USOO9440908B2 (12) United States Patent (10) Patent No.: US 9,440,908 B2 Himmler et al. (45) Date of Patent: Sep. 13, 2016 (54) PROCESS FOR PREPARING (58) Field of Classification Search N-(5-CHLORO-2-ISOPROPYLBENZYL) CPC C07C 17/093; CO7C 201/12: C07C 209/00; CYCLOPROPANAMINE C07C 209/26: C07C 209/365; CO7C 209/70; C07C 2101/02: C07C 211/40; C07C 245/20; Monheim (DE) CO7F 3/02 USPC ........................................... 564/384; 570/182 (72) Inventors: Thomas Himmler, Odenthal (DE); See application file for complete search history. Sandra Lehmann, Leverkusen (DE); (56) References Cited Thomas Norbert Muller, Monheim U.S. PATENT DOCUMENTS (DE); Mathias Riedrich, Cologne 6,242,493 B1* 6/2001 Gareau ................. CO7C 311/29 (DE); Lars Rodefeld, Leverkusen (DE); 516.569 Frank Volz, Cologne (DE); Sascha 2012/0065164 A1 3/2012 Bartels ................. CO7D 231/16 514.63 Von Morgenstern, Burscheid (DE) 2013/021791.0 A1* 8, 2013 Lui ....................... CO7C 209/52 560/48 (73) Assignee: BAYER CROPSCIENCE AG (DE) 2014/01484.11 A1 5/2014 Bartels et al. .................. 514.63 (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. CN 102421757 A 4/2012 EP 2251331 A1 11 2010 WO WO 2012/059585 A1 5, 2012 (21) Appl. No.: 14/396,570 WO WO 2014,076.007 * 5, 2014 OTHER PUBLICATIONS (22) PCT Filed: Apr. 25, 2013 National Center for Biotechnology Information. PubChem Com pound Database; CID=66158544, https://pubchem.ncbi.nlm.nih. (86). PCT No.: PCT/EP2013/058570 gov/compound 66158544 (accessed Nov. 23, 2015 and first made available online on Oct. 24, 2012—hereafter 544).* S 371 (c)(1), National Center for Biotechnology Information. PubChem Com (2) Date: Oct. 23, 2014 pound Database; CID=67988282, https://pubchem.ncbi.nlm.nih. e a? a 9 gov/compound/67988282 (accessed Nov. 23, 2015 and first made available online on Nov. 30, 2012—hereafter 282).* (87) PCT Pub. No.: WO2013/160387 Overberger (“m-Chlorophenylmethylcarbinol” Organic Syntheses, Coll. vol. 3, p. 200 (1955), vol. 28, p. 28 (1948).* PCT Pub. Date: Oct. 31, 2013 Obushak (“Arenediazonium Tetrachlorocuprates(II). Modified Ver sions of the Meerwein and Sandmeyer Reactions' Russian Journal (65) Prior Publication Data of Organic Chemistry, vol. 38, No. 1, 2002, p. 38-46).* US 2015/0094492 A1 Apr. 2, 2015 yer. The trying some Alkyl-substituted Benzoic Eguchi ("Halogenation Using N-Halogenocompounds. II. Acid (30) Foreign Application Priority Data Catalyzed Bromination of Aromatic Compounds with 1,3-Dibromo 5,5-dimethylhydantoin' The Chemical Society of Japan, Bull. Apr. 26, 2012 (EP) ..................................... 12165663 Chem. Soc. Jpn. 67, 1918-1921, 1994).* U.S. Appl. No. 13/883,241, filed May 2 2013 by Norbert Lui et al., 51) Int. C entitled “Process for the Preparation of Substituted (51) O 21140 2006.O1 N-(Benzyl)Cyclopropanamines by Imine Hydrogenation”. (2006.01) Office Action issued Dec. 10, 2014 in U.S. Appl. No. 13/883,241. CD7C 209/26 (2006.01) International Search Report issued Jul. 29, 2013 in corresponding C07C 17/093 (2006.01) International Application No. PCT/EP2013/058570. H.T. Nagasawa et al. “Latent Inhibitors of Aldehyde Dehydrogenase C. O C: lies, Deterrent Agents”. J. Med. Chem., 27 (10), pp. 1335 CD7C 20/2 (2006.01) Krisztina Vukics et al. “Synthesis of C-Aryl-N- C07C 209/00 (2006.01) Elgory, Synthetic Communications, vol. 33, No. 19, pp. CD7C 209/36 (2006.01) C.G. Overberger et al. “m-Chlorophenylmethylcarbinol”. Organic C07C 209/70 (2006.01) Syntheses, vol. 28, p. 28 (1948). CD7C 245/20 (2006.01) CD7C 249/02 (2006.01) * cited by examiner (52) ".c02 (2006.01) Primary Examiner — Jafar Parsa AV e. we Assistant Examiner — AmV C Bonaparte CPC ........... C07C 211/40 (2013.01); C07C 17/093 (74) Attorney, Agent, or ..., Sink Faber LLP 45/004(2013.01); (2013.01); C07C CO7C 25/06 201/12 (2013.01); (2013.01); C07C (57) ABSTRACT C07C 209/00 (2013.01); C07C 209/26 The present invention relates to a process for preparing (2013.01); C07C 209/365 (2013.01); C07C N-(5-chloro-2-isopropvlbenzVl)cyclopropanaminepropy Zyl)cycloprop by 209/70 (2013.01); C07C 245/20 (2013.01); hydrogenation of N-((5-chloro-2-isopropylphenyl)methyl C07C 249/02 (2013.01); C07F 3/02 (2013.01); enelcyclopropanamine over specific platinum catalysts. C07C 2101/02 (2013.01) 12 Claims, No Drawings US 9,440,908 B2 1. 2 PROCESS FOR PREPARING (Ber. dtsch. Chem. 1927, 1173-1182), aluminium com N-(5-CHLORO-2-ISOPROPYLBENZYL) pounds (J. Chem. Soc. Pak. 1988, 10, 393-395), platinum CYCLOPROPANAMINE catalysts (Chem. Cat. Chem. 2009. 1, 210-221. Synthesis 2003, 11, 1657-1660: additives such as ZnX (X=Cl, Br, I), aluminium(III) chloride, magnesium bromide and copper(I) CROSS-REFERENCE TO RELATED chloride and copper(II) bromide), Raney nickel (Tietze, APPLICATION(S) Eicher in Reaktionen und Synthesen. Thieme Verlag 1981, 466 ff.) and ascorbic acid (Commun. Fac. Sci. Univ. Ank. The present application is a 35 U.S.C. S371 national phase Serie B 1988, 34, 159-162). In addition, it is known in the conversion of PCT/EP2013/058570 filed on Apr. 25, 2013, literature that aromatic nitro compounds can be reduced by which claims priority of European Application No. 10 means of complex borohydrides such as Sodium borohy 12165663.1 filed on Apr. 26, 2012. Applicants claim priority dride, Sodium cyanoborohydride, Sodium acetoxyborohy to each of the foregoing applications. The PCT International dride and also aluminates Such as lithium aluminium hydride Application was published in the English language. or diisobutylaluminium hydride. Appropriate reaction con The present invention relates to a process for preparing ditions are known per se to those skilled in the art. N-(5-chloro-2-isopropylbenzyl)cyclopropanamine by 15 Preparative processes for the chlorination of aromatics by hydrogenation of N-(5-chloro-2-isopropylphenyl)methyl means of the Sandmeyer reaction are described in the enelcyclopropanamine over specific platinum catalysts. literature (e.g. Organikum 22nd edition, Wiley-VCH, 640 Preparative processes for brominating strongly deacti ff.). The diazotization of 3-bromo-4-isopropylaniline is vated aromatics such as p-alkyl-substituted nitrobenzenes or described in J. Org. Chem. 1963, 28, 1917-1919 and J. nitrobenzene itself are described in the literature. The bro Chem. Soc. 1952, 4443 ff. mination of p-nitroethylbenzene by means of iron and The conversion of a bromoaromatic into the correspond bromine has been described with very low yields (55% yield ing Grignard compound (J. Org. Chem. 1963. 28, 1917 of crude product and 34% after distillation) and with long 1919) and the reaction of this with dimethylformamide to reaction times of over 24 hours (J. Am. Chem. Soc. 1950, 72, form benzaldehyde (Synth. Commun. 1984, 228-230) has 2804). The bromination of nitrobenzene by means of iron 25 been described. The reaction of m-bromochlorobenzene and bromine is described with a yield of always 60-75% of with magnesium, with selective insertion of the magnesium isolated compound (cf. Organic Synthesis 1941, Coll. Vol. 1, into the C Br bond, and the subsequent reaction with an 123, ibid. 1928, Vol. 8, 48). A further possible way of electrophile (acetaldehyde) is likewise known (Org. Synth. brominating deactivated aromatics by means of potassium 1955, Coll. Vol. 3, 200; ibid. 1948, Vol. 28, 28). bromate is known (J. Org. Chem. 1981, 46, 2169-217 1). The reductive amination of benzaldehydes by means of However, reactions are problematical from a safety point of 30 cyclopropylamine is described in PCT/EP2011/069426. view because of the decomposition of potassium bromate in Under the conditions described there, the selective hydro over 70% strength sulphuric acid solution. Furthermore, the genation without opening of the cyclopropane ring is pos bromination of p-nitrotoluene or nitrobenzene by means of sible. However, dehalogenation of the corresponding chlo N-bromosuccinimide in half-concentrated sulphuric acid is roaromatics cf. formula (II) occurs as undesirable known (Org. Lett. 2006, 8, 645-647, J. Org. Chem. 1965, 30, 35 secondary reaction under the hydrogenation conditions. Fur 304-306). However, this reaction requires N-bromosuccin thermore, it is possible to employ a Leukart-Wallach reac imide as brominating reagent. Dimethyldibromohydantoin tion for carrying out the reductive amination (imine reduc is found to be significantly more efficient (cf. Bull. Chem. tion by means of formic acid and derivatives, cf. J. Am. Soc. Jpn. 1994, 67, 1918-1921). However, trifluorometh Chem. Soc. 1936,58, 1808-1811, ibid. 1950, 72,3073-3075. anesulphonic acid, a very expensive reagent, is used here as 40 Bull. Chem. Soc. Jap. 1976, 49, 2485-2490). proton Source, which would make an industrial process Proceeding from this prior art, it is an object of the present uneconomical. The use of Sulphuric acid as proton Source is invention to provide an alternative process for preparing also described in the same reference. However, dichlo N-(5-chloro-2-isopropylbenzyl)cyclopropanamine in high romethane, which is a problematical solvent from both an purity, yield and better quality without opening of the environmental and process engineering point of view, is cyclopropane ring and with simultaneous Suppression of the used as solvent and, in addition, a maximum yield in the 45 secondary dehalogenation reaction, with the process prefer bromination of p-nitrotoluene of 84% is achieved. Dibro ably being simple and inexpensive to carry out. In particular, moisocyanuric acid is also known as brominating reagent for the process sought should make it possible to obtain the deactivated aromatics (Organikum, 22nd edition, Wiley desired target compound without the necessity of a complex VCH, pp. 367–368.) purification. In addition, it is known that p-nitrocumene can be con 50 This object is achieved by a novel process for preparing verted into bromonitrocumene using a substoichiometric N-(5-chloro-2-isopropylbenzyl)cyclopropanamine.