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)

FIELD OF THE INVENTION

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) and poor quality tert-Butyl isocyanate (TBIC) with purity less than or equal to 85%, preferably less than or equal to 80%.

BACKGROUND OF THE INVENTION

Amicarbazone, 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide is a member of the class of triazoles that is 4,5-dihydro-1H-1,2,4-triazol-5-one which is substituted at position 1 by a tert-butylaminocarbonyl group and at position 3 by an isopropyl group. Amicarbazone, is a triazolinone-based herbicidal active compound represented by Formula I.

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4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) is represented by Formula II

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Tert-Butyl isocyanate (TBIC) is represented by Formula III

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The process for 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) is disclosed in U.S. Pat. No. 9,332,762(B2) (Indian equivalent 2071/KOLNP/2015).

U.S. Pat. No. 9,332,762(B2) (Indian equivalent 2071/KOLNP/2015) teaches process for preparation of Amicarbazone in example 10, 11 and 12 using amino-triazolinone (TAZ) and t-butyl isocyanate (TBIC). Further the process also involve the use of toluene and KOH.

Project pre-feasibility report for Proposed Expansion Project For Manufacturing of Agrochemical Active Ingredients & Intermediates and Fine Chemicals at Ankleshwar Project Proponent M/s. Deccan Fine Chemicals (India) Pvt. Ltd. (http://environmentclearance.nic.in/writereaddata/Online/TOR/03_May_2017_1900586535FXM3T5NAnnexure-Prefeasibilityreport.pdf)

This report teaches method Amicarbazone Preparation as follows,

Amicarbazone Preparation: TBIC and Triazolinone are charged into the reactor and heated less than 60° C. Tert-butylisocyanate is charged at a controlled rate at more than 65° C. After the completion of the reaction, mixture is neutralized and cooled.

Amicrabazone is isolated by filtration and then dried.

CN107162993A discloses synthesis of Amicarbazone by adding Triazolinones, potassium hydroxide, catalyst and the solvent into the reactor. Then the tertiary butyl isocyanates prepared is added dropwise, and a heating reaction is performed to obtain the amicarbazone.

Need of the Present Invention

The present inventors have observed that the production sites of Amicarbazone and site of origin of tert-Butyl isocyanate (TBIC) are generally different. At times, production sites may received poor quality (TBIC) which needs to be discarded. Tert-Butyl isocyanate may get decomposed either in transit to the production site or at the origin. Therefore, there is a need for development of a process capable of preparing Amicarbazone employing 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) and poor quality tert-Butyl isocyanate (TBIC).

Solution Provided by the Present Invention

The present inventors have surprisingly developed a robust process to produce high quality active ingredient Amicarbazone with various grades of tertiary butyl isocyanate (TBIC).

The present inventors have found that with good quality tertiary butyl isocyanate (TBIC) it is routinely possible to produce high quality of active ingredient Amicarbazone. However, with tertiary butyl isocyanate (TBIC) of poor quality, only under modified conditions of the present invention it is possible to generate active ingredient meeting the approved specifications.

The present inventors found that tertiary butyl isocyanate (TBIC) of a lower grade can be utilized, via subtle process modifications, to generate Amicarbazone technical grade active ingredient meeting quality specifications.

The present invention provide a robust approach to generate acceptable quality (per manufacturing specifications.) Amicarbazone technical grade active ingredient via the use of poorer grade of TBIC which is hitherto unknown.

Advantages of the Present Invention

1. The present invention provide a versatile process that can utilize tertiary butyl isocyanate (TBIC) of poorer quality (low purity) to generate active ingredient Amicarbazone of high purity.

2. The present invention utilize tertiary butyl isocyanate (TBIC) of poorer quality (low purity) which would be generally discarded in case the same is decomposed for example TBIC, which is a highly reactive Isocyanate, needs to maintained/transported pure via exclusion of air/moisture and if not maintained it may decomposed during transit to production site. This would lower the cost of production of Amicarbazone.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide a robust process to produce high quality active ingredient Amicarbazone with various grades of tertiary butyl isocyanate (TBIC) having low purity.

It is another object of the present invention to provide a process to produce high quality active ingredient, Amicarbazone with poor quality tert-Butyl isocyanate (TBIC) with purity equal to or less than 98%, preferably less than or equal to 85%.

