CN115960048A - Preparation method of cimetidine - Google Patents
Preparation method of cimetidine Download PDFInfo
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Abstract
The invention discloses a preparation method of cimetidine, which comprises the step of reacting a compound shown in formula I or formula II with 2- (((4-methyl-1H-imidazole-5-yl) methyl) sulfenyl) ethylamine dihydrochloride, wherein R-SH is generated instead of malodorous CH 3 And (SH). R-SH is high boiling point liquid, is not easy to volatilize and has no odor of methyl mercaptan; therefore, no odor of methyl mercaptan overflows in the preparation process, a reaction system does not need negative pressure, the consumption of alkali in post-treatment is reduced, and the generation of wastewater is reduced; the preparation method of the invention reduces energy consumption and pollution, reduces production cost, and is suitable for industrial mass production.
Description
Technical Field
The invention relates to the field of medical chemistry, in particular to a preparation method of cimetidine.
Background
Cimetidine (N' -methyl-N "- [2[ [ (5-methyl-1H-imidazol-4-yl) methyl ] thio ] ethyl ] -N-cyanoguanidine, cimetidine) is an important antacid drug for relieving stomach ache, heartburn (heartburn), acid regurgitation caused by gastric hyperacidity, CAS NO: 51486-61-9, the chemical structural formula is as follows:
at present, the main domestic synthetic route is shown in figure 1, 2- (((4-methyl-1H-imidazole-5-yl) methyl) thio) ethylamine dihydrochloride is used as a substrate to prepare cimetidine through reaction, and the specific process recorded in the literature is as follows:
the first step is as follows: taking 2- (((4-methyl-1H-imidazole-5-yl) methyl) sulfenyl) ethylamine dihydrochloride as a substrate, taking ethanol as a solvent, adding liquid alkali for dissociation, adding cyanoimido dimethyl dithiocarbonate for reaction, reacting at 45 ℃, absorbing generated methyl mercaptan by tail gas with liquid alkali, cooling, filtering, and drying to obtain the N-cyano-N- [2- (5-methylimidazole-4-methylthio) ethyl ] -S-methylisothiourea.
The second step is that: adding ethanol into N-cyano-N- [2- (5-methylimidazole-4-methylthio) ethyl ] -S-methylisothiourea in the first step, introducing methylamine gas into the mixture, reacting at 20-50 ℃, absorbing generated methyl mercaptan in tail gas by using liquid caustic soda, finishing the reaction, concentrating the reaction product, and taking the product to N '-methyl-N' - [2[ [ (5-methyl-1H-imidazole-4-yl) methyl ] thio ] ethyl ] -N-cyano guanidine, namely cimetidine.
The preparation method of the cimetidine has the following disadvantages:
(1) In the production process, a large amount of methyl mercaptan is generated in the two steps of reaction, the whole reaction is carried out under negative pressure, liquid alkali is used for absorbing waste gas, the methyl mercaptan and the sodium methyl mercaptide are both smelly, and the environmental pollution is serious.
(2) The process avoids odor overflow, has high requirements on tail gas treatment equipment, and virtually increases the production cost.
In order to solve the problem of methyl mercaptan, some processes change the synthetic route and avoid the generation of methyl mercaptan.
For example, chinese patent document CN 112830896A (application No. 202110206841.8) discloses a method for preparing cimetidine, in which (5-methyl-1H-imidazol-4-yl) methanol is first converted into a nitrate by nitration, and the nitrate is reacted with an ether of N-cyano-N '-methyl-N "-mercaptoethylguanidine (i.e., 1' - (dithiobis (ethane-2, 1-diyl)) bis (2-cyano-3-methylguanidine)) to obtain cimetidine. The process does not produce sulfide waste, particularly volatile methyl mercaptan.
For example, chinese patent document CN 113234018A (application number 202110512430.1) also discloses a method for preparing cimetidine without generating methanethiol, which comprises reacting 2-chloroethanol with thiocyanate to prepare an intermediate (I); reacting the intermediate (I) with methylamine to prepare an intermediate (II); oxidizing the intermediate (II) by oxyacetic acid to obtain an intermediate (III); condensing the intermediate (III) with cyanamide to obtain an Intermediate (IV); condensing the Intermediate (IV) and imidazole thiol (V) to prepare cimetidine.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of cimetidine, which is environment-friendly and convenient for industrial mass production.
