CN104557561B - A kind of preparation method of N1, N1-diisopropyl ethylenediamine or its salt - Google Patents
A kind of preparation method of N1, N1-diisopropyl ethylenediamine or its salt Download PDFInfo
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Abstract
The preparation method that the present invention relates to a kind of N1, N1-diisopropyl ethylenediamine or its salt.Described method includes: with 2-bromoacetaldehyde contracting glycol and diisopropylamine for raw material, condensation obtains 2-(diisopropylaminoethyl) acetaldehyde contracting glycol, it is hydrolyzed in acid condition and obtains 2-(diisopropylaminoethyl) acetaldehyde, N1 is obtained then through amination, N1-diisopropyl ethylenediamine, salt is become to obtain the salt of N1, N1-diisopropyl ethylenediamine.
Description
Technical field:
The preparation method that the present invention relates to N1, N1-diisopropyl ethylenediamine or its salt, described method includes: with 2-bromoacetaldehyde contracting glycol and diisopropylamine for raw material, N1 is obtained through condensation, hydrolysis, amination, N1-diisopropyl ethylenediamine, becomes salt to obtain the salt of N1, N1-diisopropyl ethylenediamine.N1, N1-diisopropyl ethylenediamine or its salt can as the important intermediate of synthesis pramiracetam.
Background technology:
According to conservative estimation, senile dementia (mainly including alzheimer disease, other also have vascular dementia, Mixed dementia and the elderly dementia caused by the systemic disease) patient of China has about 6,000,000.According to Epidemiological study, in the old people of more than 60 years old, dull-witted prevalence is 3.0%～4.0%, and old people's prevalence of over-65s is then 4.0%～5.0%, the dull-witted prevalence of China over-65s urbanite person in middle and old age is more than 6%, and increases with the age and be multiplied.
Pramiracetam be a kind of efficiently, understanding activator that low toxicity, toleration are good, belong to pyrrolidinone compounds nootropics, there is very strong improvement brain function, hypermnesis, promotes the ability of brain dexterity, and toxicity is low, better tolerance, can be used for long-term prescription, improve symptom, delay dementia of the Alzheimer type.
The structure of pramiracetam is:
N1, N1-diisopropyl ethylenediamine is the important synthetic intermediate of pramiracetam, simultaneously, N1, N1-diisopropyl ethylenediamine also has important application in the other side such as Organometallic Chemistry, combinatorial chemistry, so the discussion also great meaning of the synthetic method to N1, N1-diisopropyl ethylenediamine.
Method one: document J.Chem.Soc, 1934:104～109 are with diisopropylaminoethanol for initiation material, benzene is solvent, thionyl chloride is chlorination reagent synthesis N1, N1-diisopropyl-2-chloroethyl amine, is obtained by reacting N1, N1-diisopropylaminoethyl ethyl phthalimide with potassium phthalimide, hydrolysis obtains primary amine N1, N1-diisopropyl ethylenediamine.This kind of method employs thionyl chloride, benzene etc. and pollutes stronger reagent, is not easy to produce and amplifies.
Method two: document AnalesdeQuimica, 1974,70 (9-10) are with 1,2-Bromofume is initiation material, it is synthetically derived N-(2-bromoethyl) phthalimide with phthalimide, is obtained by reacting N1, N1-diisopropylaminoethyl ethyl phthalimide with diisopropylamine, hydrolysis obtains product N1, N1-diisopropyl ethylenediamine.This kind method yield is low, by-product is many, is not easy to purifying products.
Method three: document AnalesdeQuimica (1968-1979), 70 (9-10), 733-7；Obtaining N1, N1-diisopropyl ethylenediamine with diisopropyl ammonia, formaldehyde, hydrocyanic acid or potassium cyanide for Material synthesis in 1974, this kind of method yield is high, but employs the cyanide of severe toxicity and the condition of high-pressure hydrogenation, and production security is low, is not easy to commercial production.
Method four: document AnalesdeQuimica (1968-1979), 70 (9-10), 733-7；Report another synthetic method in 1974, be obtained by reacting N1, N1-diisopropyl ethylenediamine with diisopropyl ammonia and dimethyleneimine, but this kind of method employs aluminum chloride as catalyst, and post-processing difficulty is big, seriously polluted, and dimethyleneimine toxicity is big, it is not easy to production operation.
