CN103319411A - Preparation method of imidafenacin - Google Patents
Preparation method of imidafenacin Download PDFInfo
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- CN103319411A CN103319411A CN2013102286210A CN201310228621A CN103319411A CN 103319411 A CN103319411 A CN 103319411A CN 2013102286210 A CN2013102286210 A CN 2013102286210A CN 201310228621 A CN201310228621 A CN 201310228621A CN 103319411 A CN103319411 A CN 103319411A
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- SQKXYSGRELMAAU-UHFFFAOYSA-N imidafenacin Chemical compound CC1=NC=CN1CCC(C(N)=O)(C=1C=CC=CC=1)C1=CC=CC=C1 SQKXYSGRELMAAU-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229950005396 imidafenacin Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 88
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 57
- 238000000034 method Methods 0.000 claims abstract description 26
- NLUFHYNAQQVOTI-UHFFFAOYSA-N 4-chloro-2,2-diphenylbutanamide Chemical compound C=1C=CC=CC=1C(CCCl)(C(=O)N)C1=CC=CC=C1 NLUFHYNAQQVOTI-UHFFFAOYSA-N 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 51
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 40
- 239000012074 organic phase Substances 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 239000007787 solid Substances 0.000 claims description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 31
- 229940015043 glyoxal Drugs 0.000 claims description 23
- 238000010792 warming Methods 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000012670 alkaline solution Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 229960001701 chloroform Drugs 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims 2
- 229930013930 alkaloid Natural products 0.000 claims 1
- 150000003797 alkaloid derivatives Chemical class 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 4
- 238000001953 recrystallisation Methods 0.000 abstract description 2
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 238000004809 thin layer chromatography Methods 0.000 description 18
- 238000012544 monitoring process Methods 0.000 description 16
- 239000000843 powder Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000009827 Prunus armeniaca Nutrition 0.000 description 2
- 244000018633 Prunus armeniaca Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- KHZBQSBQWHEUKI-UHFFFAOYSA-N butanenitrile phosphoric acid Chemical compound P(=O)(O)(O)O.C(CCC)#N KHZBQSBQWHEUKI-UHFFFAOYSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 2
- 229940094989 trimethylsilane Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IHHBESJMKGMIPU-UHFFFAOYSA-N C(CCC)#N.C1(=CC=CC=C1)C1=CC=CC=C1 Chemical compound C(CCC)#N.C1(=CC=CC=C1)C1=CC=CC=C1 IHHBESJMKGMIPU-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- YZWWAMLWZIHWSG-UHFFFAOYSA-N butanenitrile;hydrochloride Chemical compound Cl.CCCC#N YZWWAMLWZIHWSG-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- UKROGNGFIXLRHI-UHFFFAOYSA-N n,n-diphenylbutanamide Chemical class C=1C=CC=CC=1N(C(=O)CCC)C1=CC=CC=C1 UKROGNGFIXLRHI-UHFFFAOYSA-N 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a preparation method of imidafenacin. In the method, 4-chloro-2, 2-diphenylbutaneamide and 2-methylimidazole are taken as raw materials for reaction in the presence of alkali, and then ethyl acetate is used for recrystallization. The method has advantages of high yield, mild reaction condition, and simple purification and is suitable for industrialized production.
Description
Technical field
Technical solution of the present invention belongs to medical technical field, particularly a kind of method for preparing imidafenacin.
Background technology
Imidafenacin, chemical name are 4-(2-methyl isophthalic acid-imidazolyl)-2, the 2-diphenyl butanamide, and its structure is suc as formula shown in (I):
Imidafenacin is the novel diphenyl butanamide class anticholinergic drug of being developed jointly by Japanese ONO Pharmaceutical Co., Ltd. and the pharmacy of apricot woods, has height bladder selectivity, is used for the treatment of overactive bladder, goes on the market in Japan in June, 2007.Chinese patent 94194450.6 discloses the preparation method of imidafenacin, the method is with 4-bromo-2,2-phenylbenzene butyronitrile and glyoxal ethyline are the at first synthetic 4-(2-methyl isophthalic acid-imidazolyl)-2 of raw material, 2-phenylbenzene butyronitrile, under 140-150 ℃, use again 70% sulfuric acid with 4-(2-methyl isophthalic acid-imidazolyl)-2,2-phenylbenzene butyronitrile is hydrolyzed into acid amides, and unnecessary sulfuric acid neutralized with alkali after reaction was finished, and its reaction formula is as follows:
The main drawback of this method is that yield is low; only be 32%; and in reaction, use 70% a large amount of sulfuric acid; sulfuric acid is denseer has relatively high expectations to production unit; huge potential safety hazard is arranged in process of production, all is acid test to workman's operant level, the construction of factory building facility, the aspects such as protection of environment.Apricot woods Co., Ltd. discloses the another kind of method for preparing imidafenacin at Chinese patent 200580042599.4 again subsequently, at first with 4-(2-methyl isophthalic acid-imidazolyl)-2,2-phenylbenzene butyronitrile and 85% phosphoric acid or concentrated hydrochloric acid reaction generate 4-(2-methyl isophthalic acid-imidazolyl)-2,2-phenylbenzene butyronitrile phosphoric acid salt or 4-(2-methyl isophthalic acid-imidazolyl)-2,2-phenylbenzene butyronitrile hydrochloride, use again 86% potassium hydroxide and Virahol with 4-(2-methyl isophthalic acid-imidazolyl)-2,2-phenylbenzene butyronitrile phosphoric acid salt is hydrolyzed into phosphoric acid salt or the hydrochloride of acid amides, and then crude product changed into acid amides, recrystallization obtains imidafenacin after removing impurity, the shortcoming of the method is that yield is not high, be 45%, and in reaction, use concentrated acid, concentrated base is had relatively high expectations to production unit, and the purifying trouble, be not suitable for suitability for industrialized production.
