Title of Invention	IMPROVED PROCESS FOR THE SYNTHESIS OF PARA-NITROBENZYL BROMIDE
Abstract	An improved process for the preparation of p-nitrobenzyl bromide from p-nitrotoluene is disclosed wherein large excess of the reactant in carbon tetrachloride is treated with 2:1 bromide-bromate reagent and the product is isolated efficiently and with high purity through selective cold crystallization from reaction mass so as to allow the mother liquor to be recycled in a subsequent batch without any further work up. The cycles are continued so long as product of desired quality is obtained in adequate yield. Thereafter, the solvent and p-nitrotoluene are recovered from the mother liquor and the residue is treated with sodium borohydride to convert impurities back into reactant or product which is then recycled in the process thereby circumventing the problem of waste disposal and simultaneously yielding the desired product with >95 % yield with respect to p-nitrotoluene and >88 % bromine atom efficiency.

Title of Invention

IMPROVED PROCESS FOR THE SYNTHESIS OF PARA-NITROBENZYL BROMIDE

Abstract

An improved process for the preparation of p-nitrobenzyl bromide from p-nitrotoluene is disclosed wherein large excess of the reactant in carbon tetrachloride is treated with 2:1 bromide-bromate reagent and the product is isolated efficiently and with high purity through selective cold crystallization from reaction mass so as to allow the mother liquor to be recycled in a subsequent batch without any further work up. The cycles are continued so long as product of desired quality is obtained in adequate yield. Thereafter, the solvent and p-nitrotoluene are recovered from the mother liquor and the residue is treated with sodium borohydride to convert impurities back into reactant or product which is then recycled in the process thereby circumventing the problem of waste disposal and simultaneously yielding the desired product with >95 % yield with respect to p-nitrotoluene and >88 % bromine atom efficiency.

