A kind of preparation method of cimetidine

Abstract

The invention discloses a method for preparing cimetidine. The compound of formula I or formula II is reacted with 2-(((4-methyl-1H-imidazole-5-yl)methyl)thio)ethylamine dihydrochloride. R-SH is produced after the reaction instead of CH3SH with a foul odor. 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

[0001] The invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing cimetidine. Background Art

[0002] Cimetidine (N'-methyl-N"-[2[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]-N-cyanoguanidine, cimetidine) is an important acid-suppressing drug used to relieve stomach pain, heartburn, and acid reflux caused by excessive gastric acid. CAS NO: 51486-61-9, chemical structure is as follows:

[0003] .

[0004] The main synthetic routes in China are Figure 1 , 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride is used as a substrate to react and prepare cimetidine. The specific process described in the literature is as follows:

[0005] The first step: using 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride as a substrate, ethanol as a solvent, adding liquid alkali to free it, adding dimethyl cyanoimidodithiocarbonate to react, reacting at 45 degrees, using liquid alkali to absorb the generated methyl mercaptan in the tail gas, after the reaction is completed, cooling, filtering, and drying to obtain N-cyano-N-[2-(5-methylimidazole-4-methylthio)ethyl]-S-methylisothiourea.

[0006] The second step: take the first step and add ethanol to N-cyano-N-[2-(5-methylimidazole-4-methylthio)ethyl]-S-methylisothiourea, pass methylamine gas, react at 20-50 degrees, absorb the generated methyl mercaptan with liquid alkali in the tail gas, and after the reaction is completed, concentrate to obtain N'-methyl-N"-[2[[(5-methyl-1H-imidazole-4-yl)methyl]thio]ethyl]-N-cyanoguanidine, namely cimetidine.

[0007] The preparation method of above-mentioned cimetidine has the following disadvantages:

[0008] (1) During the production process, both steps of the reaction produce a large amount of methyl mercaptan gas. The entire reaction must be carried out under negative pressure, and liquid alkali must be used to absorb the waste gas. Both methyl mercaptan and sodium methyl mercaptan are very smelly, causing serious environmental pollution.

[0009] (2) In order to avoid odor overflow, the above process has too high requirements on the exhaust gas treatment equipment, which invisibly increases the production cost.

[0010] In order to solve the problem of methyl mercaptan, some processes change the synthesis route to avoid the production of methyl mercaptan.

[0011] For example, Chinese patent document CN 112830896A (application number 202110206841.8) discloses a method for preparing cimetidine, wherein (5-methyl-1H-imidazol-4-yl)methanol is first converted into a nitrate ester by nitration, and the nitrate ester is reacted with the ether of N-cyano-N'-methyl-N"-mercaptoethylguanidine (i.e., 1,1'-(disulfadiylbis(ethane-2,1-diyl))bis(2-cyano-3-methylguanidine)) to obtain cimetidine. This method does not produce sulfide waste, especially volatile methyl mercaptan.

[0012] For example, Chinese patent document CN 113234018A (application number 202110512430.1) also discloses a method for preparing cimetidine without producing methyl mercaptan, wherein 2-chloroethanol is first reacted with thiocyanate to obtain an intermediate (I); the intermediate (I) is reacted with methylamine to obtain an intermediate (II); the intermediate (II) is oxidized with oxyacetic acid to obtain an intermediate (III); the intermediate (III) is condensed with cyanamide to obtain an intermediate (IV); and the intermediate (IV) is condensed with imidazolethiol (V) to obtain cimetidine. Summary of the invention

[0013] The technical problem to be solved by the present invention is to provide a method for preparing cimetidine which is environmentally friendly and convenient for industrial mass production.

[0014] The first technical solution for achieving the purpose of the present invention is a method for preparing cimetidine, comprising the following steps:

[0015] ① React N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide to prepare a compound of formula (I)

[0016] (I), in the compound of formula (I), the R group 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.

[0017] ② 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride is reacted with the compound of formula (I) to obtain an intermediate compound.

[0018] ③ The intermediate compound obtained in step ② reacts with methylamine to obtain the target product.

[0019] In the above step ①, the molar ratio of N-cyanimino-S,S-disulfide potassium salt or N-cyanimino-S,S-disulfide sodium salt to benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide is 1:1.8-3.0.

