antagonist aclidinium bromide intermediate for the treatment of and synthesis field thereof, particularly a kind of 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds and preparation method thereof.
Background technology
Chronic obstructive pulmonary disease (Chronic obstructive pulmonary disease, COPD) is common respiratory system disease, be a kind of have flow limitation be feature can the disease of prevention and therapy.Its flow limitation not exclusively reversible and in Progressive symmetric erythrokeratodermia development, with lungs, the abnormal inflammatory sucking the obnoxious flavoures such as tobacco smoke, vehicle exhaust and chemical stimulation or particle is reacted relevant.Aclidinium bromide (Aclidinium bromide) its chemical name is: (3R)-(2-hydroxyl-2,2-bis-thiophene-2-base acetoxyl group)-1-(3-benzene oxygen propyl group)-1-azabicyclo [2.2.2] octane bromide, by developments such as forest research institute and Almirall companies, aclidinium bromide imbedibility pulvis (trade(brand)name: Tudorza Pressair) ratifies listing, as the long term maintenance therapy medicine of the bronchospasm that COPD causes in July, 2012 through FDA (Food and Drug Adminstration) FDA.Aclidinium bromide is 2 medications every day, and belong to the long-acting anti-M choline medicine of imbedibility, this medicine is selectivity M
3receptor antagonist, can be used for the bronchospasm (pulmonary airways narrows) that long term maintenance therapy chronic obstructive pulmonary disease (COPD) is relevant, comprises chronic bronchitis and pulmonary emphysema.Aclidinium bromide is after ipratropium bromide and tiotropium bromide, and the anticholinergic bronchodilators of the 3rd listing, its onset speed is faster than tiotropium bromide, close to ipratropium bromide.It is to M
3cholinergic receptor has high selectivity, to enter after in body can with M
2and M
3receptors bind, but itself and M
3receptors bind more firm, the transformation period is M
26 times of acceptor, therefore, its long action time, belongs to long-acting cholinergic receptor antagonist, and its antagonism M
2the untoward reaction of acceptor is as tachycardia etc., then relatively less.In addition, after aclidinium bromide is amino quaternized by uncle, reduce its oral administration biaavailability and the ability through hemato encephalic barrier, after inhalation, systemic adverse reactions is less.(Stone,L.E.；Skelley,J.W.；Kyle,J.A.；Elmore,L.K.Aclidinium bromide for the treatment of chronicobstructive pulmonary disease.American Journal of Health-System Pharmacy,2014,71(5):386-393.；Jones,P.Aclidinium Bromide Twice Daily for the Treatment of Chronic ObstructivePulmonary Disease:A Review.Advances in Thearpy,2013,30(4):354-368.)。
About the synthesis of aclidinium bromide, the synthetic route of bibliographical information mainly contains following 2 kinds of synthetic methods, the first synthetic method is by 2,2-bis-thiophene ethanol acid methyl esters (2) and R-3-quinuclidinol (3) condensation in toluene, obtain 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester (4), yield only has 40%, then react with 3-benzene oxygen propyl bromide (5) and carry out quaterisation, obtained aclidinium bromide (1) (Prat, M., Fernandez, D., Buil, M.A., Crespo, M.I., Casals, G., Ferrer, M., Tort, L., Castro, J., Monleon, J.M., Gavalda, A., Miralpeix, M., Ramos, I., Domenech, T., Vilella, D., Anton, F., Huerta, J.M., Espinosa, S., Lopez, M., Sentellas, S., Gonzalez, M., Alberti, J., Segarra, V., Cardenaa, A., Beleta, J., Ryder, H..Discovery of Novel QuaternaryAmmonium Derivatives of (3R)-Quinuclidinol Esters as Potent and Long-Acting MuscarinicAntagonists with Potential for Minimal Systemic Exposure after Inhaled Administration:Identification of (3R)-3-{ [Hydroxy (di-2-thienyl) acetyl] oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo [2.2.2] octane Bromide (Aclidinium Bromide), Journal of MedicinalChemistry, 2009:52 (16), 5076-5092.).Xu Yan etc. also report and 2,2-bis-thiophene ethanol acid methyl esters and 3-hydroxyl quinuclidinol are reacted, and product is without separation, and direct and 3-bromopropyl reacts, and adopts one pot synthesis to obtain aclidinium bromide.In this synthetic route, condensation one step yield is low, and uses the 3-quinuclidinol of chirality, and synthesis cost is high.(Wang Xu, Hou Chun, Ma Sufeng, one kettle way prepares the technique of aclidinium bromide, application number: 201410004516.3, the applying date: on January 6th, 2014 for Xu Yan, Wang Tao, Gou Yuancheng, yellow Liza.)
