Preparation method of biuret compound

Abstract

The invention provides a preparation method of a biuret compound, which comprises the following specific reaction steps: taking secondary amine or primary amine as a raw material, reacting with KOCN to generate a urea intermediate, further reacting with acyl chloride, and performing ammonification to prepare the biuret compound as shown in the formula I. The reaction formula is # imgabs0 #, and R1 and R2 are independently or non-independently hydrogen, substituted or unsubstituted alkyl, aryl, oxo-alkyl, aza-alkyl, oxygen heterocyclic ring and nitrogen heterocyclic ring. The preparation method provided by the invention is high in yield, low in raw material cost and preparation cost, short in reaction period, mild in reaction condition, easy to operate and less in generated three wastes.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a biuret compound. Background Art

[0002] Biuret compounds have a wide range of applications, covering fields such as biochemical detection, medicine, agriculture, industry, and materials science.

[0003] Patent GB1230473 reported that the product can be obtained by reacting N-substituted urea with chlorosulfonyl isocyanate and then quenching with water. The specific technical solution is as follows: .

[0004] The disadvantages of this process route are low yield, only 40%, and high preparation cost, which is not suitable for industrial production. Summary of the Invention

[0005] In order to overcome the technical problems existing in the prior art, the present invention adopts the following technical solutions.

[0006] The present invention provides a preparation method of a biuret compound, which is prepared by subjecting a urea compound of formula II to a substitution reaction with an acyl chloride and then ammoniation, , wherein, R1 and R2 are independently or non-independently hydrogen, substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxacycle, azacycle.

[0007] Specifically, when R1 and R2 are independent, R1 is hydrogen, and R2 is substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxacycle, azacycle; when R1 and R2 are non-independent, they are substituted or unsubstituted cycloalkyl, aryl, oxacycle, azacycle.

[0008] Among them, the substitution reaction is carried out in the presence of an organic base, and the organic base is triethylamine, DIPEA, DBU, etc., and triethylamine is more preferred.

[0009] Among them, the acyl chloride used in the substitution reaction is oxalyl chloride, thionyl chloride, etc., and oxalyl chloride is more preferred.

[0010] Among them, the reaction solvent for the substitution reaction is acetonitrile, dichloromethane, tetrahydrofuran, etc.; dichloromethane and tetrahydrofuran are more preferred.

[0011] Among them, the ammoniating reagent in the ammoniation reaction is ammonia water, ammonium chloride, ammonia methanol, etc., and ammonia water is more preferred.

[0012] Among them, the reaction temperature of the substitution reaction is 10°C to 50°C, and 20 to 30°C is more preferred.

[0013] The present invention further provides a method for preparing the above-mentioned urea compound of formula II, which is prepared by reacting a corresponding secondary amine or primary amine with KOCN. , Wherein, R1 and R2 are independently or non-independently hydrogen, substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxacycle, azacycle.

[0014] Specifically, when R1 and R2 are independent, R1 is hydrogen, and R2 is substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxacycle, azacycle; when R1 and R2 are non-independent, they are substituted or unsubstituted cycloalkyl, aryl, oxacycle, azacycle.

[0015] Among them, the reaction with KOCN is carried out in the presence of hydrochloric acid.

[0016] Among them, the reaction temperature of the reaction with KOCN is -10°C to 10°C.

[0017] The present invention uses secondary amine or primary amine as raw materials, reacts with KOCN to generate urea intermediate compounds, reacts with oxalyl chloride and then undergoes ammoniation to prepare biuret compounds. The raw materials are convenient and easy to obtain, the reaction conditions are mild, the reaction cycle is short, the yield is high, it is easy to operate, and the amount of three wastes generated is small. Specific Embodiments

[0018] In order to further understand the present invention, the following is a detailed description of a method for preparing a biuret compound provided by the present invention in conjunction with embodiments. It should be understood that these embodiments are only for further detailed description of the features of the present invention, rather than a limitation on the scope of the present invention or the scope of the claims of the present invention.

[0019] Example 1: Synthesis of N-carbamoylpiperidine-1-carboxamide from piperidine

[0020] Piperidine (19.58 g, 0.23 mol), concentrated hydrochloric acid (27.98 g, 0.28 mol) and water (58.7 ml, 3 Vol) were added to a 250 ml flask, and stirring was started. Potassium cyanate (27.99 g, 0.35 mol) was added to water (39.2 ml, 2 Vol) to dissolve it clearly. At room temperature, the potassium cyanate solution was added dropwise to the piperidine solution. After the addition was completed, the reaction was carried out for 6 h until the raw materials reacted completely. The temperature was lowered to 0°C, and stirring was maintained for crystallization for 2 - 3 h, followed by filtration. The solid was then rinsed with ice water (9.8 ml, 0.5 Vol). 24.17 g of white piperidine-1-carboxamide was obtained, with a yield of 82%.

[0021] Add piperidine-1-carboxamide (24.17 g, 0.19 mol), triethylamine (28.84 g, 0.29 mol) and dichloromethane (217.6 ml, 10 Vol) into a 500 ml flask, and stir at 0 - 10 °C. Dropwise add oxalyl chloride (36.18 g, 0.29 mol). After the addition is complete, raise the temperature to room temperature and react for 3 h until the raw materials are completely reacted. Cool down to 0 °C, dropwise add ammonia water (48.3 ml, 2 Vol). After the addition is complete, raise the temperature to room temperature and react for 3 h. After the reaction is complete, concentrate under reduced pressure to remove dichloromethane. After concentration, raise the temperature to 70 °C, carry out slurry stirring for 0.5 h, cool down to room temperature, stir for 1 h, and filter to obtain 27.44 g of N-carbamoylpiperidine-1-carboxamide with a yield of 85%. ( 1 1H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H), 7.95 (s, 1H), 6.82 (s, 1H), 3.38 - 3.36 (m, 4H), 1.58 - 1.52 (m, 2H), 1.46 - 1.400 (m, 4H).

[0022] Example 2: Preparation of N-carbamoylpiperidine-1-carboxamide by chlorosulfonyl isocyanate method

[0023] Add piperidine-1-carboxamide (24.17 g, 0.19 mol) and dichloromethane (120.9 ml, 5 Vol) into a 500 ml flask, and stir at 0 - 10 °C. Dropwise add chlorosulfonyl isocyanate (26.68 g, 0.19 mol). After the addition is complete, raise the temperature to room temperature and react for 1 h until the raw materials are completely reacted. Add water (120.9 ml, 5 Vol). After the addition is complete, concentrate under reduced pressure to remove dichloromethane. After concentration, raise the temperature to 70 °C, carry out slurry stirring for 0.5 h, cool down to room temperature, stir for 1 h, and filter to obtain 12.91 g of white N-carbamoylpiperidine-1-carboxamide with a yield of 40%.

[0024] Example 3: Synthesis of N-carbamoyl-3-fluoropyrrolidine-1-carboxamide from 3-fluoropyrrolidine

[0025] Add 3-fluoropyrrolidine (20.50 g, 0.23 mol), concentrated hydrochloric acid (27.98 g, 0.28 mol) and water (61.5 ml, 3 Vol) to a 250 ml flask and start stirring. Potassium cyanate (27.99 g, 0.35 mol) is added to water (41.0 ml, 2 Vol) to dissolve it completely. At room temperature, the potassium cyanate solution is added dropwise to the 3-fluoropyrrolidine solution. After the addition, the reaction is carried out for 6 h until the raw materials react completely. The temperature is lowered to 0 °C, and stirring is maintained for crystallization for 2 - 3 h. Then, it is filtered, and the solid is rinsed with ice water (10.3 ml, 0.5 Vol). 24.62 g of white 3-fluoropyrrolidine-1-carboxamide is obtained, with a yield of 81%.

[0026] Add 3-fluoropyrrolidine-1-carboxamide (24.62 g, 0.19 mol), triethylamine (28.84 g, 0.29 mol) and dichloromethane (246.2 ml, 10 Vol) to a 250 ml flask, and stir at 0 - 10 °C. Oxalyl chloride (36.18 g, 0.29 mol) is added dropwise. After the addition, the temperature is raised to room temperature, and the reaction is carried out for 3 h until the raw materials react completely. The temperature is lowered to 0 °C, and ammonia water (49.2 ml, 2 Vol) is added dropwise. After the addition, the temperature is raised to room temperature, and the reaction is carried out for 3 h. After the reaction is completed, dichloromethane is removed by concentration under reduced pressure. After concentration, the temperature is raised to 70 °C, and it is stirred for pulping for 0.5 h. Then, the temperature is lowered to room temperature, and it is stirred for 1 h. 27.41 g of N-carbamoyl-3-fluoropyrrolidine-1-carboxamide is obtained by filtration, with a yield of 84%. ( 1 1H NMR(400 MHz, DMSO-d6): δ 8.71 (s, 1H), 7.91 (s, 1H), 6.94 (s, 1H), 5.38 - 5.25 (d, 1H, J = 52.9Hz), 3.93 - 3.34 (m, 4H), 2.14 - 2.00 (m, 2H).

[0027] Example 4: Synthesis of N-carbamoylpyrrolidine-1-carboxamide from pyrrolidine

[0028] Add pyrrolidine (16.36 g, 0.23 mol), concentrated hydrochloric acid (27.98 g, 0.28 mol) and water (49.1 ml, 3 Vol) to a 250 ml flask and start stirring. Potassium cyanate (27.99 g, 0.35 mol) is added to water (32.7 ml, 2 Vol) to dissolve it completely. At room temperature, the potassium cyanate solution is added dropwise to the pyrrolidine solution. After the addition, the reaction is carried out for 6 h until the raw materials react completely. The temperature is lowered to 0 °C, and stirring is maintained for crystallization for 2 - 3 h. Then, it is filtered, and the solid is rinsed with ice water (8.2 ml, 0.5 Vol). 21.76 g of white pyrrolidine-1-carboxamide is obtained, with a yield of 83%.

[0029] Add pyrrolidine-1-carboxamide (21.76 g, 0.19 mol), triethylamine (28.84 g, 0.29 mol) and dichloromethane (217.6 ml, 10 Vol) into a 500 ml flask, and stir at 0 - 10°C. Dropwise add oxalyl chloride (36.18 g, 0.29 mol). After dropping, raise the temperature to room temperature and react for 3 h until the raw materials react completely. Cool down to 0°C, dropwise add ammonia water (43.5 ml, 2 Vol). After dropping, raise the temperature to room temperature and react for 3 h. After the reaction is completed, concentrate under reduced pressure to remove dichloromethane. After concentration, raise the temperature to 70°C, carry out pulping and stirring for 0.5 h, cool down to room temperature, stir for 1 h, and filter to obtain 25.47 g of N-carbamoyl-pyrrolidine-1-carboxamide with a yield of 85%. 1 H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1H), 8.03 (s, 1H), 6.84 (s, 1H), 3.32 - 3.31 (m, 4H), 3.93 - 3.34 (m, 4H), 1.80 (s, 4H).

[0030] Example 5: Synthesis of N-carbamoylmorpholine-4-carboxamide from morpholine

[0031] Add morpholine (20.04 g, 0.23 mol), concentrated hydrochloric acid (27.98 g, 0.28 mol) and water (60.0 ml, 3 Vol) into a 250 ml flask, and start stirring. Dissolve potassium cyanate (27.99 g, 0.35 mol) in water (40.0 ml, 2 Vol) until clear. Dropwise add the potassium cyanate solution to the morpholine solution at room temperature. After dropping, react for 6 h until the raw materials react completely. Cool down to 0°C, keep stirring for crystallization for 2 - 3 h, filter, and wash the solid with ice water (10.0 ml, 0.5 Vol). Obtain 26.35 g of white morpholine-4-carboxamide with a yield of 88%.

[0032] Add morpholine-4-carboxamide (24.73 g, 0.19 mol), triethylamine (28.84 g, 0.29 mol) and dichloromethane (217.6 ml, 10 Vol) into a 500 ml flask, and stir at 0 - 10 °C. Dropwise add oxalyl chloride (36.18 g, 0.29 mol). After the addition, raise the temperature to room temperature and react for 3 h until the raw materials are completely reacted. Cool down to 0 °C, dropwise add ammonia water (49.5 ml, 2 Vol). After the addition, raise the temperature to room temperature and react for 3 h. After the reaction is completed, concentrate under reduced pressure to remove dichloromethane. After concentration, raise the temperature to 70 °C, carry out pulping and stirring for 0.5 h, cool down to room temperature, stir for 1 h, and filter to obtain 28.63 g of N-carbamoyl morpholine-4-carboxamide, with a yield of 87%. ( 1 H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 7.87 (s, 1H), 6.90 (s, 1H), 3.55 - 3.53 (dd, 4H), 3.41 - 3.38 (dd, 4H).)

[0033] Example 6: Synthesis of phenyl biuret from aniline

[0034] Add aniline (21.42 g, 0.23 mol), concentrated hydrochloric acid (27.98 g, 0.28 mol) and water (64.3 ml, 3 Vol) into a 250 ml flask and start stirring. Dissolve potassium cyanate (27.99 g, 0.35 mol) in water (42.8 ml, 2 Vol) until clear. Dropwise add the potassium cyanate solution to the aniline solution at room temperature. After the addition, react for 6 h until the raw materials are completely reacted. Cool down to 0 °C, keep the temperature and stir for crystallization for 2 - 3 h, filter, and wash the solid with ice water (10.0 ml, 0.5 Vol). Obtain 28.18 g of white phenylurea, with a yield of 90%.

[0035] Add phenylurea (25.87 g, 0.19 mol), triethylamine (28.84 g, 0.29 mol) and dichloromethane (217.6 ml, 10 Vol) into a 500 ml flask, and stir at 0 - 10 °C. Dropwise add oxalyl chloride (36.18 g, 0.29 mol). After the addition, raise the temperature to room temperature and react for 3 h until the raw materials react completely. Cool down to 0 °C, dropwise add ammonia water (51.7 ml, 2 Vol), after the addition, raise the temperature to room temperature and react for 3 h. After the reaction is completed, concentrate under reduced pressure to remove dichloromethane. After concentration, raise the temperature to 70 °C, carry out pulping and stirring for 0.5 h, cool down to room temperature, stir for 1 h, and filter to obtain 29.28 g of phenylbiuret, with a yield of 86%. (1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.85 (s, 1H), 7.49 - 7.42 (m, 2H), 7.32 - 7.28 (m, 2H), 7.06 - 7.02 (m, 1H), 6.88 (br s, 2H).).

Claims

1. A method for preparing a biuret compound, characterized in that, The compound of formula I is prepared by subjecting the urea compound of formula II to a substitution reaction with an acyl chloride followed by ammoniation. ， Wherein, R1 and R2 are independently or non-independently hydrogen, substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxacycle, azacycle.

2. The preparation method according to claim 1, characterized in that, The substitution reaction is carried out in the presence of an organic base.

3. The preparation method according to claim 1, characterized in that, The acyl chloride used in the substitution reaction is oxalyl chloride or thionyl chloride.

4. The preparation method according to claim 1, characterized in that, The reaction solvent for the substitution reaction is acetonitrile, dichloromethane or tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that, The ammoniating reagent in the ammoniation reaction is ammonia water, ammonium chloride or ammonia in methanol.

6. The preparation method according to claim 1, wherein The reaction temperature of the substitution reaction is 10°C to 50°C.

7. The preparation method according to claim 1, wherein The urea compound of formula II is prepared by reacting the corresponding secondary amine or primary amine with KOCN: ， Wherein, R1 and R2 are independently or non-independently hydrogen, substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxacycle, azacycle.

8. The preparation method according to claim 7, characterized in that, The reaction with KOCN is carried out in the presence of hydrochloric acid.

9. The preparation method according to claim 7, characterized in that, The reaction temperature of the reaction with KOCN is -10°C to 10°C.

10. A method for preparing a biuret-type I compound, characterized in that, Using a secondary amine or a primary amine as a raw material, reacting with KOCN to form a urea intermediate compound of formula II, and further reacting with an acyl chloride and then subjecting to ammoniation to prepare a biuret compound of formula I , Wherein, R1 and R2 are independently or non-independently hydrogen, substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxacycle, azacycle.

Images