Scribd Logo
Upload

Welcome to Scribd!

  • Us 5952531

    Uploaded by

    Yohana Meliantha
    21 views7 pages
    sdsdsdsds

    Copyright

    © © All Rights Reserved

    Available Formats

    PDF or read online from Scribd

    Did you find this document useful?

    Is this content inappropriate?

    Report this Document
    sdsdsdsds

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    21 views7 pages

    Us 5952531

    Uploaded by

    Yohana Meliantha
    sdsdsdsds

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    of 7
    United States Patent 11» Priestley et al. [54] NITRATION PROCI [75] Inventors: Ian Jeffrey Grassham Priestley, Blackley; James Peter Muxworthy, Huddersfield; John Heatheote Atherton, Huddersfield; Mar Lennon, Huddersfield; Stephen Martin Brown, Huddersfield, all of United Kingdom [73] Assignee: Zeneca Limited, London, United Kingdom [21] Appl. No. 08/960,924 [22] Filed: Oct, 30, 1997 [30] Foreign Application Priority Data Nov. 1, 1996 [GB] United Kingdom 9622784 Jul. 28,1997 [GB] United Kingdom 9715846 [51] Int. cL? CO7C 43400, CO7C 205,00; OIE 29100 [52] US. CL ‘68/585; 568,939; $68/840, 568424; 568/306; 560/21; 562/434; 562/435: 562/438, [58] Field of Search 568/939, 585, 568/840, 424, 306; 360/21; 562/434, 435, 438 [56] References Cited U.S, PATENT DOCUMENTS 2435314 2/1948 Kokatnur 200,167 USONS9S25314, uy) Patent Number: 5,952,531 [45] Date of Patent: Sep. 14, 1999 245544 21948 Kokatnur 260548 Soon ios te sot SasmRs os Fo a soo FOREIGN PATENT DOCUMENTS cn3416 61979. Faroean Pat. Of oss 00 8/1908 European Pt OF oioieg 31997 WIPO OTHER PUBLICATIONS Bisagni ot al, Tetrahedron, 1996, vol. $2, No. 31s pp 10427-10440, “A convenient way 1 dibenzo [esh}1, 5-naphthyridines (L1-a2a-benzofe] phenanthridines)" Masci, Tetrahedron, 1989, vol. 45(a), 2719-2730, “The Selectivity of Electrophilie Aromatic’ Nitration and the Effect of the Organic Solvents”, Primary Examiner—Paul 5. Killos Assistant Examiner-—Jafar Parsa (57) ABSTRACT Approcess for the nitration of an aromatic or heteroaromatic ‘compound with & nitrating agent comprising nitric acid or a ‘mixture of nitric and sulphuric acids, characterised in that nitration is performed in a solvent comprising at least 50% vv of a C,-C, alkyl ester of « C,-C, carboxylic acid. The process is'of particular use for the nitration of diphenyl ethers to give compounds whieh are useful as herbicides or as intermediates in the synthesis of herbicides. 16 Claims, No Drawings 5,952,531 1 NITRATION PROCESS ‘The present invention relates to a process for nitration and, in particular, to a process for the nitration of aromatic and heteroaromatic compounds. The process is of particular use for nitrating diphenyl ethers to give compounds which are useful as herbicides or as intermediates in the synthesis Of herbicides. Various processes are known forthe nitration of aromatic and heteroaromatic compounds, The most commonly used system employs sulphuric acid as the solvent or fluidising agent, and nitric acid or an alkali metal nitrate as the nitrating agent, Although effective ia many cases, large ‘quantities of waste sulphuric acid are often generated and recovery or disposal of this acid poses environmental prob- lems. The use of an organic solvent can result in reduced disposal problems and, in some cases, improved yields. Chlorinated solvents have been described as suitable for this purpose, for example, EP-A-0022610, which relates to her- bicides of the formula: ‘coon ‘Nos wherein X and ¥ may be H, F, Cl, Br CR, OCF.CHZ, (ZaCI, Br, Fy, OCH,, CN, CO.R Relower alkyl), Cols, O-alkyl, NOx oF SOs-lower alkyl describes a process for making these compounds by niteating @ compound of the formula: ‘coon ‘wherein X and Y are as defined above, Suggested nitrating agents for this reaction include mixtures of nitric and sulphuric acids and the recommended reaction solvent is dichloromethane. The nitration process is said to give a yield ‘0f 75.4% but no details are given of the purity of the produet fr the presence of other nitrated isomers. US. Pat. No. 4,031,131 describes similar compounds to the above which are prepared ia a similar manner. Suggested nitrating agents include potassium nitrate or mixed nitric and ‘sulphuric acids and the reaction is carried out ia dichlo- romethane. An extremely high yield (295%) is claimed for the nitration reaction but, again, there are no details given about the purity of the product. Nitration reactions using mixed nitric and sulphuric acids may also be carried out in the presence of acetic anhydride. EP-A-0003416 and EP-A.0274194 both relate to the synthesis of herbicidal compounds of the formula: 0 as os ss 4s ss 6s ® coNR'S0:8! Nos wherein R! is alkyl optionally substituted with fluorine or ‘optionally substituted phenyl; R° is H, F, Cl, Br I, alkyl, trifluoromethyl or CN; R'is H, F, Cl, Br [or trifluoromethyl; R° is F, Cl, Bs I or triffuoromethyl; and R® is Hor C.