CN115960048B - A kind of preparation method of cimetidine - Google Patents
A kind of preparation method of cimetidine Download PDFInfo
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Abstract
本发明公开了一种甲氰咪胍的制备方法，使用式Ⅰ或者式Ⅱ化合物与2‑(((4‑甲基‑1H‑咪唑‑5‑基)甲基)硫基)乙胺二盐酸盐反应，反应后产生的是R‑SH，而不是恶臭的CH3SH。R‑SH是高沸点液体，不易挥发，没有甲硫醇的臭味；因此本发明的制备过程没有甲硫醇臭味溢出，反应体系不需要负压，同时降低了后处理时碱的用量，减少废水产生；本发明的制备方法降低能耗和污染，降低了生产成本，适宜工业化大生产。The invention discloses a method for preparing cimetidine. The method comprises reacting a compound of formula I or II with 2-(((4-methyl-1H-imidazole-5-yl)methyl)thio)ethylamine dihydrochloride, and generating R-SH instead of malodorous CH 3 SH after the reaction. R-SH is a high-boiling-point liquid, is not easily volatile, and has no odor of methyl mercaptan. Therefore, the preparation process of the invention does not have methyl mercaptan odor overflow, the reaction system does not require negative pressure, and the amount of alkali used in post-treatment is reduced, thereby reducing the generation of wastewater. The preparation method of the invention reduces energy consumption and pollution, reduces production costs, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of medicinal 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 acid inhibitor for relieving gastralgia, heartburn and acid regurgitation caused by gastric hyperacidity, and has the following chemical structural formula:
。
At present, the main domestic synthetic route is shown in figure 1, and 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride is used as a substrate for reaction to prepare cimetidine, and the specific process described in the literature is as follows:
The first step, 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride is taken as a substrate, ethanol is taken as a solvent, liquid alkali is added for dissociation, cyanoiminodithio-methyl carbonate is added for reaction, the reaction is carried out at 45 ℃, methyl mercaptan generated by absorption of tail gas by liquid alkali is reacted, the reaction is completed, the temperature is reduced, the suction filtration is carried out, and the N-cyano-N- [2- (5-methylimidazole-4-methylthio) ethyl ] -S-methyl isothiourea is obtained after drying.
And step two, the first step is carried out to N-cyano-N- [2- (5-methylimidazole-4-methylthio) ethyl ] -S-methylisothiourea, ethanol is added to introduce methylamine gas, reaction is carried out at 20-50 ℃, methyl mercaptan generated by absorption of tail gas by liquid alkali is carried out, reaction is finished, concentration is carried out, and N '-methyl-N' - [2[ [ (5-methyl-1H-imidazol-4-yl) methyl ] thio ] ethyl ] -N-cyanoguanidine is carried out, namely cimetidine.
The preparation method of the cimetidine has the following defects:
(1) In the production process, a large amount of gas methyl mercaptan is generated in the two steps of reaction, the whole reaction is carried out under negative pressure, waste gas is absorbed by liquid alkali, and the methyl mercaptan and sodium methyl mercaptan are both smelly and have serious environmental pollution.
(2) The process has high requirements on tail gas treatment equipment in order to avoid odor overflow, and the production cost is increased intangibly.
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 CN 112830896a (application No. 202110206841.8) discloses a process for the preparation of cimetidine, which comprises first nitrifying (5-methyl-1H-imidazol-4-yl) methanol to nitrate, and reacting the nitrate with an ether of N-cyano-N '-methyl-N "-mercaptoethylguanidine (i.e. 1,1' - (dithiodiylbis (ethane-2, 1-diyl)) bis (2-cyano-3-methylguanidine)) to obtain cimetidine. The method does not produce sulfide waste, especially volatile methyl mercaptan.
Also, for example, chinese patent document CN 113234018a (application No. 202110512430.1) discloses a method for preparing cimetidine without methyl mercaptan, which comprises reacting 2-chloroethanol with thiocyanate to obtain intermediate (I), reacting intermediate (I) with methylamine to obtain intermediate (II), oxidizing intermediate (II) with oxyacetic acid to obtain intermediate (III), condensing intermediate (III) with cyanamide to obtain Intermediate (IV), and condensing Intermediate (IV) with imidazole mercaptan (V) to obtain cimetidine.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of cimetidine, which is environment-friendly and is convenient for industrialized 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 Preparation of the Compounds of formula (I) by reaction of N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide
(I) The R group in the compound of the formula (I) is one of benzyl, m-methylbenzyl, 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 and p-ethylbenzyl.