[0020] In the above step ②, the molar ratio of 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride to the compound of formula (I) is 1:1.0-3.0.

[0021] In the above step ③, the molar ratio of the intermediate compound obtained in step ② to methylamine is 1:1.0-10.0.

[0022] A second technical solution for achieving the purpose of the present invention is a method for preparing cimetidine, comprising the following steps:

[0023] ① React N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide to prepare a compound of formula (I)

[0024] (I), in the compound of formula (I), the R group 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.

[0025] ② The compound of formula (I) is reacted with methylamine to obtain the compound of formula (II).

[0026] (II)

[0027] ③ 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride reacts with the compound of formula (II) to obtain the target product.

[0028] In the above step ①, the molar ratio of N-cyanimino-S,S-disulfide potassium salt or N-cyanimino-S,S-disulfide sodium salt to benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide is 1:1.8-3.0.

[0029] In the above step ②, the molar ratio of the compound of formula (I) to methylamine is 1:0.8-1.2.

[0030] In the above step ③, the molar ratio of 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride to the compound of formula (II) is 1:1.0-3.0.

[0031] The present invention has positive effects:

[0032] The present invention does not use dimethyl cyanoimido dithiocarbonate as a reaction raw material, but uses a compound of formula I or II to react with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, and produces R-SH (R is benzyl or substituted benzyl) instead of malodorous CH3SH after the reaction. R-SH is a high-boiling liquid, is not easily volatile, and has no odor of methyl mercaptan; therefore, the preparation process of the present invention does not have methyl mercaptan odor overflow, the reaction system does not require negative pressure, and at the same time reduces the amount of alkali used in post-treatment, reducing the generation of wastewater.

[0033] The invention provides a synthesis route without generating methyl mercaptan. The preparation method of the invention reduces energy consumption and pollution, reduces production cost, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is the synthesis route map of the main domestic processes.

[0035] Figure 2 This is the first synthesis route of the present invention.

[0036] Figure 3 This is the full H NMR spectrum of the product obtained in Example 1.

[0037] Figure 4 The side chain nuclear magnetic resonance H spectrum of the product obtained in Example 1.

[0038] Figure 5 The HPLC spectrum of the product obtained in Example 1.

[0039] Figure 6 This is the HPLC spectrum of the product obtained by the second route of Example 24. DETAILED DESCRIPTION

[0040] (Example 1)

[0041] The synthetic route of cimetidine in this embodiment is shown in Figure 2 , the preparation method comprises the following steps:

[0042] ① Preparation of m-methyl dibenzyl cyanoimidodithiocarbonate, the reaction formula is as follows:

[0043] (I), R is m-methylbenzyl.

[0044] 100.0 g of N-cyanoimido-S, S-dithio potassium salt (CAS NO.13145-41-0, purchased from Changzhou Biowe Biotechnology Co., Ltd.) was dissolved in 300.0 g of water, 145.0 g of m-methylbenzyl chloride was added dropwise to the solution, and the mixture was reacted at room temperature (15°C-35°C) for 20-24 hours. After the reaction was completed, the mixture was cooled to 0-10°C, filtered, dried, and recrystallized from ethanol to obtain 122.84 g of m-methylbenzyl cyanoimidodithiocarbonate for standby use, with a yield of 80%.

[0045] ② Add 50.0g of ethanol and 10.0g of 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride (CAS NO.38603-72-4) into the reaction bottle, start stirring, and then add 12.0g of 30% liquid alkali.

[0046] 13.0 g of m-methyl dibenzyl cyanimidodithiocarbonate was added to the above solution, and the mixture was reacted at 0°C to 100°C for 1.0 to 24.0 hours.

[0047] After the reaction is completed, most (70%-80%) of the ethanol is evaporated, 500.0 g of water is added, the temperature is lowered to 0°C-5°C, and the intermediate product is obtained by suction filtration. There is no need to dry it, and it can be directly fed to the next step at a yield of 100%.

[0048] ③ The intermediate product obtained in step ② was dispersed in 50.0 g of ethanol, 13.0 g of 30% methylamine aqueous solution was added, and the mixture was reacted at 50° C. for 5.0-24.0 hours.

[0049] After the reaction is completed, 70% to 80% of ethanol is evaporated, 20.0 g of water is added, and the temperature is lowered to 0°C to 5°C. Solids are precipitated, filtered, and dried to obtain 8.34 g of product with a yield of 80.0% and a purity of 99.8772%.

[0050] The H NMR spectrum of the product obtained in this example is shown in Figure 3 , side chain NMR H spectrum see Figure 4 , HPLC spectrum see Figure 5 .

[0051] (Example 2)

[0052] The synthetic route of cimetidine in this embodiment is shown in Figure 2 , the preparation method comprises the following steps:

[0053] ① Preparation of dibenzyl cyanimidodithiocarbonate, the reaction formula is as follows:

[0054] (I), R is benzyl.

[0055] 100.0 g of N-cyano-S, S-dithio potassium salt (CAS NO.13145-41-0, purchased from Changzhou Bioway Biotechnology Co., Ltd.) was dissolved in 300.0 g of water, 145.0 g of benzyl chloride was added dropwise to the solution, and the mixture was reacted at room temperature (15°C-35°C) for 20-24 hours. After the reaction was completed, the temperature was lowered to 0-10°C, and 107.48 g of dibenzyl cyano-imido-dithiocarbonate was obtained after suction filtration, drying, and ethanol recrystallization for standby use, with a yield of 70%.

[0056] ② Add 50.0g of ethanol and 10.0g of 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride (CAS NO.38603-72-4) into the reaction bottle, start stirring, and then add 11.0g of 30% liquid alkali to obtain a white suspension.

[0057] To the above white suspension, add 12.3 g of dibenzyl cyanimidodithiocarbonate, and react at 0°C to 100°C for 1.0 to 24.0 hours.

[0058] After the reaction is completed, most of the ethanol is evaporated, 500.0 g of water is added, the temperature is lowered to 0°C-5°C, and the intermediate product is obtained by suction filtration. There is no need to dry it, and it can be directly fed to the next step at a yield of 100%.

[0059] ③ The intermediate product obtained in step ② was dispersed in 30.0 g of ethanol, 10.6 g of 30% methylamine aqueous solution was added, and the mixture was reacted at 50° C. for 5.0-24.0 hours.

[0060] After the reaction was completed, 70% to 80% of the ethanol was evaporated, 20.0 g of water was added, and the temperature was lowered to 0°C to 5°C. Solids precipitated, which were filtered and dried to obtain 7.3 g of the product with a yield of 70.0%.

[0061] (Example 3)

[0062] The preparation method of this embodiment is the same as that of embodiment 2 except that:

[0063] In step ①, benzyl bromide is reacted with N-cyanoimido-S,S-dithio potassium salt to obtain dibenzyl cyanoimidodithiocarbonate.

[0064] Specifically, 100.0 g of N-cyano-S, S-dithio potassium salt was dissolved in 300.0 g of water, 176.0 g of benzyl bromide was added dropwise to the solution, and the reaction was carried out at room temperature for 4.0 to 24.0 hours. After the reaction was completed, the temperature was lowered to 0° C. to 10° C., and 117.0 g of cyano-imido-dithiocarbonate was obtained after suction filtration, drying, and ethanol recrystallization for standby use, with a yield of 77%.

[0065] (Example 4)

[0066] The preparation method of this embodiment is the same as that of embodiment 2 except that:

[0067] In step ①, N-cyanoimido-S, S-dithiosodium salt (purchased from Changzhou Biowe Biotechnology Co., Ltd.) is reacted with benzyl bromide to obtain dibenzyl cyanoimidodithiocarbonate.

[0068] Specifically, 100.0 g of N-cyano-S, S-dithiosodium salt was dissolved in 600.0 g of water, 212.0 g of benzyl bromide was added dropwise to the solution, and the reaction was carried out at room temperature for 4.0 to 24.0 hours. After the reaction was completed, the temperature was lowered to 0° C. to 10° C., and 132.3 g of dibenzyl cyano-imido-dithiocarbonate was obtained after suction filtration, drying, and ethanol recrystallization for standby use, with a yield of 72%.

[0069] (Example 5)

[0070] The preparation method of this embodiment is the same as that of embodiment 2 except that:

[0071] In step ①, N-cyanoimido-S, S-dithiosodium salt (purchased from Changzhou Biowe Biotechnology Co., Ltd.) is reacted with benzyl chloride to obtain dibenzyl cyanoimidodithiocarbonate.

[0072] Specifically, 100.0 g of N-cyano-S, S-dithiosodium salt was dissolved in 600.0 g of water, 164.72 g of benzyl chloride was added dropwise to the solution, and the reaction was carried out at room temperature for 2.0 to 24.0 hours. After the reaction was completed, the temperature was lowered to 0° C. to 10.0° C., and 138.0 g of dibenzyl cyano-imido-dithiocarbonate was obtained after suction filtration, drying, and ethanol recrystallization for standby use, with a yield of 75%.

[0073] (Example 6)

[0074] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0075] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is o-methylbenzyl.

[0076] In step ①, what reacts with N-cyanimino-S, S-disulfide potassium salt or N-cyanimino-S, S-disulfide sodium salt is o-methylbenzyl chloride; the molar ratio of N-cyanimino-S, S-disulfide potassium salt / sodium salt to o-methylbenzyl chloride is 1:2.3.

[0077] In step ②, o-methyldibenzyl cyanimidodithiocarbonate is added to the white suspension.

[0078] The product that reacts with methylamine in step ③ is the corresponding intermediate product obtained in step ②.

[0079] (Example 7)

[0080] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0081] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is p-methylbenzyl.

[0082] In step ①, the substance reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt is p-methylbenzyl chloride; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to p-methylbenzyl chloride is 1:2.2.

[0083] In step ②, what is added to the white suspension is methyl dibenzyl cyanimidodithiocarbonate.

[0084] The product that reacts with methylamine in step ③ is the corresponding intermediate product obtained in step ②.

[0085] (Example 8)

[0086] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0087] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is m-nitrobenzyl.

[0088] In step ①, what reacts with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt is m-nitrobenzyl chloride; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to m-nitrobenzyl chloride is 1:2.5.

[0089] In step ②, what is added to the white suspension is m-nitrodibenzyl cyanimidodithiocarbonate.

[0090] The product that reacts with methylamine in step ③ is the corresponding intermediate product obtained in step ②.

[0091] (Example 9)

[0092] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0093] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is o-nitrobenzyl.

[0094] In step ①, o-nitrobenzyl chloride is reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to o-nitrobenzyl chloride is 1:3.0.

[0095] In step ②, o-nitrobenzyl cyanimidodithiocarbonate is added to the white suspension.

[0096] The product that reacts with methylamine in step ③ is the corresponding intermediate product obtained in step ②.

[0097] (Example 10)

[0098] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0099] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is p-nitrobenzyl.

[0100] In step ①, p-nitrobenzyl chloride is reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to p-nitrobenzyl chloride is 1:2.7.

[0101] In step ②, what is added to the white suspension is p-nitrodibenzyl cyanimidodithiocarbonate.

[0102] (Example 11)

[0103] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0104] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is m-chlorobenzyl.

[0105] In step ①, the substance reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt is m-dichlorobenzyl; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to m-dichlorobenzyl is 1:2.3.

[0106] In step ②, what is added to the white suspension is m-chlorodibenzyl cyanimidodithiocarbonate.

[0107] (Example 12)

[0108] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0109] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is o-chlorobenzyl.

[0110] In step ①, what reacts with N-cyanimino-S, S-disulfide potassium salt or N-cyanimino-S, S-disulfide sodium salt is o-dichlorobenzyl; the molar ratio of N-cyanimino-S, S-disulfide potassium salt / sodium salt to o-dichlorobenzyl is 1:2.4.

[0111] In step ②, o-chlorodibenzyl cyanimidodithiocarbonate is added to the white suspension.

[0112] (Example 13)

[0113] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0114] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is p-chlorobenzyl.

[0115] In step ①, the substance reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt is p-dichlorobenzyl; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to p-dichlorobenzyl is 1:2.4.

[0116] In step ②, what is added to the white suspension is 4-chlorodibenzyl cyanimidodithiocarbonate.

[0117] (Example 14)

[0118] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0119] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is m-bromobenzyl.

[0120] In step ①, the substance reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt is meta-bromobenzyl chloride; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to meta-bromobenzyl chloride is 1:2.3.

[0121] In step ②, what is added to the white suspension is m-bromobenzyl cyanimidodithiocarbonate.

[0122] (Example 15)

[0123] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0124] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is o-bromobenzyl.

[0125] In step ①, the compound reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt is o-bromobenzyl chloride; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to o-bromobenzyl chloride is 1:2.3.

[0126] In step ②, o-bromobenzyl cyanimidodithiocarbonate is added to the white suspension.

[0127] (Example 16)

[0128] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0129] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is p-bromobenzyl.

[0130] In step ①, the substance reacted with N-cyanimino-S, S-disulfide potassium salt or N-cyanimino-S, S-disulfide sodium salt is p-bromobenzyl chloride; the molar ratio of N-cyanimino-S, S-disulfide potassium salt / sodium salt to p-bromobenzyl chloride is 1:2.1.

[0131] In step ②, p-bromobenzyl cyanimidodithiocarbonate is added to the white suspension.

[0132] (Example 17)

[0133] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0134] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is m-methoxybenzyl.

[0135] In step ①, the compound reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt is m-methoxybenzyl chloride; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to m-methoxybenzyl chloride is 1:2.2.

[0136] In step ②, what is added to the white suspension is m-methoxydibenzyl cyanimidodithiocarbonate.

[0137] The product that reacts with methylamine in step ③ is the corresponding intermediate product obtained in step ②.

[0138] (Example 18)

[0139] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0140] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is o-methoxybenzyl.

[0141] In step ①, o-methoxybenzyl chloride is reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to o-methoxybenzyl chloride is 1:2.2.

[0142] In step ②, o-methoxydibenzyl cyanimidodithiocarbonate is added to the white suspension.

[0143] The product that reacts with methylamine in step ③ is the corresponding intermediate product obtained in step ②.

[0144] (Example 19)

[0145] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0146] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is p-methoxybenzyl.

[0147] In step ①, p-methoxybenzyl chloride is reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to p-methoxybenzyl chloride is 1:2.2.

[0148] In step ②, p-methoxydibenzyl cyanoimidodithiocarbonate is added to the white suspension.

[0149] (Example 20)

[0150] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0151] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is m-ethylbenzyl.

[0152] In step ①, what reacts with N-cyanimino-S, S-disulfide potassium salt or N-cyanimino-S, S-disulfide sodium salt is m-ethylbenzyl chloride; the molar ratio of N-cyanimino-S, S-disulfide potassium salt / sodium salt to m-ethylbenzyl chloride is 1:2.0.

[0153] In step ②, what is added to the white suspension is m-ethyl dibenzyl cyanimidodithiocarbonate.

[0154] The product that reacts with methylamine in step ③ is the corresponding intermediate product obtained in step ②.

[0155] (Example 21)

[0156] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0157] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is o-ethylbenzyl.

[0158] In step ①, o-ethylbenzyl chloride is reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to o-ethylbenzyl chloride is 1:2.1.

[0159] In step ②, o-ethyl dibenzyl cyanimidodithiocarbonate is added to the white suspension.

[0160] The product that reacts with methylamine in step ③ is the corresponding intermediate product obtained in step ②.

[0161] (Example 23)

[0162] The preparation method of cimetidine in this embodiment is the same as that in Example 1, except that:

[0163] In the compound of formula I reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride, R is p-ethylbenzyl.

[0164] In step ①, the substance reacted with N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt is p-ethylbenzyl chloride; the molar ratio of N-cyano-S, S-disulfide potassium salt / sodium salt to p-ethylbenzyl chloride is 1:2.0.

[0165] In step ②, what is added to the white suspension is ethyl dibenzyl cyanimidodithiocarbonate.

[0166] The product that reacts with methylamine in step ③ is the corresponding intermediate product obtained in step ②.

[0167] (Example 24)

[0168] The reaction formula of cimetidine of the present embodiment is as follows,

[0169] , a compound of formula (II) In the above formula (A), R is m-methylbenzyl.

[0170] The preparation method comprises the following steps:

[0171] ① Preparation of m-methyl dibenzyl cyanoimidodithiocarbonate, the reaction formula is as follows:

[0172] (I), R is m-methylbenzyl.

[0173] 100.0 g of N-cyanoimido-S, S-dithio potassium salt (CAS NO.13145-41-0, purchased from Changzhou Biowe Biotechnology Co., Ltd.) was dissolved in 300.0 g of water, 145.0 g of m-methylbenzyl chloride was added dropwise to the solution, and the mixture was reacted at room temperature (15°C to 35°C) for 4.0 to 24.0 hours. After the reaction was completed, the temperature was lowered to 0°C to 10.0°C, and 135.2 g of m-methyldibenzyl cyanoimidodithiocarbonate was obtained after suction filtration, drying, and ethanol recrystallization for standby use, with a yield of 80%.