Method five: document " applied chemistry ", 22 (12), 1384-1386；Report after obtaining intermediate with diisopropyl ammonia and reacting ethylene oxide in 2005, under the pressure of 6MPa, it is obtained by reacting N1 with ammonia with after thionyl chloride chlorination, N1-diisopropyl ethylenediamine, the oxirane that this method uses is dangerous materials, and employs thionyl chloride as chlorination reagent, and post-processing difficulty is big, pollute bigger, needing high pressure reactor during final step ammonification, therefore, the method is also not susceptible to commercial production.
For problem above, this patent provides the new preparation process of a kind of N1, N1-diisopropyl ethylenediamine, and the method has production operation safely, simply, the features such as yield is high, and reaction condition is gentle.
Summary of the invention:
The preparation method that the present invention relates to N1, N1-diisopropyl ethylenediamine or its salt, described method includes: with 2-bromoacetaldehyde contracting glycol and diisopropylamine for raw material, N1 is obtained through condensation, hydrolysis, amination, N1-diisopropyl ethylenediamine, becomes salt to obtain the salt of N1, N1-diisopropyl ethylenediamine.Its step is as follows:
Step 1:2-bromoacetaldehyde contracting glycol and diisopropylamine are raw material, and condensation obtains 2-(diisopropylaminoethyl) acetaldehyde contracting glycol, for compound 1.
Step 2: compound 1 is hydrolyzed in acid condition and obtains 2-(diisopropylaminoethyl) acetaldehyde, for compound 2.
Step 3: compound 2 obtains N1, N1-diisopropylamine ethylenediamine through amination, for compound 3.
Step 4: compound 3 obtains the salt of N1, N1-diisopropyl ethylenediamine by salt-forming reaction, for compound 4,
More than in reaction, R is methyl or ethyl,
HX is selected from following several acid: hydrochloric acid, sulphuric acid, methanesulfonic acid or benzenesulfonic acid.
In 2-bromoacetaldehyde contracting glycol described in step 1, R represents methyl or ethyl, and the molar ratio example of 2-bromoacetaldehyde contracting glycol and diisopropylamine is 0.9:1～1:1, and reaction dissolvent is oxolane, and reaction temperature is 60 DEG C～80 DEG C, and the response time is 12～24 hours.
Compound described in step 21 and hydrochloric acid or dilute sulfuric acid or acetic acid reaction obtain compound 2, and reaction dissolvent is methanol or ethanol, and reaction temperature is 70 DEG C～90 DEG C, and the response time is 4～6 hours.Wherein, hydrochloric acid is optimum, and dilute sulfuric acid takes second place, and acetic acid is third.
Described in step 3, compound 2 reacts with the methanol solution of ammonia, then passes into hydrogen or add sodium borohydride or sodium cyanoborohydride or Sodium triacetoxyborohydride.
Compound that compound 3 one-tenth salt described in step 4 obtains 4 is hydrochlorate or sulfate or mesylate or benzene sulfonate etc..Wherein, hydrochlorate and sulfate are optimum, and mesylate takes second place, and benzene sulfonate is third.
Detailed step operation is as follows:
Being dissolved in oxolane by 2-bromoacetaldehyde contracting glycol, diisopropyl ammonia, be warming up to back flow reaction more than 12 hours, detect diisopropyl ammonia with TLC method and convert after completely, concentrating under reduced pressure obtains yellow oil.Molar yield is in 100%.
Being dissolved in methanol by yellow oil half thing obtained in the previous step, the hydrochloric acid of dropping 6N less than 1, is warming up to return stirring more than 4 hours to pH value, detects raw material with TLC method and converts after completely, is down to reduced pressure at room temperature concentration and obtains the grease of yellow.Molar yield is calculated for 90～100% with diisopropyl ammonia.
Under room temperature condition; yellow oil obtained in the previous step is added in the methanol dissolving of ammonia; after all dissolving, add triacetyl boron sodium chloride, be stirred at room temperature more than 4 hours; convert after completely with the detection of TLC method; dropping concentrated hydrochloric acid, to solution pH value less than 1, after continuing stirring 12 hours; it is filtrated to get white solid and is the hydrochlorate of N1, N1-diisopropyl ethylenediamine.Molar yield is 70～80%.
In sum, the advantage of the preparation method of N1, the N1-diisopropyl ethylenediamine that the present invention relates to is in that:
1. present invention employs a brand-new preparation method, easy and simple to handle, reaction condition is gentle.
2. the raw material and the reagent that use are Chemical market general types, it is easy to buying, and toxicity, danger are minimum.