Synthetic method one:
2nd kind of synthetic method is the synthesis about aclidinium bromide of the reports such as Gou Yuancheng, first oxalyl chloride and R-3-quinuclidinol are reacted, obtain oxalic acid two-R-quinine-3-base ester (7), then with react obtained Grignard reagent through 2-bromothiophene and magnesium powder and react, obtained 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester (4), last reaction with 3-benzene oxygen propyl bromide is carried out quaternized, obtains aclidinium bromide.(Gou Yuancheng, Wang Tao, yellow Liza, Hou Chun, Xu Yan, Ma Sufeng, a kind of 2-hydroxyl-2,2-bis-thiophene-2-guanidine-acetic acid-1-azabicyclic [2,2,2] pungent-3-(R)-Ji ester preparation method, application number: 201410004537.5, the applying date: on January 6th, 2014.)
Method two:
Wherein compound (4) is the key intermediate of synthesis aclidinium bromide, in above-mentioned two kinds of synthetic methods, first method is by 2,2-bis-thiophene ethanol acid methyl esters (2) and R-3-hydroxyl quinuclidinol (3) condensation in toluene, obtain 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester (4), yield only has 40%, and yield is low; Method two first oxalyl chloride and R-3-quinuclidinol is reacted, obtain oxalic acid two-R-quinine-3-base ester (7), then with react obtained Grignard reagent through 2-bromothiophene and magnesium powder and react, obtained 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester (4), employ a large amount of, expensive R-3-quinuclidinol in the reaction, production cost is high.
In sum, aforesaid method exists that reaction scheme is long, yield is low and the shortcoming such as reaction conditions requirement is harsh, and in scale operation, cost is relatively high.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds and preparation method thereof, and the inventive method shortens the reaction times, reduces three-protection design, and yield is high; Preparation method's raw material of the present invention is easy to get, and cost is low, and operation is simple, and reaction scheme is short, is easy to suitability for industrialized production.
A kind of 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds of the present invention, the structural formula of described compound is:
The preparation method of a kind of 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds of the present invention, comprising:
(1) by methyl oxalyl chloride, quinuclidinol, alkali back flow reaction (45 DEG C ~ 110 DEG C) 1-20h in a solvent, separating-purifying, obtains substance A; Wherein the mol ratio of methyl oxalyl chloride, quinuclidinol is 1.0 ~ 3.0:1.0; Wherein the usage ratio of alkali, solvent is closed and is; 1:1 ~ 20mL;
(2) in reaction solvent, add the 2-bromothiophene of magnesium powder and 1/10 ~ 3/10, add iodine initiation reaction, then residue 2-bromothiophene is dripped, after 10-40min dropwises, stirring at room temperature, then adds the substance A of step (1), after stirring at room temperature reaction 20-30min, stirring and refluxing (45 DEG C ~ 110 DEG C) reaction 4-8h, obtains 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester; Wherein the proportionlity of magnesium powder, solvent, 2-bromothiophene, substance A is 0.2-0.3mol:300-500mL:0.2-0.3mol:0.1-0.15mol.
Quinuclidinol is the one in the R-3-quinuclidinol of the 3-quinuclidinol of racemization, chirality in described step (1).
