CN116143658A - Method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid - Google Patents
Method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid Download PDFInfo
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- CN116143658A CN116143658A CN202211625646.XA CN202211625646A CN116143658A CN 116143658 A CN116143658 A CN 116143658A CN 202211625646 A CN202211625646 A CN 202211625646A CN 116143658 A CN116143658 A CN 116143658A
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- tripropylacetonitrile
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
Abstract
The invention discloses a method for preparing tripropyl acetonitrile, tripropyl amide and tripropyl acetic acid simultaneously, which uses methyl cyanoacetate as a starting material to prepare tripropyl acetonitrile, solves the problems of difficult acquisition of reaction raw materials, high energy consumption, reagent danger, more side reactions and generation of toxic and harmful gases, and can obtain high-purity tripropyl acetamide and tripropyl acetic acid by further acid catalytic hydrolysis.
Description
Technical Field
The invention relates to the technical field of preparation of tripropylacetonitrile, in particular to a method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid.
Background
Tripropylacetonitrile (compound E), tripropylamide (compound F) and tripropylacetic acid (compound G) are process impurities which need to be researched in the synthesis process of sodium valproate bulk drug, meanwhile, the European pharmacopoeia 9.0 clearly indicates that the impurities in the three impurities need to be researched, and the tripropylacetonitrile plays a key role in detecting and controlling related substances in the production of the sodium valproate bulk drug, and the structural formula is as follows:
in the preparation of intermediate 2-cyano-2-propyl methyl valerate (compound B), patent US4127604 takes ethyl cyanoacetate, bromopropane and sodium propanol as raw materials to prepare compound H, and sodium propanol is prepared by the reaction of metal sodium and propanol, so that reagents are unusual, and transesterification reaction often occurs due to the adoption of sodium propanol catalysis, so that a byproduct I is generated, and the purification of a product and the central control of the quality of the product are not facilitated.
In the preparation process of a key intermediate valproic nitrile (compound D), patent US4127604 needs to be distilled twice to obtain a qualified compound D, and the energy consumption is high.
In the preparation of compound E, prior art "process for introducing alkyl radicals into carbon chains having a functional group and compounds prepared by said process; US4377533 "preparation of tripropylvaleronitrile according to exmple 22 in the patent is mainly carried out by carbanionization of acetonitrile, sodium amide, sodium isobutanol, and then alkylation reaction with haloalkanes to give tripropylvaleronitrile.
According to the analysis of the synthesis process of EXAMPLE 1, EXAMPLE 18 and EXAMPLE 23 in the patent US4377533, the defects of the process are as follows: (1) Sodium amide is used in the alkylation process, and the reagent has relatively high risk; (2) The acetonitrile is subjected to alkylation reaction to easily produce monosubstituted product valeronitrile and disubstituted product valproic nitrile, so that side reactions are more, the properties of byproducts are similar to those of main products, and separation is difficult;
in the process of hydrolyzing cyano into carboxylic acid, most of the traditional processes are catalyzed by sulfuric acid and sodium nitrite reagents, such as patent US4127604, excessive sodium nitrite is converted into nitrous acid in the reaction, and is further decomposed into toxic gases of nitric oxide and nitrogen dioxide to pollute the atmosphere and corrode equipment.
Disclosure of Invention
The invention aims at overcoming the defects in the prior art and provides a method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
there is provided a process for the simultaneous preparation of tripropylacetonitrile, tripropylamide, tripropylacetic acid comprising the steps of:
step one, adding methyl cyanoacetate (compound A), methanol and bromopropane into a reactor, controlling the reaction temperature to be 50-65 ℃, dropwise adding a methanol solution of sodium methoxide, finishing the reaction, and performing post-treatment to obtain 2-cyano-2-propyl methyl valerate;
step two, adding the methyl 2-cyano-2-propyl valerate (compound B) prepared in the step one into a sodium hydroxide aqueous solution, heating to 50-70 ℃ for reaction, cooling to room temperature after the reaction is finished, regulating pH, and separating phases to obtain a crude product (compound C) of the 2-cyano-2-propyl valerate as an oil phase;
step three, adding the crude 2-cyano-2-propyl valeric acid obtained in the step two into a reaction bottle, installing an atmospheric distillation device, and collecting fractions with the gas phase temperature of 160-180 ℃ to obtain valproic nitrile (compound D);
adding an alkaline reagent, THF, valproic nitrile and iodopropane into a reactor, replacing nitrogen for a plurality of times, heating to 50-70 ℃, and performing aftertreatment after the reaction is finished to obtain tripropylacetonitrile (compound F);
and fifthly, adding sulfuric acid aqueous solution into a reactor, adding tripropylacetonitrile (compound E), stirring, heating to 130-150 ℃, reacting for 20-35 hours, cooling to room temperature after the reaction is finished, separating and purifying to obtain tripropylacetamide (compound F) and tripropylacetic acid (compound G) respectively.
Further, in the first step, the molar ratio of the methyl cyanoacetate to the bromopropane is 1 (2-3), and the molar ratio of the methyl cyanoacetate to the sodium methoxide is 1 (2-3).
Further, in the first step, the post-processing specifically includes: and (3) distilling methanol at normal pressure after the reaction is finished to obtain a solid-liquid mixture, adding isopropyl acetate, filtering to remove salt, rinsing salt with isopropyl acetate, combining washing liquid and filtrate, washing with water, concentrating an oil phase, and distilling.
Further, in the second step, the molar ratio of the sodium hydroxide to the 2-cyano-2-propyl methyl valerate is 1 (1-4.5); the reaction time is 5-8 hours; adding hydrochloric acid to adjust the pH to 1-1.5.
Further, in the third step, after the atmospheric distillation device is installed, the temperature is slowly raised to 140 ℃, then the temperature is gradually raised to 205 ℃, and the fraction with the gas phase temperature of 160-180 ℃ is collected.
Further, in the fourth step, the alkaline reagent is one or more of sodium hydride, calcium hydride, lithium aluminum hydride and butyl lithium; the mol ratio of the alkaline reagent to the valproic nitrile is 1 (0.3-1); the reaction time is 7-15 hours.
Further, in the fourth step, the post-processing specifically includes: slowly adding water into the reaction solution to quench, controlling the temperature below 50 ℃, removing supernatant, concentrating the supernatant under reduced pressure, adding toluene, extracting the oil phase with sodium hydroxide aqueous solution, washing with water, concentrating hydrochloric acid, washing with water, and separating phases; the oil phase is decompressed to 0.95Mpa by a water pump and distilled, the obtained oil phase is poured into a single-mouth bottle, decompressed to 0.095Mpa by the water pump and distilled, and the fraction with the gas phase temperature of 138 ℃ is collected, thus obtaining the fraction tripropylacetonitrile.
Further, in the fifth step, the mass concentration of the sulfuric acid aqueous solution is 50-70%.
Further, in the fifth step, the specific steps of separation and purification are as follows: adding toluene and water for dilution, filtering, separating phase, washing oil phase with water, adding sodium hydroxide aqueous solution into the oil phase, heating to reflux, refluxing for 20-30 min, cooling to room temperature, extracting with dichloromethane, separating phase to obtain dichloromethane solution of tripropylacetamide and tripropylacetic acid sodium water phase; adding concentrated hydrochloric acid into a sodium tripropyl acetate aqueous phase to acidify to pH=1, back-extracting with dichloromethane, separating phases, concentrating the dichloromethane phase at 30 ℃ under reduced pressure in water bath, and pumping for 1 hour under reduced pressure by using an oil pump at 60 ℃ to obtain tripropyl acetic acid; concentrating the dichloromethane phase of tripropylacetamide to dryness by using a rotary evaporator at 30-70 ℃ under reduced pressure, and pumping for 0.5 hour by using an oil pump at 70 ℃ under reduced pressure to obtain tripropylacetamide.
Compared with the prior art, the invention has the following technical effects:
the invention adopts a sodium methoxide and methanol system when preparing the compound B, and the raw materials are easy to obtain, so that the generation of transesterification byproducts I in the patent US4127604 can not occur, and the side reaction is reduced; meanwhile, the reaction of propanol and metal sodium is avoided to prepare sodium propanol, and the risk of experimental operation is reduced.
In the preparation of the compound D, the distillation device is directly arranged on the reaction bottle, so that the effect of distillation while reaction is performed is achieved, the secondary distillation in the patent US4127604 is avoided, and the energy consumption is reduced.
In the process of preparing the compound E, the alkylation reaction is carried out by using the valproic nitrile and the bromopropane, and the sodium hydride is used for catalysis, so that compared with the alkylation reaction carried out by using acetonitrile and the bromopropane in the patent US4377533, the reagent is greatly reduced in danger compared with the catalysis of an amino sodium base reagent, and meanwhile, the generation of byproducts of the valproic nitrile and the valproic nitrile is reduced, and the side reaction is also obviously reduced.
The invention uses sulfuric acid aqueous solution to catalyze at 130-150 ℃ to hydrolyze cyano into a mixture of amide and carboxylic acid, thereby avoiding the generation of poisonous and harmful gases of nitric oxide and nitrogen dioxide; three high-purity organic impurities of sodium valproate are prepared simultaneously by one synthetic route, namely, the purity of the compound E, F, G is more than 98%, so that the preparation efficiency of the impurities is greatly improved.
Detailed Description
The invention will be further illustrated, but is not limited, by the following examples. It should be noted that, without conflict, the embodiments of the present invention and features of the embodiments may be combined with each other.
Example 1
1. Preparation of methyl 2-cyano-2-propylvalerate (Compound B)
Methyl cyanoacetate (compound A,270 g), bromo-n-propane 845g and methanol 540ml are added into a 3L reaction bottle, water bath is carried out, the temperature is controlled between 30 and 65 ℃, 1108g of methanol solution of sodium methoxide (mass fraction 30%) is added dropwise, the temperature is kept between 50 and 65 ℃ for 3 hours, and a solid-liquid mixture is obtained after the reaction. Methanol is distilled under normal pressure at 40 ℃ to obtain a solid-liquid mixture, 200g of isopropyl acetate is added, filtration is carried out, sodium bromide solid is rinsed by 200g of isopropyl acetate with the concentration of 2, filtrate and washing liquid are combined, 150ml of water is used for extraction, oil phase is distilled at 35-60 ℃ under reduced pressure, and 472g of crude product is obtained. Distillation was carried out using a 40cm spike column at a pressure of 290pa, and a fraction having a gas phase temperature of 87 to 89℃was collected to obtain methyl 2 cyano-2-propylvalerate (Compound B,406g, purity 99.21%, yield 81%).
2. Preparation of 2-cyano-2-propylpentanoic acid (Compound C)
Into a two liter reaction flask, 1395g of 20% aqueous sodium hydroxide solution (compound B,300 g) was added, and the reaction temperature was controlled to 50 to 70℃for 5.5 hours. The reaction solution was neutralized to ph=1 with 923g of concentrated hydrochloric acid under an ice water bath, and phase separation was performed to obtain a crude 2-cyano-2-propylpentanoic acid (compound C,316 g).
3. Preparation of valproic nitrile (Compound D)
Crude 2-cyano-2-propylpentanoic acid (compound C,316 g) was added to a three-necked flask. The reaction flask was connected to an atmospheric distillation unit, and the temperature was slowly raised to 140℃to 205℃to collect a fraction having a gas phase temperature of 160℃to 180℃to obtain valproic nitrile (compound D,121g, purity 99.7%, 59% in terms of B).
4. Preparation of tripropylacetonitrile (Compound E)
53g of sodium hydride, 220ml of THF, 102g of valproic nitrile and 153g of 1-iodopropane are added into a 1000ml reaction bottle, the system is vacuumized and replaced for five times by nitrogen, the system is protected by oil seal, the temperature is raised to 50 ℃, gas is generated, and the temperature is kept at 50-64 ℃ for 7 hours until no gas is generated. Slowly adding 45g of water into the reaction solution to quench, controlling the temperature below 50 ℃, removing the supernatant, concentrating the supernatant to 161g at 40-45 ℃ under reduced pressure, adding 200ml of toluene, extracting the oil phase by using 190g of 20% sodium hydroxide aqueous solution, washing with 100ml of 3 water, washing with 10% concentrated hydrochloric acid and 50ml of 2 water, and separating phases. The oil phase was distilled off under reduced pressure (0.95 MPa) at 50℃for 2 hours using a water pump to give 145g of an oil phase. 145g of the oil phase was poured into a 1L single-necked flask, distilled under reduced pressure (0.095 MPa) using a water pump, and the fraction having a gas phase temperature of 138℃was collected to obtain tripropylacetonitrile (Compound E,78g, purity 98.3%, yield 57%).
The hydrogen radical results for compound E are shown in Table 1 below:
TABLE 1
Example 2
Preparation of tripropylacetamide (compound F) and tripropylacetic acid (compound G):
2, 2-dipropylvaleronitrile (Compound E,25 g) was added to a 50% aqueous sulfuric acid solution (64 g) in a 100ml reaction flask. And (3) installing a water separator, a condenser pipe thermometer, slowly heating the water separator under magnetic stirring, stopping water separation when the internal temperature reaches 140 ℃, preserving the heat for 28 hours at the internal temperature of 140 ℃, and stopping the reaction. Cooling to room temperature, adding 50ml toluene and 70ml water, filtering off carbon black, adding 10g sodium chloride for dissolution, separating phases, and extracting oil phase with 20ml water. Adding 40g of 15% sodium hydroxide aqueous solution into the oil phase, adding 10ml of water, heating to reflux, refluxing for 20min, cooling to 25 ℃, extracting with 50ml of 5-x dichloromethane, and separating phases to obtain a tripropylacetamide (compound F) dichloromethane solution, and obtaining a tripropylacetic acid sodium (compound J) aqueous phase.
Sodium tripropylacetate (compound J) aqueous phase was acidified to ph=1 by adding 15ml of concentrated hydrochloric acid, back extracted with 30ml of 2 dichloromethane, phase separated, concentrated to dryness under reduced pressure at 30 ℃ in water bath, and extracted for 1 hour under reduced pressure (290 pa) using an oil pump to obtain tripropylacetic acid (compound G,10.8G, purity 99.6%, yield 38%). The methylene chloride solution of tripropylacetamide (compound F) was concentrated to dryness under reduced pressure using a rotary evaporator at 30 to 70℃and was extracted under reduced pressure (290 pa) using an oil pump for 0.5 hours, to give tripropylacetamide (compound F,10.0g, purity 99.1%, yield 36%).
The hydrogen radical results for compound F are shown in table 2 below:
TABLE 2
The hydrogen radical results for compound G are shown in table 3 below:
TABLE 3 Table 3
The foregoing is merely illustrative of the preferred embodiments of the present invention and is not intended to limit the embodiments and scope of the present invention, and it should be appreciated by those skilled in the art that equivalent substitutions and obvious variations may be made using the teachings of the present invention, and all such variations are intended to be included within the scope of the present invention.
Claims (9)
1. A method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid, which is characterized by comprising the following steps:
step one, adding methyl cyanoacetate, methanol and bromopropane into a reactor, controlling the reaction temperature to be 50-65 ℃, dropwise adding a methanol solution of sodium methoxide, finishing the reaction, and performing post-treatment to obtain 2-cyano-2-propyl methyl valerate;
step two, adding the methyl 2-cyano-2-propyl valerate prepared in the step one into a sodium hydroxide aqueous solution, heating to 50-70 ℃ for reaction, cooling to room temperature after the reaction is finished, regulating the pH value, and separating phases to obtain an oil phase which is a crude product of the 2-cyano-2-propyl valerate;
step three, adding the crude 2-cyano-2-propyl valeric acid obtained in the step two into a reaction bottle, installing an atmospheric distillation device, and collecting fractions with the gas phase temperature of 160-180 ℃ to obtain valproic nitrile;
adding an alkaline reagent, THF, valproic nitrile and iodopropane into a reactor, replacing nitrogen for multiple times, heating to 50-70 ℃, and performing aftertreatment after the reaction is finished to obtain tripropyl acetonitrile;
and fifthly, adding sulfuric acid aqueous solution into a reactor, adding tripropylacetonitrile, stirring, heating to 130-150 ℃, reacting for 20-35 hours, cooling to room temperature after the reaction is finished, separating and purifying to obtain tripropylacetamide and tripropylacetic acid respectively.
2. The method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid according to claim 1, wherein in the first step, the molar ratio of methyl cyanoacetate to bromopropane is 1 (2-3), and the molar ratio of methyl cyanoacetate to sodium methoxide is 1 (2-3).
3. The method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid according to claim 1, wherein in the first step, the post-treatment comprises the following specific steps: and (3) distilling methanol at normal pressure after the reaction is finished to obtain a solid-liquid mixture, adding isopropyl acetate, filtering to remove salt, rinsing salt with isopropyl acetate, combining washing liquid and filtrate, washing with water, concentrating an oil phase, and distilling.
4. The method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid according to claim 1, wherein in the second step, the molar ratio of sodium hydroxide to methyl 2-cyano-2-propylvalerate is 1 (1-4.5); the reaction time is 5-8 hours; adding hydrochloric acid to adjust the pH to 1-1.5.
5. The method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid according to claim 1, wherein in the third step, after the atmospheric distillation device is installed, the temperature is slowly raised to 140 ℃, and then the temperature is gradually raised to 205 ℃, and the fraction with the gas phase temperature of 160-180 ℃ is collected.
6. The method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid according to claim 1, wherein in the fourth step, the alkaline reagent is one or more of sodium hydride, calcium hydride, lithium aluminum hydride and butyllithium; the mol ratio of the alkaline reagent to the valproic nitrile is 1 (0.3-1); the reaction time is 7-15 hours.
7. The method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid according to claim 1, wherein in the fourth step, the post-treatment specifically comprises the following steps: slowly adding water into the reaction solution to quench, controlling the temperature below 50 ℃, removing supernatant, concentrating the supernatant under reduced pressure, adding toluene, extracting the oil phase with sodium hydroxide aqueous solution, washing with water, concentrating hydrochloric acid, washing with water, and separating phases; the oil phase is decompressed to 0.95Mpa by a water pump and distilled, the obtained oil phase is poured into a single-mouth bottle, decompressed to 0.095Mpa by the water pump and distilled, and the fraction with the gas phase temperature of 138 ℃ is collected, thus obtaining the fraction tripropylacetonitrile.
8. The method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid according to claim 1, wherein in the fifth step, the mass concentration of the sulfuric acid aqueous solution is 50-70%.
9. The method for simultaneously preparing tripropylacetonitrile, tripropylamide and tripropylacetic acid according to claim 1, wherein in the fifth step, the specific steps of separation and purification are as follows: adding toluene and water for dilution, filtering, separating phase, washing oil phase with water, adding sodium hydroxide aqueous solution into the oil phase, heating to reflux, refluxing for 20-30 min, cooling to room temperature, extracting with dichloromethane, separating phase to obtain dichloromethane solution of tripropylacetamide and tripropylacetic acid sodium water phase; adding concentrated hydrochloric acid into a sodium tripropyl acetate aqueous phase to acidify to pH=1, back-extracting with dichloromethane, separating phases, concentrating the dichloromethane phase at 30 ℃ under reduced pressure in water bath, and pumping for 1 hour under reduced pressure by using an oil pump at 60 ℃ to obtain tripropyl acetic acid; concentrating the dichloromethane phase of tripropylacetamide to dryness by using a rotary evaporator at 30-70 ℃ under reduced pressure, and pumping for 0.5 hour by using an oil pump at 70 ℃ under reduced pressure to obtain tripropylacetamide.
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| CN116874347A (en) * | 2023-07-10 | 2023-10-13 | 湖南省湘中制药有限公司 | Preparation method of impurity dipropylvaleric acid in valproic acid process |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116874347A (en) * | 2023-07-10 | 2023-10-13 | 湖南省湘中制药有限公司 | Preparation method of impurity dipropylvaleric acid in valproic acid process |
| CN116874347B (en) * | 2023-07-10 | 2024-03-29 | 湖南省湘中制药有限公司 | Preparation method of impurity dipropylvaleric acid in valproic acid process |
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