CN103113366A - Preparation method for 3-quinuclidone - Google Patents
Preparation method for 3-quinuclidone Download PDFInfo
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- CN103113366A CN103113366A CN2013100805557A CN201310080555A CN103113366A CN 103113366 A CN103113366 A CN 103113366A CN 2013100805557 A CN2013100805557 A CN 2013100805557A CN 201310080555 A CN201310080555 A CN 201310080555A CN 103113366 A CN103113366 A CN 103113366A
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- ZKMZPXWMMSBLNO-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-one Chemical compound C1CC2C(=O)CN1CC2 ZKMZPXWMMSBLNO-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000000243 solution Substances 0.000 claims abstract description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 35
- -1 1-ethoxycarbonyl Chemical group 0.000 claims abstract description 34
- 238000010438 heat treatment Methods 0.000 claims abstract description 31
- 239000003960 organic solvent Substances 0.000 claims abstract description 26
- AOWPVIWVMWUSBD-RNFRBKRXSA-N [(3r)-3-hydroxybutyl] (3r)-3-hydroxybutanoate Chemical class C[C@@H](O)CCOC(=O)C[C@@H](C)O AOWPVIWVMWUSBD-RNFRBKRXSA-N 0.000 claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 20
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 15
- 239000012267 brine Substances 0.000 claims description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 125000003944 tolyl group Chemical group 0.000 claims description 6
- 238000010790 dilution Methods 0.000 claims description 5
- 239000012895 dilution Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 23
- 238000000034 method Methods 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000006185 dispersion Substances 0.000 abstract description 4
- 235000015110 jellies Nutrition 0.000 abstract description 3
- 239000008274 jelly Substances 0.000 abstract description 3
- 239000002585 base Substances 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 239000007864 aqueous solution Substances 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 239000012266 salt solution Substances 0.000 abstract 1
- 238000010992 reflux Methods 0.000 description 10
- 239000012467 final product Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229960001701 chloroform Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000006228 Dieckmann condensation reaction Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
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- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- 239000001117 sulphuric acid Substances 0.000 description 3
- 235000011149 sulphuric acid Nutrition 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000007126 N-alkylation reaction Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- RFDPHKHXPMDJJD-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-one;hydron;chloride Chemical compound Cl.C1CC2C(=O)CN1CC2 RFDPHKHXPMDJJD-UHFFFAOYSA-N 0.000 description 1
- FBOUYBDGKBSUES-KEKNWZKVSA-N 1-azabicyclo[2.2.2]octan-3-yl (1s)-1-phenyl-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(OC2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-KEKNWZKVSA-N 0.000 description 1
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000017925 CHRM3 Human genes 0.000 description 1
- 101150060249 CHRM3 gene Proteins 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- WUKZPHOXUVCQOR-UHFFFAOYSA-N N-(1-azabicyclo[2.2.2]octan-3-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide Chemical compound C1N(CC2)CCC2C1NC(=O)C1=CC(Cl)=CC2=C1OCC(=O)N2C WUKZPHOXUVCQOR-UHFFFAOYSA-N 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- WUTYZMFRCNBCHQ-PSASIEDQSA-N cevimeline Chemical compound C1S[C@H](C)O[C@]21C(CC1)CCN1C2 WUTYZMFRCNBCHQ-PSASIEDQSA-N 0.000 description 1
- 229960001314 cevimeline Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
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- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960005042 mequitazine Drugs 0.000 description 1
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- 208000020629 overactive bladder Diseases 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
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- OXDOWGVJMITMJL-OAQYLSRUSA-N sequifenadine Chemical compound CC1=CC=CC=C1C(O)(C=1C(=CC=CC=1)C)[C@H]1C(CC2)CCN2C1 OXDOWGVJMITMJL-OAQYLSRUSA-N 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method for 3-quinuclidone. The preparation method comprises the following steps of: mixing 1-ethoxycarbonyl methyl-4-ethyl nipecotate, low-level alkali metal alkoxide, alcohol and an organic solvent and heating for reaction, wherein the organic solvent is methylbenzene or dimethylbenzene; adding an acid solution to extract the reaction liquid to obtain ketoneester salt aqueous solution; and mixing the ketoneester salt solution with active carbon, and heating for reaction to obtain 3-quinuclidone. Compared with the prior art, the preparation method has the advantages that alcohol is added during a strong-base catalytic loop closing stage, thereby facilitating the dispersion of jelly in the organic solvent, so that the system is uniformly mixed, the smooth implementation of the reaction is facilitated, the generated by-products are reduced, and the after-treatment process is further simplified.
