WO2007007697A1

WO2007007697A1 - Methyl lithium solution and method for producing same

Info

Publication number: WO2007007697A1
Application number: PCT/JP2006/313645
Authority: WO
Inventors: Toshiyuki Kaneko
Original assignee: Tosoh Finechem Corporation
Priority date: 2005-07-12
Filing date: 2006-07-10
Publication date: 2007-01-18
Also published as: JP2007022921A

Abstract

Disclosed is a methyl lithium solution which can be easily handled while having excellent storage stability. Specifically disclosed is a methyl lithium solution obtained by diluting a methyl lithium with an unsymmetrical ether solvent represented by the following general formula (1): R1-O-R2 (In the formula, R1 represents a secondary or tertiary alkyl group having 3-10 carbon atoms or a cycloalkyl group, and R2 represents an alkyl group having 1-10 carbon atoms which is different from R1.)

Description

Specification

Methyllithium solution and method for producing the same

Technical field

[0001] The present invention relates to a methyllithium solution having excellent storage stability and a method for producing the same.

Background art

[0002] Methyllithium is widely used as a methylating agent in organic synthesis reactions.

[0003] Methyllithium is hardly soluble in hydrocarbon solvents, and is commercially available as a solution diluted with an ether solvent. However, methyllithium diluted with jetyl ether, THF, and other normal ether solvents has poor storage stability (Non-patent Document 1).

[0004] Methyllithium is generally prepared by the reaction of lithium and methyl halide. Methyllithium, which is also prepared from odorous methyl iodide or methyl iodide, is coordinated with lithium bromide or lithium iodide in a solvent. And exist. Thus, methyllithium containing lithium bromide is excellent in storage stability and is commercially available as an ether solution.

[0005] However, the solvent jetyl ether has been difficult to handle on an industrial scale because of its high volatility and low flash point and low boiling point.

[0006] On the other hand, depending on the type of reaction using methyllithium, if a large amount of an inorganic salt such as lithium bromide is present, the reactivity and selectivity may be affected. Lithium solution is desired! /

[0007] It is known that methyllithium having a low halogen content can be obtained by reacting methyl chloride and lithium in a jetyl ether solvent (Non-patent Document 2). However, the methyllithium solution thus obtained is a pyrophoric liquid in addition to the use of jetyl ether as a solvent, as described above, which makes handling more difficult. It was a thing.

[0008] As a solvent other than jetyl ether, methyllithium prepared by reacting methyl chloride with lithium using an aromatic hydrocarbon solvent and a Lewis base such as THF as a solvent is excellent in storage stability. It has been proposed as a solution (Patent Documents 1 and 2). In fact, methyllithium using cumene and THF as a solvent is commercially available. However, when a high-boiling aromatic hydrocarbon such as cumene is used as a solvent, it may be difficult to separate and remove it.

[0009] Methyl lithium using an acetal such as diethoxymethane as a solvent has also been proposed (Patent Document 3). Although dimethoxyethane can be used to obtain high-concentration methyllithium, it is a pyrophoric solution and difficult to handle.

[0010] In addition, when THF or diethoxymethane is used as a solvent, these are soluble in water so that when methyllithium is used, it is dissolved in the aqueous layer when hydrolyzed as a post-treatment of the reaction. May adversely affect the environment and may require problems such as excessive extraction with organic solvents.

Patent Document 1: Japanese Patent Laid-Open No. 5-32673

Patent Document 2: U.S. Patent No. 6,861,011

Patent Document 3: Japanese Patent Laid-Open No. 8-53465

Non-Patent Document 1: Organometallics inSynthesis A Manual.Second Edition, WILEY, 2002, p.290

Non-Patent Document 2: Organic Synthesis, CV7.346

Disclosure of the invention

Problems to be solved by the invention

[0011] An object of the present invention is to provide a methyllithium solution that is excellent in storage stability and easy to handle.

Another object of the present invention is to provide a method for producing methyl lithium with good yield.

Means for solving the problem

[0012] The above problem has been achieved by using an asymmetric ether as a diluting solvent for methyllithium.

[0013] The gist of the present invention is as follows.

1. Methyllithium is represented by the general formula (1)

R ¹ -O-R ² (1)

(Wherein R ¹ is a secondary or tertiary alkyl group having 3 to 10 carbon atoms, Alkyl is a group, R ² is methyl lithium solvent solution, characterized in that it is diluted in an asymmetric ether solvent represented by R ¹ and an alkyl group having 1 to 10 carbon atoms but not identical).

2. The methyllithium solution according to item 1, which contains 20 mol% or less of magnesium with respect to methyllithium.

3. The methyllithium solution according to item 1 or 2, wherein the halogen content is 10 mol% or less with respect to cation lithium.

4. The methyllithium solution according to 1 or 2, comprising 1.5 times mole or less of lithium bromide with respect to methyllithium.

