CN104496981B - 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
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- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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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 treat anti-chronic lung disease medicine M nachr antagonist aclidinium bromide intermediate and synthesis neck thereof
Territory, particularly to a kind of 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds and preparation method thereof.
Background technology
Chronic obstructive pulmonary disease (Chronic obstructive pulmonary disease, COPD) is common exhaling
Desorption system disease, is a kind of to have the disease can prevented and treat that flow limitation is characterized.Its flow limitation not exclusively may be used
Inverse and develop in Progressive symmetric erythrokeratodermia, with lungs to sucking the different of the harmful gass such as tobacco smoke, vehicle exhaust and chemical stimulation or granule
Often inflammatory reaction is relevant.Aclidinium bromide (Aclidinium bromide) its chemical name is: (3R)-(2-hydroxyl-2,2-two thiophene
Fen-2-base acetoxyl group)-1-(3-benzene oxygen propyl group)-1-azabicyclo [2.2.2] octane bromide, by forest academy and
Almirall companies etc. develop, and aclidinium bromide imbedibility powder (trade name: Tudorza Pressair) is in July, 2012
Through FDA (Food and Drug Adminstration) FDA approval listing, as the long term maintenance therapy medicine of the bronchospasm that COPD causes.A Di
Bromine ammonium is 2 medications every day, belongs to the long-acting anti-M choline medicine of imbedibility, and this medicine is selectivity M3Receptor antagonist, can be used for long-term
The bronchospasm (pulmonary airways narrows) that maintaining treatment chronic obstructive pulmonary disease (COPD) is relevant, including chronic bronchitis
And emphysema.Aclidinium bromide is after ipratropium bromide and tiotropium bromide, the anticholinergic bronchodilators of the 3rd listing,
Its onset speed is faster than tiotropium bromide, close to ipratropium bromide.It is to M3Cholinoceptor has high selectivity, enters internal
After can be with M2And M3Receptor combines, but itself and M3It is more firm that receptor combines, and the half-life is M26 times of receptor, therefore, it is made
Use the time long, belong to long-acting cholinergic receptor antagonist, and it resists M2The untoward reaction of receptor such as tachycardia etc., the most relatively
Few.It addition, aclidinium bromide is by after quaternized for tertiary amino, reduce its oral administration biaavailability and the ability through blood brain 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 chronic obstructive pulmonary
disease.American Journal of Health-System Pharmacy,2014,71(5):386-393.；Jones,
P.Aclidinium Bromide Twice Daily for the Treatment of Chronic Obstructive
Pulmonary Disease:A Review.Advances in Thearpy,2013,30(4):354-368.)。
About the synthesis of aclidinium bromide, the synthetic route of document report mainly has following 2 kinds of synthetic methods, the first synthesis
Method is by 2, and 2-bis-thiophene ethanol acid methyl ester (2) and R-3-quinuclidinol (3) are condensed in toluene, obtains 2,2-dithienyl-
2-hydroxyacetic acid-R-quinine-3-base ester (4), yield only has 40%, then react with 3-benzene oxygen propyl bromide (5) carry out quaternized
Reaction, prepares 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 Quaternary Ammonium Derivatives of(3R)-Quinuclidinol Esters as
Potent and Long-Acting Muscarinic Antagonists 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 Medicinal Chemistry,2009:52
(16),5076-5092.).Xu Yan etc. also report 2, and 2-bis-thiophene ethanol acid methyl ester reacts with 3-hydroxyl quinuclidinol, product
Without isolation, directly react with 3-bromopropyl, use one pot synthesis to prepare aclidinium bromide.In this synthetic route, it is condensed a step
Yield is low, and uses the 3-quinuclidinol of chirality, and synthesis cost is high.(Xu Yan, Wang Tao, Gou Yuancheng, yellow Liza, Wang Xu, Hou Chun, horse
Su Feng, one kettle way prepares the technique of aclidinium bromide, application number: 201410004516.3, the applying date: on January 6th, 2014.)
