CN103435635A - Preparation method of magnesium chloride (2,2,6,6-tetramethyl piperidine) lithium salt - Google Patents
Preparation method of magnesium chloride (2,2,6,6-tetramethyl piperidine) lithium salt Download PDFInfo
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- CN103435635A CN103435635A CN2013103330973A CN201310333097A CN103435635A CN 103435635 A CN103435635 A CN 103435635A CN 2013103330973 A CN2013103330973 A CN 2013103330973A CN 201310333097 A CN201310333097 A CN 201310333097A CN 103435635 A CN103435635 A CN 103435635A
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- tetramethyl piperidine
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Abstract
The invention discloses a preparation method of magnesium chloride (2,2,6,6-tetramethyl piperidine) lithium salt, which comprises the following steps that under inert gas shielding, anhydrous lithium chloride, 2,2,6,6-tetramethyl piperidine and a catalytic amount of 1,10-phenanthroline are dispersed in an organic solvent; under a stirring condition, an isopropyl magnesium chloride solution is dropwise added at 0-50 DEG C, and then subjected to heat preservation for reaction; and 2,2,6,6-tetramethyl piperidine . magnesium chloride .lithium chloride is obtained by treatment after complete reaction. The preparation method takes 1,10-phenanthroline as a catalyst, so that one-pot synthesis of a product is achieved; an adopted raw material is cheap; the productivity is high; and the obtained product is good in performance.
Description
Technical field
The invention belongs to the synthetic field of organometallic compound, 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 further realize the functionalization of aromatic hydrocarbons regioselectivity by this conversion, obtains various arene derivatives.Conventionally, the deprotonation of aromatic hydrocarbons (being metallization reaction) is generally used as lithium alkylide (RLi) or amido lithium (R
2nLi) etc. lithium alkali is realized.Yet, because the reactive behavior of these lithium alkali is too high, usually cause that some are difficult to the side reaction of expecting.The another one shortcoming that adopts these lithium alkali is that the tetrahydrofuran solution of these lithium alkali under room temperature (mainly to the amido lithium) is unstable, while therefore using, often needs original position to be generated.In addition, when adopting these lithium alkali to the aromatic hydrocarbons deprotonation, usually need to use low-down temperature (70～-90 ℃), this has caused, and the amplification ratio of these reactions is more difficult and sweetening agent can be applicable is limited, is generally tetrahydrofuran (THF)/normal hexane.
The people such as Borrow Ke Neixieer have reported magnesium dichloride (2,2,6, the 6-tetramethyl piperidine) lithium salts is (No. CAS: application 898838-07-8) (Org.Lett., Vol.8, No.24,2006), adopt this magnesium amides can realize the deprotonation of aromatic hydrocarbons.With the lithium alkali reagent, compare, this magnesium amides can be tolerated various active functional groups, as ester group, nitro ketone carbonyl even.After carrying out deprotonation by the aromatic hydrocarbons to containing ester group, then react and realize benzoylation with Benzoyl chloride, detailed process is expressed as follows with reaction formula:
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, to the i-PrMgClLiCl(100mL that adds fresh titration in the 250mL reaction flask, 1.2M tetrahydrofuran solution, 120mmol), then at room temperature drip 2, 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, during titration with 4-benzeneazodiphenylamine (4-(phenylazo) diphenylamine, CAS:101-75-7) as indicator, color becomes the purple explanation by yellow and reaches titration end point.
This magnesium dichloride (2,2,6,6-tetramethyl piperidine) in the preparation method of lithium salts, need to adopt i-PrMgClLiCl solution as raw material, with i-PrMgCl solution phase ratio, i-PrMgClLiCl solution much commercially available expensive, and also the i-PrMgClLiCl solution of high density relatively is difficult to obtain, therefore adopt i-PrMgCl solution to replace the synthetic magnesium dichloride (2 of i-PrMgClLiCl solution, 2,6,6-tetramethyl piperidine) the lithium salts meaning is very great.Yet the another one problem that adopts 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; the 6-tetramethyl piperidine) preparation method of lithium salts, comprise the steps: under protection of inert gas, by Lithium chloride (anhydrous), 2; 1 of 2,6,6-tetramethyl piperidine and catalytic amount; the 10-phenanthroline is scattered in organic solvent, then, under agitation condition, drips the solution of isopropylmagnesium chloride during 0-50 ℃ of temperature; drip off rear insulation and reacted, after reacting completely, through processing, obtain described magnesium dichloride (2,2; 6,6-tetramethyl piperidine) solution of lithium salts.