Description
Technical field
The invention belongs to organic compound and synthesize and preparing technical field, relate in particular to the preparation method of 3-quinuclidone.
Background technology
YM 905 (solifenacin succinate), chemistry (3R)-1-azabicyclic [2 by name, 2,2] octane-3-base (1S)-1-phenyl-3,4-dihydro-isoquinoline-2-(1H)-carboxylicesters succinate, it is the selectivity muscarine M3 receptor antagonist of Japanese Astellas company research and development, 2004 first in Holland, Germany, Britain, France and Denmark's listing, went on the market in the U.S. in 2005,2009 at Discussion on Chinese Listed, clinical be used for the treatment of urgent urination is arranged, the overactive bladder of frequent micturition symptom.The lax detrusor urinae of bladder of this product energy selectivity reduces the systemic adverse reactions of anticholinergic agent in the past, overruns as dry, constipation, platycoria and heartbeat etc.
Wherein, the 3-quinuclidone is a kind of important intermediate for the synthesis of YM 905, the 3-quinuclidone is also the important intermediate of the medicines such as cevimeline, Y-25130, mequitazine and sequifenadine simultaneously, therefore study its synthetic method, help to improve the productive rate of above medicine and production cost is reduced.
Existing 3-quinuclidone mainly synthesizes by the following method: (1) 4-vinylpridine is through permanganate oxidation, hydro-reduction, the reaction such as closed loop and oxidation makes the 3-quinuclidone under the aluminum oxide effect of activation, but ring-closure reaction condition harsh (nitrogen protection, 300 ℃ of high temperature) wherein, yield only 10% is difficult for amplifying and produces; (2) Isonicotinic acid obtains the 3-quinuclidone through reactions such as esterification, N-alkylation, hydro-reduction, Dieckmann condensations, wherein esterification must be used a large amount of sulphuric acid catalysis, and is seriously polluted, and hydrogenation needs the 10MPa high pressure, the Pd-C consumption is large, and total recovery is 39%; (3) esterification under the trimethylchlorosilane effect of 4-piperidine carboxylic acid makes the 4-piperidine ethyl formate, and yield is 90.4%, then obtains the 3-quinuclidone through N-alkylation and Dieckmann reaction, and total recovery is 70%.
but existing Dieckmann reaction is all to obtain 1-ethoxycarbonylmethyl group-4-piperidone by the reflux degreasing in toluene system of 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate, then through reflux decarboxylation in hydrochloric acid solution system, owing to can forming the solid dope in reaction, after temperature reduces, dope can lump, cause stirring and to carry out, the purity of the product of impact reaction, and under acidic conditions decarboxylation complete after, need to use solvent extraction, revolve to steam and obtain thick substances, again through the dilute hydrochloric acid acidifying, decompression dewaters, recrystallization obtains 3-quinuclidone hydrochloride, neutralize through alkali again, solvent extraction, dry, filter, solvent evaporated obtains final product, aftertreatment is more complicated.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of preparation method of 3-quinuclidone, and the preparation method is simple to operate, and aftertreatment is simple.