The first technical scheme for realizing the aim of the invention is a preparation method of cimetidine, which comprises the following steps:
(1) the compound of formula (I) is prepared by the reaction of N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide
(2) 2- (((4-methyl-1H-imidazole-5-yl) methyl) thio) ethylamine dihydrochloride reacts with a compound of formula (I) to prepare an intermediate compound.
(3) And (3) reacting the intermediate compound obtained in the step (2) with methylamine to obtain a target product.
In the step (1), the molar ratio of N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt to benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide is 1:1.8 to 3.0.
In the step (2), the molar ratio of 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride to the compound of formula (i) is 1:1.0 to 3.0.
In the step (3), the molar ratio of the intermediate compound obtained in the step (2) to methylamine is 1:1.0 to 10.0.
The second technical scheme for realizing the aim of the invention is a preparation method of cimetidine, which comprises the following steps:
(1) the compound of formula (I) is prepared by the reaction of N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide
(2) Reacting the compound of formula (I) with methylamine to obtain the compound of formula (II).
(3) And (3) reacting 2- (((4-methyl-1H-imidazole-5-yl) methyl) sulfenyl) ethylamine dihydrochloride with a compound shown in a formula (II) to obtain a target product.
In the step (1), the molar ratio of N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt to benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide is 1:1.8 to 3.0.
In the step (2), the molar ratio of the compound of the formula (I) to methylamine is 1:0.8 to 1.2.
In the step (3), the molar ratio of 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride to the compound of formula (ii) is 1:1.0 to 3.0.
The invention has the positive effects that:
the invention does not use cyanoimido dimethyl dithiocarbonate as a reaction sourceA compound of formula I or formula II is used for reacting with 2- (((4-methyl-1H-imidazole-5-yl) methyl) sulfenyl) ethylamine dihydrochloride, R-SH (R is benzyl or substituted benzyl) is generated after the reaction, and malodorous CH is not generated 3 And (5) SH. R-SH is high boiling point liquid, is not easy to volatilize and has no odor of methyl mercaptan; therefore, the preparation process of the invention has no odor of methyl mercaptan to overflow, the reaction system does not need negative pressure, and simultaneously, the consumption of alkali in post-treatment is reduced, and the generation of wastewater is reduced.
The invention provides a synthetic route without generating methyl mercaptan, and the preparation method of the invention reduces energy consumption and pollution, reduces production cost and is suitable for industrial mass production.
Drawings
FIG. 1 is a synthesis route chart of the main domestic processes.
FIG. 2 is a first synthetic route of the present invention.
FIG. 3 is a complete NMR spectrum of the product obtained in example 1.
FIG. 4 is a side chain NMR H spectrum of the product obtained in example 1.
FIG. 5 is an HPLC chromatogram of the product obtained in example 1.
FIG. 6 is an HPLC chromatogram of the product of the second route of example 24.
Detailed Description
(example 1)
The synthetic route of cimetidine in this example is shown in fig. 2, and the preparation method comprises the following steps:
(1) preparation of m-methyldibenzylcyanoimidodithiocarbonate, the reaction scheme is as follows:
Dissolving 100.0g of N-cyanoimino-S, S-dithio potassium salt (CAS NO.13145-41-0, available from Baiaowei Biotechnology Co., ltd., heizhou) in 300.0g of water, dropwise adding 145.0g of m-methylbenzyl chloride into the solution, reacting at room temperature (15 ℃ -35 ℃) for 20-24 hours, cooling to 0-10 ℃ after the reaction is finished, performing suction filtration, drying and ethanol recrystallization to obtain 122.84g of m-methyldibenzyl cyanoimidodithiocarbonate for later use, wherein the yield is as follows: 80 percent.