In described step (1), alkali is organic bases or mineral alkali.
Described organic bases is one or more in pyridine, triethylamine, methyl diisopropylamine; Mineral alkali is one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide.
In described step (1), solvent is the one in methylene dichloride, 1,2-ethylene dichloride, chloroform, ether, tetrahydrofuran (THF), toluene, Isosorbide-5-Nitrae-dioxane.
Substance A is the one in oxalic acid methyl-R-quinine-3-base ester hydrochloride, oxalic acid methyl-R-quinine-3-base ester, the oxalic acid methyl quinuclidine-3-base ester hydrochloride of racemization, oxalic acid methyl quinuclidine-3-base ester in described step (1).
In described step (1), separating-purifying is: reaction solution adds 2N hydrochloric acid, stirs 2-10min, separates solvent layer, pressure reducing and steaming solvent, gained oily liquids is added the saturated diethyl ether solution of hydrogenchloride.
In described step (2), solvent is tetrahydrofuran (THF); Iodine is 1-5 grain; The stirring at room temperature time is 0.5-3h.
In described step (2), separating-purifying is: add saturated ammonium chloride solution, stir 2-10min, extract by ethyl acetate, ethyl acetate layer is washed, ethyl acetate layer anhydrous sodium sulfate drying,, pressure reducing and steaming ethyl acetate obtains 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester.
Methyl oxatyl chloride (10) and R-3-quinuclidinol is adopted to react in the present invention, obtain compound (11), obtained 2-hydroxyl-2 is then reacted with 2-bromothiophene Grignard reagent (9), 2-bis-thiophene-2-guanidine-acetic acid-R-quinuclidinol-3-base ester (4), two step total recoverys reach 70%.
Concrete preparation feedback formula is as follows:
Gained 2-hydroxyl-2,2-bis-thiophene-2-guanidine-acetic acid-R-quinuclidinol-3-base ester:
Fusing point: 176-178 DEG C;
Proterties: white solid;
Nucleus magnetic hydrogen spectrum and the carbon modal data of 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester are as follows:
1H NMR(400MHz,CDCl
3)δ:1.89-2.25(m,5H),2.54(s,1H),3.32-3.38(m,5H),3.82-3.88(m,1H),3.93(s,3H),12.28(s,1H)；
13C NMR(101MHz,CDCl
3)δ:157.24,156.62,69.78,53.91,52.50,46.36,45.57,24.04,20.37,17.01。
beneficial effect
The present invention is in preparation 2; in the process of 2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester; with methyl oxalyl chloride, R-3-quinuclidinol and 2-bromothiophene for starting raw material; 2 are prepared through the two-step reaction such as acylation reaction and grignard reaction; 2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester; shorten the reaction times, reduce three-protection design, the same yield of the method is higher.This preparation method's starting raw material is easy to get, and cost is low, and operation is simple, and reaction scheme is short, is easy to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is oxalic acid methyl 3-quinuclidinol ester hydrochloride proton nmr spectra;
Fig. 2 is oxalic acid methyl 3-quinuclidinol ester hydrochloride carbon-13 nmr spectra;
Fig. 3 is 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester proton nmr spectra.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.In addition should be understood that those skilled in the art can make various changes or modifications the present invention, and these equivalent form of values fall within the application's appended claims limited range equally after the content of having read the present invention's instruction.
Embodiment 1
Get 3-quinuclidinol 63.5g (0.50mol), pyridine 60.5mL (0.75mol) and methylene dichloride 500mL is added in 1000mL round-bottomed flask, ice-water bath is cooled to 0 ~ 10 DEG C, drip methyl oxalyl chloride 67.1g (0.55mol), drip complete heated and stirred backflow 8h, reaction is finished, reaction solution is added 2N hydrochloric acid 200mL, stir 10 minutes, separate dichloromethane layer, water layer dichloromethane extraction 2 times, dichloromethane layer anhydrous sodium sulfate drying, wash with water and obtain oily matter, add the ethanolic soln that hydrogenchloride is saturated, obtain white solid oxalic acid methyl 3-quinuclidinol ester hydrochloride 83.1g, yield 78.1%, mp:162 ~ 164 DEG C.
