Claims:We claim,

1. A cost effective and environmentally friendly process for preparation of 4-bromo-2-fluoroaniline, a key intermediate in the production of flurbiprofen, which comprises;
a) reacting 2-fluoroaniline with molecular bromine in presence of dichloromethane at low temperature ranging from 0 to -50?C to selectively precipitate 4-bromo-2-Fluro aniline hydrobromide over 6-bromo-2-Fluro aniline hydrobromide salt;
b) isolating the precipitated solid, 4-bromo-2-Fluro aniline hydrobromide salt from the reaction mass by filtration; and
c) generating the 4-bromo-2-Fluro aniline free base from the hydrobromide salt by dissolving the salt in aqueous medium followed by treating with aqueous KOH.

2. The process according to claim 1, wherein, the reaction is conducted preferably at -50? C.

3. The process according to claim 1, wherein, the 4-bromo-2-Fluro aniline thus obtained is free from 6-bromo-2-Fluro aniline.
, Description:Technical filed:
This invention relates to regio-selective method for molecular bromination of substituted aniline without using any catalyst. More particularly, the invention relates to regio-selective method for preparation of 4-Bromo-2-Fluro aniline by molecular bromination of 2-Fluroaniline. 4-Bromo-2-Fluro aniline is a key intermediate in the manufacture of Flurbiprofen.

Background and prior art:
The bromination of anilines using N-bromosuccinimide in an inert organic solvent such as methylene chloride is reported in J. B. Wommack et al., J. Het.Chem.,6, 243(1969). 2-Fluoro-4-bromoaniline can be prepared by bromination of 2-fluoroaniline (Chem. Berichte, 70, 1416 (1937)) with N-bromosuccinimide. The bromination of 2-fluoroaniline is an exothermic reaction that takes place at 0° C, for several hours. The resulting reaction mixture is washed with water several times and dried with an appropriate drying agent such as anhydrous sodium sulfate. The 4-bromo-2-fluoroaniline is recovered by removal of the organic solvent under reduced pressure of 100 to 300 mm Hg. at 20°-50° C.

The use of 4-bromo-2-fluoroaniline as a starting material for the preparation of arylpropionic acids appears to be reported for the first time by K. Kuroda et al., Nippon Kagaku Kaishi, 1876 (1973); in Chem. Abstracts., 78, 43571q (1973).

US4443631 discloses a process for bromination of 2-fluoroaniline to selectively obtain high yields of 4-bromo-2-fluroaniline, which comprises bromination of 2-fluroaniline with dibromantin in a solvent consisting essentially of dimethylformamide or dimethylacetamide at a temperatures ranging from 0 to 50?C. The isolation of the product as described in the example 4 involves large volumes of solvent and also cumbersome.

US3987057 (Goddard, Oct. 19, 1976) references the production of 4-bromo-2-fluoroaniline from 2-fluoroaniline and N-bromosuccinimide.
US4138242 (Goddard, Feb. 6, 1979) relates to herbicidal compounds and their preparation from 4-chloro-2-fluoroaniline. The 4-chloro-2-fluoroaniline is prepared through the chlorination of 2-fluoroacetanilide to yield 4-chloro-2-fluoroacetanilide and subsequent hydrolysis of 4-chloro-2-fluoroacetanilide in presence of mixture of ethanol and Concentrated HCl(1:1) at a temperature of 70 to 90° C and at atmospheric pressure to obtain the hydrochloride salt of 4-chloro-2-fluoroaniline, which is further basified to obtain the free base.

US5053542 and WO1991011430 report catalytic bromination of 2-fluoroaniline using molecular bromine in the presence of quaternary ammonium halide (bromide) catalyst in an inert solvent.The process for the preparation of 4-bromo-2-fluoroaniline, comprising:(a) providing a mixture of bromine and quaternary ammonium bromide in an inert solvent;(b) adding 2-fluoroaniline to said mixture; and(c) precipitating 4-bromo-2-fluoroaniline as its hydrobromide salt and d) neutralizing said hydrobromide salt to yield 4-bromo-2-fluoroaniline.

Green Chemistry Letters and Reviews, Vol. 1, No. 4, December 2008, 223230 discloses bromination of 2-fluoroaniline using KBr and H3BO3 in H2O2 system to obtain 4-bromo-2-fluoroaniline in about 80% yield.

Another conventional process includes a step of protecting 2-fluoroaniline using acetic anhydride, then bromination followed by deprotection of acetate leading to 4-bromo-2-fluoroaniline. This process involves substantial increase in manufacturing and operational costs to the production as well use of brominating regents such as NBS or DBH, as shown in scheme 1.

However, bromination of 2-fluoroaniline without protection will have impact on overall production cost as shown in Scheme 2 below, due to the mixture obtained.

There are very few reports regarding molecular bromination of Fluroaniline available in literature, however they have certain limitations with regard to the use of higher boiling solvent or the catalysts as well the limitation in regio-selectivity of bromianation. This lead the present inventors to study the molecular bromination of anilines and have observed the limitations of prior art methods such as use of the catalyst; use of higher boiling solvents and the processes reported lack the selectivity of bromination and thus yield mixture of bromo compounds.

In the light of the foregoing, there remains a need in the art to provide a cost-effective process for production of 4-bromo-2-fluoroaniline, which becomes the objective of the present invention for which the protection is sought.

Summary of the invention:
In line with the above objective, the present invention provides a cost effective and environmentally friendly process for preparation of 4-bromo-2-fluoroaniline, a key intermediate in the production of flurbiprofen.

In accordance with the same, the process comprises;
a) reacting 2-fluoroaniline with molecular bromine in presence of dichloromethane as the most suitable solvent at low temperature to selectively precipitate 4-bromo-2-Fluro aniline hydrobromide over 6-bromo-2-Fluro aniline hydrobromide salt;
b) isolating the precipitated solid, 4-bromo-2-Fluro aniline hydrobromide from the reaction mass by filtration; and
c) generating the 4-bromo-2-Fluro aniline free base from the hydrobromide salt by dissolving the salt in aqueous medium followed by treating with aqueous KOH.
The low temperature as referred herein encompasses a temperature range of 0?C to -50? C.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Accordingly, the present invention provides a cost effective and environmentally friendly process for preparation of 4-bromo-2-fluoroaniline, a key intermediate in the production of flurbiprofen, which comprises;
a) reacting 2-fluoroaniline with molecular bromine in presence of dichloromethane solvent at low temperature to selectively precipitate 4-bromo-2-Fluro aniline hydrobromide over 6-bromo-2-Fluro aniline hydrobromide salt;
b) isolating the precipitated solid, 4-bromo-2-Fluro aniline hydrobromide from the reaction mass by filtration; and
c) generating the 4-bromo-2-Fluro aniline free base from the hydrobromide salt by dissolving the salt in aqueous medium followed by treating with aqueous KOH.

The low temperature as referred herein encompasses a temperature range of 0?C to -50? C.

The change of the solvent from DMF (US4443631) to MDC as in the present invention, although results in quantitative yield of 4-bromo2-Fluro aniline HBr salt; however, the same is contaminated with trace amounts of 6-Bromo-2-Fluroaniline hydrobromide. The presence of 6-Bromo-2-Fluroaniline hydrobromide in the final product; although in minor quantities, led the present inventors to assess the role of tetrabutyl ammonium bromide as catalyst (US5053542). We have noticed that the catalyst do not have any role in bromination, as the reaction progresses in absence of catalyst and afforded within 1 hour 71% of the solid as a precipitate consisting a mixture of 4-bromo-2-Fluro and 6-bromo-2-Fluro aniline hydrobromide. Therefore, the challenge is to reduce formation of undesired 6-Bromo-2-Fluroaniline hydrobromide. To circumvent this problem, the present inventors have proved that regio-selectivity could be achieved by thermodynamically controlling thereaction conditions that is addition of bromine at lower temperatures as shown in Scheme 3.