(2) To a reaction flask were added 50.0g of ethanol and 10.0g of 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride (CAS No. 38603-72-4), and stirring was started, followed by addition of 12.0g of 30% liquid base.
13.0g of m-methyldibenzyl cyanoimidodithiocarbonate was added to the above solution, and the reaction was carried out at 0 ℃ to 100 ℃ for 1.0 to 24.0 hours.
After the reaction is finished, most (70-80%) of ethanol is evaporated, and water is added: 500.0g, cooling to 0-5 ℃, filtering to obtain an intermediate product, drying is not needed, and feeding is directly carried out according to 100% yield.
(3) Dispersing the intermediate product obtained in the step (2) in 50.0g of ethanol, adding 13.0g of 30% methylamine aqueous solution, and reacting at 50 ℃ for 5.0-24.0 hours.
After the reaction is finished, evaporating 70-80% of ethanol, adding water: 20.0g, cooling to 0-5 ℃, separating out solids, filtering, and drying to obtain 8.34g of a product, wherein the yield is 80.0%, and the purity is 99.8772%.
The NMR H spectrum of the product obtained in this example is shown in FIG. 3, the side chain NMR H spectrum is shown in FIG. 4, and the HPLC spectrum is shown in FIG. 5.
(example 2)
The synthetic route of cimetidine in this example is shown in fig. 2, and the preparation method comprises the following steps:
(1) preparation of dibenzyl cyanoimidodithiocarbonate, the reaction scheme is as follows:
Dissolving 100.0g of N-cyanoimino-S, S-dithio potassium salt (CAS NO.13145-41-0, purchased from Baiaowei Biotechnology Co., ltd., changzhou) in 300.0g of water, dropwise adding 145.0g of benzyl chloride into the solution, reacting for 20-24 hours at room temperature (15 ℃ -35 ℃), cooling to 0-10 ℃ after the reaction is finished, performing suction filtration, drying, and recrystallizing in ethanol to obtain 107.48g of dibenzyl cyanoimidodithiocarbonate for later use, wherein the yield is as follows: 70 percent.
(2) To a reaction flask were added 50.0g of ethanol and 10.0g of 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride (CAS No. 38603-72-4), and stirring was started, followed by addition of 11.0g of 30% caustic soda solution to give a white suspension.
12.3g of dibenzyl cyanoimidodithiocarbonate was added to the above white suspension, and the mixture was reacted at 0 ℃ to 100 ℃ for 1.0 to 24.0 hours.
After the reaction is finished, evaporating most of ethanol, and adding water: 500.0g, cooling to 0-5 ℃, filtering to obtain an intermediate product, drying is not needed, and feeding is directly carried out according to 100% yield.
(3) Dispersing the intermediate product obtained in the step (2) in 30.0g of ethanol, adding 10.6g of 30% methylamine water solution, and reacting at 50 ℃ for 5.0-24.0 hours.
After the reaction is finished, evaporating 70-80% of ethanol, adding water: 20.0g, cooling to 0-5 ℃, separating out solids, filtering, and drying to obtain 7.3g of product with yield of 70.0%.
(example 3)
The preparation method of the present example is otherwise the same as example 2, except that:
in the step (1), benzyl bromide is used to react with N-cyanoimido-S, S-dithio potassium salt to obtain the dibenzyl cyanoimido dithiocarbonate.
Specifically, 100.0g of N-cyanoimino-S, S-dithio potassium salt is dissolved in 300.0g of water, 176.0g of benzyl bromide is dripped into the solution, the reaction is carried out at room temperature for 4.0 to 24.0 hours, the temperature is reduced to 0 to 10 ℃ after the reaction is finished, and 117.0g of dibenzyl cyanoimidodithiocarbonate is obtained after suction filtration, drying and ethanol recrystallization, wherein the yield is as follows: 77 percent.
(example 4)
The preparation method of the present example is otherwise the same as example 2, except that:
in step (1), N-cyanoimido-S, S-dithio sodium salt (available from Halocarb Biotech, inc.) is reacted with benzyl bromide to obtain dibenzyl cyanoimidodithiocarbonate.
