(12) United States Patent (10) Patent No.: US 9,440,908 B2 Himmler Et Al

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 b y 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. amount (0.5 equivalents) of silver sulphate (cf. WO 2009/ The present invention relates to a process for preparing 05674, J. Org. Chem. 1963, 28, 1917-1919). Furthermore, N-(5-chloro-2-isopropylbenzyl)cyclopropanamine of the the desired compound is isolated in a yield of only 18% in formula (I) WO 2009/055674. Both lead to very high production costs. 55 The reduction of nitrohaloaromatics is likewise described in the literature. Suitable reducing agents are sodium dithi onite (Tietze, Eicher in Reaktionen und Synthesen. Thieme (I) Verlag 1981, 136 ff.), sodium sulphide, ammonium sulphide (Applied Catalysis A. General 2006, 301, 251-258), sodium 60 disulphide (tin in Reduction of Nitroarenes, Organic Reac tions (New York), 1973, 20, 455-477), hydrazine hydrate (Chem. Rev. 1965, 65, 51-68), iron in combination with mineral acid Such as hydrochloric acid, Sulphuric acid, acetic acid (Adv. Synth. Catal. 2005, 347, 217-219), formic acid or 65 C Lewis acids such as iron (II) sulphate (Org. Synth. 1955, Coll. Vol. 3, 56; ibid. 1948, Vol. 28, 11), iron(III) chloride US 9,440,908 B2 3 characterized in that (d) N-(5-chloro-2-isopropylphenyl)methylenecyclopro (I) panamine of the formula (III) H3C CH3

(III) H3C CH3 c r SN1H N 1 N 10 C

characterized in that (b) the Grignard compound of the formula (V) C 15 is hydrogenated over specific platinum catalysts. (V) The present invention also relates to a process for pre CH paring N-(5-chloro-2-isopropylbenzyl)cyclopropanamine of the formula (I) 2O MgBr

(I) HC CH C -A 25 N H is react with a dialkylformamide of the formula (VI)

(VI) C 30 O R ls characterized in that s H (c) 5-chloro-2-isopropylbenzaldehyde of the formula (II) R 35

(II) where R is independently from each other C-C-alkyl, preferably independently methyl or n-butyl, even more preferably methyl, and 40 (c) the resulting 5-chloro-2-isopropylbenzaldehyde of the formula (II) (II) HC CH

C 45 no is reacted with cyclopropylamine in a first step and (d) the resulting N-(5-chloro-2-isopropylphenyl)methyl enecyclopropanamine of the formula (III) 50 C is reacted with cyclopropylamine, and (III) (d) the resulting N-(5-chloro-2-isopropylphenyl)methyl HC CH enecyclopropanamine of the formula (III) 55 1SN -A (III) HC CH

60 C 1S N -A is hydrogenated over specific platinum catalysts in a second step. The present invention also relates to a process for pre- 65 C paring N-(5-chloro-2-isopropylbenzyl)cyclopropanamine of the formula (I) is hydrogenated over specific platinum catalysts. US 9,440,908 B2 5 6 The present invention also relates to a process for pre (c) the resulting 5-chloro-2-isopropylbenzaldehyde of the paring N-(5-chloro-2-isopropylbenzyl)cyclopropanamine of formula (II) the formula (I) (II) (I) H3C CH3

N1 10 H

C 15 is reacted with cyclopropylamine, and (d) the resulting N-(5-chloro-2-isopropylphenyl)methyl characterized in that enecyclopropanamine of the formula (III) (a) 2-bromo-4-chloro-1-isopropylbenzene of the formula (IV) 2O (III) HC CH 1N -A (IV) N H3C CH3 25

Br C

30 is hydrogenated over specific platinum catalysts. N-(5-chloro-2-isopropylbenzyl)cyclopropanamine of the C1 formula (I) (I) H3C CH3 35 is reacted with magnesium with selective insertion of the magnesium into the C-Br bond, and N (b) the resulting Grignard compound of the formula (V) H 40 (V) C is new and likewise provided by the present invention. It has surprisingly been found that the reaction of the MgBr 45 benzaldehyde (II) with cyclopropylamine likewise leads to the desired product, even though the aromatic part bears chlorine Substituent. Dehalogenations in the hydrogenation of haloaromatics are described in the literature (J. Org. Chem. 1977, 42, 3491-3494). In the case of the present C invention, this secondary reaction was able to be very 50 largely suppressed. 5-Chloro-2-isopropylbenzaldehyde of the formula (II) is obtained by (a) reacting 2-bromo-4-chloro-1-isopropylbenzene of the is reacted with a dialkylformamide of the formula (VI) 55 formula (IV)

(VI) (IV) O H3C CH3 R ls 60 s H Br R

where R is independently from each other C-C-alkyl, 65 preferably independently methyl or n-butyl, even more C preferably methyl, and US 9,440,908 B2 7 8 with magnesium with selective insertion of the magnesium The present invention further relates to the process for into the C Brbond and subsequently preparing 2-Bromo-4-chloro-1-isopropylbenzene of the for (b) reacting the resulting Grignard compound of the formula mula (IV) by (V) 5 (h) reacting the ammonium salts of the formula (VIII)

(V) (VIII) H3C CH3 CH

MgBr 10 Br

C 15 NHHX with a dialkylformamide of the formula (VI)

(vi) 20 O where X is HSO, Cl, Br, HCO, CHCO, or HPO. with NaNO and/or KNO or C-Co-alkyl nitrites, and R NN l H Subsequently l 25 (i) reacting the resulting diazonium salts of the formula (IX)

where R is independently C-C-alkyl, preferably inde (IX) pendently methyl or n-butyl, particularly preferably CH methyl. 2-Bromo-4-chloro-1-isopropylbenzene of the formula 30 Br (IV)

(IV) is

40 where X is as above defined, with CuCl. FeC1 or FeSO and aqueous HCl or metal chloride, wherein metal is sodium, potassium, caesium, is new and likewise provided by the present invention. 45 calcium or magnesium. The present invention further relates to the process for preparing 2-Bromo-4-chloro-1-isopropylbenzene of the for The present invention further relates to the process for mula (IV) by preparing 2-Bromo-4-chloro-1-isopropylbenzene of the for (i) react the diazonium salts of the formula (IX) mula (IV) by 50 (g) firstly converting 3-bromo-4-isopropylaniline of the for mula (VII) (IX)

(VII) Br 55 CH

Nt 60 | X N NH2 where X is HSO, Cl, Br, HCO, CHCO, or HPO. with CuCl. FeC1 or FeSO and aqueous HCl or metal 65 by means of acids (preferably HSO, HCl, HBr, HCOH, chloride, wherein metal is sodium, potassium, caesium, CHCO2H or HPO, particularly preferably HSO or calcium or magnesium. HCl) into the ammonium salts of the formula (VIII) US 9,440,908 B2 9 10 (f) reducing the resulting 2-bromo-1-isopropyl-4-nitroben (VIII) Zene of the formula (XI) H3C CH3

Br 5 (XI) HC CH

Br,

NH2HX 10

which are then NO (h) reacted with NaNO and/or KNO or C-Co-alkyl nitrites to form the diazonium salts of the formula (IX) is and (g) converting the resulting 3-bromo-4-isopropylaniline of (IX) the formula (VII) HC CH

Br 2O (VII) H3C CH3

Nt 25 | x NH2 (i) which are subsequently reacted with CuCl. FeC1 or FeSO and aqueous HCl or metal chloride, wherein metal 30 is sodium Sh caesium, calcium or magnesium by means of acids (preferably HSO, HCl, HCOH, p s 9. CHCO2H or HPO, particularly preferably HSO or 3-Bromo-4-isopropylaniline of the formula (VII) is HCl) into the ammonium salts of the formula (VIII) obtained by (e) firstly brominating p-nitrocumene of the formula (X) 35 (VIII) HC CH (X) HC CH Br 40