5. The dielectric constant of an asymmetric ether solvent at 25 ° C is 4.0 or higher. 4. The methyllithium solution according to item 4, wherein the displacement force is item 1.

6. The methyllithium solution according to item 1, wherein the asymmetric ether solvent is cyclopentyl methyl ether.

7. General formula (1)

R ¹ -O-R ² (1)

(Wherein R ¹ is a secondary or tertiary alkyl group having 3 to 10 carbon atoms, or a cycloalkyl group, and R ² is an alkyl group having 1 to 10 carbon atoms that is not the same as R ^1. A method for producing a methyllithium solution, wherein lithium is dispersed in an asymmetric ether solvent represented by the formula (1), methyl halide is added to the mixture and reacted, and then insolubles are removed by filtration.

8. General formula (1)

R ¹ -O-R ² (1)

(Wherein R ¹ is a secondary or tertiary alkyl group having 3 to 10 carbon atoms, or a cycloalkyl group, and R ² is an alkyl group having 1 to 10 carbon atoms that is not the same as R ^1. A method for producing a methyllithium solution, wherein lithium and magnesium are dispersed in an asymmetric ether solvent represented by the formula (1), methyl halide is added thereto and reacted, and then insoluble materials are removed by filtration.

9. Methyl according to item 7 or 8, characterized in that the methyl halide is methyl chloride A method for producing a lithium solution.

10. The method for producing a methyllithium solution according to any one of 7 to 9, wherein the dielectric constant of the asymmetric ether solvent at 25 ° C. is 4.0 or more.

11. The method for producing a methyllithium solution according to any one of 7 to 9, wherein the asymmetric ether solvent is cyclopentyl methyl ether.

The invention's effect

[0014] The methyllithium solution of the present invention is excellent in storage stability and easy to handle.

[0015] Also provided is a method for producing a methyllithium solution with good yield.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the asymmetric ether represented by the general formula (1) R ¹ O—R ² is used as a dilution solvent for methyllithium. R ¹ is a secondary to tertiary alkyl group having 3 to 10 carbon atoms, or a cycloalkyl group, specifically, isopropyl, sbutyl, t-butyl, tamyl group, cyclopropyl, cyclobutyl, cyclopentyl, Examples include a cyclohexyl group. R ² is not the same as R ¹ and is an alkyl group having 1 to 10 carbon atoms, and specific examples include methyl, ethyl, and n-propyl groups. Specific examples of the asymmetric ether in the present invention include t-butyl methyl ether, t-butyl ethinoreatenore, t-amino retinoreatenore, s butinoremethino reeenore, and cyclopentyl methyl ether. The Since this diluting solvent can be used as a solvent during the synthesis of methyllithium, a highly polar solvent is preferred from the viewpoint of methyllithium yield and methyllithium solubility. Ether having a dielectric constant of 4.0 or more is preferable. Furthermore, from the viewpoint of workability and safety in the post-treatment of the reaction when using a methyllithium solution, a solvent is preferred because of low solubility in water. From this perspective, cyclopentyl methyl ether, which has a relatively high dielectric constant of 4.76 at 25 ° C and a water solubility of 1.1 g / 100 g (23 ° C), is particularly a solvent. As preferred! /.

[0017] The reason why the asymmetric ether is preferable is considered as follows. Degradation of the methyllithium solution during storage proceeds by extracting the α-position proton of the ether due to its strong basicity. This abstraction reaction is suppressed by using a hydrocarbon group bonded to the oxygen atom of the ether as a secondary or tertiary alkyl group! / ヽ as a cycloalkyl group. can do. On the other hand, from the viewpoint of the polarity of the solvent, it is preferable that unpaired electrons on oxygen are exposed. Ethers in which two bulky alkyl groups are bonded to the oxygen atom have a decreased polarity, and the solubility of methyllithium is reduced. As a result, the yield during production of methyllithium is reduced. Thus, from the viewpoints of productivity and stability of the methyllithium solution, the asymmetric ether indicated by V in the present invention is a particularly well-balanced solvent.

[0018] Although the methyllithium solution in the present invention is stable at normal temperature as it is, it has become clear that the storage stability is further improved by including magnesium in the solution. Magnesium seems to be dissolved as dimethylmagnesium in the methyllithium solution. The amount of magnesium contained in the methyllithium solution of the present invention is preferably such that the molar ratio of magnesium to methyllithium is 0.2: 1 or less. If a large amount of magnesium is present in excess of this amount, the reactivity and selectivity of the reaction using a methyllithium solution may change significantly.

[0019] The methyl lithium in the present invention may contain lithium bromide. A methyllithium solution containing lithium bromide also improves storage stability. When lithium bromide is included, the molar ratio of lithium bromide to methyllithium is preferably 1.5: 1 or less. If a large amount of lithium bromide is present in excess of this amount, it may be difficult to handle the viscosity of the methyllithium solution.

