CN101993444A - Method to synthesize quinuclidine hydrochloride - Google Patents
Method to synthesize quinuclidine hydrochloride Download PDFInfo
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- CN101993444A CN101993444A CN2009100564959A CN200910056495A CN101993444A CN 101993444 A CN101993444 A CN 101993444A CN 2009100564959 A CN2009100564959 A CN 2009100564959A CN 200910056495 A CN200910056495 A CN 200910056495A CN 101993444 A CN101993444 A CN 101993444A
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- 0 *=C(C1CCNCC1)O Chemical compound *=C(C1CCNCC1)O 0.000 description 1
- OBXXSRPAQLOXJN-UHFFFAOYSA-N CCOC(CN(CC1)CCC1C(OCC)=O)=O Chemical compound CCOC(CN(CC1)CCC1C(OCC)=O)=O OBXXSRPAQLOXJN-UHFFFAOYSA-N 0.000 description 1
- ZKMZPXWMMSBLNO-UHFFFAOYSA-N O=C1C(CC2)CCN2C1 Chemical compound O=C1C(CC2)CCN2C1 ZKMZPXWMMSBLNO-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a method to synthesize intermediates, particularly a method to synthesize quinuclidine hydrochloride, which has simple operation and low cost and is suitable for extensive industrial production. The method comprises the following steps of: carrying out esterification, addition, condensation and decarboxylation on 4-piperidine formic acid which is used the raw material; and carrying out improved Huangminglong reduction to obtain the quinuclidine hydrochloride.
Description
Technical field
The present invention relates to the synthetic method of intermediate in the pharmaceutical chemistry technical field, concrete is a kind of synthetic method of rubane hydrochloride, be to be starting raw material,, obtain the rubane hydrochloride through improved Huang Min-lon reduction again through esterification, addition, condensation, decarboxylation with the 4-piperidine carboxylic acid.
Background technology
Rubane is the complexing agent of organometallic compound, and it also is important medicine intermediate simultaneously, is the emphasis of domestic and international pharmaceutical industries research and concern always.Document (Journal of theChemical Society; 1937; 1989) reported that two kinds is the method that starting raw material synthesizes rubane with the 3-quininone hydrochlorate: one, be starting raw material with the 3-quininone hydrochlorate, with the hydrazine hydrate is reductive agent, obtains target compound through high pressure, pyroreaction in sodium ethylate/ethanol system.Synthetic route has adopted high pressure-temperature, and operation inconvenience, unsuitable industry's enlarging production; Being starting raw material with 3-quinuclidone hydrochloride two,, is reductive agent with the zinc amalgam, and refluxing in the presence of concentrated hydrochloric acid obtains target compound.The zinc amalgam reagent that adopts in the route, and the preparation of zinc amalgam itself just need be used the contour toxic agent of mercury bichloride, this has just limited the feasibility of its suitability for industrialized production greatly.So, but seek a kind of method of comparatively safe, with low cost while large-scale industrial production, be the emphasis that the researchist pays close attention to all the time.
Summary of the invention
The purpose of this invention is to provide a kind of simple to operate, the rubane hydrochloride synthetic method of applicable large-scale industrial production with low cost.
For achieving the above object, technical scheme of the present invention is: the synthetic method of rubane hydrochloride, be to be raw material, through esterification and addition (II), condensation and decarboxylation (III), be dehydrated into hydrazone (IV), obtain rubane hydrochloride (V) through improved Huang Min-lon reduction again with 4-piperidine carboxylic acid (I).Method of the present invention can be represented with following reaction formula:
Embodiment 1:
Synthesizing of 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (II), realize by following step:
1) method one:
400g 4-piperidine carboxylic acid (I) is thrown in the 10L there-necked flask, added the absolute alcohol solvent, present embodiment is the dehydrated alcohol of 4L.Other adds 2mL N, and dinethylformamide, temperature control drip the 46.1g sulfur oxychloride below 30 ℃.Dropwise, remove ice bath, reflux 3-8h (preferably 6h), reaction solution clarification.Cool to below 50 ℃, be generally room temperature, add the 1280g Anhydrous potassium carbonate, drip the halogenated acetic acids ethyl ester, present embodiment is the 420g ethyl chloroacetate, temperature rising reflux 3-8h (preferably 5h).Reaction solution is reduced to room temperature, and suction filtration, filtrate concentrate, and reclaim ethanol.Add organic solvent in concentration residue, present embodiment is the methyl tertiary butyl ether of 1L, methylene dichloride, ethyl acetate also can, gentle agitation 0.5h.Suction filtration, filtrate is used anhydrous magnesium sulfate drying, the filter cake about 600mL of 25-28% ammonia solvent, PH=10.With methyl tertiary butyl ether extraction (300mL * 3), merge organic phase again.Anhydrous acid magnesium drying, suction filtration, filtrate concentrates, and the underpressure distillation of gained oily liquids gets 208g colourless oil liquid 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (II).Purity: 97.2% (GC), moisture: 0.06% (KF), yield 27.6%.