Synthetic method one:
2nd kind of synthetic method is the synthesis about aclidinium bromide that Gou Yuan really waits report, first by oxalyl chloride and R-3-Kui
Thujol reacts, and obtains oxalic acid two-R-quinine-3-base ester (7), then reacts prepared Grignard reagent with through 2-bromothiophene and magnesium powder
Reaction, prepares 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester (4), and last reaction with 3-benzene oxygen propyl bromide is carried out
Quaternized, prepare aclidinium bromide.(Gou Yuancheng, Wang Tao, yellow Liza, Hou Chun, Xu Yan, Ma Sufeng, a kind of 2-hydroxyl-2,2-bis-thiophene
Fen-2-guanidine-acetic acid-1-azabicyclic [2,2,2] octyl-3-(R)-base ester preparation method, application number: 201410004537.5, application
Day: on January 6th, 2014.)
Method two:
Wherein compound (4) is the key intermediate of synthesis aclidinium bromide, the first side in above two synthetic method
Method is by 2, and 2-bis-thiophene ethanol acid methyl ester (2) and R-3-hydroxyl quinuclidinol (3) are condensed in toluene, obtains 2, and 2-dithienyl-
2-hydroxyacetic acid-R-quinine-3-base ester (4), yield only has 40%, and yield is low；Method two is first by oxalyl chloride and R-3-Kui
Thujol reacts, and obtains oxalic acid two-R-quinine-3-base ester (7), then reacts prepared Grignard reagent with through 2-bromothiophene and magnesium powder
Reaction, prepares 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester (4), employs a large amount of, expensive R-in the reaction
3-quinuclidinol, production cost is high.
In sum, said method exists that reaction scheme length, yield be low and the shortcoming such as reaction condition requirement is harsh, on big rule
During mould produces, cost is of a relatively high.
Summary of the invention
The technical problem to be solved is to provide a kind of 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base
Ester compounds and preparation method thereof, the inventive method shortens the response time, reduces three-protection design, and yield is high；System of the present invention
Preparation Method raw material is easy to get, low cost, and operation is simple, and reaction scheme is short, it is easy to industrialized production.
The one 2 of the present invention, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds, described compound
Structural formula is:
The one 2 of the present invention, the preparation method of 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds, bag
Include:
(1) by methyl oxalyl chloride, quinuclidinol, alkali back flow reaction in a solvent (45 DEG C～110 DEG C) 1-20h, separating-purifying,
Obtain substance A；Wherein methyl oxalyl chloride, the mol ratio of quinuclidinol are 1.0～3.0:1.0；Wherein alkali, the usage ratio of solvent are closed
System is；1:1～20mL；
(2) in reaction dissolvent, add magnesium powder and the 2-bromothiophene of 1/10～3/10, add iodine initiation reaction, then drip
Residue 2-bromothiophene, after 10-40min dropping, is stirred at room temperature, is subsequently adding the substance A of step (1), reaction is stirred at room temperature
After 20-30min, it is stirred at reflux (45 DEG C～110 DEG C) reaction 4-8h, obtains 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-
3-base ester；Wherein magnesium powder, solvent, 2-bromothiophene, the proportionate relationship of substance A are 0.2-0.3mol:300-500mL:0.2-
0.3mol:0.1-0.15mol.
One during quinuclidinol is the R-3-quinuclidinol of the 3-quinuclidinol of racemization, chirality in described step (1).
In described step (1), alkali is organic base or inorganic base.
Described organic base is one or more in pyridine, triethylamine, methyl diisopropylamine；Inorganic base be potassium carbonate,
One or more in sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide.
In described step (1), solvent is dichloromethane, 1,2-dichloroethanes, chloroform, ether, oxolane, toluene, 1,4-
One in dioxane.
In described step (1), substance A is oxalic acid methyl-R-quinine-3-base ester hydrochloride, oxalic acid methyl-R-quinine-3-base
One in ester, the oxalic acid methyl quinuclidine-3-base ester hydrochloride of racemization, oxalic acid methyl quinuclidine-3-base ester.
