A method for preparing a bisulphite compound

Abstract

The application provides a preparation method of a bisurea compound, and the specific reaction steps are as follows: taking a secondary amine or a primary amine as a raw material, reacting with KOCN to generate a urea intermediate, further reacting with an acyl chloride, and then preparing a bisurea compound of formula I through amination. A reaction formula is as follows: wherein R1 and R2 are independently or non-independently hydrogen, a substituted or unsubstituted alkyl group, an aryl group, an oxoalkyl group, an azalkyl group, an oxacycle, or an azacycle. The preparation method provided by the application has the advantages of high yield, low raw material cost and preparation cost, short reaction period, mild reaction condition, easy operation, and less three wastes.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical engineering, and specifically relates to a method for preparing biuret compounds. Background Technology

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

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

[0004] .

[0005] The disadvantages of this process route are low yield (only 40%) and high preparation cost, making it unsuitable for industrial production. Summary of the Invention

[0006] In order to overcome the technical problems existing in the prior art, the present invention adopts the following technical solution.

[0007] This invention provides a method for preparing biuret compounds, which are prepared by reacting a urea compound of formula II with an acyl chloride via a substitution reaction, followed by amination.

[0008] ,

[0009] Wherein, R1 and R2 are hydrogen independently or independently, substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxoheterocyclic, and azaheterocyclic.

[0010] Specifically, when R1 and R2 are independent, R1 is hydrogen and R2 is substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxoheterocyclic, or azacyclic; when R1 and R2 are not independent, they are substituted or unsubstituted cycloalkyl, aryl, oxoheterocyclic, or azacyclic.

[0011] The substitution reaction is carried out in the presence of an organic base, such as triethylamine, DIPEA, or DBU, with triethylamine being the preferred choice.

[0012] The acyl chloride used in the substitution reaction is oxalyl chloride, thionyl chloride, etc., with oxalyl chloride being the preferred choice.

[0013] The reaction solvent for the substitution reaction is acetonitrile, dichloromethane, tetrahydrofuran, etc.; dichloromethane and tetrahydrofuran are preferred.

[0014] The amination reagent in the amination reaction is ammonia water, ammonium chloride, ammonia methanol, etc., with ammonia water being the preferred choice.

[0015] The reaction temperature of the substitution reaction is 10℃~50℃, preferably 20~30℃.

[0016] This invention further provides a method for preparing the above-mentioned urea compounds of formula II, by reacting the corresponding secondary or primary amine with KOCN.

[0017] ,

[0018] Wherein, R1 and R2 are hydrogen independently or independently, substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxoheterocyclic, and azaheterocyclic.

[0019] Specifically, when R1 and R2 are independent, R1 is hydrogen and R2 is substituted or unsubstituted alkyl, aryl, oxoalkyl, azaalkyl, oxoheterocyclic, or azacyclic; when R1 and R2 are not independent, they are substituted or unsubstituted cycloalkyl, aryl, oxoheterocyclic, or azacyclic.

[0020] The reaction with KOCN is carried out in the presence of hydrochloric acid.

[0021] The reaction temperature with KOCN is -10℃ to 10℃.

[0022] This invention uses secondary or primary amines as raw materials, reacts with KOCN to generate urea intermediate compounds, reacts with oxalyl chloride and then aminations to prepare biuret compounds. The raw materials are readily available, the reaction conditions are mild, the reaction cycle is short, the yield is high, the operation is easy, and the amount of waste generated is small. Detailed Implementation

[0023] To further understand the present invention, a method for preparing a biuret compound provided by the present invention will be described in detail below with reference to embodiments. It should be understood that these embodiments are described only to further illustrate the features of the present invention, and are not intended to limit the scope of the present invention or the scope of the claims.

[0024] Example 1: Synthesis of N-carbamoylpiperidine-1-carboxamide from piperidine

[0025]

[0026] In a 250 mL flask, 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 and stirred. Potassium cyanate (27.99 g, 0.35 mol) was dissolved in water (39.2 mL, 2 Vol). The potassium cyanate solution was added dropwise to the piperidine solution at room temperature. After the addition was complete, the reaction was allowed to proceed for 6 h until the reactants had completely reacted. The mixture was then cooled to 0 °C and stirred to crystallize for 2–3 h. The crystals were filtered, and the solid was 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%.

