CN116120187A - Method for synthesizing lithium diisopropylamide serving as large-steric-hindrance organic base - Google Patents
Method for synthesizing lithium diisopropylamide serving as large-steric-hindrance organic base Download PDFInfo
- Publication number
- CN116120187A CN116120187A CN202310406039.2A CN202310406039A CN116120187A CN 116120187 A CN116120187 A CN 116120187A CN 202310406039 A CN202310406039 A CN 202310406039A CN 116120187 A CN116120187 A CN 116120187A
- Authority
- CN
- China
- Prior art keywords
- reaction kettle
- lithium diisopropylamide
- reaction
- serving
- finished
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of synthetic chemistry, and relates to a method for synthesizing lithium diisopropylamide serving as a large steric hindrance organic base, which comprises the following steps: step 1, cleaning and drying a reaction kettle, replacing the reaction kettle with inert gas for three times, and introducing inert gas into the reaction kettle until the reaction is finished after the replacement is finished; step 2, adding lithium hydride solid into a reaction kettle, opening the reaction kettle for stirring, adding an organic solvent into the reaction kettle, and controlling the temperature to be-30-0 ℃; and 3, dropwise adding diisopropylamine into the reaction kettle when the temperature in the reaction kettle reaches the requirement in the step 2, keeping the temperature in the reaction kettle at-30-0 ℃ during dropwise adding, and continuing to react at room temperature after dropwise adding is finished to obtain the lithium diisopropylamide solution. According to the synthesis method, diisopropylamine is used as a raw material, lithium hydride is used for replacing n-butyllithium in the prior art, the reaction condition is relatively mild, and the potential safety hazard is reduced.
Description
Technical Field
The invention belongs to the technical field of synthetic chemistry, and particularly relates to a method for synthesizing lithium diisopropylamide serving as a large-steric-hindrance organic base.
Background
Lithium diisopropylamide (Lithium Diisopropylamide) is LDA for short, and is a common organic strong base with large steric hindrance and non-nucleophilicity in the organic chemical synthesis process. LDA is widely used as an organic strong base in tetrahydrofuran where pka=36 is the unit reaction of enolization, deprotonation to form carbanions, halogen-lithium exchange, etc. of aldehyde ketone alfa-sites.
Lithium diisopropylamide is widely used. The existing method for preparing the lithium isopropylamide has the disadvantages of severe reaction, easy material flushing of reaction liquid in the reaction process, potential safety hazard, and difficult storage because of the existing preparation method. The Chinese patent application 201710339587.2 provides a method for preparing the lithium diisopropylamide, which takes diisopropylamine and n-butyllithium as raw materials, but the n-butyllithium has strict use condition, and accurate temperature control requirement during feeding, so that energy is wasted and certain potential safety hazard exists.
Disclosure of Invention
The invention aims to solve the technical problems that: the application provides a method for synthesizing lithium diisopropylamide serving as a large-steric-hindrance organic base, which uses diisopropylamine as a raw material, adopts lithium hydride to replace n-butyllithium, has relatively mild reaction conditions, and reduces potential safety hazards.
The technical scheme adopted for solving the technical problems is as follows: the synthesis method of the lithium diisopropylamide serving as the large steric hindrance organic base comprises the following steps:
step 1, cleaning and drying a reaction kettle, replacing the reaction kettle with inert gas for three times, and introducing inert gas into the reaction kettle until the reaction is finished after the replacement is finished;
step 2, adding lithium hydride solid into a reaction kettle, opening the reaction kettle for stirring, adding an organic solvent into the reaction kettle, and controlling the temperature to be-30-0 ℃;
and 3, dropwise adding diisopropylamine into the reaction kettle when the temperature in the reaction kettle reaches the requirement in the step 2, keeping the temperature in the reaction kettle at-30-0 ℃ during dropwise adding, and continuing to react at room temperature after dropwise adding is finished to obtain the lithium diisopropylamide solution.
Further, the molar ratio of lithium hydride to diisopropylamine is 1:1.
Further, the organic solvent is one or more of tetrahydrofuran and diethyl ether.
Further, the molar amount of diisopropylamine to the volume of the organic solvent is (1.5-2): 1 (moL/L).
Further, the reaction time of the step 3 at room temperature is 1-2 h.
Further, the inert gas is nitrogen.
The beneficial effects of the invention are as follows:
by adopting the scheme, diisopropylamine is used as a raw material, lithium hydride is used for replacing n-butyllithium, hydrogen generated during the reaction is discharged out of the reaction kettle along with inert gas, no other impurities are generated, the raw material conversion rate is high, and the obtained lithium diisopropylamide solution has high purity and high yield.
Compared with the prior art, the lithium hydride solid is convenient to take compared with n-butyllithium, the reaction conditions are only controlled to be-30-0 ℃, and the reaction conditions are mild, so that the energy consumption is reduced, and the potential safety hazard is reduced.
The reaction sequence of dropwise adding diisopropylamine into lithium hydride/organic solution is adopted, the reaction process is controllable, the material flushing phenomenon in the prior art is reduced, and the safety coefficient of the reaction is further improved.
The method for synthesizing the lithium diisopropylamide serving as the large steric hindrance organic base is simple in preparation process, can be used for mass production, ensures that the concentration of the lithium diisopropylamide in the lithium diisopropylamide solution prepared by the method is between 1.5 and 2.0M, and can be used for customizing corresponding concentration according to customer requirements.
The lithium diisopropylamide in the lithium diisopropylamide solution prepared by the method for synthesizing the lithium diisopropylamide with large steric hindrance provided by the invention has good stability, can be stored for a long time, and avoids the shortcomings of the prior art that lithium diisopropylamide is currently used for preparation.
Detailed Description
The present invention will be further described in detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
The synthesis method of the lithium diisopropylamide serving as the large steric hindrance organic base comprises the following steps:
step 1, cleaning and drying a 100L reaction kettle, replacing the reaction kettle with nitrogen for one time, continuously introducing nitrogen for 10min after the replacement is finished, performing secondary replacement of the reaction kettle with nitrogen, continuously introducing nitrogen for 10min after the replacement is finished, performing tertiary replacement of the reaction kettle with nitrogen again, completing the replacement of the reaction kettle with nitrogen for three times, and continuously introducing nitrogen into the reaction kettle until the reaction is finished;
step 2, adding 357.8g of lithium hydride solid into a reaction kettle, opening the reaction kettle for stirring, adding 30L of tetrahydrofuran into the reaction kettle, and controlling the temperature to be minus 30 ℃;
and 3, dropwise adding 4.55kg of diisopropylamine into the reaction kettle when the temperature in the reaction kettle reaches the requirement in the step 2, keeping the temperature in the reaction kettle between-30 and 0 ℃ during dropwise adding, and continuing the reaction at room temperature after dropwise adding is finished for 2 hours to obtain a lithium diisopropylamide solution, wherein the concentration of the target product lithium diisopropylamide solution is 1.5M.
Example 2
The synthesis method of the lithium diisopropylamide serving as the large steric hindrance organic base comprises the following steps:
step 1, cleaning and drying a 100L reaction kettle, replacing the reaction kettle with nitrogen for one time, continuously introducing nitrogen for 10min after the replacement is finished, performing secondary replacement of the reaction kettle with nitrogen, continuously introducing nitrogen for 10min after the replacement is finished, performing tertiary replacement of the reaction kettle with nitrogen again, completing the replacement of the reaction kettle with nitrogen for three times, and continuously introducing nitrogen into the reaction kettle until the reaction is finished;
step 2, adding 357.8g of lithium hydride solid into a reaction kettle, opening the reaction kettle, stirring, adding 30L of diethyl ether into the reaction kettle, and controlling the temperature to be-30-0 ℃;
and 3, dropwise adding 4.55kg of diisopropylamine into the reaction kettle when the temperature in the reaction kettle reaches the requirement in the step 2, keeping the temperature in the reaction kettle at-30-0 ℃ during dropwise adding, and continuing the reaction at room temperature after dropwise adding is finished for 1.5h to obtain a lithium diisopropylamide solution, wherein the concentration of the target product lithium diisopropylamide solution is 1.5M.
