An improved process for the preparation of amicarbazone

Abstract

The present invention relates to an improved process for the preparation of amicarbazone. The present invention more particularly relates to an improved process for the preparation of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (i.e. amicarbazone) by coupling of 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) with tert-butyl isocyanate (TBIC) of less than or equal to 98%, preferably less than or equal to 85% purity. The process of the present invention can utilize poor quality (low purity) tert-butyl isocyanate (TBIC) to produce the active ingredient amicarbazone of high purity, which will reduce the production cost of amicarbazone.

Description

TECHNICAL FIELD

[0001] The present invention relates to an improved process for the preparation of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (amicarbazone). The present invention more particularly relates to an improved process for the preparation of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (amicarbazone) by coupling of 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) with low quality tert-butyl isocyanate (TBIC) having purity less than or equal to 85%, preferably less than or equal to 80%. BACKGROUND

[0002] Amicarbazone, i.e. 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide, is a triazole class member of 4,5-dihydro-1H-1,2,4-triazol-5-ones substituted with tert-butyl aminocarbonyl group at position 1 and isopropyl group at position 3. Amicarbazone is a triazolinone based herbicidal active compound represented by the following formula I:

[0003]

[0004] 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) is represented by formula II:

[0005]

[0006] tert-butyl isocyanate (TBIC) is represented by formula III

[0007]

[0008] US9332762 (B2) (Indian counterpart application 2071 / KOLNP / 2015) discloses a process for the preparation of amicarbazone by coupling of 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) and tert-butyl isocyanate (TBIC).

[0009] US9332762 (B2) (Indian counterpart application 2071 / KOLNP / 2015) teaches the process for the preparation of amicarbazone in examples 10, 11 and 12 using amino-triazolinone (TAZ) and tert-butyl isocyanate (TBIC). Further, the process also involves use of toluene and KOH.

[0010] A project pre-feasibility report for proposed expansion project of M / s. Deccan Fine Chemicals (India) Pvt. Ltd for agrochemical active ingredients and intermediates and fine chemicals production at Ankleshwar project site. (http: / / environmentclearance.nic.in / writereaddata / Online / TOR / 03_May_2017_1900586535FXM3T5NAnnexure-Prefeasibilityreport.pdf)

[0011] The report teaches the preparation of amicarbazone as follows,

[0012] Preparation of amicarbazone: TBIC and triazolinone are charged into a reactor and heated to below 60°C. Tert-butyl isocyanate is added at a controlled rate above 65°C. After completion of the reaction, the mixture is neutralized and cooled. Amicarbazone is isolated by filtration and then dried.

[0013] CN107162993A discloses synthesis of amicarbazone by adding triazolinone, potassium hydroxide, catalyst and solvent to a reactor. Then, prepared tert-butyl isocyanate is added dropwise and heated to obtain amicarbazone. SUMMARY

[0014] Need of the invention:

[0015] The present inventors have observed that the production site of amicarbazone and the source site of tert-butyl isocyanate (TBIC) are usually different. Sometimes, the production site can receive low quality (TBIC) which needs to be discarded. The tert-butyl isocyanate can decompose during transportation to the production site or at the source site. Therefore, there is a need to develop a process which can produce amicarbazone using 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) and low quality tert-butyl isocyanate (TBIC).

[0016] Solution provided by the invention:

[0017] The present inventors have surprisingly developed a robust process to produce high quality active ingredient amicarbazone using various grades of tert-butyl isocyanate (TBIC).

[0018] The present inventors have found that using high quality tert-butyl isocyanate (TBIC), it is usually possible to produce high quality active ingredient amicarbazone. However, using low quality tert-butyl isocyanate (TBIC), it is only possible to produce active ingredient meeting the approved specifications under the improved conditions of the present invention.

[0019] The inventors have discovered that, through minor process improvements, it is possible to produce industrial-grade active ingredients of aminopyrazosulfan that meet quality specifications using lower-grade tert-butyl isocyanate (TBIC).