Full Text	FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of p-nitrobenzyl bromide. The compound is widely used for esterification of carboxylic acids especially where deprotection is required such as in the synthesis of ß-lactam antibiotic analogs, cephalosporine analogs, penicillin ester analogs, fusidic acid analogs and thienamycin analogs. It is also used as a starting material in the preparation of the drug rizatriptan benzoate. BACKGROUND OF THE INVENTION Reference may be made to the paper entitled "Bromination of ß-nitrotoluene" by J. F. Brewster (J. Am. Chem. Soc; 1918; 40(2); 406-407). The reaction was carried out by reacting p-nitrotoluene with liquid bromine in carbon tetrachloride at elevated temperature (on a hot plate) with exposure to sunlight. ß-nitrobenzyl bromide was obtained in 71% overall yield. The bromine atom efficiency was computed to be 40%. Reference may be made to the procedure reported by G. H. Coleman et. al. in Organic Syntheses, Coll. Vol. 2, p.443 (1943); Vol. 16, p.54 (1936), wherein vapor phase bromination of p-nitrotoluene is disclosed. The reaction was carried out in the presence of liquid bromine at 145-150°C. The yield of isolated product was 53-59 percent. HBr is obtained as byproduct and the overall atom efficiency vis-a-vis product formation is computed to be 28%. Reference may be made to the same article above, wherein it is stated that the procedure of Brewster referred to above can be conveniently adopted by using artificial light in place of sunlight and that the light from two 300-watt tungsten lamps is satisfactory for the bromination of 300 g of p-nitrotoluene. The isolated yield of p-nitrobenzyl bromide is 60-70 per cent of the theoretical amount. Reference may again be made to the same article above wherein it is reported that although p-nitrobenzyl bromide is usually prepared by brominating p-nitrotoluene, it can also be prepared by treating p-nitrobenzyl alcohol with hydrobromic acid and by nitrating benzyl bromide. Reference may also be made to the paper entitled "A note on Bromination of p-nitrotoluene" by G. W. K. Cavill (J. of the Soc. OfChem. Industry, 1946, 40, 124), wherein the bromination of p-nitrotoluene in the presence of liquid bromine and antimony tribromide is reported to yield p-nitrobenzyl bromide in 76% isolated yield. The reaction is undertaken at 120-130°C for 9-10 hrs. The bromine atom efficiency is computed to be 38%. Reference may be made to U.S. Patent 6,740,253, which discloses the use of 2:1 sodium bromide-sodium bromate as atom efficient brominating agent. The reagent can be prepared cost-effectively from the 5:1 sodium bromide-sodium bromate intermediate obtained in the process of producing liquid bromine from sea bittern by the "cold process". Besides being a cost-effective reagent, the use of liquid bromine is avoided and higher bromine atom efficiencies are realized. The said brominating agent is disclosed for the preparation of p-nitrobenzyl bromide from p-nitrotoluene (S. Adimurthy et al. Green Chem., 2008, 10, 232). process has several advantages over the above stated prior art using liquid bromine but, even so, the conversion with respect to p-nitrotoluene is only 78% and with respect to Br it is 66%. Moreover, the work up of the reaction and purification of the product are tedious and there is a problem of management of organic waste containing largely dibromo impurity. Reference may also be made to the same paper, wherein it is stated that impurity formation can be reduced by taking large excess of p-nitrotoluene. However, the data provided is for the crude reaction mixture and nothing is mentioned about the work up of the reaction which would undoubtedly pose serious difficulties if the operations described in the paper are to be followed. The present invention seeks to overcome the above drawbacks of the process of preparation of p-nitrobenzyl bromide from p-nitrotoluene employing the bromide/bromate couple of the prior art. The invention specifically discloses an improved process that is simple to execute and exhibits high yield of desired product with respect to bothp-nitrotoluene and bromide/bromate reagent. Reference may be also made to the paper by Bell et. Al. (Bell, H. M.; Brown, H. C. J. Am. Chem. Soc. 1966, 88, 1473 pg) wherein a procedure is disclosed for the conversion of various benzyl bromides to substituted toluene derivative using NaBH4 in dimethoxy ethane/water as a solvent. This is an important prior art in the context of the present invention which seeks to recycle over-brominated organic waste residue as one of the objects. OBJECTS OF THE INVENTION The main object of the present invention is therefore to provide an improved process for the preparation of p-nitrobenzyl bromide from p-nitrotoluene using 2:1 bromide-bromate reagent which obviates the drawbacks of the prior art. Another object of the present invention is to provide a process wherein the use of a single solvent for reaction, product isolation and purification eliminates the problem of contamination of one solvent with another and the process is made simple. Yet another object of the present invention is to provide a process wherein p-nitrobenzyl bromide is selectively crystallized out from reaction mass through a chilling process which enables the mother liquor containing excess p-nitrotoluene and all of the solvent to be recycled directly. Still another object of the present invention is to obtain product having >98% purity without recourse to re-crystallization. A further object of the present invention is to provide a process which minimizes impurity formation and, consequently, leads to higher bromine atom efficiency. Still another object of the present invention is to treat the residue remaining after distillation with sodium borohydride/ dimethoxy ethane (DME) to convert dibromo impurity back into p-nitrotoluene / p-nitrobenzyl bromide so that the mass can be once again recycled thereby converting waste into product, thereby circumventing the problem of organic waste disposal. SUMMARY OF THE INVENTION The present invention provides an improved process for the preparation of p-nitrobenzyl bromide from p-nitrotoluene, wherein large excess of the reactant in carbon tetrachloride is treated with 2:1 bromide-bromate reagent and the product is isolated efficiently and with high purity through selective cold crystallization from reaction mass so as to allow the mother liquor to be recycled in a subsequent batch without any further work up. The cycles are continued so long as product of desired quality is obtained in adequate yield. Thereafter, the solvent and p-nitrotoluene are recovered from the mother liquor and the residue is treated with sodium borohydride to convert impurities back into reactant or product which is then recycled in the process thereby circumventing the problem of waste disposal and simultaneously yielding the desired product with >95 % yield with respect to p-nitrotoluene and >88 % bromine atom efficiency. The major features of the present invention involve the following: (i) selection of carbon tetrachloride as single organic solvent which enables the reaction to proceed in facile manner under reflux conditions and which also facilitates easy recovery of the desired product through chilling of the reaction mass, (ii) taking two-fold excess of p-nitrotoluene to minimize over-bromination of product, (iii) recycling of the mother liquor and washings from an earlier batch in a consequent batch so as to maintain same total p-nitrotoluene equivalent (i.e., unreacted p-nitrotoluene and p- nitrotoluene -based product/by-product), (iv) taking brominating agent in subsequent batch to the same extent that p-nitrobenzyl bromide product was isolated in the previous batch so as to maintain consistency of stoichiometric ratio from batch-to-batch, (v) avoiding cumbersome work up and instead, subjecting the mother liquor containing excess p-nitrotoluene and p-nitrobenzyl bromide to chilling at minus 15°C to minus 20°C temperature to crystallize out the latter selectively, thereafter allowing the mass to attain a temperature of minus 4°C, following which the mother liquor is separated out rapidly in a continuous centrifuge. The solid product is then washed in the centrifuge with chilled (minus 4°C) carbon tetrachloride (2:1 v/w) collected towards the end of the reaction to attain >98% purity. (vi) minimizing carbon tetrachloride loss by carrying out the work up under chilled conditions in continuous centrifuge. (vii) recovering carbon tetrachloride by ordinary distillation and p-nitrotoluene by vacuum distillation from mother liquor of last (8th) batch and treating the waste residue with NaBH4 to convert dibromo impurity into p-nitrotoluene and p-nitrobenzyl bromide, which can be recycled to eliminate the problem of waste while increasing overall yield with respect to p-nitrotoluene and reagent. Accordingly, the present invention provides an improved process for the preparation of p- nitrobenzyl bromide, wherein the steps comprising: (i) dissolving 1.09 to 2.18 moles of a solid brominating reagent in water and adding into a reaction vessel; (ii) adding a solution of p-nitrotoluene in carbon tetrachloride into the reaction vessel of step (i) to obtain a reaction mass; (iii) raising the temperature of the reaction mass of step (ii) gradually to 80 to 90 degree C under continuous illumination and stirring; (iv) adding a mineral acid in gradual amounts to the reaction mass of step (iii) as per the stoichiometric requirement; (v) continuing the stirring under reflux conditions for additional 1.0-2.0 hours at the end of which the reaction mass becomes almost colorless; (vi) switching from reflux mode as in step (v) to distillation mode and distilling out a part of the carbon tetrachloride which is chilled to a temperature in the range of minus 5 to minus 20 degree C for washing of the centrifuged product as mentioned in (xi) below; (vii) discontinuing the heating in step (vi) and allowing the reaction mass to cool to a temperature in the range of 35 to 40 degree C; (viii) separating the organic and aqueous layers from the cooled reaction mass of step (vii); (ix) chilling the organic layer as obtained in step (viii) in a freezer to crystallize out p- nitrobenzyl bromide selectively; (x) allowing the crystallized p-nitrobenzyl bromide of step (ix) to warm up to a temperature in the range of 0 to 10 degree C followed by centrifuging to separate the crystals from the mother liquor; (xi) washing the crystals as obtained in step (x) with the chilled carbon tetrachloride as obtained in step (vi) above to obtain purified p-nitrobenzyl bromide (having mp of 97-100 °C and GC purity of ca. 98%); (xii) putting back mother liquor as obtained in step (x) and the washings as obtained in step (xi) into the reaction vessel for next cycle and topping up with required amount of p- nitrotoluene, brominating reagent and carbon tetrachloride; (xiii) repeating the process of steps (iii) to (xii) over several cycles; (xiv) recovering carbon tetrachloride and p-nitrotoluene successively from mother liquor and obtaining a residual mass; (xv) dissolving the residual mass as obtained in step (xiv) in dimethoxy ethane and reacting under ambient condition with sodium borohydride to convert over-brominated products into a mixture of p-nitrotoluene and p-nitrobenzyl bromide; (xvi) adding the mixture of p-nitrotoluene and p-nitrobenzyl bromide obtained in (xv) into the organic layer of step (viii). DETAILED DESCRIPTION OF THE INVENTION The aim of the present invention is to improve upon the synthesis of p-nitrobenzyl bromide from p-nitrotoluene utilizing 2:1 mole ratio of Br":BrO3 brominating reagent. Such brominating reagent is disclosed in the prior art to be produced cost-effectively from the 5:1 mole ratio of Br" :BrO3 obtained as intermediate in the cold process of bromine manufacture and further disclosed in the prior art to be useful for the synthesis of a large number of organo-bromine compounds including p-nitrobenzyl bromide (eq 1). More specifically, the utility highlighted is the ease of operation and the higher bromine atom efficiency. However, in the case ofp-nitrobenzyl bromide preparation with 1.2 eqv of p-nitrotoluene with respect to brominating agent, the bromine atom efficiency reported employing the reagent is only 66% with generation of an organic waste which is difficult to dispose. Moreover, the process involves stripping off the solvent (methylene chloride/ethylene dichloride) followed by recrystallisation with hexane which is tedious. It has been indicated in the same prior art that higher ratio of p-nitrotoluene to brominating agent reduces impurity formation but no method of work up has been disclosed. 3C7H7NO2 + 2NaBr + (Equation Removed) The present invention discloses an improved process for the synthesis of p-nitrobenzyl bromide, wherein: (a) the reaction is carried out with large excess of p-nitrotoluene to achieve high yield and bromine atom efficiency of desired product; (b) use of a single solvent throughout the process; (c) isolation of desired product with high purity without recourse to recrystallization; (d) recovery and reuse of excess p-nitrotoluene; (e) elimination of organic waste. The aforesaid improved process comprises the following major steps: (i) dissolving solid brominating reagent in appropriate amount of water and adding into reaction vessel; (ii) adding required amount of solution of p-nitrotoluene in carbon tetrachloride into the reaction vessel; (iii) raising the temperature of the reaction mass gradually and carrying out the reaction under illumination; (iv) adding in gradual amounts mineral acid as per the stoichiometry of equation 1; (v) continuing the stirring under reflux condition for additional 1.0 to 2.0 hours at the end of which the reaction mass becomes almost colorless; (vi) switching from reflux to distillation mode and collecting a part of the carbon tetrachloride for washing of the centrifuged product as mentioned in (xi) below; (vii) discontinuing the heating and allowing the reaction mass to attain room temperature; (viii) separating the organic and aqueous layers after cooling to room temperature; (ix) chilling the organic layer in a freezer to crystallize out p-nitrobenzyl bromide selectively; also chilling the collected carbon tetrachloride ; (x) removing from freezer and allowing the mass to warm up and thereafter centrifuging to separate the crystals from the mother liquor; (xi) washing the crystals with the chilled carbon tetrachloride to obtain purified product (having mp of 97-100°C and GC purity of ca. 98%); (xii) putting back mother liquor and the washings into the reaction vessel for next cycle and topping up with required amount of p-nitrotoluene, brominating reagent and carbon tetrachloride; (xiii) repeating the process of steps (iii) to (xii) and continuing for a total of seven recycles, i.e., 8 batches in all; (xiv) recovering the carbon tetrachloride from mother liquor by ordinary distillation; (xv) recovering p-nitrotoluene in the residue by vacuum distillation; (xvi) dissolving the residual mass in dimethoxy ethane and reacting with sodium borohydride to convert over-brominated products into a mixture of p-nitrotoluene and p-nitrobenzyl bromide; (xvii) adding the mixture of p-nitrotoluene and p-nitrobenzyl bromide obtained in (xv) into the organic layer of step (viii); (xviii) recovering the DME by distillation and then leaching out water soluble impurities from the residue and utilize the resultant product in recycle steps. In an embodiment of the present invention, the active bromine content in the solid brominating reagent (2:1 mole ratio of Br7BrO3") used in step (i) above is 42.0% (w/w) while the active Br concentration in the aqueous solution is 2.4 M. In another embodiment of the present invention, commercial grade p-nitrotoluene is used and its initial concentration in carbon tetrachloride is in the range of 0.15 to 0.35 kg/L. In still another embodiment of the present invention, 0.388 kg of brominating reagent containing 2.189 moles of active Br is dissolved in 0.9 L water and used in the form of aqueous brominating reagent in step (i) above. In yet still another embodiment of the present invention, the mole equivalent of p-nitrotoluene to moles of active bromine is in the range of 1.0 to 5.0. In still another embodiment of the present invention, the reaction vessel used in step (i) above is a jacketed 10 L capacity 3-neck round bottom glass reactor having bottom discharge and equipped with reflux-cum-distillation assembly, mechanical stirrer, side arm liquid addition facility and three externally fitted 100 W tungsten filament lamps. In yet another embodiment of the present invention, 6.57 mole of commercial grade p- nitrotoluene is used in step (ii) above. In another embodiment of the present invention, the brominating reagent used has a bromide ion to bromate ion mole ratio in the range of 1.8:1 to 2.1:1 and its concentration (total Br) is in the range of 2 to 3 molar in water. In still another embodiment of the present invention, 4.8 L of commercial grade carbon tetrachloride is used in step (ii) above. In yet another embodiment of the present invention, 1 to 4 light bulbs of 40-250 W power rating are used for illumination. In a further embodiment of the present invention, the contents of the reactor are heated slowly with a water condenser to maintain a temperature of 90 ±1°C in step (iii) above. In still another embodiment of the present invention, 1.04 equivalents of 15% (w/v) sulfuric acid (w.r.t. Br equivalent taken) are added to the hot reaction mixture in step (iv) above, under continuous stirring. In another embodiment of the present invention, 0.5 to 2.5 molar sulphuric acid is added over a period of 0.5 to 3 hours in step (iv). In yet another embodiment of the present invention, the reflux conditions in step (v) above are maintained for an additional 2 hours under constant stirring. In still another embodiment of the present invention, after the reaction became colorless in step (vi) above, the reflux is switched to distillation mode and 0.6 L carbon tetrachloride is collected for washing the centrifuged product as mentioned in step (xi) above. In still another embodiment of the present invention, the amount of carbon tetrachloride distilled out in step (vi) is in the range of 10-20% of the total amount taken which is chilled to a temperature of minus 5 to minus 20 degree C, preferably to 10°C. In yet another embodiment of the present invention, the heating in step (vii) above is discontinued and the reaction mixture is allowed to attain room temperature. In still another embodiment of the present invention, in step (viii) above, the aqueous and organic phases are separated. In yet another embodiment of the present invention, the organic phase in step (ix) above is kept for chilling at -20 to -15 °C for 12.0 hrs. In still another embodiment of the present invention, the carbon tetrachloride distilled off in step (vi) above, is also kept for chilling. In yet another embodiment of the present invention, the mass in step (x) above is allowed to attain the room temperature and thereafter the product is isolated by centrifuging at minus 4°C in a continuous centrifuge. In yet another embodiment of the present invention, the centrifuged mass in step (xi) above is washed twice with chilled 0.6L carbon tetrachloride collected by distillation in step (vi) above. In another embodiment of the present invention, the crystals having a melting point in the range of 97 -100 °C and GC purity of ca. 98 % are collected in step (xi). In yet another embodiment of the present invention, the mother liquor obtained in step (x) above and the washings obtained in step (xi) above are put back into the reaction vessel for next cycle in step (xii) above. In still another embodiment of the present invention, the reaction vessel in step (xii) above is topped up with 1.68 moles of commercial grade /7-nitrotoluene, 0.332 kg of brominating reagent containing 1.872 moles of active Br; and 6.17 moles of carbon tetrachloride. In yet another embodiment of the present invention, the process of steps (iii) to (xii) are repeated and continued for a total of seven recycles, i.e., 8 batches in all to give 2.947 kg of/?