In the present invention, by add 1 of catalytic amount in reaction system, 10-phenanthroline (CAS:5144-89-8), make isopropylmagnesium chloride, lithium chloride and 2,2,6, one pot of 6-tetramethyl piperidine is reacted, and with higher yield, has obtained product magnesium dichloride (2,2,6,6-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 that the 10-phenanthroline is contained and lithium chloride, increase the solubility property of lithium chloride, and carry out coordination with the magnesium of isopropylmagnesium chloride, increased the reactive behavior of this grignard reagent simultaneously.
As preferably, described rare gas element is nitrogen or argon gas.
As preferably, described 1, the consumption of 10-phenanthroline is described 2,2,6,0.1～1% of the molar weight of 6-tetramethyl piperidine, more preferably 0.1～0.5%; Described 1, the consumption of 10-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 gets final product about equally, 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, can make raw material react completely more fully, reduce unreacted raw material.
Described organic solvent is can be by described raw material solvent and the solvent do not reacted with described isopropylmagnesium chloride, the general ether solvent of selecting, 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 difficult for excessive, raw material fully can be disperseed to get final product, otherwise can cause the product concentration that obtains 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 improve the concentration of product, avoid having reacted rear further concentrating product.
As preferably, when the solution of described isopropylmagnesium chloride drips, controls temperature is 0-20 ℃, now, can prevent that the local temperature of reaction system is too high, the generation of minimizing side reaction.
As preferably, after the solution of described isopropylmagnesium chloride drips off, 10～30 ℃ of insulations, reacted, in this temperature, to be reacted, 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 the time of the insulation reaction after the solution that drips off isopropylmagnesium chloride, and 6～12h can make the reaction raw materials primitive reaction complete.
After having reacted, described processing comprises following operation: at room temperature be incubated sedimentation about 2 hours, with the filtration of sand plate funnel, organic solvent washing, obtain 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 strict especially requirement.
Compared with the existing technology, beneficial effect of the present invention is embodied in: in reaction system, added 1,10-phenanthroline as catalyzer, realized magnesium dichloride (2,2,6, the 6-tetramethyl piperidine) one kettle way of lithium salts is synthetic, and the raw material used is comparatively cheap, and the productive rate of reaction is high.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1
Get the 1000ml there-necked flask, with argon gas, reaction flask is replaced three times, open a little argon gas after replacing, make this there-necked flask interior in argon atmosphere, then add Lithium chloride (anhydrous) (42.4g in this there-necked flask, 1mol), 2, 2, 6, 6-tetramethyl piperidine (141.3g, 1mol) He 1, 10-phenanthroline (0.54g, 3mmol), then add the 150mL tetrahydrofuran (THF), control temperature to 0-5 ℃, stir after 10 minutes, tetrahydrofuran solution (the 500mL of the isopropylmagnesium chloride that dropping concentration is 2.0M, 1mol), control temperature in the dropping process and be no more than 10 ℃, after dropwising, be warming up to 20～25 ℃, continue to stir 8 hours, after reaction finishes, at room temperature be incubated sedimentation about 2 hours, with sand plate funnel, filter, the tetrahydrofuran (THF) washing, the magnesium dichloride (2 that to obtain concentration be 1.3M, 2, 6, the 6-tetramethyl piperidine) the tetrahydrofuran solution 692mL(yield 90% of lithium salts).
The concentration of the tetrahydrofuran solution of magnesium dichloride (2,2,6,6-tetramethyl piperidine) lithium salts adopts benzoic tetrahydrofuran solution to carry out titration, usings the 4-benzeneazodiphenylamine during titration as indicator, and color becomes the purple explanation by yellow and reaches titration end point.Detailed process can be with reference to Org.Lett., Vol.8, No.24,2006 and the document quoted.
Embodiment 2
Get the 1000ml there-necked flask, with argon gas, reaction flask is replaced three times, open a little argon gas after replacing, make this there-necked flask interior in argon atmosphere, then add Lithium chloride (anhydrous) (42.4g in this there-necked flask, 1mol) He 2, 2, 6, 6-tetramethyl piperidine (141.3g, 1mol), then add the 150mL tetrahydrofuran (THF), control temperature to 0-5 ℃, stir after 10 minutes, tetrahydrofuran solution (the 500mL of the isopropylmagnesium chloride that dropping concentration is 2.0M, 1mol), control temperature in the dropping process and be no more than 10 ℃, after dropwising, be warming up to 20～25 ℃, continue to stir 8 hours, after reaction finishes, at room temperature be incubated sedimentation about 2 hours, with sand plate funnel, filter, the tetrahydrofuran (THF) washing, the magnesium dichloride (2 that to obtain concentration be 1.1M, 2, 6, the 6-tetramethyl piperidine) the tetrahydrofuran solution 682mL(yield 75% of lithium salts).The result of embodiment 2 shows, under the condition that lacks 1,10-phenanthroline, the transformation efficiency of reaction reduces greatly.