1H NMR(400MHz,CDCl
3)δ:1.89-2.25(m,5H),2.54(s,1H),3.32-3.38(m,5H),3.82-3.88(m,1H),3.93(s,3H),12.28(s,1H)；
13C NMR(101MHz,CDCl
3)δ:157.24,156.62,69.78,53.91,52.50,46.36,45.57,24.04,20.37,17.01.ESI-MS:240[M+H]
+。
Embodiment 2
Get anhydrous tetrahydro furan 500mL, 2-bromothiophene 48.9g (0.30mol), magnesium powder 7.2g (0.3mol), first in reaction solution, add a small amount of 2-bromothiophene, add 2 iodine initiation reactions, then residue 2-bromothiophene is dripped, within 30 minutes, drip off, continue stirring at room temperature reaction 2h, stir lower gradation and add oxalic acid methyl 3-quinuclidinol ester hydrochloride 37.4g (0.15mol), drip and finish, drip complete stirring at room temperature and react 30 minutes, then heated and stirred backflow 6h, reaction is finished, add saturated ammonium chloride solution 200mL, stir 10 minutes, extract by ethyl acetate, ethyl acetate layer is washed, ethyl acetate layer anhydrous sodium sulfate drying, whole desolventizing of reducing pressure obtains white 30.2g, yield 57.7%, mp:149 ~ 151 DEG C.
1H NMR(400MHz,DMSO)δ:1.25(m,1H),1.54-1.58(m,3H),1.92(s,1H),2.43-2.46(m,1H),2.58-2.60(m,3H),3.08-3.13(m,1H),4.82(s,1H),7.01(s,2H),7.10-7.12(s,2H),7.49-7.51(m,2H)。
Embodiment 3
3-quinuclidinol in embodiment 1 is replaced, obtained oxalic acid methyl 3-quinine alcohol ester, yield 68.5%, mp:176 ~ 178 DEG C with R-3-quinuclidinol.
Embodiment 4
Embodiment 2 mesoxalic acid methyl quinuclidine-3-base ester is replaced, obtained 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester, yield 58.0%, mp:176 ~ 178 DEG C with oxalic acid methyl-R-3-quinine alcohol ester.
1H NMR(400MHz,DMSO)δ:1.25(s,1H),1.52(d,J＝17.5Hz,3H),1.92(s,1H),2.54(dt,J＝31.9,19.8Hz,6H),3.10(dd,J＝12.9,8.1Hz,1H),4.82(s,1H),7.01(d,J＝3.3Hz,2H),7.12(s,2H),7.49(s,2H).
Embodiment 5
Getting 3-quinuclidinol 63.5g (0.50mol) is dissolved in methylene dichloride 500mL solution, ice-water bath is cooled to 0 ~ 10 DEG C, drip methyl oxalyl chloride 67.1g (0.55mol), drip complete stirring at room temperature reaction 8h, reaction is finished, reaction solution is added 2N hydrochloric acid 200mL, stir 10 minutes, separate dichloromethane layer, water layer dichloromethane extraction 2 times, dichloromethane layer anhydrous sodium sulfate drying, wash with water and obtain oily matter, add the ethanolic soln that hydrogenchloride is saturated, obtain white solid oxalic acid methyl 3-quinuclidinol ester hydrochloride 59.5g, yield 55.8%, mp:162 ~ 163 DEG C.