SUMMARY OF THE INVENTION

According to an aspect of the present invention there is provided a process for the preparation of Amicarbazone comprising the step of:

i. Preparing a solution of 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ), Potassium hydroxide and toluene;
ii. Raising the temperature of the solution obtained in step (i) to the range of 50° C. to 70° C.;
iii. Adding tert-Butyl isocyanate (TBIC) without distillation to the solution of step (ii)
iv. Heating the solution obtained at temperature in the range of 60° C. to 75° C.;
v. Cooling the solution obtained in step (iv) to form Amicarbazone.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 show Amicarbazone purity (HPLC) achieved by the process of the present invention (Exp #21).

FIG. 2 show impurities (HPLC) detected in the Amicarbazone prepared by the process of the present invention (Exp #21).

FIG. 3 show Amicarbazone purity (HPLC) achieved by the process of the present invention (Exp #23).

FIG. 4 show impurities (HPLC) detected in the Amicarbazone prepared by the process of the present invention (Exp #23).

FIG. 5 show Amicarbazone purity (HPLC) achieved by the process of the present invention (Exp #25).

FIG. 6 show impurities (HPLC) detected in the Amicarbazone prepared by the process of the present invention (Exp #25).

DETAILED DESCRIPTION OF THE INVENTION

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).

In an embodiment the present invention provide 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) and poor quality tert-Butyl isocyanate (TBIC) with purity less than or equal to 88%, preferably less than or equal to 80%.

In another embodiment the present invention provide a process for the preparation of Amicarbazone comprising the step of.

i. Preparing a solution of 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ), Potassium hydroxide and toluene;
ii. Raising the temperature of the solution obtained in step (i) to the range of 50° C. to 70° C.;
iii. Adding tert-Butyl isocyanate (TBIC) without distillation to the solution of step (ii)
iv. Heating the solution obtained at temperature in the range of 60° C. to 75° C.;
v. Cooling the solution obtained in step (iv) to form Amicarbazone.

In the process of the present invention step (iii) comprises at least 18% molar excess of TBIC with respect to TAZ;

In the process of the present invention the solution is cooled to the temperature in the range of 40° C. to 50° C.;

In the process of the present invention the cooled solution is optionally seeded with Amicarbazone.

Poor quality tert-Butyl isocyanate (TBIC) is defined as a compound with purity less than or equal to 98%.

In an embodiment of the present invention the tert-Butyl isocyanate (TBIC) used in the process of the present invention have purity in the range of 80% to 98%.

In another embodiment of the present invention the tert ert-Butyl isocyanate (TBIC) used in the process of the present invention have purity less than 85%.

In yet another embodiment the present invention the Amicarbazone obtained as a final product have purity more than 97%.

In yet another embodiment the Heating, Cooling and Filtration may be carried out using conventional processes.

FIG. 1, FIG. 3 and FIG. 5 show Amicarbazone purity (HPLC) achieved according to coupling process of 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) and poor quality tert-Butyl isocyanate (TBIC) with purity less than or equal to 80%, in order to get good quality of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (Amicarbazone).

FIG. 2, FIG. 4 and FIG. 6 show impurities (HPLC) detected in Amicarbazone when prepared by the process of the present invention.

The Results Achieved by Experiment 21 (FIGS. 1 and 2) are Tabulated in Table 1

TABLE 1

Component
Specification
Result

Amicarbazone purity, % w/w
Minimum 96.5%
97.3%

Bis-Acyl compound, % w/w
Maximum 1.30%
1.16%

Di-tert-butil-urea, % w/w
Maximum 0.60%
0.15%

3H-1,2,4-triazol-3-one,
Maximum 0.40%
0.48%

4 amino-2,4-dihydro-5-(1-

methylethul), % w/w (Common name:

Aminotriazolinone)

Toluene, % w/w
Maximum 0.50%
0.11%

Karl Fischer, % ww
Maximum 0.30%
0.14%

The Results Achieved by Experiment 23 (FIGS. 3 and 4) are Tabulated in Table 2

TABLE 2

Component
Specification
Result

Amicarbazone purity, % w/w
Minimum 96.5%
97.4%

Bis-Acyl compound, % w/w
Maximum 1.30%
0.97

Di-tert-butil-urea, % w/w
Maximum 0.60%
0.12

3H-1,2,4-triazol-3-one,
Maximum 0.40%
0.18

4 amino-2,4-dihydro-5-(1-

methylethul), % w/w (Common name:

