EP 2 266 949 A1 ” DOOQUOOOOANA ty EP 2 266 949 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int 29.12.2010 Bulletin 2010/52 core 231/002 — core 2ex/25¢e00") (21) Application number: 09425226.9 (22) Date of fing: 106.2009 (84) Designated Contracting States: AT BE BG CH CY CZ DE DK EE ES FIFR GB GR HR HUIEISITLILTLU LV MC MK MT NL NO PL. PTROSESISKTR Designated Extension States: AL BARS. (71) Applicant: Gregoria, Liberata £84125 Salerno (IT) (72) Inventor: Venneri, Filippo {84125 Salerno (IT) (74) Representative: Cioncoloni, Giul ‘Studio Consulenza Brevetti Cioncoloni S.r Via Filippo Tura, 76 (00185 Roma (IT) (6) cleaving the ether with hycrobromic ac in an inert (54) “Fast, high-efficiency quantitative synthesis of paracetamol" (57) Methodtorproducing paracetamolincluding the stages of (a) reacting phenol and neopentyl bromide or sodium pphenoxide and neopentyliodide ina solvent, with forma: tion of neopentyiphenyl ether, (6) nitrating the neopentyipheny| ether with formation of ‘a phenylamine; (c)cetelvically reducing the phenylamine with hydrogen; {d)acetylating the reaction producto the catalyticredue: tion, in position pare, wth formation of an ether solvent or respectively wth hydtiodic acidin an inert sol vent, with formation of paracetamol and neopentyl bro- mide or respectively neopentyl iocide, and advanta- geously (recovering the paracetamol by fitration, and recover- ing the neopentyl bromide or respectively neopentylio- dlde by distilation and returning It to stage (a)8 EP 2.266 949 At Description TECHNICAL FIELD [0001] The present invention relates toa method forthe production of paracetamol PRIOR ART. [0002] Peracetamol is an active metaboite of phenacetin resulting from the oxidizing reaction of O-dealkylation. [0003] Traditionally paracetamolisproducedby nitration of phenolwith formation of pare-nitrophenol t andsubsequent reduction and acetylation ofthis one with formation of paracetamol, according tthe following reaction scheme: NHa, NHCOCHS, NO, om 9° ty Que ml) OH ou ol OH [0004] However, the traditional method for producing paracetamol is affected by two basic shortcomings: (1st) the reactions that take place init are not quantitative with respect to paracetamol, owing tothe fact that in the nitration of phenol -to obtain the pare-nitropheno! of interest, ths one belng the precursor of paracetamol- however the reaction product in the position orto- of phenyi rng, s equal to as much as 66%, both because one has two ‘equivalent attachment positions inthe postion orto- and ony one inthe position para, and for the formation of a hyarogen bond between hydroxyl and one of the two oxygen atoms of nitro group (-NO;), which bring a partial negative charge and therefore inthis case form a very strong hydrogen bond, energetically favouring orto-nitrophenol with respect to pare-ritrophenol of interest; (@nd) it results in byproducts which can hardly be separated and are polluting. DISCLOSURE OF THE INVENTION [0005] In view of the shortcomings referred above, i isthe object ofthe present invention to provide a method for a fast, high-eficiency quantitative synthesis for the production of paracetamol [0006] Ite a further object ef the present invention to provide a synthesis method forthe production of paracetamol, that is also not polling, [0007] Such objects are achieved according tothe present invention with @ method for the production of paracetamol including the stages of (@) reacting phenol and neopentyl bromide or sodium phenoxide and neopenty| iodide in a solvent, with formation ‘of neopentyipheny/ ether: (0) nitrating said neopentyiphenyl ether with formation ofa phenyiamine; the nitration gives a strong prevalence of reaction product inthe postion para, so that all subsequent stages are {quantitative and fast reactions, without polluting or haraly separable byproducts such as in the acetylation which takes place inthe traditional synthesis of paracetamol, which is not