2) method two:
400g 4-piperidine carboxylic acid (I) is thrown in the 10L there-necked flask, added the 4L dehydrated alcohol.Other adds 2mL N, and dinethylformamide, temperature control drip the 46.1g sulfur oxychloride below 30 ℃.Dropwise, remove ice bath, reflux 6h, reaction solution clarification.Cool to below 50 ℃, add the 1280g Anhydrous potassium carbonate, Dropwise 5 70g ethyl bromoacetate, temperature rising reflux 5h.The TLC/GC detection reaction is complete.Reaction solution is reduced to room temperature, and suction filtration, concentrated filtrate reclaim ethanol.The methyl tertiary butyl ether that in concentration residue, adds 1L, gentle agitation 0.5h.Suction filtration, filtrate is used anhydrous magnesium sulfate drying, the filter cake about 600mL of 25-28% ammonia solvent, PH=10 is again with methyl tertiary butyl ether extraction (300mL * 3).Merge organic phase, anhydrous magnesium sulfate drying.Suction filtration, filtrate is concentrated into dried, gets 655.4g light brown liquid 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (II), purity: 96.2% (GC), moisture: 0.08% (KF), yield 86.4%.
3) method three:
400g4-piperidine carboxylic acid (I) is thrown in the 10L there-necked flask, added the 4L dehydrated alcohol.Other adds 2mL N, and dinethylformamide, temperature control drip the 46.1g sulfur oxychloride below 30 ℃.Dropwise, remove ice bath, reflux 6h, the reaction solution clarification, the TLC detection reaction is complete.Steam and remove ethanol, residuum is joined in the 4L acetone, add the 1280g Anhydrous potassium carbonate.Drip the 420g ethyl chloroacetate then, temperature rising reflux 5h.Reaction solution is reduced to room temperature, suction filtration, and concentrated filtrate reclaims acetone.The methyl tertiary butyl ether that in concentration residue, adds 1L, gentle agitation 0.5h.Suction filtration, filtrate is used anhydrous magnesium sulfate drying, the filter cake about 600mL of 25-28% ammonia solvent, PH=10 is again with methyl tertiary butyl ether extraction (300mL * 3).Merge organic phase, anhydrous magnesium sulfate drying, suction filtration, filtrate is concentrated into dried, gets 605.4g light brown liquid 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (II), purity: 96.7% (GC), moisture: 0.10% (KF), yield 79.8%.
4) method four:
400g 4-piperidine carboxylic acid (I) is thrown in the 10L there-necked flask, added the 4L dehydrated alcohol.Other adds 2mL N, and dinethylformamide, temperature control drip the 46.1g sulfur oxychloride below 30 ℃.Dropwise, remove ice bath, reflux 6h, the reaction solution clarification, the TLC detection reaction is complete.Steam and remove ethanol, residuum is joined 3L N, in the dinethylformamide, add the 1280g Anhydrous potassium carbonate.Drip the 420g ethyl chloroacetate then, temperature rising reflux 5h.Reaction solution is reduced to room temperature, adds 6L water in reaction solution, then, and with methyl tert-butyl ether (3L x3) extraction.Organic phase is washed with saturated aqueous common salt (1.5L x 3), anhydrous magnesium sulfate drying, suction filtration, and filtrate is concentrated into dried, get 695.4g light brown liquid 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (II), purity: 95.8% (GC), moisture: 0.10% (KF), yield 91.7%.