NHHX 45 NO which are then (h) reacted with NaNO and/or KNO or C-Co-alkyl by means of dimethyldibromohydantoin in sulphuric acid nitrites to form the diazonium salts of the formula (IX) and (f) reducing the resulting 2-bromo-1-isopropyl-4-nitroben- 50 Zene of the formula (XI) (IX) HC CH3

XI H3C CH3 (XI) 55 Br

Nt 60 | X N NO (i) which are subsequently reacted with CuCl. FeC1 or The present invention further relates to the process for 65 FeSO, and aqueous HC1 or metal chloride, wherein metal preparing 2-Bromo-4-chloro-1-isopropylbenzene of the for- is sodium, potassium, caesium, calcium or magnesium, mula (IV) by wherein X is as herein defined. US 9,440,908 B2 11 12 The present invention further relates to the process for preparing 2-Bromo-4-chloro-1-isopropylbenzene of the for (IX) mula (IV) by (e) firstly brominating p-nitrocumene of the formula (X) Br

(X) H3C

Nt 10 | X N

(i) which are subsequently reacted with CuCl. FeC1 or NO 15 FeSO and aqueous HCl or metal chloride, wherein metal is sodium, potassium, caesium, calcium or magnesium, by means of dimethyldibromohydantoin in sulphuric acid wherein X is as herein defined. and It has Surprisingly been found that p-nitrocumene can be (f) reducing the resulting 2-bromo-1-isopropyl-4-nitroben brominated in very high yields (>90% chemical yield) in Zene of the formula (XI) sulphuric acid when dibromohydantoin is slowly introduced. In this mode of operation, the use of organic solvents such as dichloromethane, chloroform or tetrachloromethane can (XI) be dispensed with, which is very advantageous from an H3C CH3 environmental and process engineering point of view. Inter 25 estingly, these reaction conditions work very well for p-ni trocumene, although this Substrate is a rather more sterically Br, hindered compound (isopropyl radical in p-nitrocumene) than p-nitrotoluene (methyl radical). In addition, it is pos sible to brominate p-nitrocumene in high yields (>95%) by 30 means of bromine and catalytic amounts of iron (III) chlo NO ride in reaction times of 3-5 hours. Comparable systems (use of iron and bromine to form the system: iron(III) bromide and bromine) applied to comparable Substrates (p-nitroeth and ylbenzene) are stated in the literature to give significantly (g) converting the resulting 3-bromo-4-isopropylaniline of 35 lower yield (55%) and require very long reaction times (>24 the formula (VII) hours) (J. Am. Chem. Soc. 1950, 72, 2804). Substituted N-(benzyl)cyclopropanamines are important (VII) intermediates in the preparation of agrochemical active HC CH compounds. Appropriately Substituted N-(benzyl)cyclopro 40 panamines have been described, for example, in the synthe sis of fungicidally active pyrazolecarboxamides (cf., for Br example, WO 2007/087906, WO 2010/130767). Thus, for example, N-(5-chloro-2-isopropylbenzyl)cyclo 45 propanamine of the formula (I) can be reacted with pyrazole derivatives of the formula (P1) NH2 (P1) by means of acids (preferably HSO, HCl, HCOH, CHCO2H or HPO, particularly preferably HSO or 50 HCl) into the ammonium salts of the formula (VIII)