Therefore, further experiments have been carried out at lower temperature from 0?C to -50? C. The formation of 6-Bromo and 4- Bromo product is further monitored by TLC system in 10% ethyl acetate/Hexane with retention time (rt= 0.87) for 6- Bromo and (rt= 0.58) for 4-Bromo derivative. The bromination reaction conducted at -50?C substantially reduces formation of 6-bromoderivative, with selectivity to the desired product 4-Bromo-2-fluroaniline hydrobromide. Further reduction in temperature may even results in better exclusivity; however, not desirable in view of the cost escalation and cumbersomeness involved in scaling up the process for industrial production.

Having reduced the formation of undesired 6-bromo-2-fluroaniline hydrobromide, the next challenge is to separate these two products by avoiding chromatographic separation. Therefore, the solubility of these two salts have been studied in different solvent systems and observed that the solubility of these two salts in MDC has substantial difference. While the 6-Bromo-2-fluroaniline hydrobromide has good solubility in MDC; 4-bromo-2-fluroaniline hydrobromide is insoluble in MDC. In addition to this, the solubility of these salts in water does have substantial difference. The 6-Bromo-2-Fluroaniline hydrobromide is not soluble in water whereas the 4-bromo-2-fluroaniline hydrobromide has good solubility in water. Encouraged with these results, the present inventors have designed simple work up process to separate these salts as depicted in Scheme 4.

The reaction mass is filtered and the precipitate was repeatedly washed with MDC to remove the undesired 6-bromo-2-Fluroaniline hydrobromide. The obtained product, 4-bromo-2-fluroaniline hydrobromide is then dissolved in water. The 6-bromo- derivative does not dissolve in water, thereby, the remaining insoluble 6-bromo- derivative is filtered off and the aqueous layer containing only 4-Bromo-2-Fluraniline derivative is then is basified using 10% KOH solution to afford the 4-bromo-2-Fluro aniline (free Base) as oil. The oil layer is then extracted with ethyl acetate. However, in the case of mass production, the separated oil layer need not be extracted and can be distilled directly under reduced pressure to afford the product without any impurities. 4-bromo-2-Fluro aniline thus obtained can be used further in the synthesis of Flurbiprofen.

Thus, the process of the present invention provides 4-bromo-2-Fluro aniline which is free from 6-bromo-2-Fluro aniline.

The scope of molecular bromination as disclosed in the invention shall not be construed as limited to the 2-Fluroaniline and can be extended to other substituted anilines with milder variation of temperature and other conditions. Therefore, the minor variations can also be construed as covered under the scope of the invention.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:
Example 1
2-Fluroaniline (25 g 0.225 mole) in MDC (200 mL) was taken in 1 lit Round bottomed flask stirred with overhead stirrer. The flask was immersed in dry ice acetone bath at – 50?C. Bromine (40 gm, 0.247 mole) was taken in MDC (200 mL) was charged in addition funnel. The above prepared bromine solution was then added to the reaction flask at -50?C drop-wise; the rate of addition was controlled in such way that the temperature of reaction mass was under -30?C the addition was completed in 1.5 Hrs. The product precipitated immediately as HBr salt. The reaction mass was then filtered and the solid was washed with MDC(100 mL) The mother liquor contains 6-Bromo-2Fluroaniline HBr salt (1.2 gm, Undesired, 2%). The solid obtained (59.6 gm white solid, 98%) was further taken in water (150 mL). The suspension was stirred for 0.5 hrs to ensure the dissolution of desired HBr salt in aqueous phase. Filter the un-dissolved solid (1.82 gm, undesired, 3%). The aqueous layer was then treated with KOH( 150 mL, 10% solution in water), the desired 4-Bromo-2-Fluroaniline free base separates as oil (yellow , 40.65 g, 95%). Thus obtained crude product was distilled under reduced pressure to give 38.5 gm (90%) mp (Lit) 38–42 °C; Observed mp 36-38°C.1H-NMR (CDCL3, 400 MHz): d 7.171-7.150(d, J =8.4 Hz, 1H,), 7.017-7.061 (d, J = 6.4 Hz, 1H,), 6.686-6.651(t, J = 6.8 Hz, 1H), 3.758 (S broad, 2H, NH2), MASS (ESI) (M+1) = 191 with purity > 99%.