In described step (1), separating-purifying is: reactant liquor adds 2N hydrochloric acid, stirs 2-10min, separates solvent layer, decompression
Boil off solvent, gained oily liquids is added the diethyl ether solution that hydrogen chloride is saturated.
In described step (2), solvent is oxolane；Iodine is 1-5 grain；The time of being stirred at room temperature is 0.5-3h.
In described step (2), separating-purifying is: add saturated ammonium chloride solution, stirs 2-10min, carries by ethyl acetate
Taking, ethyl acetate layer is washed, and ethyl acetate layer anhydrous sodium sulfate is dried, decompression boils off ethyl acetate and obtains 2,2-bis-thiophene
Base-2-hydroxyacetic acid-R-quinine-3-base ester.
The present invention uses Methyl oxatyl chloride (10) react with R-3-quinuclidinol, obtain compound (11), then with 2-
Bromothiophene Grignard reagent (9) reaction prepares 2-hydroxyl-2, and 2-bis-thiophene-2-guanidine-acetic acid-R-quinuclidinol-3-base ester (4), two steps are total
Yield reaches 70%.
It is concrete that to prepare reaction equation as follows:
Gained 2-hydroxyl-2,2-two thiophene-2-guanidine-acetic acid-R-quinuclidinol-3-base ester:
Fusing point: 176-178 DEG C；
Character: white solid；
Nucleus magnetic hydrogen spectrum and the carbon modal data of 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester are as follows:
1H NMR(400MHz,CDCl3)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,CDCl3)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, during 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester, with methoxalyl
Chlorine, R-3-quinuclidinol and 2-bromothiophene are initiation material, prepare 2 through the two-step reaction such as acylation reaction and grignard reaction, 2-bis-thiophene
Fen base-2-hydroxyacetic acid-R-quinine-3-base ester, shortens the response time, reduces three-protection design, and the same yield of the method is relatively
High.This preparation method initiation material is easy to get, low cost, and operation is simple, and reaction scheme is short, it is easy to 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-hydroxyacetic acid-R-quinine-3-base ester proton nmr spectra.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.In addition, it is to be understood that after having read the content that the present invention lectures, people in the art
The present invention can be made various changes or modifications by member, and these equivalent form of values fall within the application appended claims equally and limited
Scope.
Embodiment 1
Take 3-quinuclidinol 63.5g (0.50mol), pyridine 60.5mL (0.75mol) and dichloromethane 500mL adds extremely
In 1000mL round-bottomed flask, ice-water bath is cooled to 0～10 DEG C, dropping methyl oxalyl chloride 67.1g (0.55mol), drips Bi Jiare and stirs
Mixing backflow 8h, reaction is finished, reactant liquor is added 2N hydrochloric acid 200mL, stirs 10 minutes, separate dichloromethane layer, water layer dichloro
Methane extracts 2 times, and dichloromethane layer anhydrous sodium sulfate is dried, and washes with water and obtains grease, adds the ethanol that hydrogen chloride is saturated
Solution, obtains white solid oxalic acid methyl 3-quinuclidinol ester hydrochloride 83.1g, yield 78.1%, mp:162～164 DEG C.1H
NMR(400MHz,CDCl3)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,CDCl3)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
Taking anhydrous tetrahydro furan 500mL, 2-bromothiophene 48.9g (0.30mol), magnesium powder 7.2g (0.3mol), first to reaction
Liquid adds a small amount of 2-bromothiophene, adds 2 iodine initiation reactions, then dropping residue 2-bromothiophene, within 30 minutes, drip off, continue room
Temperature stirring reaction 2h, adds oxalic acid methyl 3-quinuclidinol ester hydrochloride 37.4g (0.15mol) by several times, drips and finish under stirring, a complete room
Temperature stirring reaction 30 minutes, then heated and stirred backflow 6h, reaction is finished, and adds saturated ammonium chloride solution 200mL, stirs 10 points
Clock, extracts by ethyl acetate, and ethyl acetate layer is washed, and ethyl acetate layer anhydrous sodium sulfate is dried, and reduces pressure and whole goes solvent to obtain
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
Replace 3-quinuclidinol in embodiment 1 with R-3-quinuclidinol, prepare oxalic acid methyl 3-quinine alcohol ester, yield 68.5%,
Mp:176～178 DEG C.