Aminotriazolinone)

Toluene, % w/w
Maximum 0.50%
0.11

Karl Fischer, % ww
Maximum 0.30%
0.20

The Results Achieved by Experiment 25 (FIGS. 5 and 6) are Tabulated in Table 3

TABLE 3

Component
Specification
Result

Amicarbazone purity, % w/w
Minimum 96.5%
98.2%

Bis-Acyl compound, % w/w
Maximum 1.30%
0.93

Di-tert-butil-urea, % w/w
Maximum 0.60%
0.08

3H-1,2,4-triazol-3-one,
Maximum 0.40%
0.02

4 amino-2,4-dihydro-5-(1-

methylethul), % w/w (Common name:

Aminotriazolinone)

Toluene, % w/w
Maximum 0.50%
0.17

Karl Fischer, % ww
Maximum 0.30%
0.08%

Experiment 21, 23 and 25 are conducted in a manner as described in Example 1.

EXAMPLES

The present invention will now be explained in detail by reference to the following formulation examples and a test example, which should not be construed as limiting the scope of the present invention.

Example 1
Process for 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) and Poor Quality tert-Butyl isocyanate (TBIC) with Purity Less than or Equal to 80%

i. Weight the required amount of Toluene, TAZ and Potassium hydroxide and put it under stirring into the 4-Neck Flask;

ii. Drying (azeotropic drying (through the distillation column)) of TAZ under vacuum of 167 mmHg under controlled temperature between 61 to 67° C. until get the moisture level of 0.04% in the toluene;

iii. Raise the temperature inside the flask and keep at 60° C. (±1° C.);

iv. Increase agitation and add slowly and in constant flow in 30 minutes the required amount of TBIC undistilled in order to have 18% molar excess in relation to TAZ amount;

v. Raise the temperature inside the flask slowly and in constantly heating to 70° C. (1° C.) in 10 min and keep it for 5 minutes;

vi. Cool down the temperature slowly and in constantly inside the flask until 50° C. (1° C.) in 10 minutes and keep it;

vii. Adding seed of Amicarbazone and keep stirring for 10 min;

viii. Stop stirring and cool down the temperature inside the flask until 10° C. in 2 hours;

ix. Filter the product formed and wash the crystals with the required amount of water;

x. Dry the crystals under vacuum (200-400 mmHg) at 35-40° C. until get maximum 0.30% of moisture;

xi. Assay the crystals using the specific method.

Example 2
Process for 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) and Poor Quality tert-Butyl isocyanate (TBIC) with Purity Less than or Equal to 80%

i. 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) and Potassium hydroxide solution drying under vacuum at 176 mmHg at 67° C.

ii. Poor quality of tert-Butyl isocyanate (TBIC) without distillation adding under nitrogen atmosphere and controlled temperature of 60° C.;

iii. Temperature raising until 70° C.;

iv. Temperature cooling down until 50° C.;

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

vi. Cooling down until 10° C. in 2 hours;

vii. Filtration;

viii. Drying under vacuum at 35-40° C.

The 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (Amicarbazone) purity and tert-Butyl isocyanate (TBIC) molar excess compared to 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) are tabulated in Table 4.

TABLE 4

tert-Butyl

isocyanate
4-amino-N-tert-butyl-4,5-dihydro-3-

Sr.
Experiment
(TBIC) molar
isopropyl-5-oxo-1H-1,2,4-triazole-1-

No
No.
excess
carboxamide (Amicarbazone) purity

1
Exp#25
18.00%
98.20%

2
Exp#28
20.00%
98.70%

3
Exp#29
22.00%
98.40%

Conclusion: The molar excess equal to or greater than 18.00% of Poor quality of tert-Butyl isocyanate (TBIC) compared to 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) achieve high purity of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (Amicarbazone).

Comparative Example 1
Process for 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) and Poor Quality tert-Butyl isocyanate (TBIC) with Purity Less than or Equal to 80%

i. 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) and Potassium hydroxide solution drying under vacuum at 176 mmHg at 67° C.

ii. Poor quality of tert-Butyl isocyanate (TBIC) without distillation adding under nitrogen atmosphere and controlled temperature of 60° C.;

iii. Temperature raising until 70° C.;

iv. Temperature cooling down until 50° C.;

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

vi. Cooling down until 10° C. in 2 hours;

vii. Filtration;

viii. Drying under vacuum at 35-40° C.

TABLE 5

tert-Butyl

isocyanate
4-amino-N-tert-butyl-4,5-dihydro-3-

Sr.
Experiment
(TBIC) molar
isopropyl-5-oxo-1H-1,2,4-triazole-1-

No
No.
excess
carboxamide (Amicarbazone) purity

1
Exp#4
4.00%
73.20%

2
Exp#6
9.50%
83.50%

3
Exp#27
10.00%
88.50%

Conclusion: The molar excess less than 18.00% of poor quality of tert-Butyl isocyanate (TBIC) compared to 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) achieve low purity of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (Amicarbazone).

Comparative Example 2
Process for 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) and Pure tert-Butyl isocyanate (TBIC) with Purity Higher than or Equal to 98%

i. 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) and Potassium hydroxide solution drying under vacuum at 176 mmHg at 67° C.

ii. Pure tert-Butyl isocyanate (TBIC) without distillation adding under nitrogen atmosphere and controlled temperature of 60° C.;

iii. Temperature raising until 70° C.;

iv. Temperature cooling down until 50° C.;

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

vi. Cooling down until 10° C. in 2 hours;

vii. Filtration;

viii. Drying under vacuum at 35-40° C.

TABLE 6

tert-Butyl

isocyanate
4-amino-N-tert-butyl-4,5-dihydro-3-

Sr.
Experiment
(TBIC) molar
isopropyl-5-oxo-1H-1,2,4-triazole-1-

No
No.
excess
carboxamide (Amicarbazone) purity

1
Exp#54
4.00%
97.25%

2
Exp#60
3.00%
98.27%

3
Exp#61
5.00%
98.27%

Conclusion: The molar excess less than 18.00% of Good quality of tert-Butyl isocyanate (TBIC) (i.e. 4-5% of TBIC molar excess) as compared to 4-Amino-2,4-dihydro-5-(1-methylethyl)-3H-1,2,4-triazol-3-one (TAZ) achieve high purity of 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-carboxamide (Amicarbazone).

Experimental Data

Reagents

Reactants
Purity (%)
B1
B2
B3
B4
B5

TBIC
81.20%
21.2923
21.2923
51.5728
51.5728
21.2936

(Poor quality)

TBIC
98.50%
--
--
--
---
--

(Good quality)

TAZ
97.71%
30
30
72.664
72.664
30

Toluene
99.27%
103.6276
103.6276
300
251.8384
123.8577

KOH (51.81%)
51.81%
0.4471
0.4471
1.0829
1.2995
0.6706

Washing Water
--
not measured
not
not
not
not

measured
measured
measured
measured

moles TBIC

0.215
0.215
0.520
0.520
0.215

moles TAZ

0.206
0.206
0.500
0.500
0.206

Moles Ratio

4.0%
4.0%
4.0%
4.0%
4.0%

TBIZ/TAZ

TAZ
Azeotropic
No
No
No
No
No

drying under

vacuum?

TBIC adding
Was used TBIC
No
No
No
No
No

distilled?

Temperature
60
60
60
60
60

inside the flask,

° C.

Adding time,
15
15
15
15
21

min

Molar excess of

4.00%
4.00%
4.00%
4.00%
4.01%

TBIC compared

to TAZ

Time kept at

10
10
10
10
22.5

70° C., min

Time for cooling

down until 50° C.,

not measured
not
not
not
not

min

measured
measured
measured
measured

Time for cooling

---
---
---
---
---

down at 10° C.,

min

Amicarbazone

17.0%
62.0%
49.8%
73.0%
55.2%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying of TAZ under vacuum = No

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = 4.00%

Amicarbazone purity, % w/w = Low purity

Reagents

Reactants
Purity (%)
B6
B7
B8
B9
B10

TBIC
81.20%
38.68
34.105
22.33
22.977
22.4077

(Poor quality)

TBIC
98.50%
--
--
--
---
--

(Good quality)