Specifically, 100.0g of N-cyanoimino-S, S-sodium dithionate is dissolved in 600.0g of water, 212.0g of benzyl bromide is dropwise added into the solution, the reaction is carried out at room temperature for 4.0 to 24.0 hours, the temperature is reduced to 0 to 10 ℃ after the reaction is finished, and 132.3g of dibenzyl cyanoimidodithiocarbonate is obtained after suction filtration, drying and ethanol recrystallization for later use, wherein the yield is as follows: 72 percent.
(example 5)
The preparation method of the present example is otherwise the same as example 2, except that:
in step (1), N-cyanoimino-S, S-dithio sodium salt (available from Halocarb Biotech, inc.) is reacted with benzyl chloride to obtain dibenzyl cyanoimidodithiocarbonate.
Specifically, 100.0g of N-cyanoimino-S, S-sodium dithionate is dissolved in 600.0g of water, 164.72g of benzyl chloride is dropwise added into the solution, the reaction is carried out at room temperature for 2.0 to 24.0 hours, the temperature is reduced to 0 to 10.0 ℃ after the reaction is finished, and 138.0g of dibenzyl cyanoimidodithiocarbonate is obtained after suction filtration, drying and ethanol recrystallization for standby, wherein the yield is as follows: and 75 percent.
(example 6)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
in the compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, R is o-methylbenzyl.
In the step (1), o-methyl benzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to o-methylbenzyl chloride is 1:2.3.
to the white suspension in step (2) was added o-methyldibenzylcyanoimidodithiocarbonate.
The reaction with methylamine in step (3) is the corresponding intermediate obtained in step (2).
(example 7)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, wherein R is p-methylbenzyl.
In the step (1), p-methyl benzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to p-methylbenzyl chloride is 1:2.2.
to the white suspension in step (2) was added p-methyldibenzylcyanoiminodithiocarbonate.
The reaction with methylamine in step (3) is the corresponding intermediate obtained in step (2).
(example 8)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, wherein R is m-nitrobenzyl.
In the step (1), m-nitrobenzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to m-nitro benzyl chloride is 1:2.5.
in step (2), m-nitrodibenzyl cyanoimidodithiocarbonate is added to the white suspension.
The reaction with methylamine in step (3) is the corresponding intermediate obtained in step (2).
(example 9)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, wherein R is o-nitrobenzyl.
In the step (1), o-nitro benzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to o-nitrobenzyl chloride is 1:3.0.
in step (2), o-nitrodibenzyl cyanoimidodithiocarbonate is added to the white suspension.
The step (3) is reacted with methylamine to obtain corresponding intermediate product in the step (2).
(example 10)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
in the compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, R is p-nitrobenzyl.
In the step (1), p-nitro benzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to p-nitrobenzyl chloride is 1:2.7.
in step (2), p-nitrodibenzyl cyanoimidodithiocarbonate was added to the white suspension.
(example 11)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula i reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, wherein R is m-chlorobenzyl.
In the step (1), m-dichlorobenzyl reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to m-dichlorobenzyl is 1:2.3.
in step (2), m-chlorodibenzyl cyanoimidodithiocarbonate is added to the white suspension.
(example 12)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula I, wherein R is o-chlorobenzyl, is reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride.
In the step (1), o-dichlorobenzyl reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to o-dichlorobenzyl is 1:2.4.
in step (2), o-chlorodibenzyl cyanoimidodithiocarbonate was added to the white suspension.
(example 13)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
in the compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, R is p-chlorobenzyl.
In the step (1), p-dichlorobenzyl reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to p-dichlorobenzyl is 1:2.4.
in step (2), p-chlorodibenzyl cyanoimidodithiocarbonate was added to the white suspension.
(example 14)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, wherein R is m-bromobenzyl.
In the step (1), m-bromochlorobenzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to m-bromobenzyl chloride is 1:2.3.
in step (2), m-bromodibenzyl cyanoimidodithiocarbonate is added to the white suspension.
(example 15)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
in the compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, R is o-bromobenzyl.
