CN103435635B - A kind of preparation method of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts - Google Patents
A kind of preparation method of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts Download PDFInfo
- Publication number
- CN103435635B CN103435635B CN201310333097.3A CN201310333097A CN103435635B CN 103435635 B CN103435635 B CN 103435635B CN 201310333097 A CN201310333097 A CN 201310333097A CN 103435635 B CN103435635 B CN 103435635B
- Authority
- CN
- China
- Prior art keywords
- tetramethyl piperidine
- lithium salts
- preparation
- magnesium dichloride
- solution
- 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.)
- Active
Links
Abstract
The invention discloses a kind of magnesium dichloride (2; 2; 6; 6-tetramethyl piperidine) preparation method of lithium salts; comprise the steps: under protection of inert gas, by Lithium chloride (anhydrous), 2,2; 6; 1,10-phenanthroline of 6-tetramethyl piperidine and catalytic amount is scattered in organic solvent, then under agitation; the solution of isopropylmagnesium chloride is dripped at 0-50 DEG C of temperature; drip off rear insulation to react, after reacting completely, obtain described 2,2 through process; 6,6-tetramethyl piperidine magnesium chloride lithium chloride.This preparation method as catalyzer, achieves the one pot process of product by employing 1,10-phenanthroline, and the raw material of employing is cheap, and productive rate is high, the product obtained functional.
Description
Technical field
The invention belongs to organometallic compound synthesis field, be specifically related to the preparation method of a kind of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts.
Background technology
The metallization reaction of aromatic hydrocarbons is a kind of important conversion in organic synthesis, can be realized the functionalization of aromatic hydrocarbons regioselectivity further, obtain various arene derivatives by this conversion.Conventionally, the deprotonation (i.e. metallization reaction) of aromatic hydrocarbons generally uses as lithium alkylide (RLi) or amido lithium (R
2etc. NLi) lithium alkali realizes.But due to the reactive behavior of these lithium alkali too high, usually cause some be difficult to expect side reaction.Adopt the another one shortcoming of these lithium alkali to be that the tetrahydrofuran solution of these lithium alkali (mainly to amido lithium) under room temperature is unstable, when therefore using, often need original position to generate.In addition, when adopting these lithium alkali to aromatic hydrocarbons deprotonation, usually need to use low-down temperature (-70 ~-90 DEG C), the amplification ratios which results in these reactions are more difficult and sweetening agent that is that can be suitable for is limited, are generally tetrahydrofuran (THF)/normal hexane.
The people such as Borrow Ke Neixieer report magnesium dichloride (2,2,6,6-tetramethyl piperidine) application (Org.Lett., Vol.8, the No.24 of lithium salts (No. CAS: 898838-07-8), 2006) this magnesium amides, is adopted can to realize the deprotonation of aromatic hydrocarbons.Compare with lithium alkali reagent, this magnesium amides can tolerate various active functional group, as ester group, nitro even ketone carbonyl.After carrying out deprotonation to the aromatic hydrocarbons containing ester group, then react with Benzoyl chloride and realize benzoylation, detailed process reaction formula is expressed as follows:
The people such as Borrow Ke Neixieer also disclose preparation method (Org.Lett., Vol.8, No.24,2006 of a kind of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts (TMPMgClLiCl), WO2008/087057A1), this preparation method comprises the steps: under nitrogen protection, the i-PrMgClLiCl(100mL of fresh titration is added in 250mL reaction flask, the tetrahydrofuran solution of 1.2M, 120mmol), then at room temperature 2 are dripped, 2, 6, 6-tetramethyl piperidine (TMPH) (19.8g, 126mmol, 1.05equiv), reaction mixture at room temperature stirs 24h and has reacted, obtain the solution of TMPMgClLiCl, production concentration adopts benzoic tetrahydrofuran solution to carry out titration, with 4-benzeneazodiphenylamine (4-(phenylazo) diphenylamine during titration, CAS:101-75-7) as indicator, color from yellow becomes purple explanation and reaches titration end point.
This magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts preparation method in, need to adopt i-PrMgClLiCl solution as raw material, compare with i-PrMgCl solution, i-PrMgClLiCl solution much commercially available expensive, and the i-PrMgClLiCl solution of high density compares and is difficult to obtain, therefore i-PrMgCl solution is adopted to replace i-PrMgClLiCl solution synthesis magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts meaning is very great.But the another one problem adopting i-PrMgCl solution to encounter for the synthesis of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts is that transformation efficiency is not high enough.
