CN105348279B - A kind of (2 thienyl) base esters of 2 hydroxyacetic acid quinine 3 of R 2,2 2 and its preparation and application - Google Patents
A kind of (2 thienyl) base esters of 2 hydroxyacetic acid quinine 3 of R 2,2 2 and its preparation and application Download PDFInfo
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- CN105348279B CN105348279B CN201510894315.XA CN201510894315A CN105348279B CN 105348279 B CN105348279 B CN 105348279B CN 201510894315 A CN201510894315 A CN 201510894315A CN 105348279 B CN105348279 B CN 105348279B
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- 0 *=C(C(c1ccc[s]1)(c1ccc[s]1)O)OC1C(CC2)CCN2C1 Chemical compound *=C(C(c1ccc[s]1)(c1ccc[s]1)O)OC1C(CC2)CCN2C1 0.000 description 1
- SYHWYWHVEQQDMO-UHFFFAOYSA-N COC(C(c1ccc[s]1)(c1ccc[s]1)O)=O Chemical compound COC(C(c1ccc[s]1)(c1ccc[s]1)O)=O SYHWYWHVEQQDMO-UHFFFAOYSA-N 0.000 description 1
- GYDFTKNRHZMENP-UHFFFAOYSA-N OC(C(OC1C(CC2)CCN2C1)=O)(c1ccc[s]1)c1ccc[s]1 Chemical compound OC(C(OC1C(CC2)CCN2C1)=O)(c1ccc[s]1)c1ccc[s]1 GYDFTKNRHZMENP-UHFFFAOYSA-N 0.000 description 1
- IVLICPVPXWEGCA-UHFFFAOYSA-N OC1C(CC2)CCN2C1 Chemical compound OC1C(CC2)CCN2C1 IVLICPVPXWEGCA-UHFFFAOYSA-N 0.000 description 1
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- 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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Abstract
The present invention relates to a kind of (2 thienyl) base esters of 2 hydroxyacetic acid quinine 3 of R 2,2 two and its preparation and application, the structural formula of compound is：By 2,2 two (2 thienyl) 2 hydroxy methyl acetates and 3 quinuclidinols react, obtain 2 hydroxyls 2, the quinine base ester of 2 two (2 thienyl) acetic acid 3, then chiral acid splits, alkalized in aqueous slkali, obtain final product R 2,2 two (2 thienyl) base ester of 2 hydroxyacetic acid quinine 3.The base ester operation of R configurations 2,2 two (2 thienyl) 2 hydroxyacetic acid quinine 3 prepared by the present invention is simple, and high income is cheap, and reaction scheme is short, and the three wastes are few, it is easy to industrialized production.
Description
Technical field
Prepared the invention belongs to anti-chronic obstructive pulmonary disease aclidinium bromide intermediate and application field, more particularly to one
Plant R-2,2- bis- (2- thienyls) -2- hydroxyacetic acids quinine -3- base esters and its preparation and application.
Background technology
Aclidinium bromide (Aclidinium bromide) is ground by American Forest laboratory drugmaker, Almirall companies
System exploitation, ratifies to list, for treating chronic obstructive pulmonary disease (Chronic obstructive for 2013 through U.S. FDA
Pulmonary disease, COPD) active drug, trade name Tudorza Pressair.Current aclidinium bromide imbedibility
Pulvis is approved to be used as the long term maintenance therapy medicine of the bronchial spasm that chronic obstructive pulmonary disease (COPD) causes.This product is daily 2
Secondary medication, belongs to the long-acting anticholinergic agent of imbedibility, and its mechanism of action is by suppressing acetylcholine to tracheal smooth muscle muscarine
The effect of acceptor, promotes bronchiectasis.This product belongs to the long-acting anti-M choline medicine of imbedibility, and the medicine is selectivity M3Receptor antagonist
Agent, can be used for for (the pulmonary airways change of the related bronchial spasm of long term maintenance therapy COPD (COPD)
It is narrow), including chronic bronchitis and pulmonary emphysema.Aclidinium bromide be after after Ipratropium Bromide and Tiotropium Bromide, the 3rd listing it is anti-
Cholinergic bronchodilators, its action speed is faster than Tiotropium Bromide, close to Ipratropium Bromide.It is to M3Cholinergic recepter has
High selectivity, into vivo after can be with M2And M3Acceptor is combined, but itself and M3It is more firm that acceptor is combined, and half-life period is M2
6 times of acceptor, therefore, its long action time belongs to long-acting cholinergic receptor antagonist, and it resists M2The adverse reaction of acceptor is such as
Tachycardia etc., then it is relatively fewer.In addition, aclidinium bromide by tertiary amino it is quaternized after, reduce its oral administration biaavailability and
Through the ability of blood-brain barrier, by the way that after inhalation, systemic adverse reactions are less.(Jones PW.Clinical
potential of aclidinium bromide in chronic obstructive pulmonary
disease.International journal of chronic obstructive pulmonary disease,2015,
10:677-687.；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 Therapy,2013,30(4):354-368.) wherein, R configurations 2,2- bis- (2- thienyls) -2-
Hydroxyacetic acid quinine -3- base esters (1) is the important intermediate for synthesizing aclidinium bromide.(the beam Western Zhou Dynasty, the synthesis of aclidinium bromide, China
Chemical trade, 2014,6,280)
Relevant R configurations 2, the synthesis of 2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters, the synthesis of document report
Route mainly has following 3 kinds of synthetic methods, and the first synthetic method is by 2,2- bis- (2- thienyls) methyl glycollate (2) and R-
3- quinuclidinols (3) are condensed in toluene, obtain 2,2- bis- (2- thienyls) -2- hydroxyacetic acids-R- quinine -3- base esters (1), yield
Only 40%.(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. is also reported and is reacted (2- the thienyls) -2- hydroxy methyl acetates of 2,2- bis- and R-3- quinuclidinols, product without isolation,
Directly with 3- benzene oxygen propyl group bromine reactions, aclidinium bromide is obtained using one pot synthesis.In the synthetic route, a step yield is condensed
It is low, and using chiral R-3- quinuclidinols, synthesize high cost.(Xu Yan, Wang Tao, Gou Yuancheng, yellow Liza, Wang Xu, Hou Chun, Ma Su
Peak, one kettle way prepares the technique of aclidinium bromide, Chinese Patent Application No.：201410004516.3, the applying date：January 6 in 2014
Day.) synthetic route is as follows：
Zhao Shengyin etc. is reacted using Methyl oxatyl chloride (4) with R-3- quinuclidinols, obtains oxalic acid methyl quinuclidine -3- base esters
(5) the RMgBr reaction for, then being prepared with 2- bromothiophenes and magnesium powder, due to sterically hindered reason, RMgBr and three-dimensional position
The small methyl esters reaction of resistance obtains 2- hydroxyl -2,2- bis- (2- thienyls) acetic acid -3- (R) quinuclidinols base ester (4), finally by R-2- hydroxyls
Base -2,2- two (2- thienyls) acetic acid -3- quinines base ester (4) instead gives birth to quaterisation with 3- benzene oxygen propyl bromide and obtains Ah 's bromine
Ammonium, total recovery is up to 20%.A kind of (Zhao Shengyin, Wang Ming 2,2- bis- (2- thienyls) -2- hydroxy-acetic acid-R- quinine -3- base esters
Compound and preparation method thereof, application number：201410853893.4, the applying date：On December 26th, 2014.) synthetic route is as follows：
Gou Yuan really etc. is reported and is reacted oxalyl chloride and R-3- quinuclidinols, obtains-R- quinine -3- base esters (9) of oxalic acid two, and
Reacted with through 2- bromothiophenes and the obtained RMgBr of magnesium powder reaction afterwards, (2- the thienyls) -2- hydroxyacetic acids of 2,2- bis--R- is obtained
Quinine -3- base esters (1).(Gou Yuancheng, Wang Tao, yellow Liza, Hou Chun, Xu Yan, Ma Sufeng, a kind of 2- hydroxyl -2,2- Dithiophenes -2-
Guanidine-acetic acid -1- azabicyclic [2,2,2] octyl- 3- (R)-base ester preparation method, Chinese Patent Application No.：201410004537.5,
The applying date：On January 6th, 2014.), synthetic route is as follows：
First method is by 2,2- bis- (2- thienyls) methyl glycollate (2) and R-3- hydroxyls in above-mentioned three kinds of synthetic methods
Base quinuclidinol (3) is condensed in toluene, obtains 2,2- bis- (2- thienyls) -2- hydroxyacetic acids-R- quinine -3- base esters (1), yield
Only 40%, yield is low；Method two and the third method have used R-3- quinuclidinols largely, expensive in the reaction, cause 2,
2- bis- (2- thienyls) -2- hydroxyacetic acid-R- quinine -3- base ester (1) production cost is higher.