② 2- (((4-Methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride is reacted with a compound of formula (I) to give an intermediate compound.
③ The intermediate compound obtained in the step ② reacts with methylamine to obtain the target product.
In the step ①, the molar ratio of the N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt to benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide is 1:1.8-3.0.
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 1:1.0-10.0.
The second technical scheme for realizing the aim of the invention is a preparation method of cimetidine, which comprises the following steps:
① Preparation of the Compounds of formula (I) by reaction of N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide
(I) The R group in the compound of the formula (I) is one of benzyl, m-methylbenzyl, 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 and p-ethylbenzyl.
② Reacting a compound of formula (I) with methylamine to obtain a compound of formula (II).
(II)
③ 2- (((4-Methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride is reacted with a compound of formula (II) to give the target product.
In the step ①, the molar ratio of the N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt to benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide is 1:1.8-3.0.
In the step ②, the molar ratio of the compound of formula (I) to methylamine is 1:0.8-1.2.
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:
In the invention, cyanoiminodithio dimethyl carbonate is not used as a reaction raw material, a compound shown in a formula I or a formula II is used for reacting with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride, and R-SH (R is benzyl or substituted benzyl) is generated after the reaction instead of malodorous CH 3 SH. R-SH is a high boiling point liquid, is not easy to volatilize, and has no odor of methyl mercaptan, so that the preparation process of the invention has no odor overflow of methyl mercaptan, 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 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 synthetic route diagram of the main process in China.
Fig. 2 is a first synthetic route diagram of the present invention.
FIG. 3 is a full view of the nuclear magnetic resonance H spectrum of the product obtained in example 1.
FIG. 4 is a side chain nuclear magnetic resonance H-spectrum of the product obtained in example 1.
FIG. 5 is an HPLC chart of the product obtained in example 1.
FIG. 6 is an HPLC plot of the product of the second route of example 24.
Detailed Description
Example 1
The synthesis route of cimetidine in this example is shown in fig. 2, and the preparation method comprises the following steps:
① The reaction formula for preparing the cyano iminodithiocarbonate m-methyl dibenzyl ester is as follows:
(I) R is m-methylbenzyl.
100.0G N-cyanoimino-S, S-dithiopotassium salt (CAS No.13145-41-0, purchased from BAUWER Biotechnology Co., ltd.) is dissolved in 300.0g of water, 145.0g of m-methylbenzyl chloride is added dropwise into the solution, the reaction is carried out at room temperature (15-35 ℃) for 20-24 hours, the temperature is reduced to 0-10 ℃ after the reaction is finished, and 122.84g of m-methyldibenzyl cyanoiminodithiocarbonate is obtained for standby after suction filtration, drying and ethanol recrystallization, wherein the yield is 80%.
② To the 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 turned on, and 12.0g of 30% liquid base was further added.
13.0G of m-methyl dibenzyl cyano iminodithiocarbonate is added into the solution and reacted for 1.0 to 24.0 hours at the temperature of 0 to 100 ℃.
After the reaction is finished, most (70% -80%) of ethanol is distilled off, 500.0g of water is added, the temperature is reduced to 0-5 ℃, an intermediate product is obtained through suction filtration, drying is not needed, and the material is directly fed downwards according to 100% yield.
③ The intermediate obtained in step ② was dispersed in 50.0g of ethanol, 13.0g of 30% aqueous methylamine was added and reacted at 50℃for 5.0-24.0 hours.
After the reaction is finished, 70% -80% of ethanol is distilled off, 20.0g of water is added, the temperature is reduced to 0 ℃ -5 ℃, solids are separated out, the product is obtained by suction filtration and drying, and the yield is 80.0% and the purity is 99.8772%.
The nuclear magnetic resonance H spectrum of the product prepared in the embodiment is shown in figure 3, the side chain nuclear magnetic resonance H spectrum is shown in figure 4, and the HPLC spectrum is shown in figure 5.
Example 2
The synthesis route of cimetidine in this example is shown in fig. 2, and the preparation method comprises the following steps:
① The preparation of dibenzyl cyanoiminodithiocarbonate has the following reaction formula:
(I) R is benzyl.
100.0G N-cyanoimino-S, S-dithiopotassium salt (CAS No.13145-41-0, purchased from Biotechnology Co., ltd.) is dissolved in 300.0g of water, 145.0g of benzyl chloride is added dropwise to the solution, the reaction is carried out at room temperature (15-35 ℃) for 20-24 hours, the temperature is reduced to 0-10 ℃ after the reaction is finished, and 107.48g of cyanoborodithio-dibenzyl carbonate is obtained for standby use after suction filtration, drying and ethanol recrystallization, wherein the yield is 70%.
② To the 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 turned on, and 11.0g of 30% liquid base was further added to obtain a white suspension.
To the white suspension, 12.3g of dibenzyl cyanoiminodithiocarbonate was added and reacted at 0℃to 100℃for 1.0 to 24.0 hours.
After the reaction is finished, most of ethanol is distilled off, 500.0g of water is added, the temperature is reduced to 0-5 ℃, the intermediate product is obtained through suction filtration, drying is not needed, and the material is directly fed downwards according to 100 percent of yield.
③ The intermediate obtained in step ② was dispersed in 30.0g of ethanol, 10.6g of 30% aqueous methylamine solution was added and reacted at 50℃for 5.0-24.0 hours.
After the reaction is finished, 70% -80% of ethanol is distilled off, 20.0g of water is added, the temperature is reduced to 0 ℃ -5 ℃, solid is separated out, the solid is filtered out in a pumping way, and the product is obtained by drying, and the yield is 70.0%.
Example 3
The preparation method of this example is otherwise the same as that of example 2, except that:
In step ①, benzyl bromide is reacted with N-cyanoimino-S, S-dithiopotassium salt to afford dibenzyl cyanoiminodithiocarbonate.
Specifically, 100.0g N-cyanoimino-S, S-dithiopotassium salt is dissolved in 300.0g of water, 176.0g of benzyl bromide is added dropwise into the solution, the reaction is carried out for 4.0 to 24.0 hours at room temperature, the temperature is reduced to 0 to 10 ℃ after the reaction is finished, and 117.0g of cyano iminodithio dibenzyl carbonate is obtained for standby after suction filtration, drying and ethanol recrystallization, wherein the yield is 77%.
Example 4
The preparation method of this example is otherwise the same as that of example 2, except that:
In step ①, N-cyanoimino-S, S-dithiosodium salt (available from BAUGAR Biotechnology Co., ltd.) is reacted with benzyl bromide to give dibenzyl cyanoiminodithiocarbonate.
Specifically, 100.0g N-cyanoimino-S, S-dithiosodium salt is dissolved in 600.0g of water, 212.0g of benzyl bromide is added dropwise into the solution, the reaction is carried out for 4.0 to 24.0 hours at room temperature, the temperature is reduced to 0 to 10 ℃ after the reaction is finished, and 132.3g of cyano iminodithiodibenzyl carbonate is obtained for standby use after suction filtration, drying and ethanol recrystallization, wherein the yield is 72%.
Example 5
The preparation method of this example is otherwise the same as that of example 2, except that:
In step ①, N-cyanoimino-S, S-dithiosodium salt (available from BAUGAR Biotechnology Co., ltd.) is reacted with benzyl chloride to give dibenzyl cyanoiminodithiocarbonate.
Specifically, 100.0g N-cyanoimino-S, S-dithiosodium salt is dissolved in 600.0g of water, 164.72g of benzyl chloride is added dropwise into the solution, the reaction is carried out for 2.0-24.0 hours at room temperature, the temperature is reduced to 0-10.0 ℃ after the reaction is finished, 138.0g of cyano iminodithiodibenzyl carbonate is obtained for standby after suction filtration, drying and ethanol recrystallization, and the yield is 75%.
Example 6
The preparation method of cimetidine of this example is 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 step ①, o-methylbenzyl chloride is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, and the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to o-methylbenzyl chloride is 1:2.3.
To the white suspension in step ② was added cyano iminodithiocarbonate o-methyl dibenzyl.
Reacted with methylamine in step ③ is the corresponding intermediate obtained in step ②.
Example 7
The preparation method of cimetidine of this example is 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-methylbenzyl.
In step ①, p-methylbenzyl chloride is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, and the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to p-methylbenzyl chloride is 1:2.2.