In the step (1), o-bromobenzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to o-bromobenzyl chloride is 1:2.3.
in step (2), o-bromobenzyl cyanoimidodithiocarbonate was added to the white suspension.
(example 16)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
in the compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, R is p-bromobenzyl.
In the step (1), p-bromobenzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to p-bromobenzyl chloride is 1:2.1.
in step (2), p-bromobenzyl cyanoimidodithiocarbonate was added to the white suspension.
(example 17)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, wherein R is m-methoxybenzyl.
In the step (1), m-methoxyl benzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to m-methoxy benzyl chloride is 1:2.2.
in step (2), m-methoxydibenzyl cyanoimidodithiocarbonate is added to the white suspension.
The reaction with methylamine in step (3) is the corresponding intermediate obtained in step (2).
(example 18)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, wherein R is o-methoxybenzyl.
In the step (1), the o-methoxy benzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to o-methoxy benzyl chloride is 1:2.2.
in step (2), o-methoxydibenzyl cyanoimidodithiocarbonate is added to the white suspension.
The step (3) is reacted with methylamine to obtain corresponding intermediate product in the step (2).
(example 19)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, wherein R is p-methoxybenzyl.
In the step (1), p-methoxy benzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to p-methoxy benzyl chloride is 1:2.2.
in step (2), p-methoxydibenzyl cyanoimidodithiocarbonate is added to the white suspension.
(example 20)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, wherein R is m-ethylbenzyl.
In the step (1), m-ethyl benzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to m-ethyl benzyl chloride is 1:2.0.
in step (2), m-ethyldibenzyl cyanoimidodithiocarbonate was added to the white suspension.
The step (3) is reacted with methylamine to obtain corresponding intermediate product in the step (2).
(example 21)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
in the compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, R is o-ethylbenzyl.
In the step (1), o-ethylbenzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to o-ethylbenzyl chloride is 1:2.1.
to the white suspension in step (2) was added o-ethyldibenzyl cyanoimidodithiocarbonate.
The reaction with methylamine in step (3) is the corresponding intermediate obtained in step (2).
(example 23)
The procedure for preparing cimetidine in this example was the same as in example 1 except that:
a compound of formula I reacted with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, wherein R is p-ethylbenzyl.
In the step (1), p-ethylbenzyl chloride reacts with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt; the molar ratio of N-cyanoimino-S, S-dithio potassium salt/sodium salt to p-ethylbenzyl chloride is 1:2.0.
in step (2), p-ethyldibenzyl cyanoimidodithiocarbonate was added to the white suspension.
The step (3) is reacted with methylamine to obtain corresponding intermediate product in the step (2).
(example 24)
The reaction formula of cimetidine in this example is as follows,
The preparation method comprises the following steps:
(1) preparation of m-methyldibenzylcyanoimidodithiocarbonate, the reaction scheme is as follows:
Dissolving 100.0g of N-cyanoimino-S, S-dithio potassium salt (CAS NO.13145-41-0, available from Baiaowei Biotechnology Co., ltd., hezhou) in 300.0g of water, dropwise adding 145.0g of m-methylbenzyl chloride into the solution, reacting at room temperature (15 ℃ -35 ℃) for 4.0-24.0 hours, cooling to 0 ℃ -10.0 ℃ after the reaction is finished, performing suction filtration, drying and ethanol recrystallization to obtain 135.2g of m-methylbenzyl cyanoimidodithiocarbonate for later use, wherein the yield is as follows: 80 percent.
(2) Preparing S-m-methylbenzyl-N-cyano-N' -methylisothiourea.
The reaction formula is as follows:
dispersing 100g of m-methyldibenzyl cyanoimidodithiocarbonate in methanol, adding 32.0g of 30% methylamine water solution, reacting at 20-65 ℃ for 4.0-24.0 hours, cooling to 0-10.0 ℃ after the reaction is finished, performing suction filtration and drying to obtain 47.0g of S-m-methylbenzyl-N-cyano-N' -methylisothiourea, wherein the yield is as follows: 70 percent.