(VIII) H3C CH 55

Br where 60 X' is fluorine or chlorine (preferably fluorine), X is fluorine or chlorine (preferably fluorine), HX R" is hydroxy, fluorine, chlorine or bromine, optionally in the presence of a diluent, optionally in the which are then 65 presence of a condensing agent and optionally in the pres (h) reacted with NaNO and/or KNO or C-Co-alkyl ence of an acid binder, to form pyrazolecarboxylic acids of nitrites to form the diazonium salts of the formula (IX) the formula (P2) US 9,440,908 B2 13 14 dibutyl Sulphoxide, diisoamyl Sulphoxide; Sulphones Such as (P2) dimethyl Sulphone, diethyl Sulphone, dipropyl Sulphone, 2 X2 HC CH3. dibutyl Sulphone, diphenyl Sulphone, dihexyl Sulphone, X methyl ethyl sulphone, ethyl propyl sulphone, ethyl isobutyl Sulphone and pentamethylene Sulphone; aliphatic, cycloali ^ N phatic or aromatic hydrocarbons such as pentane, hexane, N heptane, octane, nonane and industrial hydrocarbons, for N XI example white spirits containing components having boiling H3C points in the range from, for example, 40° C. to 250° C. C 10 cymene, petroleum spirit fractions in a boiling range from 70° C. to 190° C., cyclohexane, methylcyclohexane, petro Step (c) leum ether, ligroin, octane, benzene, toluene, nitrobenzene The conversion of 5-chloro-2-isopropylbenzaldehyde of and Xylene. Among the abovementioned solvents, prefer the formula (II) into the corresponding N-(5-chloro-2- 15 ence is given to methanol, Xylene, cyclohexane and particu isopropylphenyl)methylenelcyclopropanamine of the for lar preference is given to methanol, ethanol, toluene. mula (III) is effected by reaction with cyclopropylamine In a further embodiment of process (c), the reaction of process (c). cyclopropylamine with the carbonyl compound of the for In carrying out process (c), an acid can optionally be mula (II), can also be carried out in bulk. added as catalyst. Examples are acetic acid, p-toluenesul If the reaction is carried out in a solvent, the solvent can phonic acid and trifluoroacetic acid. Preference is given to be removed by being distilled off after the end of the using acetic acid. Acidic salts, e.g. KHSO or NaHSO, can reaction. This can be carried out under atmospheric pressure also be used. If appropriate catalysts are used, the amount of or reduced pressure at room temperature or elevated tem these can be from 0.01 to 10 percent by weight, based on the peratures. However, the mixture can also be transferred cyclopropylamine used. 25 directly to the hydrogenation, which is particularly advan Process (c) can also be carried out with the water formed tageous for economic reasons. In this embodiment of the by condensation in the reaction between cyclopropylamine process, a work-up of the imine of the formula (III) is then and 5-chloro-2-isopropylbenzaldehyde of the formula (II) dispensed with. When the imine of the formula (III) is being removed from the reaction mixture. This is possible, isolated, yields of greater than 95% have been observed. for example, by use of water-binding agents, for example 30 Sodium Sulphate, magnesium Sulphate or molecular sieves, Step (d) or by use of an apparatus for removing water. However, the The reaction of N-(5-chloro-2-isopropylphenyl)methyl hydrogenation can also be carried out without removal of the enecyclopropanamine of the formula (III) to form N-(5- Water. chloro-2-isopropylbenzyl)cyclopropanamine of the formula Process (c) can generally be carried out under reduced 35 (I) is carried out as a catalytic hydrogenation process (d). pressure, at atmospheric pressure or under Superatmospheric In the catalytic hydrogenation to reduce the compound of the pressure. The temperatures employed can vary as a function formula (III), any hydrogenation catalyst can be used as of the substrates used and can easily be determined by a catalyst. Suitable catalysts optionally contain one or more person skilled in the art by means of routine tests. For metals of groups 8-10 of the Periodic Table on any conven example, the reaction for preparing the compounds of the 40 tional inorganic Support. Possibilities are, for example, general formula (I) can be carried out at a temperature of noble metal catalysts such as ruthenium catalysts, palladium from -20 to +200° C., preferably from +10 to +100° C. The catalysts, platinum catalysts and rhodium catalysts, Raney reaction is particularly preferably carried out at atmospheric nickel catalysts and Raney cobalt and Lindlar catalysts. pressure and temperatures of from +10 to +100° C. However, apart from these heterogeneous catalysts, hydro Process (c) can also be carried out in the presence of 45 genations can also be carried out over homogeneous cata solvents (diluents). The solvents are preferably also used in lysts, for example over the Wilkinson catalyst. The corre this process step in Such an amount that the reaction mixture sponding catalysts can also be used in Supported form, for remains readily stirrable during the entire reduction process. example applied to carbon (charcoal or activated carbon), Possible solvents for carrying out the process for preparing aluminium oxide, silicon dioxide, Zirconium dioxide, cal the imine of the formula (III) are all organic solvents which 50 cium carbonate or titanium dioxide. Such catalysts are are inert under the reaction conditions. Examples which may known to those skilled in the art. Particular preference is be mentioned are: alcohols such as methanol, ethanol, given to palladium catalysts. The catalysts can be used either isopropanol, butanol; ethers such as ethyl propyl ether, moist with water or in dry form. The catalyst used is methyl tert-butyl ether, n-butyl ether, anisole, phenetole, preferably reused for a plurality of reactions. cyclohexyl methyl ether, dimethyl ether, diethyl ether, dim 55 In the process, the catalyst is used in a concentration of ethylglycol diphenyl ether, dipropyl ether, diisopropyl ether, from about 0.01 to about 30% by weight, based on the imine di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene of the formula (III) used. The catalyst is preferably used in glycol dimethyl ether, isopropyl ethyl ether, tetrahydrofuran, a concentration of from about 0.1 to about 5% by weight, dioxane, bis(chloroethyl) ether and polyethers of ethylene particularly preferably from about 0.1 to about 2.0% by oxide and/or propylene oxide; nitrohydrocarbons such as 60 weight. nitromethane, nitroethane, nitropropane, nitrobenzene, chlo The catalytic hydrogenation can be carried out under ronitrobenzene, o-nitrotoluene; nitriles Such as acetonitrile, Superatmospheric pressure in an autoclave or at atmospheric methylnitrile, propionitrile, butyronitrile, isobutyronitrile, pressure in a hydrogen gas atmosphere. The hydrogen gas benzonitrile, phenylnitrile, m-chlorobenzonitrile and also atmosphere can additionally contain inert gases, for example compounds such as tetrahydrothiophene dioxide and dim 65 argon or nitrogen. The catalytic hydrogenation is preferably ethyl Sulphoxide, tetramethylene Sulphoxide, dipropyl Sul carried out at a temperature of from 10 to 200° C., particu phoxide, benzyl methyl sulphoxide, diisobutyl sulphoxide, larly preferably from 10 to 150° C., very particularly pref US 9,440,908 B2 15 16 erably from 10 to 60° C. The hydrogen pressure is usually and in addition dehalogenation of the chloroaromatic is also from 0.1 to 50 bar, preferably from 0.1 to 30 bar, particularly observed to only a small extent. preferably from 1 to 6 bar. The work-up (purification) and isolation of the imine of Further reagents and hydrogenation conditions used for the formula (III) can, for example, be carried out by crys the hydrogenation of imines are described in the publica tallization and/or distillation. tions by Harada, in Patai, “The Chemistry of the Carbon Step (a) Nitrogen Double Bond', pages 276 to 293; by Nishimura, The conversion of the bromochloro compound of the “Handbook of Heterogeneous Catalytic Hydrogenation for formula (IV) into the corresponding Grignard compound of Organic Synthesis”, pages 226 to 250, John Wiley and Sons, the formula (V) is effected by reaction with magnesium 10 process (a). New York, 2001 and by Rylander, “Catalytic Hydrogenation The process (a) is preferably carried out in a temperature over Platinum Metals, pages 291 to 303, Academic Press, range from -80° C. to +120° C., particularly preferably at New York, 1967. temperatures of from 10° C. to +70° C. In general, it is advantageous to carry out the process of The process (a) is generally carried out under atmospheric hydrogenation of the imines in the presence of Solvents 15 pressure. However, it is also possible as an alternative to (diluents). Solvents are advantageously used in Such an work under reduced pressure or under Superatmospheric amount that the reaction mixture remains readily stirrable pressure. during the entire process of reduction. Possible solvents for The reaction time is not critical and can be selected in a carrying out the process are all organic solvents which are region of one and more hours, depending on the batch size inert under the reaction conditions, with the type of solvents and on the temperature. used depending on the way in which the reduction is carried When carrying out process (a), from 0.4 mol to 1.8 mol, Out. preferably from 0.9 mol to 1.5 mol, particularly preferably Examples which may be mentioned are alcohols such as from 1.0 to 1.2 mol, of magnesium is used per mole of the methanol, ethanol, isopropanol, butanol; ethers such as ethyl bromochlorocumene of the formula (IV). propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, 25 After the reaction is complete, the organomagnesium phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl Solution obtained can be used directly in the next process ether, dimethyl glycol diphenyl ether, dipropyl ether, diiso step process (b). The Grignard compound is usually propyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl formed in quantitative chemical yield. For the Subsequent ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, reaction, it is advisable to filter the organomagnesium com tetrahydrofuran, methyltetrahydrofuran, dioxane, bis(chlo 30 pound of the formula (V) obtained as a solution in suitable roethyl) ether and polyethers of ethylene oxide and/or pro organic solvents. pylene oxide: amines such as trimethylamine, triethylamine, Suitable solvents for process (a) are, for example, ali tripropylamine, tributylamine, N-methylmorpholine, pyri phatic, alicyclic or aromatic hydrocarbons such as toluene, dine, alkylated pyridines and tetramethylenediamine; ali o-, m- and p-Xylenes, mesitylene, ethers such as ethyl propyl phatic, cycloaliphatic or aromatic hydrocarbons such as 35 ether, tert-amyl methyl ether, methyl tert-butyl ether, n-butyl pentane, n-hexane, n-heptane, n-octane, nonane and indus ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl trial hydrocarbons which can be substituted by fluorine and ether, diethyl ether, dimethyl