Claims:We Claim,
1. An improved process for preparing 3-Methyl-4-nitroiminoperhydro-1,3,5-oxadiazine comprising condensing a wet cake of 1-methyl-3-nitroguanidine with paraformaldehyde in the presence of an acid catalyst and an organic solvent, with a proviso that the said process does not involve the use of formic acid.
2. A process according to claim 1, wherein the acid catalyst used is selected from alkyl or aryl sulfonic acid, preferably p-toluene sulfonic acid, methane sulfonic acid; sulfuric acid or mixtures thereof.
3. A process according to claim 2, wherein the acid catalyst used either alone or in combination, is in a concentration of 10 %.
4. A process according to claim 1, wherein the organic solvent used is selected from toluene, 1,4-dioxane, tetrahydrofuran, chlorobenzene, o-dichlorobenzene and nitrobenzene.
5. A process according to claim 1, wherein the reaction is carried out at a temperature of 90-110°C.
6. An improved process for preparing 3-Methyl-4-nitroiminoperhydro-1, 3, 5-oxadiazine comprising condensing a wet cake of 1-methyl-3-nitroguanidine with paraformaldehyde in the presence of an acid catalyst and an organic solvent, with a proviso that the said process does not involve the use of formic acid, wherein the time required for preparing 3-Methyl-4-nitroiminoperhydro-1, 3, 5-oxadiazine from 1-methyl-3-nitroguanidine is 5-6 hours.
7. A process according to preceding claims, wherein 3-Methyl-4-nitroiminoperhydro-1, 3, 5-oxadiazine is characterized by HPLC purity of greater than 99.5%.
8. A process according to preceding claims, wherein 3-Methyl-4-nitroiminoperhydro-1, 3, 5-oxadiazine obtained is useful as an intermediate for the synthesis of Thiamethoxam.
9. A process for preparing 1-methyl-3-nitroguanidine, comprising alkylating 1-nitroguanidine with methylamine in the presence of a dilute acid to yield a wet cake, useful for synthesis of 3-Methyl-4-nitroiminoperhydro-1, 3, 5-oxadiazine.
10. A process according to claim 9, wherein the dilute acid is selected from sulfuric acid and acetic acid.
, Description:
Field of Invention
The present invention relates to an improved process for the preparation of 3-Methyl-4-nitroiminoperhydro-1,3,5-oxadiazine (MNIO) which is economical and commercially feasible. MNIO prepared in accordance with the present invention may be used as an intermediate to manufacture a broad-spectrum insecticide, Thiamethoxam.
Background of the Invention
3-Methyl-4-nitroiminoperhydro-1,3,5-oxadiazine (MNIO) also chemically known as 3-Methyl-4-nitroamino-1,2,3,6-tetrahydro-1,3,5-oxadiazine is used as an intermediate for the manufacture of Thiamethoxam.
Thiamethoxam is a broad-spectrum insecticide first developed by Novartis Corporation in 1991, approved for use in the US in 1999 as an antimicrobial pesticide wood preservative and as a pesticide. It is the first commercial neonicotinoid insecticide from the thianicotinyl subclass, which acts by binding to nicotinic acetylcholine receptors. It exhibits exceptional systemic characteristics and provides excellent control of a broad range of commercially important pests such as aphids, jassids, whiteflies, thrips, rice hoppers, Colorado potato beetle, flea beetles and wireworms, as well as some lepidopteran species.
Thiamethoxam is prepared by reacting two intermediates: 2-chloro-5-chloromethyl thiazole (CCMT) and 3-methyl-N-nitroimino perhydro-1,3,5-oxadiazine. MNIO is structurally represented as:

The methods of preparation of MNIO have been disclosed in the literature. MMG 445 Basic Biotechnology eJournal pp. 46-52, 2006 describes the synthesis of 4-nitroimino-1,3,5-oxadinazinane, comprising reacting S-methyl-N-nitroisothiourea and methylamine in 50 °C ethanol and this produced the monosubstituted nitroguanidine in 94% yield. The mono-substituted nitroguanidine is heated in a 1:1 mixture of aqueous formaldehyde solution and formic acid to 90°C for several hours. This procedure produces the 4-nitroimino-1,3,5-oxadiazinane in 71% yield. Alkylation of 4-nitroimino-1,3,5-oxadiazinane with 2-chlrothiazol-5-ylmethyl chloride in N,N-dimethylformamide (DMF) in the presence of potassium carbonate led to Thiamethoxam.
US Patent 5,852,012 B2 and its divisional patents US 6,022,871, US 6,376,487, US 6,627,753, US 7,655,650 describes a process for synthesizing MNIO starting from N-methylnitroguanidine, wherein the process comprises reacting 1-methyl-3-nitroguanidine with paraformaldehyde in the presence of dioxane, toluene and using a base triethylamine. The process takes place in the presence of acids like p-toluene sulfonic acid or methyl sulfonic acid as catalysts. The reaction is carried out for 18-20 hours for the completion of the reaction.
However, the process as disclosed above has considerable disadvantages. It is a lengthy process requiring around 18-20 hours for the completion of the reaction. Dioxane and toluene are to be separated in this process and triethylamine cannot be recovered. Also, the process involves crystallization by methanol. This not only leads to longer times in a production cycle but also add to the cost to the manufacturer making the entire process lesser efficient.
Indian patent No. 270837 describes preparation of 3-methyl-N-nitroiminoperhydro-1,3,5-oxadiazine (MNIO), wherein wet cake of 1-methyl-3-nitroguanidine is dried under vacuum and converted to MNIO by condensing with paraformaldehyde in presence of formic acid without using an acid catalyst and a solvent, wherein formic acid is recycled repeatedly to about 5-6 times to a strength of about 55%. However, formic acid is corrosive in nature and repeated recycling leads to long cycle times in a production cycle but also add to the cost to the manufacturer making the entire process lesser efficient. Furthermore, the existing process nowhere discloses the repeated recycling of starting material formic acid which is again problematical from ecological and toxicological viewpoint.
Chinese patent application CN 105622541A discloses a process for preparing MNIO, wherein methylnitroguanidine and paraformaldehyde are used as starting materials in a mixed acid system of formic acid and sulfuric acid.
Chinese patent CN 103613560 describes a process for preparing 3-methyl-4-nitroiminoperhydro-1,3,5-oxadiazine employing 1-methyl-3-nitroguanidine and paraformaldehyde as raw materials in the presence of aqueous acetic acid solvent and macroporous strongly acidic cation exchange resin as a catalyst. However, the use of cation exchange resin may not be commercially feasible due to its higher cost.
There is therefore a need in the art to develop a process for preparation of MNIO with an improved and simplified synthesis which significantly reduces the time cycle in a production cycle as compared to existing methods.
Surprisingly, the present inventors have found that the process of the present invention is resulting in 3-Methyl-4-nitroiminoperhydro-1,3,5-oxadiazine (MNIO), being highly reproducible, suitable for commercial production. Moreover, the process also significantly improves the purity of MNIO.
The present invention provides an improved economical, commercially feasible process for preparing MNIO, which involves the use of reagents and solvents that are environment friendly and reduce the ecological and toxicological problems arising from the existing methods.
Object of Invention
An object of the invention is to provide an improved, economical and simplified process for the synthesis of 3-methyl-N-nitroiminoperhydro-1,3,5-oxadiazine (MNIO), useful as an intermediate for the synthesis of Thiamethoxam, a broad-spectrum insecticide.
