CS233160B1 - Method of h2-antihistamining intermediate products making - Google Patents

Abstract

with omega-substituted alkylamines provide the compounds of formula (I) in that the compound is reacted of Formula II with a primary amine in a 1: 1.0 to 1.5 molar ratio in lower alcohols with number carbon atoms 1 to 3 mixed with polar aprotic solvent by volume 30: 1 to 3 or 2-methoxy / ethoxy / ethanol, whereupon the product III in the same solvent system by treatment with an omega-substituted alkylamine in a 1: 1 to 3 molar ratio at a reaction temperature of 50 to 120 ° C to a compound of formula (I) which is after evaporation of some of the solvents from the reaction the mixture is isolated in the form of crystals.

Description

The invention relates to a process for the preparation of compounds of the formula I

X- / CH _2/5 NH-C-NH-R / 1 /

NCN where R is methyl, allyl or propargyl,

X is OH or SH and n is 2 or 3;

Said compounds of formula (I) are important intermediates in the synthesis of [beta] -antihistamines. Currently, H2-antihistamines are some of the most effective and progressive drugs in the treatment of gastrointestinal diseases / see, e.g., Chronicles of Drag Discovery, Vol. 1, p. 1, J.Wiley, New York 1982, Chem.Eng.News, April 12, p. 24 (1982), Biochem. Transaction 114, (1980), Trends, Pharmacol. Sci. 2, 310 (1981). They are used in the treatment of gastric and duodenal ulcer disease and gastric juice secretion. Cimetidine and Ranitidine, followed by tiotidine and etintidine, are the best known and widespread drug.

The known processes for the preparation of the compounds of the formula I utilize the reaction of N-methyl-N- (2-haloethyl) thiourea with lead cyanamide (DOS 2,855,836) or starting from readily available dimethyl cyaniminodithium carbonate or 2,2-bis (methylthio) -1-dimethyl ester. nitroethylene, the preparation of which is described in Chem. Ber. 100, 591 (1967), Acta Chem. Scand 21, 2797 (1967), J. Org. Chem. 32, 1566 (1967), Chem. Rev. The conversion of these compounds to the desired products of formula (I) is carried out by a two-step synthesis and the cell is prepared in the first reaction step by treatment with the corresponding primary amine N-cyano-N-alkyl / alkynyl / -S-methylisothiourea or corresponding to 2-alkylamino-2-methylthio-1-nitroethylene which is reacted further

233 160 of chloro / bromo / ethylamine is converted to the desired product of formula (I) wherein X is either NCN or CHNO2. Reverse procedures have also been described, i.e., in the first step, A and B are treated with 2-chloro (bromo) ethylamine followed by a primary amine (see, e.g., U.K.). U.S. Pat. US Patent Nos. 2,038,798 and 2,038,804, U.S. Pat. Nos. 4,158,013 and 4,157,340 and 4,157,347; JP 82 11 954 Spanish. Nos. 458 139 and 458 042 /. The first of these methods using lead cyanamide has the disadvantage that the reaction proceeds at elevated temperatures using relatively expensive high boiling solvents which prevent easy and simple isolation of the product. Furthermore, the increased lead content of the product is pharmacologically unacceptable.

In the other alternatives mentioned above, the reaction is carried out in an environment of acetonitrile (methyl cyanide), which is classified as a particularly dangerous poison. In terms of occupational safety, this requires special safety measures, ie a technological and economic disadvantage of the procedure.

These known processes are followed in a positive way by the process according to the invention, which removes the drawbacks.

The process of the invention employs readily available compounds of formula II,

CEfeS CCH--C * / ^11/9 II '

NCNs that are prepared from carbon disulfide and cyanamide according to procedures described in the literature / Chem. Ber. 100, 59 (1967), Acta Chem. Scand. 21, 2797 (1967). The next step is converted to a compound of formula (III), ch ₅ sc-nhr (111) by treatment with a primary amine R-NH 2, where R is as defined above.

NCN wherein R is as defined above.

Compound III by treatment with an omega-substituted alkylamine gives the desired product of formula I. This reaction sequence can be carried out without isolation of the individual intermediates III, with yields of product of formula I being on average 5 to 8% higher. Next

The advantage of this process is a substantial reduction in the amount of solvents, energy and labor.

In the process according to the invention, a molar ratio of 1: 1.0 to 1.5 is used in the reaction of II with the primary amine RNHg. The reaction is carried out in a lower alcohol having a carbon number of 1-5 and preferably dimethylformamide in a ratio of 30: 1 to 3 or 2-methoxy (ethoxy) ethanol. After completion of the reaction, some of the solvents were distilled off and after cooling, the precipitated crystals were filtered off with suction. The product of formula (III) thus obtained is sufficiently pure for the next synthesis step in which, by treatment with an omega-substituted alkylamine, it is converted to the product of formula (I). 3. The reaction is carried out at a temperature of 50 to 120 ° C, after which the solvents are distilled off and the product is purified by crystallization. If the reaction sequence is carried out without isolation of intermediates III, it is preferred to carry out the reaction in 2-methoxy / ethoxy / ethanol.

The advantages of the process according to the invention are simple execution, the use of readily available, cheap and safe solvents, high product yields and low energy consumption.

The process according to the invention and its effects are illustrated in several examples, which are illustrative only and do not limit the scope of the invention in any way.