Embodiment 3
Get the 250mL there-necked flask, with argon gas, reaction flask is replaced three times, open a little argon gas after replacing, make this there-necked flask interior in argon atmosphere, then to the tetrahydrofuran solution (CAS:745038-86-2 that adds i-PrMgClLiCl in this there-necked flask, purchased from the lark prestige) (92mL, 1.3M, 120mmol).Then at room temperature drip 2,2,6,6-tetramethyl piperidine (17.8g, 126mmol), after dripping off, stirring reaction 24 hours, reaction at room temperature is incubated sedimentation about 2 hours after finishing, with sand plate funnel, filter, tetrahydrofuran (THF) washing, the magnesium dichloride (2,2 that to obtain concentration be 0.7M, 6,6-tetramethyl piperidine) the tetrahydrofuran solution 146mL(yield 85% of lithium salts).This embodiment shows, while directly using i-PrMgClLiCl not add 1,10-phenanthroline to be reacted, 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; add isoquinoline 99.9 (703mg, 5.45mmol) and 5mL tetrahydrofuran (THF) in the 25mL flask, then at room temperature; drip wherein the magnesium dichloride (2 that embodiment 1 prepares; 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 ℃, 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 the water extracted with diethyl ether, anhydrous sodium sulfate drying, filter, and is spin-dried for solution and obtains crude product, and resulting crude product, by the Filter column chromatogram purification, obtains yellow crystals 1-iodo isoquinoline 99.9 (1.32g, 95%), fusing point 74-76 ℃;
1h NMR (300MHz, CDCl
3) δ: 8.24(d, J=5.6Hz, 1H), 8.06(d, J=8.4Hz, 1H) and, 7.71-7.64(m, 3H), 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.The reactivity worth of the product that this application examples shows to adopt embodiment 1 method to make is good.
Claims (8)
1. a magnesium dichloride (2; 2; 6; the 6-tetramethyl piperidine) preparation method of lithium salts, is characterized in that, comprises the steps: under protection of inert gas; by Lithium chloride (anhydrous), 2; 1 of 2,6,6-tetramethyl piperidine and catalytic amount; the 10-phenanthroline is scattered in organic solvent; then under agitation condition, drip the solution of isopropylmagnesium chloride during 0-50 ℃ of temperature, drip off rear insulation and reacted; obtain described magnesium dichloride (2 through processing after reacting completely; 2,6,6-tetramethyl piperidine) solution of lithium salts.
2. the preparation method of magnesium dichloride according to claim 1 (2,2,6,6-tetramethyl piperidine) lithium salts, is characterized in that, described 1, and the consumption of 10-phenanthroline is described 2,2,6,0.1～1% of the molar weight of 6-tetramethyl piperidine.
3. magnesium dichloride according to claim 1 (2,2,6, the 6-tetramethyl piperidine) preparation method of lithium salts, 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.
4. the preparation method of magnesium dichloride according to claim 1 (2,2,6,6-tetramethyl piperidine) lithium salts, is characterized in that, described organic solvent is tetrahydrofuran (THF).
5. the preparation method of magnesium dichloride according to claim 4 (2,2,6,6-tetramethyl piperidine) lithium salts, is characterized in that, the solvent in the solution of described isopropylmagnesium chloride is tetrahydrofuran (THF), and concentration is 1.0～2.0M.
6. 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, the control temperature is 0-20 ℃.
7. 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, 10～30 ℃ of insulations, reacted.
8. the preparation method of magnesium dichloride according to claim 7 (2,2,6,6-tetramethyl piperidine) lithium salts, is characterized in that, the time of reaction is 6～12h.
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Cited By (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 |
| CN109232385A (en) * | 2018-10-27 | 2019-01-18 | 阜新孚隆宝医药科技有限公司 | A kind of preparation method of magnesium dichloride (2,2,6,6- tetramethyl piperidine) lithium salts |
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| 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 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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)
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|---|
| MARC MOSRIN, ET AL.: "Regio- and Chemoselective Metalation of Chloropyrimidine Derivatives with TMPMgCl·LiCl and TMP2Zn·2MgCl2·2 LiCl", 《CHEM. EUR. J.》, vol. 15, 29 December 2008 (2008-12-29), pages 1468 - 1477 * |
| WENWEI LIN, ET AL.: "Highly functionalized benzene syntheses by directed mono or multiple magnesiations with TMPMgCl·LiCl", 《ORGANIC LETTERS》, vol. 8, no. 24, 3 November 2006 (2006-11-03), pages 5673 - 5676 * |
Cited By (3)
| 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 |
| CN109232385A (en) * | 2018-10-27 | 2019-01-18 | 阜新孚隆宝医药科技有限公司 | A kind of preparation method of magnesium dichloride (2,2,6,6- tetramethyl piperidine) lithium salts |
| 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 |
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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. |