In addition, also have some patent documentations also to disclose similar preparation method, as: the preparation method of the imidafenacin of Chinese patent 200810079474.4 and 201210254496.6 reports, all be with 4-(glyoxal ethyline-1-yl)-2,2-phenylbenzene butyronitrile is that raw material is prepared, but does not deal with problems equally.Therefore, the method yield of above four kinds of synthetic imidafenacins is low, purifying complex, and in reaction, use the vigorous reaction conditions such as strong acid, highly basic, and production unit is had relatively high expectations, be not suitable for suitability for industrialized production.Therefore, need to develop the synthetic method that yield is high and reaction conditions is gentle in the industrial production.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of brand-new imidafenacin.The method is with 4-chloro-2, and the 2-diphenyl butanamide is raw material, and glyoxal ethyline reacts in the presence of alkali and obtains the target product imidafenacin.
Reaction scheme of the present invention is as follows:
With 4-chloro-2,2-diphenyl butanamide, glyoxal ethyline and reaction solvent add in the reaction vessel, heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip alkaline solution, the control temperature of reaction is no more than 45 ℃, after dropwising, be warming up to 50 ℃, use the thin-layer chromatography monitoring reaction.After question response is complete, reaction solution is poured in the separating funnel, in this separating funnel, added again methylene dichloride and water, separate organic phase and water, with the organic phase evaporated under reduced pressure, the solid re-crystallizing in ethyl acetate with evaporated under reduced pressure obtains namely obtains the target product imidafenacin.
In the aforesaid method, described reaction solvent is selected from a kind of in DMF, methyl-sulphoxide, tetrahydrofuran (THF), methylene dichloride, the trichloromethane, and preferred reaction solvent is methyl-sulphoxide.
In the aforesaid method, described alkaline solution is selected from a kind of in sodium hydroxide, potassium hydroxide, yellow soda ash or the salt of wormwood.
The concentration of alkaline solution is 5mol/L in the aforesaid method, namely 20%.
In the aforesaid method, 4-chloro-2, the molar ratio of 2-diphenyl butanamide, glyoxal ethyline, alkaline solution are 2:3:3.
The present invention has following beneficial effect: 1). and reaction conditions is gentle, and the temperature of reaction that reaction is adopted is 50 ℃, and the concentration of the alkali of use is lower, and is little to production unit pressure, and little to environmental disruption; 2). yield is at 73%-81%, is greatly improved than existing preparation method's yield; 3). step is short, and purifying is simple, is conducive to produce.
In sum, the method for preparing imidafenacin disclosed in this invention is a kind of easy, environmental protection, the economic method that prepare imidafenacin, suitable suitability for industrialized production.
Specific embodiment
Below be the specific embodiment of content of the present invention, be used for to set forth the concrete technical scheme that present specification is wanted the technical solution problem, but realization of the present invention be not limited to these embodiment, and these embodiment unrestricted scope of the present invention also.The experimental technique of not marked actual conditions in the following example, according to ordinary method and condition, the reaction raw materials in unreceipted source and reagent are commercially available.
Below among each embodiment:
The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.The mensuration of NMR is that measuring solvent is deuterochloroform (CDC with Varian-Inova-400 type nuclear magnetic resonance analyser
L3), in be designated as trimethyl silane (TMS), chemical shift is with 10
-6(ppm) provide as unit.The mensuration of MS MAT212 magnetic-type mass spectrograph.