[0020] The method for producing a methyllithium solution in the present invention is achieved by dispersing lithium in a solvent, reacting the halogenated methyl with this, and then removing insolubles by filtration. . A methyllithium solution containing magnesium can be produced by reacting methyl halide with a suspension in which magnesium is dispersed together with lithium, and removing insolubles by filtration.

[0021] The shape of lithium used in the production of the methyllithium solution includes agglomerated, granular, wire, and dish purge, and any of them may be used, but from the viewpoint of reactivity, the ratio is as much as possible. It is preferable to use lithium having a large surface area. In addition, in order to increase the reactivity with methyl halides, lithium arrays containing a small amount of sodium or lithium arrays containing naphthalene or 4,4, -di-tert-butyl biphenyl and other arene compounds are added. You can also use -do. [0022] As the halogen methyl, methyl chloride, methyl odor and methyl iodide are used. In particular, when methyl chloride is used as the methyl halide, the lithium chloride produced by the reaction with lithium is difficult to produce a coordination compound with methyllithium. A lithium solution can be obtained. The halogen content in a methyllithium solution synthesized using methyl chloride is 10 mol% or less with respect to methyllithium. When a reaction using methyllithium is performed, the presence of an inorganic salt is considered to be reactive or selective. It can be suitably used in a reaction system that adversely affects the reaction.

On the other hand, when lithium bromide is used as the methyl halide, a methyllithium solution containing 0.8 to 1.2 equivalents of lithium bromide with respect to methyllithium can be obtained. A methyllithium solution containing lithium bromide can be suitably used in a reaction system in which the presence of an inorganic salt is useful or negligible.

[0024] In the production of the methyllithium solution, the amount of methyl halide used for lithium is preferably 0.5 equivalent or less. If methyl halide is used in excess of this, unreacted methyl halide may remain in the methyllithium solution, and the storage stability of the methyllithium solution may deteriorate.

[0025] The amount of magnesium used when preparing a methyllithium solution containing magnesium is preferably 0.2 equivalent or less with respect to the methyl halide used. If magnesium is used in excess of this, the molar ratio of magnesium to methyllithium in the resulting methyllithium solution will be 0.2: 1 or more, and the reactivity and selectivity of the reaction using the methyllithium solution will be improved. It can change greatly.

[0026] The reaction temperature between lithium and methyl halide is preferably 20 to 60 ° C. If the reaction is carried out beyond this range, the produced methyllithium may be decomposed. If the temperature is lower than this range, the reaction rate during the production of methyllithium is lowered.

[0027] According to the method of the present invention, a methyllithium solution having a concentration of 2 to: LOwt% can be prepared.

[0028] Examples of the present invention will be described below.

Example 1 [0029] To a flask equipped with a stirrer and a thermometer, 3.51 g (0.51 gram atoms) of lithium dispersion containing 3% sodium and 130 mL of cyclopentyl methyl ether were added under an argon atmosphere. To this, 11. lg (0.22 mol) of methyl chloride was added for 1 hour with stirring on ice. After the addition, the mixture was stirred at room temperature for 1 hour, and the insoluble matter was removed with a glass filter to obtain 105 g of a colorless and transparent 4.27 wt% methyllithium cyclopentylmethyl ether solution (92% yield). Chlorine content in the solution is 0. 39 wt%, corresponding to 5.4 mol ^_0/0 for methyl lithium.

[0030] This methyllithium solution was not pyrophoric. When the obtained methyllithium was stored at 23 ° C under a nitrogen atmosphere, the concentration of methyllithium after one month was 4.13 wt%, the concentration after two months was 4.10 wt%, and the decomposition rate was about 0.07% —Methyllithium Z days.

Example 2

[0031] Lithium dispersion containing 3% sodium in an argon atmosphere with a stirrer and thermometer 2.95 g (0.43 gram atom), magnesium piece 0.53 g (0.02 gram atom) ) And 85 mL of cyclopentyl methyl ether. To this, 10.6 g (0.21 mol) of methyl chloride was added over 1 hour with stirring under ice cooling. After the addition, the mixture was stirred at room temperature for 1 hour, and the insoluble matter was removed by a glass filter to obtain 85 g of a colorless and transparent 4.86 wt% methyllithium cyclopentylmethyl ether solution (yield 89%). Chlorine content in the solution is 0. 20 wt%, corresponding to 3.0 mol ^_0/0 for methyl lithium. Magnesium is 0.57 wt%, which corresponds to 12.6 mol% with respect to methyllithium.

[0032] This methyllithium solution was not pyrophoric.

[0033] When the obtained methyllithium was stored at 23 ° C under a nitrogen atmosphere, the concentration after 2 months was 4.74 wt%, and the decomposition rate was about 0.04% -methyllithium Z days. there were.

Example 3

[0034] Lithium dispersion containing 3% sodium in an argon atmosphere in a flask equipped with a stirrer and thermometer 2.70 g (0.39 gram atom), magnesium piece 0.47 g (0.02 gram atom) ) And 140 mL of cyclopentyl methyl ether. To this, 8.8 g (0.17 mol) of methyl chloride was added over 1 hour with stirring on ice. After addition, stir at room temperature for 1 hour The insoluble matter was removed with a glass filter to obtain 116 g of a colorless and transparent cyclopentylmethyl ether solution of 2.87 wt% methyllithium (yield 93%). Chlorine content in the solution is 0. 17 wt%, corresponding to 4.0 mol ^_0/0 for methyl lithium. Magnesium is 0.27 wt%, corresponding to 9.2 mol% with respect to methyllithium.

[0035] This methyl lithium solution was not pyrophoric.

[0036] When the obtained methyl lithium was stored at 23 ° C in a nitrogen atmosphere, the concentration did not decrease even after 2 months.

Example 4

[0037] A flask equipped with a stirrer and a thermometer was charged with 8.52 g (l. 23 gram atom) of lithium dispersion containing 3% sodium and 26 mL of cyclopentyl methyl ether under an argon atmosphere. To this, 39. Og of odorous methyl (0.41 mol) was added over 2.5 hours with stirring on ice. After the addition, the mixture was stirred at room temperature for 1 hour, and the insoluble matter was removed with a glass filter to obtain 241.7 g of a 3.5 lwt% methyllithium cyclopentylmethyl ether solution (yield 94%). The amount of lithium in the solution is 2.23 wt%, the amount of bromine is 13.16 wt%, and lithium bromide equivalent to 1.0 mol per 1 mol of methyllithium coexists in the solution.

[0038] This methyllithium solution was not pyrophoric.

[0039] When the obtained methyllithium was stored at 40 ° C under a nitrogen atmosphere, the concentration of methyllithium was 3.31 wt% and the decomposition rate was about 0.18% -methyllithium Z days. . Comparative Example 1

[0040] Lithium and methyl chloride were reacted in the same manner as in Example 1 except that dibutyl ether was used as a solvent instead of cyclopentyl methyl ether.

[0041] Methyllithium was not detected in the colorless and transparent solution obtained after filtration (yield 0%

) o

[0042] Dibutyl ether has a dielectric constant of 3.08, and it is considered that the reaction did not proceed because of its low polarity.

Industrial applicability

[0043] The methyllithium solution of the present invention is excellent in storage stability and easy to handle. Thus, it is useful as a methylating agent in organic synthesis reactions.

Claims

The scope of the claims

[1] Methyllithium is represented by the general formula (1)

R ¹ -O-R ² (1)

(Wherein R ¹ is a secondary or tertiary alkyl group having 3 to 10 carbon atoms, or a cycloalkyl group, and R ² is an alkyl group having 1 to 10 carbon atoms that is not the same as R ^1. A methyllithium solution characterized by being diluted with an asymmetric ether solvent represented by

[2] The methyllithium solution according to [1], which contains 20 mol% or less of magnesium with respect to methyllithium.

[3] The methyllithium solution according to [1] or [2], wherein the methyl and lithium content is 10 mol% or less relative to the lithium lithium content.

[4] The methyllithium solution according to [1] or [2], comprising 1.5 times mole or less of lithium bromide with respect to methyllithium.

[5] The methyllithium solution according to claim 1, wherein the dielectric constant of the asymmetric ether solvent at 25 ° C. is 4.0 or more, and the deviation force 1 is 4.

[6] The methyllithium solution according to any one of items 1 to 4, wherein the asymmetric ether solvent is cyclopentyl methyl ether.

[7] General formula (1)

R ¹ -O-R ² (1)

[8] General formula (1)

R ¹ -O-R ² (1)

(Wherein R ¹ is a secondary or tertiary alkyl group having 3 to 10 carbon atoms, or a cycloalkyl group, and R ² is an alkyl group having 1 to 10 carbon atoms that is not the same as R ^1. is there) A method for producing a methyllithium solution, comprising dispersing lithium and magnesium in an asymmetric ether solvent represented by the formula, adding and reacting methyl and rogenated thereto, and then removing insolubles by filtration.

[9] The method for producing a methyllithium solution according to [7] or [8], wherein the methylated and rogenated methyl is methyl chloride.

[10] The method for producing a methyllithium solution according to claim 7, wherein the dielectric constant of the asymmetric ether solvent at 25 ° C. is 4.0 or more.

[11] The method for producing a methyllithium solution according to any one of [7] to [9], wherein the asymmetric ether solvent is cyclopentyl methyl ether.