The invention provides a kind of preparation method of 3-quinuclidone, comprise the following steps:
A) 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate, elementary alkali metal alkoxide, alcohol are mixed with organic solvent, reacting by heating after adding the acid solution extraction, obtains the ketone ester salt brine solution, and described organic solvent is toluene or dimethylbenzene;
B) described ketone ester salt brine solution and gac are mixed, after reacting by heating, obtain the 3-quinuclidone.
Preferably, described step B also comprises:
After reacting by heating, add alkali to neutralize, then filter successively, extraction, concentrated, drying obtains the 3-quinuclidone.
Preferably, described alkali is selected from one or more in sodium hydroxide, potassium hydroxide, sodium carbonate and salt of wormwood.
Preferably, described elementary alkali metal alkoxide is selected from sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium butylate, butanols potassium, sodium tert-butoxide or potassium tert.-butoxide.
Preferably, described alcohol is the alcoholic solvent of C3～C5.
Preferably, described acid solution is hydrochloric acid soln or dilution heat of sulfuric acid.
Preferably, the add-on of described alcohol is 1～20% of 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate quality.
Preferably, in described steps A, the temperature of reacting by heating is 95 ℃～112 ℃.
Preferably, in described step B, the temperature of reacting by heating is 55 ℃～100 ℃, and the time of reacting by heating is 7～8h.
Preferably, described steps A is specially:
Elementary alkali metal alkoxide, alcohol are mixed with organic solvent, heating, the mixing solutions of dropping 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate and organic solvent, reacting by heating after adding the acid solution extraction, obtains the ketone ester salt brine solution; Described organic solvent is toluene or dimethylbenzene.
The invention provides a kind of preparation method of 3-quinuclidone, 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate, elementary alkali metal alkoxide, alcohol are mixed with organic solvent, and reacting by heating is after adding the acid solution extraction, obtain the ketone ester salt brine solution, described organic solvent is toluene or dimethylbenzene; Described ketone ester salt brine solution and gac are mixed, after reacting by heating, obtain the 3-quinuclidone.Compared with prior art, the present invention adds alcohol in the highly basic catalysis cyclization stage, helps the dispersion of jelly in organic solvent, and system is mixed, and is beneficial to carrying out smoothly of reaction, reduces the generation of by product, and then has simplified the process of aftertreatment.
Experimental result shows, preparation method's of the present invention yield can reach 90%, obtains the purity of product greater than 98%.
Description of drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the 3-quinuclidone for preparing in the embodiment of the present invention 1;
Fig. 2 is the carbon-13 nmr spectra figure of the 3-quinuclidone for preparing in the embodiment of the present invention 1.
Embodiment
The invention provides a kind of preparation method of 3-quinuclidone, comprise the following steps: A) 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate, elementary alkali metal alkoxide, alcohol are mixed with organic solvent, reacting by heating, after adding the acid solution extraction, obtain the ketone ester salt brine solution, described organic solvent is toluene or dimethylbenzene; B) described ketone ester salt brine solution and gac are mixed, after reacting by heating, obtain the 3-quinuclidone.
All raw materials of the present invention are not particularly limited its source, and that buys on market gets final product.
The present invention is take 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate as starting raw material, and it is 1-ethoxycarbonylmethyl group well known to those skilled in the art-4-piperidine ethyl formate, and its source be there is no special restriction.
The present invention is take the elementary alkali metal alkoxide as catalyzer, and described elementary alkali metal alkoxide is that elementary alkali metal alkoxide well known to those skilled in the art gets final product, and there is no special restriction.The metal alkoxide of elementary alkali described in the present invention is preferably sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium butylate, butanols potassium, sodium tert-butoxide or potassium tert.-butoxide, more preferably sodium tert-butoxide or potassium tert.-butoxide, wherein the catalytic activity of potassium tert.-butoxide is the strongest, without the reaction of side reaction, be almost most preferred catalyzer.The mol ratio of described elementary alkali metal alkoxide and 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate is preferably (1.5～2.5): 1, more preferably (1.8～2.2): 1.
