前苏联专利SU1122222A3 Method of obtaining cymetidine

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专利摘要:
I. THE METHOD OF OBTAINING SCHSHETID11HA by the interaction of 5-methyl-1H-imidazole and N-cyano N-methyl-guanidine derivatives, taken in equimolar amounts, in an aqueous medium in the presence of alkali, is characterized by to simplify the process, 4-halomethyl-5-methyl-1H-imidazole and N-cyano-M-methyl-M are used as derivatives of 5-methyl-1H-imidazole and N-cyano-Mmethyl-guanidine
公开号:SU1122222A3
申请号:SU813322501
申请日:1981-08-18
公开日:1984-10-30
发明作者:Юхани Каирисало Пекка；Юхани Хонканен Эркки
申请人:Орион-Ихтюмя Ой (Фирма)；
IPC主号:

专利说明:

The invention relates to an improved process for the preparation of cimetidine-N-cyano-C-methyl-H-2 (5-methyl 1H-imidazol-4-yl;) methyl thio | -ethyl} guanidine, a biologically active compound used in medicine. A known method for the preparation of cimetidine by reacting 4-methyl;, 5- (2-aminoethyl thiomethylimidazole with, |-cyano-N, S-dimethyl yuchovino I in acetonitrile by boiling for 24 hours L1.J. However, the product, polite, This method is heavily polluted. Additional purification and crystallization are required, difficult to carry out on a 1F1 scale.The yield of the product is not indicated.There is a method for producing cymetidine, consisting in the interaction of cyano-M-methyl-H- (2-mercal to ethyl ) -guanidine with 4-chloromethyl-5-methylimidazole Q2J. The disadvantage of this method is the difficulty of its implementation on an industrial scale, since its implementation requires the use of absolutely dry solutions, sodium alkoxides and requires additional purification and recrystallization of the target product. The closest to the proposed method is the production of cimetidine by the interaction of 4-TI9methyl5-methylimidazole and N -cyano-N-methyl / N - (2-chlorostil) -guanidine (taken in equimolar amount) at room; TehjnepaType in aliphatic alcohol or acetonitrile in the presence of 50% aqueous solution of caustic soda and metilkaprilammoniyhlorida or triztilbenzilammoniyhlorida taken ies as a phase transfer catalyst; product yield - 90%. However, the known method is difficult to control when it is carried out on an industrial scale, since the starting compounds 4-mercaptoeth nol-5-methylimidazole and N-cyano-K-methyl-N -2-chloroethylgianidine are unstable and difficult to access. In addition, for its implementation, it is necessary to use expensive phase transfer catalysts. The purpose of the invention is to simplify the process. This goal is achieved by the proposed method of obtaining cy22I methidine by reacting 4-halomethyl-5-methyl-1H-imidazolium and Nt .- (% x cyano-N-methyl-H- (2-mercaptoethyl) -guanidine, taken in equimolar amounts in an aqueous medium or in a mixture of water-methanol (5: 1 by volume) at a pH of 8.59, 0 and a temperature of from -5 to + 5 ° C in an inert gas atmosphere. In addition, the process is carried out at a temperature from 0 to. In addition, 4-chloromethyl-5-methyl-1H-imidazole hydrochloride, suspended in methanol, is added to a suspension of an equimolar amount of N-cyanoM-methyl- - 2-m ercaptoethyl) -guanidine in water for 1-3 hours. The distinguishing features of the method are the use of 4-halomethyl-5-methyl-1Nimidazole and N-cyano-1C ethyl-N- (2-mercaptoztil) -guanidine as starting materials, carrying out the process in water or in a mixture of water and methanol (5: 1 by volume) at pH 8.59, 0 and temperature from -5 to in an inert gas atmosphere. The implementation of the proposed method allows to obtain high purity cimetidine (7–99%) in good yield (70%) through the use of stable starting compounds, to exclude phase transfer catalysts, which greatly simplifies the process and allows it to be carried out on a progressed scale. Example 1. N-Ciano-N-methylN-U-mercaptoethyl) -guanidine. A solution containing 102 g (0.9 mol / cysteamine hydrochloride, 700 mp of water, 200 methanol, G16 g (0.9 mol) of N, S -dimethyl-N-cyanoisotopic acid and 144 g of 50% sodium hydroxide solution ( 1.8 mop) is refluxed under nitrogen for 1 hour under a nitrogen atmosphere .. The resulting solution contains approximately 0.9 mol of the desired component. N -UHaHo-7N-methyl- {2-, {(5-methylimidazole-4 -yl) methyl) -thioZ-ethyl guanidine. The pH of this solution was adjusted to 0.9 with concentrated hydrochloric acid and heated to -5 at atmosphere. 144 g of a 50% solution of sodium chloride (1.8 mol) and a solution containing 150 and a solution containing 150 g (0.9 mol) of 4-chloromethyl-5-methyl-imidazole hydrochloride, 30 mp of concentrated hydrochloric acid and 120 ml of water is added simultaneously when
3i
vigorous stirring to the indicated solution. When adding the pH of the solution support in the range from 8.5 to 9.0, and the temperature is below. After the addition, the solution is stirred for about 20 hours at about. The crystallized product is filtered off, washed with cold water and dried. Obtain 170 g (75% of theoretical yield) of the desired product.
4-Chl6-rmethyl-5-methyl-imidazole hydrochloride, used as a starting material, was prepared as follows.
55 g (1.3 mol) of thionyl chloride are added with stirring to a mixture containing 112 g (1 mol) of 4-hydroxymethyl-5-methylimidazole and 1000 ml of dichloromethane. The mixture is heated under reflux for 2 to 3 hours, cooled and filtered. The filtered product is washed with dichloromethane and dried. This gives 167 g (100%) of the desired product (etc., from 218 to 221СЬ /
Example2. N-Cyano-GI -methyl; N- (2-mercaptoethyl) iguanidine.
The solution, prepared as in Example 1, is acidified (to a pH of about 4) with hydrochloric acid and extracted with ethyl acetate. The extract is dried and ethyl acetate is evaporated, with the result that the desired product is formed as a colorless oil, f. f.
N-Cyano-N-nvtil-N - {2-c5-methylimidazol-4-yl) -methyl) tyo1-ethyl guanidine.
22224
14.2 g (0.09 mol) of the product obtained analogously to example 1, is mixed with 110 ml of water under a nitrogen atmosphere and at a temperature from 0 to.
J The pH of the mixture was adjusted to 9 with 5 N sodium hydroxide solution. 150 g (0.09 mol) of 4-chloromethyl-5-methyl-imidazole hydrochloride suspended in 30 ml is added over 2 hours
0 methanol. When adding the temperature is maintained in the range from About to, and pH in the range from 8.5 to 9.0. The mixture is stirred for 18 h, filtered, the precipitate is washed
5 with water and dried. 16.1 g (71%) of cimetidine are obtained.
PRI me R 3. 4-Bromomethyl-5metnlimieadol hydrobromide.
A mixture containing 82 g (1 mol)
0 5-methylimidazole, 35 g of paraformaldehyde and 1000 ml of 48% hydrobromic acid, is refluxed for 1 hour. Excess hydrobromic acid
5 is evaporated under reduced pressure and the residue is crystallized from ethanol. 245 g (96%) of 4-bromomethyl-5-methylimidazole hydrobromide are obtained (mp: 200 to).
N-Cyano-N-methyl-N - 2- (5-methylimidazol-4-yl) -methyl) thio) -ethyl guanidine.
Using the method described in Example 1, instead of adding methyl-5-methyl-imidazole hydrochloride 4-bromomethyl-5-methylimidazole hydrobromide instead of 4-hpor5 of methyl-5-methyl-imidazol hydrochloride, cimetidine is obtained in 65% yield.