quantitative and brings to many products to be separated; (c) catalytcaly reducing said phenylammine with hydrogen; (@ scetylating the reaction product of sald catalytic reduction, in pastion para, with formation of an ether; the acetylation takes place quantitatively and very fastly, because an unstable intermediate reaction product is formed, Le. ecetyipyridinium chloride, which is even more reactive than acetyl chloride and reacts fastly with amino group, ‘acetyating itn @ quanttative manner, achieving the objects of the present invention [0008] Moreover, acety chiride costs much less than acetic anhyatide and having a molecular weight lesser thanEP 2.266 949 A1 acetic anhydride, the weight being equal one has mare moles of acetyl chloride and then the economic advantage increases, achieving the objects of the present invention [0009] A disadvantage of the rational synthesis of paracetamol that in order to avoid the acetylation of oxygen, in this case one having to acetyite a para-amino phenol, one is to use acetic antiyaride, which is much less reactive than acetyl pyridinium chloride: the reactions tobe carried out under particular conditions in order to avoldthe acetyiation cof the hydroxyl and therefore the product isnot quantitative, Moreover, though nat wiling to be bound to any theory, the Inventor holds that as oxygen isan attractor of electrons, its the amino group, which i lese electronegative, that tends to have the conjugative effect with the benzene ring of para-amino phenol, For this reason the nucieophilty is depressed, ‘and moreover inthe resonance form, in which nitrogen conjugates the doublet wth the benzene ring, one has anegatve charge of 33% in postion pare- in which oxygen is bound, Therefore, oxygen becomes richer of electrons and therefore ‘more nucleophilic. The Inventor holds therefore that hydroxy is actllated too in a minimum portion, so a lat of products resulting, to be separated: non-acetylated para-amino phenol, the paracetamal of interest, para-amino phenol acetate ‘and acetic acd, whichis the byproduct of acetic antydide. As opposite, in the inventive method one only has insoluble pyridinium chloride as the byproduct ofthe fourth reaction in the environment, and the pure product soluble in pyridine. [0010] Pyridine chiride can be titrated with soda and thereafter, once the sodium chioride removed, the pyridine can be recovered by azeotropic detllaton. In this way there is @ recovery ofthe solvent and one has no environmental effect in wasting the residues ofthe synthesis, these ones being water and sodium chiotide, achieving the inventive objects; () leaving aid ether with hydrobromic acid in an inert solvent or respectively with hydriocicacid in an inert solvent, with formation of paracetamol and neopenty| bromide or respectively neopentyl iodide. [0011] Advantageously, the Inventive method further includes the stage of: (recovering seid paracetamol by fitration, and recevering said neopentyl bromide or respectively neopentyl iodide by distilation and retuming ito stage (a) [0012] By virtue of retuning neopenty bromide or neopenty iodide to the first reecton, though the inventive method envisages two adaitional stages with respect to the traditional method, however one does not have an economic loss ‘as regards the intial reactant, this one being recovered pure inthe final reaction, [0013] The synthesis of paracetamol taught by the present invention turns out to be of a high efficiency, and advan- tagoeus from the economical standpoint, because the only additional reactant that is employed is hydrobromic acid or hhydriodio acid, which is a low-cost product [0014] The advantages of the inventive method, definitely, derive from the fact thet whilst in traditional synthesis attachments are predominatingly formed in postion oto, In the Inventive synthesis attachments in position para- are predominatingy obtained. [0015] Therefore itis the subject of the present