EP1957440A1

EP1957440A1 - Process for preparing 3-amino-3-methyl-1-butanol

Info

Publication number: EP1957440A1
Application number: EP06819495A
Authority: EP
Inventors: Andreas Pletsch; Wolfgang Siegel
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2005-11-25
Filing date: 2006-11-15
Publication date: 2008-08-20
Also published as: WO2007060122A1; DE102005056594A1

Abstract

The present invention relates to a process for preparing 3 amino-3-methyl-1-butanol (I) by, in a first step, reacting 3-methylbut-3-en-1-ol (IIa) or 3-methylbut-2-en-1-ol (IIb) with a nitrile of the formula (III) in the presence of an acidic condensation agent; and, in a second step, reacting the reaction product obtained in the first step with aqueous potassium hydroxide solution and extracting the compound of the formula (I) with a suitable solvent.

Description

Process for the preparation of 3-amino-3-methyl-1-butanol

The present invention relates to a process for the preparation of 3-amino-3-methyl-1-butanol (I).

H ₂ IS ^{v ^} OH ^(l)

The compound of formula I is an intermediate for pharmaceutical agents and can be prepared by various methods.

DE 2 200 108, for example, describes a process for preparing 3-amino-3-methyl-1-butanol by reacting 3-methylbut-3-en-1-ol (IIa) or 3-methylbut-2-en-1 ol (IIb) in the presence of an acid condensing agent with anhydrous hydrogen cyanide at - 40 to 80 ° C and the resulting reaction product is then hydrolyzed. In this case, sodium hydroxide or calcium hydroxide is used as base and extracted with benzene.

(IIa) (IIb)

Furthermore, P. M. Pavel in Zh. Org. Khim. 18, 178 (1982) that 3-amino-3-methyl-1-butanol can be obtained by hydrolyzing 2-vinyl-4,4-dimethyl-5,6-dihydrooxazine with aqueous potassium hydroxide solution and extracting with diethyl ether. The dihydrooxazine used as starting material can according to P.M. Pavel be obtained by reacting a corresponding substituted oxetane with acrylonitrile. However, according to DE 2 049 160 it is also possible to react dihydrooxazines by reacting 3-methylbut-3-en-1-ol (IIa) or 3-methylbut-2-en-1-ol (IIb) in the presence of an acid condensing agent to obtain a nitrile. Furthermore, PM Pavel describes that 3-amino-3-methyl-1-butanol can be obtained by hydrolyzing the corresponding amides of 3-amino-3-methyl-1-butanol with potassium hydroxide, the amides in turn by hydrolysis of corresponding Dihydrooxazines are obtained.

Since the processes described use benzene as the extraction agent, the reaction of the process described in DE 2 200 108 is linked on an industrial scale with high safety requirements, which lead to high costs. In addition, there are problems in the transmission of the described method in the technical scale, since salts precipitate, which prevent easy processing and which lead to a reduction in the yield. It was therefore an object of this invention to provide a process for the preparation of 3-amino-3-methyl-1-butanol on an industrial scale.

It has now been found that 3-amino-3-methyl-1-butanol can be prepared by reacting in a first step 3-methylbut-3-en-1-ol (IIa) or 3-methylbut-2-ene 1-ol (IIb) in the presence of an acid condensing agent with a nitrile of the formula IM,

R ¹ -CN (IM)

where R ^{1 is} hydrogen, C ¹ -C 6 -alkyl, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-prop-1-yl, 1, 1-dimethyleth- 1-yl, 1-pentyl or 1-hexyl, C2-C6 alkenyl, such as vinyl, prop-2-en-2-yl or prop-2-en-1-yl, phenyl or phenyl, which has one or more Carries radicals that are inert under the reaction conditions, such as halogen - for example, chlorine or bromine -; stands

reacted;

and in a second step, reacting the reaction product obtained in the first step with aqueous potassium hydroxide solution and extracting the compound of formula I with a suitable solvent.

The starting compounds used are 3-methylbut-3-en-1-ol (IIa) or 3-methylbut-2-en-1-ol (Mb), preferably 3-methylbut-3-en-1-ol (IIa). These alkenols are known from the literature.