-C, alkyl. In EP-A-0003416, these compounds may be obtained by nitating the corresponding carboxylic acid or carboxamide and then converting tothe sulphonamide, or by nitrating the sulphonamide itself, A nitration reaction is described in Example 7 where the solvent is 1,2-ichloroethane and the nitating agent is a mixture of potassium nitrate and con- centrated sulphuric acid EP-A-0274194 describes a process for the nitration of ‘compounds of the formula: ‘The nitration reaction is carried out using anit such as concentrated nitric acid or sodium nitrate, or mix- tures ofthese with sulphuric acid, The reaction solvent is one which is resistant to nitration, examples of such solvents include halogenated solvents such as dichloromethane, dichloroethane, dichloropropane, chilorofluorocarbons and aromatic solvents such as nitrobenzene. However, none of the above mentioned methods are particularly satisfactory for use on an industrial seale because they all have the common problem that the reaction yields a mixture of the required product and other nitrated isomers. Nitrated isomers of diphenyl ether compounds are often extremely difficult to separate from one another and the quantity of other isomers is often too high for the final prodluct to fulfil the requirements of the regulatory authori- ties for herbicides. The problem tends to be further exacer- bated if the nitrated product is an intermediate in the synthesis of a herbicide rather than the required herbicide itself, because the mixture of nitrated compounds means that larger quantities of other reagents must be used than would be necessary if the nitrated isomers could be separated satisfactorily. It is therefore important to ensure that the nitration process produces a product mixture containing the highest possible proportion of the desired isomer. “The problem of obtaining mixtures of isomers from such nitration process was recognised in GB-A-2103214 which describes process in which a compound of the formula: 5,952,531 wherein cach of Xj, X- and X, is Hy F, Cl, Br, CFs, ‘OCFCHZ, (where Zis F, Clor Be), OCF, CN, COR (Ris lower alkyl), phenyl, lower alkoxy, NOs or SO3R (Ris lower alkyl), and atleast one of X,, X, and X, is, other than Hi and Y is COR (R is lower alkyl) or earboxys is nitrated to give a product ofthe formula: % sels ys « os wherein X,, Xo, X, and Y are as defined above ‘The nitration is carried out using & mixture of nitric and sulphuric scids ia an organic solvent such as. dichlo- romethane. The desirability of keeping the reaction system anhydrous by the addition of acetic anhydride is stressed, GB-A-2103214 states that this makes it possible to improve the selectivity with respect to acifluorfen (the desired nitrated product). The recommended ratio of starting mate- Fialsolventiacetic anhydride is 1:2.66:1.4. The reaction is ‘conducted at a temperature of 45° C. and left for 3 hours “The reaction mixture is then allowed 10 sland So that the ‘organic and aqueous phases separate and the organic solvent removed by distillation. PCT/GB96V01892 relates to a simi lar process in which the preferred solvent is again a halo- senated solvent, namely terachloroethylene (TCE). "The prior at nitration processes described above are thus senerally conducted in halogenated solvents. Whilst these are useful solvents in-many respects, they do have disadvantages, one of the most serious’ being that they present a threat 0 the environment if they are released, Processes which lead to environmental damage are becom. ing less and less acceptable and it would therelore be of great benefit if alternative solvents could be found, however, despite their potential eavironmental benefits, non chlorinated solvents have rarely been used i industrial niteations, Schofild, “Aromatic Nitration”, Cambridge University Press, 1981, deserbes the use of acetic acid, nitromethane, sulpholane, acetonitrile and ethers as nitration solvents, U.S. Pat. No. 