Title of Invention

"A PROCESS FOR THE PREPARATION OF N,N'-DICHLORO BIS (2,4,6-TRICHLOROPHENYL) UREA"

Abstract

The present invention relates to the development of an efficient process for preparation of N,N'-Dichlor bis (2,4,6-trichlorophenyl) urea (CC-2) a potent reactive decontaminant of Chemical Welfare Agent (CWA) Sulphur mustard. More particularly, the present invention relates to development of industrially viable one pot procedure for production of CC-2, which is to be used as key ingredient in a formulation developed as personal chemical de-toxicant against sulphur mustard.

Full Text

FIELD OF INVENTION The present invention relates to the development of an efficient process for preparation of N,N'-Dichlor bis (2,4,6-trichlorophenyl) urea (CC-2) a potent reactive decontaminant of Chemical Welfare Agent (CWA) Sulphur mustard. More particularly, the present invention relates to development of industrially viable one pot procedure for production of CC-2, which is to be used as key ingredient in a formulation developed as personal chemical de-toxicant against sulphur mustard. PRIOR ART Decontamination of CWAs is required in case of chemical attack by adversaries or terrorists. Decontamination is one of the important combating activities (detection protection and decontamination) against CWAs. Decontamination of CWAs is achieved either by physically removing the toxic chemicals from contaminated surfaces (materials in the field like vehicles, buildings, equipments etc. and living objects) or by chemically converting them into relatively less or non-toxic substances (R. Trapp, 'The detoxification and Natural Degradation of Chemical Warfare Agents' Stockholm International Peace Research Institute, SIPRI , Taylor & Francis, London and Philadelphia 1985). For physical removal of CWAs from contaminated site, adsorbents like Fuller's earth (native aluminium silicate) and detergent / soap solutions are used. Since these decontaminants do not detoxify the CWAs, hence are not considered as reliable means. Second major problem of physical removal and is their safe disposal. Physical decontaminants themselves get contaminated during dcontamination operation; their subsequent safe disposal requires further treatment to neutralise CWAs. Another problem of physical removal is secondary contamination, which is caused by the ensuing desorption of adsorbed CWAs. Yet another problem of physical removal like washing solutions is spreading of contaminated area, since during washing operation the solution is spread over contaminated surface. Chemical deactivation of CWAs with reactive decontaminants is a better choice. (Yang Y.C. Chem. Ind. 1995, May 1, 334). Currently used reactive de-toxicant include nucleophile/base-amine mixtures and bleach formulations. (Yang Y.C; Baker J.A.; Ward J.R. Chem. Rev. 1992, 92, 1729; R.P.Seiders, US Patent H366, 1987; and Govan Norman, Int. Patent A62D3/00 & Eur. Patent A62D3/00E, 1998 ; Yang Y.C, Szfraniec L.L.,'Beaudry W.T., Davis F.A. Proceedings of the 1988 US Army CRDEC -SP-013, Aberdeen Proving Ground Maryland August 1989, Vol 1 ). These formulations are although effective in decontamination of CWAs cannot be used as personal protective formulation because, they are highly corrosive and toxic. Hence, there was need to develop safe and effective decontaminant formulation against CWAs for human application. A requirement for a topical skin protectant to protect skin from CWAs is recognised. Although several creams and ointments were made but none of them was effective in detoxifying the toxic chemicals. So, a concentrated effort to develop ointments for protection sulphur mustard a toxic chemical was made at Edgewood Arsenal, Maryland USA. Which resulted in development of M-5 ointment but it left room for improvement. For several years, research concentrated to introduce active ingredients like alkalies, chelators, sorbents etc into polyethylene based formulations. However, none of them provided the required protection (D.K Liu, R.W. Wannemacher, T.H.Snider, T.L.Hayes, J.Appl.Toxicol. 1999, 19, 541). Recently, two compounds have been used as active ingredients in the formulations made to protect human skin. A substance coded as S-330 (1,3,4,6-tetrachloro-7,8-diphenyl-2,5-diiminoglycoluril) (J.C.Speck Jr. US Patent No 5607,979, 1997) was mixed with perfluorinated ethers and evaluated as a reactive decontaminant against sulphur mustard (M.L.Shih, W.D.Korte, J.R.Smith, L.L.Szfraniec , J.Appl.Toxicol. 1999, 19, S89). But the main disadvantages of this system are use of uneconomic and non-ecofriendly perfluorinated compound as base material and S-330 decomposes within 2-3 weeks at room temperature in presence of even little moisture (E.H.Brau, J.Appl.Toxicol. 