Example 3
The synthesis method of the lithium diisopropylamide serving as the large steric hindrance organic base comprises the following steps:
step 1, cleaning and drying a 100L reaction kettle, replacing the reaction kettle with nitrogen for one time, continuously introducing nitrogen for 10min after the replacement is finished, performing secondary replacement of the reaction kettle with nitrogen, continuously introducing nitrogen for 10min after the replacement is finished, performing tertiary replacement of the reaction kettle with nitrogen again, completing the replacement of the reaction kettle with nitrogen for three times, and continuously introducing nitrogen into the reaction kettle until the reaction is finished;
step 2, adding 357.8g of lithium hydride solid into a reaction kettle, opening the reaction kettle for stirring, adding 30L of organic solvent (mixed solution prepared by tetrahydrofuran and diethyl ether in a volume ratio of 1:1) into the reaction kettle, and controlling the temperature to be-30-0 ℃;
and 3, dropwise adding 4.55kg of diisopropylamine into the reaction kettle when the temperature in the reaction kettle reaches the requirement in the step 2, keeping the temperature in the reaction kettle at-30-0 ℃ during dropwise adding, and continuing the reaction at room temperature after dropwise adding is finished for 1.0h to obtain a lithium diisopropylamide solution, wherein the concentration of the target product lithium diisopropylamide solution is 1.5M.
Example 4
The synthesis method of the lithium diisopropylamide serving as the large steric hindrance organic base comprises the following steps:
step 1, cleaning and drying a 100L reaction kettle, replacing the reaction kettle with nitrogen for one time, continuously introducing nitrogen for 10min after the replacement is finished, performing secondary replacement of the reaction kettle with nitrogen, continuously introducing nitrogen for 10min after the replacement is finished, performing tertiary replacement of the reaction kettle with nitrogen again, completing the replacement of the reaction kettle with nitrogen for three times, and continuously introducing nitrogen into the reaction kettle until the reaction is finished;
step 2, adding 477g of lithium hydride solid into a reaction kettle, opening the reaction kettle for stirring, adding 30L of organic solvent (mixed solution prepared by tetrahydrofuran and diethyl ether in a volume ratio of 1:1) into the reaction kettle, and controlling the temperature to be-30-0 ℃;
and 3, dropwise adding 6.07kg of diisopropylamine into the reaction kettle when the temperature in the reaction kettle reaches the requirement in the step 2, keeping the temperature in the reaction kettle at-30-0 ℃ during dropwise adding, and continuing to react at room temperature after dropwise adding is finished for 1.3h to obtain a lithium diisopropylamide solution, wherein the concentration of the target product lithium diisopropylamide solution is 2.0M.
Example 5
The synthesis method of the lithium diisopropylamide serving as the large steric hindrance organic base comprises the following steps:
step 1, cleaning and drying a 100L reaction kettle, replacing the reaction kettle with nitrogen for one time, continuously introducing nitrogen for 10min after the replacement is finished, performing secondary replacement of the reaction kettle with nitrogen, continuously introducing nitrogen for 10min after the replacement is finished, performing tertiary replacement of the reaction kettle with nitrogen again, completing the replacement of the reaction kettle with nitrogen for three times, and continuously introducing nitrogen into the reaction kettle until the reaction is finished;
adding 429.3g of lithium hydride solid into a reaction kettle, opening the reaction kettle, stirring, adding 30L of organic solvent (mixed solution prepared by tetrahydrofuran and diethyl ether in a volume ratio of 1:1) into the reaction kettle, and controlling the temperature to be-30-0 ℃;
and 3, dropwise adding 5.46kg of diisopropylamine into the reaction kettle when the temperature in the reaction kettle reaches the requirement in the step 2, keeping the temperature in the reaction kettle at-30-0 ℃ during dropwise adding, and continuing the reaction at room temperature after dropwise adding is finished for 1.2h to obtain a lithium diisopropylamide solution, wherein the concentration of the target product lithium diisopropylamide solution is 1.8M.
The organic solvent, reaction time, yield and concentration used for the lithium diisopropylamide solution of the large steric hindrance organic base prepared in the above examples 1-5 were as follows:
the results show that the reaction time is greatly reduced and the yield is improved compared with the reaction time of singly adopting tetrahydrofuran or diethyl ether by adopting the mixed solution with the volume ratio of tetrahydrofuran to diethyl ether of 1:1 as an organic solvent; the yield of the lithium diisopropylamide solution prepared by the method can meet the requirement of 1.5-2.0M, and the method has the advantages of mild reaction conditions, convenient raw material taking, high reaction safety coefficient and capability of customizing corresponding concentration according to the needs of customers; the preparation amount is large, and the method is suitable for large-scale production.
The stability test is carried out after the sealing, transferring and packaging of the above embodiments, and the lithium diisopropylamide solution of the above 5 embodiments still has good activity after 24 months, the concentration is still 1.5-2.0M, the stability is good, and the lithium diisopropylamide solution can be stored for a long time.
With the above-described preferred embodiments according to the present invention as an illustration, the above-described descriptions can be used by persons skilled in the relevant art to make various changes and modifications without departing from the scope of the technical idea of the present invention. The technical scope of the patent of the invention is not limited to the description, but must be determined according to the scope of the claims.
Claims (6)
1. The synthesis method of the lithium diisopropylamide serving as the large steric hindrance organic base is characterized by comprising the following steps of:
step 1, cleaning and drying a reaction kettle, replacing the reaction kettle with inert gas for three times, and introducing inert gas into the reaction kettle until the reaction is finished after the replacement is finished;
step 2, adding lithium hydride solid into a reaction kettle, opening the reaction kettle for stirring, adding an organic solvent into the reaction kettle, and controlling the temperature to be-30-0 ℃;
and 3, dropwise adding diisopropylamine into the reaction kettle when the temperature in the reaction kettle reaches the requirement in the step 2, keeping the temperature in the reaction kettle at-30-0 ℃ during dropwise adding, and continuing to react at room temperature after dropwise adding is finished to obtain the lithium diisopropylamide solution.
2. The method for synthesizing the lithium diisopropylamide serving as a large steric hindrance organic base according to claim 1, wherein the method comprises the following steps: the molar ratio of the lithium hydride to the diisopropylamine is 1:1.
3. The method for synthesizing the lithium diisopropylamide serving as a large steric hindrance organic base according to claim 1, wherein the method comprises the following steps: the organic solvent is one or more of tetrahydrofuran and diethyl ether.
4. The method for synthesizing the lithium diisopropylamide serving as a large steric hindrance organic base according to claim 1, wherein the method comprises the following steps: the volume of the diisopropylamine and the organic solvent is (1.5-2) 1 (moL/L).
5. The method for synthesizing the lithium diisopropylamide serving as a large steric hindrance organic base according to claim 1, wherein the method comprises the following steps: and 3, the reaction time at room temperature in the step is 1-2 h.
6. The method for synthesizing the lithium diisopropylamide serving as a large steric hindrance organic base according to claim 1, wherein the method comprises the following steps: the inert gas is nitrogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310406039.2A CN116120187A (en) | 2023-04-17 | 2023-04-17 | Method for synthesizing lithium diisopropylamide serving as large-steric-hindrance organic base |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310406039.2A CN116120187A (en) | 2023-04-17 | 2023-04-17 | Method for synthesizing lithium diisopropylamide serving as large-steric-hindrance organic base |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116120187A true CN116120187A (en) | 2023-05-16 |
Family
ID=86299485
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310406039.2A Pending CN116120187A (en) | 2023-04-17 | 2023-04-17 | Method for synthesizing lithium diisopropylamide serving as large-steric-hindrance organic base |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116120187A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10016802C1 (en) * | 2000-04-05 | 2001-12-06 | Chemetall Gmbh | Process for the preparation of alkali metal monohydridoboronates and aluminates and their use |
| CN101805360A (en) * | 2010-05-06 | 2010-08-18 | 江西赣锋锂业股份有限公司 | Novel synthesis process of lithium alkyl |
| CN105967159A (en) * | 2016-04-29 | 2016-09-28 | 南京远淑医药科技有限公司 | Method for preparing lithium bis(fluorosulfonyl)imide from aromatic methyl amine |
| CN107089995A (en) * | 2017-05-15 | 2017-08-25 | 江苏维祥生物科技有限公司 | A kind of method for preparing lithium diisopropylamine |
-
2023
- 2023-04-17 CN CN202310406039.2A patent/CN116120187A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10016802C1 (en) * | 2000-04-05 | 2001-12-06 | Chemetall Gmbh | Process for the preparation of alkali metal monohydridoboronates and aluminates and their use |
| CN101805360A (en) * | 2010-05-06 | 2010-08-18 | 江西赣锋锂业股份有限公司 | Novel synthesis process of lithium alkyl |
| CN105967159A (en) * | 2016-04-29 | 2016-09-28 | 南京远淑医药科技有限公司 | Method for preparing lithium bis(fluorosulfonyl)imide from aromatic methyl amine |
| CN107089995A (en) * | 2017-05-15 | 2017-08-25 | 江苏维祥生物科技有限公司 | A kind of method for preparing lithium diisopropylamine |
Non-Patent Citations (1)
| Title |
|---|
| WOLSTENHOLME等: "Homopolar Dihydrogen Bonding in Alkali Metal Amidoboranes: Crystal Engineering of Low-Dimensional Molecular Materials", 《J. AM. CHEM. SOC.》, vol. 135, pages 2439 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101891621A (en) | Compounding method for 3- ethyoxyl-4-ethoxycarbonyl phenylacetic acid | |
| CN116120187A (en) | Method for synthesizing lithium diisopropylamide serving as large-steric-hindrance organic base | |
| CN117209446B (en) | Method for preparing 2-acetylthiazole by micro-channel method | |
| CN105461593A (en) | Continuous preparing method for 6-cyano-5-hydroxyl-3-oxohexanoate tert-butyl ester | |
| CN109305912B (en) | Method for preparing 2,2, 4-trimethyl-1, 3-pentanediol monoisobutyrate by condensing isobutyraldehyde | |
| CN110922373B (en) | Synthesis method of methyl broad maleate | |
| CN107652226B (en) | Preparation method of N-Boc-4-piperidine formaldehyde | |
| CN105669374A (en) | Synthetic method of lithium methoxide | |
| CN110396072B (en) | Method for producing(s) -3-hydroxytetrahydrofuran | |
| CN220386510U (en) | Device for continuously producing sodium tert-butoxide | |
| CN101696153A (en) | Preparation method of 3,3-dimethyl-1-butanol | |
| CN116041161B (en) | Preparation method of 4-p-hydroxyphenyl-3-butene-2-ketone | |
| CN114797988B (en) | Synthesis of composite catalyst and method for preparing beta-isophorone | |
| CN102649728B (en) | Method for producing oxalate through gas-phase reaction of carbon monoxide | |
| CN115672363B (en) | Catalyst for synthesizing tetramethoxysilane and preparation method and application thereof | |
| CN109232152A (en) | The new synthetic method of one kind 9,9- dimethyl fluorene | |
| CN109796373A (en) | The carbamic synthetic method of cis-4- methoxycyclohexyl -1- | |
| CN102659520A (en) | Synthetic method of 2,3,5,6-tetrafluorobenzyl alcohol | |
| CN115477576B (en) | Preparation method of Carlongic acid | |
| CN112645914A (en) | Preparation method of 3-hydroxy tetrahydropyrane | |
| CN108727173A (en) | The method for preparing 1,1,3- trichloroacetones | |
| CN100386330C (en) | Process for preparing diethyl zinc | |
| CN116253678A (en) | Method for rapidly preparing 2, 6-dichloropyridine-3-carboxylic acid based on micro-channel continuous flow technology | |
| CN104557947A (en) | Method of producing 2-hydroxymethyl triethylenediamine continuously | |
| CN116947610A (en) | New synthetic route for cyclobutanone |
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 |