Furthermore, nitriles of the formula IM are used. These are also known from the literature. Usually, nitriles are used, where R ^{1 is} hydrogen, C ¹ -C ₄ -alkyl, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-prop-1-yl, or 1, 1-dimethyleth-1-yl, C 2 -C 4 alkenyl, such as vinyl, prop-2-en-2-yl or prop-2-en-1-yl, phenyl or halo-substituted phenyl. Preference is given to using HCN, acetonitrile, propionitrile, butyronitrile, acrylonitrile, methacrylonitrile, benzonitrile, 3,5-dichlorobenzonitrile and 2,6-dichlorobenzonitrile, in particular acetonitrile.

Suitable acid condensing agents are, for example, strong acids such as inorganic acids, for example sulfuric acid, phosphoric acid or hydrofluoric acid, sulfonic acids, for example methanesulfonic acid or benzenesulfonic acid, or alkanecarboxylic acids, such as formic acid or acetic acid. Preferably, inorganic acids are used, preferably at least 80% sulfuric acid or phosphoric acid, in particular at least 95% sulfuric acid. The reaction of the alkenol of the formula IIa or IIb with the nitrile of the formula III is usually carried out at -30 to 40 ° C., preferably at -20 to 30 ° C. In general, the reaction is carried out at atmospheric pressure.

The reaction can be carried out in the presence of an inert solvent, such as diethyl ether, methyl tert-butyl ether or cyclohexane. Preferably, however, no solvent is used.

In general, the molar ratio between the alkenol of the formula IIa or IIb and the nitrile of the formula III is 1: 1 to 1: 3, preferably 1: 1, 5 to 1: 2.5, in particular 1: 1, 9 to 1: 2.1.

The molar ratio between the acid condensing agent and the alkenol of the formula II can be varied within wide limits and is generally from 10: 1 to 1:10, preferably from 5: 1 to 1: 1, in particular from 3: 1 to 1, 5: 1 ,

The reaction is carried out by initially introducing the acid condensing agent, adding the nitrile of the formula III and then adding the alkenol of the formula IIa or Mb in portions or continuously at -30 to 40 ° C., preferably at -20 to 30 ° C. The mixture is subsequently stirred until complete reaction.

This reaction can be carried out batchwise, e.g. in a stirred tank or continuously, for example in a stirred tank cascade or a mixing circuit. The heat of reaction liberated during the reaction must be removed.

The reaction mixture thus obtained is then reacted with an aqueous potassium hydroxide solution. Usually, the molar ratio between the alkenol of the formula IIa or Mb and the base is in the range from 1:20 to 1: 1, preferably 1:10 to 1: 2. Usually, a 20 to 50% aqueous solution of the base used.

The reaction is generally carried out at -30 ° C. to the reflux temperature of the reaction mixture, preferably at -20 to 90 ° C. Usually, the reaction is carried out at atmospheric pressure.

The 3-amino-3-methyl-1-butanol formed is then extracted with a suitable solvent and can be separated by conventional methods, such as by distillation. Suitable solvents are higher alcohols, such as 1-butanol or 1-pentanol, aliphatic ethers such as diethyl ether or methyl tert-butyl ether, or cyclic ethers such as tetrahydrofuran, 1, 3-dioxane or 1, 4-dioxane. In a particular embodiment, the solvent used is an aliphatic ether, for example diethyl ether or methyl tert-butyl ether, preferably methyl tert-butyl ether. det. In a further particular embodiment, the solvent used is a cyclic ether, such as tetrahydrofuran, 1, 3-dioxane or 1, 4-dioxane, preferably tetrahydrofuran.

On a case-by-case basis, during hydrolysis, salts such as, for example, the potassium salts of the inorganic or organic acids used, for example potassium sulfate, precipitate on hydrolysis. These are usually separated by conventional methods, for example by filtration, prior to extraction.

The hydrolysis of the reaction product, from the alkenol of the formula IIa or IIb with the nitrile of the formula III, with the aqueous potassium hydroxide solution is usually carried out by adding to the aqueous potassium hydroxide solution at -30 to 40 ° C, preferably at 0 to 20 ° C. , the reaction mixture described above, containing the reaction product from the alkenol of the formula IIa or IIb with the nitrile of the formula IM, added continuously or in portions and then stirred until complete reaction. From case to case, it may be advantageous to carry out the stirring at elevated temperature, at 30 ° C to reflux temperature of the reaction mixture.

After cooling, any precipitated salts are filtered off, extracted with a suitable solvent, preferably a cyclic ether, and recovered by subsequent distillation of 3-amino-3-methyl-1-butanol.

The following example serves to further illustrate the invention.

example 1

In a stirred reactor to 1 176 g (11, 5 mol) of 95% sulfuric acid with stirring at 10 ° C 461, 5 g (1 1, 25 mol) of acetonitrile was added and then 442.0 g (5.1 mol) 3-methyl-3-en-1-ol. After stirring at room temperature for 12 h, the resulting brown solution was added dropwise with stirring at 10 ° C. to 6014 g (42.9 mol) of aqueous potassium hydroxide solution. After 12 h stirring at 85 ° C was cooled, precipitated salts are filtered off and the filtrate extracted three times with 1300 ml of tetrahydrofuran. The combined organic phases were dried over sodium sulfate and then distilled. This gave 440.0 g of 3-amino-3-methyl-1-butanol, which still 9% water.

Comparative example

A) Preparation of 2,4,4-trimethyl-5,6-dihydro-1,3-oxazine

In a stirred reactor 1347 g (32.8 mol) of acetonitrile were added to 3300 g (31, 3 mol) of 95% sulfuric acid with stirring at 10 ° C and then 1284 g (14.9 mol) of 3-methylbut-3 -en-1-ol. After stirring for 12 h at room temperature, the resulting brown solution was added with stirring at 10 ° C. to 1 l of 142 g (69.6 mol) of aqueous sodium hydroxide solution. dropped hydroxide solution. This resulted in a mixture of an organic, an aqueous phase and a salt which did not separate. Addition of methyl tert-butyl ether succeeded in separating the phases and separating off the organic phase containing 2,4,4-trimethyl-5,6-dihydro-1,3-oxazine. The extract thus obtained was freed from the solvent and the residue in step B) was used without further purification.

B) Preparation of 3-amino-3-methyl-1-butanol

The residue obtained in stage A) was dissolved in 775 ml of water and added at 85 ° C to 3555 g (33.552 mol) of 40% sodium hydroxide solution. After 12 h stirring at 85 ° C was cooled and extracted four times with 4500 ml of methyl tert-butyl ether. Here, too, precipitated salts, which had to be filtered off in the meantime. The combined organic extracts were freed from the solvent. 875 g of 3-amino-3-methyl-1-butanol were obtained.

Claims

claims

1. A process for the preparation of 3-amino-3-methyl-1-butanol, characterized in that - in a first step 3-methylbut-3-en-1-ol (IIa) or 3-methylbut-2-ene -1- ol (IIb)

in the presence of an acid condensing agent with a nitrile of the formula

III,

R ¹ -CN (IM)

wherein R ^{1 is} hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, phenyl or phenyl which carries one or more radicals which are inert under the reaction conditions; stands;

reacted; and

in a second step, the reaction product obtained in the first step with aqueous potassium hydroxide solution and the resulting 3-amino-3-methyl-1-butanol extracted with a suitable solvent.

2. The method according to claim 1, characterized in that R ^{1 is} CrC ₄ -AlkVl.

3. The method according to claim 2, characterized in that R ^{1 is} methyl.

4. Process according to claims 1 to 3, characterized in that at least 80% sulfuric acid is used as the acid condensing agent.

5. Process according to claims 1 to 4, characterized in that the solvent used in the extraction is a cyclic ether.

6. The method according to claim 5, characterized in that is used as the solvent in the extraction of tetrahydrofuran, 1, 3-dioxane or 1, 4-dioxane.

7. The method according to claim 6, characterized in that the solvent used in the extraction tetrahydrofuran.