1999, 19, S47; O.Koper, E.Lucas, K.J.Klabunde J.Appl.Toxicol. 1999, 19, S59). Another disadvantage of this system is that it is not very fast acting, which is the prime requirement of any decontaminant. The second compound which was found very efficient, fast acting, and effective at sub-zero temperature also in decontaminating the sulphur mustard is N,N'-Dichloro bis(2,4,6-trichlorophenyl) urea (CC-2) (D.K.Dubey, R.C.Malhotra, R.Vaidyanathaswamy , R.Vijayaraghava. J.Org.Chem. 1999, 64, 8031). Formulations made by incorporating CC-2 in different bases like Gum acasia and hydroxypropyl cellulose were found to be very effective, stable, safe and provided the best protection against topically applied sulphur mustard in Mice and Rats. The CC-2 based formulation has been approved by competent authority for introduction in to services after passing through necessary toxicological and pharmacological tests and trials (R.vijayraghavan, P.Kumar, D.K.Dubey, and R.Singh, Biomedical and Environmental Sciences 2002, 15, 25; Vijayraghavan R, Praveen Kumar, Dubey D K, Ram Singh, Sachan A S, Pant S C, Bhattacharya R, Ind. J. Pharmacol,2002, 34, 321 ). The first requirement to produce CC-2 based formulation in large quantities is to develop technology for preparation of CC-2 itself. The methods reported in literature for preparation of CC-2 are inadequate to meet the requirement of an industrially viable process. In one method CC-2 is prepared by reacting diphenyl urea with chlorine for 48 hours in two steps (F.D.Chattaway, K.J.P.Orton, Berichte 1901, 34, 1073). This method has several disadvantages such as i) complete chlorination of aromatic rings did not take place ii) yield of the CC-2 is NEED FOR THE INVENTION Keeping in view the hazards of CWAs, their decontamination is of paramount importance. It is required on the battle field, laboratories, production and storage plants, destruction sites and more importantly in case of sabotage and usage of CWAs by the terrorists. Of the various known CWAs, sulphur mustard (SM) is an alkylating agent, and is a potent incapacitant and lethal in large quantities. SM causes serious blisters on the skin upon contact, and it is cytotoxic and radiomimetic. There are no specific antidotes for SM toxicity and it is a challenge even today in chemical warfare scenario. Since SM is highly lipophilic and gets absorbed very quickly after contact with skin, the best way of protection from SM is to decontaminate it instantaneously after contact with skin without causing any damage to delicate human skin. This stringent requirement of decontaminant was successfully met by developing a CC-2 based formulation that deactivated the topically applied SM instantaneously without causing any irritation or harm to the skin. Keeping in view the requirement of production of CC-2 based formulation, and limitations of existing synthetic procedures (as defined above) of CC-2, there was dire need to develop an industrially viable process for production of CC-2. More importantly, there was need for development of one pot process (without any requirement of isolation of intermediates or precursors) to produce CC-2 by making use of indigenously available chemicals. OBJECTS OF THE INVENTION The main object of the present invention is to develop a process for production of N,N'-Dichloro bis(2,4,6-trichlorophenyl) urea (CC-2), the potent decontaminant of sulphur mustard. Another objective of the present invention is to develop a synthetic procedure for CC-2 by making use of indigenously available chemicals like N,N'-bis (phenyl)urea and chlorine gas. Yet another object of the present invention is to optimise the reaction conditions for preparation of CC-2 such as use of appropriate solvent, temperature, time and catalyst. Still another object of the present invention is to screen the Lewis acid and Bronsted base catalysts to obtain the pure CC-2 in high yields in minimum possible time. Further object of the present invention is to optimise the recrystallisation conditions of CC-2 from crude product to eliminate the co-products formed during process. Still another objective of this invention is to optimise the pH of reaction mixture for N-chlorination of precursor (HCC-2), which is generated in-situ during process. STATEMENT OF INVENTION The present invention relates to a process for preparation of N,N'-dichloro bis (2,4,6 - trichlorophenyl) urea which comprising: i) dissolving N,N'- bis (phenyl) urea in organic solvent and amine, ii) reacting N,N'- bis (phenyl) urea with Chlorine till reaction is complete to obtain bis (2,4,6 - trichlorophenyl) urea, iii) cooling the mixture to 5-15° C and neutralizing it with alkali hydroxide, iv) reacting bis (2,4,6 - trichlorophenyl) urea with chlorine till organic matter is dissolved to obtain N,N'-dichloro bis (2,4,6 trichlorophenyl) urea, v) the mixture is poured into water to precipitate N,N'-dichloro bis (2,4,6 - trichlorophenyl) urea, and vi) washing the precipitate and recrystallizing the same. The chlorination of aromatic rings can also be affected by the protic organic acids such as acetic acid and propionic acid, would be more appropriate as organic solvent. However, acetic acid is preferred as solvent because N,N'-bis (phenyl) urea is easily dissolved in it at a temperature of 20-100 °C. The alkali hydroxide used in the process is selected from sodium hydroxide and potassium hydroxide. In the present invention chlormation of N,N'-bis (phenyl) urea is carried out in acetic acid in the presence of amines such as pyridine or any primary, secondary and tertiary amines including diamines to hexamines to neutralize or scavenge the generated hydrochloric acid. In the present invention chlorine gas is dried before reacting with N,N' bis (phenyl) urea by passing it through calcium chloride and sulfuric acid. The chlorination of N,N'- bis (phenyl) urea is carried out at 20 -100° C. The chlorination of bis (2,4,6 - trichlorophenyl) urea is carried out at 0 -70° C. In present invention aromatic electrophilic substitution of phenylic hydrogens at 2,4,6 positions by chlorine could be facilitated by use of Lewis acid catalysts such as aluminium chloride, boron trifiuoride etherate and iron (IIi) chloride. In the present invention use of Bronsted bases (more particularly amines) as scavenger of generated hydrochloric acid to drive the reaction in forward direction and check the incomplete chlorination of phenyl rings, which is quite possible if sufficient scavenger of hydrochloric acid, is not present in the reaction mixture. In the present invention, vigorous mechanical stirring and intermittent cleaning of passing tube (of chlorine gas) in reaction mixture is done as it gets chocked by precipitation of HCC-2. In the present invention, N-chlorination is achieved by passing chlorine gas through reaction mixture containing HCC-2, whose pH 6-7 is maintained by intermittent addition of sodium hydroxide at 70°C, till the precipitated of HCC-2 is dissolved. Although the invention has been described in detail with reference to a preferred embodiment it is to be understood that the above description of the present invention is susceptible to considerable modifications, variations and adaptations by those skilled in the art, such modification are intended to be considered to be within the scope and spirit of the present invention. DESCRIPTION OF THE PROCESS According to the present invention, the process for preparation of CC-2 involves following steps. CC-2 is prepared from N,N'-bis (phenyl) urea by chlorinating it in two steps in same pot. N,N'-bis (phenyl) urea in acetic acid in the presence of pyridine (25-100 mole %) is first chlorinated at 20-100°C and then chlorinating in acetic acid to which sodium hydroxide is added to adjust pH 6-7 at 20-70°C. This successive aromatic and N-chlorination yielded 80% CC-2. N,N'-bis (phenyl) urea (DPU) is first suspended in acetic acid and pyridine (or any primary, secondary and tertiary amines including diamines to hexamines). It is heated up to 20-100°C with stirring to completely dissolve DPU. Chlorine gas is gently bubbled through this solution after passing through a calcium chloride and sulfuric acid traps. Chlorine is absorbed in the reaction mixture, where chlorination of phenyl rings takes place at 2,4,6 positions. As the reaction proceeds and aromatic chlorination is achieved, the precipitation of hexachlorocarbanilide (HCC-2) occurs and absorption of chlorine gas gradually ceases. During this step intermittent cleaning of the passing tube is necessary as it gets chocked by precipitation of HCC-2. This initial aromatic chlorination is complete with in 4-6 hours. The reaction mixture is cooled to 0-70°C and sodium hydroxide is added intermittently to attain pH 6-7. Chlorine is again passed 3-4 hours with stirring. N-chlorination takes place during this step which is evident by re-dissolution of fluffy precipitate earlier formed. After complete dissolution of fluffy precipitate, the reaction mixture is poured into ice cold water to precipitate CC-2, which is filtered and dried. This CC-2 is washed with n-hexane to wash away the dark brown coloured impurities. White amorphous powder is obtained after washing with hexane, which is recrystallised from dichloromethane hexane mixture. Pure CC-2 has melting point of 178-180 °C, with single peak in 1H NMR at 8 = 7.2. (Formula Removed) Example -1 25 gms N,N'-Bis(phenyl) urea (0.117 moles) was dissolved in 300 mL of acetic acid containing 18 gms (0.225 moles) of pyridine by stirring at 70 °C. The reaction flask was equipped with water condenser and mounted on a mechanical stirrer. It was chlorinated by passing chlorine for 5 hours with stirring; absorption of chlorine ceased with complete precipitation of bis(2,4,6 trichlorophenyl) urea (HCC-2). The mixture was cooled to 10 °C and sodium hydroxide was added in portions to bring the pH of the mixture at 7. Chlorine was further passed till the organic matter was completely re-dissolved. The mixture was poured in to water to precipitate CC-2, which was washed with water, filtered, and recrystllised from dichloromethane / hexane mixture after drying. The yield of CC-2, (prismatic crystals, m.p.178-180 °C) was 45 gms (79 %). The positive chlorine of CC-2 was checked by standard iodometric titration. Example -2 10 gms N,N'-Bis(phenyl) urea (0.047 moles) was dissolved in 200 mL of acetic acid containing 5 gms (0.0625 moles) of pyridine by stirring at 60 °C. The reaction flask was equipped with water condenser and mounted on a mechanical stirrer. It was chlorinated by passing chlorine for 4 hours with stirring; absorption of chlorine ceased with complete precipitation of bis(2,4,6 trichlorophenyl) urea (HCC-2). The mixture was cooled to 15 °C and sodium hydroxide was added in portions to bring the pH of the mixture at 7. Chlorine was further passed till the organic matter was completely re-dissolved. The mixture was poured in to water to precipitate CC-2, which was washed with water, filtered, and recrystllised from dichloromethane / hexane mixture after drying. The yield of CC-2 was 19 gms (82%). Example -3 70 N,N'-Bis(phenyl) urea (0.33 moles) was dissolved in 400 mL of acetic acid containing 20 gms (0.25 moles) of pyridine by stirring at 80°C. The reaction flask was equipped with water condenser and mounted on a mechanical stirrer. It was chlorinated by passing chlorine for 6 hours with stirring; absorption of chlorine ceased with complete precipitation of bis (2,4,6 trichlorophenyl) urea (HCC-2). The mixture was cooled to 10 °C and sodium hydroxide was added in portions to bring the pH of the mixture at 7. Chlorine was further passed till the organic matter was completely re-dissolved. The mixture was poured in to water to precipitate CC-2, which was washed with water, filtered, and recrystllised from dichloromethane / hexane mixture after drying, 116 gms pure CC-2 was obtained. We Claim: 1. A process for preparation of N,N'- dichloro bis (2,4,6 - trichlorophenyl) urea which comprising: i) dissolving N,N'- bis (phenyl) urea in organic solvent and amine, ii) reacting N,N'- bis (phenyl) urea with Chlorine till reaction is complete to obtain bis (2,4,6 - trichlorophenyl) urea, iii) cooling the mixture to 5-15° C and neutralizing it with alkali hydroxide, iv) reacting bis (2,4,6 - trichlorophenyl) urea with chlorine till organic matter is dissolved to obtain N,N'-dichloro bis (2,4,6 trichlorophenyl) urea, v) the mixture is poured into water to precipitate N,N'-dichloro bis (2,4,6 - trichlorophenyl) urea, and vi) washing the precipitate and recrystallizing the same. 2. A process as claimed in claim 1, wherein organic solvent is selected from acetic acid and propionic acid. 3. A process as claimed in claim 1, wherein alkali hydroxide is selected from sodium hydroxide and potassium hydroxide. 4. A process as claimed in claim 1, wherein amine is pyridine or any primary, secondary and tertiary amines including diamine to hexamines. 5. A process as claimed in claim I, wherein chlorine gas is dried before reacting with N, N' bis (phenyl) urea by passing it through calcium chloride and sulfuric acid. 6. A process as claimed in claim 1, wherein chlorination in step (ii) is carried out at 20-100° C. 7. A process as claimed in claim 1, wherein chlorination in step (iv) of bis (2,4,6- trichlorophenyl) urea is carried out at pH 6-7 and at 0-70° C. 8. A process as claimed in claim 1, wherein chlorination is carried out in presence of Lewis acid and Bronsted base catalyst.

Documents:

391-del-2005-abstract.pdf

391-DEL-2005-Claims-(16-12-2011).pdf

391-DEL-2005-Claims-(22-03-2012).pdf

391-del-2005-claims.pdf

391-DEL-2005-Correspondence Others-(22-03-2012).pdf

391-DEL-2005-Correspondence-Others-(16-12-2011).pdf

391-del-2005-correspondence-others.pdf

391-del-2005-description (complete).pdf

391-DEL-2005-Form-1-(16-12-2011).pdf

391-del-2005-form-1.pdf

391-del-2005-form-18.pdf

391-del-2005-form-2.pdf

391-DEL-2005-Form-3-(16-12-2011).pdf

391-del-2005-form-3.pdf

391-del-2005-gpa.pdf