(3) To a reaction flask were added 50.0g of ethanol and 10.0g of 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride (CAS No. 38603-72-4), stirring was started, and 11.0g of 30% caustic soda was added to give a white suspension.
9.47g of S-m-methylbenzyl-N-cyano-N' -methylisothiourea is added to the white suspension, and the mixture is reacted at 60 to 70 ℃ for 20.0 to 24.0 hours.
After the reaction is finished, evaporating 60-80% of ethanol, adding water: 20.0g, cooling to 0-5 ℃, separating out solids, filtering, drying to obtain 6.25g of a product, and obtaining a 60.0% yield by HPLC (high performance liquid chromatography) pattern shown in figure 6.
(example 25)
The preparation process of this example is otherwise the same as that of example 24, except that:
in the compound of formula (I), R is benzyl; in the compound of formula (II), R is benzyl.
Step (1) preparing dibenzyl cyanoimidodithiocarbonate; the reaction with N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt is benzyl chloride or benzyl bromide.
And (3) reacting the product obtained in the step (2) with methylamine to obtain S-benzyl-N-cyano-N' -methylisothiourea.
In addition to the compounds of formula (ii) described in detail in examples 24 and 25, the R group in the compound of formula (ii) may be one of o-methylbenzyl, p-methylbenzyl, m-nitrobenzyl, o-nitrobenzyl, p-nitrobenzyl, m-chlorobenzyl, o-chlorobenzyl, p-chlorobenzyl, m-bromobenzyl, o-bromobenzyl, p-bromobenzyl, m-methoxybenzyl, o-methoxybenzyl, p-methoxybenzyl, dimethyl-substituted benzyl, dinitro-substituted benzyl, dichloro-substituted benzyl, dibromo-substituted benzyl, m-ethylbenzyl, o-ethylbenzyl, p-ethylbenzyl.
The preparation method comprises the following steps: on the basis of the compounds of the formula (I) already described in the preceding examples 1 to 23, the corresponding compounds of the formula (II) are obtained by reaction with methylamine separately and then with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride to give the desired product.
Claims (8)
1. The preparation method of cimetidine is characterized by comprising the following steps:
(1) the compound of formula (I) is prepared by the reaction of N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide
(2) reacting 2- (((4-methyl-1H-imidazole-5-yl) methyl) thio) ethylamine dihydrochloride with a compound shown in a formula (I) to prepare an intermediate compound;
(3) and (3) reacting the intermediate compound obtained in the step (2) with methylamine to obtain a target product.
2. The method for preparing cimetidine as set forth in claim 1, wherein:
in the step (1), the molar ratio of N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt to benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide is 1:1.8 to 3.0.
3. The method for preparing cimetidine according to claim 1, wherein:
in step (2), the molar ratio of 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride to the compound of formula (i) is 1:1.0 to 3.0.
4. The method for preparing cimetidine as set forth in claim 1, wherein: in the step (3), the molar ratio of the intermediate compound obtained in the step (2) to methylamine is 1:1.0 to 10.0.
5. The preparation method of cimetidine is characterized by comprising the following steps:
(1) the compound of formula (I) is prepared by the reaction of N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide
(2) reacting a compound shown in a formula (I) with methylamine to prepare a compound shown in a formula (II);
(3) and (3) reacting 2- (((4-methyl-1H-imidazole-5-yl) methyl) sulfenyl) ethylamine dihydrochloride with a compound shown in a formula (II) to obtain a target product.
6. The method for preparing cimetidine as set forth in claim 5, wherein:
in the step (1), the molar ratio of N-cyanoimino-S, S-dithio potassium salt or N-cyanoimino-S, S-dithio sodium salt to benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide is 1:1.8 to 3.0.
7. The method for preparing cimetidine as set forth in claim 5, wherein:
in step (2), the molar ratio of the compound of formula (i) to methylamine is 1:0.8 to 1.2.
8. The method for preparing cimetidine as set forth in claim 5, wherein:
in step (3), the molar ratio of 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride to the compound of formula (ii) is 1:1.0 to 3.0.
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