[0020] This invention provides a robust method for producing industrial-grade active ingredient of azoxystrobin of acceptable quality (according to production specifications) by using a previously unknown, lower grade of TBIC.

[0021] Advantages of this invention:

[0022] 1. This invention provides a general method for producing high-purity active ingredient aminopyrazol using tert-butyl isocyanate (TBIC) of poor quality (low purity).

[0023] 2. This invention utilizes lower-quality (low-purity) tert-butyl isocyanate (TBIC), which is typically discarded upon decomposition. TBIC, for example, is a highly reactive isocyanate that requires maintaining its purity through the removal of air and moisture during transport; otherwise, it may decompose during transport to the production site. This will reduce the production cost of aminopyrazosulfan.

[0024] The purpose of this invention:

[0025] One object of the present invention is to provide a robust method for producing high-quality active ingredient aminopyrazolone using various grades of tert-butyl isocyanate (TBIC) with low purity.

[0026] Another object of the present invention is to provide a method for producing high-quality active ingredient aminopyrazolone using low-quality tert-butyl isocyanate (TBIC) with a purity of 98% or less, preferably 85% or less. Summary of the Invention

[0028] According to one aspect of the present invention, a method for preparing azoxystrobin is provided, comprising the following steps:

[0029] i. Preparation of a solution of 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ), potassium hydroxide, and toluene;

[0030] ii. Raise the temperature of the solution obtained in step (i) to a range of 50°C to 70°C;

[0031] iii. Add undistilled tert-butyl isocyanate (TBIC) to the solution from step (ii).

[0032] iv. The solution obtained by heating in the temperature range of 60°C to 75°C;

[0033] v. Cool the solution obtained in step (iv) to form azoxystrobin. Attached Figure Description

[0034] Figure 1 The purity (HPLC) of amoxicillin obtained by the method of the present invention (Experiment #21) is shown.

[0035] Figure 2 Impurities detected in amoxicillin prepared by the method of the present invention (Experiment #21) are shown (HPLC).

[0036] Figure 3 The purity (HPLC) of amoxicillin obtained by the method of the present invention (Experiment #23) is shown.

[0037] Figure 4 Impurities detected in amoxicillin prepared by the method of the present invention (Experiment #23) are shown (HPLC).

[0038] Figure 5 The purity (HPLC) of amoxicillin obtained by the method of the present invention (Experiment #25) is shown.

[0039] Figure 6 Impurities detected in amphetamine (Experiment #25) prepared by the method of the present invention are shown (HPLC). Invention Details

[0041] This invention relates to an improved method for preparing 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (aminoxamethonium).

[0042] In one embodiment, the present invention provides an improved method for preparing 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (amazolidinone) by coupling 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazole-1-carboxamide (TAZ) with a purity of less than or equal to 88%, preferably less than or equal to 80%.

[0043] In another embodiment, the present invention provides a method for preparing ampicillin, comprising the following steps:

[0044] i. Preparation of a solution of 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ), potassium hydroxide, and toluene;

[0045] ii. Raise the temperature of the solution obtained in step (i) to a range of 50°C to 70°C;

[0046] iii. Add undistilled tert-butyl isocyanate (TBIC) to the solution from step (ii).

[0047] iv. The solution obtained by heating at a temperature of 60°C to 75°C;

[0048] v. Cool the solution obtained in step (iv) to form azoxystrobin.

[0049] In the method of the present invention, step (iii) comprises an excess of TIBC of at least 18% molar relative to TAZ;

[0050] In the method of the present invention, the solution is cooled to a temperature in the range of 40°C to 50°C; in the method of the present invention, the cooled solution is optionally introduced with aminopyrazosulfan crystals.

[0051] Low-quality tert-butyl isocyanate (TBIC) is defined as a compound with a purity of 98% or less.