glycol diphenyl ether, dipropyl chlorine atoms, e.g. methylene chloride, dichloromethane, ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, trichloromethane, carbon tetrachloride, fluorobenzene, chlo disoamyl ether, ethylene glycol dimethyl ether, isopropyl robenzene or dichlorobenzene: for example white spirits 40 ethyl ether, tetrahydrofuran, methyltetrahydrofuran, diox containing components having boiling points in the range ane, bis(chloroethyl) ether and polyethers of ethylene oxide from, for example, 40° C. to 250° C., cymene, petroleum and/or propylene oxide. Particular preference is given to spirit fractions in a boiling range from 70° C. to 190° C. using tetrahydrofuran, methyltetrahydrofuran, methyl tert cyclohexane, methylcyclohexane, petroleum ether, ligroin, butyl ether and mixtures of tetrahydrofuran, methyl tetra octane, benzene, toluene, chlorobenzene, bromobenzene, 45 hydrofuran, methyl tert-butyl ether with toluene and/or nitrobenzene, Xylene; esters such as methyl acetate, ethyl Xylenes. The amounts of solvents used in the reaction acetate, butyl acetate, isobutyl acetate and also dimethyl according to process (a) can be varied in a wide range. In carbonate, dibutyl carbonate, ethylene carbonate; and ali general, the amounts of solvents used are in the range from phatic alcohols such as methanol, ethanol, n-propanol and a 1-fold to 50-fold amount of solvent, particularly preferably isopropanol and n-butanol. Among the abovementioned 50 from a 2-fold to 40-fold amount of solvent, in particular Solvents, preference is given to methanol. Xylene, cyclo from a 2-fold to 30-fold amount of solvent, in each case hexane and particular preference is given to methanol, based on the bromochlorocumene of the formula (IV) used. ethanol, toluene. Step (b) The reaction according to process (d) can be carried out The conversion of the Grignard compound of the formula in bulk or without solvents. 55 (V) into the corresponding 5-chloro-2-isopropylbenzalde The amounts of Solvents used in the reaction according to hyde of the formula (II) is effected by reaction with dialky process (d) can be varied in a wide range. In general, the lformamides of the formula (VI) process (b). amounts of solvent used are in the range from a 1-fold to The process (b) is preferably carried out in a temperature 50-fold amount of solvent, particularly preferably from a range from 80° C. to +120° C., particularly preferably at 2-fold to 40-fold amount of solvent, in particular from a 60 temperatures of from -10° C. to +70° C. 2-fold to 30-fold amount of solvent, in each case based on The process (b) is generally carried out under atmospheric the N-(5-chloro-2-isopropylphenyl)methylenecyclopro pressure. However, it is also possible as an alternative to panamine of the formula (III) used. work under reduced pressure or under Superatmospheric It has surprisingly been observed that apart from the pressure. known reaction, hydrogenolysis of the cyclopropyl Substitu 65 The reaction time is not critical and can be selected in the ents is observed to only a small extent in process (d) under region of one and more hours, depending on the batch size the particularly preferred reaction conditions for the process and on the temperature. US 9,440,908 B2 17 18 When carrying out process (b), from 1.0 mol to 5.0 mol, example, 40° C. to 250° C., cymene, petroleum spirit preferably from 1.0 mol to 2 mol, particularly preferably fractions in a boiling range from 70° C. to 190° C., cyclo from 1.0 to 1.5 mol, of dialkylformamide of the formula (VI) hexane, methylcyclohexane, petroleum ether, ligroin, is used per mol of the Grignard compound of the formula octane, benzene, toluene, chlorobenzene, dichlorobenzene, (V). bromobenzene, nitrobenzene, Xylene; esters such as methyl After the reaction is complete, the reaction Solution acetate, ethyl acetate, butyl acetate, isobutyl acetate and also obtained can be admixed with aqueous mineral acids. dimethyl carbonate, dibutyl carbonate, ethylene carbonate: 5-Chloro-2-isopropylbenzaldehyde of the formula (II) is and aliphatic alcohols such as methanol, ethanol, n-propanol formed in yields of 85-95% of the chemical yield. and isopropanol and n-butanol. Among the abovementioned Suitable solvents for the process (b) are, for example, 10 Solvents, preference is given to alcohols, in particular metha aliphatic, alicyclic or aromatic hydrocarbons such as tolu nol, ethanol, and water, especially water. ene, o-, m- and p-Xylenes, mesitylene, ethers such as ethyl After the reaction is complete, the reaction Solution propyl ether, tert-amyl methyl ether, methyl tert-butyl ether, obtained can be subjected directly to diazotization. The n-butyl ether, anisole, phenetole, cyclohexyl methyl ether, ammonium salts are usually formed in quantitative chemical dimethyl ether, diethyl ether, dimethylglycol diphenyl ether, 15 yield. dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl Step (h) ether, diisoamyl ether, ethylene glycol dimethyl ether, iso The conversion of the ammonium salts of the formula propyl ethyl ether, tetrahydrofuran, methyltetrahydrofuran, (VIII) into the corresponding diazonium salts (IX) is dioxane, bis(chloroethyl) ether and polyethers of ethylene effected by reaction with nitrites (NaNO and/or KNO or oxide and/or propylene oxide. Particular preference is given C1-C20-alkyl nitrites, particularly preferably with NaNO to using tetrahydrofuran, methyltetrahydrofuran, methyl and/or KNO) process (h). tert-butyl ether ether and mixtures of tetrahydrofuran, meth Process (h) is preferably carried out in a temperature yltetrahydrofuran, methyl tert-butyl ether with toluene and/ range from -30° C. to +80° C., particularly preferably at or Xylenes. The amounts of Solvents used in the reaction temperatures of from -10° C. to +50° C. according to process (b) can be varied in a wide range. In 25 The process (h) is generally carried out under atmospheric general, the amounts of solvent used are in the range from pressure. However, it is also possible as an alternative to a 1-fold to 50-fold amount of solvent, particularly preferably work under reduced pressure or under Superatmospheric from a 2-fold to 40-fold amount of solvent, in particular pressure. from a 2-fold to 30-fold amount of solvent, in each case The reaction time is not critical and can be selected in the based on the Grignard compound of the formula (V) used. 30 region of one or more hours, depending on the batch size and Step g: on the temperature. The conversion of the aniline compound of the formula When carrying out the process (h), from 1.0 mol to 5.0 (VII) into the corresponding ammonium salts of the formula mol, preferably from 1.0 mol to 2 mol, particularly prefer (VIII) is effected by reaction with mineral acids and/or ably from 1.0 to 1.5 mol, of nitrites (NaNO and/or KNO organic acids process (g). 35 or C1-C20-alkyl nitrites, particularly preferably with The process (g) is preferably carried out in a temperature NaNO and/or KNO) is used per mol of the ammonium range from -30° C. to +120° C., particularly preferably at salts of the formula (VIII). temperatures of from -10° C. to +70° C. After the reaction is complete, the reaction Solution The process (g) is generally carried out under atmospheric obtained can be subjected directly to conversion into the pressure. However, it is also possible, as an alternative, to 40 corresponding 2-bromo-4-chloro-1-isopropylbenzene of the work under reduced pressure or under Superatmospheric formula (IV). The diazonium salts of the formula (IX) are pressure. usually formed in quantitative chemical yield. The reaction time is not critical and can be selected in the Suitable solvents for the process (h) are water, organic region of one and more hours, depending on the batch size acids such as acetic acid, propionic acid, trifluoroacetic acid and on the temperature. 45 or in mixtures of organic acids with water or in a 2-phase When carrying out the process (g), from 1.0 mol to 5.0 system with organic solvents such as ethers, e.g. ethyl propyl mol, preferably from 1.0 mol to 4.0 mol, particularly pref ether, methyl tert-butyl ether, n-butyl ether, cyclohexyl erably from 1.0 to 3.0 mol of acids (HSO, HCl, HBr, methyl ether, dimethyl ether, diethyl ether, dimethyl glycol HCOH, CHCOH, HPO, particularly preferably HSO, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl HCl) is used per mol of the aniline compound of the formula 50 ether, diisobutyl ether, diisoamyl ether, ethylene glycol (VII). dimethyl ether, isopropyl ethyl ether, tetrahydrofuran, meth Suitable solvents for process (g) are water, alcohols such yltetrahydrofuran, dioxane, bis(chloroethyl) ether and as methanol, ethanol, isopropanol, butanol; ethers such as polyethers of ethylene oxide and/or propylene oxide: ali ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phatic, cycloaliphatic or aromatic hydrocarbons such as anisole, phenetole, cyclohexylmethyl ether, dimethyl ether, 55 pentane, n-hexane, n-heptane, n-octane, nonane and indus diethyl ether, dimethylglycol diphenyl ether, dipropyl ether, trial hydrocarbons which may be substituted by fluorine and diisopropyl ether, di-n-butyl ether, diisobutyl ether, diiso chlorine atoms, e.g. methylene chloride, dichloromethane, amyl ether, ethylene glycol dimethyl ether, isopropyl ethyl trichloromethane, carbon tetrachloride, fluorobenzene; for ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, bis example white spirits containing components having boiling (chloroethyl) ether and polyethers of ethylene oxide and/or 60 points in the range from, for example, 40° C. to 250° C. propylene oxide; aliphatic, cycloaliphatic or aromatic hydro cymene, petroleum spirit fractions in a boiling range from carbons such as pentane, n-hexane, n-heptane, n-octane, 70° C. to 190° C., cyclohexane, methylcyclohexane, petro nonane and industrial hydrocarbons which may be substi leum ether, ligroin, octane, chlorobenzene, dichlorobenzene, tuted by fluorine and chlorine atoms, e.g. methylene chlo bromobenzene, nitrobenzene, esters such as methyl acetate, ride, dichloromethane, trichloromethane, carbon tetrachlo 65 ethyl acetate, butyl acetate, isobutyl acetate and also dim ride, fluorobenzene; for example white spirits containing ethyl carbonate, dibutyl carbonate, ethylene carbonate. components having boiling points in the range from, for Among the abovementioned solvents, preference is given to US 9,440,908 B2 19 20 mixtures of water with organic acids and particular prefer reaction according to process (i) can be varied in a wide ence is given to water. The amounts of solvents used in the range. In general, the amounts of Solvents used are in the reaction according to process (h) can be varied in a wide range from a 1-fold to 50-fold amount of solvent, particu range. In general, the amounts of Solvents used are in the larly preferably from a 2-fold to 40-fold amount of solvent, range from a 1-fold to 50-fold amount of solvent, particu 5 in particular from a 2-fold to 