4,306,900 discloses acetic acid asa solvent forthe nitration of diphenyl ethers. However, i all ofthese cases, the solvents are dificult to handle and are water miscible making recovery and reuse problematic “Tetrahedron, 1989, 45(9), 2719-2730, d tigation into the selectivity of aromatic nitrations using BU,NNO, and (CF,CO),0 in a variety of organic solvents including’ ethyl acetate and halogenated solvents such as dichloromethane. Tetrahedron, 1996, 52(31), 10427-10440, deseribes the nitration of -phenylisoquinoline-1-(2H)-ones using nitric 0 as os ss 4s 50 ss 6s 4 about 20% wi ethyl acetate, to give S-phenyl-4-nitro-isoquinoline-1-2H)-ones. and traces of other uncharacterised nitrated derivatives. "The present invention provides a process for the aitration of an aromatic or heteroaromatic compound with a nitrating agent comprising nitric acid or a mixture of nitric and Shiphurie acids, characterised i that nitration x pedformed in a solvent comprising at least 50¥% viv of a C,-Ce alkyl ester of a C,-C, carboxylic acid. In the process of the invention it is an aromatic ring carbon of the aromatic or heteroaromatic compound which is nitrated. The aromatic or heteroaromatic compound is preferably selectively mono-nitrated using the process of the invention ‘The esters used as solvents in the process of the present application are non-toxic, readily recoverable and do not present a threat to the environment in the event of an accidental release It would have been expected that in order to obtain the environmental benefit of using a non- halogenated solvent, the efficiency of the process would suffer in some way. However, this has, surprisingly, been found not to be the ease when the nitration is performed in solvent comprising at least 50% viv of a Cy-C alkyl ester of a CC, earboxsli acid In the context of the present invention the term “aromatic compound” refers to a compound comprising an aromatic ring system which may be mooo-,bi- or tricyclic. Examples of such ring systems include phenyl, naphthalenyl, anthrac cenyl and phenanthrenyl ‘The term “heteroaromatic compound” refers a compound comprising an atomatic ring system containing af feast one heteroatom which may be mono-, bi-or tricyclic. Preferably, single rings will contain up to four, and bieyelie systems up to five heteroatoms, these are preferably chosen from nitrogen, oxygen and sulphur. Nitrogen atoms in the cing may be quatemised or oxidised. Examples of such cing systems. include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4triazolyl, tetrazolyl, oxazolyl, ‘isoxazolyl, thiazolyi, isothiazolyl, 1,2,3- oxadiazolyl, 1,2,4-0xadiazolyl, 1,34-oxadiazolyl, 1,2.5- oxadiazolyl, 1;2;3-thiadiazolyl, 1,2,4-thiadiazolyl, 133,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,34-0xatrizolyi, 12,3, S-oxatriazolyl,”1,2,3,4-thiatriazolyi, 1,2,3,5-thitriazolyl, pyridyl, pyrimidinyl, pyridazinyl, pytazingl, 1,2,3-triazinyl, 1,2,4-Iriazinyl, 1,3,5-triazinyl, 1,2,4,5-letrazinyl, benzofuryl, benrisofuryl, benzothienyl,, benzisothienyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phibalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl, pteridinyl and indolizinyl ‘The aromatic or heteroaromatic compound to be nitrated according to the process of the invention may optionally be substituted with one or more substituents. Examples. of substituents include C,-C, alkyl, Cs-C, alkenyl or C.-C, alkynyl any of which may optionally be substituted with one 6or more substituents selected from, for example, halogen and hydroxy; halo e.g. thuoro, chloro, bromo or iodo; C,-C, alkoxy optionally substituted by halogen eg. methoxy, ethoxy, n-propoxy, iso-propoxy, diioromethoxy, tifluo- romnethoxy or fetrafluoroethoxy; aryl e.g. optionally subst- tuted phenyl; aryloxy e.g. optionally substituted phenyloxy; cyano; nitro; amino; mono- or di-C,-C,.alkylamino; hydroxylamino; acyl eg. acetyl or trifluoroacetyl; S(O), CC, alkyl of S(0),, CC, haloalkyl wherein n is 0,1 of 2c. methylthio, methylsuiphinyl, methylsulphonyl, tf- Iioromethylthio triluoromethylsulphinyl or triffuorometh- ylsulphonyl; SCN; SF COOR', COR®; CONR'R® or ‘CONHSO,R'; wherein R* and R® are cach independently hydrogen or C,-C, alkyl optionally substituted with onc or more halogen atoms and Risa halogen atom or a group R’ 5,952,531 5 ‘When there is more than one substituent, the substituents may be the same or different. The aromatic or heteroaromatic compound tobe nitrated according to the process of the invention preferably com- prises a substituted phenyl ring. More preferably the aromatic or beteroaromatic com- pound to be nitrated according to the process of the inven- tion comprises a diphenyl ether the phenyl rings of which are independently optionally substituted by one or more groups selected from C.