3. often walking without specially purification, product precipitates out in the way of becoming salt.
Below by way of correction data, further illustrate beneficial effects of the present invention
Detailed description of the invention:
By specific examples below, the present invention is further illustrated, but without limitation.
Embodiment 1
19.6 grams of 2-bromo-acetaldehyde diethyl acetal, 10 grams of diisopropyl ammonia are dissolved in 100 milliliters of oxolanes, add 13.7 grams of potassium carbonate, it is warming up to back flow reaction more than 12 hours, detect diisopropyl ammonia with TLC method to convert after completely, being down to room temperature to filter, filtrate reduced in volume obtains 30.2 grams of yellow oil.Molar yield is in 100%.
Embodiment 2
It is dissolved in 100 milliliters of oxolanes with 16.7 grams of 2-bromoacetaldehyde dimethyl acetals, 10 grams of diisopropyl ammonia, add 13.7 grams of potassium carbonate, it is warming up to back flow reaction more than 12 hours, detect diisopropyl ammonia with TLC method to convert after completely, being down to room temperature to filter, filtrate reduced in volume obtains 20.1 grams of yellow oil.Molar yield is in 100%.
Embodiment 3
30.2 grams of grease solutions embodiment 1 obtained are in 100 ml methanol, and the hydrochloric acid of dropping 6N less than 1, is warming up to return stirring more than 4 hours to pH value, detect raw material with TLC method and convert after completely, are down to reduced pressure at room temperature concentration and obtain 16.8 grams of grease.For calculating molar yield for 93.9% with diisopropyl ammonia.
Embodiment 4 and embodiment 5 10% sulphuric acid and 50% acetic acid replace the hydrochloric acid of 6N, carry out the experiment of step 2, operate identical, and result is shown in following table:
| Acid | Transforming degree | Response time | Way of purification | |
| Embodiment 4 | 10% sulphuric acid | Convert completely | 4 hours | Without purification |
| Embodiment 5 | 50% acetic acid | Convert completely | 6 hours | Without purification |
Embodiment 6
Under room temperature condition; 16.8 grams of grease obtained in the previous step are added in ammonia methanol solution 200 milliliters saturated; PH is more than 10 in detection; add 17.9 grams of Sodium triacetoxyborohydride by amount, continue stirring more than 4 hours, detect raw material with TLC method and convert completely; drip 5 milliliters of shrends to go out reaction; drip 20 milliliters of dense salt to stir 12 hours, filter 14.1 grams and obtain white solid and be the hydrochlorate of N1, N1-diisopropyl ethylenediamine.Molar yield is calculated for 77.8% with N, N-diisopropylamine.
Embodiment 7
Under room temperature condition, 16.8 grams of grease obtained in the previous step are added in ammonia methanol solution 200 milliliters saturated, PH is more than 10 in detection, add 9.68 grams of tricyano sodium borohydrides by amount, continue stirring more than 4 hours, detect raw material with TLC method and convert completely, drip 5 milliliters of shrends to go out reaction, drip 20 milliliters of dense salt to stir 12 hours, filter 14.1 grams and obtain white solid and be the hydrochlorate of N1, N1-diisopropyl ethylenediamine.Molar yield is calculated for 78.2% with N, N-diisopropylamine.
Embodiment 8, embodiment 9, embodiment 10 replace concentrated hydrochloric acid to become salt with sulphuric acid, methanesulfonic acid, benzenesulfonic acid respectively, and other operations are identical, and result is shown in following table:
| Acid | Molar yield | |
| Embodiment 8 | 10% sulphuric acid | 77.8% |
| Embodiment 9 | Methanesulfonic acid | 76.3% |
| Embodiment 10 | Benzenesulfonic acid | 70.9% |
Embodiment 11
After the thick product of hydrochlorate of N1, the N1-diisopropyl ethylenediamine of synthesis is respectively adopted following different solvent process, under in each sample, the content of impurity is shown in.
The content of impurity in each sample after the process of thick product different solvents
| Solvent | Impurity (%) |
| Methanol | 0.73 |
| Ethanol | 0.80 |
| Dichloromethane | 0.85 |
| Ethyl acetate | 0.84 |
| Acetone | 0.71 |
| Ethyl acetate: methanol (1:1) | 0.53 |
| Ethyl acetate: methanol (1:5) | 0.62 |
| Ethyl acetate: methanol (1:4) | 0.61 |
| Ethyl acetate: methanol (2:1) | 0.37 |
| Ethyl acetate: methanol (4:1) | 0.52 |
| Ethyl acetate: methanol (5:1) | 0.62 |
Therefore ethyl acetate is selected: methanol (2:1v/v) is as recrystallization reagent.
