CN115991653B - Preparation method of prazoracetam key intermediate N, N-diisopropyl ethylenediamine - Google Patents
Preparation method of prazoracetam key intermediate N, N-diisopropyl ethylenediamine Download PDFInfo
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- CN115991653B CN115991653B CN202211597916.0A CN202211597916A CN115991653B CN 115991653 B CN115991653 B CN 115991653B CN 202211597916 A CN202211597916 A CN 202211597916A CN 115991653 B CN115991653 B CN 115991653B
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- CURJNMSGPBXOGK-UHFFFAOYSA-N n',n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)N(C(C)C)CCN CURJNMSGPBXOGK-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims abstract description 31
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 23
- 238000010438 heat treatment Methods 0.000 claims abstract description 21
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 229940043279 diisopropylamine Drugs 0.000 claims abstract description 10
- 239000012044 organic layer Substances 0.000 claims abstract description 10
- 238000004321 preservation Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 239000003507 refrigerant Substances 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000012544 monitoring process Methods 0.000 claims abstract description 3
- 238000001816 cooling Methods 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 34
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 239000012267 brine Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 7
- 150000007530 organic bases Chemical group 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical group C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000004064 recycling Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims 2
- 230000008020 evaporation Effects 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 238000006845 Michael addition reaction Methods 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000002351 wastewater Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000007142 ring opening reaction Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- NZBXLJWHCSCCFE-WCCKRBBISA-N (2s)-pyrrolidine-2-carboxylic acid;trifluoromethanesulfonic acid Chemical compound OC(=O)[C@@H]1CCCN1.OS(=O)(=O)C(F)(F)F NZBXLJWHCSCCFE-WCCKRBBISA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 238000005642 Gabriel synthesis reaction Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 238000006957 Michael reaction Methods 0.000 description 1
- -1 N, N-diisopropylaminopropionamide Chemical compound 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000006606 decarbonylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- LYFLFVYTFVHDGN-UHFFFAOYSA-N n-(1-chloroethyl)-n-propan-2-ylpropan-2-amine;hydrochloride Chemical compound Cl.CC(C)N(C(C)C)C(C)Cl LYFLFVYTFVHDGN-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a prazoracetam key intermediate N, N-diisopropyl ethylenediamine, which comprises the following steps: adding acrylamide, water and a catalyst into a reaction bottle, dropwise adding diisopropylamine under ice bath, heating the dropwise added system to 30-70 ℃, and preserving heat for 6-12 hours until the raw materials react completely; cooling the system to 0-5 ℃, slowly adding 40% sodium hydroxide solution, and stirring for 15 minutes; maintaining the system at 0-5 ℃, slowly dripping sodium hydroxide solution of NaClO or NaBrO solution, and performing heat preservation reaction for 0.5 hour; removing the refrigerant, naturally heating to room temperature, and stirring for reaction for 1 hour; continuously heating to 30-80 ℃ to react for 2-6 hours, and monitoring that the reaction raw materials are not remained; the system is cooled to room temperature, extracted by methylene dichloride, the organic layer is washed, dried, filtered, concentrated and distilled to remove methylene dichloride for later use, and the residue is distilled under vacuum and reduced pressure to obtain N, N-diisopropyl ethylenediamine. The method has the advantages of simple process and short production period, and is suitable for industrial production for rapidly synthesizing the N, N-diisopropyl ethylenediamine.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and medicine, and particularly relates to a preparation method of a key intermediate N, N-diisopropyl ethylenediamine of prazoracetam.
Background
Pracetin (figure 1) is a high-efficiency, low-toxicity and well-tolerated cognitive activator developed by the pharmaceutical company of Pake-Davis, U.S. and is used for the prevention of attention and memory disorders, benign aging amnesia, alzheimer's disease in the elderly. N, N-diisopropylethylenediamine is a key intermediate for the synthesis of prazoracetam, and the structure is shown in figure 2. Therefore, it is important to explore a method for synthesizing N, N-diisopropylethylenediamine rapidly, in high yield and purity.
The method for synthesizing N, N-diisopropyl ethylenediamine is reported at present as follows:
(1) Li Maolin is equal to applied chemistry 2005, 22 (12), 1384-1386, reporting the ammonification of ethylene oxide by ring-opening addition of ethylene oxide with N, N-diisopropylamine in water medium, chlorination by thionyl chloride. Finally, benzene is used as solvent to carry out ammonolysis under high temperature and high pressure to prepare the hydrochloride of the N, N-diisopropyl ethylenediamine. However, the route uses reagents with high toxicity such as thionyl chloride, benzene and the like, which cause environmental pollution and physical damage to workers, and the reaction process requires high temperature and high pressure, so that potential safety hazards exist in production and the yield is low.
(2) Peng Zhenyun, xuzhou medical college, 1999,19 (4), 273-274, reports that the target product is prepared by condensing N, N-diisopropylamino-chloroethane hydrochloride and phthalimide potassium salt in a solvent and then hydrolyzing hydrazine hydrate in ethanol by using Gabriel synthesis method, but the route uses flammable and explosive hydrazine hydrate, and the yield is low and the production cost is high.
(3) Dong Yanfei et al in chemical industry and engineering, 2007, 24 (4), 367-369, report an aziridine ring opening method, wherein ethanolamine is used as a starting material, and the target product is obtained through esterification, condensation and ring opening reaction. However, the route requires severe high-temperature conditions, generates a large amount of wastewater containing Al 3+ in the process to pollute the environment, and is not suitable for industrial production.
(4) Liu Shuangxi in "zilu medical matters, 2012, 31 (11), 631-651" reports that diisopropylamine is used as a starting material, and the target compound is obtained through two-step reaction synthesis of Michael addition and Hofmann degradation, and the target compound has the characteristics of low yield, overlong reaction time and the like. Shi Xiangjun et al adopt proline triflate as a catalyst to improve the method, the reaction time is shortened, but the input amount of diisopropylamine as a reaction raw material is overlarge, the post-treatment needs high vacuum distillation for removal, the atomic utilization rate is low, the environment-friendly requirement is not met, and the yield is low.
Comprehensive literature reports that the target compound is synthesized by taking diisopropylamine and acrylamide as starting materials through two steps of reaction of Michael addition and Hofmann degradation, and has better industrial prospect. However, the prior art can be realized by a two-pot two-step method, the steps are complicated, the time consumption is long, and the optimization of personnel, equipment, productivity and cost can not be obtained.
Disclosure of Invention
The invention aims to provide a preparation method of a pracetam key intermediate N, N-diisopropyl ethylenediamine, which aims to overcome the defects of the prior art, improve the yield and purity of a target product N, N-diisopropyl ethylenediamine and accelerate the reaction process, and provides a method for rapidly synthesizing N, N-diisopropyl ethylenediamine, which has the advantages of simple process, short production period and suitability for industrial production: namely, one-pot two-step method is used for rapidly synthesizing N, N-diisopropyl ethylenediamine.
In order to achieve the above purpose, the invention provides a preparation method of a prazoracetam key intermediate N, N-diisopropyl ethylenediamine, which comprises the following steps:
Step S1: adding acrylamide, water and a catalyst into a reaction bottle, dropwise adding diisopropylamine under ice bath, strictly controlling the dropwise adding temperature to be lower than 10 ℃, heating the dropwise adding system to 30-70 ℃, and preserving heat for 6-12 hours until the raw materials react completely;
Step S2: the system in the step S1 is cooled to 0-5 ℃, 40% sodium hydroxide solution is slowly added, and the mixture is stirred for 15 minutes; maintaining the system at 0-5 ℃, slowly dripping sodium hydroxide solution of NaClO or sodium hydroxide solution of NaBrO, and performing heat preservation reaction for 0.5 hour; removing the refrigerant, naturally heating to room temperature, and stirring for reaction for 1 hour; continuously heating to 30-80 ℃ to react for 2-6 hours, and monitoring that the reaction raw materials are not remained; the system is cooled to room temperature, extracted by methylene dichloride, the organic layer is washed, dried, filtered, concentrated and distilled to remove methylene dichloride for later use, and the residue is distilled under vacuum and reduced pressure to obtain N, N-diisopropyl ethylenediamine.