Embodiment 6
Get 3-quinuclidinol 63.5g (0.50mol), triethylamine 138.0mL (1.0mol) and methylene dichloride 500mL is added in 1000mL three-necked bottle, ice-water bath is cooled to 0 ~ 10 DEG C, drip methyl oxalyl chloride 67.1g (0.55mol), drip complete heated and stirred backflow 10h, reaction is finished, reaction solution is added 2N hydrochloric acid 200mL, stir 10 minutes, separate dichloromethane layer, water layer dichloromethane extraction 2 times, dichloromethane layer anhydrous sodium sulfate drying, wash with water and obtain oily matter oxalic acid methyl 3-quinine alcohol ester 97.2g, yield 78.1%, be directly used in the next step.
Embodiment 7
Get anhydrous tetrahydro furan 400mL, 2-bromothiophene 27.4g (0.17mol), magnesium powder 7.2g (0.3mol), first in reaction solution, add a small amount of 2-bromothiophene, add 2 iodine initiation reactions, then 2-bromothiophene is dripped, within 30 minutes, drip off, continue stirring at room temperature reaction 2h, stir lower gradation and add oxalic acid methyl 3-quinine alcohol ester 31.9g (0.15mol), drip and finish, drip complete stirring at room temperature and react 30 minutes, then heated and stirred backflow 6h, reaction is finished, add saturated ammonium chloride solution 200mL, stir 10 minutes, extract by ethyl acetate, ethyl acetate layer is washed, ethyl acetate layer anhydrous sodium sulfate drying, pressure reducing and steaming solvent obtains white solid 34.2g, yield 65.3%, mp:148 ~ 151 DEG C.
Embodiment 8
3-quinuclidinol in embodiment 6 is replaced, obtained oxalic acid methyl 3-quinine alcohol ester, yield 68.5%, mp:168 ~ 171 DEG C with R-3-quinuclidinol.
Embodiment 9
Embodiment 7 mesoxalic acid methyl quinuclidine-3-base ester is replaced, obtained 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester, yield 58.0%, mp:177 ~ 179 DEG C with oxalic acid methyl-R-3-quinine alcohol ester.
Embodiment 10
Pyridine in embodiment 1 is replaced, obtained oxalic acid methyl 3-quinuclidinol ester hydrochloride, yield 38.5%, mp:168 ~ 171 DEG C with salt of wormwood.
Embodiment 11
Get 3-quinuclidinol 63.5g (0.50mol), pyridine 60.5mL (0.75mol) and methylene dichloride 800mL is added in 1000mL round-bottomed flask, ice-water bath is cooled to 0 ~ 10 DEG C, drip methyl oxalyl chloride 183.0g (1.50mol), drip complete heated and stirred backflow 6h, reaction is finished, reaction solution is added 2N hydrochloric acid 200mL, stir 10 minutes, separate dichloromethane layer, water layer dichloromethane extraction 2 times, dichloromethane layer anhydrous sodium sulfate drying, wash with water and obtain oily matter, add the ethanolic soln that hydrogenchloride is saturated, obtain white solid oxalic acid methyl 3-quinine alcohol ester 87.3g, yield 82.1%, mp:165 ~ 167 DEG C.
Claims (10)
1. a dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds, is characterized in that: the structural formula of described compound is:
2. the preparation method of 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds as claimed in claim 1, comprising:
(1) by back flow reaction 1-20h under methyl oxalyl chloride, quinuclidinol, alkali 45 DEG C in a solvent ~ 110 DEG C conditions, separating-purifying, obtains substance A; Wherein the mol ratio of methyl oxalyl chloride, quinuclidinol is 1.0 ~ 3.0:1.0; Wherein the usage ratio of alkali, solvent is closed and is; 1:1 ~ 20mL;
(2) in reaction solvent, add the 2-bromothiophene of magnesium powder and 1/10 ~ 3/10, add iodine initiation reaction, then residue 2-bromothiophene is dripped, after 10-40min dropwises, stirring at room temperature 30min ~ 1h, then adds the substance A of step (1), after stirring at room temperature reaction 20-30min, 45 DEG C ~ 110 DEG C stirring and refluxing reaction 4-8h, obtain 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester; Wherein the proportionlity of magnesium powder, solvent, 2-bromothiophene, substance A is 0.2-0.3mol:300-500mL:0.2-0.3mol:0.1-0.15mol.