Another object of the invention is to provide an improved, commercially feasible process for the synthesis of MNIO using 1-methyl-3-nitroguanidine as the starting material, wherein the 1-methyl-3-nitroguanidine may be formed in-situ or isolated as a wet cake.
It is also an object of the invention to provide an improved and commercially feasible process for the synthesis of MNIO from 1-methyl-3-nitroguanidine and paraformaldehyde in the presence of an acid catalyst and an organic solvent.
Also an object of the invention is to provide an improved, economical process for preparing MNIO, wherein the process does not involve the use of formic acid and therefore does not require repeated, time-taking recycling procedure thereof as observed with the existing methods in the art.
Yet another object of the invention is to provide an improved and simplified process for the synthesis of MNIO where the overall cost to the manufacturer is significantly reduced.
Further an object of the invention is to provide an improved process for the synthesis of MNIO which significantly reduces the ecological and toxicological problems thereby making the process environment friendly.
Summary of Invention
In one embodiment, the present invention relates to an improved, economical process for the preparation of 3-methyl-4-nitroiminoperhydro-1,3,5-oxadiazine (MNIO), using 1-methyl-3-nitroguanidine and paraformaldehyde in the presence of an acid catalyst and an organic solvent.
In a second embodiment, the present invention relates to an improved, economical process for the preparation of 3-methyl-4-nitroiminoperhydro-1, 3, 5-oxadiazine (MNIO), using 1-methyl-3-nitroguanidine and paraformaldehyde in the presence of an acid catalyst and an organic solvent, with a proviso that the said process does not utilize formic acid.
In a third embodiment, the present invention provides an improved, commercially feasible process for preparing MNIO, wherein the process comprises the following steps:
(i) Converting Guanidine nitrate to Nitroguanidine by intra-molecular rearrangement to obtain wet cake of Nitroguanidine;
(ii) Alkylating wet cake of Nitroguanidine with an alkylating agent such as methyl amine to obtain wet cake of 1-methyl-3-nitroguanidine;
(iii) Condensing wet cake of 1-methyl-3-nitroguanidine with paraformaldehyde in the presence of an acid catalyst and an organic solvent to obtain 3-methyl-N-nitroiminoperhydro-1,3,5-oxadiazine; further wherein water of the reaction is removed azeotropically.
In an alternative embodiment, 1-methyl-3-nitroguanidine may be prepared by alkylating nitroguanidine with methylamine in the presence of a dilute acid to yield a wet cake, useful for synthesis of MNIO.
In a fourth embodiment, the present invention provides an improved process, wherein 1-methyl-3-nitroguanidine is formed in-situ or isolated as a wet cake, which results in significant improvement in the yield and the purity of the MNIO obtained therefrom.
In a fifth embodiment, the present invention provides an improved process for preparing 3-methyl-4-nitroiminoperhydro-1,3,5-oxadiazine, wherein the reaction solution containing 1-methyl-3-nitroguanidine or wet cake of 1-methyl-3-nitroguanidine is proceeded without further drying to react with paraformaldehyde in the presence of 10% p-toluene sulfonic acid and toluene.
In a sixth embodiment, the present invention provides an improved, commercially feasible process for the synthesis of MNIO, useful as an intermediate for the synthesis of Thiamethoxam, a broad-spectrum insecticide.
In a seventh embodiment, the present invention provides an improved process for preparing MNIO, advantageous in that the reaction time is reduced to 5-6 hours which is significantly lesser when compared to 18-20 hours taken by the known processes and results in desired compound with high purity and better yields.
Detailed Description of the Invention
The present invention relates to an improved process for the preparation of 3-methyl-N-nitroiminoperhydro-1,3,5-oxadiazine (MNIO), represented by a compound of formula I.

MNIO prepared in accordance with the present invention can be used as an intermediate to manufacture a broad-spectrum insecticide, Thiamethoxam.
In an embodiment of the present invention, MNIO of formula (I) is prepared by condensation of 1-methyl-3-nitroguanidine of formula (II) with paraformaldehyde in presence of an acid catalyst and organic solvent. The acid catalyst is selected from R-SO3H, wherein R is an alkyl, aryl group preferably methane sulfonic acid, p-toluene sulfonic acid; and sulfuric acid. Organic solvent is selected from 1,4-dioxane, tetrahydrofuran, toluene, chlorobenzene, o-dichlorobenzene and nitrobenzene preferably toluene or 1,4-dioxane. The reaction can be carried out at temperatures ranging from about 90°C to about 110°C.
In the present disclosure, 1-methyl-3-nitroguanidine (II) may be prepared according to a process, wherein guanidine nitrate (IV) is converted to nitroguanidine (III) by intermolecular rearrangement in the presence of sulfuric acid, wherein nitroguanidine is obtained in the form of wet cake.

In an embodiment, the wet cake of nitroguanidine (III) is alkylated with an alkylating agent in the presence of a dilute acid to obtain 1-methyl-3-nitroguanidine (II), wherein compound II is formed in-situ or isolated as a wet cake. In preferred embodiments of the invention, the alkylating agent used is methylamine and the dilute acid is selected from sulfuric acid, acetic acid. The compound II is not dried and proceeded further for next reaction.

In one preferred embodiment, MNIO (I) is prepared by condensing 1-methyl-3-nitroguanidine (II) obtained as a wet cake, with paraformaldehyde in the presence of p-toluene sulfonic acid (PTSA), preferably 10% PTSA and toluene.

In other preferred embodiment, MNIO (I) is prepared by condensing 1-methyl-3-nitroguanidine (II) with paraformaldehyde in the presence of p-toluene sulfonic acid (PTSA), preferably 10% PTSA and 1,4-dioxane.

In yet another embodiment, MNIO (I) is prepared by condensing 1-methyl-3-nitroguanidine (II) with paraformaldehyde in the presence of sulfuric acid, preferably 10% sulfuric acid and 1,4-dioxane.

In another embodiment, MNIO (I) is prepared by condensing 1-methyl-3-nitroguanidine (II) with paraformaldehyde in the presence of sulfuric acid, preferably 10% sulfuric acid and toluene.

In another embodiment of the invention, the water of the reaction formed during the condensation of 1-methyl-3-nitroguanidine (II) and paraformaldehyde is removed azeotropically.
In some embodiments of the invention, MNIO may also be prepared by condensing a wet cake of 1-methyl-3-nitroguanidine (II) with paraformaldehyde in the presence of an organic solvent and a mixture of acid catalysts selected from R-SO3H.
In one preferred embodiment, MNIO (I) is prepared by condensing 1-methyl-3-nitroguanidine (II) with paraformaldehyde in the presence of toluene and a mixture of 5% p-toluene sulfonic acid (PTSA) and 5% sulfuric acid.

In another preferred embodiment, MNIO (I) is prepared by condensing 1-methyl-3-nitroguanidine (II) with paraformaldehyde in the presence of 1,4-dioxane and a mixture of 5% p-toluene sulfonic acid (PTSA) and 5% sulfuric acid.

In another embodiment, the improved process of the present invention results in 3-methyl-N-nitroiminoperhydro-1,3,5-oxadiazine (MNIO) having HPLC purity of about 99% or more and yields in the range of 80-95%. In preferred embodiments, the process of the present invention results in 3-methyl-N-nitroiminoperhydro-1,3,5-oxadiazine having a HPLC purity of about 99.5% or more and yields greater than 85%.
The present inventors have found that the improved process of the present invention for preparing MNIO, useful as an intermediate for synthesizing Thiamethoxam was found to be superior to the existing methods in that it is cost-effective, commercially scalable and showed reproducible results.
Table 1 demonstrates the purity of MNIO obtained with synthetic methods known in the art.
Table 1
S.No Reagent Solvent Purity %
1 Paraformaldehyde, Formic acid -- 96-97
2 Paraformaldehyde Formic acid + 30% Sulfuric acid 98.5
3 Paraformaldehyde + Amberlyst (catalyst) Aq. Acetic acid 99.3