invention a method for producing paracetamol according to annexed lain 1 [0016] _Itis also the subject of the present invention a method for producing paracetamol according to annexed Claim 2, BEST WAY FOR CARRYING OUT THE INVENTION [0017] The present invention wl be fully understood based on the folowing detailed description ofa preferred em- bodiment thereof, only given as a matter of example, absolutly not of restriction ofthe teaching provided thereby. [0018] The inventive method for producing paracetamol includes five reactions. [0019] The first reaction is a reaction between phenol and neopentyl bromide in triethylamine, with formation of neo- ppentylphenyl ether and tethy! ammonium bromide. Inthe first reaction also hydobromilc acd is formed, The solvent (triethylamine), protonated by hydrobromic acid, may be recovered by trating it with soda, which forms sodium bromide and water, and by simply separating i after fitering sodium bromide, as water and tiethy’amine are not miscible with ‘each other, and in case one would proceed by ditilaton, they do not form an azeotrope and therefore the cistilation is simple to be brought to its end, and so the triethylamine re-enters the production cycle and waste products are not polluting, being water and sodium bromide, so the Inventive objects being achieved. [0020] Its envisaged that the phenol may aiso be under the form of the derivative of phenol composed of sodium pPhenoxid, reacted with neopentyl iodide in a sultable solvent. [0021] The second reaction is a nitration of neopenty| phenyl ether formed inthe first reaction. The nitration can be carried out with the known nitrating mix, composed of nitric acid and suffuric acid in an inert solvent, such as e.g tetrahydrofuran or the cheaper like. [0022] Oxygen in the ethereal form always keeps a conjugative effect with benzene ring which is ofto- and pera- Corientating. Rather, the union ofan electron release alkyl group increases the conjugative effect, whereby the reactionEP 2.266 949 A1 proceeds in an even more efficent way. The product of this second reaction is predominatingly in postion para. Without willing to be bound to any theory, itis held that this ensues from two factors: (1st) the high directive power of neopenty! {g0up, owing to the high steric encumbrance thereof. During the reaction, it makes the attachment more dificult of ritronium cation on postions orte; (2nd) a repulsive etfect between alkyl groups donors of electrons and the two partially negative oxygen atoms present on nitrogen when the product in position orto- is formed, which moreover restits the rotational degrees of freedom and therefore tyhe product in postion orto- is energetically unfavoured, The solvent and the nitrating mix are recovered and disposed of by conventional methods. [0023] The third reaction is a catalytic reduction with hycrogen of the reaction product of the second reaction, Le. of the nitration of neopentyl phenyl ether. [0024] The fourth reaction is an acetylation, in position para, ofthe reection product of the third reaction, of catalytic reduction. The fourth reaction takes place with formation of an ether. The fourth reaction may be carried out with acety! Chloride in anhydrous pyridine, bacaise oxygen, blocked in ethereal form, cannat be acetylated [0025] As the byproduct ofthe fourth reaction only pyridinium chloride is formed, which can be trated with soda and thereafter, once sodium chloride removed, pyridine can be recovered by azeotropic cstlation. [0026] |The fith reaction isthe final one, which brings tothe formation of pure paracetamol. is a simple cleavage of fan ether with hydrobromic acd in pentane, benzene or another solvent. Panliculary a solvent that is cheap and has ‘minimum environmental impact and disposal costs may be selected for the purpose. Water not being present in the reaction environment one does not have the hydralyss ofthe amide. [0027] In this reaction pure