权利要求:
Claims (3)
[1]
1. METHOD FOR PRODUCING CIMETHIDINE by reacting derivatives of 5-methyl-1H-imidazole and N-cyano N'-methyl-guanidine, taken in equimolar amounts, in an aqueous medium in the presence of alkali, characterized in that, in order to simplify the process, as derivatives of 5-methyl-1H-imidazole and N-cyano-M'methyl-guanidine use 4-halogen-methyl-5-methyl-ΙΗ-imidazole and N-cyano-Ν'-methyl-N * - (2-mercaptoethyl) -guanidine , the process is conducted in water or in a water-methanol mixture (5: 1 by volume) at a pH of 8.5-9.0 and a temperature of from -5 to + 5 ° C in an inert gas atmosphere.
[2]
2. The method according to claim 1, characterized in that the process is carried out at a temperature of from 0 to +5 C.
[3]
3. The method according to π, 1, characterized in that 4-chloromethyl-5methyl-1H-imidazole hydrochloride suspended in methanol is added to a suspension of equimolar amount of N-cyano-Y'-methyl-N- (2-mercaptoethyl) guanidine in water for
1-3 hours
SU _<w 1122222>
1 122222

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引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

US4093621A|1974-09-02|1978-06-06|Smith Kline & French Laboratories Limited|Process for preparing heterocyclicalkylthioalkyl-N-cyanoguanidines and thioureas|

US4215217A|1975-10-29|1980-07-29|Sk&F Lab Co.|Process for preparing 4-substituted imidazole compounds|

ES458042A1|1977-04-06|1978-08-16|Ricorvi S A|Gastric ulcer inhibiting guanidine deriv. prodn. - by reacting 4-chloromethyl-5-methyl imidazole with 1-cyano-2-methyl-3- ethyl guanidine|

US4112234A|1977-08-22|1978-09-05|Bristol-Myers Company|Imidazolylmethylthioethyl alkynyl guanidines|JPS622592B2|1983-01-14|1987-01-20|Tokawa Tetsuo|

GB8618846D0|1986-08-01|1986-09-10|Smithkline Beckman Corp|Chemical process|

JPH064601B2|1987-11-04|1994-01-19|三井石油化学工業株式会社|Method for purifying N-cyano-N'-methyl-N "-[2-{ methylthio} ethylguanidine|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

FI802649A|FI63753C|1980-08-21|1980-08-21|FOERFARANDE FOER FRAMSTAELLNING AV KRISTALLINT SIMETIDIN.|

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