-C alkyl, C.-C, alkenyl or Co-C, alkynyl any of which may optionally be substituted with one or more substituents selected from halogen and hycroxy; halo; COOR*; COR® CONR'R’ or CONHSOSR®, wherein Rt and R® ‘are each independently hydrogen or C,-C, alkyl ‘optionally substituted with one or more halogen atoms and Risa halogen atom or a group ‘The process according 10 the present in invention is of particular use forthe nitration of diphenyl ether compounds ‘which are useful as herbicides or as intermediates in the synthesis of herbicides. ‘Therefore, according to a further aspect of the present invention, there is provided a process for the preparation of a compound of formula I: 0 as ss wherein R! is hydrogen or CC, alkyl, C.-C, alkenyl or C.-C, alkyoyl (any of which may optionally be substituted ‘with one or more substitients selected from halogen and hydroxy) or COOR*, COR®, CONR'R? or CONHSO.R'S R° is hydrogen or halo; RY is C.-C, alkyl, C.-C, alkenyl or C.-C, alkynyl (any ‘of which may optionally be substituted with one or more halogen atoms) or halo; R° and R° independently represent hydrogen or C.-C, alkyl optionally substituted with one or more halogen atoms; and R° is a halogen atom or a group Rs the process comprising reacting a compound of formula I: 4s we ® ss Rt wherein R!, R? and R® are as defined for formula T; ‘with a nitrating agent comprising nittie acid or a mixture ‘of nitric and sulpburic acids, characterised in that nitration is performed in a solvent comprising at least 50% viv of a C.-C, alkyl ester of a C,-C, carboxylic acid, 6s 6 ‘The term “C,-C, alkyl” refers to a saturated straight oF branched hydrocarbon chain containing from 1 to 6 carbon atoms, Examples include methyl, ethyl, a-propyl, t-butyl, ‘pentyl and n-hexyl. The term “C,-C, alkyl" is a subset of C.-C, alkyl and refers to an alkyl group baving from 1 to 4 carbon atoms, ‘The term “C.-C, alkenyl” refers to a straight or branched hydrocarbon chain containing from 2to 6 carbon atoms and hhaving at least one double bond. Examples include etteayl, allyl, propenyl and bexenyl. The term “C.-C, alkenyl” is a subset of C.-C, alkenyl and refers to an alkenyl group having from 2 10 4 carbon atoms, ‘The term “C.-C, alkynyl” refers toa straight or branched hhydrocarbon chain containing from 210 6 carbon atoms and hhaving at least one triple bond. Examples include ethyayl, propyayl and hexyayl. The term “C.-C, alkynyl" is a subset of CC, alkynyl and refers to an alkynyl group having from 2 to 4 carbon atoms, ‘The term “halogen” refers to fluorine, chlorine, bromine or iodine and the corresponding term “halo” refers to fluoro, chioro, bromo or iodo. In the context of the present invention, compounds of general formula T ase designated 4-nitco isomers. Various isomers may be generated inthe nitration reaction other than the required 4-nitro isomer and these include the following ‘mono-nitro isomers: the 2-niteo isomer: ® 0 and the G-aitzo isomer: ®. Q ow Rt ‘There are also at least three different dinitro isomers which may be generated ‘The process of the present invention is particulary favor- able as it leads to very low levels of dinitration. Indeed the proportion of dinitrated isomers is far lower than that when the reaction is conducted in TCE, which is deseribed in PCT/GB96/01892 as a particularly favorable solvent. The levels of dinitro-isomers are also lower than with other hhalogenated solvents such as ethylene dichloride (EDC). [Not only are the levels of dinitrated isomers lower using, the process of the present invention than with comparable processes carried out in halogenated solvents, but the pro- portions of the 2- and 6-nitro isomers are also considerably ower than with many halogenated solvents. In PCT/GB96) (01892, TCE is the solvent of choice because its use leads to 5,952,531 7 ‘extremely low proportions of 2- and 6-aitro isomers in the product mixture. Unexpectedly, it has been found that when at least S0% viv of a C,-C, alkylester of a C,~C, carboxylic acid is used as solvent, the levels of the 2- and 6-nitro isomers are comparable to the levels when the