30-fold amount of solvent, in larly preferably from a 2-fold to 40-fold amount of solvent, each case based on the diazonium salts of the formula (IX) in particular from a 2-fold to 30-fold amount of solvent, in used. each case based on the ammonium salts of the formula (VIII) After the reaction is complete, the 2-bromoo-4-chloro-1- used. isopropylbenzene of the formula (IV) can be extracted. This Step (i) 10 gives 2-bromo-4-chloro-1-isopropylbenzene of the formula The conversion of the diazonium salts of the formula (IX) (IV) in chemical yields of about 60-92%. into the corresponding 2-bromo-4-chloro-1-isopropylben Step (e) Zene of the formula (IV) is effected by reaction with copper The bromination of p-nitrocumene of the formula (X) to (I) chloride and/or copper (II) chloride or iron (II) sulphate, form the corresponding 2-bromo-1-isopropyl-4-nitroben iron (II) chloride or sodium chloride or potassium chloride 15 Zene of the formula (XI) is effected by reaction with bro or mixtures of the aforementioned acids with hydrochloric minating reagents such as N-bromosuccinimide, dimethyl acid, particularly preferably with copper (I) chloride, iron dibromohydantoin, dibromocyanuric and tribromocyanuric (II) chloride or iron (II) sulphate in combination with acid in Sulphuric acid, bromine, bromine and Lewis acids aqueous hydrochloric acid process (i). such as iron(III) chloride, iron(III) bromide, aluminium(III) Process (i) is preferably carried out in a temperature range chloride, aluminium(III) bromide, titanium(IV) chloride from -30°C. to +80°C., particularly preferably at tempera process (e). tures of from -10° C. to +50° C. The process (e) is preferably carried out in a temperature The process (i) is generally carried out under atmospheric range from -20° C. to +120° C., particularly preferably at pressure. However, it is also possible as an alternative to temperatures of from -10° C. to +40° C. work under reduced pressure or under Superatmospheric 25 The process (e) is generally carried out under atmospheric pressure. pressure. However, it is also possible as an alternative to The reaction time is not critical and can be selected in the work under reduced pressure or under Superatmospheric region of one or more hours, depending on the batch size and pressure. on the temperature. The reaction time is not critical and can be selected in the When carrying out the process (i), from 1.0 mol to 5.0 30 region of one and more hours, depending on the batch size mol, preferably from 1.0 mol to 2 mol, particularly prefer and on the temperature. ably from 1.0 to 1.5 mol, of copper (I) chloride and/or When carrying out the process (e), from 0.4 mol to 1.4 copper(II) chloride, iron (II) chloride or iron (II) sulphate or mol, preferably from 0.9 mol to 1.2 mol, particularly pref sodium chloride or potassium chloride or mixtures of the erably from 0.50 to 0.65 mol, of dimethyldibromohydantoin aforementioned salts are used per mol of diazonium salts of 35 or 0.4-2 mol of bromine with 0.01-1 mol of iron(III) the formula (IX). chloride, preferably 0.8-1.7 mol of bromine with 0.05-0.8 When carrying out the process (i), from 1.0 mol to 5.0 mol of iron(III) chloride, particularly preferably 0.8-1.4 mol mol, preferably 1.0 mol to 2 mol, particularly preferably of bromine with 0.1-0.5 mol of iron(III) chloride, is used per from 1.0 mol to 1.5 mol of aqueous HCl are used per mol of mol of p-nitrocumene of the formula (X). the diazonium salt of the formula (IX). 40 When carrying out the process (e), in the case of dibro Suitable solvents for the process (i) are water, organic mohydantoin from 1 mol to 6 mol, preferably from 1.5 mol acids such as acetic acid, propionic acid, trifluoroacetic acid to 4 mol, particularly preferably from 2 to 3.5 mol, of or in mixtures of organic acids with water or in a 2-phase Sulphuric acid are used per mol of p-nitrocumene of the system with organic solvents such as ethers, e.g. ethyl propyl formula (X), and in the case of bromine with iron(III) ether, methyl tert-butyl ether, n-butyl ether, cyclohexyl 45 chloride, the reaction is carried out in chlorinated aliphatic methyl ether, dimethyl ether, diethyl ether, dimethyl glycol and/or aromatic hydrocarbons, particularly preferably with diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl out solvent. ether, diisobutyl ether, diisoamyl ether, ethylene glycol The reaction of process (e) can be carried out in bulk dimethyl ether, isopropyl ethyl ether, tetrahydrofuran, meth without solvent, which leads to an improved space yield. yltetrahydrofuran, dioxane, bis(chloroethyl) ether and 50 After the reaction is complete, the Sulphuric acid can be polyethers of ethylene oxide and/or propylene oxide: ali separated off by phase separation and optionally be reused. phatic, cycloaliphatic or aromatic hydrocarbons such as The crude 2-bromo-1-isopropyl-4-nitrobenzene of the for pentane, n-hexane, n-heptane, n-octane, nonane and indus mula (XI) is, for example, washed with aqueous Sodium trial hydrocarbons which may be substituted by fluorine and hydroxide solution, potassium hydroxide solution, Sodium chlorine atoms, e.g. methylene chloride, dichloromethane, 55 carbonate or potassium carbonate and obtained in yields of trichloromethane, carbon tetrachloride, fluorobenzene; for 88-95%. In the case of bromine/iron(III) chloride, the mix example white spirits containing components having boiling ture is admixed with water and subsequently extracted with points in the range from, for example, 40° C. to 250° C. organic solvents. The 2-bromo-1-isopropyl-4-nitrobenzene cymene, petroleum spirit fractions in a boiling range from of the formula (XI) obtained in this way is obtained in very 70° C. to 190° C., cyclohexane, methylcyclohexane, petro 60 good yield (>90%) and purity without further work-up. leum ether, ligroin, octane, chlorobenzene, dichlorobenzene, Process (e) can also be carried out in the presence of a bromobenzene, nitrobenzene, esters such as methyl acetate, Solvent. Suitable solvents are, for example, aliphatic, alicy ethyl acetate, butyl acetate, isobutyl acetate and also dim clic or aromatic halogenated hydrocarbons, e.g. chloroben ethyl carbonate, dibutyl carbonate, ethylene carbonate. Zene, dichlorobenzene, dichloromethane, chloroform, tetra Among the abovementioned solvents, preference is given to 65 chloromethane, dichloroethane or trichloroethane, nitriles mixtures of water with organic acids and particular prefer Such as acetonitrile, propionitrile, n-butyronitrile or isobu ence is given to water. The amounts of solvents used in the tyronitrile or benzonitrile and water and aliphatic, alicyclic US 9,440,908 B2 21 22 carboxylic acids. Particular preference is given to using sodium disulphide and iron with hydrochloric acid. Particu chlorobenzene, dichlorobenzene, dichloromethane, chloro lar preference is given to sodium Sulphide and sodium form, dichloroethane, trichlorethane, acetic acid, propionic disulphide. acid, butanoic acid, acetonitrile, butyronitrile and water. The process (f) is preferably carried out in a temperature Step (f) 5 range from -30° C. to +150° C., particularly preferably at The conversion of the bromonitrocumene of the formula temperatures of from 20° C. to +100° C. (XI) into the corresponding 3-bromo-4-isopropylaniline of The reaction time is not critical and it can be selected in the formula (VII) is effected by reaction with catalysts and the region of one and more hours, depending on the batch hydrogen process (f). size and on the temperature. Any hydrogenation catalyst can be used as catalyst for the 10 When carrying out the process (f), from 1.0 mol to 5.0 mol catalytic hydrogenation to reduce the bromonitrocumene of of sodium sulphide and/or sodium disulphide, preferably the formula (XI). Suitable catalysts optionally contain one or from 1.0 mol to 3.0 mol of sodium sulphide and/or sodium more metals of groups 8-10 of the Periodic Table on any disulphide, particularly preferably from 1.0 to 2.0 mol of conventional inorganic Support. Possibilities are, for Sodium Sulphide and/or sodium disulphide, are used per mol example, noble metal catalysts such as ruthenium catalysts, 15 of the bromonitrocumene of the formula (XI). palladium catalysts, platinum catalysts and rhodium cata Suitable solvents for the process (f) are mixtures of lysts, Raney nickel catalysts and Raney cobalt and Lindlar alcohols such as methanol, ethanol, isopropanol, butanol and catalysts. However, apart from these heterogeneous cata water; ethers such as ethyl propyl ether, methyl tert-butyl lysts, hydrogenations can also be carried out over homoge ether, n-butyl ether, anisole, phenetole, cyclohexyl methyl neous catalysts, for example over the Wilkinson catalyst. 20 ether, dimethyl ether, diethyl ether, dimethyl glycol diphenyl The corresponding catalysts can also be used in Supported ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, form, for example Supported on carbon (charcoal or acti disobutyl ether, diisoamyl ether, ethylene glycol dimethyl vated carbon), aluminium oxide, silicon dioxide, Zirconium ether, isopropyl ethyl ether, tetrahydrofuran, methyltetrahy dioxide, calcium carbonate or titanium dioxide. Such cata drofuran, dioxane, bis(chloroethyl) ether and polyethers of lysts are known per se to those skilled in the art. Particular 25 ethylene oxide and/or propylene oxide; aliphatic, cycloali preference is given to palladium and platinum catalysts with phatic or aromatic hydrocarbons such as pentane, n-hexane, or without addition of Lewis acids such as ZnX (X=Cl, Br, n-heptane, n-octane, nonane and industrial hydrocarbons I), aluminium(III) chloride, magnesium bromide and copper which may be substituted by fluorine and chlorine atoms, (I) chloride and copper(II) bromide. The catalysts can be e.g. methylene chloride, dichloromethane, trichloromethane, used both moist with water and in dry form. The catalyst 30 carbon tetrachloride, fluorobenzene; for example white spir used is preferably reused for a plurality of reactions. its containing components having boiling points in the range In process (f), the catalyst is used in a concentration of from, for example, 40° C. to 250° C., cymene, petroleum from about 0.01 to about 30% by weight, based on the spirit fractions in a boiling range from 70° C. to 190° C., bromonitrocumene of the formula (XI) used. The catalyst is cyclohexane, methylcyclohexane, petroleum ether, ligroin, preferably used in a concentration of from about 0.1 to about 35 octane, benzene, toluene, chlorobenzene, dichlorobenzene, 5% by weight, particularly preferably from about 0.1 to bromobenzene, nitrobenzene, Xylene; esters such as methyl about 2.0% by weight. acetate, ethyl acetate, butyl acetate, isobutyl acetate and also The catalytic hydrogenation can be carried out under dimethyl carbonate, dibutyl carbonate, ethylene carbonate: Superatmospheric pressure in an autoclave or at atmospheric and aliphatic alcohols such as methanol, ethanol, n-propanol pressure in a hydrogen gas atmosphere. The hydrogen gas 40 and isopropanol and n-butanol. Among the abovementioned atmosphere can additionally contain inert gases, for example Solvents, preference is given to alcohols, in particular metha argon or nitrogen. The catalytic hydrogenation is preferably nol, ethanol, isopropanol in admixture with water. The carried out at a temperature of from 10 to 200° C., particu amounts of solvents used in the reaction according to larly preferably from 10 to 150° C., very particularly pref process (i) can be varied in a wide range. In general, the erably from 10 to 60° C. The hydrogen pressure is usually 45 amounts of Solvents used are in the range from a 1-fold to from 0.1 to 50 bar, preferably from 0.1 to 30 bar, particularly 50-fold amount of solvent, particularly preferably from a preferably from 1 to 6 bar. 2-fold to 40-fold amount of solvent, in particular from a It is generally advantageous to carry out the process of 2-fold to 30-fold amount of solvent, in each case based on hydrogenation of bromonitrocumene of the formula (XI) in the bromonitrocumene of the formula (XI) used. the presence of solvents (diluents). Solvents are advanta- 50 After the reaction is complete, 3-bromo-4-isopropylani geously used in Such an amount that the reaction mixture line of the formula (VII) can be extracted. This gives remains readily stirrable during the entire process of reduc 3-bromo-4-isopropylaniline of the formula (VII) in chemical tion. Possible solvents for carrying out the process are all yields of about 60-85%. organic solvents which are inert under the reaction condi The present invention further provides for the use of the tions, with the type of solvent used depending on the way in 55 compounds of the formulae (II) to (XI) for preparing the which the reduction is carried out. compound of the formula (I). The reduction can also be carried out using reducing agents such as Sodium dithionite, Sodium Sulphide, ammo PREPARATIVE EXAMPLES nium Sulphide, sodium disulphide, hydrazine hydrate (Chem. Rev. 1965, 65, 51-68), iron in combination with 60 Example 1 mineral acid Such as hydrochloric acid, Sulphuric acid, acetic acid, formic acid or Lewis acids such as iron(II) sulphate, 2-Bromo-1-isopropyl-4-nitrobenzene of the formula iron(III) chloride, aluminium compounds and also complex (XI) borohydrides such as example: Sodium borohydride, sodium cyanoborohydride, Sodium acetoxyborohydride and alumi- 65 1,3-Dibromo-5,5-dimethylhydantoin (86.9 g, 0.298 mol) nates such as lithium aluminium hydride or diisobutylalu was added in about 5 g portions to a solution of p-nitroc minium hydride. Preference is given to Sodium Sulphide, umene (X) (100 g, 0.581 mol, GC purity 96%) and sulphuric US 9,440,908 B2 23 24 acid (178 g, 1.743 mol, 98% strength) over a period of 5 3-Bromo-4-Isopropylaniline of the Formula (VII) hours. The mixture was then warmed to room temperature and stirred for another 1 hour. The reaction mixture was H-NMR (600 MHz, (CDC1): 8–7.04 (d. 1H), 6.89 (d. poured onto 200 g of ice water and admixed with sodium 1H), 6.61 (dd. 1H), 3.56 (brs, 2H), 3.25 (heptet, 1H), 1.19 bisulphite (15.1 g, 0.06 mol) and toluene (300 g). The phases (s, 3H), 1.18 (S. 3H) ppm. were then separated. The organic phase was washed with 5% GC-MS: m/e=213 M. strength aqueous sodium hydroxide and the toluene was 2-Bromo-1-isopropyl-4-nitrobenzene (XI) (50 g, 0.192 distilled off under reduced pressure. 2-Bromo-1-isopropyl mol, 93.5 GC-% by area), 100 ml of water, ironpowder 4-nitrobenzene (147g, 93.6 GC-% by area, 97% of theory) (40.71 g, 0.718 mol) were heated to 70° C. and hydrochloric was obtained as a pale yellow oil. 10 acid (193.7 g, 1.647 mol, 31% in water) was added over a A solution of p-nitrocumene (X) (50 g, 0.300 mol, GC period of 2 hours. The mixture was then cooled to 0°C. and purity: 99.1%) and iron(III) chloride was heated to 40° C. the suspension was filtered with suction. The solvent obtained was dried overnight at 50° C. in a vacuum drying and bromine (59.92 g, 0.375 mol) was added dropwise over oven. 3-Bromo-4-isopropylaniline hydrochloride (48 g. a period of 3 hours. The reaction mixture was poured into 15 120 ml of water, sodium hydrogensulphite (40% strength in purity: 88.7%, contains: 8.6% of iron, 88.7% of theory) was water, 20.81 g, 0.078 mol) was added dropwise and the obtained as a light-brown solid. mixture was extracted with 100 ml of chlorobenzene. After 3-Bromo-4-isopropylaniline hydrochloride of the phase separation, the chlorobenzene phase was washed with Formula (VIII) 100 ml of 5% strength aqueous HC1. Removal of the chlorobenzene under reduced pressure gave 2-bromo-1- 'H-NMR (600 MHz, d-MeOD): 8–7.62 (d. 1H), 7.52 (d. isopropyl-4-nitrobenzene (74.05 g, 96.9 GC-% by area, 98% 1H), 7.38 (dd. 1H), 4.83 (bs, 2H), 3.40 (heptet, 1H), 1.26 (s, of theory) as a yellow oil. 3H), 1.25 (s, 3H) ppm. 'H-NMR (600 MHz, CDC1): 8–8.41 (d. 1H), 8.14 (dd, 1H), 7.45 (d. 1H), 3.45 (heptet, 1H), 1.29 (d. 3H), 1.27 (d. 25 Example 3 3H) ppm. GC-MS: m/ez=24.5 M). 2-Bromo-4-chloro-1-isopropylbenzene of the Formula (IV) Example 2 30 Hydrochloric acid (152 g, 31% strength, 1.29 mol) was 3-Bromo-4-Isopropylaniline of the Formula (VII) added dropwise to a suspension of 3-bromo-4-isopropylani line (VII) (100 g, 0.43 mol) and water (150 g) at room A solution of sodium sulphide (31.2 g, 0.24 mol) and temperature. The Suspension was Subsequently cooled to 5' sulphur (7.7 g., 0.24 mol) was stirred at 80° C. for 15 C. and a solution of sodium nitrite (32.7 g., 0.46 mol) in minutes. Isopropanol (160 g) was Subsequently added and 35 water (140 g) was added dropwise over a period of 2 hours. the mixture was stirred at 75° C. for a further 15 minutes and After stirring for another 1 hour, amidosulphuric acid (2.5 g. 2-bromo-1-isopropyl-4-nitrobenzene (XI) (50 g, 0.19 mol) 0.026 mol) was added. Copper(I) chloride (10.8 g., 0.11 was finally added dropwise over a period of 30 minutes. mol), hydrochloric acid (202 g, 31%, 1.72 mol) and water After stirring for another 5 hours, the reaction was complete. (75 g) were placed in a second flask and the diazonium salt For the work-up, the isopropanol was firstly distilled off and 40 generated previously was added dropwise over a period of the remaining mixture was extracted with toluene?chlo 30 minutes. After stirring for another 1.5 hours, the mixture robenzene. The combined organic phases were distilled was extracted with dichloromethane (250 g), the phases under reduced pressure. 3-Bromo-4-isopropylaniline (42 g, were separated and dichloromethane was distilled off under 91 GC-% by area, 93% of theory) was obtained as a red oil. reduced pressure. The crude product obtained was purified 2-Bromo-1-isopropyl-4-nitrobenzene (XI) (20 g, 79.1 45 by distillation. 2-Bromo-4-chloro-1-isopropylbenzene (62.6 mmol, 96.5 GC 96 by area), methanol 400 ml), platinum on g, 94.8 GC-% by area. 59% of theory) was obtained as a carbon (1% of platinum, 2% of vanadium, moist with water) colourless oil. (1.0 g, 0.018 mmol) and zinc dibromide (90 mg, 0.40 mmol) 'H-NMR (600 MHz, CDC1): 8–7.54 (d. 1H), 7.24 (dd, were placed in a 600 ml autoclave. The autoclave was 1H), 7.19 (d. 1H), 3.32 (heptett, 1H), 1.22 (s, 3H), 1.21 (s, subsequently flushed with nitrogen and pressurized to 5 bar 50 3H) ppm. with hydrogen at room temperature. The contents of the autoclave were filtered through Celite, washed with metha nol and the solvent was distilled off under reduced pressure. Example 4 3-Bromo-4-isopropylaniline (17.1 g, 93 LC-% by area, 98.3 GC-% by area, 98% of theory) was obtained as a brown oil. 55 5-Chloro-2-isopropylbenzaldehyde of the Formula 2-Bromo-1-isopropyl-4-nitrobenzene (XI) (20 g, 78.1 (II) mmol. 95.8 GC 96 by area), methanol (400 ml), platinum on carbon (5% of platinum, poisoned with sulphur, moist with Magnesium (4.6 g., 0.189 mol) together with tetrahydro water) (1.0 g, 0.090 mmol) and Zinc dibromide (265 mg. furan (65 ml) were placed in a reaction vessel and heated 1.18 mmol) were placed in a 600 ml autoclave. The auto 60 while stirring to 40°C. About 5% of a solution of 2-bromo clave was Subsequently flushed with nitrogen and pressur 4-chloro-1-isopropylbenzene (IV) (43 g, 0.180 mol) in tet ized to 5 bar with hydrogen at room temperature. The rahydrofuran (95 ml) is then added dropwise. After the contents of the autoclave were filtered through Celite, reaction has commenced, the remainder of the 2-bromo-4- washed with methanol and the solvent was distilled off under chloro-1-isopropylbenzene in tetrahydrofuran was added reduced pressure. 3-Bromo-4-isopropylaniline (17.4g, 94.5 65 under gentle reflux over a period of 1 hour. The mixture was LC-% by area, 97.7 GC-% by area, >99% of theory) was then cooled to 0°C. and dimethylformamide (13.8 g. 0.189 obtained as a brown oil. mol) was added dropwise over a period of 1 hour. The US 9,440,908 B2 25 26 reaction mixture obtained was stirred for another 1 hour and 'H-NMR (600 MHz, DMSO): 8–7.36 (d. 1H), 7.27 (d. hydrochloric acid (86.7 g., 0.369 mol) was added in such a 1H), 7.23 (dd. 1H), 3.76 (s. 2H), 3.23 (hept., 1H), 2.09 (m, way that the temperature was kept below 30°C. The phases 1H), 1.18 (s, 3H), 1.17 (s, 3H), 0.37 (m, 2H), 0.26 (m, 2H) were then separated and extracted with toluene (2x50 ml). ppm. The combined organic phases were distilled under reduced GC-MS: m/e=223 M. pressure and the crude product obtained was recrystallized from isopropanol/water 4:1. 5-Chloro-2-isopropylbenzalde The invention claimed is: hyde (25.7g, 99 GC-% by area, 77% of theory) was obtained 1. A compound, N-(5-Chloro-2-isopropylbenzyl)-cyclo as a colourless Solid. propanamine of the formula (I) 'H-NMR (600 MHz, CDC1): 8–10.3 (s, 1H), 7.78 (d. 10 1H), 7.50 (dd. 1H), 7.39 (d. 1H), 3.89 (hept., 1H), 1.31 (s, 3H), 1.29 (s.3H) ppm. (I) GC-MS: m/e=182 Mt. Example 5 15 N-(5-Chloro-2-isopropylphenyl)methylenecyclo propanamine of the Formula (III) Cyclopropylamine (39.2 g, 0.69 mol) was added to a solution of 5-chloro-2-isopropylbenzaldehyde (II) (120 g, 2. A process for preparing N-(5-chloro-2-isopropylben 0.65 mol, 99.6 GC-% by area) in methanol (1200 ml) and the Zyl)-cyclopropanamine of the formula (I) mixture was stirred at room temperature for 2 hours. The Solvent was Subsequently removed under reduced pressure 25 and N-(5-chloro-2-isopropylphenyl)-methylenecyclopro (I) panamine (144 g. 99.2 GC-% by area, 98.5% of theory) was H3C CH obtained as a light-yellow oil. 'H-NMR (600 MHz, CDC1): 8–8.87 (s, 1H), 7.69 (t, 1H), N 7.34 (d. 2H), 3.48 (hept., 1H), 1.15 (m. 1H), 1.26 (s, 3H), 30 H 1.25 (s, 3H), 0.95 (m, 4H) ppm. GC-MS: m/e=221 M. The imine obtained in this way can be isolated as C described above. As an alternative, it is left in the respective 35 Solvent, the catalyst is added and hydrogen is injected, comprising the step of hydrogenating N-(5-chloro-2- which is described below: isopropylphenyl)methylenecyclopropanamine of the formula (III) Example 6 40 (III) N-(5-Chloro-2-isopropylbenzyl)cyclopropanamine H3C CH3 of the Formula (I)

Cyclopropylamine (3.26 g., 0.057 mol) was added to a 45 N N -A solution of 5-chloro-2-isopropylbenzaldehyde (II) (10 g, 0.054 mol, 99.3 GC% by area) in methanol (100 ml) and the mixture was stirred at room temperature for 1 hour. Platinum on activated carbon (0.2 g 5% Pt, dry) was subsequently C added, the reaction vessel was flushed with nitrogen and 50 pressurized to 6 bar with hydrogen at a maximum of 25°C. for 8 hours. The contents of the autoclave were filtered over a platinum catalyst. through Celite, washed with methanol and the solvent was 3. A process according to claim 2, wherein N-(5-chloro distilled off under reduced pressure. N-(5-Chloro-2-isopro 2-isopropylphenyl)methylenecyclopropanamine of the for pylbenzyl)cyclopropanamine (9.8 g., 96.8 GC-% by area, 55 mula (III) 78.0% of theory) was obtained as a light-yellow oil. Platinum on activated carbon (5 g, 5% Pt, dry) was added (III) to a solution of N-(5-chloro-2-isopropylphenyl)methylene HC CH cyclopropanamine (III) (160.8 g. 0.725 mol) in methanol 60 (1350 ml). The reaction vessel was subsequently flushed N with nitrogen and pressurized with 6 bar of hydrogen at a N maximum of 25° C. for 8 hours. The contents of the autoclave were filtered through Celite, washed with metha nol and the solvent was distilled off under reduced pressure. N-(5-Chloro-2-isopropylbenzyl)cyclopropanamine of the 65 C formula (I) (153.5g, 97.1 GC-% by area, 91.9% of theory) was obtained as a light-yellow oil. US 9,440,908 B2 27 28 is prepared by the step of: is prepared by the step of: reacting 5-chloro-2-isopropylbenzaldehyde of the for reacting 2-bromo-4-chloro-1-isopropylbenzene of the mula (II) formula (IV)