The invention relates to a method for synthesizing N, N-diisopropyl ethylenediamine, which comprises the following reaction equation in the synthesis process:
Preferably, the feeding molar ratio of the acrylamide to the diisopropylamine in the step S1 is 1:1.1-1.5, and the feeding ratio of the acrylamide to the solvent water in the step S1 is 1g:1.5g. In order to integrate the reaction progress and the raw material cost, more preferably, the feeding mole ratio of acrylamide to diisopropylamine is 1:1.1.
Preferably, in the step S1, the catalyst is an organic base catalyst, and the molar ratio of acrylamide to catalyst is 1:0.1 to 0.2. More preferably, the acrylamide to catalyst feed molar ratio is 1:0.1.
Preferably, the organic base catalyst is 1, 8-diazabicyclo undec-7-ene.
Preferably, the heating temperature in the step 1 is 40-50 ℃, and the heat preservation time is 8-9 hours.
Preferably, the molar ratio of the acrylamide in the step 2 to the 40% sodium hydroxide is 1:1.
Preferably, the effective chlorine content of the sodium hydroxide solution slowly added with NaClO in the step 2 is 5% -13%. Considering that the NaBrO solution needs bromine to be prepared on site, bromine is a type of easily-made pipe product which is not easy to obtain, bromine-containing wastewater has great harm to environmental protection facilities and the like, the sodium hydroxide solution of NaClO is selected.
Preferably, the sodium hydroxide solution to which the NaClO is added dropwise in the step 2 has an effective chlorine content of 13%, and the molar ratio of acrylamide to NaClO is: 1:1.1 to 2.0. More preferably, the molar ratio of acrylamide to NaClO is: 1:1.1.
Preferably, the heating temperature in the step 2 is 40-50 ℃, and the heat preservation time is 3-4 hours.
The reaction equation for synthesizing N, N-diisopropyl ethylenediamine is as follows:
preferably, the system in the step 2 is cooled to room temperature, dichloromethane is used for extraction, an organic layer is washed by brine, anhydrous Na 2SO4 is used for drying, filtration, concentration and distillation are carried out to remove dichloromethane for recycling, and the residue is distilled under high vacuum and reduced pressure to obtain N, N-diisopropyl ethylenediamine.
Therefore, the preparation method of the N, N-diisopropyl ethylenediamine, which adopts the key intermediate of the prazobactam with the structure, has the following beneficial effects:
(1) The one-pot two-step method avoids the complicated separation operation of N, N-diisopropylaminopropionamide generated by the Michael addition reaction in the first step, saves labor hour, increases productivity and reduces wastewater.
(2) DBU is used as an alkaline catalyst to catalyze Michael addition reaction to be completed rapidly, so that the reaction time is greatly reduced from 48 hours to 8 hours.
(3) The sodium hydroxide solution (the effective chlorine content is 13%) of the NaClO which is cheap and easy to obtain is used as the second-step Huffman degradation reaction reagent instead of the pure NaClO solution, because the sodium hypochlorite is unstable, chlorine is easily released into the air, and the sodium hydroxide is added to ensure the stability of the sodium hypochlorite solution in the dropping stage, so that the active chlorine is more stable, the use amount of the NaClO solution is reduced, the equipment utilization rate is improved, the waste water amount is reduced, and the material cost and the waste water treatment cost are reduced.
(4) The 1, 8-diazabicyclo undec-7-ene (DBU) is used as a catalyst for Michael reaction, so that the generation of side reaction is avoided, and the reaction is more complete and thorough; sodium hydroxide solution of NaClO is used for carrying out Huffman degradation reaction, natural temperature rise and heat preservation are added to trigger exothermic rearrangement, decarbonylation reaction is carried out at a mild temperature, and side reaction is reduced. The yield of the target product is up to 80 percent and the purity is up to 99 percent.
(5) The method for synthesizing the target product N, N-diisopropyl ethylenediamine provided by the invention has the advantages of simple operation process and short production period, and is suitable for industrial production.
The technical scheme of the invention is further described in detail through examples and drawings.
Drawings
FIG. 1 is a chemical structural formula of prazobactam;
FIG. 2 is a chemical structural formula of intermediate N, N-diisopropylethylenediamine.
Detailed Description
The present invention will be further described below, and it should be noted that the present embodiment provides a detailed implementation manner and a specific operation procedure on the premise of the present technical solution, but the present invention is not limited to the present embodiment.
Example 1
The preparation method of the prazobactam key intermediate N, N-diisopropyl ethylenediamine comprises the following steps:
Step 1: acrylamide (28.4 g,0.4 mol), DBU (6.1 g,0.04mol,0.1 eq) and water (40 mL) were added dropwise to the flask under ice bath (< 10 ℃) to give diisopropylamine (44.5 g,0.44mol,1.1 eq), the drop temperature was strictly controlled to be lower than 10℃and then heated to 40℃to allow the reaction to proceed for 8 hours.
Step 2: the temperature of the system is reduced to 0-5 ℃, 40g of 40% sodium hydroxide solution is slowly added, and the mixture is stirred for 15 minutes. Slowly dropwise adding sodium hydroxide solution (with 13% of available chlorine content, 120.4g,0.44mol and 1.1 eq) of NaClO at the temperature of 0-5 ℃ of the system, and keeping the temperature for reaction for 0.5 hour; removing the refrigerant, naturally heating to room temperature, and stirring for reaction for 1 hour; heating to 40 ℃ is continued to react for 3 hours. The system was cooled to room temperature, extracted with dichloromethane (120 ml×3), the organic layer was washed with brine, dried over anhydrous Na 2SO4, filtered, concentrated, and the residue was distilled under high vacuum under reduced pressure to give 46.16g of N, N-diisopropylethylenediamine with a purity (GC) of 99.0%, yield 80% as a colorless transparent liquid.
Examples 1-1 to 1-6 were each prepared by changing the incubation time in example 1, and the other conditions were the same as in example 1, and the results were shown in Table 1 below:
TABLE 1
Examples 1-7 to 1-10 were prepared by changing the kind of catalyst or the molar ratio of acrylamide to catalyst in step 1 of example 1, respectively, and the other materials were fed in the same molar amounts and under the same reaction conditions as in example 1, and the results are shown in Table 2 below:
TABLE 2
Examples 1-11 to 1-15 were single changes in the molar ratio of the materials or changes in the holding temperature, control changes in single variables, and the remaining reaction conditions were the same as in example 1, with the results shown in Table 3 below:
TABLE 3 Table 3
Comparative example 1
The sodium hydroxide solution dropwise added with NaClO in the step 2 of the example 1 is changed into NaClO solution dropwise, and the other conditions are the same as those in the example 1, and the concrete steps are as follows:
Step 1: as in example 1.
Step 2: the temperature of the system is reduced to 0-5 ℃,40 g of 40% sodium hydroxide solution is slowly added, and the mixture is stirred for 15 minutes. Maintaining the system at 0-5 ℃, slowly dripping NaClO solution (the effective chlorine content is 13%,120.4g,0.44mol,1.1 eq) and keeping the temperature for reaction for 0.5 hour; removing the refrigerant, naturally heating to room temperature, and stirring for reaction for 1 hour; heating to 40 ℃ is continued to react for 3 hours. The system was cooled to room temperature, extracted with dichloromethane (120 ml×3), the organic layer was washed with brine, dried over anhydrous Na 2SO4, filtered, concentrated, and the residue was distilled under high vacuum under reduced pressure to give 41.43g of N, N-diisopropylethylenediamine with a purity (GC) of 98.1% and a yield of 71.8% as a colorless transparent liquid.
Comparative example 2
The amount of NaClO solution was varied, and the remaining reaction conditions were the same as in comparative example 1, and the specific procedures were as follows:
Step 1: as in example 1.
Step 2: the temperature of the system is reduced to 0-5 ℃, 40g of 40% sodium hydroxide solution is slowly added, and the mixture is stirred for 15 minutes. Maintaining the system at 0-5 ℃, slowly dropwise adding NaClO solution (effective chlorine content 13%,218.8g,0.8mol,2.0 eq), and keeping the temperature for reaction for 0.5 hours; removing the refrigerant, naturally heating to room temperature, and stirring for reaction for 1 hour; heating to 40 ℃ is continued to react for 3 hours. The system was cooled to room temperature, extracted with dichloromethane (120 ml×3), the organic layer was washed with brine, dried over anhydrous Na 2SO4, filtered, concentrated, and the residue was distilled under high vacuum under reduced pressure to give 42.18g of N, N-diisopropylethylenediamine with a purity (GC) of 98.2% and a yield of 74.3% as a colorless transparent liquid.
Comparative example 3
The sodium hydroxide solution dropwise added with NaClO in the step 2 of the example 1 is changed into NaBrO solution dropwise added, and the other conditions are the same as those in the example 1, and the concrete steps are as follows:
Step 1: as in example 1.
Step 2: the temperature of the system is reduced to 0-5 ℃, 40g of 40% sodium hydroxide solution is slowly added, and the mixture is stirred for 15 minutes. Maintaining the system at 0-5 ℃, slowly dripping NaBrO solution (self-made, effective bromine content 13.0%,0.44mol,271g,1.1 eq) and keeping the temperature for reaction for 0.5 hours; removing the refrigerant, naturally heating to room temperature, and stirring for reaction for 1 hour; heating to 40 ℃ is continued to react for 3 hours. The system was cooled to room temperature, extracted with dichloromethane (120 ml×3), the organic layer was washed with brine, dried over anhydrous Na 2SO4, filtered, concentrated, and the residue was distilled under high vacuum under reduced pressure to give 46.39g of N, N-diisopropylethylenediamine with a purity (GC) of 98.9%, yield 80.4% as a colorless transparent liquid.
Comparative example 4
Step 1: as in example 1.
Step 2: the temperature of the system is reduced to 0-5 ℃, 40g of 40% sodium hydroxide solution is slowly added, and the mixture is stirred for 15 minutes. Slowly dropwise adding sodium hydroxide solution (with 13% of available chlorine content, 120.4g,0.44mol and 1.1 eq) of NaClO at the temperature of 0-5 ℃ of the system, and keeping the temperature for reaction for 0.5 hour; the system was heated directly to 40℃and reacted for 4 hours. The system was cooled to room temperature, extracted with dichloromethane (120 ml×2), the organic layer was washed with brine, dried over anhydrous Na 2SO4, filtered, concentrated, and the residue was distilled under high vacuum under reduced pressure to give 44.03g of N, N-diisopropylethylenediamine with a purity (GC) of 98.5%, yield 76.3% as a colorless transparent liquid.
Therefore, the preparation method of the N, N-diisopropyl ethylenediamine, which is the key intermediate of pracetam, is simple in process, short in production period and suitable for industrial production, and the method is provided: namely, one-pot two-step method is used for rapidly synthesizing N, N-diisopropyl ethylenediamine.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention and not for limiting it, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that: the technical scheme of the invention can be modified or replaced by the same, and the modified technical scheme cannot deviate from the spirit and scope of the technical scheme of the invention.
Claims (8)
1. The preparation method of the prazobactam key intermediate N, N-diisopropyl ethylenediamine is characterized by comprising the following steps of:
Step S1: adding acrylamide, water and a catalyst into a reaction bottle, dropwise adding diisopropylamine under ice bath, strictly controlling the dropwise adding temperature to be lower than 10 ℃, heating the dropwise adding system to 30-70 ℃, and preserving heat for 6-12 hours until the raw materials react completely;
Step S2: the system in the step S1 is cooled to 0-5 ℃, 40% sodium hydroxide solution is slowly added, and the mixture is stirred for 15 minutes; maintaining the system at 0-5 ℃, slowly dripping sodium hydroxide solution of NaClO or sodium hydroxide solution of NaBrO, and performing heat preservation reaction for 0.5 hour; removing the refrigerant, naturally heating to room temperature, and stirring for reaction for 1 hour; continuously heating to 30-80 ℃ to react for 2-6 hours, and monitoring that the reaction raw materials are not remained; cooling the system to room temperature, extracting with dichloromethane, washing an organic layer, drying, filtering, concentrating, evaporating to remove dichloromethane, recovering for later use, and distilling the residue under reduced pressure in vacuum to obtain N, N-diisopropyl ethylenediamine;
in the step S1, the catalyst is an organic base catalyst, and the feeding mole ratio of the acrylamide to the catalyst is 1:0.1-0.2;
the organic base catalyst is 1, 8-diazabicyclo undec-7-ene.
2. The preparation method of the prazoracetam key intermediate N, N-diisopropylethylenediamine as claimed in claim 1, wherein the feeding molar ratio of acrylamide to diisopropylamine in the step S1 is 1:1.1-1.5, and the feeding ratio of acrylamide to solvent water in the step S1 is 1g:1.5g.
3. The preparation method of the prazoracetam key intermediate N, N-diisopropylethylenediamine as claimed in claim 1, wherein the heating temperature in the step 1 is 40-50 ℃, and the heat preservation time is 8-9 hours.
4. The method for preparing a key intermediate N, N-diisopropylethylenediamine of plaracetam according to claim 1, wherein the molar ratio of acrylamide to 40% sodium hydroxide in step 2 is 1:1.
5. The preparation method of the prazoracetam key intermediate N, N-diisopropyl ethylenediamine according to claim 1, wherein the effective chlorine content of the sodium hydroxide solution slowly added dropwise in the step 2 is 5% -13%.
6. The preparation method of the prazoracetam key intermediate N, N-diisopropyl ethylenediamine according to claim 5, wherein the sodium hydroxide solution added dropwise with NaClO in the step 2 has an effective chlorine content of 13%, and the molar ratio of acrylamide to NaClO is: 1:1.1-2.0.
7. The preparation method of the prazoracetam key intermediate N, N-diisopropyl ethylenediamine according to claim 1, wherein the heating temperature in the step 2 is 40-50 ℃, and the heat preservation time is 3-4 hours.
8. The preparation method of the prazoracetam key intermediate N, N-diisopropyl ethylenediamine according to claim 1, wherein the system in the step 2 is cooled to room temperature, dichloromethane is used for extraction, an organic layer is washed by brine, anhydrous Na 2SO4 is dried, filtration, concentration and evaporation are carried out to remove dichloromethane for recycling, and residues are distilled under high vacuum and reduced pressure to obtain the N, N-diisopropyl ethylenediamine.
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| CN102249928A (en) * | 2011-06-03 | 2011-11-23 | 浙江工业大学 | Synthesis method of N,N-diisopropyl quadrol |
| CN104557561A (en) * | 2014-12-15 | 2015-04-29 | 北京悦康科创医药科技有限公司 | Method for preparing N1,N1-diisoprylamino ethylamine or salts of N1,N1-diisoprylamino ethylamine |
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| CN102249928A (en) * | 2011-06-03 | 2011-11-23 | 浙江工业大学 | Synthesis method of N,N-diisopropyl quadrol |
| CN104557561A (en) * | 2014-12-15 | 2015-04-29 | 北京悦康科创医药科技有限公司 | Method for preparing N1,N1-diisoprylamino ethylamine or salts of N1,N1-diisoprylamino ethylamine |
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