Table 2 demonstrates the purity and yields of MNIO prepared in accordance with the processes of the present invention.
Table 2
S.No Acid catalyst Solvent Purity % % Yield
1 10% p-toluene sulfonic acid Toluene 99.87 >92%
2 10% p-toluene sulfonic acid 1,4-Dioxane 99.75 >92%
3 10% Sulfuric acid Toluene 99.61 >90%
4 10% Sulfuric acid 1,4-Dioxane 99.54 >90%
5 5% p-toluene sulfuric acid + 5% sulfuric acid Toluene 99.55 >80%
6 5% p-toluene sulfuric acid + 5% sulfuric acid 1,4-Dioxane 99.52 >80%
Advantages of the Invention:
The present invention provides an improved process for the synthesis of 3-
Methyl-N-nitroiminoperhydro-1,3,5-oxadiazine (MNIO) which is simplified, ecological, environment friendly and cost effective.
The present invention provides an improved process for the synthesis of
MNIO from 1-methyl-3-nitroguanidine wherein reaction time is significantly reduced to 5-6 hours when compared to 18-20 hours in known methods.
The present invention provides an improved process for the synthesis of MNIO without drying 1-methyl-3-nitroguanidine and in the presence of an acid catalyst and a solvent, resulting in an increase in yield and purity.
The present invention provides an improved process for the synthesis of MNIO which does not involve the use of formic acid, thereby avoiding the need for repeated recycling which would otherwise increase the production costs.
The present invention is also advantageous in that it does not involve the use of expensive catalysts such as cation exchange resins as used in the prior art.
The present invention is further explained in the form of following examples.
Example 1:
Preparation of Nitroguanidine (III):
Charge 835.5 gm of sulfuric acid into a round bottom flask and cool to 0-10ºC under stirring, slowly add 500 gm of guanidine nitrate at same temperature for 1 hour. After addition, raise the temperature to 25-30ºC and maintain it for 18-20 hours. After maintenance, quench the reaction mass into 3000ml water below 10ºC. After quenching, maintain for one hour and filter the solid followed by washing with chilled water. Take the wet compound and charge 1750 ml of water, heat to 90±5ºC and maintain at 30ºC. After maintenance cool the reaction mass to 5-10ºC, and maintain for one hour. Filter the product and wash with chilled water to obtain a wet cake of nitroguanidine (Weight: 586gm).
Example 2:
Preparation of 1-methyl-3-nitroguanidine (II):
Charge 680 ml of water and 477 gm of mono methylamine into the round bottom flask at 20-25ºC. Slowly add 79.18 gm of dilute sulfuric acid into the round bottom flask at same temperature. Then add wet cake of nitroguanidine obtained from Example 1 at 20-25ºC and maintain it for 22-24 hours. After the completion of reaction, cool the reaction mass to 5-10ºC, and maintain it for 1-2 hours. Filter the solid obtained and wash with chilled water to obtain a wet cake of 1-methyl-3-nitroguanidine (Weight: 530gm).
Example 3:
Preparation of 3-Methyl-4-nitroiminoperhydro-1,3,5-oxadiazine (I):
Charge wet cake of 1-methyl-3-nitroguanidine(II) obtained from Example 2 and toluene (5 volumes) at room temperature, then heat to reflux. Water is removed azeotropically. Cool the reaction mass to 30ºC. Charge 296.68 gm of paraformaldehyde, 38.89 gm of 10% p-toluene sulfonic acid and heat to 92±5°C, maintain it for one hour. After removing water maintain the reaction mass at 105±5ºC for 5-6 hours. After completion of reaction, distill the toluene under vacuum below 65ºC. After the solvent is removed, charge water and stir for 10 min. Slowly cool the reaction mass to 25-30ºC and adjust the pH to 7 ± 0.5 using 50% NaOH solution. Cool the reaction mass to 5-10ºC and maintain for 30 min. Filter the product and wash with chilled water, dried to yield 415 gm of 3-Methyl-4-nitroiminoperhydro-1,3,5-oxadiazine (HPLC purity = 99.87%; Yield = 92%).

However, it is to be understood that these examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without limiting or departing from the scope of the invention.