Summary of the invention
The invention provides the preparation method of a kind of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts, the reagent that this preparation method uses is cheap, and the transformation efficiency of reaction is higher.
A kind of magnesium dichloride (2; 2; 6; 6-tetramethyl piperidine) preparation method of lithium salts; comprise the steps: under protection of inert gas, by Lithium chloride (anhydrous), 2,2; 6; 1,10-phenanthroline of 6-tetramethyl piperidine and catalytic amount is scattered in organic solvent, then under agitation; the solution of isopropylmagnesium chloride is dripped during 0-50 DEG C of temperature; drip off rear insulation to react, after reacting completely, obtain described magnesium dichloride (2,2 through process; 6,6-tetramethyl piperidine) solution of lithium salts.
In the present invention, by adding 1 of catalytic amount in reaction system, 10-phenanthroline (CAS:5144-89-8), makes isopropylmagnesium chloride, lithium chloride and 2,2,6,6-tetramethyl piperidine one pot reacts, and obtains product magnesium dichloride (2,2 with higher yield, 6,6-tetramethyl piperidine) lithium salts.Wherein, the reason that 1,10-phenanthroline can make reaction yield improve may be: 1, the lithium ion coordination of the N contained by 10-phenanthroline and lithium chloride, increase the solubility property of lithium chloride, and carry out coordination with the magnesium of isopropylmagnesium chloride simultaneously, add the reactive behavior of this grignard reagent.
As preferably, described rare gas element is nitrogen or argon gas.
As preferably, the consumption of 1,10-described phenanthroline is 0.1 ~ 1% of the molar weight of 2,2,6,6-described tetramethyl piperidines, more preferably 0.1 ~ 0.5%; The consumption of 1,10-described phenanthroline is too low, and catalytic effect is not obvious, and productive rate can not get enough raisings, and the consumption of 1,10-phenanthroline is too high, likely can introduce impurity in reaction system, affects follow-up use.
In the present invention, described 2,2,6, the consumption of 6-tetramethyl piperidine, Lithium chloride (anhydrous) and isopropylmagnesium chloride is roughly equal, as preferably, and described 2,2, the mol ratio of 6,6-tetramethyl piperidine, Lithium chloride (anhydrous) and isopropylmagnesium chloride is 1:0.9 ~ 1.2:0.9 ~ 1.2, now, raw material can be made to react completely more fully, reduce unreacted raw material.
Described organic solvent is the solvent that can react by described Materials Solvents and not with described isopropylmagnesium chloride, general selection ether solvent, as ether, tetrahydrofuran (THF) and 2-methyltetrahydrofuran etc., as preferably, described organic solvent is tetrahydrofuran (THF), now, the transformation efficiency of reaction is the highest.The consumption of described organic solvent is not easily excessive, raw material fully can be disperseed, otherwise the product concentration that obtains can be caused too small, and generally, the amount ratio of 2,2,6,6-tetramethyl piperidine and organic solvent is about 3 ~ 15mol:1L.
As further preferred, solvent in the solution of described isopropylmagnesium chloride is tetrahydrofuran (THF), and concentration is 1.0 ~ 2.0M, and the concentration of the solution of described isopropylmagnesium chloride is higher, be conducive to the concentration improving product, avoid having reacted rear concentrating further product.
As preferably, when the solution of described isopropylmagnesium chloride drips, control temperature is 0-20 DEG C, now, the local temperature of reaction system can be prevented too high, reduces the generation of side reaction.
As preferably, after the solution of described isopropylmagnesium chloride drips off, react 10 ~ 30 DEG C of insulations, react in this temperature, reaction yield is higher, and side reaction is less.
As further preferred, the time of reaction is 6 ~ 12h; The time of this reaction refers to time of the insulation reaction after the solution dripping off isopropylmagnesium chloride, and 6 ~ 12h can make reaction raw materials primitive reaction complete.
After having reacted, described process comprises following operation: at room temperature heat preservation settlement 2 hours, and filter with sand plate funnel, organic solvent washing, obtains the solution of described magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts.
In the present invention, the stir speed (S.S.) of reaction is without requirement strict especially.
Compared with the existing technology, beneficial effect of the present invention is embodied in: in reaction system, add 1,10-phenanthroline as catalyzer, achieve magnesium dichloride (2,2,6,6-tetramethyl piperidine) one pot process of lithium salts, inexpensively, the productive rate of reaction is high for the raw material used.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1
Get 1000ml there-necked flask, with argon gas, reaction flask is replaced three times, a little argon gas is opened after replacing, make to be in argon atmosphere in this there-necked flask, then in this there-necked flask, Lithium chloride (anhydrous) (42.4g is added, 1mol), 2, 2, 6, 6-tetramethyl piperidine (141.3g, 1mol) He 1, 10-phenanthroline (0.54g, 3mmol), then 150mL tetrahydrofuran (THF) is added, control temperature is to 0-5 DEG C, stir after 10 minutes, drip the tetrahydrofuran solution (500mL that concentration is the isopropylmagnesium chloride of 2.0M, 1mol), in dropping process, control temperature is no more than 10 DEG C, after dropwising, be warming up to 20 ~ 25 DEG C, continue stirring 8 hours, after reaction terminates, at room temperature heat preservation settlement 2 hours, filter with sand plate funnel, tetrahydrofuran (THF) washs, obtain the magnesium dichloride (2 that concentration is 1.3M, 2, 6, 6-tetramethyl piperidine) the tetrahydrofuran solution 692mL(yield 90% of lithium salts).
Magnesium dichloride (2,2,6,6-tetramethyl piperidine) concentration of tetrahydrofuran solution of lithium salts adopts benzoic tetrahydrofuran solution to carry out titration, using 4-benzeneazodiphenylamine as indicator during titration, color from yellow becomes purple explanation and reaches titration end point.Detailed process can with reference to Org.Lett., Vol.8, No.24, and 2006 and the document quoted.
Embodiment 2
Get 1000ml there-necked flask, with argon gas, reaction flask is replaced three times, a little argon gas is opened after replacing, make to be in argon atmosphere in this there-necked flask, then in this there-necked flask, Lithium chloride (anhydrous) (42.4g is added, 1mol) He 2, 2, 6, 6-tetramethyl piperidine (141.3g, 1mol), then 150mL tetrahydrofuran (THF) is added, control temperature is to 0-5 DEG C, stir after 10 minutes, drip the tetrahydrofuran solution (500mL that concentration is the isopropylmagnesium chloride of 2.0M, 1mol), in dropping process, control temperature is no more than 10 DEG C, after dropwising, be warming up to 20 ~ 25 DEG C, continue stirring 8 hours, after reaction terminates, at room temperature heat preservation settlement 2 hours, filter with sand plate funnel, tetrahydrofuran (THF) washs, obtain the magnesium dichloride (2 that concentration is 1.1M, 2, 6, 6-tetramethyl piperidine) the tetrahydrofuran solution 682mL(yield 75% of lithium salts).The result of embodiment 2 shows, under the condition lacking 1,10-phenanthroline, the transformation efficiency of reaction reduces greatly.
Embodiment 3
Get 250mL there-necked flask, with argon gas, reaction flask is replaced three times, a little argon gas is opened after replacing, make to be in argon atmosphere in this there-necked flask, then in this there-necked flask, add the tetrahydrofuran solution (CAS:745038-86-2 of i-PrMgClLiCl, purchased from lark prestige) (92mL, 1.3M, 120mmol).Then at room temperature 2 are dripped, 2,6,6-tetramethyl piperidine (17.8g, 126mmol), after dripping off, stirring reaction 24 hours, after reaction terminates, at room temperature heat preservation settlement 2 hours, filter with sand plate funnel, tetrahydrofuran (THF) washs, and obtains the magnesium dichloride (2,2 that concentration is 0.7M, 6,6-tetramethyl piperidine) the tetrahydrofuran solution 146mL(yield 85% of lithium salts).This embodiment shows, directly use i-PrMgClLiCl not add 1,10-phenanthroline when reacting, reaction yield decreases, and is limited to the concentration of i-PrMgClLiCl solution, and the relative concentration of product is lower.
