CN110372677B - Method for preparing atorvastatin key intermediate L1 by solvent-free method - Google Patents
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Abstract
The invention discloses a novel method for preparing atorvastatin key intermediate L1 by a solvent-free method, which belongs to the technical field of pharmaceutical chemical synthesis and comprises the following steps: taking M4 and A9 as raw materials, directly stirring at constant temperature under the action of a phase transfer catalyst and an acid catalyst and in the absence of a solvent, carrying out a melting reaction for 5-7 hours, wherein the reaction temperature is 80-140 ℃, water is distributed in the reaction process, and after the reaction is finished, the temperature is reduced, and recrystallization is carried out to obtain an atorvastatin intermediate L1; the method adopts a phase transfer catalyst and an acid catalyst, the mother nucleus M4 and the chiral side chain A9 are stirred for melting reaction in the absence of a solvent, and after the reaction is finished, ethanol/water is directly used for recrystallization to obtain the L1.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a method for preparing atorvastatin key intermediate L1 by a solvent-free method.
Background
Atorvastatin is a statin lipid-lowering drug jointly developed by Warner Lambert and Pfizer of the United states, can strongly inhibit the activity of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, is a competitive and selective HMG-CoA reductase inhibitor, can obviously reduce the content of total cholesterol and low-density lipoprotein cholesterol, and has the characteristics of strong lipid regulating effect, high safety and small toxic and side effects. Because atorvastatin is a first drug sold in billions of dollars all over the world and has a very wide application prospect, atorvastatin is favored by people, and great economic benefits stimulate researchers to continuously improve the technological level of atorvastatin.
The chemical name of atorvastatin key intermediate L1 is: (4R-cis) -6- [2- [2- (4-fluorophenyl) -5- (1-isopropyl) -3-phenyl-4- [ (aniline) carbonyl ] -1H-pyrrol-1-yl ] ethyl ] -2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester having the formula:
the compound L1 is prepared by the following typical reaction equation of a mother nucleus [ 4-fluoro-alpha- (2-methyl-1-oxopropyl) -gamma-oxo-N, beta-diphenylbenzenebutanamide ] (M4) and chiral side chain (4R, Cis) -6-aminoethyl-2, 2-dimethyl-1, 3-dioxane-tert-butyl acetate (A9) through a classical Paal-Knorr condensation reaction to generate 2 molecules of water under the catalysis of acid:
there are many reports on the above reaction methods, such as:
european patent publication No. EP1659110A1 reports a preparation method of L1, raw materials M4 and A9 are subjected to reflux reaction for 40 hours in a ternary mixed solvent toluene/N-heptane/tetrahydrofuran system under catalysis of pivalic acid, the toluene is firstly added for dilution after the post-treatment, 0.5N sodium hydroxide solution washing, 0.5N hydrochloric acid solution washing, 10% sodium chloride solution washing and activated carbon decoloration treatment are sequentially adopted, and then isopropanol/water mixed solvent recrystallization is carried out to obtain L1;
chinese patent publication No. CN102127060A reports that a binary mixed solvent system toluene/n-heptane (1:4) is adopted for reflux water separation reaction, TLC detection reaction is performed, when 50% of the reaction is performed, pivalic acid is added, when 80% of the reaction is performed, part of the solvent is removed by a water separator, fresh solvent is added again, the reaction is performed for 12h-14h, evaporation is performed after the reaction is completed, ethyl acetate is dissolved, saturated sodium bicarbonate is washed to be alkaline, saturated sodium chloride is used for washing, an organic layer is dried with anhydrous sodium sulfate, filtration is performed, activated carbon is used for recrystallization after decoloration, and L1 is obtained, and the yield is more than 80%. The reaction process needs to supplement pivalic acid and solvent, the operation and the post-treatment are complex, and the reaction is carried out according to the patent conditions, so that the yield is only 62%;
chinese patent with publication number CN102344401A reports that an n-heptane/tetrahydrofuran binary mixed solvent is adopted for reflux reaction for 28h, and methanol is adopted for recrystallization to obtain L1; chinese patent with publication number CN101429195A reports that n-heptane/n-butyl ether binary mixed solvent is adopted for reflux reaction, and the product is recrystallized by using isopropanol/water mixed solvent; chinese patent with publication number CN102766136A reports that a tetrahydrofuran/n-butyl ether binary mixed system is added with triethylamine to react for 18 hours, the mixture is subjected to post-treatment and evaporation to dryness, ethyl acetate and water are added, and the mixture is subjected to acid washing, water washing, concentration and ethanol crystallization;
chinese patent with publication number CN104151286A reports that under the protection of nitrogen, 1-p-fluorophenyl-2-phenyl-ethanone is selected; 1-anilino-4-methyl- (1, 3-pentanedione); (4R,6R) -6-aminoethyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester; the method comprises the steps of putting the materials into a synthesis kettle, adding formic acid as a catalyst, adding benzene as a solvent, gradually heating to 110 ℃ and refluxing for 10 hours, and then carrying out subsequent treatment.
It can be seen from the above prior art that the poor solubility of the raw material M4 in the solvent results in long reaction time, slow reaction rate, low conversion rate of the raw material, and complicated solvent recovery when binary or ternary mixed solvents are used; the catalyst is prepared by reflux reaction for about 12-40h, and has the defects of complex post-treatment, long reaction time, low reaction speed, difficult solvent recovery, high cost, high energy consumption and the like.
Disclosure of Invention
The invention aims to provide a method for preparing atorvastatin key intermediate L1 by a solvent-free method, so as to solve the problems of long reaction time, complex post-treatment, high energy consumption and difficult solvent recovery of the existing process.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: taking M4 and A9 as raw materials, directly stirring at constant temperature under the action of a phase transfer catalyst and an acid catalyst and in the absence of a solvent, carrying out a melting reaction for 5-7 hours, wherein the reaction temperature is 80-140 ℃, water is separated during the reaction process, and after the reaction is finished, the temperature is reduced, and recrystallization is carried out to obtain the atorvastatin intermediate L1.
A typical reaction equation for the present invention is as follows:
as a preferred technical scheme: the molar ratio of the phase transfer catalyst to M4 is 0.3-0.8: 1.
As a preferred technical scheme: the molar ratio of the raw materials M4 and A9 is 1:0.8-1: 3.0.
As a further preferable technical scheme: the molar ratio of the raw materials M4 to A9 is 1: 2. This ratio gives high reaction conversions, while the amount of A9 used is relatively small.
As a preferred technical scheme: the acid catalyst is organic acid or inorganic acid with 1-8 carbon atoms; the organic acid is selected from one of formic acid, acetic acid, n-butyric acid, n-valeric acid, pivalic acid, n-caproic acid, benzoic acid, tartaric acid, citric acid, trichloroacetic acid, isobutyric acid, isovaleric acid, succinic acid, malonic acid, malic acid, oxalic acid and benzoic acid; the inorganic acid is selected from one of hydrochloric acid, sulfuric acid, phosphoric acid and polyacid.
As a further preferable technical scheme: the organic acid is preferably pivalic acid.
As a further preferable technical scheme: the ratio of the acid catalyst to M4 was 0.52: 1.
As a further preferable technical scheme: the phase transfer catalyst is tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltributylammonium bromide, benzyltrioctylammonium bromide and benzyltriphenylphosphonium bromide, and preferably tetrabutylammonium hydrogen sulfate is used as the phase transfer catalyst.
As a preferred technical scheme: the reaction temperature was 120 ℃. The reaction process is optimal.
As a preferred technical scheme: the recrystallization solvent is 95% ethanol/water. "95% ethanol" according to the invention means that the ethanol is present in a percentage of 95% by volume.
As a further preferable technical scheme: the volume ratio of the 95% ethanol to the water is 1:2-1:4, preferably 1:3.
As a preferred technical scheme: the number of recrystallization times is two.
The method of the invention does not adopt solvent, avoids the operation of solvent concentration and has no problem of mixed solvent recovery; the problem of poor solubility of the reaction raw material M4 is solved skillfully, the experimental operation is simplified, and the cost is reduced;
the reaction time for synthesizing the L1 is 5.5h, and the conversion rate of the L1 can reach 90%; greatly shortens the reaction time and has higher reaction conversion rate.
After the reaction is finished, directly cooling to 95 ℃, crystallizing by using ethanol/water to obtain a crude product of L1, recrystallizing twice to obtain a qualified product, and performing simple post-treatment;
compared with the prior art, the invention has the advantages that: the method adopts pivalic acid as a catalyst, the mother nucleus M4 and the chiral side chain A9 are stirred for melting reaction under the condition of no solvent, and after the reaction is finished, the L1 is obtained by directly using ethanol/water for recrystallization.
Drawings
FIG. 1 is a diagram: l1 of1An H-NMR spectrum;
FIG. 2 is a diagram of: l1 of13A C-NMR spectrum;
FIG. 3 is a diagram of: MS spectrum of L1;
FIG. 4 is a diagram of: HPLC profile of L1.
Detailed Description
The invention will be further explained with reference to the drawings.
Example 1
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M425 g (59.88mmol), tetrabutylammonium hydrogen sulfate 6.25g (18.41mmol), pivalic acid 3.15g (30.84mmol) and A932.86g (119.76mmol) into a three-port reaction bottle, stirring, heating for melting reaction (the external temperature is 120 ℃), separating water by using a water separator, and enabling the reaction system to be in a yellow brown thick state;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% acetonitrile, 5.5h reaction complete. The HPLC content of the raw material M4 is less than 1 percent, and the content of L1 is more than 90 percent;
after the reaction is completed, cooling the reaction system to 95 ℃, adding ethanol to dissolve the reaction system until the reaction system is clear, dropwise adding water until the reaction system is turbid, cooling and crystallizing to obtain 28.55g of a light yellow powdery solid crude product, drying the crude product, and recrystallizing twice with 95% ethanol/water (1:3v/v) to obtain 27.29g of a white powdery solid, wherein the HPLC detection shows that the product content is 99.87%, and the yield is 69.6%; subjecting the obtained product to1H-NMR、13The results of C-NMR and LC-MS detection and HPLC analysis are shown in FIG. 1, FIG. 2, FIG. 3 and FIG. 4, respectively.
1H-NMR、13The results of C-NMR and LC-MS are as follows:
1H-NMR(600MHz,CDCl3)(ppm):7.21–7.14(m,9H,Ar-H),7.07(d,J＝7.8Hz,2H,Ar-H),6.99(dd,J＝11.1,6.1Hz,3H,Ar-H),6.85(s,1H,CONH),4.19–4.12(m,1H,CHCH2CH),4.11–4.03(m,1H,NCH2),3.86–3.78(m,1H,NCH2),3.72–3.66(m,1H,CHCH2CH),3.57(dt,J＝14.2,7.0Hz,1H,CH(CH3)2),2.38(dd,J＝15.3,6.9Hz,1H,CH2COO),2.24(dd,J＝15.3,6.2Hz,1H,CH2COO),1.70–1.63(m,2H,NCH2CH2),1.60(s,1H,CHCH2CH),1.53(d,J＝7.1Hz,6H,CH(CH3)2),1.43(s,9H,C(CH3)3),1.36(s,3H,C(CH3)2),1.30(s,3H,C(CH3)2),1.05(dd,J＝24.0,11.7Hz,1H,CHCH2CH).
13C-NMR(600MHz,CDCl3)(ppm):172.39,170.29,164.88,163.16,161.52,141.59,138.46,134.70,133.29,133.23,130.58,128.85,128.76,128.43,128.33,126.64,123.59,121.82,119.64,115.51,115.37,101.55,98.76,80.81,66.49,65.98,42.53,40.93,38.15,36.05,30.00,28.17,26.16,21.82,21.64,19.75.
LC-MS(m/z):655.3[M+1]+.
example 2
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M425 g (59.88mmol), tetrabutylammonium hydrogen sulfate 6.25g (18.41mmol), pivalic acid 3.15g (30.84mmol) and A932.86g (119.76mmol) into a three-port reaction bottle, stirring, heating for melting reaction (external temperature 130 ℃), separating water by using a water separator, and enabling the reaction system to be brown and thick;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% of acetonitrile, the reaction is completed in 6.5h, the HPLC content of the raw material M4 is less than 3%, the L1 content is more than 87%, and the reaction is completed;
after the reaction is completed, cooling the reaction system to 95 ℃, adding 95% ethanol for dissolving, dripping water until the mixture is turbid, cooling and crystallizing to obtain 32g of a light yellow powdery solid crude product, drying the crude product, and recrystallizing for three times by using 95% ethanol/water (1:2v/v) to obtain 25.57g of a white powdery solid. The content of the product is up to 99.71 percent by HPLC detection; the yield thereof was found to be 65.21%.
Example 3
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M425 g (59.88mmol), tetrabutylammonium hydrogen sulfate 6.25g (18.41mmol), pivalic acid 3.15g (30.84mmol) and A919.72g (71.87mmol) into a three-port reaction bottle, stirring, heating, melting and reacting (the external temperature is 120 ℃), and separating water by using a water separator to obtain a brown thick reaction system;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% of acetonitrile, and the reaction is complete in 7 h;
after the reaction is completed, cooling the reaction system to 95 ℃, adding ethanol clear solution, dripping water until the reaction system is turbid, cooling and crystallizing to obtain 26.67g of a light yellow powdery solid crude product, drying the crude product, and recrystallizing twice to obtain 24.59g of a white powdery solid. The content of the product is up to 99.84 percent by HPLC detection; the yield thereof was found to be 62.71%.
Example 4
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M425 g (59.88mmol), benzyltriethylammonium chloride 4.196g (18.41mmol), pivalic acid 3.15g (30.84mmol) and A932.86g (119.76mmol) into a three-port reaction bottle, stirring, heating for melting reaction (the external temperature is 120 ℃), and separating water by using a water separator to obtain a tawny thick reaction system;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% of acetonitrile, and the reaction is complete within 5 h;
monitoring the reaction end point by using an HPLC detection method, wherein the HPLC content of the raw material M4 is less than 1%, the content of L1 is more than 90%, and the reaction is complete;
after the reaction is completed, the temperature of the reaction system is reduced to 95 ℃, ethanol is added, water is added dropwise until the reaction system is turbid, the reaction system is cooled and crystallized to obtain 28.27g of powdery solid crude product, and the powdery solid crude product is dried and recrystallized twice by using 95% ethanol/water (1:3v/v) to obtain 26.93g of white powdery solid. The content of the product is up to 99.75 percent by HPLC detection; the yield thereof was found to be 68.68%.
Example 5
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M45 g (11.98mmol), tetrabutylammonium hydrogen sulfate 1.25g (3.68mmol), pivalic acid 0.63g (6.17mmol) and A93.18g (11.59mmol) into a three-port reaction bottle, stirring, heating, melting and reacting (external temperature 80 ℃), separating water by using a water separator, and enabling a reaction system to be light yellow thick;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% acetonitrile, 58.44% conversion of L1 when the reaction reached equilibrium.
Example 6
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M45 g (11.98mmol), tetrabutylammonium hydrogen sulfate 1.25g (3.68mmol), pivalic acid 0.63g (6.17mmol) and A93.18g (11.59mmol) into a three-port reaction bottle, stirring, heating, melting and reacting (the external temperature is 120 ℃), separating water by using a water separator, and enabling a reaction system to be in a red brown thick state;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% acetonitrile, 75.44% conversion of L1 when the reaction reaches equilibrium.
Example 7
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M45 g (11.98mmol), tetrabutylammonium hydrogen sulfate 1.25g (3.68mmol), pivalic acid 0.63g (6.17mmol) and A93.18g (11.59mmol) into a three-port reaction bottle, stirring, heating, melting and reacting (the external temperature is 140 ℃), separating water by using a water separator, and enabling a reaction system to be dark brown thick;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% acetonitrile, 67.38% conversion of L1 when the reaction reached equilibrium.
Example 8
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M425 g (59.88mmol), tetrabutylammonium hydrogen sulfate 6.25g (18.41mmol), hydrochloric acid 3.12g (30.81mmol) and A932.86g (119.76mmol) into a three-port reaction bottle, stirring, heating, melting, reacting (external temperature 120 ℃), separating water by a water separator, and enabling the reaction system to be in a yellow brown transparent liquid state;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% acetonitrile, conversion of L1 after 8h of reaction 45.91%.
Example 9
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M425 g (59.88mmol), tetrabutylammonium hydrogen sulfate 6.25g (18.41mmol), sulfuric acid 3.02g (30.79mmol) and A932.86g (119.76mmol) into a three-port reaction bottle, stirring, heating, melting and reacting (the external temperature is 120 ℃), separating water by using a water separator, and enabling a reaction system to be in a light yellow thick state;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% acetonitrile, conversion of L1 after 8h of reaction 27.65%.
Example 10
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M45 g (11.98mmol), tetrabutylammonium bromide 1.18g (3.66mmol), pivalic acid 0.63g (6.17mmol) and A93.9g (14.21mmol) into a three-port reaction bottle, stirring, heating for melting reaction (the external temperature is 120 ℃), separating water by using a water separator, and enabling a reaction system to be dark brown thick;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% acetonitrile, 79.56% conversion of L1 after 6h reaction.
Example 11
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M45 g (11.98mmol), benzyltriethylammonium chloride 2.18g (9.58mmol), pivalic acid 0.63g (6.17mmol) and A93.9g (14.21mmol) into a three-port reaction bottle, stirring, heating for melting reaction (the external temperature is 120 ℃), separating water by using a water separator, and enabling a reaction system to be dark brown thick;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% acetonitrile, 78.02% conversion of L1 after 7h reaction.
