JPS5841842A - Preparation of chloroalkylamine hydrochloride - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a synthetic intermediate of the raw material of pharmaceuticals, etc., in high yield and efficiency, using a low-cost chlorinating agent, by reacting a molten alkanolamine salt with hydrogen chloride as a chlorinating agent while removing water from the system. CONSTITUTION:The objective compound is prepared by (1) reacting an alkanolamine with hydrochloric acid to obtain molten alkanolamine hydrochloride (DAAE.HCl) and (2) introducing hydrogen chloride into the molten DAAE.HCl at a rate of 0.05-0.5mol/Hr based on 1mol of DAAE.HCl at 140-150 deg.C for 35-40hr while removing water from the reaction system. The unreacted hydrogen chloride is reused after dehydration or recovered as hydrochloric acid by dissolving in water. EFFECT:The objective compound can be prepared easily with simplified apparatus and operations, and the unreacted hydrogen chloride can be reused as it is to the reaction. USE:A starch modifier, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing loloalkylamine in the form of a hydrochloride, which is useful as a synthetic intermediate for raw materials for pharmaceuticals and agricultural chemicals.

R1 Chloroalkylamine is a general 2Cg-A-N\R2(A
is represented by an alkylene group), and those without a substituent on N such as 3-chloropropylamine (R1=R2=H) and diethylaminoethyl chloride (A=ethylene group, R'
=R''=ethyl group), and the present invention can be applied to obtain any of them.In the present invention, the chloroalkylamine is obtained in the form of a hydrochloride. It is usually used in its original form or often as an aqueous solution.Of course, it can also be used by changing from the salt form to the free form if necessary.

Diethylamine ethyl chloride hydrochloride (DEAC)
-HC#) is a typical object of the present invention and is useful as a starch modifier.

Furthermore, Japanese Patent Publications No. 29-2434 and No. 36-21342 describe the use of tertiary aminoalkyl halides to synthesize phenothiazine compounds used as medicines. In the above general formula, A has 2 to 6 carbon atoms, preferably 3. ~
4 is a divalent lower alkylene group, and R2 is a nasal alkyl group, preferably a methyl group, an ethyl group, or an isopropyl group, and R and R are bonded to a nitrogen atom to form a heterocyclic ring, preferably a pyrrolidino group or a piperidino group. (Japanese Patent Publication No. 36-21342).

As a method for synthesizing chloroalkylamine (hydrochloride), a method for chlorinating the corresponding amino alcohol is generally known. The present invention will be explained below by taking the synthesis of DEAC-H(l as an example and comparing it with the prior art).

As a method for chlorinating diethylaminoethanol (hereinafter abbreviated as DEAE), a method using thionyl chloride (U.S. Pat. No. 2,163,181, U.S. Pat. No. 2,45,8823, etc.) has been known for a long time, and it reacts easily at a relatively low temperature and provides a high yield. However, it requires a solvent such as a halogenated hydrocarbon for the reaction, and has the disadvantage of coloring during the solvent removal process. Reaction of DEAE and phosphorus trichloride (Fel'dman.

1949) also requires a solvent such as a halogenated hydrocarbon, and requires purification steps such as alkali neutralization and distillation to separate by-product phosphorus compounds and DEAC-HCβ, which is disadvantageous as an industrial production method. Furthermore, when relatively expensive thionyl chloride and phosphorus trichloride are used as chlorinating agents, it is inevitable that the resulting chloralkylamine hydrochloride will be expensive.

Since these known methods involve various industrial difficulties, the present inventor conducted intensive studies to efficiently obtain chloralkylamine hydrochloride using a cheaper chlorinating agent.
Alkanolamine is used in the form of its hydrochloride, hydrogen chloride is selected as the chlorinating agent, and the alkanolamine hydrochloride is reacted in a heated and molten state while removing water produced by the reaction (by which the above-mentioned purpose can be easily achieved). The present inventors have discovered that the following can be achieved, and have completed the present invention.

That is, the hydrogen chloride used in the method of the present invention is an inexpensive chlorinating agent, and the target substance can be produced with a higher yield than conventional production methods using extremely simplified equipment and operations. The economic benefits are enormous.

In particular, in the organic chlorine compound manufacturing industry, hydrogen chloride is often produced as a by-product in the reaction process, and the present invention allows this hydrogen chloride to be used as is in the reaction, which also has important industrial significance. A method of chlorinating an alcoholic hydroxyl group with hydrochloric acid or hydrogen chloride is known. For example, if butanol is reacted with concentrated hydrochloric acid using a zinc chloride catalyst, butyl chloride can be obtained with a yield of 76-78% (OrganicSynthesis C
o11. Vol. 1, p. 142), 3-chloro-1-propatol can be obtained from trimethylene glycol and hydrogen chloride in a yield of 50-60% (p. 533).

Although the above-mentioned literature does not show an example of chlorinating an alcohol having an amine group by such a method, according to the experiments of the present inventor, a mixture of DEAE and 3 moles of hydrochloric acid was chlorinated at 120
Even if the reaction was carried out at ~130°C, only the hydrochloride of diethylamine ethanol (DEAE@HC/?) was obtained, and the target product was hardly obtained. When the reaction was carried out using hydrogen chloride instead of hydrochloric acid, coloring was significant at high temperatures and a large amount of by-products were produced, making it impossible to obtain the desired DEAC-HC/It in a high yield.

The present invention solves these difficulties in the chlorination of alkanolamines with hydrogen chloride, and differs from the prior art in that the alkanolamines are first converted into a hydrochloride form and then reacted with hydrogen chloride in a molten state. The method of using a reaction between molten salt and hydrogen chloride is new in the field of this reaction.

Incidentally, an example of the bromination reaction of ethanolamine with hydrobromic acid is known (OrganicSynthes
is Co11. Vol. U, 91), there is no disclosure of a method in which ethanolamine is converted into -H hydrohalide salt, which is then brought into a molten state and further reacted while adding hydrogen halide.

The alkanolamine hydrochloride used in the present invention can be obtained by reacting an alkanolamine with hydrochloric acid or hydrogen chloride. The alkanolamine hydrochloride obtained in this reaction can be heated and melted in the same reactor and subjected to reaction with hydrogen chloride to produce chloroalkylamine hydrochloride. In this case, a chloroalkylamine hydrochloride is produced from an alkanolamine through a two-step reaction.

The following two-step reaction from DEAE-r DEAC-HCn
The present invention will be explained in detail by taking as an example the case of manufacturing a .

As the reaction apparatus, a hydrochloric acid-resistant reactor with a heating jacket equipped with a stirrer, a hydrogen chloride inlet pipe, an eluate condenser, an unreacted hydrochloric acid absorption tower, etc. is used.

When making DEAE salt using hydrochloric acid, for example, if you charge hydrochloric acid in a reactor, add water of equimolar DEAE% (weight) and introduce a chloride water groove, DEAE can be produced with less heat consumption. -HCe can be obtained. Regardless of which method is used, if the neutralization reaction temperature is 100'C or higher, coloring will occur significantly, so if the neutralization reaction temperature is 100'C or lower, DEAE
- It is necessary to make HCl3. However, DEAE・HCA
Since the melting point of DEAE and hydrogen chloride is 134°C, when DEAE and hydrogen chloride are reacted, crystals will precipitate in the middle and the reaction cannot continue. Preferably, at least 10% by weight of water is added beforehand.

DEAE-HC/? obtained in this way? is heated and dehydrated while blowing in hydrogen chloride, and the process proceeds to a chlorination reaction in the molten state. The melting point of DEAC-H (1) obtained in this reaction is 2
Since the temperature is 10°C, it is expected that the reaction temperature to maintain the molten state will be about 200°C. However, at such high temperatures, the product becomes noticeably discolored, and DEAC and DEAE or D
The yield deteriorates due to side reactions such as reaction between EAE and formation of bis-diethylaminoethyl ether. The upper limit of the temperature restricted from this point varies depending on the object, but is approximately 150'C in the case of DEAC.

Fortunately, however, it was found that the impurities present in the reaction system caused a drop in the melting point, and that the reaction could actually be carried out without solidification even at a reaction temperature of 120°C. In practice, the optimum reaction temperature is about 140 to 150'C, and the chlorination reaction proceeds while the by-product water is removed dropwise. If the reaction temperature is too low, the dehydration and chlorination reaction will be slow and disadvantageous. At 150°C or higher, the reaction is rapid, but as mentioned above, there are disadvantages such as coloring of the product and reduction in yield. The optimum reaction temperature depends on the type of alkanolamine and can be determined experimentally for each individual case.

The higher the blowing rate of hydrogen chloride in the chlorination reaction, the shorter the reaction time, but on the other hand, the amount of unreacted HCn increases.
A blowing rate of 5 to 0.5 mol/Hr is suitable. Unreacted hydrogen chloride can be dehydrated and recycled or absorbed into water and recovered as hydrochloric acid.

The chlorination reaction is judged to be complete when no by-product water is distilled out. It usually takes 35 to 40 hours.

Since the obtained DEAC-HC, # crystallizes at temperatures below 120°C, it is usually dissolved in water and used as an aqueous solution.

Example-1 36% hydrochloric acid 60817 (60 mol) was charged into a 113 glass reactor, and monoethanolamine 36% was added while stirring.
6,j9 (6.0 mol) was added dropwise over 30 minutes from 32 to 81'C to obtain an aqueous hydrochloride solution.

Next, hydrogen chloride at 27N per hour! The mixture was dehydrated by heating while being blown in at a rate of 150°C, and the temperature was raised to 150°C in 4 hours.

Subsequently, the mixture was heated at 145 to 150°C for 36 hours to react with hydrogen chloride in a molten state while removing by-product water, and 689 g of the reaction solution was heated.
I got it. 2-chloroethylamine hydrochloride in the reaction solution is 9
85, the yield based on monoethanolamine is 975
It was a lot.

Example-2 3.0417 (3.0 mol) of 36% hydrochloric acid was added to the reactor.
and without stirring, add 315 g of jetanolamine (
30 mol) was added dropwise over 25-60'C for 130 minutes, and the resulting hydrochloride was dehydrated by heating while blowing hydrogen chloride at a rate of 27 N per hour, and the temperature was raised to 150'C in 3 hours (7, continued to melt). Reacted with hydrogen chloride for 46 hours at 146-151°C.

Bis(2-chloroethyl)amine hydrochloride in reaction solution 520I was 98.0%, and the yield based on jetanolamine was 952%.

Example 3 An aqueous solution of the obtained salts, including 406 g (40 mol) of 36-thihydrochloric acid and 30 g (to mol) of 3-aminopropanol, was dehydrated by heating while blowing hydrogen chloride at a rate of 28 N/hour, I3, and was heated for 3 hours. The temperature was raised to 190'C to bring it into a molten state. Subsequently, while adding hydrogen chloride, chlorination reaction was carried out at 185 to 191°C for 16 hours to obtain 516 g of a reaction liquid. The content of 3-chloropropylamine hydrochloride in the reaction solution was 98.3%, and the yield relative to 3-aminopropatol was 978%.

Example 4 An aqueous solution of hydrochloride obtained from dimethylamine ethanol 267J7 (3.0 mol) and 4 mol of hydrochloric acid was heated and dehydrated while blowing hydrogen chloride at a rate of 8 N/hour.
The temperature was raised to 40°C.

Subsequently, the mixture was reacted with hydrogen chloride for 36 hours in a molten state at 137 to 143°C to obtain 466 g of a reaction solution.The amount of dimethylaminoethyl chloride hydrochloride in the reaction solution was 878%, and the yield relative to dimethylaminoethanol was 947%. Ta.

Example-5 DEAE obtained by reacting diethylaminoethanol 3609 (3.1 mol) and the same mol of hydrochloric acid at 29 to 82°C
・H(1) Aqueous solution was heated and dehydrated while blowing hydrogen chloride at a rate of 15 tUt per hour, and the temperature was raised to 140°C in 3 hours.Subsequently, it was reacted with hydrogen chloride for 37 hours in a molten state at 138-143°C, and the reaction solution was Diethylaminoethyl chloride hydrochloride (pEAE-Hc-1) was obtained in the reaction solution.
was 902%, bisdiethylaminoethyl ether hydrochloride was 1.6%, and the reaction yield of DEAC-HCl3 with respect to DEAE was 938%.

Example-6 11 360 ml of diethylaminoethanol in a glass reactor
i (3.1 mol) and water 3611 were charged and reacted at 26 to 81° C. for 1 hour while blowing hydrogen chloride at a rate of 67 Np/hour to obtain DEAE-HC4.

Next, heating and dehydration were carried out while blowing hydrogen chloride at a rate of 15 N8 per hour, and the temperature was raised to 140° C. in 1 hour. Subsequently, the mixture was reacted with hydrogen chloride (35)(r) at 137-141° C. in a molten state to obtain 552 g of a reaction solution.

The DEAC-HCe in the reaction solution was 896%, the bisdiethylaminoethyl ether hydrochloride was 21%, and the reaction yield of DEAC-HCe with respect to DEAE was 928%.

patent applicant Daicel Chemical Industries, Ltd.

Claims (1)

[Claims] A method for producing chloroalkylamine hydrochloride, which comprises reacting alkanolamine hydrochloride in a molten state with hydrogen chloride while removing water.