In sum, the shortcomings of there is reaction scheme long, low yield and production cost high in the above method, in large-scale production
Middle cost is of a relatively high.Therefore, new synthetic route is researched and developed, to reduce production cost, simplifies operation, with important meaning
Justice.
The content of the invention
The technical problems to be solved by the invention be to provide a kind of (2- the thienyls) -2- hydroxyacetic acids of R-2,2- bis- quinine -
3- base esters and its preparation and application, present invention reduces the reaction time, reduce production cost, prepared by three-protection design, the present invention
Initiation material is easy to get, low cost, and operation is simple, and reaction scheme is short, it is easy to industrialized production.
A kind of R-2 of the invention, 2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters, the structure of the compound
Formula is：
Fusing point：176~178 DEG C, proterties：White solid.
The nucleus magnetic hydrogen spectrum and mass spectrometric data of R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters are as follows：
1H NMR(400MHz,DMSO-d6)δ:1.25 (s, 1H), 1.52 (d, J=17.5Hz, 3H), 1.92 (s, 1H),
2.78-2.45 (m, 5H), 3.10 (dd, J=12.9,8.1Hz, 1H), 4.82 (s, 1H), 7.01 (d, J=3.3Hz, 2H), 7.12
(s,2H),7.39(s,1H),7.49(s,2H).
MS(EI,m/z):349(M+),197,196,195,126,111,110,42.
The preparation method of a kind of R-2 of the invention, 2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters, including：
(1) by 2,2- bis- (2- thienyls) -2- hydroxy methyl acetates, quinine -3- alcohol and alkali add solvent in, back flow reaction
1~20h, separating-purifying is obtained 2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters；Wherein (the 2- thiophene of 2,2- bis-
Base) -2- hydroxy methyl acetates, quinine -3- alcohol mol ratio be 1.0~2.0:1.0；2,2- bis- (2- thienyls) -2- hydroxyl second
The ratio of sour methyl esters, quinine -3- alcohol and solvent is 1.0~2.0mole:1.0mole:800~1500mL；
(2) 2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters, R- or S- configuration chiral acid resolving agents are added
In entering organic solvent, reaction 10min~10h is refluxed, then cooled down, separating-purifying, obtain R-2,2- bis- (2- thienyls)-
The salt that 2- hydroxyacetic acids quinine -3- base esters and resolving agent are formed, is then neutralized with alkali, obtains final product R configurations 2, and 2- bis- (2- thienyls) -
2- hydroxyacetic acid quinine -3- base esters；Wherein 2,2- bis- (2- thienyls) -2- hydroxyacetic acids quinine -3- base esters and resolving agent rub
You are than being 1.0:1.0~2.0.
Alkali is one or more in sodium hydride, sodium methoxide, caustic alcohol and potassium tert-butoxide in the step (1)；Solvent is
Toluene, dimethylbenzene, ether, isopropyl ether, tetrahydrofuran or dioxane.
Resolving agent is R- or S- configurations (also known as D or L- configurations) chiral acid resolving agent in the step (2).
The sour resolving agent is：L-TARTARIC ACID, D- tartaric acid, L-TARTARIC ACID dibenzoate, D- tartaric acid dibenzoic acids
Ester, L-TARTARIC ACID two (p-methylbenzoic acid) ester, D- tartaric acid two (p-methylbenzoic acid) ester, L- camphorsulfonic acids, D- camphor sulphurs
One or more in acid, L- mandelic acids, D- mandelic acids, L-configuration N- acetyl group leucine, D configuration N- acetyl group leucines.
In the step (2) organic solvent be dichloromethane, 1,2- dichloroethanes, chloroform, ether, tetrahydrofuran, toluene,
One or more in acetone, 2- butanone, 1,4- dioxane, methyl alcohol, ethanol, isopropanol and n-butanol etc..
Reflux temperature is the reflux temperature of room temperature~solvent for use in the step (2).
In the step (2) in alkali and alkali used be organic base or inorganic base.The inorganic base be potassium carbonate, sodium carbonate,
One or more in sodium acid carbonate, potassium hydroxide, NaOH；Organic base is in pyridine, triethylamine, ethyl diisopropyl amine
One or more.
The application of a kind of R-2 of the invention, 2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters, R-2,2- bis-
(2- thienyls) -2- hydroxyacetic acids quinine -3- base esters answering in the anti-chronic obstructive pulmonary disease aclidinium bromide for the treatment of is prepared
With.
The present invention reacts (2- the thienyls) -2- hydroxy methyl acetates of 2,2- bis- and 3- quinuclidinols, obtains 2- hydroxyl -2,2-
Two (2- thienyls) acetic acid -3- quinine base esters, then chiral acid splits, and alkalization obtains R-2- hydroxyl -2,2- in aqueous slkali
Two (2- thienyls) acetic acid -3- quinine base esters, total recovery is up to 20%.
Aclidinium bromide operation prepared by the present invention is simple, and high income is cheap, and reaction scheme is short, and the three wastes are few, easily
In industrialized production, synthetic route is as follows：
Beneficial effect
The present invention is preparing R-2, during 2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters, by 2,2- bis-
(2- thienyls) -2- hydroxy methyl acetates react with 3- quinuclidinols, obtain 2,2- bis- (2- thienyls) -2- hydroxy-acetic acid -3- Kuis
Peaceful base ester, then chiral acid splits, and alkalization obtains R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid -3- Kuis in aqueous slkali
Peaceful base ester, total recovery is up to 20%；
Present invention reduces the reaction time, production cost is reduced, three-protection design, the same yield of the method is higher；The system
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.
Brief description of the drawings
Fig. 1 is the proton nmr spectra of R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters；
Fig. 2 is the hydrogen nuclear magnetic resonance of R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters-L-TARTARIC ACID salt
Spectrum.
Specific embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.In addition, it is to be understood that after the content for having read instruction of the present invention, people in the art
Member can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims and limited
Scope.
Embodiment 1
To 3- quinuclidinols (38.1g, 0.3mol), 600mL dry toluenes is added in 1000mL there-necked flasks, it is dividedly in some parts
60% sodium hydride (13.2g, 0.33mol), after 15min is stirred at room temperature, is dividedly in some parts 2- hydroxyl -2,2- bis- (2- thienyls) acetic acid
Methyl esters (76.2g, 0.3mol), back flow reaction 6h.Reaction is finished, the 250mL that adds water stirring 20min, separates toluene layer, anhydrous sodium sulfate
Dry rotation and remove solvent, strive for solvent afforded crude material.Ethyl alcohol recrystallization, obtains 54.5g white solids, yield：52.1%.Mp:175~
177℃。IR(KBr):3435,3075,2946,2876,2735,1732,1637,1566,1423,1354,1320,1232,
1132,1085,997,837,784,689.1H-NMR(400MHz,DMSO-d6)δ:1.24(m,2H),1.54-1.58(m,3H),
1.91(m,1H),2.45(m,1H),2.58-2.60(m,3H),3.07-3.36(m,1H),4.80-4.82(m,1H),6.69-
7.02(m,2H),7.11-7.12(m,2H),7.36(m,1H),7.49-7.51(m,2H).
Embodiment 2
To sequentially added in 250mL eggplant-shape bottles 2,2- bis- (2- thienyls) -2- hydroxy-acetic acid -3- quinines ester (15.0g,
0.043mol), L-TARTARIC ACID (6.45g, 0.043mol), 180mL absolute ethyl alcohols, are heated to the 30min that flows back, reaction solution clarification.
Room temperature is cooled to, white solid is separated out.Suction filtration obtains 8.4g white solids, yield 39.1%.[α]D 25=+116.1 ° of (c=0.8g/
100mL,H2O)。1H NMR(400MHz,DMSO-d6)δ:1.08 (d, J=6.4Hz, 2H), 1.65 (dd, J=66.5,27.4Hz,
4H), 2.13 (s, 1H), 2.93 (t, J=33.3Hz, 5H), 3.41 (dd, J=19.3,12.0Hz, 2H), 4.06 (s, 2H),
5.04(s,1H),7.01(s,2H),7.14(s,2H),7.50(s,2H),7.73(s,2H).
2,2- bis- (2- thienyls) -2- hydroxy-acetic acid -3- quinine ester-L- wine is obtained to step on being added in 100mL eggplant-shape bottles
Stone hydrochlorate, 50mL ethanol, add sodium hydroxide solution to adjust pH to 7~8, and reaction 30min, cooling, chloroform extraction is stirred at room temperature.Remove
Solvent is removed, 5.1g white solid R-2- hydroxyl -2,2- bis- (2- thienyls) quinin(e) acetate ester, Mp are obtained:175-178 DEG C, yield is
33.8%, [α]D 21.5=35.4 ° (c=0.125g/100mL 1N HCl).1H NMR(400MHz,DMSO-d6)δ:1.25(s,
1H), 1.52 (d, J=17.5Hz, 3H), 1.92 (s, 1H), 2.78-2.45 (m, 5H), 3.10 (dd, J=12.9,8.1Hz,
1H), (s, the 2H) .MS (m/z) of 4.82 (s, 1H), 7.01 (d, J=3.3Hz, 2H), 7.12 (s, 2H), 7.39 (s, 1H), 7.49:
349(M+),197,196,195,126,111(74.53),110,42.
Embodiment 3
To 3- quinuclidinols (25.4g, 0.2mol), 500mL dry toluenes is added in 1000mL there-necked flasks, first is dividedly in some parts
Sodium alkoxide (11.9g, 0.22mol), after 15min is stirred at room temperature, is dividedly in some parts 2,2- bis- (2- thienyls) 2- hydroxy methyl acetates
(53.5g, 0.21mol), back flow reaction 8h.Reaction is finished, the 250mL that adds water stirring 20min, separates toluene layer, and anhydrous sodium sulfate is done
It is dry, boil off solvent afforded crude material.Ethyl alcohol recrystallization, obtains 35.1g white solids 2,2- bis- (2- thienyls) -2- hydroxy-acetic acid -3- Kuis
Peaceful ester, yield 48.1%, mp:176~178 DEG C.
Embodiment 4
To 3- quinuclidinols (44.5g, 0.35mol), 600mL dioxane is added in 1000mL there-necked flasks, it is dividedly in some parts
Caustic alcohol (27.2g, 0.4mol), after 15min is stirred at room temperature, is dividedly in some parts 2- hydroxyl -2,2- bis- (2- thienyls) methyl acetate
(76.2g, 0.30mol), back flow reaction 6h.Reaction is finished, and is boiled off solvent and is added water 250mL, ethyl acetate 500mL, stirs 10min,
Ethyl acetate is separated, anhydrous sodium sulfate drying boils off solvent afforded crude material.Ethyl alcohol recrystallization, obtains 47.1g white solids 2,2- bis-
(2- thienyls) -2- hydroxy-acetic acid -3- quinine esters, yield 45.0%, mp:175~177 DEG C.
Embodiment 5
To sequentially added in 1000mL eggplant-shape bottles 2,2- bis- (2- thiophene) -2- hydroxyacetic acid -3- quinines ester (34.9g,
0.10mol), L- bis- (benzoyl) tartaric acid (71.6g, 0.20mol), 300mL absolute ethyl alcohols, are heated to the 30min that flows back, instead
Liquid is answered to clarify.Room temperature is cooled to, is stirred 2 hours, separate out white solid.Suction filtration obtains 24.4g white solids, yield 34.5%.
(2- the thiophene) -2- of R-2,2- bis- hydroxyls-guanidine-acetic acid -3- quinine base esters are obtained to step on being added in 500mL eggplant-shape bottles
L- bis- (benzoyl) tartrate, 200mL ethanol, add 10% NaOH ethanol solution to adjust pH to 7~8, are stirred at room temperature
Reaction 30min, cooling, chloroform extraction.Solvent is removed, 10.1g white solid R-2- hydroxyl -2,2- bis- (2- thienyls) acetic acid are obtained
3- quinine base esters, yield is 29.0%, Mp:175-178℃.
Embodiment 6
To sequentially added in 250mL eggplant-shape bottles 2,2- bis- (2- thienyls) -2- hydroxy-acetic acid -3- quinines base ester (15.0g,
0.043mol), L- bis- is heated to the 30min that flows back to toluoyltartaric (16.6g, 0.043mol), 250mL absolute ethyl alcohols,
Reaction solution is clarified.Room temperature is cooled under stirring, continues to stir 4h, separate out white solid.Suction filtration obtains 12.0g white solids, yield
38.0%.
White solid, 100mL95% ethanol is obtained to step on being added in 250mL eggplant-shape bottles, adds sodium hydroxide solution to adjust
PH is stirred at room temperature reaction 30min, cooling, chloroform extraction to 7~8.Solvent is removed, 4.6g white solid R-2- hydroxyl -2,2- are obtained
Two (2- thienyls) quinin(e) acetate -3- esters, Mp:176-178 DEG C, yield is 30.5%.
Embodiment 7
To sequentially added in 250mL eggplant-shape bottles 2,2- bis- (2- thienyls) -2- hydroxyacetic acid -3- quinines base ester (17.5g,
0.05mol), L- camphorsulfonic acids (11.6g, 0.05mol), 250mL absolute ethyl alcohols, are heated to the 30min that flows back, reaction solution clarification.
Room temperature is cooled under stirring, continues to stir 4h, separate out white solid.Suction filtration obtains 9.9g white solids, yield 34.1%.
2,2- bis- (2- thienyls) -2- hydroxy-acetic acid -3- quinine base esters L- is obtained to step on being added in 250mL eggplant-shape bottles
Camsilate, 100mL95% ethanol, add sodium hydroxide solution to adjust pH to 7~8, and reaction 30min, cooling, chlorine is stirred at room temperature
Imitative extraction.Solvent is boiled off, 5.6g white solid R-2- hydroxyl -2,2- bis- (2- thienyls) acetic acid -3- quinine base esters are obtained, yield is
32.0%, Mp:175-178℃.
Embodiment 8
To sequentially added in 1000mL eggplant-shape bottles 2,2- bis- (2- thienyls) -2- hydroxyacetic acid -3- quinines base ester (34.9g,
0.10mol), L- mandelic acids (15.2g, 0.10mol), 300mL absolute ethyl alcohols, are heated to backflow 1 hour, reaction solution clarification.It is cold
But to room temperature, white solid is separated out.Suction filtration obtains 18.8g white solids, yield 37.5%.
2,2- bis- (2- thienyls) -2- hydroxy-acetic acid -3- quinine base esters L- is obtained to step on being added in 500mL eggplant-shape bottles
Mandelate, 200mL ethanol, add 10% NaOH ethanol solution to adjust pH to 7~8, and reaction 30min is stirred at room temperature, and cool down,
Chloroform is extracted.Solvent is boiled off, 9.6g white solid R-2- hydroxyl -2,2- bis- (2- thienyls) acetic acid -3- quinine base esters, yield are obtained
It is 27.6%, Mp:175-178℃.
Embodiment 9
To sequentially added in 1000mL eggplant-shape bottles 2,2- bis- (2- thienyls) -2- hydroxyacetic acid -3- quinines ester (34.9g,
0.10mol), L- configurations N- acetyl group leucine (17.3g, 0.10mol), 300mL absolute ethyl alcohols, are heated to backflow 2 hours, instead
Liquid is answered to clarify.Room temperature is cooled to, white solid is separated out.Suction filtration obtains 16.4g white solids, yield 31.5%.
2,2- bis- (2- thienyls) -2- hydroxy-acetic acid -3- quinine esters L-N- is obtained to step on being added in 500mL eggplant-shape bottles
Acetyl group leucine salt, 200mL ethanol, add 10% NaOH ethanol solution to adjust pH to 7~8, and reaction is stirred at room temperature
30min, cooling, chloroform extraction.Solvent is boiled off, 9.3g white solid R-2- hydroxyl -2,2- bis- (2- thienyls) acetic acid -3- Kuis are obtained
Peaceful base ester, yield is 26.5%, Mp:174-176℃.
Claims (7)
1. a kind of R-2, the preparation method of 2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters, including：
(1) by 2,2- bis- (2- thienyls) -2- hydroxy methyl acetates, quinine -3- alcohol and alkali add solvent in, back flow reaction 1-
20h, separating-purifying is obtained 2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters；Wherein 2,2- bis- (2- thienyls)-
2- hydroxy methyl acetates, the mol ratio of quinine -3- alcohol are 1.0~2.0:1.0；2,2- bis- (2- thienyls) -2- hydroxyacetic acid first
The ratio of ester, quinine -3- alcohol and solvent is 1.0~2.0mol:1.0mol:800~1500mL；
(2) by 2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters, resolving agent addition organic solvent, it is refluxed
Reaction 10min~10h, then cools down, separating-purifying, obtains R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters
Chiral hydrochlorate, is then neutralized with alkali, and the product that dissociates obtains final product R configurations 2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- bases
Ester；The mol ratio of wherein 2,2- bis- (2- thienyls) -2- hydroxyacetic acids quinine -3- base esters and resolving agent is 1.0:1.0~2.0；
The structural formula of wherein R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters is：
2. the preparation side of a kind of R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters according to claim 1
Method, it is characterised in that：Alkali is one or more in sodium hydride, sodium methoxide, caustic alcohol and potassium tert-butoxide in the step (1)；
Solvent is toluene, dimethylbenzene, ether, isopropyl ether, tetrahydrofuran or dioxane.
3. the preparation side of a kind of R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters according to claim 1
Method, it is characterised in that：Resolving agent is R- or S- configuration chiral acid resolving agents in the step (2).
4. the preparation side of a kind of R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters according to claim 1
Method, it is characterised in that：The sour resolving agent is：L-TARTARIC ACID, D- tartaric acid, L-TARTARIC ACID dibenzoate, D- tartaric acid two
Benzoic ether, L-TARTARIC ACID two (p-methylbenzoic acid) ester, D- tartaric acid two (p-methylbenzoic acid) ester, L- camphorsulfonic acids, D-
One kind in camphorsulfonic acid, L- mandelic acids, D- mandelic acids, L- configuration N- acetyl group leucine, D-form N- acetyl group leucines
Or it is several.
5. the preparation side of a kind of R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters according to claim 1
Method, it is characterised in that：Organic solvent is dichloromethane, 1,2- dichloroethanes, chloroform, ether, tetrahydrochysene furan in the step (2)
Mutter, one or more in toluene, acetone, 2- butanone, 1,4- dioxane, methyl alcohol, ethanol, isopropanol and n-butanol.
6. the preparation side of a kind of R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters according to claim 1
Method, it is characterised in that：Reflux temperature is the reflux temperature of room temperature~solvent for use in the step (2).
7. the preparation side of a kind of R-2,2- bis- (2- thienyls) -2- hydroxyacetic acid quinine -3- base esters according to claim 1
Method, it is characterised in that：In the step (2) in alkali and alkali used be organic base and/or inorganic base；Wherein inorganic base is carbonic acid
One or more in potassium, sodium carbonate, sodium acid carbonate, potassium hydroxide, NaOH；Organic base is pyridine, triethylamine, ethyl two
One or more in isopropylamine.
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| WO2011048607A1 (en) * | 2009-09-25 | 2011-04-28 | Cadila Healthcare Limited | Processes for the preparation of solifenacin or a salt thereof |
| 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 |
| CN104478871A (en) * | 2014-12-26 | 2015-04-01 | 东华大学 | Choline M receptor antagonist aclidinium bromide and preparation method thereof |
| CN104496981A (en) * | 2014-12-26 | 2015-04-08 | 东华大学 | 2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011048607A1 (en) * | 2009-09-25 | 2011-04-28 | Cadila Healthcare Limited | Processes for the preparation of solifenacin or a salt thereof |
| 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 |
| CN104478871A (en) * | 2014-12-26 | 2015-04-01 | 东华大学 | Choline M receptor antagonist aclidinium bromide and preparation method thereof |
| CN104496981A (en) * | 2014-12-26 | 2015-04-08 | 东华大学 | 2,2-dithienyl-2-hydroxycaproic acid-R-quinine-3-ester compound and preparation method thereof |
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