(II) (IV) HC CH H3C CH3 No 10 c r Br

C C 15 with cyclopropylamine. 4. A process according to claim 3, wherein 5-chloro-2- with magnesium with selective insertion of the mag isopropylbenzaldehyde of the formula (II) nesium into the C Br bond. 6. A compound 2-Bromo-4-chloro-1-isopropylbenzene of 2O the formula (IV) (II) HC CH (IV) H3C CH3 Y No 25 Br.

C 30 is prepared by the step of: cC reacting the Grignard compound of the formula (V) (V) 7. A process for preparing 2-bromo-4-chloro-1-isopropy 35 lbenzene of the formula (IV)

MgBr (IV) H3C CH3

40 Br C with a dialkylformamide of the formula (VI) (VI) 45 O C R l H comprising the step of reacting: R 50 a diazonium salt of the formula (IX) where each R is a C-C-alkyl independently from the other. (IX) 5. A process according to claim 4, wherein the Grignard CH compound of the formula (V) 55 Br (V)

MgBr 60 X

C as where X is HSO, Cl, Br, HCO, CH,CO, or HPO, with at least one of CuCl, FeC1 or FeSO and also with at least one of aqueous HCl or metal chloride. US 9,440,908 B2 29 30 8. The process according to claim 7 wherein the diazo- 10. The process according to claim 9 wherein 3-bromo nium salt of the formula (IX) 4-isopropylaniline of the formula (VII)

(IX) 5 (VII) H3C CH3 CH3 CH3

Br Br

Nt NH2

N 15 is prepared by reducing 2-bromo-1-isopropyl-4-nitrobenzene of the is prepared by formula (XI) reacting an ammonium salt of the formula (VIII)

2O (XI) (VIII) CH CH H3C CH3 Br. Br 25

NO NH2HX 30 11. The process according to claim 10 wherein 2-bromo where X is HSO, Cl, Br, HCO, CHCO, or HPO. 1-isopropyl-4-nitrobenzene of the formula (XI) with at least one of NaNO or KNO. 9. The process according to claim 8 wherein the ammo (XI) nium salt of the formula (VIII) 35 CH3 CH3

Br (VIII) HC CH 40 Br NO

45 is prepared by NHHX bromination of p-nitrocumene of the formula (X)

is prepared by (X) H3C CH3 converting 3-bromo-4-isopropylaniline of the formula 50 (VII)

(VII) CH3 CH3 55

Br NO by means of dimethyldibromohydantoin in sulphuric acid. 12. The process according to claim 9 wherein the acid 60 used to convert 3-bromo-4-isopropylaniline of the formula (VII) into the ammonium salts of the formula (VIII) is NH2 selected from the group consisting of HSO, HCl, HCOH, and HPO. by means of at least one acid.