Example 1

N-cyano-N- (2-mercaptoethyl) -N-methylguanidine (1, X = SH, n = 2)

To a mixture of 0.645 g (5 mmol) of N, S-dimethyl-N-cyanisothiourea (111), 0.568 g (5 mmol) of cysteamine hydrochloride in 10 ml of ethanol and 0.5 ml of dimethylformamide was added a solution of 1.56 g of potassium hydroxide in the same solvent. After boiling the reaction mixture for 1 hour (the progress of the reaction was monitored by thin layer chromatography) the solvents were distilled off on a rotary evaporator and crystallization of the residue from dichloromethane methanol gave

233 160, 0.679 g (86%) of product I was obtained, where X-SH, n = 2, mp 86-88 ° C. In the NMR spectrum there were signals at cf * (ppm): 2.83 (3H, s, GH ₅ ), 2.91 (2H, t, CH2 ₎ and 3.56 (2Ή, t, CH2 ₎ confirming the structure product.

Example 2

N-AHyl-N-cyano-S-methylisotniourea (111, R = CH ₂ CH = CH ₂ )

To a solution of 4.4 g (30 mmol) of dithiocarbonate II in 30 ml of ethanol and 0.7 ml of dimethylformamide, 1.71 g (30 mmol) was added dropwise with stirring, and the reaction mixture was stirred at 50 ° C for 30 minutes. washed with a little ether. 4.32 g (93.3%) of the product was obtained. 108-109 ° C, in which

NMR spectrum signals at (ppm) 2.56 (ΗΗ, β, ΟΗΟΗ), 3.96 (2H, d, CH ₂ ), 5.14 (2H, t, GH ₂ ), 5.78 AH, m, CH / confirm the proposed structure.

Example 3

N-Allyl-N '- (2-hydroxyethyl) -N''- cyanguanidine / 1, where R = GH ₂ GH = GH ₂ , X = OH, n = 2)

A mixture of 2.6 g of N-allyl-N-cyano-5-methylisothiourea, 3.05 g of 2-aminoethanol, 20 ml of 2-methoxyethanol and 1 ml of dimethylformamide was heated to boiling for 3 hours and then the solvents were evaporated. Crystallization of the distillation residue with chloroform-methanol gave 2.70 g (95.7%) of the product, mp 86-88 ° C. The ¹H NMR spectrum showed signals at <Ζ ~ / ρρπι / 3.41 / 2H, t, GH ₂ /, 3.72 / 2H, t, _CH2 /, 3.91 / 2H, m, GH ₂ /, 5.31 (2H, m, CH2 ₎ , 5.93 AH, m, CH), which is in accordance with the proposed structure.

Example 4

N-cyano-N'-propargyl-S-methyisothiourea (III, where R = CH ₂ C = CH)

To a solution of 4.0 g (27.4 mmol) of dithiocarbonate II in 15 ml of a mixture of ethanol and dimethylformamide (10: 1) was added 1.51 g (27.4 mmol) of propargylamine and after working up the reaction mixture analogously to Example 2, 3.35 g (80%) of the product of m.p. Mp 161-163 ° C. 1 H-NMR spectrum in [delta] (ppm) 2.48 (3H, s, CH3),

3.10 (1H, s, CH), 3.95 (2H, d, CH2 ₎ and 8.71 AH, s, NH) confirm the proposed structure.

- 5 233 160

Example 5

N-Propargyl-N ^from - (2-mercaptoethyl) -N ^, 1-cyanoguanidine / 1, where R = CH ₂ C = CH, X = SH, n = 2)

From 1.5 g of N-propargyl-S-methylisothiourea, 1.15 g of cysteamine hydrochloride and 0.56 g of potassium hydroxide dissolved in 15 ml of a mixture of 2-methoxyethanol and dimethylformamide (10: 1 ratio) gave 1, 55 g (75.5%) of product m.p.

155-158 ° C, NMR spectrum contains signals at (ppm) 1.78 (2H, t, CH ₂ ), 2.05 (1H, s, CH), 5.51 (2H, t, GH ₂₎ (5.82 (2H, m, CH2 ₎ ), which are consistent with the proposed structure.

Example 6

N- (5-hydroxypropyl) -N'-cyano-N '- methylguanidine / 1, where R - CH5,

X = OH, n = 5

From 1.29 g of N, S-dimethyl-N'-cyanisothiourea (III, R = GH5) and 0.85 g of 5-aminopropanol, 1.51 g of product (96.8%) were obtained according to Example 5, 1 H NMR spectrum shows signals at OT (ppm) (1.74 (2H, m, CH ₂ ), 2.76 (5H, s, CH ₅ ), 5.28 (2H, t, GH ₂ ), 5.58) 2H, t, CH2 ₎ , which are in accordance with the proposed structure.

233 160

Claims (3)

SUBJECT OF THE INVENTION 1. A process for producing intermediates of formula -antihistaminik ^ ^T 'X- / GH ₂ / _n-NH-C-NHR / 1 / "NGN wherein R is methyl, allyl or propargyl, X represents OH or SH group, n is 2 or 3 by prepared from readily available compounds of formula II, CH-SC SCH / ^11/5 i! CN ⁵ treatment of primary amines RNH2, where R has the abovementioned meaning, to give a compound of formula III, CHCl 3 -G-NHR (111) ^yl NCN wherein R is as defined above to give compounds of formula I by reaction with omega-substituted alkylamines, characterized in that the reaction of a compound of formula II with a primary amine in a molar ratio of 1: 1.0 to 1.5 is carried out in an environment of lower alcohols having a carbon number of 1 to 3 in a mixture with a polar aprotic solvent in a ratio of 30: 1 to 3 or 2-methoxy / ethoxy / ethanol, whereupon the product obtained in the same solvent system is converted by omega-substituted alkylamine molar ratio of components 1; 1-3 at a reaction mixture temperature of 50-120 ° C to a compound of formula I which is isolated as crystals after evaporation of the solvents from the reaction mixture. 2. A process according to claim 1 wherein the polar aprotic solvent is dimethylformamide. 3. The process of claim 1 wherein the entire reaction sequence is carried out without isolation of the intermediate in the same solvent. Printed by Moravian Printing Works,