[0052] In one embodiment of the invention, the tert-butyl isocyanate (TBIC) used in the method of the invention has a purity in the range of 80% to 98%.

[0053] In another embodiment of the invention, the tert-butyl isocyanate (TBIC) used in the method of the invention has a purity of less than 85%.

[0054] In yet another embodiment of the invention, the final product obtained is aminopyrazolone with a purity of over 97%.

[0055] In yet another implementation, heating, cooling, and filtration can be performed using conventional processes.

[0056] Specifically, the present invention relates to the following aspects:

[0057] Aspect 1. A method for preparing aminopyrazosulfuron, the method comprising reacting 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one with tert-butyl isocyanate having low purity.

[0058] Aspect 2. The method of aspect 1, wherein the tert-butyl isocyanate has a purity of less than or equal to 80% and uses TBIC in a molar excess of at least 18% relative to TAZ.

[0059] Aspect 3. A method for preparing ampicillin, the method comprising the following steps:

[0060] i. Preparation of a solution of 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ), potassium hydroxide, and toluene;

[0061] ii. Raise the temperature of the solution obtained in step (i) to a range of 50°C to 70°C;

[0062] iii. Add undistilled tert-butyl isocyanate (TBIC) to the solution from step (ii).

[0063] iv. The solution obtained by heating in the temperature range of 60°C to 75°C;

[0064] v. Cool the solution obtained in step (iv) to form azoxystrobin.

[0065] Aspect 4. The method as described in aspect 1, wherein step iii) comprises an excess of TBIC of at least 18% molar relative to TAZ.

[0066] Aspect 5. The method as described in aspect 1, wherein the solution is cooled to a temperature range of 40°C to 50°C.

[0067] Aspect 6. The method as described in aspect 1, wherein ammoniac seed crystals are optionally added to the cooled solution.

[0068] Aspect 7. The method as described in aspect 1, wherein tert-butyl isocyanate (TBIC) has a purity of 98% or less.

[0069] Aspect 8. The method as described in aspect 1 or 5, wherein tert-butyl isocyanate (TBIC) has a purity of 85% or less.

[0070] Aspect 9. The method as described in aspect 2, wherein the molar excess of tert-butyl isocyanate (TBIC) is 18% to 22% relative to 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ).

[0071] Aspect 10. The method of aspect 1, wherein the azoxystrobin obtained in step (v) has a purity greater than 97%.

[0072] Aspect 11. Ammoniazide prepared by reacting 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one with tert-butyl isocyanate with a purity of less than or equal to 80%.

[0073] Figure 1 , Figure 3 and Figure 5The purity (HPLC) of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazol-3-one (TAZ) and low-quality tert-butyl isocyanate (TBIC) with a purity of less than or equal to 80% is shown to obtain high-quality 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazol-1-carboxamide (aminoazol).

[0074] Figure 2 , Figure 4 and Figure 6 The impurities detected in amoxicillin when prepared by the method of the present invention are shown (HPLC).

[0075] Experiment 21 Figure 1 and Figure 2 The results are listed in Table 1.

[0076] Table 1

[0077]

[0078] Experiment 23 Figure 3 and Figure 4 The results are listed in Table 2.

[0079] Table 2

[0080]

[0081] Experiment 25 Figure 5 and Figure 6 The results are listed in Table 3.

[0082] Table 3

[0083]

[0084] Experiments 21, 23 and 25 were conducted in the manner described in Example 1. Detailed Implementation

[0085] The present invention will now be described in detail with reference to the following formulation examples and test examples, which should not be construed as limiting the scope of the invention.

[0086] Example 1

[0087] 4-Amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-lH-l,2,4-triazole-l- carboxamide (amibuzin) was prepared by coupling 4-amino-2,4-dihydro-5- (l-methylethyl)-3H-l,2,4-triazol-3-one (TAZ) and tert-butyl isocyanate (TBIC) of poor quality with a purity less than or equal to 80%. Example 2 4-Amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-lH-l,2,4-triazole-l- carboxamide (amibuzin) was prepared by coupling 4-amino-2,4-dihydro-5- (l-methylethyl)-3H-l,2,4-triazol-3-one (TAZ) and tert-butyl isocyanate (TBIC) of poor quality with a purity less than or equal to 80%. Methods involving ketones.