-nitrobenzyl bromide with average of 98.2% purity. In still another embodiment of the present invention, the repetition of cycles as mentioned in step (xiii) is preferably done for a total of seven cycles so long as the average purity of product over all the accumulated cycles is > 98%. In a further embodiment of the present invention, the carbon tetrachloride in step (xiv) above, is recovered from mother liquor by ordinary distillation. In another embodiment of the present invention, carbon tetrachloride is recovered from spent mother liquor by distillation and /7-nitrotoluene by vacuum distillation at 10-40 mm of Hg and distillation temperature in the range of 130-155°C. In still another embodiment of the present invention, 3.75 moles of/7-nitrotoluene is recovered in step (xv) above, from the residue by vacuum distillation. In yet another embodiment of the present invention, the ratio of residual mass to dimethoxy ethane in step (xvi) is in the range of 1:2 to 1:5 w/v. In still another embodiment of the present invention, 0.323 kg of black residue enriched with dibromo impurity is obtained in step (xv) above, which is used in step (xvi). In yet another embodiment of the present invention, 0.5 to 4.0 mole equivalents of sodium borohydride is taken together with the residual mass in a solvent followed by adding a 2.5:1 v/v solution of dimethoxy ethane : water gradually under stirring in step (xvi). In another embodiment of the present invention, in step (xvi) above, 0.052 kg of black residue enriched with dibromo impurity is dissolved in 0.012 L DME to which is added 0.027 kg of NaBtLt at room temperature and then a mixture of 0.012 1 DME + 0.005 L H2O is added drop wise and allowed to stir for 2 hours. In yet another embodiment of the present invention, the DME in step (xvii) above is distilled and the water soluble impurities are leached out. Further, the resultant product is utilized in recycle steps. In another embodiment of the present invention, in step (xvii) the mole ratio op-nitrotoluene to p-nitrobenzyl bromide is 2:1 to 1:3. In still another embodiment of the present invention, the yield of nitrobenzyl bromide is 90- 98% with respect to p-nitrotoluene and the bromine atom efficiency is 88-92 %. In yet another embodiment of the present invention, the average purity of p-nitrobenzyl bromide is > 98% (GC area %). In still another embodiment of the present invention, the process is free of organic waste. The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention. EXAMPLE 1 60 g (437.9 mmoles) of p-nitrotoluene was dissolved in 324 mL of carbon tetrachloride and added into a 1.0 L capacity glass reactor fitted with addition funnel and reflux condenser/distillation assembly. 90 mL of brominating agent containing 145.9 mmole active Br was added so that the p-nitrotoluene to p-nitrobenzyl bromide ratio is > 2:1 throughout the reaction. The contents were heated to reflux temperature and illuminated externally with a 100 W tungsten filament bulb. 7.3 g of 98% H2SO4 (72.5 mmole) in 30 mL of water was taken in the addition funnel and the acid was added over a period of 2 h. (Caution: If the reaction mass develops brown color stop the addition and allow color to disappear before continuing addition of acid.) Reflux conditions were maintained for an additional 1 h. The reaction mass was allowed to cool to room temperature and the organic and aqueous layers were then separated. The organic phase was poured into a beaker and kept in the freezer compartment of a refrigerator overnight. Crystal formation was observed. The mass was allowed to warm up to 0 - 4 °C and filtered under vacuum. The crystals which collected in the funnel were washed with chilled carbon tetrachloride. The collected p-nitrobenzyl bromide was kept for crystallisation in 4.8 w/v carbon tetrachloride. The yield of collected p-nitrobenzyl bromide was 15.00 g (69.44 mmol). The mother liquor along with washings was put back into the glass reactor. Fresh 18.8 g (137.2) mmol ofp-nitrotoluene were added and brominating reagent was taken at the mole ratio of 1.1-1.2 with respect to fresh p-nitrotoluene added. The reaction was repeated to obtain additional amount of p-nitrobenzyl bromide, while the mother liquor & washings were once again recycled. Four such recycled batches were carried out as shown in Table 1 below. Carbon tetrachloride (density = 1.5842 g/cm3) was recovered from the mother liquor for reuse. Table 1 (Table Removed) The above example teaches us that p-nitrobenzyl bromide can be selectively crystallized out in the reaction solvent itself at sub-zero temperature even in presence of large excess of p-nitrotoluene. This enables easy recycling of the mother liquor to realize a bromine atom efficiency of nearly 83%. The yield of product with respect to p-nitrotoluene consumed is also nearly quantitative but it is only 45% in the absence of recovery of p-nitrotoluene lost in the final mother liquor. EXAMPLE 2 0.9 kg (6.57 mole) ofp-nitrotoluene was dissolved in 4.8 L of carbon tetrachloride and added into a 10L capacity glass reactor fitted with addition funnel and reflux condenser/distillation assembly. 1.09 L of brominating agent containing 2.18 mole active Br was added so that the p -nitrotoluene to p-nitrobenzyl bromide ratio is > 2:1 throughout the reaction. The contents were heated to reflux temperature and illuminated externally with 3 x 100 W tungsten filament bulbs. 112 g of 98% H2S04 (1.12 mole) in 0.6 L of water was taken in the addition funnel and the acid was added over a period of 2 h. (Caution: If the reaction mass develops brown color stop the addition and allow color to disappear before continuing addition of acid.) Reflux conditions were maintained for an additional 1 h. The reaction mass was allowed to cool to ca. 40°C temperature and the contents discharged into a separating column. The organic phase was poured into a suitable wide mouth glass vessel and kept for crystallization in a deep freezer after inserting 3 broomsticks to promote crystallization. The organic phase attained a temperature of - 17.5±2.5 ° C and was removed after 12 hours. Crystal formation was seen. The contents were allowed to warm up to 5±2.5 ° C to re-dissolve p-nitrotoluene which had co-crystallized with the product. The lumps of crystals were broken up and the contents centrifuged in a continuous centrifuge which operation required barely a couple of minutes (note that the mother liquor warmed up to around 7.5±2.5 ° C during the centrifuging). The collected p-nitrobenzyl bromide weighed 0.264 kg (1.22 moles) and exhibited 95% (GC area %) purity. The mother liquor was put back into the glass reactor. Fresh 0.167 kg 1.22 moles of p-nitrotoluene, equivalent to the amount of p-nitrobenzyl bromide crystallized out was added and brominating reagent was taken at the mole ratio as shown in Table 2 below. The reaction was repeated in the same manner as above but towards the end of the reaction 0.6 L of carbon tetrachloride was collected by changing over from reflux mode to distillation mode and kept for chilling. Cold crystallization was repeated to obtain p-nitrobenzyl bromide from the reaction mass. The crude p-nitrobenzyl bromide was washed in the centrifuge with the chilled carbon tetrachloride and centrifuged. The mother liquor and washings were once again recycled. Seven such recycled batches were carried out and the data on p-nitrobenzyl bromide yield and purity for each cycle and also the total yield and average purity are provided in table2 below. Carbon tetrachloride was recovered from the final mother liquor for reuse. Table 2 (Table Removed) This example teaches us that the laboratory process is easily amenable to scale up and that by carrying out the operations more efficiently and recycling the mother liquor seven times instead of only four times, the yield of p-nitrobenzyl bromide with respect to p-nitrotoluene was increased to 68.2% while bromine atom efficiency was 84.8%. The example further teaches us that mere washing of the crystals with chilled carbon tetrachloride is sufficient to yield a product of high purity. EXAMPLE 3 The experiment of Example 2 was repeated and the stoichiometry of reagents for each cycle as also yield and purity of product are shown in Table 3 below. After the 8th cycle, carbon tetrachloride was recovered from the mother liquor as before and the residue was then subjected to vacuum distillation. For this purpose, the residue was first melted and purged with nitrogen. Thereafter, the temperature was raised while applying vacuum and the /7-nitrotoluene distilled over at the reduced pressure [temperature: 140 °C (initial)-155 °C (final); pressure: 40 mm (initial) -10 mm (final) Hg]. The amount of p-nitrotoluene recovered was 0.514 kg (3.75 moles). Note: small amounts of p-nitrobenzyl bromide were also found to distill over. The recovered p-nitrotoluene amount was deducted from the total amount of p-nitrotoluene charged for the purpose of calculating conversion with respect to p-nitrotoluene. As calculated based on the data of Table 3 below, the yield of p-nitrobenzyl bromide was 91.7% with respect to p-nitrotoluene consumed while the bromine atom efficiency was 87.3%. Table 3 (Table Removed) Examples 3 teaches us that it is simple to recover p-nitrotoluene from the residue of the final cycle and that this makes it feasible to carry out the reaction with large excess of p -nitrotoluene to realize the benefit of lower impurity formation. EXAMPLE 4 The dark residue weighing 323 g recovered in Example 3 after vacuum distillation of p-nitrotoluene was analyzed by GC-MS and NMR and found to comprise 71.1% dibromo (NCVAr-CHBr2) impurity and 26.9%p-nitrobenzyl bromide as the main constituents. 5.23 g of this residue was dissolved in 12.5 ml of dimethoxy ethane (DME). 2.69 g of NaBH4was added next. A solution made from 12.5 ml DME and 5 ml water was then added gradually over 1 h under stirring at room temperature. The DME was then distilled at reduced pressure to yield a solid, which was washed with water to give 2.1 g of pale yellow solid whose GC indicated that the dibromo impurity in residue was converted into p-nitrotoluene and p-nitrobenzyl bromide, giving a composition comprising 60.5% P-nitrotoluene and 39.5% p-nitrobenzyl bromide based on GC area %. It would be evident that the converted residue having nearly 2:1 ratio of p-nitrotoluene: p-nitrobenzyl bromide can be recycled. This way the conversion increased to 96% with respect to p-nitrotoluene consumed and the bromine atom efficiency increased to 90%. EXAMPLE 5 The aqueous effluent from 8th batch of Example 3 was collected and analyzed. The data is provided in Table 4 below. It can be seen that the aqueous effluent has low levels of organic matter and unreacted bromide. Table 4. Data showing details of aqueous effluent from 8th batch of Example 3 (Table Removed) The main advantages of the present invention are : 1. By using a single solvent for reaction, product isolation and purification, the problem of contamination of one solvent with another is eliminated and the process made simple. 2. p-nitrobenzyl bromide is selectively crystallized out from reaction mass through a chilling process, which enables the mother liquor containing excess p-nitrotoluene and all of the solvent to be recycled directly. 3. p-nitrobenzyl bromide having >98% purity is obtained merely by washing the product with chilled carbon tetrachloride. 4. The present process minimizes solvent losses. 5. The process minimizes impurity formation and consequently, leads to higher bromine atom efficiency. 6. Excess p-nitrotoluene required to minimize impurity formation is easily recovered. 7. Waste organic residue comprising largely dibromo impurity is converted back into p-nitrotoluene/p-nitrobenzyl bromide, which not only increases the yield with respect to p-nitrotoluene but also circumvents the problem of organic waste disposal. 8. The aqueous effluent contains minimum organic load. We claim: 1. An improved process for the preparation of p-nitrobenzyl bromide, wherein the steps comprising: (i) adding a solution of p-nitrotoluene in carbon tetrachloride having concentration in the range of 0.15 to 0.35 kg/L into a reaction vessel; (ii) dissolving 2:1 alkali bromide/alkali bromate solid brominating reagent in water to a concentration of 2-3 M active Br and adding into the reaction vessel of step (i) maintaining substrate to active bromine (in reagent) ratio in the range of 1:1 to 5:1; (iii) raising the temperature of the reaction mass of step (ii) gradually from ambient to 50-60°C under continuous illumination; (iv) adding stoichiometric amount of 0.5-2.5 M mineral acid such as sulphuric acid and hydrochloric acid into the reaction mass of step (iii) over a period of 0.5-3.0 h under continuous stirring; (v) continuing the stirring under reflux conditions for additional 1.0-2.0 hours at the end of which the reaction mass becomes almost colorless; (vi) switching from reflux mode of step (v) to distillation mode and distilling out 10-15% of the carbon tetrachloride taken which is thereafter chilled to a temperature in the range of -5 to -20°C for washing of the centrifuged product as mentioned in (xi) below; (vii) discontinuing the heating after the distillation of step (vi) and allowing the reaction mass to cool to 35-40°C; (viii) separating the organic and aqueous layers from the cooled reaction mass of step (vii); (ix) chilling the organic layer obtained in step (viii) in a freezer to crystallize out p- nitrobenzyl bromide selectively in the temperature range of -5 to -20°C; (x) allowing the crystallized p-nitrobenzyl bromide of step (ix) to warm up to a temperature in the range of 0-10°C followed by centrifuging to separate the crystals from the mother liquor; (xi) washing the crystals obtained in step (x) with the chilled carbon tetrachloride obtained in step (vi) to obtain purified p-nitrobenzyl bromide having mp of 97-100°C and GC purity of ca. 98%; (xii) putting back mother liquor of step (x) and washings of step (xi) into the reaction vessel for next cycle and topping up with required amounts of p-nitrotoluene, brominating reagent and carbon tetrachloride; (xiii) repeating the process of steps (iii) to (xii) over several cycles; (xiv) distilling out under atmospheric pressure carbon tetrachloride in the spent organic layer after completion of recycles and thereafter distilling out p-nitrotoluene at under 130-155 °C under a reduced pressure of 10-40 mm of Hg. (xv) dissolving the residual mass (RM) of step (xiv) in dimethoxy ethane(DME) in the RM:DME ratio of 1:2 to 1:5 (w/v) and thereafter treating the mass under stirring at room temperature with sodium borohydride (NaBH4) in the RM:NaBH4 weight ratio of 3:1 to 1.5:1 to convert over-brominated products into a mixture of p-nitrotoluene and p-nitrobenzyl bromide; (xvi) adding the mixture of p-nitrotoluene and p-nitrobenzyl bromide obtained in (xv) into the organic layer of step (viii) prior to continuing the operations of steps (ix) to (xv) and thereby eliminating organic waste. 2. A process as claimed in claim 1, wherein the reaction temperature in step (iii) is preferably raised to 50° C. 3. A process as claimed in claim 1, wherein 1 to 4 light bulbs of 40-250 W power rating were used in step (iii) when the glass reactor vessel size was 1-10 L. 4. A process as claimed in claim 1, wherein the organic layer in step (x) is preferably warmed up to a temperature in the range of-2 to 5°C. 5. A process as claimed in claim 1, wherein 7-10 recycles of mother liquor are undertaken before subjecting the spent mother liquor to the operations of steps (xiii) to (xvi). 6. A process as claimed in claim 1, wherein dimethoxy ethane is recovered by distillation and the product washed with water as part of the operations in step (xv). 7. A process as claimed in claim 1, wherein in step (xvi) the mole ratio of p-nitrotoluene to p-nitrobenzyl bromide after mixing of the organic layers is in the ratio of 2:1 to 1:3 8. A process as claimed in any preceding claims, wherein the yield of p-nitrobenzyl bromide is 90-98% with respect top-nitrotoluene and the bromine atom efficiency is 88-92 %. 9. A process as claimed in any preceding claims, wherein the average purity of p-nitrobenzyl bromide is > 98% (GC area %). 10. An improved process for the preparation of para-nitrobenzyl bromide substantially as herein described with reference to the foregoing examples.

Full Text

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of p-nitrobenzyl bromide. The compound is widely used for esterification of carboxylic acids especially where deprotection is required such as in the synthesis of ß-lactam antibiotic analogs, cephalosporine analogs, penicillin ester analogs, fusidic acid analogs and thienamycin analogs. It is also used as a starting material in the preparation of the drug rizatriptan benzoate.
BACKGROUND OF THE INVENTION
Reference may be made to the paper entitled "Bromination of ß-nitrotoluene" by J. F. Brewster (J. Am. Chem. Soc; 1918; 40(2); 406-407). The reaction was carried out by reacting p-nitrotoluene with liquid bromine in carbon tetrachloride at elevated temperature (on a hot plate) with exposure to sunlight. ß-nitrobenzyl bromide was obtained in 71% overall yield. The bromine atom efficiency was computed to be 40%.
Reference may be made to the procedure reported by G. H. Coleman et. al. in Organic Syntheses, Coll. Vol. 2, p.443 (1943); Vol. 16, p.54 (1936), wherein vapor phase bromination of p-nitrotoluene is disclosed. The reaction was carried out in the presence of liquid bromine at 145-150°C. The yield of isolated product was 53-59 percent. HBr is obtained as byproduct and the overall atom efficiency vis-a-vis product formation is computed to be 28%.
Reference may be made to the same article above, wherein it is stated that the procedure of Brewster referred to above can be conveniently adopted by using artificial light in place of sunlight and that the light from two 300-watt tungsten lamps is satisfactory for the bromination of

300 g of p-nitrotoluene. The isolated yield of p-nitrobenzyl bromide is 60-70 per cent of the theoretical amount. Reference may again be made to the same article above wherein it is reported that although p-nitrobenzyl bromide is usually prepared by brominating p-nitrotoluene, it can also be prepared by treating p-nitrobenzyl alcohol with hydrobromic acid and by nitrating benzyl bromide.
Reference may also be made to the paper entitled "A note on Bromination of p-nitrotoluene" by G. W. K. Cavill (J. of the Soc. OfChem. Industry, 1946, 40, 124), wherein the bromination of p-nitrotoluene in the presence of liquid bromine and antimony tribromide is reported to yield p-nitrobenzyl bromide in 76% isolated yield. The reaction is undertaken at 120-130°C for 9-10 hrs. The bromine atom efficiency is computed to be 38%.
Reference may be made to U.S. Patent 6,740,253, which discloses the use of 2:1 sodium bromide-sodium bromate as atom efficient brominating agent. The reagent can be prepared cost-effectively from the 5:1 sodium bromide-sodium bromate intermediate obtained in the process of producing liquid bromine from sea bittern by the "cold process". Besides being a cost-effective reagent, the use of liquid bromine is avoided and higher bromine atom efficiencies are realized. The said brominating agent is disclosed for the preparation of p-nitrobenzyl bromide from p-nitrotoluene (S. Adimurthy et al. Green Chem., 2008, 10, 232). process has several advantages over the above stated prior art using liquid bromine but, even so, the conversion with respect to p-nitrotoluene is only 78% and with respect to Br it is 66%. Moreover, the work up of the reaction and purification of the product are tedious and there is a problem of management of organic waste containing largely dibromo impurity. Reference may also be made to the same paper, wherein it

is stated that impurity formation can be reduced by taking large excess of p-nitrotoluene. However, the data provided is for the crude reaction mixture and nothing is mentioned about the work up of the reaction which would undoubtedly pose serious difficulties if the operations described in the paper are to be followed.
The present invention seeks to overcome the above drawbacks of the process of preparation of p-nitrobenzyl bromide from p-nitrotoluene employing the bromide/bromate couple of the prior art. The invention specifically discloses an improved process that is simple to execute and exhibits high yield of desired product with respect to bothp-nitrotoluene and bromide/bromate reagent.
Reference may be also made to the paper by Bell et. Al. (Bell, H. M.; Brown, H. C. J. Am. Chem. Soc. 1966, 88, 1473 pg) wherein a procedure is disclosed for the conversion of various benzyl bromides to substituted toluene derivative using NaBH4 in dimethoxy ethane/water as a solvent. This is an important prior art in the context of the present invention which seeks to recycle over-brominated organic waste residue as one of the objects.
OBJECTS OF THE INVENTION
The main object of the present invention is therefore to provide an improved process for the preparation of p-nitrobenzyl bromide from p-nitrotoluene using 2:1 bromide-bromate reagent which obviates the drawbacks of the prior art.

Another object of the present invention is to provide a process wherein the use of a single solvent for reaction, product isolation and purification eliminates the problem of contamination of one solvent with another and the process is made simple.
Yet another object of the present invention is to provide a process wherein p-nitrobenzyl bromide is selectively crystallized out from reaction mass through a chilling process which enables the mother liquor containing excess p-nitrotoluene and all of the solvent to be recycled directly.
Still another object of the present invention is to obtain product having >98% purity without recourse to re-crystallization.
A further object of the present invention is to provide a process which minimizes impurity formation and, consequently, leads to higher bromine atom efficiency.
Still another object of the present invention is to treat the residue remaining after distillation with sodium borohydride/ dimethoxy ethane (DME) to convert dibromo impurity back into p-nitrotoluene / p-nitrobenzyl bromide so that the mass can be once again recycled thereby converting waste into product, thereby circumventing the problem of organic waste disposal.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of p-nitrobenzyl bromide from p-nitrotoluene, wherein large excess of the reactant in carbon tetrachloride is treated with 2:1 bromide-bromate reagent and the product is isolated efficiently and with high purity through

selective cold crystallization from reaction mass so as to allow the mother liquor to be recycled in a subsequent batch without any further work up. The cycles are continued so long as product of desired quality is obtained in adequate yield. Thereafter, the solvent and p-nitrotoluene are recovered from the mother liquor and the residue is treated with sodium borohydride to convert impurities back into reactant or product which is then recycled in the process thereby circumventing the problem of waste disposal and simultaneously yielding the desired product with >95 % yield with respect to p-nitrotoluene and >88 % bromine atom efficiency.
The major features of the present invention involve the following:
(i) selection of carbon tetrachloride as single organic solvent which enables the reaction to
proceed in facile manner under reflux conditions and which also facilitates easy recovery of
the desired product through chilling of the reaction mass, (ii) taking two-fold excess of p-nitrotoluene to minimize over-bromination of product, (iii) recycling of the mother liquor and washings from an earlier batch in a consequent batch so
as to maintain same total p-nitrotoluene equivalent (i.e., unreacted p-nitrotoluene and p-
nitrotoluene -based product/by-product), (iv) taking brominating agent in subsequent batch to the same extent that p-nitrobenzyl bromide
product was isolated in the previous batch so as to maintain consistency of stoichiometric
ratio from batch-to-batch, (v) avoiding cumbersome work up and instead, subjecting the mother liquor containing excess
p-nitrotoluene and p-nitrobenzyl bromide to chilling at minus 15°C to minus 20°C
temperature to crystallize out the latter selectively, thereafter allowing the mass to attain a
temperature of minus 4°C, following which the mother liquor is separated out rapidly in a

continuous centrifuge. The solid product is then washed in the centrifuge with chilled (minus 4°C) carbon tetrachloride (2:1 v/w) collected towards the end of the reaction to attain >98% purity.
(vi) minimizing carbon tetrachloride loss by carrying out the work up under chilled conditions in continuous centrifuge.
(vii) recovering carbon tetrachloride by ordinary distillation and p-nitrotoluene by vacuum distillation from mother liquor of last (8th) batch and treating the waste residue with NaBH4 to convert dibromo impurity into p-nitrotoluene and p-nitrobenzyl bromide, which can be recycled to eliminate the problem of waste while increasing overall yield with respect to p-nitrotoluene and reagent.
Accordingly, the present invention provides an improved process for the preparation of p-
nitrobenzyl bromide, wherein the steps comprising:
(i) dissolving 1.09 to 2.18 moles of a solid brominating reagent in water and adding into a
reaction vessel; (ii) adding a solution of p-nitrotoluene in carbon tetrachloride into the reaction vessel of step (i)
to obtain a reaction mass; (iii) raising the temperature of the reaction mass of step (ii) gradually to 80 to 90 degree C under
continuous illumination and stirring; (iv) adding a mineral acid in gradual amounts to the reaction mass of step (iii) as per the
stoichiometric requirement; (v) continuing the stirring under reflux conditions for additional 1.0-2.0 hours at the end of
which the reaction mass becomes almost colorless;

(vi) switching from reflux mode as in step (v) to distillation mode and distilling out a part of the
carbon tetrachloride which is chilled to a temperature in the range of minus 5 to minus 20
degree C for washing of the centrifuged product as mentioned in (xi) below; (vii) discontinuing the heating in step (vi) and allowing the reaction mass to cool to a
temperature in the range of 35 to 40 degree C; (viii) separating the organic and aqueous layers from the cooled reaction mass of step (vii); (ix) chilling the organic layer as obtained in step (viii) in a freezer to crystallize out p-
nitrobenzyl bromide selectively; (x) allowing the crystallized p-nitrobenzyl bromide of step (ix) to warm up to a temperature in
the range of 0 to 10 degree C followed by centrifuging to separate the crystals from the
mother liquor; (xi) washing the crystals as obtained in step (x) with the chilled carbon tetrachloride as obtained
in step (vi) above to obtain purified p-nitrobenzyl bromide (having mp of 97-100 °C and
GC purity of ca. 98%); (xii) putting back mother liquor as obtained in step (x) and the washings as obtained in step (xi)
into the reaction vessel for next cycle and topping up with required amount of p-
nitrotoluene, brominating reagent and carbon tetrachloride; (xiii) repeating the process of steps (iii) to (xii) over several cycles; (xiv) recovering carbon tetrachloride and p-nitrotoluene successively from mother liquor and
obtaining a residual mass; (xv) dissolving the residual mass as obtained in step (xiv) in dimethoxy ethane and reacting
under ambient condition with sodium borohydride to convert over-brominated products into
a mixture of p-nitrotoluene and p-nitrobenzyl bromide;

(xvi) adding the mixture of p-nitrotoluene and p-nitrobenzyl bromide obtained in (xv) into the organic layer of step (viii).
DETAILED DESCRIPTION OF THE INVENTION
The aim of the present invention is to improve upon the synthesis of p-nitrobenzyl bromide from p-nitrotoluene utilizing 2:1 mole ratio of Br":BrO3 brominating reagent. Such brominating reagent is disclosed in the prior art to be produced cost-effectively from the 5:1 mole ratio of Br" :BrO3 obtained as intermediate in the cold process of bromine manufacture and further disclosed in the prior art to be useful for the synthesis of a large number of organo-bromine compounds including p-nitrobenzyl bromide (eq 1). More specifically, the utility highlighted is the ease of operation and the higher bromine atom efficiency. However, in the case ofp-nitrobenzyl bromide preparation with 1.2 eqv of p-nitrotoluene with respect to brominating agent, the bromine atom efficiency reported employing the reagent is only 66% with generation of an organic waste which is difficult to dispose. Moreover, the process involves stripping off the solvent (methylene chloride/ethylene dichloride) followed by recrystallisation with hexane which is tedious. It has been indicated in the same prior art that higher ratio of p-nitrotoluene to brominating agent reduces impurity formation but no method of work up has been disclosed. 3C7H7NO2 + 2NaBr +
(Equation Removed)
The present invention discloses an improved process for the synthesis of p-nitrobenzyl bromide, wherein:
(a) the reaction is carried out with large excess of p-nitrotoluene to achieve high yield and bromine atom efficiency of desired product;

(b) use of a single solvent throughout the process;
(c) isolation of desired product with high purity without recourse to recrystallization;
(d) recovery and reuse of excess p-nitrotoluene;
(e) elimination of organic waste.
The aforesaid improved process comprises the following major steps:
(i) dissolving solid brominating reagent in appropriate amount of water and adding into
reaction vessel; (ii) adding required amount of solution of p-nitrotoluene in carbon tetrachloride into the
reaction vessel; (iii) raising the temperature of the reaction mass gradually and carrying out the reaction under
illumination; (iv) adding in gradual amounts mineral acid as per the stoichiometry of equation 1; (v) continuing the stirring under reflux condition for additional 1.0 to 2.0 hours at the end of
which the reaction mass becomes almost colorless; (vi) switching from reflux to distillation mode and collecting a part of the carbon tetrachloride
for washing of the centrifuged product as mentioned in (xi) below; (vii) discontinuing the heating and allowing the reaction mass to attain room temperature; (viii) separating the organic and aqueous layers after cooling to room temperature; (ix) chilling the organic layer in a freezer to crystallize out p-nitrobenzyl bromide selectively;
also chilling the collected carbon tetrachloride ; (x) removing from freezer and allowing the mass to warm up and thereafter centrifuging to
separate the crystals from the mother liquor;

(xi) washing the crystals with the chilled carbon tetrachloride to obtain purified product (having
mp of 97-100°C and GC purity of ca. 98%); (xii) putting back mother liquor and the washings into the reaction vessel for next cycle and
topping up with required amount of p-nitrotoluene, brominating reagent and carbon
tetrachloride; (xiii) repeating the process of steps (iii) to (xii) and continuing for a total of seven recycles, i.e., 8
batches in all; (xiv) recovering the carbon tetrachloride from mother liquor by ordinary distillation; (xv) recovering p-nitrotoluene in the residue by vacuum distillation; (xvi) dissolving the residual mass in dimethoxy ethane and reacting with sodium borohydride to
convert over-brominated products into a mixture of p-nitrotoluene and p-nitrobenzyl
bromide; (xvii) adding the mixture of p-nitrotoluene and p-nitrobenzyl bromide obtained in (xv) into the
organic layer of step (viii); (xviii) recovering the DME by distillation and then leaching out water soluble impurities from
the residue and utilize the resultant product in recycle steps.
In an embodiment of the present invention, the active bromine content in the solid brominating reagent (2:1 mole ratio of Br7BrO3") used in step (i) above is 42.0% (w/w) while the active Br concentration in the aqueous solution is 2.4 M.
In another embodiment of the present invention, commercial grade p-nitrotoluene is used and its initial concentration in carbon tetrachloride is in the range of 0.15 to 0.35 kg/L.

In still another embodiment of the present invention, 0.388 kg of brominating reagent containing
2.189 moles of active Br is dissolved in 0.9 L water and used in the form of aqueous brominating
reagent in step (i) above.
In yet still another embodiment of the present invention, the mole equivalent of p-nitrotoluene to
moles of active bromine is in the range of 1.0 to 5.0.
In still another embodiment of the present invention, the reaction vessel used in step (i) above is a
jacketed 10 L capacity 3-neck round bottom glass reactor having bottom discharge and equipped
with reflux-cum-distillation assembly, mechanical stirrer, side arm liquid addition facility and
three externally fitted 100 W tungsten filament lamps.
In yet another embodiment of the present invention, 6.57 mole of commercial grade p-
nitrotoluene is used in step (ii) above.
In another embodiment of the present invention, the brominating reagent used has a bromide ion
to bromate ion mole ratio in the range of 1.8:1 to 2.1:1 and its concentration (total Br) is in the
range of 2 to 3 molar in water.
In still another embodiment of the present invention, 4.8 L of commercial grade carbon
tetrachloride is used in step (ii) above.
In yet another embodiment of the present invention, 1 to 4 light bulbs of 40-250 W power rating
are used for illumination.
In a further embodiment of the present invention, the contents of the reactor are heated slowly
with a water condenser to maintain a temperature of 90 ±1°C in step (iii) above.
In still another embodiment of the present invention, 1.04 equivalents of 15% (w/v) sulfuric acid
(w.r.t. Br equivalent taken) are added to the hot reaction mixture in step (iv) above, under
continuous stirring.

In another embodiment of the present invention, 0.5 to 2.5 molar sulphuric acid is added over a
period of 0.5 to 3 hours in step (iv).
In yet another embodiment of the present invention, the reflux conditions in step (v) above are
maintained for an additional 2 hours under constant stirring.
In still another embodiment of the present invention, after the reaction became colorless in step
(vi) above, the reflux is switched to distillation mode and 0.6 L carbon tetrachloride is collected
for washing the centrifuged product as mentioned in step (xi) above.
In still another embodiment of the present invention, the amount of carbon tetrachloride distilled
out in step (vi) is in the range of 10-20% of the total amount taken which is chilled to a
temperature of minus 5 to minus 20 degree C, preferably to 10°C.
In yet another embodiment of the present invention, the heating in step (vii) above is discontinued
and the reaction mixture is allowed to attain room temperature.
In still another embodiment of the present invention, in step (viii) above, the aqueous and organic
phases are separated.
In yet another embodiment of the present invention, the organic phase in step (ix) above is kept
for chilling at -20 to -15 °C for 12.0 hrs.
In still another embodiment of the present invention, the carbon tetrachloride distilled off in step
(vi) above, is also kept for chilling.
In yet another embodiment of the present invention, the mass in step (x) above is allowed to
attain the room temperature and thereafter the product is isolated by centrifuging at minus 4°C in
a continuous centrifuge.
In yet another embodiment of the present invention, the centrifuged mass in step (xi) above is
washed twice with chilled 0.6L carbon tetrachloride collected by distillation in step (vi) above.

In another embodiment of the present invention, the crystals having a melting point in the range of 97 -100 °C and GC purity of ca. 98 % are collected in step (xi).
In yet another embodiment of the present invention, the mother liquor obtained in step (x) above and the washings obtained in step (xi) above are put back into the reaction vessel for next cycle in step (xii) above.
In still another embodiment of the present invention, the reaction vessel in step (xii) above is topped up with 1.68 moles of commercial grade /7-nitrotoluene, 0.332 kg of brominating reagent containing 1.872 moles of active Br; and 6.17 moles of carbon tetrachloride. In yet another embodiment of the present invention, the process of steps (iii) to (xii) are repeated and continued for a total of seven recycles, i.e., 8 batches in all to give 2.947 kg of/?-nitrobenzyl bromide with average of 98.2% purity.
In still another embodiment of the present invention, the repetition of cycles as mentioned in step (xiii) is preferably done for a total of seven cycles so long as the average purity of product over all the accumulated cycles is > 98%.
In a further embodiment of the present invention, the carbon tetrachloride in step (xiv) above, is recovered from mother liquor by ordinary distillation.
In another embodiment of the present invention, carbon tetrachloride is recovered from spent mother liquor by distillation and /7-nitrotoluene by vacuum distillation at 10-40 mm of Hg and distillation temperature in the range of 130-155°C.
In still another embodiment of the present invention, 3.75 moles of/7-nitrotoluene is recovered in step (xv) above, from the residue by vacuum distillation.
In yet another embodiment of the present invention, the ratio of residual mass to dimethoxy ethane in step (xvi) is in the range of 1:2 to 1:5 w/v.

In still another embodiment of the present invention, 0.323 kg of black residue enriched with
dibromo impurity is obtained in step (xv) above, which is used in step (xvi).
In yet another embodiment of the present invention, 0.5 to 4.0 mole equivalents of sodium
borohydride is taken together with the residual mass in a solvent followed by adding a 2.5:1 v/v
solution of dimethoxy ethane : water gradually under stirring in step (xvi).
In another embodiment of the present invention, in step (xvi) above, 0.052 kg of black residue
enriched with dibromo impurity is dissolved in 0.012 L DME to which is added 0.027 kg of
NaBtLt at room temperature and then a mixture of 0.012 1 DME + 0.005 L H2O is added drop
wise and allowed to stir for 2 hours.
In yet another embodiment of the present invention, the DME in step (xvii) above is distilled and
the water soluble impurities are leached out. Further, the resultant product is utilized in recycle
steps.
In another embodiment of the present invention, in step (xvii) the mole ratio op-nitrotoluene to
p-nitrobenzyl bromide is 2:1 to 1:3.
In still another embodiment of the present invention, the yield of nitrobenzyl bromide is 90-
98% with respect to p-nitrotoluene and the bromine atom efficiency is 88-92 %.
In yet another embodiment of the present invention, the average purity of p-nitrobenzyl bromide
is > 98% (GC area %).
In still another embodiment of the present invention, the process is free of organic waste.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLE 1
60 g (437.9 mmoles) of p-nitrotoluene was dissolved in 324 mL of carbon tetrachloride and added into a 1.0 L capacity glass reactor fitted with addition funnel and reflux condenser/distillation assembly. 90 mL of brominating agent containing 145.9 mmole active Br was added so that the p-nitrotoluene to p-nitrobenzyl bromide ratio is > 2:1 throughout the reaction. The contents were heated to reflux temperature and illuminated externally with a 100 W tungsten filament bulb. 7.3 g of 98% H2SO4 (72.5 mmole) in 30 mL of water was taken in the addition funnel and the acid was added over a period of 2 h. (Caution: If the reaction mass develops brown color stop the addition and allow color to disappear before continuing addition of acid.) Reflux conditions were maintained for an additional 1 h. The reaction mass was allowed to cool to room temperature and the organic and aqueous layers were then separated. The organic phase was poured into a beaker and kept in the freezer compartment of a refrigerator overnight. Crystal formation was observed. The mass was allowed to warm up to 0 - 4 °C and filtered under vacuum. The crystals which collected in the funnel were washed with chilled carbon tetrachloride. The collected p-nitrobenzyl bromide was kept for crystallisation in 4.8 w/v carbon tetrachloride. The yield of collected p-nitrobenzyl bromide was 15.00 g (69.44 mmol). The mother liquor along with washings was put back into the glass reactor. Fresh 18.8 g (137.2) mmol ofp-nitrotoluene were added and brominating reagent was taken at the mole ratio of 1.1-1.2 with respect to fresh p-nitrotoluene added. The reaction was repeated to obtain additional amount of p-nitrobenzyl bromide, while the mother liquor & washings were once again recycled. Four such recycled batches were carried out as shown in Table 1 below. Carbon tetrachloride (density = 1.5842 g/cm3) was recovered from the mother liquor for reuse.

Table 1
(Table Removed)

The above example teaches us that p-nitrobenzyl bromide can be selectively crystallized out in the reaction solvent itself at sub-zero temperature even in presence of large excess of p-nitrotoluene. This enables easy recycling of the mother liquor to realize a bromine atom efficiency of nearly 83%. The yield of product with respect to p-nitrotoluene consumed is also nearly quantitative but it is only 45% in the absence of recovery of p-nitrotoluene lost in the final mother liquor.
EXAMPLE 2
0.9 kg (6.57 mole) ofp-nitrotoluene was dissolved in 4.8 L of carbon tetrachloride and added into a 10L capacity glass reactor fitted with addition funnel and reflux condenser/distillation assembly. 1.09 L of brominating agent containing 2.18 mole active Br was added so that the p -nitrotoluene to p-nitrobenzyl bromide ratio is > 2:1 throughout the reaction. The contents were heated to reflux temperature and illuminated externally with 3 x 100 W tungsten filament bulbs. 112 g of 98% H2S04 (1.12 mole) in 0.6 L of water was taken in the addition funnel and the acid was added

over a period of 2 h. (Caution: If the reaction mass develops brown color stop the addition and allow color to disappear before continuing addition of acid.) Reflux conditions were maintained for an additional 1 h. The reaction mass was allowed to cool to ca. 40°C temperature and the contents discharged into a separating column. The organic phase was poured into a suitable wide mouth glass vessel and kept for crystallization in a deep freezer after inserting 3 broomsticks to promote crystallization. The organic phase attained a temperature of - 17.5±2.5 ° C and was removed after 12 hours. Crystal formation was seen. The contents were allowed to warm up to 5±2.5 ° C to re-dissolve p-nitrotoluene which had co-crystallized with the product. The lumps of crystals were broken up and the contents centrifuged in a continuous centrifuge which operation required barely a couple of minutes (note that the mother liquor warmed up to around 7.5±2.5 ° C during the centrifuging). The collected p-nitrobenzyl bromide weighed 0.264 kg (1.22 moles) and exhibited 95% (GC area %) purity. The mother liquor was put back into the glass reactor. Fresh 0.167 kg 1.22 moles of p-nitrotoluene, equivalent to the amount of p-nitrobenzyl bromide crystallized out was added and brominating reagent was taken at the mole ratio as shown in Table 2 below. The reaction was repeated in the same manner as above but towards the end of the reaction 0.6 L of carbon tetrachloride was collected by changing over from reflux mode to distillation mode and kept for chilling. Cold crystallization was repeated to obtain p-nitrobenzyl bromide from the reaction mass. The crude p-nitrobenzyl bromide was washed in the centrifuge with the chilled carbon tetrachloride and centrifuged. The mother liquor and washings were once again recycled. Seven such recycled batches were carried out and the data on p-nitrobenzyl bromide yield and purity for each cycle and also the total yield and average purity are provided in table2 below. Carbon tetrachloride was recovered from the final mother liquor for reuse.
Table 2
(Table Removed)

This example teaches us that the laboratory process is easily amenable to scale up and that by
carrying out the operations more efficiently and recycling the mother liquor seven times instead
of only four times, the yield of p-nitrobenzyl bromide with respect to p-nitrotoluene was
increased to 68.2% while bromine atom efficiency was 84.8%. The example further teaches us
that mere washing of the crystals with chilled carbon tetrachloride is sufficient to yield a product
of high purity.
EXAMPLE 3
The experiment of Example 2 was repeated and the stoichiometry of reagents for each cycle as also yield and purity of product are shown in Table 3 below. After the 8th cycle, carbon tetrachloride was recovered from the mother liquor as before and the residue was then subjected to vacuum distillation. For this purpose, the residue was first melted and purged with nitrogen. Thereafter, the temperature was raised while applying vacuum and the /7-nitrotoluene distilled over at the reduced pressure [temperature: 140 °C (initial)-155 °C (final); pressure: 40 mm (initial) -10 mm (final) Hg]. The amount of p-nitrotoluene recovered was 0.514 kg (3.75 moles).
Note: small amounts of p-nitrobenzyl bromide were also found to distill over. The recovered p-nitrotoluene amount was deducted from the total amount of p-nitrotoluene charged for the purpose of calculating conversion with respect to p-nitrotoluene. As calculated based on the data of Table 3 below, the yield of p-nitrobenzyl bromide was 91.7% with respect to p-nitrotoluene consumed while the bromine atom efficiency was 87.3%.
Table 3
(Table Removed)

Examples 3 teaches us that it is simple to recover p-nitrotoluene from the residue of the final cycle and that this makes it feasible to carry out the reaction with large excess of p -nitrotoluene to realize the benefit of lower impurity formation.
EXAMPLE 4
The dark residue weighing 323 g recovered in Example 3 after vacuum distillation of p-nitrotoluene was analyzed by GC-MS and NMR and found to comprise 71.1% dibromo (NCVAr-CHBr2) impurity and 26.9%p-nitrobenzyl bromide as the main constituents. 5.23 g of this residue was dissolved in 12.5 ml of dimethoxy ethane (DME). 2.69 g of NaBH4was added next. A solution made from 12.5 ml DME and 5 ml water was then added gradually over 1 h under stirring at room temperature. The DME was then distilled at reduced pressure to yield a solid, which was washed with water to give 2.1 g of pale yellow solid whose GC indicated that the dibromo impurity in residue was converted into p-nitrotoluene and p-nitrobenzyl bromide, giving a composition comprising 60.5% P-nitrotoluene and 39.5% p-nitrobenzyl bromide based on GC area %. It would be evident that the converted residue having nearly 2:1 ratio of p-nitrotoluene:

p-nitrobenzyl bromide can be recycled. This way the conversion increased to 96% with respect to p-nitrotoluene consumed and the bromine atom efficiency increased to 90%.
EXAMPLE 5
The aqueous effluent from 8th batch of Example 3 was collected and analyzed. The data is provided in Table 4 below. It can be seen that the aqueous effluent has low levels of organic matter and unreacted bromide.
Table 4. Data showing details of aqueous effluent from 8th batch of Example 3
(Table Removed)

The main advantages of the present invention are :
1. By using a single solvent for reaction, product isolation and purification, the problem of contamination of one solvent with another is eliminated and the process made simple.

2. p-nitrobenzyl bromide is selectively crystallized out from reaction mass through a chilling process, which enables the mother liquor containing excess p-nitrotoluene and all of the solvent to be recycled directly.
3. p-nitrobenzyl bromide having >98% purity is obtained merely by washing the product with chilled carbon tetrachloride.
4. The present process minimizes solvent losses.
5. The process minimizes impurity formation and consequently, leads to higher bromine atom efficiency.
6. Excess p-nitrotoluene required to minimize impurity formation is easily recovered.
7. Waste organic residue comprising largely dibromo impurity is converted back into p-nitrotoluene/p-nitrobenzyl bromide, which not only increases the yield with respect to p-nitrotoluene but also circumvents the problem of organic waste disposal.
8. The aqueous effluent contains minimum organic load.

We claim:
1. An improved process for the preparation of p-nitrobenzyl bromide, wherein the steps comprising: (i) adding a solution of p-nitrotoluene in carbon tetrachloride having concentration in the
range of 0.15 to 0.35 kg/L into a reaction vessel; (ii) dissolving 2:1 alkali bromide/alkali bromate solid brominating reagent in water to a
concentration of 2-3 M active Br and adding into the reaction vessel of step (i)
maintaining substrate to active bromine (in reagent) ratio in the range of 1:1 to 5:1; (iii) raising the temperature of the reaction mass of step (ii) gradually from ambient to
50-60°C under continuous illumination; (iv) adding stoichiometric amount of 0.5-2.5 M mineral acid such as sulphuric acid and
hydrochloric acid into the reaction mass of step (iii) over a period of 0.5-3.0 h under
continuous stirring; (v) continuing the stirring under reflux conditions for additional 1.0-2.0 hours at the
end of which the reaction mass becomes almost colorless; (vi) switching from reflux mode of step (v) to distillation mode and distilling out 10-15%
of the carbon tetrachloride taken which is thereafter chilled to a temperature in the
range of -5 to -20°C for washing of the centrifuged product as mentioned in (xi)
below; (vii) discontinuing the heating after the distillation of step (vi) and allowing the reaction
mass to cool to 35-40°C; (viii) separating the organic and aqueous layers from the cooled reaction mass of step (vii);

(ix) chilling the organic layer obtained in step (viii) in a freezer to crystallize out p-
nitrobenzyl bromide selectively in the temperature range of -5 to -20°C; (x) allowing the crystallized p-nitrobenzyl bromide of step (ix) to warm up to a
temperature in the range of 0-10°C followed by centrifuging to separate the crystals
from the mother liquor; (xi) washing the crystals obtained in step (x) with the chilled carbon tetrachloride
obtained in step (vi) to obtain purified p-nitrobenzyl bromide having mp of 97-100°C
and GC purity of ca. 98%; (xii) putting back mother liquor of step (x) and washings of step (xi) into the reaction
vessel for next cycle and topping up with required amounts of p-nitrotoluene,
brominating reagent and carbon tetrachloride; (xiii) repeating the process of steps (iii) to (xii) over several cycles; (xiv) distilling out under atmospheric pressure carbon tetrachloride in the spent organic
layer after completion of recycles and thereafter distilling out p-nitrotoluene at under
130-155 °C under a reduced pressure of 10-40 mm of Hg. (xv) dissolving the residual mass (RM) of step (xiv) in dimethoxy ethane(DME) in the
RM:DME ratio of 1:2 to 1:5 (w/v) and thereafter treating the mass under stirring at
room temperature with sodium borohydride (NaBH4) in the RM:NaBH4 weight ratio
of 3:1 to 1.5:1 to convert over-brominated products into a mixture of p-nitrotoluene
and p-nitrobenzyl bromide; (xvi) adding the mixture of p-nitrotoluene and p-nitrobenzyl bromide obtained in (xv) into
the organic layer of step (viii) prior to continuing the operations of steps (ix) to (xv)
and thereby eliminating organic waste.

2. A process as claimed in claim 1, wherein the reaction temperature in step (iii) is preferably raised to 50° C.
3. A process as claimed in claim 1, wherein 1 to 4 light bulbs of 40-250 W power rating were used in step (iii) when the glass reactor vessel size was 1-10 L.
4. A process as claimed in claim 1, wherein the organic layer in step (x) is preferably warmed up to a temperature in the range of-2 to 5°C.
5. A process as claimed in claim 1, wherein 7-10 recycles of mother liquor are undertaken before subjecting the spent mother liquor to the operations of steps (xiii) to (xvi).
6. A process as claimed in claim 1, wherein dimethoxy ethane is recovered by distillation and the product washed with water as part of the operations in step (xv).
7. A process as claimed in claim 1, wherein in step (xvi) the mole ratio of p-nitrotoluene to p-nitrobenzyl bromide after mixing of the organic layers is in the ratio of 2:1 to 1:3
8. A process as claimed in any preceding claims, wherein the yield of p-nitrobenzyl bromide is 90-98% with respect top-nitrotoluene and the bromine atom efficiency is 88-92 %.
9. A process as claimed in any preceding claims, wherein the average purity of p-nitrobenzyl bromide is > 98% (GC area %).
10. An improved process for the preparation of para-nitrobenzyl bromide substantially as herein described with reference to the foregoing examples.

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Patent Number

271026

Indian Patent Application Number

2513/DEL/2008

PG Journal Number

06/2016

Publication Date

05-Feb-2016

Grant Date

29-Jan-2016

Date of Filing

06-Nov-2008

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

ANUSANDHAN BHAWAN, RAFI MARG, NEW DELHI-110 001,INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	MANOJ KUNJABIHARI AGRAWAL	CENTRAL SALT & MARINE CHEMICALS RESEARCH INSTITUTE, GIJUBHAI BADHEKA MARG, BHAVNAGAR 364 002 GUJARAT, INDIA
2	PUSHPITO KUMAR GHOSH	CENTRAL SALT & MARINE CHEMICALS RESEARCH INSTITUTE, GIJUBHAI BADHEKA MARG, BHAVNAGAR 364 002 GUJARAT, INDIA
3	MAHESHKUMAR RAMNIKLAL GANDHI	CENTRAL SALT & MARINE CHEMICALS RESEARCH INSTITUTE, GIJUBHAI BADHEKA MARG, BHAVNAGAR 364 002 GUJARAT, INDIA
4	SUMESH CHANDRA UPADHYAY	CENTRAL SALT & MARINE CHEMICALS RESEARCH INSTITUTE, GIJUBHAI BADHEKA MARG, BHAVNAGAR 364 002 GUJARAT, INDIA
5	SUBBARAYAPPA ADIMURTHY	CENTRAL SALT & MARINE CHEMICALS RESEARCH INSTITUTE, GIJUBHAI BADHEKA MARG, BHAVNAGAR 364 002 GUJARAT, INDIA
6	GADDE RAMCHANDRAIAH	CENTRAL SALT & MARINE CHEMICALS RESEARCH INSTITUTE, GIJUBHAI BADHEKA MARG, BHAVNAGAR 364 002 GUJARAT, INDIA
7	PARESH U.PATOLIYA	CENTRAL SALT & MARINE CHEMICALS RESEARCH INSTITUTE, GIJUBHAI BADHEKA MARG, BHAVNAGAR 364 002 GUJARAT, INDIA
8	GIRDHAR JOSHI	CENTRAL SALT & MARINE CHEMICALS RESEARCH INSTITUTE, GIJUBHAI BADHEKA MARG, BHAVNAGAR 364 002 GUJARAT, INDIA
9	HARSHAD BRAHMBHATT	CENTRAL SALT & MARINE CHEMICALS RESEARCH INSTITUTE, GIJUBHAI BADHEKA MARG, BHAVNAGAR 364 002 GUJARAT, INDIA
10	RAHUL JASVANTRAI SANGHAVI	CENTRAL SALT & MARINE CHEMICALS RESEARCH INSTITUTE, GIJUBHAI BADHEKA MARG, BHAVNAGAR 364 002 GUJARAT, INDIA

PCT International Classification Number

C07D499/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA