CN111377826A - Green synthesis process of key intermediate of quinolone - Google Patents
Green synthesis process of key intermediate of quinolone Download PDFInfo
- Publication number
- CN111377826A CN111377826A CN202010206942.0A CN202010206942A CN111377826A CN 111377826 A CN111377826 A CN 111377826A CN 202010206942 A CN202010206942 A CN 202010206942A CN 111377826 A CN111377826 A CN 111377826A
- Authority
- CN
- China
- Prior art keywords
- reaction
- sodium
- cooling
- dimethylamino
- acrylate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
Abstract
The invention relates to the field of chemistry, in particular to a green synthesis process of a key intermediate of quinolone, which directly takes an amine exchange byproduct dimethylamine hydrochloride aqueous solution as a raw material, amine is synthesized into N, N-dimethylamino acrylate under the action of a catalyst, substituted benzoyl chloride and N, N-dimethylamino acrylate are further taken as raw materials, and the quinolone intermediate amine compound is synthesized by a condensation and amine exchange one-pot method.
Description
Technical Field
The invention relates to the field of chemistry, and particularly relates to a green synthesis process of a key intermediate of quinolone.
Background
Quinolone antibacterial agents have been widely used in the field of medicine in China. The quinolone antibiotics have the advantages of wide bactericidal spectrum, small toxic and side effects and moderate price, and are antibiotics which are developed rapidly in recent years. The developed and mass-produced quinolone antibiotics in China mainly comprise norfloxacin, ciprofloxacin, ofloxacin and the like, and account for about 98 percent of the total yield of the quinolone antibiotics in China. Quinolones are generally obtained by synthesizing fluorine-containing quinoline compounds from fluorine-containing benzene rings and condensing with piperazine (or methylpiperazine). China is one of the countries with the largest capacity of fluorine-containing medicines and intermediates in the world. The intermediate N, N-dimethylamino ethyl acrylate is mainly researched in great amount in the last 80 th century by Germany Bayer company and is finally applied to the production of moxifloxacin.
Various carbostyrils are produced by condensation of various acyl chlorides and N, N-dimethylamino ethyl acrylate, amine exchange, cyclization and piperazine condensation, and the basic main line is reported and published in the last 80 th century. The first reports of quinolone synthesis using substituted aminoacrylates appeared in JACS of 1946.
The synthesis of ethyl N, N-dimethylaminoacrylate, first known in 1932 from Annales de Chimie, Germany, reported the use of ethyl 3-hydroxyacrylate sodium salt in reaction with dimethylamine hydrochloride in absolute ethanol, long reaction times (7-8 h), low yields (41%), difficult work-up.
Dynamit-Nobel powder company (Germany) obtained U.S. Pat. No. 5,4772711 in 1988, using ethyl 3-hydroxyacrylate sodium salt and dimethylamine hydrochloride to react in water at 20-30 ℃ gives a fast reaction with a yield of up to 75%. The sodium salt of ethyl-3-hydroxyacrylate used may be carbon monoxide or the reaction of a formic acid ester with an acetic acid ester under sodium alcoholate.
German Bayer corporation acquired U.S. Pat. No. 5,5030747 in 1991, which indicates that the reaction is completed in 2 hours by Nobel using water as solvent, but the product is difficult to separate from the system and the loss is large. Moreover, the reactant 3-hydroxyethyl acrylate is degraded in water quickly, and the contact between the two must be minimized, which causes great difficulties in reaction and process. The Bayer is specialized in using an aprotic solvent or a mixed solvent with a protic solvent, and the sodium salt of the 3-hydroxy ethyl acrylate and dimethylamine hydrochloride react in a solid-solid form, so that the possibility of water degradation of the 3-hydroxy ethyl acrylate is avoided, and the yield reaches over 90 percent. However, in actual examination, it was found that the above-mentioned disadvantages could be theoretically improved by using an aprotic solvent as a reaction medium, but actually the reaction is a competitive reaction, and one molecule of water is generated at the same time as one molecule of the product is generated, and the generated water decomposes ethyl 3-hydroxypropionate, and further progress of the reaction is prevented. And because of solid-solid reaction, the mass transfer requirement of the reaction is high, and the reaction is not easy to be completed.
Condensing N, N-dimethylamino ethyl acrylate and 2, 4-dichloro-5-fluorobenzoyl chloride, further performing amine exchange with cyclopropylamine to obtain ciprofloxacin amide, and continuously cyclizing to obtain the cyclopropyl main ring. The process was developed by Bayer official Germany in the last 80 th century, and Canadian patent CA1333715 was applied in the earliest 1987, wherein different solvents are used in each step, and the total yield is over 70%. In US6229017 obtained in 2001, bayer corporation improved the process, and used the same nonpolar or slightly polar solvent to synthesize the main ring by multi-step reaction, so that the process is simple, the yield is increased, and the method is widely used at home and abroad.
However, the main disadvantages of the prior art are as follows:
1) the dimethylamine produced by amine exchange (see reaction formula 4 for details) is extremely difficult to treat, and the conventional method is to change the dimethylamine into dimethylamine hydrochloride aqueous solution by using hydrochloric acid for separation, but the dimethylamine in the solution can hardly be degraded by bacteria in a biochemical pool; the other method is to remove water to make the ammonium salt and the ammonium chloride become dimethylamine hydrochloride solid, and because the purity is not high and no further utilization value exists, the ammonium salt and the ammonium chloride can still become ammonia nitrogen pollutants which can not be degraded and have great influence on the environment; in the prior art, dimethylamine hydrochloride aqueous solution is used for synthesizing N, N-dimethylamino acrylate, so that the yield is low, the impurities are more, and side reactions exist;
2) the amine exchange has a reaction equilibrium relation, and the reaction is incomplete;
3) the process conditions are harsh, side reactions are easy to occur, the yield is low, the amount of three wastes is large, and the method is not suitable for industrial production;
4) a large amount of acid washing and alkali washing are carried out in the production process, and a large amount of high-salt high-COD wastewater is produced.
Therefore, a new green synthesis process of key intermediate of quinolone is urgently needed to be developed to meet the requirement of industrial mass production.
Disclosure of Invention
Aiming at the defects of the prior art and aiming at solving the application problem of dimethylamine hydrochloride solution as a byproduct of amine exchange in the production process of quinolone, the invention provides a green synthesis process for producing a key intermediate of quinolone by using the dimethylamine hydrochloride solution as a byproduct of amine exchange in the production process of quinolone as a reaction raw material, wherein the process comprises the steps of carrying out amination reaction on 3-hydroxy acrylate sodium salt and dimethylamine hydrochloride solution under the action of a catalyst to generate N, N-dimethylamino acrylate,
wherein R is1Is an alkyl group, preferably C1-C4Alkyl groups, more preferably methyl and ethyl groups.
Wherein the catalyst is a rare earth chloride catalyst.
The method can fully and circularly utilize the aqueous solution of the meglumine hydrochloride generated in the subsequent reaction step of producing the quinolone compounds, so that the aqueous solution of the meglumine hydrochloride can be directly applied to the synthesis of the N, N-dimethylamino acrylate, and the whole green synthesis cycle of the key intermediate of the quinolone is completed. The process can reduce the reaction rate of the 3-hydroxy acrylate and water, greatly accelerate the reaction of the 3-hydroxy acrylate sodium salt and the dimethylamine hydrochloride by using the high-selectivity rare earth chloride catalyst, obtain high yield, and have simple post-treatment, thereby completing the key one-ring of green quinolone synthesis.
Preferably, the rare earth chloride catalyst is cerium trichloride, lanthanum trichloride, yttrium trichloride or scandium trichloride;
the adding amount of the catalyst is 0.2-1% of the mass of the 3-hydroxy acrylate sodium salt, and the preferable amount is 0.5%;
preferably, in the industrial production, a reaction solvent, a rare earth chloride catalyst and a methylamine hydrochloride aqueous solution are added into a reaction kettle, the mixture is cooled to below 0 ℃, a reaction solvent solution of an addition product is added, the temperature is kept at 0 ℃ after the addition for 5 hours of reaction, after the temperature is kept, the mixture is washed and layered, refined hydrochloric acid and the reaction solvent are added into a water layer to adjust the pH value to be neutral, the mixture is extracted and layered, the separated water layer is subjected to reduced pressure concentration, crystallization and suction filtration to recover by-product sodium chloride, an organic phase is combined, reduced pressure rectification is performed to recover the reaction solvent for reuse, and high vacuum distillation is performed to obtain the N, N dimethylamino acrylate finished product.
The invention uses rare earth chloride as amination catalyst for synthesizing N, N-dimethylamino acrylate. Compared with the traditional Lewis acid, the rare earth chlorides such as cerium trichloride and the like have the advantages of water resistance, low toxicity, low price, easy obtaining and the like, and can effectively promote the smooth proceeding of various organic reactions under mild reaction conditions, thereby showing good application prospect. In the reaction of the invention, cerium trichloride and the like have great advantages as catalysts: firstly, the method has the advantages of high activity, high selectivity, mild reaction conditions, easy product separation and the like; secondly, not only can improve the selectivity of the reaction and the conversion rate of the product, but also can reduce the energy consumption and the discharge amount of wastes.
The reaction solvent is preferably xylene and toluene;
the reaction temperature is-20 to 5 ℃, preferably-5 to 0 ℃;
further, the sodium salt of 3-hydroxy acrylate is prepared by the addition reaction of acetate, carbon monoxide and sodium alkoxide,
wherein the carbon monoxide to acetate ester molar ratio is from 1:1.1 to 1:1.5, more preferably from 1:1.15 to 1: 1.25;
the molar ratio of sodium alkoxide to acetate is 1:1-1:1.2, more preferably 1:1.05-1: 1.1;
the pressure of the reaction system is 1.0-2.5MPa, and more preferably 1.0-2.0 MPa;
the reaction temperature is 60-100 ℃, and more preferably 70-90 ℃;
preferably, the xylene suspension of sodium alkoxide is transferred into a gas-liquid-solid high-efficiency reaction tank, acetic ester is added, CO gas is introduced to ensure that the system pressure is 1.0Mpa, the temperature is increased to 80 ℃, the pressure in the tank is kept below 2.0Mpa, the temperature is kept at 80 ℃ for 3 hours, the reaction is finished, the mixture is cooled and evacuated, low-boiling-point substances (mixed liquid containing alcohol and reaction solvent is evaporated under reduced pressure, and the mixture is recycled after rectification) to obtain reaction solvent solution of the addition product, and the reaction solvent solution is cooled to below 0 ℃ for later use.
In industrial production, the reaction step uses a high-efficiency gas-liquid-solid reaction tank for reaction. The carbon monoxide gas in the upper cavity of the tank is continuously conveyed to the bottom of the tank, so that the effect of comprehensive gas-liquid mixing reaction is achieved; meanwhile, the baffle plates arranged in a double-layer staggered manner on the tank wall and the S-shaped baffle plates on the outer static outer sleeves of the stirring paddles are combined to achieve a material crushing effect, so that the overall stirring and mixing effect is remarkably improved, the reaction time is greatly shortened, and the reaction yield is improved.
The high-efficiency gas-liquid-solid reaction tank comprises a tank body 3, a reaction cavity 8 is formed in the tank body 3, a gas guide column 1 is arranged in the reaction cavity 8, the upper end of the gas guide column 1 is fixedly connected with the tank body 3, and the lower end of the gas guide column extends towards the bottom of the reaction cavity 8. The air guide column 1 is provided with an air inlet 11 and an air outlet 12, an air passage 13 communicating the air inlet 11 with the air outlet 12 is arranged in the air guide column 1, and the air inlet 11 is positioned above the air outlet 12.
As shown in fig. 2, the reactor further comprises a stirring blade 7 disposed in the reaction chamber 8, and a stirring shaft and a driving device 2 for driving the stirring blade 7 to rotate, wherein the driving device 2 may be a motor, and the stirring shaft is partially or completely disposed in the reaction chamber 8. The stirring shaft is inserted into the air passage 13 from the upper end along the length direction of the air passage 13, penetrates out from the bottom of the air guide column 1 and extends into the reaction cavity 8, and a gap is reserved between the stirring shaft and the inner wall of the air passage 13. The stirring shaft comprises a transmission section 61 positioned in the air passage 13 and a stirring section 62 extending out of the bottom of the air guide column 1, and the stirring blade 7 is positioned on the stirring section 62.
When the liquid material is filled, the filling amount of the liquid material is higher than the gas outlet 12 and lower than the gas inlet 11, which is the liquid level of the liquid material as shown at a in fig. 2. After the filling of the material is completed, the liquid material flow enters the air channel 13 until the liquid level is basically equal to the liquid level in the reaction chamber 8, and the residual space at the upper end in the reaction chamber 8 is filled with the gaseous material. In the reaction process, the driving device 2 drives the stirring shaft and the stirring paddle 7 to rotate at a high speed, so that the liquid material in the reaction cavity 8 flows at a high speed in a certain direction and at a certain speed, the relative flow rate of the liquid material in the air passage 13 is small, and the material in the air passage 13 gradually flows back to the reaction cavity 8 from the air outlet 12 according to the law of large flow rate and small pressure in hydrodynamics. In the process of liquid material backflow in the air channel 13, the gaseous material is synchronously supplemented into the air channel 13 from the air inlet 11 until the liquid material completely flows back into the reaction cavity 8, and the gaseous material starts to enter the liquid material from the air outlet 12, so that the mixing of the solid material and the liquid material is realized.
Gaseous materials are directly introduced into the liquid materials through the gas guide column 1 and efficiently mixed with the liquid materials in a high-speed rotating state of the liquid materials, so that the reaction time is effectively shortened, the product yield is improved, and the production cost is reduced.
Further, the sodium alkoxide is prepared by reacting alcohol with sodium.
Preferably, the sodium metal and the reaction solvent are added into a reaction kettle, the temperature is raised to 130 ℃, the alcohol is dripped, the temperature is kept at about 130 ℃, about 5 hours are dripped, the temperature is kept for 2 hours, and the low-boiling-point substances (the mixed solution of the alcohol and the reaction solvent is recycled after rectification) are recovered by reduced pressure distillation to obtain the solvent suspension of the sodium alkoxide for later use.
Further, the N, N-dimethylamino acrylic ester prepared by the reaction and the substituted benzoyl chloride are condensed in the presence of trialkylamine to prepare the compound shown in the formula I,
the general formula of the N, N-dimethylamino acrylate is as follows:
the R is1The definitions are the same as above;
that is, the N, N-dimethylamino acrylate is preferably N, N-dimethylamino ethyl acrylate and N, N-dimethylamino methyl acrylate;
the general formula of the substituted benzoyl chloride is as follows:
the R is2Is a polysubstituted benzene ring or pyridine ring, and is preferably 2, 4-dichlorofluorobenzene, 2, 4-dichloro-5-fluoropyridine, tetrafluorobenzene, trifluoromethoxybenzene, trifluoro-2-methoxybenzene, tetrafluoro-5-nitrobenzene, 2, 4-dichloro-5-fluoro-6-methylbenzene, 2, 4-difluoro-3-methoxybenzene, 2, 4-difluoro-3-cyano-5-fluorobenzene, or the like;
that is, the substituted benzoyl chloride is preferably 2, 4-dichloro-5-fluorobenzoyl chloride, 2, 4-dichloro-5-fluoronicotinoyl chloride, tetrafluorobenzoyl chloride, trifluoro-2-methoxybenzoyl chloride, tetrafluoro-5-nitrobenzoyl chloride, 2, 4-dichloro-5-fluoro-6-methylbenzoyl chloride, 2, 4-difluoro-3-methoxybenzoyl chloride, 2, 4-difluoro-3-cyano-5-fluorobenzoyl chloride, or the like;
the trialkylamine has the general formula: (R)3)3N；
The R is3Is C1-C4Alkyl, preferably n-butyl and propyl;
that is, the trialkylamine is preferably tri-n-butylamine and tripropylamine;
preferably, the molar ratio of the N, N-dimethylamino acrylate to the substituted benzoyl chloride is 1:1-1:1.1, more preferably 1:1-1: 1.05;
preferably, the molar ratio of the N, N-dimethylamino acrylate to the trialkylamine is 1:1 to 1:1.1, more preferably 1:1 to 1: 1.05;
preferably, the reaction temperature is 120 ℃ to 140 ℃, more preferably 120 ℃ to 130 ℃;
in the step, the condensation reaction of the N, N-dimethylamino acrylic acid ester and the substituted benzoyl chloride is completed in a solvent-free mode.
Further, the compound of formula I obtained by the reaction is subjected to substitution reaction with primary amine in the presence of trialkylamine to obtain a compound of formula II,
the primary amine has the general formula: r4-NH2；
The R is4Is C1-C4Alkyl or cycloalkyl, preferably ethyl and cyclopropyl;
the primary amine is preferably ethylamine or cyclopropylamine;
the molar ratio of the compound of formula I to the primary amine is 1:1 to 1:1.1, more preferably 1:1 to 1: 1.05;
the molar ratio of the compound of formula I to trialkylamine is 1:1 to 1:1.1, more preferably 1:1 to 1: 1.05;
the reaction temperature is 40-70 ℃, and more preferably 50-60 ℃;
preferably, in the industrial production, adding N, N-dimethylamino acrylate, 2, 4-dichloro-5-fluorobenzoyl chloride and trialkylamine into a reaction kettle, slowly heating to 50 ℃, adding primary amine, keeping the temperature for reaction for 3 hours, adding water after the reaction is finished, stirring for 1 hour, standing for layering, recycling a water layer as a byproduct, mechanically applying the water layer to the production of the N, N-dimethylamino acrylate, adding alcohol into an organic layer, stirring, cooling to 0 ℃ for crystallization, cooling to-15 ℃, performing suction filtration, leaching a filter cake with alcohol, and performing vacuum drying to obtain an aminated substance. The filtered mother liquor is subjected to reduced pressure distillation to recover alcohol and trialkylamine for reuse.
The method can complete amine exchange by a one-pot method, skillfully applies the trialkyl amine as an acid-binding agent of a condensation reaction, and because the salt-forming capability is dimethylamine, the trialkyl amine and the primary amine, the primary amine of the raw material of the amine exchange cannot form salt, the concentration of reactants is not influenced, and the product of the dimethylamine becomes hydrochloride to be separated out from the system, thereby breaking the amine exchange balance, ensuring the reaction to be complete, and the hydrochloride of the trialkyl amine becomes a donor of dimethylamine salt formation in the amine exchange and becomes a solvent of the product of aminated substance, so that the product of aminated substance is well separated from the aqueous solution of dimethylamine hydrochloride, and. And the dimethylamine hydrochloride aqueous solution generated by the reaction is directly applied to the synthesis of N, N-dimethylamino acrylate, and the whole green synthesis cycle of the key intermediate of the quinolone is completed.
The process of the invention takes substituted benzoyl chloride and N, N-dimethylamino acrylate as raw materials, and the raw materials are synthesized by a condensation and amine exchange one-pot method, the synthesis process is simple, the reaction yield is high, the impurities are few, the byproduct dimethylamine hydrochloride is recycled as the raw material for synthesizing the N, N-dimethylamino acrylate, the condensation reaction is close to an equimolar reaction, the amine exchange reaction with primary amine is an equimolar reaction, and the used trialkylamine, alcohol and the like are recycled and reused. In conclusion, compared with the prior art, the invention has the following beneficial effects:
1. the reaction of the 3-hydroxy acrylate sodium salt and the dimethylamine hydrochloride is greatly accelerated by applying the high-selectivity catalyst, so that high yield is obtained, and the post-treatment is simple;
2. synthesizing N, N-dimethylamino acrylic acid ester by using a high-efficiency gas-liquid-solid reaction kettle. The whole mixing effect is obviously improved, the reaction time is greatly shortened, and the reaction yield is improved;
3. trialkylamine, alcohol and the like used in the process are recycled and reused, and a byproduct, namely dimethylamine hydrochloride is recycled and used as a raw material for synthesizing the N, N-dimethylamino acrylate;
4. the raw material source is convenient, the cost is low, the reaction condition is friendly, the by-products are greatly reduced, the total yield is high, the raw material utilization rate is high, the production cost is low, the purity is high, and the method is suitable for large-scale industrial continuous production;
5. the process route is short, the atom economy is high, the reaction system is simple, the operation of the production process is simple, and the labor intensity is greatly reduced;
6. the condensation reaction is close to equimolar reaction, the amine exchange reaction with primary amine is equimolar reaction, the reaction yield is high, and the byproduct impurities are few.
Drawings
FIG. 1 is a GC spectrum of the purity of N, N dimethylamino ethyl acrylate prepared in example 3.
FIG. 2 is a schematic structural diagram of a high-efficiency gas-liquid-solid reaction tank.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the teachings of the present invention, and such equivalents also fall within the scope of the appended claims.
Examples 1 to 5
1. Preparing sodium alkoxide: adding 23kg of sodium metal and xylene into a reaction kettle, heating to 130 ℃, dropwise adding 59.8kg of ethanol, keeping the temperature at about 130 ℃, keeping the temperature for about 5 hours, keeping the temperature for 2 hours, and recovering low-boiling-point substances (mixed liquid containing ethanol and xylene, and recovering and recycling after rectification) by reduced pressure distillation to obtain xylene suspension (containing 68kg of sodium ethoxide) of the sodium ethoxide for later use.
2. Addition reaction: transferring the xylene suspension of sodium ethoxide into a gas-liquid-solid efficient reaction tank, adding 88kg of ethyl acetate, introducing 33kg of CO gas to ensure that the system pressure reaches 1.0Mpa, heating to 80 ℃, keeping the pressure in the tank below 2.0Mpa, keeping the temperature at 80 ℃ for 3 hours, finishing the reaction, cooling, evacuating, decompressing and evaporating low-boiling-point substances (mixed liquid containing ethanol and xylene, recovering and recycling after rectification), obtaining xylene solution (containing 138kg of the adduct) of the adduct, and cooling to below 0 ℃ for later use.
3. Amination reaction: adding dimethylbenzene, cerium trichloride with different qualities and dimethylamine hydrochloride aqueous solution (containing 81.5kg of dimethylamine hydrochloride and derived from recycling of amide byproducts) into a reaction kettle, cooling to below 0 ℃, adding xylene solution (containing 138kg of adduct) of the adduct, preserving heat at 0 ℃ for reaction for 5 hours after the addition, preserving heat, washing with water for layering, adding refined hydrochloric acid and dimethylbenzene into a water layer to adjust the pH value to be neutral, extracting for layering, carrying out reduced pressure concentration, crystallization and suction filtration on the separated water layer to recover by-product sodium chloride, combining organic phases, carrying out reduced pressure rectification and dimethylbenzene recycling, and carrying out high vacuum distillation to obtain the N, N-dimethylaminoethyl acrylate finished product.
4. Amine compound synthesis: adding 143kg of N, N-dimethylamino ethyl acrylate, 227.5kg of 2, 4-dichloro-5-fluorobenzoyl chloride and 185.35kg of tri-N-butylamine into a reaction kettle, slowly heating to 50 ℃, adding 57kg of cyclopropylamine, keeping the temperature for reaction for 3 hours, adding water after the reaction is finished, stirring for 1 hour, standing for layering, recycling a water layer as a byproduct, mechanically applying the water layer to the production of N, N-dimethylamino ethyl acrylate, adding absolute ethyl alcohol into an organic layer, stirring, cooling to 0 ℃, crystallizing, cooling to-15 ℃, performing suction filtration, leaching a filter cake with ethanol, and performing vacuum drying to obtain a corresponding amide compound.
Note that the yield of N, N dimethylaminoethyl acrylate is the total yield of addition reaction and amination reaction, and the purity is the GC purity of N, N dimethylaminoethyl acrylate ① GC spectrum of the purity of N, N dimethylaminoethyl acrylate prepared in example 3 is shown in figure 1 of the specification, and the integrated area corresponding to figure 1 is shown in the data in the following table.
DET1
| Peak number | Retention time | Height | Area of | Name of | Area% | |
| 1 | 0.872 | 1886 | 3409 | 0.023 | ||
| 2 | 1.187 | 397 | 688 | 0.005 | ||
| 3 | 1.242 | 513 | 958 | 0.006 | ||
| 4 | 1.463 | 204 | 400 | 0.003 | ||
| 5 | 2.095 | 894 | 2496 | 0.017 | ||
| 6 | 2.174 | 262 | 794 | 0.005 | ||
| 7 | 2.314 | 413 | 1136 | 0.008 | ||
| 8 | 2.489 | 126 | 419 | 0.003 | ||
| 9 | 2.705 | 844 | 5609 | 0.037 | ||
| 10 | 3.293 | 2980 | 10785 | 0.072 | ||
| 11 | 3.497 | 3274199 | 14939478 | 99.481 | ||
| 12 | 3.636 | 1516 | 5657 | 0.038 | ||
| 13 | 3.823 | 1191 | 3546 | 0.024 | ||
| 14 | 4.152 | 5280 | 15860 | 0.106 | ||
| 15 | 4.292 | 163 | 460 | 0.003 | ||
| 16 | 4.430 | 716 | 3818 | 0.025 | ||
| 17 | 4.699 | 137 | 427 | 0.003 | ||
| 18 | 5.385 | 1721 | 6212 | 0.041 | ||
| 19 | 5.450 | 576 | 1802 | 0.012 | ||
| 20 | 5.683 | 1336 | 3843 | 0.026 | ||
| 21 | 6.337 | 433 | 1265 | 0.008 | ||
| 22 | 6.764 | 361 | 1107 | 0.007 | ||
| 23 | 7.261 | 233 | 869 | 0.006 | ||
| 24 | 7.604 | 1057 | 5083 | 0.034 | ||
| 25 | 9.744 | 384 | 1366 | 0.009 | ||
| Total of | 3297821 | 15017487 | 100.000 |
Examples 6 to 10
1. Preparing sodium alkoxide: adding 23kg of sodium metal and xylene into a reaction kettle, heating to 130 ℃, dropwise adding 59.8kg of ethanol, keeping the temperature at about 130 ℃, keeping the temperature for about 5 hours, keeping the temperature for 2 hours, and recovering low-boiling-point substances (mixed liquid containing ethanol and xylene, and recovering and recycling after rectification) by reduced pressure distillation to obtain xylene suspension (containing 68kg of sodium ethoxide) of the sodium ethoxide for later use.
2. Addition reaction: transferring the xylene suspension of sodium ethoxide into a gas-liquid-solid efficient reaction tank, adding 88kg of ethyl acetate, introducing 33kg of CO gas to ensure that the system pressure reaches 1.0Mpa, heating to 80 ℃, keeping the pressure in the tank below 2.0Mpa, keeping the temperature at 80 ℃ for 3 hours, finishing the reaction, cooling, evacuating, decompressing and evaporating low-boiling-point substances (mixed liquid containing ethanol and xylene, recovering and recycling after rectification), obtaining xylene solution (containing 138kg of the adduct) of the adduct, and cooling to below 0 ℃ for later use.
3. Amination reaction: adding dimethylbenzene, cerium trichloride 0.69kg and dimethylamine hydrochloride aqueous solution (containing 81.5kg of dimethylamine hydrochloride and derived from recycling amide byproducts) into a reaction kettle, cooling to a temperature below T1, adding dimethylbenzene solution (containing 138kg of adduct) of the adduct, keeping the temperature of T1 for reaction for 5 hours after the addition, keeping the temperature, washing and layering, adding refined hydrochloric acid and dimethylbenzene into a water layer to adjust the pH to be neutral, extracting and layering, carrying out reduced pressure concentration, crystallization and suction filtration on the separated water layer to recover by-product sodium chloride, combining organic phases, carrying out reduced pressure rectification and recovering dimethylbenzene for use, and carrying out high vacuum distillation to obtain the finished product of the N, N dimethylamino ethyl acrylate.
4. And (2) synthesizing an aminated substance, namely adding 143kg of N, N-dimethylamino ethyl acrylate, 227.5kg of 2, 4-dichloro-5-fluorobenzoyl chloride and 185.35kg of tri-N-butylamine into a reaction kettle, slowly heating to 50 ℃, adding 57kg of cyclopropylamine, keeping the temperature for reaction for 3h, adding water after the reaction is finished, stirring for 1 h, standing for layering, recycling a water layer as a byproduct, mechanically applying the water layer to the production of the N, N-dimethylamino ethyl acrylate, adding absolute ethanol into an organic layer, stirring, cooling to 0 ℃, crystallizing, cooling to-15 ℃, performing suction filtration, leaching a filter cake with ethanol, and performing vacuum drying to obtain the corresponding aminated substance.
Examples 11 to 14
1. Preparing sodium alkoxide: adding 23kg of sodium metal and xylene into a reaction kettle, heating to 130 ℃, dropwise adding 59.8kg of ethanol, keeping the temperature at about 130 ℃, keeping the temperature for about 5 hours, keeping the temperature for 2 hours, and recovering low-boiling-point substances (mixed liquid containing ethanol and xylene, and recovering and recycling after rectification) by reduced pressure distillation to obtain xylene suspension (containing 68kg of sodium ethoxide) of the sodium ethoxide for later use.
2. Addition reaction: transferring the xylene suspension of sodium ethoxide into a gas-liquid-solid efficient reaction tank, adding 88kg of ethyl acetate, introducing 33kg of CO gas to ensure that the system pressure reaches 1.0Mpa, heating to 80 ℃, keeping the pressure in the tank below 2.0Mpa, keeping the temperature at 80 ℃ for 3 hours, finishing the reaction, cooling, evacuating, decompressing and evaporating low-boiling-point substances (mixed liquid containing ethanol and xylene, recovering and recycling after rectification), obtaining xylene solution (containing 138kg of the adduct) of the adduct, and cooling to below 0 ℃ for later use.
3. Amination reaction: adding dimethylbenzene, 0.69kg of different catalysts and dimethylamine hydrochloride aqueous solution (containing 81.5kg of dimethylamine hydrochloride and derived from the recycling of amide byproducts) into a reaction kettle, cooling to below 0 ℃, adding xylene solution (containing 138kg of adduct) of the adduct, preserving the temperature at 0 ℃ for reaction for 5 hours after the addition, preserving the temperature, washing and layering, adding refined hydrochloric acid and the dimethylbenzene into a water layer to adjust the pH value to be neutral, extracting and layering, carrying out reduced pressure concentration, crystallization and suction filtration on the separated water layer to recover sodium chloride as a byproduct, combining organic phases, carrying out reduced pressure rectification and xylene recovery for reuse, and carrying out high vacuum distillation to obtain the finished product of the N, N dimethylamino ethyl acrylate.
4. The synthesis of the aminated substance comprises the steps of adding 143kg of N, N-dimethylamino ethyl acrylate, 227.5kg of 2, 4-dichloro-5-fluorobenzoyl chloride and 185.35kg of tri-N-butylamine into a reaction kettle, slowly heating to 50 ℃, adding 57kg of cyclopropylamine, keeping the temperature for reaction for 3 hours, adding water after the reaction is finished, stirring for 1 hour, standing for layering, recycling a water layer as a byproduct, mechanically applying the water layer to the production of N, N-dimethylamino ethyl acrylate, adding absolute ethyl alcohol into an organic layer, stirring, cooling to 0 ℃, crystallizing, cooling to-15 ℃, carrying out suction filtration, leaching a filter cake with ethanol, and carrying out vacuum drying to obtain 335.62kg of the corresponding aminated substance with the yield of 97%.
Example 15
1. Preparing sodium alkoxide: adding 23kg of sodium metal and toluene into a reaction kettle, heating to 130 ℃, dropwise adding 59.8kg of ethanol, keeping the temperature at about 130 ℃, keeping the temperature for about 5 hours after dropwise adding, keeping the temperature for 2 hours, and recovering low-boiling-point substances (mixed liquid containing ethanol and toluene, and recovering and recycling after rectification) by reduced pressure distillation to obtain toluene suspension (containing 68kg of sodium ethoxide) of the sodium ethoxide for later use.
2. Addition reaction: transferring the toluene suspension of sodium ethoxide into a gas-liquid-solid efficient reaction tank, adding 88kg of ethyl acetate, introducing 33kg of CO gas to ensure that the system pressure is 1.0Mpa, heating to 80 ℃, keeping the pressure in the tank below 2.0Mpa, keeping the temperature at 80 ℃ for 3 hours, completing the reaction, cooling, evacuating, decompressing and evaporating low-boiling-point substances (mixed liquid containing ethanol and toluene, recovering and recycling after rectification), obtaining toluene solution (containing 138kg of the addition compound) of the addition compound, and cooling to below 0 ℃ for later use.
3. Amination reaction: adding toluene, 0.69kg of cerium trichloride and dimethylamine hydrochloride aqueous solution (containing 81.5kg of dimethylamine hydrochloride and derived from recycling amide byproducts) into a reaction kettle, cooling to below 0 ℃, adding the toluene solution of an addition product (containing 138kg of the addition product), keeping the temperature at 0 ℃ for reaction for 5 hours after the addition, keeping the temperature, washing and layering, adding refined hydrochloric acid and toluene into a water layer to adjust the pH value to be neutral, extracting and layering, carrying out reduced pressure concentration, crystallization and suction filtration on the separated water layer to recover byproduct sodium chloride, combining organic phases, carrying out reduced pressure rectification and recovering toluene for reuse, and carrying out high vacuum distillation to obtain the finished product of N, N dimethylamino ethyl acrylate, wherein the purity is 98.5%, and the yield is 98.7%.
4. The synthesis of the aminated substance comprises the steps of adding 143kg of N, N-dimethylamino ethyl acrylate, 227.5kg of 2, 4-dichloro-5-fluorobenzoyl chloride and 143.27kg of tripropylamine into a reaction kettle, slowly heating to 50 ℃, adding 45kg of ethylamine, keeping the temperature for reaction for 3 hours, adding water after the reaction is finished, stirring for 1 hour, standing for layering, recycling a water layer as a byproduct, mechanically applying the water layer to the production of the N, N-dimethylamino ethyl acrylate, adding absolute ethyl alcohol into an organic layer, stirring, cooling to 0 ℃, crystallizing, cooling to-15 ℃, carrying out suction filtration, rinsing a filter cake with ethanol, and carrying out vacuum drying to obtain 327.32kg of the corresponding aminated substance with the yield of 98%.
Example 16
1. Preparing sodium alkoxide: adding 23kg of metal sodium and xylene into a reaction kettle, heating to 130 ℃, dropwise adding 41.6kg of methanol, keeping the temperature at about 130 ℃, keeping the temperature for about 5 hours after dropwise adding, keeping the temperature for 2 hours, and recovering low-boiling-point substances (a mixed solution containing methanol and xylene, and recovering and recycling after rectification) by reduced pressure distillation to obtain a xylene suspension (containing 54kg of sodium methoxide) of the sodium methoxide for later use.
2. Addition reaction: transferring the xylene suspension of sodium methoxide into a gas-liquid-solid high-efficiency reaction tank, adding 88kg of methyl acetate, introducing 33kg of CO gas to ensure that the system pressure is 1.0Mpa, heating to 80 ℃, keeping the pressure in the tank below 2.0Mpa, keeping the temperature at 80 ℃ for 3 hours, finishing the reaction, cooling, evacuating, distilling out low-boiling-point substances (containing methanol and xylene mixed liquid, recovering and recycling after rectification) under reduced pressure to obtain xylene solution (containing 124kg of the adduct) of the adduct, and cooling to below 0 ℃ for later use.
3. Amination reaction: adding dimethylbenzene, 0.69kg of lanthanum trichloride and dimethylamine hydrochloride aqueous solution (containing 81.5kg of dimethylamine hydrochloride and derived from recycling amide byproducts) into a reaction kettle, cooling to below 0 ℃, adding dimethylbenzene solution (containing 124kg of adduct) of the adduct, preserving heat at 0 ℃ for reaction for 5 hours after the addition, washing and layering, adding refined hydrochloric acid and dimethylbenzene into a water layer to adjust the pH value to be neutral, extracting and layering, carrying out reduced pressure concentration, crystallization and suction filtration on the separated water layer to recover byproduct sodium chloride, carrying out reduced pressure rectification on the combined organic phase to recover dimethylbenzene for reuse, and carrying out high vacuum distillation to obtain a finished product of N, N dimethylamino methyl acrylate with the purity of 98.4% and the yield of 98.7%.
4. The synthesis of the aminate comprises the steps of adding 139kg of N, N-dimethylamino methyl acrylate, 227.5kg of 2, 4-dichloro-5-fluorobenzoyl chloride and 143.27kg of tripropylamine into a reaction kettle, slowly heating to 50 ℃, adding 57kg of cyclopropylamine, keeping the temperature for reaction for 3 hours, adding water after the reaction is finished, stirring for 1 hour, standing for layering, recycling a water layer as a byproduct, mechanically applying the water layer to the production of the N, N-dimethylamino methyl acrylate, adding methanol into an organic layer, stirring, cooling to 0 ℃, crystallizing, cooling to-15 ℃, performing suction filtration, leaching a filter cake with methanol, and performing vacuum drying to obtain 322.04kg of the corresponding aminate with the yield of 97%.
Claims (10)
1. A green synthesis process of key intermediate of quinolone includes amination reaction of 3-hydroxy acrylate sodium salt and dimethylamine hydrochloride water solution in the presence of catalyst to produce N, N-dimethylamino acrylate,
wherein R is1Is an alkyl group, preferably C1-C4An alkyl group, a carboxyl group,
wherein the catalyst is a rare earth chloride catalyst.
2. The process of claim 1, wherein the rare earth chloride catalyst is cerium trichloride, lanthanum trichloride, yttrium trichloride, or scandium trichloride.
3. The synthetic process of claim 1, further comprising the steps of: acetic ester, carbon monoxide and sodium alcoholate are subjected to addition reaction to prepare 3-hydroxy acrylic ester sodium salt,
wherein R is1Is as defined in claim 1.
4. The synthetic process of claim 3, further comprising the steps of: the alcohol reacts with sodium to prepare sodium alkoxide.
5. The synthetic process of claim 1, further comprising the steps of: the N, N-dimethylamino acrylic ester and substituted benzoyl chloride are subjected to condensation reaction in the presence of trialkylamine to prepare a compound shown in the formula I,
wherein:
R1is as defined in claim 1;
R2is a polysubstituted benzene ring or pyridine ring;
R3is C1-C4An alkyl group.
6. The process of claim 5, wherein the reaction is carried out in a solvent-free system.
7. The synthetic process of claim 5, further comprising the steps of: the compound of the formula I and primary amine are subjected to substitution reaction in the presence of trialkylamine to prepare a compound of a formula II,
wherein R is1,R2,R3Is as defined in claim 5, R4Is C1-C4Alkyl or cycloalkyl.
8. The synthetic process of claim 1, adding a reaction solvent, a rare earth chloride catalyst and a dimethylamine hydrochloride aqueous solution into a reaction kettle, cooling to below 0 ℃, adding a reaction solvent solution of an adduct, keeping the temperature for reaction after the addition, washing with water for layering, adding refined hydrochloric acid and the reaction solvent into a water layer to adjust the pH value to be neutral, extracting for layering, concentrating the separated water layer under reduced pressure, crystallizing, performing suction filtration to recover by-product sodium chloride, combining organic phases, performing reduced pressure rectification to recover the reaction solvent, and performing high vacuum distillation to obtain the N, N-dimethylamino acrylate finished product.
9. The synthetic process of claim 8, further comprising the steps of: transferring the xylene suspension of sodium alkoxide into a gas-liquid-solid efficient reaction tank, adding acetic ester, introducing CO gas, carrying out heat preservation reaction, cooling and emptying, decompressing and steaming out low-boiling-point substances to obtain a reaction solvent solution of an addition product, and cooling for later use.
10. The synthetic process of claim 8, further comprising the steps of: adding N, N-dimethylamino acrylate, 2, 4-dichloro-5-fluorobenzoyl chloride and trialkylamine into a reaction kettle, slowly heating, adding primary amine, carrying out heat preservation reaction, adding water after the reaction is finished, stirring, standing for layering, recycling a water layer as a byproduct, applying the water layer to the production of the N, N-dimethylamino acrylate, adding alcohol into an organic layer, stirring and cooling to crystallize, cooling again, carrying out suction filtration, drying in vacuum to obtain an amide, and filtering a mother liquor, and recycling the alcohol and the trialkylamine for application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010206942.0A CN111377826B (en) | 2020-03-23 | 2020-03-23 | Green synthesis process of key intermediate of quinolone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010206942.0A CN111377826B (en) | 2020-03-23 | 2020-03-23 | Green synthesis process of key intermediate of quinolone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111377826A true CN111377826A (en) | 2020-07-07 |
| CN111377826B CN111377826B (en) | 2021-03-02 |
Family
ID=71221676
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010206942.0A Active CN111377826B (en) | 2020-03-23 | 2020-03-23 | Green synthesis process of key intermediate of quinolone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111377826B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112159359A (en) * | 2020-10-27 | 2021-01-01 | 新乡瑞诚科技股份有限公司 | Green preparation method of uracil |
| CN113912539A (en) * | 2021-12-13 | 2022-01-11 | 山东国邦药业有限公司 | Synthesis method of cyclopropanecarboxylic acid |
| CN114105792A (en) * | 2022-01-14 | 2022-03-01 | 山东国邦药业有限公司 | Preparation method of ciprofloxacin key intermediate |
| CN114436875A (en) * | 2022-03-01 | 2022-05-06 | 江苏飞宇医药科技股份有限公司 | Preparation method of cyclopropylethyl amide |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5030747A (en) * | 1989-03-23 | 1991-07-09 | Bayer Aktiengesellschaft | Process for the preparation of μ-amino-acrylic acid esters |
| CN101781313A (en) * | 2010-03-05 | 2010-07-21 | 浙江京新药业股份有限公司 | Method for synthesizing quinolone medicaments |
| CN105646257A (en) * | 2014-11-12 | 2016-06-08 | 南京卓业医药技术有限公司 | N,N-dimethylamino ethyl acrylate preparation method |
| CN105693535A (en) * | 2016-02-26 | 2016-06-22 | 中国科学院长春应用化学研究所 | Preparation method of 3-N,N-dimethylamino ethyl acrylate |
| CN105732410A (en) * | 2016-04-05 | 2016-07-06 | 苏州开元民生科技股份有限公司 | Synthesizing method of 3-N,N-dimethylamino ethyl acrylate |
| CN109553543A (en) * | 2017-12-29 | 2019-04-02 | 浙江本立科技股份有限公司 | A kind of synthetic method of N, N- dimethylamino ethyl acrylate |
-
2020
- 2020-03-23 CN CN202010206942.0A patent/CN111377826B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5030747A (en) * | 1989-03-23 | 1991-07-09 | Bayer Aktiengesellschaft | Process for the preparation of μ-amino-acrylic acid esters |
| CN101781313A (en) * | 2010-03-05 | 2010-07-21 | 浙江京新药业股份有限公司 | Method for synthesizing quinolone medicaments |
| CN105646257A (en) * | 2014-11-12 | 2016-06-08 | 南京卓业医药技术有限公司 | N,N-dimethylamino ethyl acrylate preparation method |
| CN105693535A (en) * | 2016-02-26 | 2016-06-22 | 中国科学院长春应用化学研究所 | Preparation method of 3-N,N-dimethylamino ethyl acrylate |
| CN105732410A (en) * | 2016-04-05 | 2016-07-06 | 苏州开元民生科技股份有限公司 | Synthesizing method of 3-N,N-dimethylamino ethyl acrylate |
| CN109553543A (en) * | 2017-12-29 | 2019-04-02 | 浙江本立科技股份有限公司 | A kind of synthetic method of N, N- dimethylamino ethyl acrylate |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112159359A (en) * | 2020-10-27 | 2021-01-01 | 新乡瑞诚科技股份有限公司 | Green preparation method of uracil |
| CN113912539A (en) * | 2021-12-13 | 2022-01-11 | 山东国邦药业有限公司 | Synthesis method of cyclopropanecarboxylic acid |
| CN114105792A (en) * | 2022-01-14 | 2022-03-01 | 山东国邦药业有限公司 | Preparation method of ciprofloxacin key intermediate |
| CN114436875A (en) * | 2022-03-01 | 2022-05-06 | 江苏飞宇医药科技股份有限公司 | Preparation method of cyclopropylethyl amide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111377826B (en) | 2021-03-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111377826B (en) | Green synthesis process of key intermediate of quinolone | |
| CN108430999B (en) | Preparation method of oxazolidinone intermediate | |
| CN106674002A (en) | Preparation method of hindered phenol antioxidant | |
| CN103347847B (en) | Diamines is prepared by preparing amino-nitrile | |
| CN100591667C (en) | N-amino-1,2-cyclopentanediformylimine and preparation method thereof | |
| CN109232178B (en) | Novel method for preparing high-purity hydroxytyrosol | |
| CN111269115A (en) | Preparation method of cinnamate in eutectic solvent | |
| CN108997128B (en) | Preparation method of pregabalin intermediate 3-nitromethyl-5-ethyl methylhexanoate | |
| CN109942446B (en) | Preparation method of pregabalin | |
| CN109438237B (en) | Preparation method of 3-ethoxy ethyl acrylate | |
| CN104710402A (en) | Dicyclohexyl crown ether synthesis method | |
| CN103044468A (en) | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid | |
| CN108164423B (en) | Preparation method of naftifine hydrochloride | |
| CN100457722C (en) | Method for synthesis of rivastigmine | |
| CN110683992B (en) | Method for synthesizing econazole nitrate by one-pot method | |
| CN104860980A (en) | Ezetimibe synthesis intermediate and preparation method and application thereof | |
| CN103193609B (en) | Synthesizing process of (S)-2-benzyloxy-pentan-3-one | |
| CN108484484B (en) | Preparation method of 2-oxo-3-ethyl piperidinecarboxylate | |
| CN108203396B (en) | Synthesis of enkephalinase inhibitor | |
| CN116693406B (en) | Preparation method of salbutamol sulfate | |
| CN115286504B (en) | Method for synthesizing (R) -2- (2- (tert-butoxy) -2-oxyethyl) pentanoic acid | |
| CN112851518B (en) | Synthesis method of N-methyl o-fluoroaniline | |
| CN111484523B (en) | Preparation method of optically pure trans-2- (diphenylphosphino) -1-cyclohexanecarboxylic acid | |
| CN104744416A (en) | Preparation method of simvastatin | |
| CN101665420A (en) | Method for preparing vanilline |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |