CN102584661A - Preparation method of substituted phenylthiosemicarbazide compound - Google Patents

Abstract

The invention relates to biological design, in particular to a preparation method of a substituted anilinothiourea compound. Specifically, the raw material substituted aniline is dissolved in a solvent and reacted with carbon disulfide and alkali at a reaction temperature of 0-100°C for 1-10 hours to generate a substituted phenylthiocarbamate; the obtained substituted phenylthiocarbamate The carbamate is dissolved in a solvent, reacted with sodium chloroacetate and hydrazine hydrate in sequence, the reaction temperature is 0-100° C., and the reactant is reacted for 1-12 hours. The reactant is concentrated and dried to obtain a substituted anilinothiourea compound. The reaction condition of the substituted anilinothiourea compound produced by the method of the invention is mild, the reaction can be performed at room temperature, the use of highly toxic reagents is reduced, and the yield is high.

Description

A kind of preparation method of substituted anilinothiourea compound

technical field

The invention relates to biological design, in particular to a preparation method of a substituted anilinothiourea compound.

Background technique

Thiosemicarbazones are a class of active substances obtained from the condensation reaction of thiosemicarbazides with appropriate aldehydes or ketones. Because its structure contains heteroatoms such as N and S, it has various biological activities such as antibacterial, antibacterial, antiviral, antitumor, and antiparasitic. Some thiosemicarbazone derivatives are effective against tuberculosis, leprosy, rheumatism, Malaria, smallpox and certain tumors have certain pharmacological activity. Therefore, the synthesis of thiosemicarbazone compounds with various structures has always been a research hotspot.

Thiosemicarbazide is the key intermediate for the synthesis of thiosemicarbazone, and its main synthesis methods are: (1) substituted amine and thiophosgene to generate substituted phenyl isothiocyanate and then react with hydrazine hydrate to generate thiosemicarbazide (2) Isothiourea condenses with amine to form thiosemicarbazide. Method (1) uses highly toxic thiophosgene; method (2) uses highly toxic dimethyl sulfate when preparing isothiourea, and is a multi-step reaction with side reactions.

Contents of the invention

The object of the present invention is to provide a kind of preparation method of substituted anilinothiourea compound.

To achieve the above object, the technical scheme adopted in the present invention is:

A preparation method of a substituted anilinothiourea compound,

1) dissolving the raw material substituted aniline in a solvent to react with carbon disulfide and alkali at a reaction temperature of 0-100°C for 1-10 hours to generate a substituted phenylthiocarbamate;

2) Dissolve the substituted phenylthiocarbamate obtained in step 1) in a solvent, react with sodium chloroacetate and hydrazine hydrate in turn, the reaction temperature is 0-100°C, and react for 1-12 hours. The reactant, the reactant After concentration and drying, the substituted anilinothiourea compound is obtained, as shown in formula I,

In formula I, R is alkyl, substituted alkyl, alkoxy, halogen, nitro, trifluoromethyl; said R is preferably C1-C8 alkyl, C1-C5 substituted alkyl, C1-C5 Alkoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl; R is preferably monosubstituted or polysubstituted.

The volume mass ratio of the solvent to the substituted aniline in the step 1) is 10-100:1; the molar ratio of the substituted aniline, carbon disulfide and the base is 1:1-5:1-5. The step 1) solvent is one or a combination of water, ethanol, methanol, benzene, toluene. The step 1) base is concentrated ammonia water, sodium hydroxide, potassium hydroxide, triethylamine, pyridine or triethylenediamine. The volume mass ratio of the solvent to the substituted phenylthiocarbamate in the step 1) is 10-100: 1; the substituted phenylthiocarbamate, sodium chloroacetate and hydrazine hydrate molar ratio The ratio is 1:1-5:1-5; the reaction product is concentrated, filtered with suction, washed with a solvent, recrystallized, and dried at 30-50° C. to obtain a substituted anilinothiourea compound after drying. The step 2) solvent is one or a combination of water, methanol, ethanol, benzene, toluene. In the step 2) solvent washing, the solvent is one or both of water, methanol, and ethanol; the solvent for recrystallization is one or both of water, methanol, and ethanol.

The invention has the advantages that the substituted anilinothiourea compound produced by the method of the invention has mild reaction conditions, can react at room temperature, reduces the use of highly toxic reagents, and has a high yield.

Detailed ways

The present invention will be further described below in conjunction with the examples, and the protection scope of the present invention is not limited only to the following examples.

The preparation of embodiment 1 o-fluoroanilinothiourea

Add o-fluoroaniline (0.1moL) and triethylenediamine (0.1moL) to 100mL of toluene, add carbon disulfide (6mL) dropwise at room temperature, finish adding in half an hour, continue to react for 2 hours, reactants are suction filtered, washed, Dry at 40°C to obtain 30.9 g of yellow powder, yield: 99%. That is triethylene diammonium salt of o-fluorophenylthiocarbamate.

Add triethylene diammonium o-fluorophenylthiocarbamate (0.05moL) and sodium chloroacetate (0.05moL) to a solvent of 120mL of ethanol and water (volume ratio of ethanol/water=5:1), and stir at room temperature After 1 hour, 6 mL of 85% hydrazine hydrate was added dropwise, and the reaction was continued for 4 hours. The reactant was concentrated, suction filtered, washed with water, recrystallized, and dried at 40°C to obtain 9.1 g of milky white powder, with a yield of 90.5%. That is, o-fluoroanilinothiourea is shown in formula I:

The obtained compound ¹ H NMR (DMSO, 600M): δ9.35 (s, 1H, NH), 8.05 (d, 1H, Ph-H), 7.16-7.23 (m, 2H, Ph-H), 7.15 (d, 1H, Ph-H), 4.88 (br s, 2H, NH ₂ ), 2.93 (s, 1H, NH).

The preparation of embodiment 2 o-chloroanilinothiourea

Add o-chloroaniline (0.4moL) and triethylenediamine (0.4moL) to 400mL of toluene, add carbon disulfide (24mL) dropwise at room temperature, finish adding in half an hour, continue to react for 8 hours, reactants are suction filtered, washed, Dry at 40°C to obtain 119.3 g of yellow powder, yield: 90.5%. That is, triethylene diammonium salt of o-chlorophenylthiocarbamate.

Add triethylene diammonium o-chlorophenylthiocarbamate (0.1moL) and sodium chloroacetate (0.1moL) to a solvent of 240mL of ethanol and water (volume ratio of ethanol/water=5:1), and stir at room temperature After 1 hour, 12 mL of 85% hydrazine hydrate was added dropwise, and the reaction was continued for 4 hours. The reactant was concentrated, filtered with suction, washed with water, recrystallized, and dried at 40°C to obtain 20.7 g of white powder, with a yield of 95.6%. Be that o-chloroanilinothiourea is shown in formula I:

The obtained compound ¹ H NMR (DMSO, 600M): δ9.44 (s, 1H, NH), 8.06 (d, 1H, Ph-H), 7.48 (dd, 1H, Ph-H), 7.31 (dd, 1H, Ph-H), 7.16 (d, 1H, Ph-H), 5.02 (br s, 2H, _NH2 ), 3.00 (s, 1H, NH).

Claims (7)

1. the preparation method of a substituted anilinic thiourea compound is characterized in that:

1) the raw material substituted aniline is dissolved in the solvent and dithiocarbonic anhydride and alkali reaction, temperature of reaction is 0-100 ℃, reacts 1-10 hour, generates substituted phenyl thiocarbamate;

2) the substituted phenyl thiocarbamate of step 1) gained is dissolved in the solvent, with sodium chloroacetate, Hydrazine Hydrate 80 reaction, temperature of reaction is 0-100 ℃, reacts 1-12 hour reactant, obtains the substituted anilinic thiourea compound behind the reactant concentrate drying successively.

2. by the preparation method of the described substituted anilinic thiourea compound of claim 1, it is characterized in that: solvent described in the said step 1) is 10-100 with the volume mass ratio of substituted aniline: 1; The mol ratio of substituted aniline, dithiocarbonic anhydride and alkali is 1: 1-5: 1-5.

3. by the preparation method of claim 1 or 2 described substituted anilinic thiourea compounds, it is characterized in that: said step 1) solvent is one or more combination in water, ethanol, methyl alcohol, benzene, the toluene.

4. by the preparation method of the described substituted anilinic thiourea compound of claim 3, it is characterized in that: said step 1) alkali is strong aqua, sodium hydroxide, Pottasium Hydroxide, triethylamine, pyridine or triethylene diamine.

5. by the preparation method of the described substituted anilinic thiourea compound of claim 1, it is characterized in that: solvent described in the said step 1) is 10-100 with the volume mass ratio of substituted phenyl thiocarbamate: 1; Substituted phenyl thiocarbamate, sodium chloroacetate and Hydrazine Hydrate 80 mol ratio are 1: 1-5: 1-5; Reactant concentrates, suction filtration, and solvent wash, recrystallization carries out drying under 30-50 ℃, obtain the substituted anilinic thiourea compound after the drying.

6. by the preparation method of claim 1 or 5 described substituted anilinic thiourea compounds, it is characterized in that: said step 2) solvent is one or more combination in water, methyl alcohol, ethanol, benzene, the toluene.

7. by the preparation method of the described substituted anilinic thiourea compound of claim 5, it is characterized in that: said step 2) solvent is in water, methyl alcohol, the ethanol one or both in the solvent wash; The solvent of recrystallization is one or both in water, methyl alcohol, the ethanol.