3. according to claim 2 a kind of 2, the preparation method of 2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds, is characterized in that: quinuclidinol is the one in the R-3-quinuclidinol of the 3-quinuclidinol of racemization, chirality in described step (1).
4. the preparation method of a kind of 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds according to claim 2, is characterized in that: in described step (1), alkali is organic bases or mineral alkali.
5. the preparation method of a kind of 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds according to claim 4, is characterized in that: described organic bases is one or more in pyridine, triethylamine, methyl diisopropylamine; Mineral alkali is one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide.
6. according to claim 2 a kind of 2, the preparation method of 2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds, it is characterized in that: in described step (1), solvent is methylene dichloride, 1, one in 2-ethylene dichloride, chloroform, ether, tetrahydrofuran (THF), toluene, Isosorbide-5-Nitrae-dioxane.
7. according to claim 2 a kind of 2, the preparation method of 2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds, is characterized in that: substance A is the one in oxalic acid methyl-R-quinine-3-base ester hydrochloride, oxalic acid methyl-R-quinine-3-base ester, the oxalic acid methyl quinuclidine-3-base ester hydrochloride of racemization, oxalic acid methyl quinuclidine-3-base ester in described step (1).
8. according to claim 2 a kind of 2, the preparation method of 2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds, it is characterized in that: in described step (1), separating-purifying is: reaction solution adds 2N hydrochloric acid, stir 2-10min, separate solvent layer, pressure reducing and steaming solvent, adds the saturated diethyl ether solution of hydrogenchloride, obtains substance A by gained oily liquids.
9. the preparation method of a kind of 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds according to claim 2, is characterized in that: in described step (2), solvent is tetrahydrofuran (THF); Iodine is 1-5 grain; The stirring at room temperature time is 0.5-3h.
10. according to claim 2 a kind of 2, the preparation method of 2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester cpds, it is characterized in that: in described step (2), separating-purifying is: add saturated ammonium chloride solution, stir 2-10min, extract by ethyl acetate, ethyl acetate layer is washed, ethyl acetate layer anhydrous sodium sulfate drying, pressure reducing and steaming ethyl acetate obtains 2,2-dithienyl-2-oxyacetic acid-R-quinine-3-base ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410853893.4A CN104496981B (en) | 2014-12-26 | 2014-12-26 | 2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410853893.4A CN104496981B (en) | 2014-12-26 | 2014-12-26 | 2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104496981A true CN104496981A (en) | 2015-04-08 |
| CN104496981B CN104496981B (en) | 2017-01-11 |
Family
ID=52938455
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410853893.4A Expired - Fee Related CN104496981B (en) | 2014-12-26 | 2014-12-26 | 2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104496981B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348279A (en) * | 2015-12-07 | 2016-02-24 | 东华大学 | R-2,2-di(2-thienyl)-2-glycolic acid quinine-3-ester and preparation and application thereof |
| WO2018150437A1 (en) * | 2017-02-14 | 2018-08-23 | Gbr Laboratories Pvt. Ltd | A process for preparing aclidinium bromide and intermediates thereof |
| CN108794464A (en) * | 2018-04-03 | 2018-11-13 | 安徽赛诺制药有限公司 | A kind of new method aclidinium bromide synthesis and purified |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755699A (en) * | 2014-01-06 | 2014-04-30 | 万特制药(海南)有限公司 | Preparation method of 2-hydroyxl-2,2-dithienyl-2-polyglycolic acid-1-azabicyclo[2, 2, 2] octyl-3(R)-base ester |