Embodiment 2:
Synthesizing of quinuclidone (III), realize by following step:
Method one:
Get 100g intermediate 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (II), add 100mL toluene, stir, be added drop-wise in the basic solvent, present embodiment is that reaction solution becomes light red by clarification in the 200mL toluene reaction solution of 56g sodium ethylate.Dropwise, temperature of reaction system is about 80～90 ℃ (preferred: 85 ℃).Under the condition of normal pressure, reaction solvent to the system temperature that boils off in the system reaches about 80～110 ℃, reaction 6～10h, and it is complete that TLC/GC detects raw material reaction.Stopped reaction is reduced to room temperature, adds diluted acid (as dilute hydrochloric acid or dilute sulphuric acid), and present embodiment is 200mL dilute hydrochloric acid (2mol/L), stirs 0.5h, leaves standstill, and tells water.Add diluted acid to toluene in mutually again, present embodiment is 175mL dilute hydrochloric acid (2mol/L), stirs 15min, leaves standstill, and tells water.Merge above-mentioned water, be warming up to 100～120 ℃ of decarboxylation 8～12h that are hydrolyzed, stopped reaction removes moisture under reduced pressure substantially to doing, and reduces to room temperature.Add the alkaline solution neutralization earlier, present embodiment is that the NaOH 2mol/L of 50mL stirs 15min, adds the 150g Anhydrous potassium carbonate then and stirs into pulpous state, PH=10～12.With dichloromethane extraction pulpous state liquid (150mL * 4), methylene dichloride is on the upper strata, and TLC confirms that extraction fully.Merge organic phase, anhydrous MgSO4 drying, suction filtration, filtrate concentrates.Get brown oil 47.0g, this brown oil is dissolved in the 200mL methyl tert-butyl ether, the ice-water bath cooling feeds dry hydrogen chloride gas down, to PH＜1, separates out a large amount of red-brown solids.Recrystallizing methanol, the hydrochloride of 13.0g light brown pressed powder quinuclidone (III).Purity: 96.3% (GC), moisture: 0.12% (KF), yield 19.5%.
1) method two:
Get 100g intermediate 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (II), add 100mL toluene, stir, be added drop-wise in the 200mL toluene reaction solution of 69.4g potassium ethylate, reaction solution becomes garnet by clarification.Drip and finish, temperature of reaction system is about 80～90 ℃, and under the condition of normal pressure, reaction solvent to the system temperature that boils off in the system reaches about 100 ℃, reaction 6h.It is complete that TLC/GC detects raw material reaction.Stopped reaction is reduced to room temperature, adds the rare HCl of 200mL (2mol/L), stirs 0.5h, leaves standstill, and tells water.Add the rare HCl of 175mL (2mol/L) to toluene in mutually again, stir 15min, leave standstill, tell water.Merge above-mentioned water, be warming up to 110 ℃ of decarboxylation 10h that are hydrolyzed, stopped reaction removes moisture under reduced pressure to dried substantially, reduces to room temperature.Add 50mL 20%NaOH earlier and stir 15min, add the 150g Anhydrous potassium carbonate then and stir into pulpous state, PH=10～12.Add DCM extraction pulpous state liquid (150mL * 4), DCM is on the upper strata, and TLC confirms that extraction fully.Merge organic phase, anhydrous MgSO4 drying, suction filtration, concentrated get 35.0g light brown pressed powder quinuclidone (III).Purity: 97.4% (GC), moisture: 0.11% (KF), yield 68.1%.
2) method three:
Get 100g intermediate 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (II), add 100mL toluene, stir, be added drop-wise in the 200mL toluene reaction solution of 92g potassium tert.-butoxide, reaction solution becomes garnet by clarification.Drip and finish, temperature of reaction system is about 80～90 ℃, and under the condition of normal pressure, reaction solvent to the system temperature that boils off in the system reaches about 100 ℃, reaction 5～8h, and water is warming up to 110 ℃ of decarboxylation 8h that are hydrolyzed.Stopped reaction removes moisture under reduced pressure to dried substantially, reduces to room temperature.Add 50mL 20%NaOH earlier and stir 15min, add the 150g Anhydrous potassium carbonate then and stir into pulpous state, PH=10～12.Add DCM extraction pulpous state liquid (150mL * 4), DCM is on the upper strata, and TLC confirms that extraction fully.Merge organic phase, anhydrous MgSO4 drying, suction filtration, concentrated organic phase get 41.1g brown solid quinuclidone (III), purity: 99.3% (GC), moisture: 0.10% (KF), yield 80% to doing.
3) method four:
Get the 32g potassium metal, careful repeatedly join in the 3L reaction flask that fills in the 1L ethanol strong reaction heat release venting, temperature rising reflux.After treating the potassium metal total overall reaction, restir 0.5h, normal pressure steam and remove excess ethanol to the reaction solution pulp, and adding 200mL toluene temperature rising reflux is standby.Get 100g intermediate 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (II), add 100mL toluene, stir, be added drop-wise in the above-mentioned reaction solution, reaction solution becomes garnet by clarification.Drip and finish, temperature of reaction system is about 80～90 ℃, and under the condition of normal pressure, reaction solvent to the system temperature that boils off in the system reaches about 100 ℃, picks up counting reaction 15h.It is complete that TLC/GC detects raw material reaction, and reaction solution is reduced to room temperature.Add the rare HCl of 200mL (2mol/L), stir 0.5h, leave standstill, tell water.Add the rare HCl of 175mL (2mol/L) to toluene in mutually again, stir 15min, leave standstill, tell water.Merge above-mentioned water, be warming up to 110 ℃ of decarboxylation 18h that are hydrolyzed.Stopped reaction removes moisture under reduced pressure substantially to doing, and reduces to room temperature.Add 50mL 20%NaOH earlier and stir 15min, add the 150g Anhydrous potassium carbonate then and stir into pulpous state, PH=10～12.Add DCM extraction pulpous state liquid (150mL * 4), DCM is on the upper strata, and TLC confirms that extraction fully.Merge organic phase, anhydrous MgSO4 drying, suction filtration concentrates organic phase to doing.Get 33.0g brown solid quinuclidone (III), purity: 99.3% (GC), moisture: 0.10% (KF), yield 64%.
Embodiment 3:
Synthesizing of rubane hydrochloride (V), realize by following step:
1) method one:
Get 1Kg quininone (III) hydrochloride, under the condition of ice bath in a small amount in repeatedly the sodium hydroxide solution of the 2N that joins 2.9L, add 65.6g yellow soda ash solid then, stir 0.5h, use methylene dichloride (1.5L * 3) extraction then, combined dichloromethane layer, anhydrous sodium sulfate drying, concentrate drying obtains 670g intermediate quininone, yield 87%.Above-mentioned quininone is repeatedly joined in 1.3L 95% hydrazine hydrate on a small quantity at leisure, and 120 ℃ of reflux are spent the night then, cooling, and in 0 ℃ of placement 3h, crystal is separated out.Filter, crystal is placed refrigerator repetition aforesaid operations with uncle's 800mL butyl ether rinsing 3 times, filtering mother liquor, merges to obtain white crystal 3-rubane hydrazone 670g.Above-mentioned 670g 3-rubane hydrazone, alkali (present embodiment is a 810g potassium hydroxide) and 3.4L high-boiling point alcohol (can be water-soluble high boiling point alcohols such as ethylene glycol, tirethylene glycol, triethylene Glycol) are stirred 5～6h (a large amount of nitrogen gas generation are wherein arranged) for 175 ℃.Cooling, pressure reducing and steaming 2.5L high-boiling point alcohol, with methylene dichloride or trichloromethane or tetracol phenixin or 1, the 2-ethylene dichloride waits (3L * 3) extraction, anhydrous sodium sulfate drying, filter rapidly, pour at leisure in the 2N ethyl acetate hydrogen chloride solution that stirs under the 2.5L ice bath, concentrate, filter gained white solid recrystallization in 1.0L Virahol or methyl alcohol or ethanol or n-propyl alcohol, cold filtration obtains rubane hydrochloride 500g, yield 70%.Purity: 99.5% (ELSD).
2) method two:
Get 1Kg quininone (III) hydrochloride, under the condition of ice bath in a small amount in repeatedly the sodium hydroxide solution of the 2N that joins 2.9L, add 65.6g yellow soda ash solid then, stir 0.5h, use methylene dichloride (1.5L * 3) extraction then, combined dichloromethane layer, anhydrous sodium sulfate drying, concentrate drying obtain 675g intermediate quininone.Above-mentioned quininone is repeatedly joined in 1.3L 95% hydrazine hydrate on a small quantity at leisure, and 120 ℃ of reflux are spent the night then, cooling, and in 0 ℃ of placement 3h, crystal is separated out.Filter, crystal is placed refrigerator repetition aforesaid operations with uncle's 800mL butyl ether rinsing 3 times, filtering mother liquor, merges to obtain white crystal 3-rubane hydrazone 650g.Above-mentioned 650g3-rubane hydrazone, 1380g sodium ethylate and 3.4L ethylene glycol are stirred 5～6h (a large amount of nitrogen gas generation are wherein arranged) for 175 ℃.Cooling, pressure reducing and steaming 2.5L ethylene glycol, with methylene dichloride (3L * 3) extraction, anhydrous sodium sulfate drying filters rapidly, pour at leisure in the ethyl acetate hydrogen chloride solution that stirs 2N under the 2.5L ice bath, concentrate, filter, the gained white solid is recrystallization in the 1.0L Virahol, cold filtration obtains rubane hydrochloride 250g, yield 35%.Purity: 99.2% (ELSD).
3) method three:
Get 1Kg quininone (III) hydrochloride, under the condition of ice bath in a small amount in repeatedly the sodium hydroxide solution of the 2N that joins 2.9L, add 65.6g yellow soda ash solid then, stir 0.5h, use methylene dichloride (1.5L * 3) extraction then, combined dichloromethane layer, anhydrous sodium sulfate drying, concentrate drying obtain 665g intermediate quininone.Above-mentioned quininone is repeatedly joined in 1.3L 95% hydrazine hydrate on a small quantity at leisure, and 120 ℃ of reflux are spent the night then, cooling, and in 0 ℃ of placement 3h, crystal is separated out.Filter, crystal is placed refrigerator repetition aforesaid operations with uncle's 800mL butyl ether rinsing 3 times, filtering mother liquor, merges to obtain white crystal 3-rubane hydrazone 668g.Above-mentioned 668g 3-rubane hydrazone, 2300g potassium tert.-butoxide (triplication) and 3.4L ethylene glycol are stirred 5～6h (a large amount of nitrogen gas generation are wherein arranged) for 175 ℃.Cooling, pressure reducing and steaming 2.5L ethylene glycol, with methylene dichloride (3L * 3) extraction, anhydrous sodium sulfate drying filters rapidly, pour at leisure in the ethyl acetate hydrogen chloride solution that stirs 2N under the 2.5L ice bath, concentrate, filter, the gained white solid is recrystallization in the 1.0L Virahol, cold filtration obtains rubane hydrochloride 400g, yield 56%.Purity: 99% (ELSD).
Claims (9)
1. the synthetic method of a rubane hydrochloride is characterized in that, may further comprise the steps:
1) in the alcoholic solvent, 4-piperidine carboxylic acid (I) reacts under condition of ice bath with sulfur oxychloride, after finishing, drip the halogenated acetic acids ethyl ester, temperature rising reflux 3-8h, reduce to below 50 ℃, handle filtrate,, merge organic phase through extraction, drying, suction filtration, filtrate concentrate, and get oily object---1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (worker I);
2) 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (I worker) and toluene react under alkaline condition, system temperature 80-90 ℃, boil off solvent in the system under the normal pressure to 80～110 ℃ of system temperatures, reaction 6～10h, after question response finishes, stopped reaction, reduce to room temperature, add diluted acid and stir, leave standstill and tell water, add diluted acid to toluene in mutually again, stir, leave standstill and tell water, merge water, be warming up to 110～120 ℃ of decarboxylation 8～12h that are hydrolyzed, stopped reaction, remove moisture under reduced pressure, reduce to room temperature, add in the alkali and unnecessary acid, transferring pH is 10～12, extraction, drying, suction filtration, concentrate, get brown solid powder---quinuclidone (III);
3) with a small amount of slowly the joining in the hydrazine hydrate repeatedly of above-mentioned quinuclidone (III), 110～120 ℃ of following reflux are spent the night, cooling, crystallization.Filter, washing crystal, the mother liquor behind the washing and filtering is put into the refrigerator repetitive operation, merge more white crystal 3-rubane hydrazones, this white crystal 3-rubane hydrazone and doses alkali, high-boiling point alcohol are stirred 5～6h, cooling, the pressure reducing and steaming high-boiling point alcohol, extraction, drying, filter, slowly pour in the ethyl acetate/hydrogen chloride solution that stirs under the ice bath, concentrate, filter, reflux in Virahol or methyl alcohol or ethanol or n-propyl alcohol, cool off rubane hydrochloride (V);
Above-mentioned reaction formula is as follows:
2. the synthetic method of rubane hydrochloride according to claim 1 is characterized in that, the alcoholic solvent in the described step 1) is an ethanol, and the halogenated acetic acids ethyl ester is bromoethyl acetate or chloracetic acid ethyl ester.