reaction is ‘conducted in TCE and far lower than when the reaction is ‘conducted in other halogenated solvents such as EDC. Most significantly of al, the use of at least 50% viv of a C,-Cy alkyl ester of a C,-C, carboxylic acid as solvent ‘enables far better solubilisation ofthe reactants and products than is achievable with halogenated solvents. This in turn increases the efficiency of the reaction, ‘The benefits of the present invention would certainly not have been predicted from the prior art as all previous similar nitrations have been conducted in halogenated solveats ‘Although any C,-C, alkyl ester of a C,-C, carboxylic acid, oF misture thereof, can be used, shorter chain alkyl xgroups are preferred. Therefore, the preferred solvents for the present invention are C,~C, alkyl esters, e.g. ethyl, propyl or n-butyl esters, of C\-C, carboxylic acids. The reason for this is that it is necessary to use a solvent of Sullicient polarity to dissolve the starting material and the proxluct and the shorter chain esters are more polar than the longer chain ones. Similarly, esters of acetic acid and propionic acid may be more suitable than esters of butanoie acid, Preferred solvents include ethyl acetate and n-butyl acetate, especially n-butyl acetate. ‘The Solvent sed in the process according tothe invention preferably comprises atleast 75% viv of aC,-C, alkyl ester of a CC, carboxylic acid, and more preferably at least 90% viv of a C,-Ce alkyl ester of a C,-C, carboxylic acid Ithas also been found that there are benefits ifthe process ‘of the invention is conducted in the presence of acetic anhydride. The molar ratio of acetic anhydride to starting material, €g. compound of formula II, is preferably from about 1:1 10 about 3:1, Reaction temperature plays a role in determining the proportions of the various mono-nitrated isomers, with a ‘greater proportion of the required isomer being produced as the reaction temperature is reduced. The reaction emperature, is thus a compromise since, clearly, it would not be economically viable t operate the reaction if the temperature were below a certain level because of the amount of cooling required. The preferred temperature range for the process of the present invention is from about =15° to about 15° C., preferably =10° to 10° C., and more preferably <0° C, thas also been found advantageous to have a weight ratio ‘of solvent to starting material, e.g- compound of formula Tt {including any isomers present), of no greater than 8.5:1, and itis preferred that the ratio is from 1.5:1 to 4:1, ‘AS mentioned, the nitrating agent used in the process is nitric acid or a'mixture of nitric and sulphurie acids. A mixture of nitric and sulphuric acids (mixed acid) may ‘contain, for example, from about 30 t0 45% of pure nitric acid, more typically from about 30 to 35% pure nitric acid. ‘When the chosen nitrating agent is a mixed acid, it will, typically be added to the reaction mixture over a period of about 30 minutes to 15 hours. The rate of addition will, however, vary according 10 the reaction solvent which is ‘chosen, With addition over about 1 to 6 hours, or preferably 2 to 4 hours, being appropriate for many solvents. ‘When both itrie and sulphuric acids are used in the process of the invention itis possible to further reduce the level of over nitration by adding these acids sequentially to the reaction mixture, It bas been found particularly advan- 0 as 20 os ss 4s ss 6s 8 tageous to add the sulphuric acid to a mixture of the starting material, e.g. compound of formula I, and acetic anhydride inthe chosen solvent, followed by addition ofthe nite aid ‘When a sequential addition ofthe sulphuric and ntsc acids is used the nitic acid is preferably’ 290% stength, ex 90-97% strength. The use Of nitric acid of 290% strcagth hha the advantage that it equires a shorter reaction time than comparable reactions using eg, 70% strength nitric acid. ‘The molar ratio of sulphuric aciistating material used in the waction will generally be up to 5:1, however a ratio of sulphur sesartng mater of fom Oc fo 02:1 8 PSWhen the process of the invention is used forthe prepa ration of a compound of formula I its especially prefered that R® is chloro and R° is teifluorometbyl. Pantculaaly preferred compounds of formula I age those in which Ris COOH or CONHSO.CH,. These compounds. are 5+( chloro-c,a,a-trlluoro-4-tolyloxy)-2. (Geittucefen) and 52-chloro-

    You might also like