| CN103755698A (en) * | 2014-01-06 | 2014-04-30 | 万特制药(海南)有限公司 | Technology for preparing aclidinium bromide employing one-pot process |
-
2014
- 2014-12-26 CN CN201410853893.4A patent/CN104496981B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755699A (en) * | 2014-01-06 | 2014-04-30 | 万特制药(海南)有限公司 | Preparation method of 2-hydroyxl-2,2-dithienyl-2-polyglycolic acid-1-azabicyclo[2, 2, 2] octyl-3(R)-base ester |
| CN103755698A (en) * | 2014-01-06 | 2014-04-30 | 万特制药(海南)有限公司 | Technology for preparing aclidinium bromide employing one-pot process |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348279A (en) * | 2015-12-07 | 2016-02-24 | 东华大学 | R-2,2-di(2-thienyl)-2-glycolic acid quinine-3-ester and preparation and application thereof |
| CN105348279B (en) * | 2015-12-07 | 2017-06-06 | 东华大学 | A kind of (2 thienyl) base esters of 2 hydroxyacetic acid quinine 3 of R 2,2 2 and its preparation and application |
| WO2018150437A1 (en) * | 2017-02-14 | 2018-08-23 | Gbr Laboratories Pvt. Ltd | A process for preparing aclidinium bromide and intermediates thereof |
| CN108794464A (en) * | 2018-04-03 | 2018-11-13 | 安徽赛诺制药有限公司 | A kind of new method aclidinium bromide synthesis and purified |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104496981B (en) | 2017-01-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5563161A (en) | Alcohols and ethers with aromatic substituents as tachykinin-antagonists | |
| CA2582297A1 (en) | Chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors | |
| CN104356009A (en) | Production technology for synthetizing salbutamol sulphate | |
| CN104496981A (en) | 2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound and preparation method thereof | |
| CN104478871B (en) | A kind of choline m receptor antagonist aclidinium bromide and preparation method thereof | |
| CN101157691B (en) | Production technique of hydrochloric acid palonosetron | |
| CA2673454A1 (en) | Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors | |
| US20080214820A1 (en) | Enantiomers of 3-Heteroaryl-8H-8-Azabicyclo (3.2.1) Oct-2-Ene and their Use as Monoamine Neurotransmitter Re-Uptake Inhibitors | |
| CA2641916A1 (en) | Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors | |
| CN101875666B (en) | Optical pure 1,3-alkamine compound as well as preparation method and application thereof in preparing Dapoxetine and analogues thereof | |
| CN101948479B (en) | Prasugrel intermediate and preparation method thereof | |
| CN103864630A (en) | Synthesis method of (S)-1-(4-ethyoxyl benzyl)-3-azapentane-1,5-diamine trihydrochloride | |
| CN105348279A (en) | R-2,2-di(2-thienyl)-2-glycolic acid quinine-3-ester and preparation and application thereof | |
| CN106831756A (en) | A kind of high-purity high-yield is adapted to the aclidinium bromide preparation method of industrialized production | |
| EP2121677B1 (en) | Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors | |
| CN105440030A (en) | Choline M receptor antagonist aclidinium bromide and preparation method thereof | |
| CN108358893A (en) | A kind of method of one pot process tetrahydro benzo-[1,4]-diazepan derivatives | |
| CN107365301B (en) | Synthesis method of crizotinib and preparation method of intermediate thereof | |
| CN105884625A (en) | Synthesis method of R-salmeterol | |
| CN101812061A (en) | Method for producing tetrahydroberineper from berberine hydrochloride | |
| US20100286195A1 (en) | Novel benzooxazol-and benzooxathiol-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors | |
| CN114057683A (en) | Preparation method of tiotropium bromide intermediate | |
| CN114195798A (en) | 7 alpha-methyl fused ring morphine derivatives, and preparation method and application thereof | |
| CN114057684A (en) | Synthesis method of tiotropium bromide intermediate methyl di (2-dithienyl) glycolate | |
| US8022081B2 (en) | Naphthyl substituted azabicyclo derivatives and their use as monomine neurotransmitter re-uptake inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170111 Termination date: 20191226 |