Example 12
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M45 g (11.98mmol), tetrabutylammonium hydrogen sulfate 1.25g (3.68mmol), pivalic acid 0.63g (6.17mmol) and A96.6g (24.05mmol) into a three-port reaction bottle, stirring, heating, melting and reacting (the external temperature is 90 ℃), and separating water by using a water separator to obtain a reaction system in a light yellow thick state;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% acetonitrile, 48.04% conversion of L1 after 7h reaction.
Example 13
A solvent-free process for preparing atorvastatin key intermediate L1, comprising the steps of: sequentially adding M45 g (11.98mmol), tetrabutylammonium hydrogen sulfate 1.25g (3.68mmol), pivalic acid 0.63g (6.17mmol) and A96.6g (24.05mmol) into a three-port reaction bottle, stirring, heating, melting and reacting (at an external temperature of 130 ℃), and separating water by using a water separator to obtain a reaction system in a dark reddish brown thick state;
the reaction progress is monitored by HPLC detection method, and the mobile phase conditions are as follows: 75% acetonitrile, 79.60% conversion of L1 after 7h reaction;
after 7h of reaction, the reaction system is cooled to 95 ℃, ethanol is added, water is added dropwise until the mixture is turbid, and the mixture is cooled and crystallized to obtain 5.7g of a yellow powdery solid crude product with the content of 96.6 percent by HPLC detection. The crude yield was 72.7%.
The above examples show that the process for preparing atorvastatin key intermediate L1 is simple to operate, reaction time is obviously shortened, conversion rate is high, post-treatment is simple and convenient, energy consumption is saved, and cost is reduced.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (12)
1. A method for preparing atorvastatin key intermediate L1 by a solvent-free method is characterized by comprising the following steps: taking M4 and A9 as raw materials, directly stirring and melting at constant temperature for 5-7 hours under the action of a phase transfer catalyst and an acid catalyst under the condition of no solvent, carrying out constant-temperature stirring and melting reaction at the reaction temperature of 120-140 ℃, dividing water in the reaction process, cooling after the reaction is finished, and then carrying out recrystallization to obtain an atorvastatin intermediate L1;
wherein the phase transfer catalyst is one of tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltributylammonium bromide and benzyltrioctylammonium bromide;
the acid catalyst is organic acid with 1-8 carbon atoms; the organic acid is selected from one of formic acid, acetic acid, n-butyric acid, n-valeric acid, pivalic acid, n-caproic acid, tartaric acid, citric acid, trichloroacetic acid, isobutyric acid, isovaleric acid, succinic acid, malonic acid, malic acid, oxalic acid and benzoic acid;
the M4 is a structure shown as follows:
a9 has the following structure:
l1 has the structure shown below:
2. the solvent-free process of claim 1 for preparing atorvastatin key intermediate L1, wherein: the molar ratio of the phase transfer catalyst to M4 is 0.3-0.8: 1.
3. The solvent-free process of claim 1 for preparing atorvastatin key intermediate L1, wherein: the molar ratio of the raw materials M4 and A9 is 1:0.8-1: 3.0.
4. The solvent-free process of claim 3 for preparing atorvastatin key intermediate L1, wherein: the molar ratio of the raw materials M4 to A9 is 1: 2.
5. The solvent-free process of claim 1 for preparing atorvastatin key intermediate L1, wherein: the organic acid is pivalic acid.
6. The solvent-free process of claim 1 for preparing atorvastatin key intermediate L1, wherein: the ratio of the acid catalyst to M4 was 0.52: 1.
7. The solvent-free process of claim 1 for preparing atorvastatin key intermediate L1, wherein: the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.
8. The solvent-free process of claim 1 for preparing atorvastatin key intermediate L1, wherein: the reaction temperature was 120 ℃.
9. The solvent-free process of claim 1 for preparing atorvastatin key intermediate L1, wherein: the recrystallization solvent is 95% ethanol/water.
10. The solvent-free process of claim 9 for preparing atorvastatin key intermediate L1, wherein: the volume ratio of the 95% ethanol to the water is 1:2-1: 4.
11. The solvent-free process of claim 10 for preparing atorvastatin key intermediate L1, wherein: the volume ratio of the 95% ethanol to the water is 1:3.
12. The solvent-free process of claim 1 for preparing atorvastatin key intermediate L1, wherein: the number of recrystallization times is two.
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| 利用Paal-Knorr反应在无催化剂和溶剂条件下合成吡咯衍生物;杜玉英 等;《化学通报》;20061231(第4期);第306-308页 * |
| 甲酸催化的室温无溶剂条件下利用Paal-Knorr合成吡咯衍生物的方法;朱新海 等;《有机化学》;20081231;第28卷(第1期);第115-119页 * |
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