[0088] i. Weigh the required amounts of toluene, TAZ, and potassium hydroxide and add them to a four-necked flask with stirring;

[0089] ii. Dry TAZ under a vacuum of 167 mmHg at a controlled temperature of 61°C to 67°C (azeotropic drying (by distillation column)) until the water content in toluene is 0.04%;

[0090] iii. Raise the temperature inside the flask and maintain it at 60℃ (±1℃);

[0091] iv. Increase the stirring speed and slowly add the required amount of undistilled TBIC at a constant flow rate over 30 minutes in a 18% molar excess relative to the TAZ amount;

[0092] v. Slowly increase the temperature inside the flask and continue heating to 70°C (±1°C) over 10 minutes, then maintain this temperature for 5 minutes;

[0093] vi. Slowly and continuously cool the flask to 50°C (±1°C) over 10 minutes and maintain that temperature;

[0094] vii. Add aminopyrazosulfan seed crystals and continue stirring for 10 minutes;

[0095] viii. Stop stirring and cool the flask to 10°C within 2 hours;

[0096] ix. Filter the resulting product and wash the crystals with the required amount of water;

[0097] x. Dry the crystals under vacuum (200-400 mmHg) at 35-40℃ until a maximum moisture content of 0.30% is obtained;

[0098] xi. To analyze crystals using specific methods.

[0099] Method for preparing 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-lH- 1,2,4-triazole-l-carboxamide (amibuzin) by coupling 4-amino-2,4-dihydro-5- (l-methylethyl)-3H-l,2,4-triazol-3-one (TAZ) and tert-butyl isocyanate (TBIC) of poor quality with a purity less than or equal to 80%.

[0100] Comparative Example 1 4-Amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-lH-l,2,4-triazole-l- carboxamide (amibuzin) was prepared by coupling 4-amino-2,4-dihydro-5- (l-methylethyl)-3H-l,2,4-triazol-3-one (TAZ) and tert-butyl isocyanate (TBIC) of poor quality with a purity less than or equal to 80%. Method for preparing 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-lH- 1,2,4-triazole-l-carboxamide (amibuzin) by coupling 4-amino-2,4-dihydro-5- (l-methylethyl)-3H-l,2,4-triazol-3-one (TAZ) and tert-butyl isocyanate (TBIC) of poor quality with a purity less than or equal to 80%. .

[0101] i. 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) and potassium hydroxide solution were vacuum dried at 176 mmHg and 67 °C.

[0102] ii. Add undistilled low-mass tert-butyl isocyanate (TBIC) under a nitrogen atmosphere and a controlled temperature of 60°C;

[0103] iii. Increase the temperature to 70℃;

[0104] iv. Cool the temperature to 50°C;

[0105] v. Add 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (amazolidinone) seed crystals;

[0106] vi. Cool to 10°C within 2 hours;

[0107] vii. Filtering;

[0108] viii. Vacuum dry at 35-40℃.

[0109] The purity of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (amazolidinone) and the molar excess of tert-butyl isocyanate (TBIC) relative to 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazole-3-one (TAZ) are listed in Table 4.

[0110] Table 4

[0111]

[0112] Conclusion: Compared with 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ), a molar excess of low-mass tert-butyl isocyanate (TBIC) of 18.00% or greater yields high-purity 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazol-1-carboxamide (amazolidinone).

[0113] Comparative Example 2

[0114] 4-Amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-lH-l,2,4-triazole-l- carboxamide (amibuzin) was prepared by coupling 4-amino-2,4-dihydro-5- (l-methylethyl)-3H-l,2,4-triazol-3-one (TAZ) and tert-butyl isocyanate (TBIC) of poor quality with a purity less than or equal to 80%. Method for preparing 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-lH- 1,2,4-triazole-l-carboxamide (amibuzin) by coupling 4-amino-2,4-dihydro-5- (l-methylethyl)-3H-l,2,4-triazol-3-one (TAZ) and tert-butyl isocyanate (TBIC) of poor quality with a purity less than or equal to 80%. Experimental data

[0115] i. 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) and potassium hydroxide solution were dried under vacuum at 176 mmHg and 67 °C.

[0116] ii. Add undistilled low-mass tert-butyl isocyanate (TBIC) under a nitrogen atmosphere and a controlled temperature of 60°C;

[0117] iii. Increase the temperature to 70℃;

[0118] iv. Cool the temperature to 50°C;

[0119] v. Add 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (amazolidinone) seed crystals;

[0120] vi. Cool to 10°C within 2 hours;

[0121] vii. Filtering;

[0122] viii. Vacuum dry at 35-40℃.

[0123] The purity of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (amazolidinone) and the molar excess of tert-butyl isocyanate (TBIC) relative to 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazole-3-one (TAZ) are listed in Table 5.

[0124] Table 5

[0125]

[0126] Conclusion: Compared with 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ), the low-mass tert-butyl isocyanate (TBIC) has a molar excess of less than 18.00%, achieving low-purity 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazol-1-carboxamide (amazolidinone).

[0127] ​

[0128] ​ ​ ​ .

[0129] i. 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) and potassium hydroxide solution were vacuum dried at 176 mmHg and 67 °C.

[0130] ii. Add undistilled pure tert-butyl isocyanate (TBIC) under a nitrogen atmosphere and a controlled temperature of 60°C;

[0131] iii. Increase the temperature to 70℃;

[0132] iv. Cool the temperature to 50°C;

[0133] v. Add 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (amazolidinone) seed crystals;

[0134] vi. Cool to 10°C within 2 hours;

[0135] vii. Filtering;

[0136] viii. Vacuum dry at 35-40℃.

[0137] The purity of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (amazolidinone) and the molar excess of tert-butyl isocyanate (TBIC) relative to 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazole-3-one (TAZ) are listed in Table 6.

[0138] Table 6

[0139]

[0140] Conclusion: Compared with 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ), the high-quality tert-butyl isocyanate (TBIC) has a molar excess of less than 18.00% (i.e., a 4-5% TBIC molar excess), achieving high-purity 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazol-1-carboxamide (aminoxamethonium).

[0141] ​

[0142]

[0143] Low quality – TBIC = 81.20% purity

[0144] TAZ vacuum azeotropic drying = No

[0145] Does distilled TBIC use? = No

[0146] Compared to TAZ, the TBIC molar excess is 4.00%.

[0147] Ampicillin purity, %w / w = low purity

[0148]

[0149] Low quality – TBIC = 81.20% purity

[0150] Vacuum azeotropic drying = Yes

[0151] Is distilled TBIC used? = Yes

[0152] Compared to TAZ, the TBIC molar excess is less than 18%.

[0153] Ampicillin purity, %w / w = low purity

[0154]

[0155]

[0156] Low quality – TBIC = 81.20% purity

[0157] Vacuum azeotropic drying = Yes

[0158] Does distilled TBIC use? = No

[0159] Compared to TAZ, the TBIC molar excess is greater than 18%.

[0160] Ampicillin purity, %w / w = high purity

[0161]

[0162]

[0163] Low quality – TBIC = 81.20% purity

[0164] TAZ vacuum azeotropic drying = is

[0165] Does distilled TBIC use? = No

[0166] Compared to TAZ, the TBIC molar excess is greater than 18%.

[0167] Ampicillin purity, %w / w = high purity

[0168]

[0169]

[0170] Low quality – TBIC = 81.20% purity

[0171] TAZ vacuum azeotropic drying = is

[0172] Does distilled TBIC use? = No

[0173] Compared to TAZ, the TBIC molar excess is greater than 18%.