Application examples 1
Under argon shield; isoquinoline 99.9 (703mg, 5.45mmol) and 5mL tetrahydrofuran (THF) is added, then at room temperature in 25mL flask; drip the magnesium dichloride (2 that embodiment 1 prepares wherein; 2,6,6-tetramethyl piperidine) tetrahydrofuran solution (4.6mL of lithium salts; 1.3M; 6.0mmol), after being added dropwise to complete, continue to stir 2h.Then, be cooled to-20 DEG C, slowly add I
2tetrahydrofuran solution (6mL, 1M, 6.0mmol), add rear stirring 30 minutes, use NH
4cl saturated aqueous solution (10mL) cancellation reaction mixture.By aqueous phase extracted with diethyl ether, anhydrous sodium sulfate drying, filter, be spin-dried for solution and obtain crude product, the crude product obtained, by Filter column chromatogram purification, obtains yellow crystals 1-iodo isoquinoline 99.9 (1.32g, 95%), fusing point 74-76 DEG C;
1h NMR (300MHz, CDCl
3) δ: 8.24(d, J=5.6Hz, 1H), 8.06(d, J=8.4Hz, 1H), 7.71-7.64(m, 3H) and, 7.52(d, J=5.6Hz, 1H);
13c NMR (75MHz, CDCl
3) δ: 142.94,136.15,132.81,131.93,131.08,128.99,127.45,127.21,121.27.This application examples shows that the reactivity worth of the product adopting embodiment 1 method to obtain is good.
Claims (6)
1. a magnesium dichloride (2,2,6,6-tetramethyl piperidine) preparation method of lithium salts, it is characterized in that, comprise the steps: under protection of inert gas, by Lithium chloride (anhydrous), 2,1 of 2,6,6-tetramethyl piperidine and catalytic amount, 10-phenanthroline is scattered in organic solvent, then under agitation, drip the solution of isopropylmagnesium chloride during 0-50 DEG C of temperature, drip off rear insulation and react, described magnesium dichloride (2 is obtained through process after reacting completely, 2,6,6-tetramethyl piperidine) solution of lithium salts;
The consumption of 1,10-described phenanthroline is 0.1 ~ 1% of the molar weight of 2,2,6,6-described tetramethyl piperidines;
Described organic solvent is tetrahydrofuran (THF);
Solvent in the solution of described isopropylmagnesium chloride is tetrahydrofuran (THF).
2. magnesium dichloride according to claim 1 (2,2,6,6-tetramethyl piperidine) preparation method of lithium salts, it is characterized in that, described 2, the mol ratio of 2,6,6-tetramethyl piperidine, Lithium chloride (anhydrous) and isopropylmagnesium chloride is 1:0.9 ~ 1.2:0.9 ~ 1.2.
3. the preparation method of magnesium dichloride according to claim 1 (2,2,6,6-tetramethyl piperidine) lithium salts, is characterized in that, the concentration of the solution of described isopropylmagnesium chloride is 1.0 ~ 2.0M.
4. the preparation method of magnesium dichloride according to claim 1 (2,2,6,6-tetramethyl piperidine) lithium salts, is characterized in that, when the solution of described isopropylmagnesium chloride drips, control temperature is 0-20 DEG C.
5. the preparation method of magnesium dichloride according to claim 1 (2,2,6,6-tetramethyl piperidine) lithium salts, is characterized in that, after the solution of described isopropylmagnesium chloride drips off, reacts 10 ~ 30 DEG C of insulations.
6. the preparation method of magnesium dichloride according to claim 5 (2,2,6,6-tetramethyl piperidine) lithium salts, is characterized in that, the time of reaction is 6 ~ 12h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310333097.3A CN103435635B (en) | 2013-08-02 | 2013-08-02 | A kind of preparation method of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310333097.3A CN103435635B (en) | 2013-08-02 | 2013-08-02 | A kind of preparation method of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103435635A CN103435635A (en) | 2013-12-11 |
| CN103435635B true CN103435635B (en) | 2015-09-30 |
Family
ID=49689373
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310333097.3A Active CN103435635B (en) | 2013-08-02 | 2013-08-02 | A kind of preparation method of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103435635B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860889A (en) * | 2015-05-14 | 2015-08-26 | 乐普药业股份有限公司 | 2,4-substituted pyrimidine preparation method |
| CN109232385B (en) * | 2018-10-27 | 2022-02-08 | 阜新孚隆宝医药科技有限公司 | Preparation method of magnesium dichloride (2,2,6, 6-tetramethylpiperidine) lithium salt |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101370815A (en) * | 2006-01-18 | 2009-02-18 | 慕尼黑路德维格-马克西米利安斯大学 | Preparation and use of magnesium amides |
| CN102083791A (en) * | 2008-05-21 | 2011-06-01 | 凯密特尔有限责任公司 | Method for manufacturing magnesium amides |
| CN102395593A (en) * | 2009-02-13 | 2012-03-28 | 慕尼黑路德维格-马克西米利安斯大学 | Production and use of zinc amides |
-
2013
- 2013-08-02 CN CN201310333097.3A patent/CN103435635B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101370815A (en) * | 2006-01-18 | 2009-02-18 | 慕尼黑路德维格-马克西米利安斯大学 | Preparation and use of magnesium amides |
| CN102083791A (en) * | 2008-05-21 | 2011-06-01 | 凯密特尔有限责任公司 | Method for manufacturing magnesium amides |
| CN102395593A (en) * | 2009-02-13 | 2012-03-28 | 慕尼黑路德维格-马克西米利安斯大学 | Production and use of zinc amides |
Non-Patent Citations (2)
| Title |
|---|
| Highly functionalized benzene syntheses by directed mono or multiple magnesiations with TMPMgCl·LiCl;Wenwei Lin, et al.;《Organic Letters》;20061103;第8卷(第24期);5673-5676 * |
| Regio- and Chemoselective Metalation of Chloropyrimidine Derivatives with TMPMgCl·LiCl and TMP2Zn·2MgCl2·2 LiCl;Marc Mosrin, et al.;《Chem. Eur. J.》;20081229;第15卷;1468-1477 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103435635A (en) | 2013-12-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wei-Li et al. | Novel functionalized guanidinium ionic liquids: Efficient acid–base bifunctional catalysts for CO2 fixation with epoxides | |
| CN103435635B (en) | A kind of preparation method of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts | |
| CN104080791B (en) | The method separated and use (the fluoro-3-of the chloro-2-of 4-substituted-phenyl) borate | |
| CN103030660A (en) | Technological method for synthesizing methylboronic acid | |
| CN100347177C (en) | Method for producing, via organometallic compounds, organic intermediate products | |
| TW201536797A (en) | Neutral complex of cyclic silane, manufacturing method therefor, and method for manufacturing cyclic hydrogenated silane or cyclic organic silane | |
| CN109836457B (en) | High-steric-hindrance chiral P, N, N ligand and preparation method and application thereof | |
| CN103172479B (en) | Preparation method for biaryl through palladium catalysis | |
| JP4934823B2 (en) | Silicon-containing cross-coupling reagent and method for producing organic compound using the same | |
| CN105130725B (en) | A kind of method for preparing γ -one carbonyl complexs | |
| CN103787968B (en) | The preparation method of compound | |
| CN102060659A (en) | Method for preparing homoallylic alcohol | |
| CN114478351B (en) | Method for synthesizing alpha-alkyl substituted indole-3-formaldehyde compound | |
| CN102219802B (en) | Method for preparing novel isobutyl triethoxy silane | |
| CN102531985B (en) | Method for preparing ezetimibe key intermediate | |
| CN106243018B (en) | A kind of synthetic method of poly-fluorine phenyl pyridine compounds and their | |
| CN104926847B (en) | A kind of synthesis boron aminated compounds technique and products application | |
| CN113004182A (en) | Preparation method of trifluoro-isothiocyanethane | |
| CN102775268B (en) | Preparation method of 1-methyl-1-phenyl-3-phenylpropadiene compounds | |
| CN104974000B (en) | Method for di-trifluoromethylation reaction of styryl compound | |
| CN103435634B (en) | A kind of preparation method of hexyllithium | |
| CN103159705B (en) | Preparation method for cabazitaxel intermediate | |
| CN101456865A (en) | Preparation method of ethylenedioxy thiophene-2,5-dicarboxylic ester | |
| CN102001967B (en) | Method for synthesizing para-cyanobiphenyl | |
| CN110724064B (en) | Method for synthesizing 2-cyclohexane substituted benzamide under catalysis of nickel |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 312369, No. three, No. 2, Shangyu Industrial Park, Beizhen, Zhejiang, Shaoxing Patentee after: Shangyu Shaoxing Warren Chemical Co., Ltd. Address before: 312369, No. three, No. 2, Shangyu Industrial Park, Beizhen, Zhejiang, Shaoxing Patentee before: Shangyu Hualun Chemical Co., Ltd. |