CN103408507A - Preparation method for 2-amino-1,3,4-thiadiazole compounds - Google Patents

Abstract

The invention provides a method for preparing 2-amino-1,3,4 thiadiazole compounds, adding thiosemicarbazide, short-chain carboxylic acid and hydrobromic acid into the reactor; then stirring and heating to reflux, keeping the temperature React for 2-3 hours to obtain a reaction solution; lower the reaction solution to room temperature, then adjust the pH value of the reaction solution to 8-9 in an ice-water bath, wait for the solid to precipitate, and filter under reduced pressure to obtain a crude product; the crude product has a mass concentration of 30% ethanol aqueous solution was recrystallized to obtain 2-amino-1,3,4thiadiazole compounds. The present invention reacts rapidly, and product purity is high, and aftertreatment is simple, and product yield is higher simultaneously, therefore, the process of the present invention is easy to implement, has solved the long reaction time of using hydrochloric acid catalyst in the original process, the yield of sulfuric acid catalyst is not high, trichloro Oxyphosphorus is used as a catalyst for post-processing difficulties and other problems.

Description

A kind of preparation method of 2-amino-1,3,4 thiadiazole compound

technical field

The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of 2-amino-1,3,4 thiadiazole compounds. the

Background technique

1,3,4-Thiadiazole compounds are an important class of pharmaceutical intermediates, because they are five-membered heterocyclic compounds containing sulfur and nitrogen heteroatoms, and have aromaticity and conjugation effects, and are widely used in the synthesis of antibacterial Drugs, anti-tuberculosis drugs, anti-cancer drugs and anti-inflammatory drugs, etc. At present, the synthesis method of 2-amino-1,3,4-thiadiazole is mainly obtained by the ring-closure reaction of various carboxylic acids and thiosemicarbazide under the catalysis of concentrated hydrochloric acid, concentrated sulfuric acid and phosphorus oxychloride. the

Use concentrated hydrochloric acid as a catalyst, because the mass concentration of concentrated hydrochloric acid is 36-38%, the boiling point is not high, the forced increase in temperature causes hydrogen chloride loss, and the catalytic activity decreases. Although the reaction takes a long time, the yield is not high and only 47%; use concentrated hydrochloric acid Sulfuric acid is used as a catalyst. Because concentrated sulfuric acid has a higher acidity and a higher boiling point, the reaction temperature range is relatively wide, but it has strong oxidative properties and exothermic heat during pH adjustment, resulting in a yield of only 28%; Phosphorus is used as a catalyst, the reaction requirements are relatively high, and the operation is complicated. the

Contents of the invention

The object of the present invention is to provide a preparation method of 2-amino-1,3,4 thiadiazole compounds with simple operation, simple post-treatment and high yield. the

In order to achieve the above object, the technical solution adopted in the present invention comprises the following steps:

1) Add A mol thiosemicarbazide and B mol short-chain carboxylic acid to the reactor, then add hydrobromic acid with a mass concentration of 48% as a catalyst, heat up to reflux under stirring, and keep warm for 2-3 hours , to obtain the reaction solution; among them, A:B=1:(1-1.2);

2) Lower the reaction solution to room temperature, then adjust the pH value of the reaction solution to 8-9 in an ice-water bath, and filter the crude product under reduced pressure after the solid is precipitated; the crude product is recrystallized by ethanol aqueous solution with a mass concentration of 30%, 2-Amino-1,3,4thiadiazoles were obtained. the

The reactor in step 1) is dried. the

The medium-short-chain carboxylic acid in step 1) is formic acid, acetic acid, n-propionic acid or n-butyric acid. the

The amount of hydrobromic acid added in the step 1) is CmL, and A:C=1:(800-1000)

The reflux temperature in the step 1) is 100-110°C. the

In the step 2), an aqueous sodium hydroxide solution with a mass concentration of 40-45% is used to adjust the pH value of the reaction solution. the

In the step 2) after the solid is precipitated, continue to stand under the ice-water bath for 30 minutes and then suction filter. the

Compared with prior art, the beneficial effect of the present invention is:

Catalyst used in the present invention is the hydrobromic acid that acidity is stronger, concentration is bigger and boiling point is higher, so not only have wider temperature of reaction, and the yield of the product that reaction obtains is more than 90%, therefore, the present invention and Compared with the prior art, the reaction yield is high, which solves the problems of long reaction time of hydrochloric acid catalyst and low yield of sulfuric acid catalyst in the prior art; meanwhile, the present invention has simple reaction process, easy operation, short reaction time and simple aftertreatment , which solves the problem of difficult post-treatment of phosphorus oxychloride as a catalyst. the

Description of drawings

Fig. 1 is the reaction scheme diagram of embodiment 1 of the present invention. the

Detailed ways

The present invention is described in further detail below by way of examples. The yields of 2-amino-1,3,4-thiadiazole compounds in the following examples are expressed in molar yield percentages. the

Example 1:

See Figure 1, 1) Add 0.022mol of thiosemicarbazide, 0.026mol of formic acid and 18mL of hydrobromic acid with a mass concentration of 48% to a dry three-necked flask, heat up to 100°C under stirring, and keep the temperature for 2.5 hours to obtain a reaction solution ;

2) Lower the reaction solution to room temperature, then adjust the pH value of the reaction solution to 8-9 with 40% sodium hydroxide aqueous solution in an ice-water bath, and continue to stand in the ice-water bath for 30 minutes after the solid is precipitated The solid was fully separated out, and then filtered under reduced pressure to obtain the crude product; the crude product was recrystallized by 30% ethanol aqueous solution to obtain 2.02 g of white 2-amino-1,3,4 thiadiazole crystals (91% yield, m.p.: 190-191°C). the

IR(υ _max ,KBr,cm ^-1 ):3288,3082(ν _NH ,s); 1618,1611( _{νthiadiazole ring C=N} ,s); 1021(ν _=CSC= ,s); 680( ν _=CSC= ,m).

Example 2:

1) Add 0.022mol of thiosemicarbazide, 0.022mol of formic acid and 22mL of hydrobromic acid with a mass concentration of 48% to a dry three-necked flask, heat up to 110°C under stirring, and keep the reaction for 2.5 hours to obtain a reaction solution;

2) Lower the reaction solution to room temperature, then adjust the pH value of the reaction solution to 8-9 with 45% sodium hydroxide aqueous solution in an ice-water bath, and continue to stand in an ice-water bath for 30 minutes after the solid is precipitated The solid was fully separated out, and then filtered under reduced pressure to obtain the crude product; the crude product was recrystallized by a 30% aqueous ethanol solution to obtain 1.99 g of white 2-amino-1,3,4 thiadiazole crystals (90% yield, m.p.: 190-192°C). the

Example 3:

1) Add 0.022mol of thiosemicarbazide, 0.024mol of acetic acid and 22mL of hydrobromic acid with a mass concentration of 48% to a dry three-necked flask, heat up to 105°C under stirring, and keep the temperature for 2.5 hours to obtain a reaction solution;

2) Lower the reaction solution to room temperature, then adjust the pH value of the reaction solution to 8-9 with 40% sodium hydroxide aqueous solution in an ice-water bath, and continue to stand in the ice-water bath for 30 minutes after the solid is precipitated The solid was fully separated, and then filtered under reduced pressure to obtain the crude product; the crude product was recrystallized by ethanol aqueous solution with a mass concentration of 30%, and 2.38 g of white 2-amino-5-methyl-1,3,4 thiadiazole crystals were obtained (yield 94%, m.p.: 236-239°C). the

IR(υ _max , KBr, cm ^-1 ): 3324, 3100 (ν _NH , s); 2939 (ν _{methyl CH} , s); 1618, 1520 (ν _{thiadiazole ring C=N} , s); 1445, 1376 (ν _{methyl CH} ,w); 1022 (ν _=CSC= ,s); 685 (ν _=CSC= ,m).

Example 4:

1) Add 0.022mol of thiosemicarbazide, 0.024mol of n-propionic acid and 20mL of hydrobromic acid with a mass concentration of 48% to a dry three-necked flask, heat up to 108°C under stirring, and keep the temperature for 3 hours to obtain a reaction solution;

2) Lower the reaction solution to room temperature, then adjust the pH value of the reaction solution to 8-9 with 40% sodium hydroxide aqueous solution in an ice-water bath, and continue to stand in the ice-water bath for 30 minutes after the solid is precipitated The solid was fully separated, and then filtered under reduced pressure to obtain the crude product; the crude product was recrystallized by ethanol aqueous solution with a mass concentration of 30%, and 2.64 g of white 2-amino-5-ethyl-1,3,4 thiadiazole crystals were obtained (yield 93%, m.p.: 208-209°C). the

IR(υ _max , KBr, cm ^-1 ): 3287, 3104 (ν _NH , s); 2974, 2929, 2870 (ν _CH , s); 1678, 1637 (ν _{thiadiazole ring C=N} , s); 1489, 1453, 1368 (ν _CH , w); 1027, 823, 742, 691, 482 (ν _{thiadiazole ring NCS} , w).

Embodiment 5:

1) Add 0.022mol of thiosemicarbazide, 0.026mol of n-butyric acid and 22mL of hydrobromic acid with a mass concentration of 48% to a dry three-necked flask, heat up to 105°C under stirring, and keep the temperature for 3 hours to obtain a reaction solution;

2) Lower the reaction solution to room temperature, then adjust the pH value of the reaction solution to 8-9 with 40% sodium hydroxide aqueous solution in an ice-water bath, and continue to stand in the ice-water bath for 30 minutes after the solid is precipitated The solid was fully separated out, and then filtered under reduced pressure to obtain the crude product; the crude product was recrystallized by ethanol aqueous solution with a mass concentration of 30%, and 2.89 g of white 2-amino-5-n-propyl-1,3,4 thiadiazole crystals were obtained (produced Rate 92%, m.p.: 212～218℃). the

IR(υ _max ,KBr,cm ^-1 ):3433(ν _NH ,s); 2987,2927,2760(ν _CH ,s); 1639,1527( _{νthiadiazole ring C=N} ,s); 1498, 1451,1407 (ν _CH ,w); 1027,820,740,687,587 (ν _{thiadiazole ring NCS} ,w).

Embodiment 6:

1) Add 0.022mol of thiosemicarbazide, 0.0264mol of n-butyric acid and 17.6mL of hydrobromic acid with a mass concentration of 48% into a dry three-necked flask, heat up to 100°C under stirring, and keep it warm for 2 hours to obtain a reaction solution;

2) Lower the reaction solution to room temperature, then adjust the pH value of the reaction solution to 8-9 with 42% sodium hydroxide aqueous solution in an ice-water bath, and continue to stand in an ice-water bath for 30 minutes after the solid is precipitated The solid was fully separated out, and then filtered under reduced pressure to obtain the crude product; the crude product was recrystallized with 30% ethanol aqueous solution to obtain white 2-amino-5-n-propyl-1,3,4thiadiazole crystals. the

Claims (7)

1. a preparation method of 2-amino-1,3,4 thiadiazole compounds, is characterized in that, comprises the following steps: 1) Add A mol of thiosemicarbazide, B mol of short-chain carboxylic acid in the reactor, then add hydrobromic acid with a mass concentration of 48% as a catalyst, heat up to reflux under stirring, keep the temperature for 2-3 hours, Obtain the reaction solution; wherein, A:B=1:(1-1.2); 2) Lower the reaction solution to room temperature, then adjust the pH value of the reaction solution to 8-9 in an ice-water bath, and filter the crude product under reduced pressure after the solid is precipitated; the crude product is recrystallized by ethanol aqueous solution with a mass concentration of 30%, 2-Amino-1,3,4thiadiazoles were obtained. 2. The preparation method of 2-amino-1,3,4 thiadiazole compounds according to claim 1, characterized in that: the reactor in the step 1) is dried. 3. The preparation method of 2-amino-1,3,4 thiadiazole compounds according to claim 1, characterized in that: the short-chain carboxylic acid in the step 1) is formic acid, acetic acid, n-propionic acid or n-butyric acid. 4. 2-amino-1 according to claim 1, the preparation method of 3,4 thiadiazole compounds is characterized in that: the add-on of hydrobromic acid in described step 1) is CmL, and A: C=1: (800-1000). 5. The preparation method of 2-amino-1,3,4 thiadiazole compounds according to claim 1, characterized in that: the reflux temperature in the step 1) is 100-110°C. 6. The preparation method of 2-amino-1,3,4 thiadiazole compounds according to claim 1, characterized in that: in the step 2), sodium hydroxide with a mass concentration of 40-45% is used The aqueous solution adjusts the pH of the reaction solution. 7. The preparation method of 2-amino-1,3,4 thiadiazole compounds according to claim 1 or 6, characterized in that: the step 2) continues to stand under the ice-water bath after the solid is precipitated 30 minutes and then suction filtered.

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