[0174] Ampicillin purity, %w / w = high purity

[0175]

[0176]

[0177] Low quality – TBIC = 81.20% purity

[0178] TAZ vacuum azeotropic drying = is

[0179] Does distilled TBIC use? = No

[0180] Compared to TAZ, the TBIC molar excess is greater than 18%.

[0181] Ampicillin purity, %w / w = high purity

[0182]

[0183]

[0184] Low quality – TBIC = 81.20% purity

[0185] TAZ vacuum azeotropic drying = is

[0186] Does distilled TBIC use? = No

[0187] Compared to TAZ, the TBIC molar excess is greater than 18%.

[0188] Ampicillin purity, %w / w = high purity

[0189]

[0190]

[0191] Low quality – TBIC = 81.20% purity

[0192] TAZ vacuum azeotropic drying = is

[0193] Does distilled TBIC use? = No

[0194] Compared to TAZ, the TBIC molar excess is greater than 18%.

[0195] Ampicillin purity, %w / w = high purity

[0196]

[0197]

[0198] Low quality – TBIC = 81.20% purity

[0199] TAZ vacuum azeotropic drying = is

[0200] Does distilled TBIC use? = No

[0201] Compared to TAZ, the TBIC molar excess is greater than 18%.

[0202] Ampicillin purity, %w / w = high purity

[0203]

[0204] Low quality – TBIC = 81, 20% purity

[0205] TAZ vacuum azeotropic drying = is

[0206] Does distilled TBIC use? = No

[0207] Compared to TAZ, the TBIC molar excess is greater than 18%.

[0208] Ampicillin purity, %w / w = high purity

[0209]

[0210] Low quality – TBIC = 81.20% purity

[0211] TAZ vacuum azeotropic drying = is

[0212] Is distilled TBIC used? = Yes

[0213] Compared to TAZ, the TBIC molar excess is less than 18%.

[0214] Ampicillin purity, %w / w = low purity

[0215]

[0216] High quality – TBIC = 98.50% purity

[0217] TAZ vacuum azeotropic drying = is

[0218] Does distilled TBIC use? = No

[0219] Compared to TAZ, the TBIC molar excess is less than 18%.

[0220] Ampicillin purity, % w / w = high purity (due to the use of high-quality TBIC).

[0221]

[0222]

[0223] High quality – TBIC = 98.50% purity

[0224] TAZ vacuum azeotropic drying = is

[0225] Does distilled TBIC use? = No

[0226] Compared to TAZ, the TBIC molar excess is less than 18%.

[0227] Ampicillin purity, % w / w = high purity (due to the use of high-quality TBIC).

Claims

1. A method for preparing ampicillin, the method comprising the following steps: i. Preparation of a solution of 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ), potassium hydroxide, and toluene; ii. Raise the temperature of the solution obtained in step (i) to a range of 50°C to 70°C; iii. Add undistilled tert-butyl isocyanate (TBIC) to the solution from step (ii); iv. The solution obtained by heating in the temperature range of 60°C to 75°C; v. Cool the solution obtained in step (iv) to form azoxystrobin. The tert-butyl isocyanate (TBIC) described herein has a purity of less than or equal to 80% and uses TBIC in a molar excess of 18% or higher relative to TAZ.

2. The method of claim 1, wherein step (iii) comprises an excess of TBIC of at least 18% molar relative to TAZ.

3. The method of claim 1, wherein the solution of step (v) is cooled to a temperature range of 40°C to 50°C.

4. The method of claim 1, wherein ammoniac seed crystals are optionally added to the cooled solution.

5. The method of claim 1, wherein the molar excess of tert-butyl isocyanate TBIC is 18% to 22% relative to 4-amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one TAZ.

6. The method of claim 1, wherein the aminopyrazosulfuron obtained in step (v) has a purity of greater than 97%.

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