paracetamol and neopentyl bromide is formed. As this one constitutes the reactant of use in the first reaction, it may be returned tothe fist reaction. [0028] _In the embodiment reterred above ofthe use of socium phenoxide, the cleavage ofthe ethers caried out with hhydriodi acid, with formation of neopentyl Iodide, which can be retumed tothe fist reaction. [0029] The present invention has been disclosed refering to preferred embodiments thereot, but variations, daltons ‘remissions can be made without departing from the scope of protection relevant thereto, which only remains defined by the enclosed Claims. INDUSTRIAL APPLICABILITY [0030] The disclosed method is sutable for producing paracetam!industaly. Claims 11. Method for producing paracetamol incuclng the stages of (a)reacting phenol and neopenty|bromide or sodium phenoxide and neopentylfocide ina solvent, with formation of neopantylphenyl ether; (©)nitrating said neopentyiphenyl ether with formation of a phenylamine; (6) catalytically reducing said phenylammine with hydrogen; (@) acetyleting the reaction product of sald catalytic reduction, in postion pare, with formation of an ether; (@) cleaving said ether with hydrebromic acd in an inet solvent or respectively with hydriodic acd in an inert ‘solvent, wit formation of paracetamol and neopentyi bromide or respectively neopentyl iodide. 2. Method for producing paracetamol according to Claim 1, further including the stage of: (f recovering said paracetamol by fitration, and recovering sald neopenty| bromide or respectively neopentyl Todide by aistilation and returning ito stage (a).EP 2.266 949 A1 EUROPEAN SEARCH REPORT onteson wane EP 09 42 5226 DOCUMENTS CONSIDERED TO BE RELEVANT ‘lao of dmurent wh ndoaton wher appropri, SppLATION WC A |*UlImann's Encyclopedia of Industrial Chemistry, volume 2, 6th ed." 2003, WILEY-VCH , WEINHEIM , xP002551367 Page’530: 4-Hydroxyacetani lide. A |S 2004/138509 Al (BHATTACHARYA APURBA [Us] ET AL) 15 July 2004 (2004-07-15) Abstract; paragraphs [0006] [0010]. [o023)- [6026] . A JEP @ 435 263 A (NITSUI TOATSU CHEMICALS [uP]) 3 July 1991 (1991-07-03) Abstract; claims; examples. ‘A |DATABASE BEILSTEIN [Online] BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; xP902551396 Database accession no. 2240154 (BRN) Reaction 9 of 10 (RID = 3924644). & LIEBIGS ANNALEN DER CHEMIE, vol. 6, 1990, pages 509-512, ‘A |DATABASE BEILSTEIN [Online] BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-NAIN, DE: xP902551397 Database accession no. 2329887, 2356843 (BRNs) * abstract * & ARZNEIMITTEL FORSCHUNG, vol. 30, no. 5, 1980, pages 751-758, A JUS 4 80 505 A (KAWAMATSU YUTAKA ET AL) 21 March 1978 (1978-03-21) Colum 9, reference example 6: 4-neopentyloxynitrobenzene and 4-neopentyloxyaniline as intermediates. “The present serch report hasbeen dawn p frais 1,2 1,2 IW. co7te3i/e0 co7¢233/25 core Nunich 20 October 2009 Weisbrod, Thomas 2 patna lotto 5 fa tt fac tn acer 4 nogealowcngecnd § retmas moore Eee enantio cingEP 2.266 949 A1 ANNEX TO THE EUROPEAN SEARCH REPORT (ON EUROPEAN PATENT APPLICATION NO. EP 09 42 5226 “Bane art yma aig ot att oe The Europeu Patent Oe eno way habitus baltic av marty ven lr the purr ef nrmatien, edn te shovesmertoned European serch ep, 20-10-2009, Pant cooamet Pabicaton Pai tomiy Pieaton sid toarh ope ‘ie rember) ‘se US 2004138509 Al 15-07-2004 NONE EP 0435263 = A=«03-97-1991 DE 69018949 DL 01-06-1995 DE 69018949 T2 23-11-1995 JP 2801391 B2 21-09-1998 3p -3236362 8 22-10-1991 US 5221763 A 22-06-1993 US 4980505 A 21-03-1978 AU 500421 82 24-05-1979 AU «1472676 & 15-12-1977 BE 842692 AL 08-12-1976 CA 1078403 AL 27-05-1980 cH 620414 AS 28-11-1980 DE 2625163 AL 30-12-1976 ok 251276 A 19-12-1976 eS 448647 AL 01-12-1977 fl 761637 A 10-12-1976 FR 2333771 AL 01-07-1977 GR 60269 AL 20-04-1978 NL 7606250 A 13-12-1976 NO 761980 A 19-12-1976 PT 65179 & 01-07-1976 SE 7606441 A 10-12-1976 For moe des saat ths anrox oe fia Journal lth European Pater ice, No 1282