TAZ
97.71%
51.7769
47.1471
29.8909
28.0572
29.9949

Toluene
99.27%
137.3479
121 1027
79.2911
79.2911
79.567

KOH (51.81%)
51.81%
0.9823
0.8661
0.5671
0.5835
0.5691

Washing Water
--
not measured
41.3448
27.0702
27.0702
not

measured

moles TBIC

0.390
0.344
0.225
0.232
0.226

moles TAZ

0.356
0.324
0.206
0.193
0.206

Moles Ratio

9.5%
6.0%
9.5%
20.0%
9.5%

TBBI/TAZ

TAZ
Azeotropic
Yes
Yes
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
Yes
Yes
Yes
Yes
Yes

distilled?

Temperature
60
60
60
60
60

inside the flask,

° C.

Adding time,
30
30
30
30
30

min

Molar excess of

9.47%
6.00%
9.47%
20.00%
9.47%

TBIC compared

to TAZ

Time kept at

30
5
5
5
5

70° C., min

Time for cooling

not measured
30
15
10
10

down until 50° C.,

min

Time for cooling

---
150
30
60
10

down at 10° C.,

min

Amicarbazone

83.5%
63.3%
58.3%
101.9%
56.7%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying under vacuum = Yes

Was used TBIC distilled = Yes

Molar excess of TBIC compared to TAZ = Less than 18%

Amicarbazone purity, % w/w = Low purity

Reagents

Reactants
Purity (%)
B11
B12
B13
B14
B15

TBIC
81.20%
40.5817
47.7384
52.6735
55.4773
54.2132

(Poor

quality)

TBIC
98.50%
--
--
--
---
--

(Good

quality)

TAZ
97.71%
49.5542
58.2933
61.7467
65.0335
56.7425

Toluene
99.27%
144.1006
169.5132
187.0371
196.9931
192.5044

KOH

(51.81%)
51.81%
1.0306
1.2124
1.3377
1.4089
1.3768

Washing
--
27.0702
57.8723
63.8551
67.2541
65.7216

Water

moles TBIC

0.409
0.481
0.531
0.559
0.547

moles TAZ

0.341
0.401
0.425
0.447
0.390

Moles Ratio

20.0%
20.0%
25.0%
25.0%
40.0%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
Yes
Yes
No
No
No

distilled?

Temperature
60
60
60
60
60

inside the flask,

° C.

Adding time,
30
30
30
30
30

mm

Molar excess

20.00%
20.00%
25.00%
25.00%
40.00%

of TBIC

compared to

TAZ

Time kept at

5
5
5
5
5

70° C., min

Time for

10
10
10
10
10

cooling down

until 50° C.,

min

Time for

60
60
60
60
60

cooling down

at 10° C., min

Amicarbazone

90.0%
82.2%
97.5%
92.7%
92.2%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying under vacuum = Yes

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = More than 18%

Amicarbazone purity, % w/w = high purity

Reagents

Reactants
Purity (%)
B16
B17
B18
B19
B20

TBIC
81.20%
55.7794
55.4773
55.681
55.6993
64.1688

(Poor quality)

TBIC
98.50%
--
--
--
---
--

(Good quality)

TAZ
97.71%
62.8727
65.0335
67.9919
68.0143
78.3564

Toluene
99.27%
198.0658
196.9931
197.7164
197.7814
227.8555

KOH (51.81%)
51.81%
1.4874
1.4089
1.4848
1.4853
1.7111

Washing Water
--
68.6203
67.2541
67.501
67.5232
77.7906

moles TBIC

0.562
0.559
0.561
0.562
0.647

moles TAZ

0.433
0.447
0.468
0.468
0.539

Moles Ratio

30.0%
25.0%
20.0%
20.0%
20.0%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
No
No
No
No
No

distilled?

Temperature
60
60
60
60
60

inside the flask,

° C.