[0027] Piperidine-1-carboxamide (24.17 g, 0.19 mol), triethylamine (28.84 g, 0.29 mol), and dichloromethane (217.6 ml, 10 Vol) were added to a 500 ml flask and stirred at 0–10 °C. Oxaloyl chloride (36.18 g, 0.29 mol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 3 h until the reactants were fully reacted. The mixture was then cooled to 0 °C, and ammonia water (48.3 ml, 2 Vol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the dichloromethane. After concentration, the mixture was heated to 70 °C and stirred for 0.5 h. The mixture was then cooled to room temperature and stirred for 1 h. The mixture was filtered to obtain 27.44 g of N-carbamoylpiperidine-1-carboxamide, with a yield of 85%. 1 H 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).)

[0028] Example 2: Preparation of N-carbamoylpiperidine-1-carboxamide by chlorosulfonic acid isocyanate method

[0029]

[0030] Piperidine-1-carboxamide (24.17 g, 0.19 mol) and dichloromethane (120.9 ml, 5 Vol) were added to a 500 ml flask and stirred at 0–10 °C. Chlorosulfonic acid isocyanate (26.68 g, 0.19 mol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 1 h until the reactants were fully reacted. Water (120.9 ml, 5 Vol) was added, and after the addition was complete, the mixture was concentrated under reduced pressure to remove the dichloromethane. After concentration, the mixture was heated to 70 °C and stirred for 0.5 h, then cooled to room temperature and stirred for 1 h. The mixture was filtered to obtain 12.91 g of white N-carbamoylpiperidine-1-carboxamide, with a yield of 40%.

[0031] Example 3: Synthesis of N-carbamoyl-3-fluoropyrrolidine-1-carboxamide from 3-fluoropyrrolidine

[0032]

[0033] In a 250 mL flask, 20.50 g (0.23 mol) of 3-fluoropyrrolidine, 27.98 g (0.28 mol) of concentrated hydrochloric acid, and 61.5 mL (3 Vol) of water were added and stirred. Potassium cyanate (27.99 g (0.35 mol) was dissolved in 41.0 mL (2 Vol) of water. The potassium cyanate solution was added dropwise to the 3-fluoropyrrolidine solution at room temperature. After the addition was complete, the reaction was allowed to proceed for 6 h until the starting material was fully reacted. The mixture was then cooled to 0 °C and stirred for 2–3 h to crystallize. The crystals were filtered, and the solid was washed with ice water (10.3 mL (0.5 Vol) to obtain 24.62 g of white 3-fluoropyrrolidine-1-carboxamide, with a yield of 81%.

[0034] In a 250 mL flask, 24.62 g (0.19 mol) of 3-fluoropyrrolidine-1-carboxamide, 28.84 g (0.29 mol) of triethylamine, and 246.2 mL (10 Vol) of dichloromethane were added and stirred at 0–10 °C. Oxaloyl chloride (36.18 g, 0.29 mol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 3 h until the reactants were fully reacted. The mixture was then cooled to 0 °C, and 49.2 mL (2 Vol) of ammonia water was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the dichloromethane. After concentration, the mixture was heated to 70 °C and stirred for 0.5 h. The mixture was then cooled to room temperature and stirred for 1 h. The solution was filtered to obtain 27.41 g of N-carbamoyl-3-fluoropyrrolidine-1-carboxamide, with a yield of 84%. 1 H 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).)

[0035] Example 4: Synthesis of N-carbamoylpyrrolidine-1-carboxamide from pyrrolidine

[0036]

[0037] In a 250 mL flask, pyrrolidine (16.36 g, 0.23 mol), concentrated hydrochloric acid (27.98 g, 0.28 mol), and water (49.1 mL, 3 Vol) were added and stirred. Potassium cyanate (27.99 g, 0.35 mol) was dissolved in water (32.7 mL, 2 Vol). The potassium cyanate solution was added dropwise to the pyrrolidine solution at room temperature. After the addition was complete, the reaction was allowed to proceed for 6 h until the starting material was fully reacted. The mixture was then cooled to 0 °C and stirred for 2–3 h to crystallize. The crystals were filtered, and the solid was rinsed with ice water (8.2 mL, 0.5 Vol). 21.76 g of white pyrrolidine-1-carboxamide was obtained, with a yield of 83%.

[0038] In a 500 mL flask, pyrrolidine-1-carboxamide (21.76 g, 0.19 mol), triethylamine (28.84 g, 0.29 mol), and dichloromethane (217.6 mL, 10 Vol) were added and stirred at 0–10 °C. Oxaloyl chloride (36.18 g, 0.29 mol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 3 h until the reactants were fully reacted. The mixture was then cooled to 0 °C, and ammonia water (43.5 mL, 2 Vol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the dichloromethane. After concentration, the mixture was heated to 70 °C and stirred for 0.5 h. The mixture was then cooled to room temperature and stirred for 1 h. The mixture was filtered to obtain 25.47 g of N-carbamoyl-pyrrolidine-1-carboxyl, with a yield of 85%. 1 H NMR (400MHz, 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).)

[0039] Example 5: Synthesis of N-carbamoylmorpholine-4-carboxamide from morpholine

[0040]

[0041] In a 250 mL flask, morpholine (20.04 g, 0.23 mol), concentrated hydrochloric acid (27.98 g, 0.28 mol), and water (60.0 mL, 3 Vol) were added and stirred. Potassium cyanate (27.99 g, 0.35 mol) was dissolved in water (40.0 mL, 2 Vol). The potassium cyanate solution was added dropwise to the morpholine solution at room temperature. After the addition was complete, the reaction was allowed to proceed for 6 h until the starting material was fully reacted. The mixture was then cooled to 0 °C and stirred to crystallize for 2–3 h. The crystals were filtered, and the solid was rinsed with ice water (10.0 mL, 0.5 Vol). 26.35 g of white morpholine-4-carboxamide was obtained, with a yield of 88%.

[0042] Morpholine-4-carboxamide (24.73 g, 0.19 mol), triethylamine (28.84 g, 0.29 mol), and dichloromethane (217.6 ml, 10 Vol) were added to a 500 ml flask and stirred at 0–10 °C. Oxaloyl chloride (36.18 g, 0.29 mol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 3 h until the reactants were fully reacted. The mixture was then cooled to 0 °C, and ammonia water (49.5 ml, 2 Vol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the dichloromethane. After concentration, the mixture was heated to 70 °C and stirred for 0.5 h, then cooled to room temperature and stirred for 1 h. The mixture was filtered to obtain 28.63 g of N-carbamoylmorpholine-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).)

[0043] Example 6: Synthesis of Phenylacetyl Biuret from Aniline

[0044]

[0045] In a 250 mL flask, aniline (21.42 g, 0.23 mol), concentrated hydrochloric acid (27.98 g, 0.28 mol), and water (64.3 mL, 3 Vol) were added and stirred. Potassium cyanate (27.99 g, 0.35 mol) was dissolved in water (42.8 mL, 2 Vol). The potassium cyanate solution was added dropwise to the aniline solution at room temperature. After the addition was complete, the reaction was allowed to proceed for 6 h until the starting material was fully reacted. The temperature was lowered to 0 °C, and the mixture was stirred and kept at this temperature for 2–3 h to crystallize. The mixture was filtered, and the solid was then washed with ice water (10.0 mL, 0.5 Vol). 28.18 g of white phenylurea was obtained, with a yield of 90%.

[0046] In a 500 mL flask, phenylurea (25.87 g, 0.19 mol), triethylamine (28.84 g, 0.29 mol), and dichloromethane (217.6 mL, 10 Vol) were added and stirred at 0–10 °C. Oxaloyl chloride (36.18 g, 0.29 mol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 3 h until the reactants were fully reacted. The mixture was then cooled to 0 °C, and ammonia water (51.7 mL, 2 Vol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the dichloromethane. After concentration, the mixture was heated to 70 °C and stirred for 0.5 h. The mixture was then cooled to room temperature and stirred for 1 h. The mixture was filtered to obtain 29.28 g of phenylbiurea, 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 process for the preparation of a bis-urea compound of formula I ###0001### I characterized in that, The compound of formula I is prepared by substitution reaction of the urea compound of formula II with acyl chloride, and then amination, ， wherein R1, R2 are independently hydrogen, substituted or unsubstituted alkyl, aryl, oxygen heterocycle, nitrogen heterocycle; The substitution reaction is carried out in the presence of an organic base; The amination reagent in the amination reaction is ammonia, ammonium chloride, or ammonium methanol; The acyl chloride used in the substitution reaction is oxalyl chloride or dichlorosulfoxide.

2. The production method according to claim 1, characterized by, The reaction solvent of the substitution reaction is acetonitrile, dichloromethane, or tetrahydrofuran.

3. The preparation method according to claim 1, characterized in that, The reaction temperature of the substitution reaction is 10-50℃.

4. A process for the preparation of a bisulphite compound of formula I, characterized in that, The compound of formula II is prepared by reaction of a secondary amine or a primary amine with KOCN, and then the compound of formula I is prepared by the preparation method of claim 1, reaction with acyl chloride, and then amination, ， wherein R1, R2 are independently hydrogen, substituted or unsubstituted alkyl, aryl, oxygen heterocycle, nitrogen heterocycle.

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