The present invention take alcohol with organic solvent as reaction solvent, wherein, described alcohol is alcohol solution well known to those skilled in the art, there is no special restriction.Described in the present invention, alcohol is preferably the alcoholic solvent of C3～C5.The add-on of described alcohol is preferably 1～20% of 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate quality, is preferably 5～15%, and more preferably 8～10%, this add-on can make the substrate dispersion effect better, and by-product is few, and product yield is high.
According to the present invention, described steps A is mixed 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate, elementary alkali metal alkoxide, alcohol with organic solvent, reacting by heating, this process is preferably: elementary alkali metal alkoxide, alcohol and organic solvent is mixed, heating, drip the mixing solutions of 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate and organic solvent, reacting by heating.
Wherein, the temperature that adds of described elementary alkali metal alkoxide is preferably 15 ℃～25 ℃, preferably is heated to reflux state in steps A, then under the condition that stirs, drip the mixing solutions of 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate and organic solvent, then continue back flow reaction 2～3h.The temperature that in described steps A, the temperature of reacting by heating namely refluxes is preferably 95 ℃～112 ℃.
Reacting by heating adds acid solution to extract after finishing wherein, obtains the ketone ester salt brine solution.Described acid solution is that acid solution well known to those skilled in the art gets final product, and there is no special restriction.In the present invention, described acid solution is preferably hydrochloric acid soln or dilution heat of sulfuric acid, the concentration of described hydrochloric acid soln or the concentration of dilution heat of sulfuric acid are that concentration well known to those skilled in the art gets final product, there is no special restriction, more preferably massfraction is that 10～38% hydrochloric acid soln or massfraction are 10～30% dilution heat of sulfuric acid.
Adding acid solution to extract preferably under temperature is the condition of 15 ℃～35 ℃ in steps A of the present invention carries out.
Step B is take the ketone ester salt brine solution as raw material, and described ketone ester salt brine solution is that the solution that directly obtains after the acid solution extraction in this steps A gets final product, and does not need through processing.
The described ketone ester salt brine solution of step B of the present invention mixes with gac, after reacting by heating, obtains the 3-quinuclidone, and the temperature of described reacting by heating is preferably 55 ℃～100 ℃, and more preferably 80 ℃～95 ℃, the time of reacting by heating is preferably 7～8h.
According to the present invention, described step B preferably also comprises: after reacting by heating, add alkali to neutralize, then filter successively, and extraction, concentrated, drying obtains the 3-quinuclidone.
Described alkali is that alkali well known to those skilled in the art gets final product, and there is no special restriction.Alkali described in the present invention is preferably one or more in the common alkali such as sodium hydroxide, potassium hydroxide, sodium carbonate and salt of wormwood, more preferably sodium hydroxide or sodium carbonate.In order to make neutralization better, do not discharge at short notice a large amount of heat, described alkali preferably slowly adds in batches.
In the present invention, the extraction solvent for use is that organic solvent well known to those skilled in the art gets final product, there is no special restriction, be preferably methylene dichloride, trichloromethane, ethyl acetate, ether, propyl carbinol, isopropylcarbinol or benzene, more preferably methylene dichloride, trichloromethane, ether or ethyl acetate.
Described concentrated temperature is that temperature well known to those skilled in the art gets final product, and there is no special restriction, is preferably 35 ℃～50 ℃, its objective is to remove extraction organic solvent used.
The temperature of described drying is preferably 50 ℃～60 ℃, and the dry time is preferably 3～4h.
The present invention adds alcohol in the highly basic catalysis cyclization stage, helps the dispersion of jelly in organic solvent, and system is mixed, and is beneficial to carrying out smoothly of reaction, reduces the generation of by product, and then has simplified the process of aftertreatment.
Experimental result shows, preparation method's of the present invention yield can reach 90%, obtains the purity of product greater than 98%.
In order to further illustrate the present invention, below in conjunction with embodiment, the preparation method of 3-quinuclidone provided by the invention is described in detail.
In following examples, reagent used is commercially available.
Embodiment 1
1.1 4.7mol toluene and 0.07mol butanols are mixed, stir, add the 0.35mol potassium tert.-butoxide, be warming up to 105 ℃, drip the mixing solutions of 0.21mol1-ethoxycarbonylmethyl group-4-piperidine ethyl formate and 0.9mol toluene under the state that refluxes, 1.5h dropwise, continue back flow reaction 3h, the reaction of TLC detection display is completed, the reaction mixture that obtains is isolated water, then with 10% dilute hydrochloric acid of 0.55mol, organic phase is extracted after using the hydrochloric acid soln acidifying, merge water, obtain ketone ester hydrochloride solution.
1.2 with ketone ester hydrochloride solution and the 0.83mol gac that obtains in 1.1, be warming up to 60 ℃ and begin to reflux, after reaction 7h, the reaction of TLC detection display is completed, be cooled to 30 ℃, remove by filter gac, slowly and in batches add 1.8mol sodium carbonate in filtrate, the pH value is 8, after filtration, with the chloroform extraction of 1.67mol * 3 three times, separate and merge organic phase, 40 ℃ of vacuum are revolved steaming, and residue dope drying under reduced pressure obtains the 0.178mol3-quinuclidone, yield is 85.6%, and purity is 99.12%.
Utilize nucleus magnetic resonance that the 3-quinuclidone that obtains in 1.2 is analyzed, obtain its hydrogen nuclear magnetic resonance spectrogram and carbon-13 nmr spectra figure, as depicted in figs. 1 and 2, wherein Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of 3-quinuclidone, and Fig. 2 is the carbon-13 nmr spectra figure of 3-quinuclidone.
Embodiment 2
2.1 4.7mol toluene and 0.11mol butanols are mixed, stir, add the 0.43mol potassium tert.-butoxide, be warming up to 103 ℃, drip the mixing solutions of 0.21mol1-ethoxycarbonylmethyl group-4-piperidine ethyl formate and 0.9mol toluene under the state that refluxes, 1.5h dropwise, continue back flow reaction 3h, the reaction of TLC detection display is completed, the reaction mixture that obtains with 20% sulphuric acid soln acidifying after, isolate water, then with 10% dilute sulphuric acid of 0.28mol, organic phase extracted, merge water, obtain the ketone ester sulfate liquor.
2.2 with ketone ester sulfate liquor and the 0.83mol gac that obtains in 2.1, be warming up to 59 ℃ and begin to reflux, after reaction 8h, the reaction of TLC detection display is completed, be cooled to 30 ℃, remove by filter gac, slowly and in batches add 2.5mol sodium hydroxide in filtrate, the pH value is 8, after filtration, with the chloroform extraction of 1.67mol * 3 three times, separate and merge organic phase, 40 ℃ of vacuum are revolved steaming, and residue dope drying under reduced pressure obtains the 0.189mol3-quinuclidone, yield is 90.2%, and purity is 99.75%.
Embodiment 3
3.1 4.7mol toluene and 0.14mol butanols are mixed, stir, add the 0.48mol potassium tert.-butoxide, be warming up to 100 ℃, drip the mixing solutions of 0.21mol1-ethoxycarbonylmethyl group-4-piperidine ethyl formate and 0.9mol toluene under the state that refluxes, 1.5h dropwise, continue back flow reaction 2h, the reaction of TLC detection display is completed, the reaction mixture that obtains with 26% hydrochloric acid soln acidifying after, isolate water, then with 10% dilute hydrochloric acid of 0.55mol, organic phase extracted, merge water, obtain ketone ester hydrochloride solution.
3.2 with ketone ester hydrochloride solution and the 0.83mol gac that obtains in 3.1, be warming up to 60.5 ℃ and begin to reflux, after reaction 8h, the reaction of TLC detection display is completed, be cooled to 30 ℃, remove by filter gac, slowly and in batches add 1.8mol sodium carbonate in filtrate, the pH value is 8, after filtration, with the chloroform extraction of 1.67mol * 3 three times, separate and merge organic phase, 40 ℃ of vacuum are revolved steaming, and residue dope drying under reduced pressure obtains the 0.166mol3-quinuclidone, yield is 79%, and purity is 99.62%.
The above is only the preferred embodiment of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. the preparation method of a 3-quinuclidone, is characterized in that, comprises the following steps:
A) 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate, elementary alkali metal alkoxide, alcohol are mixed with organic solvent, reacting by heating after adding the acid solution extraction, obtains the ketone ester salt brine solution, and described organic solvent is toluene or dimethylbenzene;
B) described ketone ester salt brine solution and gac are mixed, after reacting by heating, obtain the 3-quinuclidone.
2. preparation method according to claim 1, is characterized in that, described step B also comprises:
After reacting by heating, add alkali to neutralize, then filter successively, extraction, concentrated, drying obtains the 3-quinuclidone.
3. preparation method according to claim 2, is characterized in that, described alkali is selected from one or more in sodium hydroxide, potassium hydroxide, sodium carbonate and salt of wormwood.
4. preparation method according to claim 1, is characterized in that, described elementary alkali metal alkoxide is selected from sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium butylate, butanols potassium, sodium tert-butoxide or potassium tert.-butoxide.
5. preparation method according to claim 1, is characterized in that, described alcohol is the alcoholic solvent of C3～C5.
6. preparation method according to claim 1, is characterized in that, described acid solution is hydrochloric acid soln or dilution heat of sulfuric acid.
7. preparation method according to claim 1, is characterized in that, the add-on of described alcohol is 1～20% of 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate quality.
8. preparation method according to claim 1, is characterized in that, in described steps A, the temperature of reacting by heating is 95 ℃～112 ℃.
9. preparation method according to claim 1, is characterized in that, in described step B, the temperature of reacting by heating is 55 ℃～100 ℃, and the time of reacting by heating is 7～8h.
10. preparation method according to claim 1, is characterized in that, described steps A is specially:
Elementary alkali metal alkoxide, alcohol are mixed with organic solvent, heating, the mixing solutions of dropping 1-ethoxycarbonylmethyl group-4-piperidine ethyl formate and organic solvent, reacting by heating after adding the acid solution extraction, obtains the ketone ester salt brine solution; Described organic solvent is toluene or dimethylbenzene.
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| CN110922401A (en) * | 2018-09-19 | 2020-03-27 | 广东东阳光药业有限公司 | Preparation method of quininone derivative |
| CN115703777A (en) * | 2021-08-05 | 2023-02-17 | 上海医药工业研究院 | A kind of separation method of 3-quinuclidone |
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| CN101993444A (en) * | 2009-08-18 | 2011-03-30 | 上海力田化学品有限公司 | Method to synthesize quinuclidine hydrochloride |
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| CN101993444A (en) * | 2009-08-18 | 2011-03-30 | 上海力田化学品有限公司 | Method to synthesize quinuclidine hydrochloride |
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| 陈年根等: "3-奎宁环酮盐酸盐的合成工艺改进", 《化学试剂》, vol. 30, no. 2, 28 February 2008 (2008-02-28), pages 145 - 146 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110922401A (en) * | 2018-09-19 | 2020-03-27 | 广东东阳光药业有限公司 | Preparation method of quininone derivative |
| CN110922401B (en) * | 2018-09-19 | 2022-07-26 | 广东东阳光药业有限公司 | Preparation method of quinuclidone derivative |
| CN115703777A (en) * | 2021-08-05 | 2023-02-17 | 上海医药工业研究院 | A kind of separation method of 3-quinuclidone |
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