Adding time,
30
30
30
30
30

min

Molar excess of

30.00%
25.00%
20.00%
20.00%
20.00%

TBIC compared

to TAZ

Time kept at

5
5
5
5
5

70° C., min

Time for cooling

10
10
10
10
10

down until 50° C.,

min

Time for cooling

60
60
120
120
120

down at 10° C.,

min

Amicarbazone

88.1%
98.0%
99.7%
99.4%
98.1%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying of TAZ under vacuum = Yes

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = More than 18%

Amicarbazone purity, % w/w = high purity

Reagents

Reactants
Purity (%)
B21
B22
B23
B24
B25

TBIC
81.20%
200.0000
64.1688
350.0000
300.0000
300.0000

(Poor quality)

TBIC
98.50%
--
--
--
---
--

(Good quality)

TAZ
97.71%
244.2196
78.3564
427.3842
366.3293
372.4959

Toluene
99.27%
710.1754
227.8555
1242.807
1065.2632
1065.2632

KOH (51.81%)
51.81%
5.3333
1.7111
9.332
7.9999
7.9999

Washing Water
--
242.4561
77.7906
424.2982
363.6842
363.6842

moles TBIC

2.017
0.647
3.529
3.025
3.025

moles TAZ

1.680
0.539
2.941
2.521
2.563

Moles Ratio

20.0%
20.0%
20.0%
20.0%
18.0%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
No
No
No
No
No

distilled?

Temperature
60
60
60
60
60

inside the flask,

° C.

Adding time,
30
30
30
30
30

min

Molar excess of

20.00%
20.00%
20.00%
20.00%
18.01%

TBIC compared

to TAZ

Time kept at

5
5
5
5
5

70° C., min

Time for cooling

10
10
10
10
10

down until 50° C.,

min

Time for cooling

120
120
120
120
120

down at 10° C.,

min

Amicarbazone

97.3%
97.2%
97.4%
97.8%
98.2%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying of TAZ under vacuum = Yes

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = More than 18%

Amicarbazone purity, % w/w = high purity

Reagents

Reactants
Purity (%)
B26
B27
B28
B29
B30

TBIC
81.20%
65.0000
62.1739
350.0000
350.0000
350.0000

(Poor quality)

TBIC
98.50%
--
--
--
---
--

(Good quality)

TAZ
97.71%
82.8223
82.8223
427.3842
420.332398
420.3324

Toluene
99.27%
230.8070
230.8070
1242.807
1242.807
1242.807

KOH (51.81%)
51.81%
1.7333
1.7333
9.332
9.4506
9.4506

Washing Water
--
78.7982
78.7982
424.2982
424.2982
424.2982

moles TBIC

0.655
0.627
3.529
3.529
3.529

moles TAZ

0.570
0.570
2.941
2.892
2.892

Moles Ratio

15.0%
10.0%
20.0%
22.0%
22.0%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
No
No
No
No
No

distilled?

Temperature
60
60
60
60
60

inside the flask,

° C.

Adding time,
30
30
30
30
30

min

Molar excess of

15.00%
10.00%
20.00%
22.01%
22.01%

TBIC compared

to TAZ

Time kept at

5
5
5
5
5

70° C., min

Time for cooling

10
10
10
10
10

down until 50° C.,

min

Time for cooling

120
120
120
120
120

down at 10° C.,

min

Amicarbazone

88.5%
88.5%
98.7%
97.8%
97.7%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying of TAZ under vacuum = Yes

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = More than 18%

Amicarbazone purity, % w/w = high purity

Reagents

Reactants
Purity (%)
B31
B32
B33
B34
B35

TBIC
81.20%
350.0000
350.0000
350.0000
116.6667
116.6667

(Poor quality)

TBIC
98.50%

(Good quality)

TAZ
97.71%
420.3324
420.3324
427.3842
142.4614
140.1108

Toluene
99.27%
1242.807
1242.807
1242.807
414.2690
414.2690

KOH (51.81%)
51.81%
9.4506
9.4506
9.4506
3.1502
3.1502

Washing Water
--
424.2982
424.2982
424,2982
141.4327
141.4327

moles TBIC

3.529
3.529
3.529
1.176
1.176

moles TAZ

2.892
2.892
2.941
0.980
0.964

Moles Ratio

22.0%
22.0%
20.0%
20.0%
22.0%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
No
No
No
No
No

distilled?

Temperature
60
60
60
60
60

inside the flask,

° C.

Adding time,
30
30
30
30
30

min

Molar excess of

22.01%
22.01%
20.00%
20.00%
22.01%

TBIC compared

to TAZ

Time kept at

5
5
5
5
5

70° C., min

Time for cooling

10
10
10
10
10

down until 50° C.,

min

Time for cooling

120
120
120
120
120

down at 10° C.,

min

Amicarbazone

90.4%
90.7%
93.5%
91.6%
92.6%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying of TAZ under vacuum = Yes

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = More than 18%

Amicarbazone purity, % w/w = high purity

Reactants

Reagents
Purity (%)
B37
B38
B39
B40

TBIC
81.20%
116.6667
115.7398
86.8049
86.8049

(Poor quality)

TBIC
98.50%

(Good quality)

TAZ
97.71%
135.6764
135.6764
104.2239
115.6264

Toluene
99.27%
414.2690
414.2690
310.7018
310.7018

KOH (51.81%)
51.81%
3.1502
3.1502
2.3626
2.3626

Washing Water
—
141.4327
141.4327
106.0746
106.0746

moles TBIC

1.176
1.167
0.875
0.875

moles TAZ

0.934
0.934
0.717
0.796

Moles Ratio

26.0%
25.0%
22.0%
10.0%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
No
No
No
No

distilled?

Temperature
60
60
60
60

inside the flask,

° C.

Adding time,
30
30
30
30

min

Molar excess of

26.00%
25.00%
22.04%
10.01%

TBIC compared

to TAZ

Time kept at

5
5
5
5

70° C., min

Time for cooling

10
10
10
10

down until

50° C., min

Time for cooling

120
120
120
120

down at 10° C.,

min

Amicarbazone

97.6%
90.8%
92.9%
89.6%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying of TAZ under vacuum = Yes

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = More than 18%

Amicarbazone purity, % w/w = high purity

Reagents

Reactants
Purity (%)
B41
B42
B43
B44
B45

TBIC
81.20%
26.6154
212.9231
26.6154
26.6154
29.1667

(Poor quality)

TBIC
98.50%
--
--
--
--
--

(Good quality)

TAZ
97.71%
30.0000
240.0000
30.4699
29.3242
35.0277

Toluene
99.27%
95.2648
762.1183
95.2648
95.2648
103.5673

KOH (51.81%)
51.81%
0.7244
5.7953
0.7244
0.7244
0.7875

Washing Water
--
32.5237
260.1896
32.5237
32.5237
35.3582

moles TBIC

0.268
2.147
0.268
0.268
0.294

moles TAZ

0.206
1.651
0.210
0.202
0.241

Moles Ratio

30.00%
30.00%
28.00%
33.00%
22.01%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
No
No
No
No
No

distilled?

Temperature
60
60
60
60
60

inside the flask,

° C.

Adding time,
30
30
30
30
30

min

Molar excess of

30.00%
30.00%
28.00%
33.00%
22.01%

TBIC compared

to TAZ

Time kept at

5
5
5
5
5

70° C., min

Time for cooling

10
10
10
10
10

down until 50° C.,

min

Time for cooling

120
120
120
120
120

down at 10° C.,

min

Amicarbazone

98.2%
97.3%
93.5%
92.9%
89.3%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying of TAZ under vacuum = Yes

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = More than 18%

Amicarbazone purity, % w/w = high purity

Reactants

Reagents
Purity (%)
B46
B47

TBIC
81.20%
29.1667
29.1667

(Poor quality)

TBIC
98.50%
—
—

(Good quality)

TAZ
97.71%
34.1898
32.8769

Toluene
99.27%
103.5673
103.5673

KOH (51.81%)
51.81%
0.7777
0.7777

Washing Water
—
35.3582
35.3582

moles TBIC

0.294
0.294

moles TAZ

0.235
0.226

Moles Ratio

25.00%
30.00%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
No
No

distilled?

Temperature
60
60

inside the flask,

° C.

Adding time,
30
30

min

Molar excess of

25.00%
30.00%

TBIC compared

to TAZ

Time kept at

5
5

70° C., min

Time for cooling

10
10

down until

50° C., min

Time for cooling

120
120

down at 10° C.,

min

Amicarbazone

92.0%
96.1%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying of TAZ under vacuum = Yes

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = More than 18%

Amicarbazone purity, % w/w = high purity

Reactants

Reagents
Purity (%)
B49
B50
B51
B52

TBIC
81.20%
30.0000
30.0000
30.0000
30.0000

(Poor quality)

TBIC
98.50%
—
—
—
—

(Good quality)

TAZ
97.71%
40.7013
38.2273
41.8644
41.8644

Toluene
99.27%
106.5263
106.5263
106.5263
106.5263

KOH (51,81%)
51.81%
0.7716
0.7716
0.7716
0.7716

Washing Water
—
36.3684
36.3684
36.3684
36.3684

moles TBIC

0.302
0.302
0.302
0.302

moles TAZ

0.280
0.263
0.288
0.288

Moles Ratio

8.01%
15.00%
5.00%
5.00%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
Yes
Yes
Yes
Yes

distilled?