Embodiment 4
Replace embodiment 2 mesoxalic acid methyl quinuclidine-3-base ester with oxalic acid methyl-R-3-quinine alcohol ester, prepare 2,2-bis-thiophene
Fen base-2-hydroxyacetic acid-R-quinine-3-base ester, yield 58.0%, mp:176～178 DEG C.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
Taking 3-quinuclidinol 63.5g (0.50mol) to be dissolved in dichloromethane 500mL solution, ice-water bath is cooled to 0～10 DEG C,
Dropping methyl oxalyl chloride 67.1g (0.55mol), drips to finish to be stirred at room temperature and reacts 8h, and reaction is finished, reactant liquor is added 2N hydrochloric acid
200mL, stirs 10 minutes, separates dichloromethane layer, water layer dichloromethane extraction 2 times, dichloromethane layer anhydrous sodium sulfate
It is dried, washes with water and obtain grease, add the ethanol solution that hydrogen chloride is saturated, obtain white solid oxalic acid methyl 3-quinine alcohol ester
Hydrochlorate 59.5g, yield 55.8%, mp:162～163 DEG C.
Embodiment 6
Take 3-quinuclidinol 63.5g (0.50mol), triethylamine 138.0mL (1.0mol) and dichloromethane 500mL adds extremely
In 1000mL three-necked bottle, ice-water bath is cooled to 0～10 DEG C, dropping methyl oxalyl chloride 67.1g (0.55mol), drips complete heated and stirred
Backflow 10h, reaction is finished, reactant liquor is added 2N hydrochloric acid 200mL, stirs 10 minutes, separate dichloromethane layer, water layer dichloromethane
Alkane extracts 2 times, and dichloromethane layer anhydrous sodium sulfate is dried, and washes with water and obtains grease oxalic acid methyl 3-quinine alcohol ester 97.2g,
Yield 78.1%, is directly used in the next step.
Embodiment 7
Taking anhydrous tetrahydro furan 400mL, 2-bromothiophene 27.4g (0.17mol), magnesium powder 7.2g (0.3mol), first to reaction
Adding a small amount of 2-bromothiophene in liquid, add 2 iodine initiation reactions, then dropping 2-bromothiophene, drips off for 30 minutes, continues room temperature and stirs
Mixing reaction 2h, stirring is lower adds oxalic acid methyl 3-quinine alcohol ester 31.9g (0.15mol) by several times, drip and finish, and drips to finish reaction is stirred at room temperature
30 minutes, then heated and stirred backflow 6h, reaction was finished, and adds saturated ammonium chloride solution 200mL, stirs 10 minutes, use acetic acid second
Ester extracts, and ethyl acetate layer is washed, and ethyl acetate layer anhydrous sodium sulfate is dried, and decompression boils off solvent and obtains white solid
34.2g, yield 65.3%, mp:148～151 DEG C.
Embodiment 8
Replace 3-quinuclidinol in embodiment 6 with R-3-quinuclidinol, prepare oxalic acid methyl 3-quinine alcohol ester, yield 68.5%,
Mp:168～171 DEG C.
Embodiment 9
Replace embodiment 7 mesoxalic acid methyl quinuclidine-3-base ester with oxalic acid methyl-R-3-quinine alcohol ester, prepare 2,2-bis-thiophene
Fen base-2-hydroxyacetic acid-R-quinine-3-base ester, yield 58.0%, mp:177～179 DEG C.
Embodiment 10
Replace pyridine in embodiment 1 with potassium carbonate, prepare oxalic acid methyl 3-quinuclidinol ester hydrochloride, yield 38.5%, mp:
168～171 DEG C.