3. the synthetic method of rubane hydrochloride according to claim 1 is characterized in that, the extraction in the described step 1) takes methyl tertiary butyl ether or methylene dichloride or ethyl acetate to carry out.
4. the synthetic method of rubane hydrochloride according to claim 1 is characterized in that, described step 2) in alkaline condition be the solution of sodium ethylate, potassium ethylate, potassium tert.-butoxide or basic metal and pure direct reaction.
5. the synthetic method of rubane hydrochloride according to claim 1 is characterized in that, described step 2) in diluted acid be dilute hydrochloric acid or dilute sulphuric acid.
6. the synthetic method of rubane hydrochloride according to claim 1 is characterized in that, described step 2) in the alkali that adds be rudimentary sodium alkoxide such as sodium methylate, potassium methylate or sodium ethylate, potassium ethylate or sodium tert-butoxide, potassium tert.-butoxide etc. or potassium.
7. the synthetic method of rubane hydrochloride according to claim 1 is characterized in that, the alkali in the described step 3) is potassium hydroxide, sodium ethylate or potassium tert.-butoxide, and its mol ratio consumption is 3 times of amounts of white crystal 3-rubane hydrazone.
8. the synthetic method of rubane hydrochloride according to claim 1 is characterized in that, high-boiling point alcohol is ethylene glycol or tirethylene glycol or triethylene Glycol in the described step 3).
9. the synthetic method of rubane hydrochloride according to claim 1 is characterized in that, extraction is to take methylene dichloride or trichloromethane or tetracol phenixin or 1 in the described step 3), and the 2-ethylene dichloride extracts.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113366A (en) * | 2013-03-13 | 2013-05-22 | 济南圣泉唐和唐生物科技有限公司 | Preparation method for 3-quinuclidone |
| CN104418851A (en) * | 2013-09-02 | 2015-03-18 | 上海龙翔生物医药开发有限公司 | Preparation method and purification method of quinuclidine derivatives |
| CN107721999A (en) * | 2017-11-03 | 2018-02-23 | 石家庄市度智医药科技有限公司 | A kind of preparation method of the quinuclidinol of optical activity 3 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012226A (en) * | 2007-01-26 | 2007-08-08 | 武汉理工大学 | Method of synthesizing 3-quininone hydrochlorate |
-
2009
- 2009-08-18 CN CN2009100564959A patent/CN101993444A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012226A (en) * | 2007-01-26 | 2007-08-08 | 武汉理工大学 | Method of synthesizing 3-quininone hydrochlorate |
Non-Patent Citations (3)
| Title |
|---|
| G.R.CLEMO AND T.P.METCALFE: "2-Ketoquinuclidine and a New Synthesis of Quinuclidine", 《J.CHEM.SOC.》 * |
| 杨志杰等: "3-奎宁环酮的制备", 《中国医药工业杂志》 * |
| 王平等: "3-奎宁酮盐酸盐的合成", 《应用化学》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113366A (en) * | 2013-03-13 | 2013-05-22 | 济南圣泉唐和唐生物科技有限公司 | Preparation method for 3-quinuclidone |
| CN104418851A (en) * | 2013-09-02 | 2015-03-18 | 上海龙翔生物医药开发有限公司 | Preparation method and purification method of quinuclidine derivatives |
| CN107721999A (en) * | 2017-11-03 | 2018-02-23 | 石家庄市度智医药科技有限公司 | A kind of preparation method of the quinuclidinol of optical activity 3 |
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Application publication date: 20110330 |