SK105998A3 - Method for producing aminoalkyl 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

A process for the production of amino acids

Technical field

The invention relates to a process for the preparation of aminoalkyl chlorides, N-alkylaminochlorides and / or N, N-dialkylaminochlorides 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.

The prior art

It is known that the preparation of N, N-diethylaminoethyl chloride is carried out by reacting N, N-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 resting phase of 13-15 hours at 10-30 ° C. This is followed by a decomposition phase at 75 to 50 ° C, distillation of unreacted thionyl chloride with some toluene, and finally isolation of N, N-diethylaminoethyl chloride hydrochloride (Rum. Pat. 67572 (197?)).

Another method favors the preparation of aminochloro derivatives via hydrochlorides, by reacting amino alcohols with hydrochloric acid at a concentration of 25 to 36X by weight, in water and toluene, and then azeotropically distilling off the water followed by chlorination with a small excess of 0.2 mol of thionyl chloride needed to cover losses releases with gaseous fumes, 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 mainly for C 1 -C 4 primary alcohols (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

Ri ».

N - ft ₃ - Cl N - R ₃ - C1.HCl

Ra ftZ

Where R 1a R a can be —H, —CH 3, —Carls, iso-C 8 (-17, -C 3 H 7, and R 3 can be

-CHa-, -Cal-U-, -C3H6- z. of aminoalcohols, N-alkylaminoalcohols, N, N-dialkylaminoalcohols and thionyl chloride is 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 a molar ratio of aminoalcohol: hydrogen chloride; : 1.002 to 1.3, at 25 to 35 ° C and atmospheric pressure and in a vigorously stirred system at 400 to 600 rpm, prepares the amino alcohol hydrochloride, followed by reaction with thionyl chloride to form the chlorosulfinic acid alkyl ester complex and its thermal decomposition to give aminoalkyl chloride and / or aminoalkyl chloride hydrochloride.

The advantage of the process for preparing 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 phase without isolation of intermediates with almost stoichiometric ratios. Another advantage is a substantial reduction in the reaction time, a high yield of the product 97Z t 2 and the saving of the starting thionyl chloride. Last but not least, it is the high quality of the product without any side-effects and color impurities, achieved even 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 a 100X conversion, but at the same time avoid undesired excess 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 reaction of HCL in situ to the free aminoalcohol so that, as a last resort, the decomposition temperature of the chlorosulphonic 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, aminoalcohols, 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, N, N-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% by weight. solid phase.

Examples, embodiments of the invention

Example 1

700 cm @ ^{3 of} toluene and 89 .mu.g of dimethylaminoethanol are metered into a ⁴ -neck 2-inch ^3- volume sulfonation 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. Then increase the temperature to 52 ^Q C and over 25 minutes. 132 g of thionyl chloride are metered in so that the temperature does not exceed 56 ° C by occasional cooling. Upon completion of the thionyl chloride feed, the contents were gradually heated to 110 ° C over a period of 1.2 hours, the thermal decomposition of the complex being accompanied by a vigorous evolution of the gaseous fumes of sulfur dioxide and hydrogen chloride, 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. The yield of DMAEC.HCl is 141.5 g, which is 98.3% of theory, and has a content of 99.5% by weight of hydrochloride and a melting point of 208.6 ° C.

Example 2

Using the procedure described in 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 2h provides thermal decomposition of the complex to DEAEC.HCl. 154.9 g is obtained, which is 90.01% of theory. Diethylaminoethyl chloride hydrochloride (DEAEC.HCl) is a pale yellow crystalline substance containing 97.1% by weight. hydrochloride and melting point 207.3 ° C.

Example 3

61.15 g of monoethanolamine in 500 cm @ ^{3 of} toluene are charged with 40.15 g of hydrogen chloride gas over a period of 1 h 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. The thermal decomposition is carried out by gradually raising the temperature to 105 ^° C over a period of 1.3 hours. The aminoethyl chloride hydrochloride obtained is a colorless crystalline substance, containing 97.6% hydrochloride, m.p. 144.5-8. Yield: IQB.feg, which represents 93.6% of theory.

Industrial usability

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

Claims (2)

PATENT CLAIMS 1 A process for the preparation of aminoalkyl chlorides of general formula N - R 5 - C 1 where R 5 and R _a are -H, -CH 3, -C 2 H 5, -C 3 H 7 or R 5 IsO-C3H7 and R5 is -CH _and -, -CbHa-, or -C3H * -, or their HydRix chlorides N-R3-C1HCl, by reaction of amino alcohols, N-alRa-cylaminoalcohols or N, N-dialkylaminoalcohols with thionyl chloride and by thermal decomposition of the chlorosulfinic acid alkyl ester, characterized in that the aminoalcohol hydrochloride is first prepared in an anhydrous medium, and then, by treatment with thionyl chloride, an alkyl chlorosulphonic acid ester. 2. The process according to claim 1, wherein Se is carried out with vigorous stirring, at a temperature of 25-35 [deg.] C. and a pH of 5.5-6.5 with dry hydrogen chloride gas, wherein the molar ratio of aminoalcohol: hydrogen chloride is 1: 1.002-1. third