To the white suspension in step ② was added p-methyldibenzyl cyanoiminodithiocarbonate.
Reacted with methylamine in step ③ is the corresponding intermediate obtained in step ②.
Example 8
The preparation method of cimetidine of this example is 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 m-nitrobenzyl.
In step ①, m-nitrobenzyl chloride is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, wherein the molar ratio of the N-cyanoimino-S, S-dithiopotassium salt/sodium salt to the m-nitrobenzyl chloride is 1:2.5.
To the white suspension in step ② was added m-nitro dibenzyl cyanoiminodithiocarbonate.
Reacted with methylamine in step ③ is the corresponding intermediate obtained in step ②.
Example 9
The preparation method of cimetidine of this example is 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-nitrobenzyl.
In step ①, o-nitrobenzyl chloride is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, wherein the molar ratio of the N-cyanoimino-S, S-dithiopotassium salt/sodium salt to the o-nitrobenzyl chloride is 1:3.0.
To the white suspension in step ② was added the cyano iminodithiocarbonate ortho-nitro dibenzyl ester.
Reacted with methylamine in step ③ is the corresponding intermediate obtained in step ②.
Example 10
The preparation method of cimetidine of this example is 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 step ①, p-nitrobenzyl chloride was reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to p-nitrobenzyl chloride being 1:2.7.
To the white suspension in step ② was added p-nitro dibenzyl cyanoiminodithiocarbonate.
Example 11
The preparation method of cimetidine of this example is 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 m-chlorobenzyl.
In step ①, m-dichlorobenzyl is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, and the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to m-dichlorobenzyl is 1:2.3.
To the white suspension in step ② was added m-chlorodibenzyl cyanoiminodithiocarbonate.
Example 12
The preparation method of cimetidine of this example is 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-chlorobenzyl.
In step ①, o-dichlorobenzyl is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, wherein the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to o-dichlorobenzyl is 1:2.4.
To the white suspension in step ② was added the cyanobiminodithiocarbonate o-chlorobenzyl ester.
Example 13
The preparation method of cimetidine of this example is 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 step ①, p-dichlorobenzyl is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, and the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to p-dichlorobenzyl is 1:2.4.
To the white suspension in step ② was added p-chlorodibenzyl cyanoiminodithiocarbonate.
Example 14
The preparation method of cimetidine of this example is 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 m-bromobenzyl.
In step ①, m-bromochlorobenzyl is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, wherein the molar ratio of the N-cyanoimino-S, S-dithiopotassium salt/sodium salt to the m-bromochlorobenzyl is 1:2.3.
To the white suspension in step ② was added m-bromodibenzyl cyanoiminodithiocarbonate.
Example 15
The preparation method of cimetidine of this example is 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 step ①, o-bromochlorobenzyl is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, wherein the molar ratio of the N-cyanoimino-S, S-dithiopotassium salt/sodium salt to the o-bromochlorobenzyl is 1:2.3.
To the white suspension in step ② was added the cyanoborodithiocarbonate o-bromodibenzyl ester.
Example 16
The preparation method of cimetidine of this example is 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 step ①, p-bromochlorobenzyl is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, wherein the molar ratio of the N-cyanoimino-S, S-dithiopotassium salt/sodium salt to the p-bromochlorobenzyl is 1:2.1.
To the white suspension in step ② was added p-bromodibenzyl cyanoiminodithiocarbonate.
Example 17
The preparation method of cimetidine of this example is 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 m-methoxybenzyl.
In step ①, m-methoxybenzyl chloride is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, and the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to m-methoxybenzyl chloride is 1:2.2.
To the white suspension in step ② was added m-methoxydibenzyl cyanoiminodithiocarbonate.
Reacted with methylamine in step ③ is the corresponding intermediate obtained in step ②.
Example 18
The preparation method of cimetidine of this example is 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-methoxybenzyl.
In step ①, o-methoxybenzyl chloride is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, and the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to o-methoxybenzyl chloride is 1:2.2.
To the white suspension in step ② was added cyano iminodithiocarbonate o-methoxydibenzyl.
Reacted with methylamine in step ③ is the corresponding intermediate obtained in step ②.
Example 19
The preparation method of cimetidine of this example is 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-methoxybenzyl.
In step ①, p-methoxybenzyl chloride is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, and the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to p-methoxybenzyl chloride is 1:2.2.