Embodiment 11
Take 3-quinuclidinol 63.5g (0.50mol), pyridine 60.5mL (0.75mol) and dichloromethane 800mL adds extremely
In 1000mL round-bottomed flask, ice-water bath is cooled to 0～10 DEG C, dropping methyl oxalyl chloride 183.0g (1.50mol), drips Bi Jiare and stirs
Mixing backflow 6h, reaction is finished, reactant liquor is added 2N hydrochloric acid 200mL, stirs 10 minutes, separate dichloromethane layer, water layer dichloro
Methane extracts 2 times, and dichloromethane layer anhydrous sodium sulfate is dried, and washes with water and obtains grease, adds the ethanol that hydrogen chloride is saturated
Solution, obtains white solid oxalic acid methyl 3-quinine alcohol ester 87.3g, yield 82.1%, mp:165～167 DEG C.
Claims (8)
1. one kind 2, the preparation method of 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds, it is characterised in that: institute
The structural formula stating compound is:
Described method includes:
(1) by back flow reaction 1-20h under the conditions of methyl oxalyl chloride, quinuclidinol, alkali in a solvent 45 DEG C～110 DEG C, separating-purifying,
Obtain substance A；Wherein methyl oxalyl chloride, the mol ratio of quinuclidinol are 1.0～3.0:1.0；Wherein alkali, the usage ratio of solvent are closed
System is；1:1～20mL；Wherein substance A is oxalic acid methyl-R-quinine-3-base ester hydrochloride, oxalic acid methyl-R-quinine-3-base ester
In one；
(2) in reaction dissolvent, add magnesium powder and the 2-bromothiophene of 1/10～3/10, add iodine initiation reaction, then drip residue
2-bromothiophene, after 10-40min dropping, is stirred at room temperature 30min～1h, is subsequently adding the substance A of step (1), is stirred at room temperature
After reaction 20-30min, 45 DEG C～110 DEG C are stirred at reflux reaction 4-8h, obtain 2,2-dithienyl-2-hydroxyacetic acid-R-Kui
Rather-3-base ester；Wherein magnesium powder, solvent, 2-bromothiophene, the proportionate relationship of substance A are 0.2-0.3mol:300-500mL:0.2-
0.3mol:0.1-0.15mol.
The system of a kind of 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds the most according to claim 1
Preparation Method, it is characterised in that: during quinuclidinol is the R-3-quinuclidinol of the 3-quinuclidinol of racemization, chirality in described step (1)
Kind.
The system of a kind of 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds the most according to claim 1
Preparation Method, it is characterised in that: in described step (1), alkali is organic base or inorganic base.
The system of a kind of 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds the most according to claim 3
Preparation Method, it is characterised in that: described organic base is one or more in pyridine, triethylamine, methyl diisopropylamine；Inorganic base
For one or more in potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide.
The system of a kind of 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds the most according to claim 1
Preparation Method, it is characterised in that: in described step (1) solvent be dichloromethane, 1,2-dichloroethanes, chloroform, ether, tetrahydrochysene furan
Mutter, one in toluene, 1,4-dioxane.
The system of a kind of 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds the most according to claim 1
Preparation Method, it is characterised in that: in described step (1), separating-purifying is: reactant liquor adds 2N hydrochloric acid, stirs 2-10min, separates molten
Oxidant layer, decompression boils off solvent, gained oily liquids is added the diethyl ether solution that hydrogen chloride is saturated, obtains substance A.
The system of a kind of 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds the most according to claim 1
Preparation Method, it is characterised in that: in described step (2), solvent is oxolane；Iodine is 1-5 grain.
The system of a kind of 2,2-dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester compounds the most according to claim 1
Preparation Method, it is characterised in that: in described step (2), separating-purifying is: add saturated ammonium chloride solution, stirs 2-10min, uses second
Acetoacetic ester extracts, and ethyl acetate layer is washed, and ethyl acetate layer anhydrous sodium sulfate is dried, and decompression boils off ethyl acetate and obtains 2,2-
Dithienyl-2-hydroxyacetic acid-R-quinine-3-base ester.
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