Thin-layer chromatography (TLC): silica gel H SGF254 (the yellow affair silica gel exploitation of Yantai City's Zhifu demonstration plant)
DMF:N, dinethylformamide
DMSO: methyl-sulphoxide
THF: tetrahydrofuran (THF)
CH
2Cl
2: methylene dichloride
CHCl
3: trichloromethane
NaOH: sodium hydroxide
KOH: potassium hydroxide
Na
2CO
3: yellow soda ash
K
2CO
3: salt of wormwood
Embodiment 1 is in the 100ml there-necked flask, add DMF30ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L NaOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1 hour afterreaction and finish, reaction solution is poured in the separating funnel, in this separating funnel, add again 30ml CH
2Cl
2With 30ml water, separate organic phase and water, there is camera to wash twice with water, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.49g, yield 78%.
MS(ESI
+，m/e)?：320.17[M+H]
+
1H-NMR(400MHz,CDCl
3)δ(ppm):7.25-7.43(m,10H),7.00(s,1H),6.91(s,1H),6.52(s,1H),6.34(s,1H),3.82-4.00(m,2H),2.62-2.71(m,2H),2.51(s,3H)
Embodiment 2 adds CH in the 100ml there-necked flask
2Cl
230ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L NaOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1.5 hours afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add again 30ml water, separate organic phase and water, water CH
2Cl
2Extract again twice, merge organic phase, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.39g, yield 75%.
Embodiment 3 adds CHCl in the 100ml there-necked flask
330ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L NaOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1.5 hours afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add again 30ml water, separate organic phase and water, water CH
2Cl
2Extract again twice, be associated with camera, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.32g, yield 73%.
Embodiment 4 is in the 100ml there-necked flask, add DMSO30ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L NaOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 50 minutes afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add 30mlCH again
2Cl
2With 30ml water, separate organic phase and water, there is camera to wash twice with water, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.58g, yield 81%.
Embodiment 5 is in the 100ml there-necked flask, add THF30ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L NaOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1 hour 0 10 minutes afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add 30mlCH again
2Cl
2With 30ml water, separate organic phase and water, there is camera to wash twice with water, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.39g, yield 75%.
Embodiment 6 is in the 100ml there-necked flask, add DMF30ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L KOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1 hour afterreaction and finish, reaction solution is poured in the separating funnel, in this separating funnel, add 30mlCH again
2Cl
2With 30ml water, separate organic phase and water, there is camera to wash twice with water, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.45g, yield 77%.
Embodiment 7 adds CH in the 100ml there-necked flask
2Cl
230ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L KOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1.5 hours afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add again 30ml water, separate organic phase and water, water CH
2Cl
2Extract again twice, be associated with camera, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.39g, yield 75%.
Embodiment 8 adds CHCl in the 100ml there-necked flask
330ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L KOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1.5 hours afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add again 30ml water, separate organic phase and water, water CH
2Cl
2Extract again twice, be associated with camera, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.36g, yield 74%.
Embodiment 9 is in the 100ml there-necked flask, add DMSO30ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L KOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 50 minutes afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add 30mlCH again
2Cl
2With 30ml water, separate organic phase and water, there is camera to wash twice with water, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.55g, yield 80%.
Embodiment 10 is in the 100ml there-necked flask, add THF30ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L KOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1 hour 0 10 minutes afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add 30mlCH again
2Cl
2With 30ml water, separate organic phase and water, there is camera to wash twice with water, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.42g, yield 76%.
Embodiment 11 adds DMF30ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol in the 100ml there-necked flask), glyoxal ethyline 1.23g(15mmol), heated and stirred when temperature of reaction rises to 40 ℃, slowly drips 5mol/L Na
2CO
3Solution 2ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, and uses the TLC monitoring reaction, stirs 1 hour afterreaction and finishes, and reaction solution is poured in the separating funnel, adds 30mlCH again in this separating funnel
2Cl
2With 30ml water, separate organic phase and water, there is camera to wash twice with water, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.42g, yield 76%.
Embodiment 12 adds CH in the 100ml there-necked flask
2Cl
230ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred when temperature of reaction rises to 40 ℃, slowly drips 5mol/L K
2CO
3Solution 2ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1.5 hours afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add again 30ml water, separate organic phase and water, water CH
2Cl
2Extract again twice, be associated with camera, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.32g, yield 73%.
Embodiment 13 adds CHCl in the 100ml there-necked flask
330ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred when temperature of reaction rises to 40 ℃, slowly drips 5mol/L K
2CO
3Solution 2ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1.5 hours afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add again 30ml water, separate organic phase and water, organic phase CH
2Cl
2Extract again twice, be associated with camera, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.36g, yield 74%.