[0174] ② Preparation of S-m-methylbenzyl-N-cyano-N'-methylisothiourea.

[0175] The reaction formula is as follows:

[0176] (II).

[0177] Disperse 100 g of m-methyl dibenzyl cyanimidodithiocarbonate in methanol, add 32.0 g of 30% aqueous methylamine solution, react at 20°C to 65°C for 4.0 to 24.0 hours, cool to 0°C to 10.0°C after the reaction, filter and dry to obtain 47.0 g of S-m-methylbenzyl-N-cyano-N'-methylisothiourea, with a yield of 70%.

[0178] ③ Add 50.0 g of ethanol and 10.0 g of 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride (CAS NO.38603-72-4) into the reaction bottle, start stirring, and then add 11.0 g of 30% liquid alkali to obtain a white suspension.

[0179] 9.47 g of S-m-methylbenzyl-N-cyano-N'-methylisothiourea was added to the above white suspension, and the mixture was reacted at 60°C to 70°C for 20.0 to 24.0 hours.

[0180] After the reaction is completed, 60% to 80% of ethanol is evaporated, 20.0 g of water is added, and the temperature is lowered to 0°C to 5°C. Solids are precipitated, filtered, and dried to obtain 6.25 g of product. The HPLC spectrum is shown in Figure 6 , yield 60.0%.

[0181] (Example 25)

[0182] The rest of the preparation method of this embodiment is the same as that of Example 24, except that:

[0183] In the compound of formula (I), R is benzyl; in the compound of formula (II), R is benzyl.

[0184] Step ① prepares dibenzyl cyanimidodithiocarbonate; benzyl chloride or benzyl bromide is reacted with N-cyanimido-S, S-dithio potassium salt or N-cyanimido-S, S-dithio sodium salt.

[0185] In step ②, after reaction with methylamine, S-benzyl-N-cyano-N'-methylisothiourea is obtained.

[0186] In addition to the compounds of formula (II) described in detail in Example 24 and Example 25, the R group in the compound of formula (II) can also 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, and p-ethylbenzyl.

[0187] The preparation method is as follows: based on the compounds of formula (I) already described in the above-mentioned Examples 1 to 23, they are first reacted with methylamine to obtain the corresponding compounds of formula (II), and then reacted with 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride to obtain the target product.

Claims

1. A method for preparing cimetidine, characterized in that The following steps are involved: ① N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt reacts with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide to prepare a compound of formula (I) (I), in the compound of formula (I), the R group 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 reacts with the compound of formula (I) to obtain an intermediate compound; ③ The intermediate compound obtained in step ② reacts with methylamine to obtain the target product.

2. The method for preparing cimetidine according to claim 1, wherein: In step ①, the molar ratio of N-cyanimino-S, S-disulfide potassium salt or N-cyanimino-S, S-disulfide sodium salt to benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide is 1:1.8-3.

0.

3. The preparation method of cimetidine according to claim 1, characterized in that: 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 1:1.0-3.

0.

4. The method for preparing cimetidine according to claim 1, wherein: In step ③, the molar ratio of the intermediate compound obtained in step ② to methylamine is 1:1.0-10.

0.

5. A method for preparing cimetidine, characterized in that The following steps are involved: ① N-cyano-S, S-disulfide potassium salt or N-cyano-S, S-disulfide sodium salt reacts with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide to prepare a compound of formula (I) (I), in the compound of formula (I), the R group 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 the compound of formula (I) with methylamine to obtain the compound of formula (II); （Ⅱ） ③ 2-(((4-methyl-1H-imidazol-5-yl)methyl)thio)ethylamine dihydrochloride reacts with the compound of formula (II) to obtain the target product.

6. The method for preparing cimetidine according to claim 5, wherein: In step ①, the molar ratio of N-cyanimino-S, S-disulfide potassium salt or N-cyanimino-S, S-disulfide sodium salt to benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide is 1:1.8-3.

0.

7. The method for preparing cimetidine according to claim 5, wherein: In step ②, the molar ratio of the compound of formula (I) to methylamine is 1:0.8-1.

2.

8. The method for preparing cimetidine according to 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 1:1.0-3.0.

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