SK283256B6 - Process for production of amino alkyl chlorides - Google Patents

Abstract

Disclosed is a production of amino alkyl chlorides and hydrochlorides thereof by the reaction of aminoalcohols, N-aminoalcohols, N,N-dialkyl aminoalcohols with thionylchloride and by thermic decomposition of the chloro sulfinic acid alkylester so that at first aminoalcohol hydrochloride is prepared and then by the effect of the thionylchloride the chloro sulfinic acid ester.

Description

Technical field

The invention relates to a process for the preparation of aminoalkyl chlorides, N-alkylaminochlorides and / or Ν, Ν-dialkylamino chlorides, and / or their hydrochlorides by substituting the hydroxyl group of amino alcohols, N-alkylaminoalcohols and N, N-dialkylaminoalcohols with thionyl chloride under mild reaction conditions.

BACKGROUND OF THE INVENTION

It is known that the preparation of Ν, Ν-diethylaminoethyl chloride is carried out by reacting Ν, etan-diethylaminoethanol with a molar excess of thionyl chloride in the ratio of 2 to 2.5: 1, in toluene under efficient cooling, at 0 to 10 ° C. thionyl chloride over a period of 2 hours followed by a "quiescent phase" of 13-15 hours at 10-30 ° C. This is followed by a decomposition phase at 75-80 ° C, distillation of unreacted thionyl chloride with some toluene, and finally isolation of Ν, Ν-diethylaminoethyl chloride hydrochloride (rum. Pat. 67572 (1979)). Another method favors the preparation of aminochloro derivatives via hydrochlorides, by reacting amino alcohols with hydrochloric acid at a concentration of 25 to 36% by weight, in a water / toluene medium, and following azeotropic distillation of water, proceeds with chlorination with a small excess of 0.2 mol. thionyl chloride required to cover losses due to leakage with gaseous products, in particular sulfur dioxide (rum. pat. 55946 (1973)).

Chlorination of alcohols can also be carried out directly with hydrogen chloride, but under considerably tougher conditions and with limited use, especially for low primary alcohols C 1 to C ₄ (U.S. Pat. No. 4,935,564 (1990)).

SUMMARY OF THE INVENTION

According to the invention, a process for the preparation of aminoalkyl chlorides and / or their hydrochlorides of the general formula

R '. Rix

N - R ₁ - Cl N - R ₃ - C 1 .HCl

R a where R ¹ and R ² can be -H, -CH 3, -C 2 H 5, iso-C ₃ H ₇ , -C ₃ H 7, and R ³ can be -CH 2 -, -C ₂ H ₄ -, -C ₃ H ₆ - from amino alcohols , N-alkylaminoalcohols, Ν, dial-dialkylaminoalcohols and thionyl chloride are carried out by first reacting from the aminoalcohol in an anhydrous medium with dry hydrogen chloride gas to a weakly acidic reaction, to a pH of 5.5 to 6.5, at an amino alcohol: hydrogen chloride molar ratio of 1: 1,002 to 1,3, at a temperature of 25 to 35 ° C and atmospheric pressure and in a vigorously stirred system with a speed of 400 to 600 / min. to prepare the aminoalcohol hydrochloride, followed by reaction with thionyl chloride to form the chlorosulphonic acid alkyl ester complex and its thermal decomposition to aminoalkyl chloride and / or aminoalkyl chloride hydrochloride.

An advantage of the process for the preparation of chloro derivatives from amino alcohols and / or N-substituted amino alcohols according to the invention is, in particular, that the reaction can be carried out under mild reaction conditions in that all reaction steps are carried out in a single step without isolation of intermediates with almost a stoichiometric ratio of reactants. Another advantage is a substantial reduction in the reaction time, a high yield of the product of 97% +2 and the saving of the starting thionyl chloride. Last but not least, it is the high quality of the product, free of by-products and color impurities, also achieved without the inclusion of lengthy and costly separation and cleaning operations.

In the first stage of the reaction of the aminoalcohol to the hydrochloride, it is important to ensure not only 100% conversion, but at the same time avoid undesirable excess of hydrogen chloride above the molar ratio of aminoalcohol: hydrogen chloride of 1.3: 1, preferably 1.005 to 1.075: 1. of the reaction of the aminoalcohol hydrochloride with thionyl chloride as a result of the exothermic HCL reaction "in situ" to the free aminoalcohol, whereby, as a last resort, the decomposition temperature of the chlorosulfic acid complex can be reached. Conversely, excess hydrogen chloride above 0.3 mole leads to the formation of polyhydrochlorides and the strongly acidic environment has a negative effect on the course of thermal decomposition and also on the quality of the product, especially the content of color impurities, crystallinity and yield. Of the hydroxy compounds, amino alcohols, e.g. ethanolamine, isopropanolamine, butanolamine, further N-alkyl substituted and N, N-dialkyl substituted amino alcohols, e.g. N-methylaminoethanol, N-ethylaminoethanol, N-ethylaminopropanol, N, N-dimethylaminoethanol, Ν, Ν-diethylaminoethanol and many others.

The chlorinating agent used is preferably thionyl chloride or phosphorus trichloride in a non-aqueous medium of an inert medium such as benzene, toluene, carbon tetrachloride, dichloroethane and others in an amount such that the resulting hydrochloride suspension contains 8.0 to 30.0 wt. solid phase.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

700 cm ^{3 of} toluene and 89.1 g of dimethylaminoethanol are metered into a 2500 ml ³ four-necked sulphonation flask equipped with a stirrer, hydrogen inlet, reflux condenser and thermometer. While cooling, dry hydrogen chloride gas (39.5 g) is passed through the calibrated capillary to a final pH of 6.5 at 31 ° C ± 2 over 1 hour. The temperature is then raised to 52 ° C and within 25 min. 132 g of thionyl chloride are metered in so that the temperature does not exceed 56 ° C by occasional cooling. Upon completion of thionyl chloride dosing, the contents were gradually heated to 110 ° C over a period of 1.2 h, the thermal decomposition of the complex being accompanied by a vigorous evolution of gaseous sulfur dioxide and hydrogen chloride gas, which were vented to the off-gas. The decomposition temperature of the complex is 60 ° C +2. During the decomposition, a suspension of crystals of dimethylaminoethyl chloride hydrochloride (DMAEC, HCl) is formed, which, after cooling to 30 ° C, is isolated by filtration, twice decanting 30 cm ^{3 of} toluene and drying in an oven at 70 ° C. DMAEC yield. HCl is 141.5 g, which represents 98.3% of theory, has a content of 99.5% by weight. hydrochloride, m.p. 208.6 ° C.

Example 2

Using the procedure of Example 1, diethylaminoethanol hydrochloride is prepared from 117.2 g of diethylaminoethanol in 600 cm @ ^{3 of} toluene, saturated with 47.5 g of hydrogen chloride gas until a pH of 5.5 is reached at 32 ± 3 ° C over 1.3 h. The temperature is then raised to 60 ° C and within 30 min. 144 g of thionyl chloride are added. Gradual heating to 115 ° C over 2 h provides thermal decomposition of the complex to DEAEC. HCI. 154.9 g (90.01% of theory) are obtained. Diethylaminoethyl chloride hydrochloride (DEAEC, HCl) is a pale yellow crystalline substance containing 97.1 wt. hydrochloride and melting point 207.3 ° C.

Example 3

To 61.08 g of monoethanolamine in 500 cm @ ^{3 of} toluene is added 40.15 g of hydrogen chloride gas over a period of 1 hour at a temperature of 28 to 32 DEG C., until a pH of 6.0 is reached. The temperature is then raised to 45 ° C and within 15 min. 132 g of thionyl chloride are metered in. Thermal decomposition is carried out by gradually raising the temperature to 105 ° C over 1.3 h. The aminoethyl chloride hydrochloride obtained is a colorless crystalline substance with a 97.6% hydrochloride content, m.p. 144.5 ° C. Yield: 108.6 g

93.6% of theory.

Industrial usability

Aminoalkyl chlorides are used in the pharmaceutical industry for the manufacture of pharmaceuticals.

Claims (2)

PATENT CLAIMS A process for the preparation of aminoalkyl chlorides of the general formula R N - Cl, R 5 where R ¹ and R ² are -H, -CH ³ , -C ₂ H ₅ , -C ₃ H ₇ or iso-C ³ H 7 and R ³ is -CH 2 -, -C ₂ H ₄ -, or -C ₃ H ₆ -, or their hydrochlorides N - R ₃ - Cl.HC] Reaction of amino alcohols, N-alkylamino alcohols or Ν, Ν-dialkylamino alcohols with thionyl chloride and thermal decomposition of the chlorosulfinic acid alkyl ester, characterized in that the aminoalcohol hydrochloride is first prepared in an anhydrous environment and then the chlorosulfinic acid alkyl ester is treated with thionyl chloride. The process according to claim 1, characterized in that it is carried out with vigorous stirring, at a temperature of 25 to 35 ° C and a pH of 5.5 to 6.5 with dry hydrogen chloride gas, wherein the molar ratio of amino alcohol: hydrogen chloride is 1: 1.002 to 1.3.