To the white suspension in step ② was added p-methoxydibenzyl cyanoiminodithiocarbonate.
Example 20
The preparation method of cimetidine of this example is 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 m-ethylbenzyl.
In step ①, m-ethylbenzyl chloride is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, and the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to m-ethylbenzyl chloride is 1:2.0.
To the white suspension in step ② was added m-ethyldibenzyl cyanoiminodithiocarbonate.
Reacted with methylamine in step ③ is the corresponding intermediate obtained in step ②.
Example 21
The preparation method of cimetidine of this example is 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 step ①, o-ethylbenzyl chloride is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, and the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to o-ethylbenzyl chloride is 1:2.1.
To the white suspension in step ② was added cyano iminodithiocarbonate o-ethyldibenzyl.
Reacted with methylamine in step ③ is the corresponding intermediate obtained in step ②.
Example 23
The preparation method of cimetidine of this example is 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-ethylbenzyl.
In step ①, p-ethylbenzyl chloride is reacted with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt, and the molar ratio of N-cyanoimino-S, S-dithiopotassium salt/sodium salt to p-ethylbenzyl chloride is 1:2.0.
To the white suspension in step ② was added p-ethyldibenzyl cyanoiminodithiocarbonate.
Reacted with methylamine in step ③ is the corresponding intermediate obtained in step ②.
Example 24
The reaction scheme of cimetidine of this example is as follows,
A compound of formula (II)Wherein R is m-methylbenzyl.
The preparation method comprises the following steps:
① The reaction formula for preparing the cyano iminodithiocarbonate m-methyl dibenzyl ester is as follows:
(I) R is m-methylbenzyl.
100.0G N-cyanoiminoS, S-dithiopotassium salt (CAS No.13145-41-0, purchased from the Biotechnology Co., ltd.) is dissolved in 300.0g of water, 145.0g of m-methylbenzyl chloride is added dropwise into the solution, the reaction is carried out for 4.0-24.0 hours at room temperature (15-35 ℃), the temperature is reduced to 0-10.0 ℃ after the reaction is finished, and 135.2g of m-methyldibenzyl cyanoiminodithiocarbonate is obtained for standby after suction filtration, drying and ethanol recrystallization, wherein the yield is 80%.
② Preparing S-m-methylbenzyl-N-cyano-N' -methyl isothiourea.
The reaction formula is as follows:
(II)。
100g of cyano iminodithiocarbonate m-methyl dibenzyl ester is dispersed in methanol, 32.0g of 30% aqueous solution of methylamine is added, the reaction is carried out for 4.0 to 24.0 hours at 20 to 65 ℃, the temperature is reduced to 0 to 10.0 ℃ after the reaction is finished, 47.0g of S-m-methylbenzyl-N-cyano-N' -methyl isothiourea is obtained through suction filtration and drying, and the yield is 70%.
③ To the 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 turned on, and 11.0g of 30% liquid base was further added to obtain a white suspension.
9.47G S-m-methylbenzyl-N-cyano-N' -methyl isothiourea is added into the white suspension liquid, and the mixture is reacted for 20.0 to 24.0 hours at the temperature of 60 to 70 ℃.
After the reaction is finished, 60-80% of ethanol is distilled off, 20.0g of water is added, the temperature is reduced to 0-5 ℃, solid is separated out, the solid is filtered and dried, 6.25g of product is obtained, the HPLC diagram is shown in figure 6, and the yield is 60.0%.
Example 25
The preparation method of this example was the same as in example 24 except that:
In the compound of the formula (I), R is benzyl, and in the compound of the formula (II), R is benzyl.
Step ① preparation of dibenzyl cyanoiminodithiocarbonate reacting with N-cyanoimino-S, S-dithiopotassium salt or N-cyanoimino-S, S-dithiosodium salt is benzyl chloride or benzyl bromide.
Step ② is reacted with methylamine to give S-benzyl-N-cyano-N' -methyl isothiourea.
In addition to the compound of formula (II) described in detail in example 24, example 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 is that on the basis of the compound of the formula (I) which is already described in the previous examples 1 to 23, the corresponding compound of the formula (II) is firstly obtained by respectively reacting with methylamine, and then the target product is obtained by reacting with 2- (((4-methyl-1H-imidazol-5-yl) methyl) thio) ethylamine dihydrochloride.
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