Temperature
60
60
60
60

inside the flask,

° C.

Adding time,
30
30
30
30

min

Molar excess of

8.01%
15.00%
5.00%
5.00%

TBIC compared

to TAZ

Time kept at

5
5
5
5

70° C., min

Time for cooling

10
10
10
10

down until

50° C., min

Time for cooling

120
120
120
120

down at 10° C.,

min

Amicarbazone

95.5%
82.6%
82.6%
87.8%

purity, % w/w

Poor quality - TBIC = 81.20% purity

Azeotropic drying of TAZ under vacuum = Yes

Was used TBIC distilled = Yes

Molar excess of TBIC compared to TAZ = less than 18%

Amicarbazone purity, % w/w = low purity

Reactants

Reagents
Purity (%)
B54
B55
B57
B58

TBIC
81.20%
—
—
—
—

(Poor quality)

TBIC
98.50%
30.0000
30.0000
30.0000
30.0000

(Good quality)

TAZ
97.71%
42.2680
42.2680
42.2680
42.2680

Toluene
99.27%
106.5263
106.5263
106.5263
106.5263

KOH (51.81%)
51.81%
0.7716
0.7716
0.7716
0.7716

Washing Water
—
36.3684
36.3684
36.3684
36.3684

moles TBIC

0.302
0.302
0.302
0.302

moles TAZ

0.291
0.291
0.291
0.291

Moles Ratio

4.00%
4.00%
4.00%
4.00%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
No
No
No
No

distilled?

Temperature
60
60
60
60

inside the flask,

° C.

Adding time,
30
30
30
30

min

Molar excess of

4.00%
4.00%
4.00%
4.00%

TBIC compared

to TAZ

Time kept at

5
5
5
5

70° C., min

Time for cooling

10
10
10
10

down until

50° C., min

Time for cooling

120
120
120
120

down at 10° C.,

min

Amicarbazone

97.25%
94.56%
93.99%
97.10%

purity, % w/w

Good quality - TBIC = 98.50% purity

Azeotropic drying of TAZ under vacuum = Yes

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = less than 18%

Amicarbazone purity, % w/w = high purity (Since Good quality of TBIC is used)

Reactants

Reagents
Purity (%)
B59
B60
B61

TBIC
81.20%
—
—
—

(Poor quality)

TBIC
98.50%
30.0000
30.0000
30.0000

(Good quality)

TAZ
97.71%
42.2680
42.6780
41.8662

Toluene
99.27%
106.5263
106.5263
106.5263

KOH (51.81%)
51.81%
0.7716
0.7716
0.7716

Washing Water
—
36.3684
36.3684
36.3684

moles TBIC

0.302
0.302
0.302

moles TAZ

0.291
0.294
0.288

Moles Ratio

4.00%
3.00%
5.00%

TBIZ/TAZ

TAZ
Azeotropic
Yes
Yes
Yes

drying under

vacuum?

TBIC adding
Was used TBIC
No
No
No

distilled?

Temperature
60
60
60

inside the flask,

° C.

Adding time,
30
30
30

min

Molar excess of

4.00%
3.00%
5.00%

TBIC compared

to TAZ

Time kept at

5
5
5

70° C., min

Time for cooling

10
10
10

down until

50° C., min

Time for cooling

120
120
120

down at 10° C.,

min

Amicarbazone

97.22%
98.27%
98.27%

purity, % w/w

Good quality - TBIC = 98.50% purity

Azeotropic drying of TAZ under vacuum = Yes

Was used TBIC distilled = No

Molar excess of TBIC compared to TAZ = less than 18%

Amicarbazone purity, % w/w = high purity (Since Good quality of TBIC is used)

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)

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

International Classifications

Abstract

Description

Claims

Priority Claims (1)