Embodiment 14 adds DMSO30ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol in the 100ml there-necked flask), glyoxal ethyline 1.23g(15mmol), heated and stirred when temperature of reaction rises to 40 ℃, slowly drips 5mol/L Na
2CO
3Solution 2ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, and uses the TLC monitoring reaction, stirs 50 minutes afterreactions and finishes, and reaction solution is poured in the separating funnel, adds 30mlCH again in this separating funnel
2Cl
2With 30ml water, separate organic phase and water, there is camera to wash twice with water, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtain white powder solid 2.49g, yield 78%.
Embodiment 15 is in the 100ml there-necked flask, add THF30ml, 4-chloro-2,2-diphenyl butanamide 2.73g(10mmol), glyoxal ethyline 1.23g(15mmol), heated and stirred, when temperature of reaction rises to 40 ℃, slowly drip 5mol/L KOH solution 3ml, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising, use the TLC monitoring reaction, stir 1 hour 0 10 minutes afterreactions and finish, reaction solution is poured in the separating funnel, in this separating funnel, add 30mlCH again
2Cl
2With 30ml water, separate organic phase and water, organic phase washes twice with water, with the organic phase evaporated under reduced pressure, with the solid re-crystallizing in ethyl acetate that evaporated under reduced pressure obtains, obtains white powder solid 2.42g, yield 76%.
Claims (8)
1. method for preparing imidafenacin is characterized in that it is comprised of following steps:
1). with 4-chloro-2,2-diphenyl butanamide and glyoxal ethyline, reaction solvent add in the reaction flask, heated and stirred;
2). when the question response temperature rises to 40 ℃, slowly drip alkaline solution, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising;
3). after reaction is finished, reaction solution is poured in the separating funnel, added methylene dichloride and water again in this separating funnel, separate organic phase and water, with the organic phase evaporated under reduced pressure, the solid re-crystallizing in ethyl acetate with evaporated under reduced pressure obtains gets final product.
2. the method for preparing imidafenacin as claimed in claim 1 is characterized in that described reaction solvent is selected from a kind of in DMF, methyl-sulphoxide, tetrahydrofuran (THF), methylene dichloride, the trichloromethane.
3. the method for preparing imidafenacin as claimed in claim 2 is characterized in that described reaction solvent is methyl-sulphoxide.
4. the method for preparing imidafenacin as claimed in claim 1 is characterized in that described alkaline solution is selected from a kind of in sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, the solution of potassium carbonate.
5. the method for preparing imidafenacin as claimed in claim 4 is characterized in that described alkaline solution is sodium hydroxide solution.
6. the method for preparing imidafenacin as claimed in claim 4, the concentration that it is characterized in that described alkaline solution is 5mol/L.
7. the method for preparing imidafenacin as claimed in claim 1 is characterized in that 4-chloro-2, and the ratio of the amount of 2-diphenyl butanamide, glyoxal ethyline, alkaloid substance is 2:3:3.
8. the method for preparing imidafenacin as claimed in claim 1 is characterized in that it is comprised of following steps:
1). with 2.73g 4-chloro-2,2-diphenyl butanamide and 1.23g glyoxal ethyline, 30ml methyl-sulphoxide add in the reaction flask, heated and stirred;
2). when the question response temperature rises to 40 ℃, slowly drip the 5mol/L sodium hydroxide solution, the control temperature of reaction is no more than 45 ℃, is warming up to 50 ℃ after dropwising;
3). after reaction is finished, reaction solution is poured in the separating funnel, in this separating funnel, added again 30ml methylene dichloride and 30ml water, separate organic phase and water, have camera to wash twice with water, with the organic phase evaporated under reduced pressure, solid re-crystallizing in ethyl acetate with evaporated under reduced pressure obtains gets final product.
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| CN103772287A (en) * | 2013-12-31 | 2014-05-07 | 北京万全德众医药生物技术有限公司 | New imidafenacin crystal form and preparation method thereof |
| CN103880751A (en) * | 2014-03-26 | 2014-06-25 | 天津药物研究院 | Preparation method of imidafenacin |
| CN105399678A (en) * | 2014-12-26 | 2016-03-16 | 开封制药(集团)有限公司 | Preparation technology for imidafenacin |
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| CN103772287A (en) * | 2013-12-31 | 2014-05-07 | 北京万全德众医药生物技术有限公司 | New imidafenacin crystal form and preparation method thereof |
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| CN105399678A (en) * | 2014-12-26 | 2016-03-16 | 开封制药(集团)有限公司 | Preparation technology for imidafenacin |
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