Thick for the hydrochlorate of N1, the N1-diisopropyl ethylenediamine product ethyl acetate by 8 times of weight and methanol=2:1 mixed solvent being dissolved, be heated to reflux temperature, continue 1 hour, room temperature is placed 12 hours, and crystallization obtains crystallization, yield 98% after sucking filtration.
It is as follows that the product that the present invention and prior art are obtained carries out HPLC analysis, purity and impurity content %:
Claims (2)
1. the preparation method of a N1, N1-diisopropyl ethylenediamine or its salt, it is characterised in that said method comprising the steps of:
Step 1: with 2-bromoacetaldehyde contracting glycol and diisopropylamine for raw material, condensation obtains compound 1,2-(diisopropyl amido) acetaldehyde contracting glycol,
Step 2: compound 1 is hydrolyzed in acid condition and obtains compound 2,2-(diisopropyl amido) acetaldehyde,
Step 3: compound 2 obtains compound 3, N1 through amination, N1-diisopropyl ethylenediamine,
Step 4: compound 3 one-tenth salt obtains the salt of N1, N1-diisopropyl ethylenediamine, in said structure, R is methyl or ethyl；The salt of described N1, N1-diisopropyl ethylenediamine is hydrochlorate；
Wherein, the method of step 1 is as follows: be dissolved in oxolane by 2-bromoacetaldehyde contracting glycol, diisopropylamine, it is warming up to back flow reaction more than 12 hours, detect diisopropylamine with TLC method to convert after completely, concentrating under reduced pressure obtains yellow oil, wherein, the molar ratio example of 2-bromoacetaldehyde contracting glycol and diisopropylamine is 0.9:1～1:1
Wherein, the method of step 2 is as follows: yellow oil step 1 obtained is dissolved in methanol, and the hydrochloric acid of dropping 6N less than 1, is warming up to return stirring more than 4 hours to pH value, detect raw material with TLC method to convert after completely, be down to reduced pressure at room temperature concentration and obtain the grease of yellow；
Wherein, step 3 and 4 method as follows: under room temperature condition, yellow oil step 2 obtained adds in the methanol solution of ammonia, after all dissolving; add Sodium triacetoxyborohydride; it is stirred at room temperature more than 4 hours, converts after completely with the detection of TLC method, drip concentrated hydrochloric acid; to solution ph less than 1; after continuing stirring 12 hours, it is filtrated to get white solid and is the hydrochlorate of N1, N1-diisopropyl ethylenediamine.
2. the preparation method of a N1, N1-diisopropyl ethylenediamine or its salt, it is characterised in that said method comprising the steps of:
19.6 grams of 2-bromo-acetaldehyde diethyl acetal, 10 grams of diisopropylamines are dissolved in 100 milliliters of oxolanes, add 13.7 grams of potassium carbonate, it is warming up to back flow reaction more than 12 hours, detect diisopropylamine with TLC method to convert after completely, it is down to room temperature to filter, filtrate reduced in volume obtains 30.2 grams of yellow oil
Being dissolved in 100 ml methanol by 30.2 grams of grease, the hydrochloric acid of dropping 6N less than 1, is warming up to return stirring more than 4 hours to pH value, detects raw material with TLC method and converts after completely, is down to reduced pressure at room temperature concentration and obtains 16.8 grams of grease,
Under room temperature condition; 16.8 grams of grease obtained in the previous step are added in ammonia methanol solution 200 milliliters saturated; pH is more than 10 in detection, adds 17.9 grams of Sodium triacetoxyborohydride by amount, continues stirring more than 4 hours; detect raw material with TLC method and convert completely; drip 5 milliliters of shrends to go out reaction, drip 20 milliliters of concentrated hydrochloric acid and stir 12 hours, be filtrated to get 14.1 grams of white solids and be N1; the hydrochlorate of N1-diisopropyl ethylenediamine
The hydrochlorate of N1, the N1-diisopropyl ethylenediamine upper step obtained ethyl acetate and the methanol=2:1 mixed solvent of 8 times amount dissolve, and are heated to reflux temperature, continue 1 hour, and room temperature is placed 12 hours, and crystallization obtains crystallization after sucking filtration.
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