US 2005O104233A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0104233 A1 Kato et al. (43) Pub. Date: May 19, 2005 (54) METHOD OF SUBSTITUENT (30) Foreign Application Priority Data INTRODUCTION THROUGH HALOGEN-METAL, EXCHANGE REACTION May 31, 2002 (JP)...................................... 2002-16O759 (76) Inventors: Shinji Kato, Aichi (JP); Nobuaki Publication Classification Nonoyama, Aichi (JP); Toshiaki Mase, Aichi (JP) (51) Int. Cl." ................................. C07F 1/02; CO7F 3/04 (52) U.S. Cl. ................................. 260/665 G; 260/665 R Correspondence Address: (57) ABSTRACT WENDEROTH, LIND & PONACK, L.L.P. 2033 K STREET N. W. A method of exchanging a halogen atom of a halide, which SUTE 800 has a group containing an acidic proton and in which one or WASHINGTON, DC 20006-1021 (US) more halogen atom(s) is/are Substituted on a carbon atom of the carbon-carbon double bond, with a metal atom by (21) Appl. No.: 10/514,935 halogen-metal-exchange reaction and introducing an elec trophilic reagent into the carbon atom to which the metal (22) PCT Filed: May 27, 2003 atom is attached. The above method is an industrially excellent method of introducing a Substituent by halogen (86) PCT No.: PCT/JP03/06624 metal eXchange reaction. US 2005/0104233 A1 May 19, 2005 METHOD OF SUBSTITUENT INTRODUCTION eXchange reaction. As a result, they found that a halide THROUGH HALOGEN-METAL, EXCHANGE which has a Substituent containing an acidic proton can be REACTION employed as a starting material without protection of the Substituent, and the condition of extreme low temperature TECHNICAL FIELD (-78 C.) can be avoided when a halide, which has a 0001. The present invention is useful in the field of fine Substituent containing an acidic proton and in which the chemicals. Such as pharmaceuticals, agricultural chemicals, carbon atom(s) of the carbon-carbon double bond is/are perfumes and the like. In more detail, the present invention Substituted by one or more halogen(s), as a starting material relates to a method of introducing a Substituent to a produc is reacted with a magnesium halide compound, a magnesium tion intermediate for a compound which is useful in the field compound, or a mixture thereof, and Subsequently reacted of pharmaceuticals and the like, and a novel production with a lithium compound and then with an electrophilic method which is advantageous for the production. reagent. The present inventors carried out further Studies on the basis of those findings, and finally completed the present BACKGROUND ART invention. 0002 Some of the compounds produced by a method of 0008 Namely, the present invention relates to: introducing a Substituent by halogen-metal eXchange reac tion according to the present invention are useful as a 0009 (1) A method of exchanging a halogenatom of production intermediate for the compound which is useful as a halide with a metal atom by halogen-metal a neuropeptide Y receptor antagonist disclosed, for example, eXchange reaction and introducing an electrophilic in WO 01/14376. reagent into a carbon atom to which the metal atom is attached, which comprises reacting a halide which 0003) A method of introducing a substituent by halogen has a group containing an acidic proton and in which metal eXchange reaction has often been utilized in the one or more halogen atom(s) is/are Substituted on a production of intermediates for pharmaceuticals, including carbon atom of the carbon-carbon double bond, with the aforementioned compounds. a magnesium halide represented by the formula (I): 0004 Known methods of introducing a substituent by halogen-metal eXchange reaction are disclosed in, for example, ACCOUNTS OF CHEMICAL RESEARCH, vol. I 15, p. 300-305, 1982, William E. parham et al., JOURNAL OF ORGANIC CHEMISTRY, vol.39, p. 2051-2053, 1974, William E. parham et al. and JOURNAL OF ORGANIC CHEMISTRY, vol. 41, p. 2628-2633, 1976, William E. Parham et al., however, those production methods disclosed in Said literatures are carried out under an extreme cold 0010) (wherein R is a hydrocarbon group, and X is a condition (-78° C). In the industrial production, setting halogen atom), or a magnesium compound represented by Such an extreme cold condition requires a particular cooling System, thus Said production methods are inefficient and not the formula (II): desirable for the industrial production. 0005 Recently, a report by Kazuya Kitagawa et al. in II) ANGEWANTE CHEMIE INTERNATIONAL EDITION, vol. 39, p. 2481-2483, and WO 01/57046 also disclosed a method of introducing a Substituent by halogen-metal eXchange reaction in which an extreme cold condition was not necessary. This method of introducing a Substituent by halogen-metal eXchange reaction, however, has a limitation 0.011) (wherein R and R are each independently a that the compound having a halogen atom, which is a hydrocarbon group), or a mixture thereof, followed by Starting material, is not applicable when it includes a Sub Successive reactions with a lithium compound represented Stituent containing an acidic proton. Therefore, in case by the formula (III): where a starting material includes a Substituent containing an acidic proton, it is necessary to protect the Substituent and Li-R III then to remove the protecting group after the reaction, 0012 (wherein R" is a hydrocarbon group), and then with resulting in additional processes, complex proceSS control an electrophilic reagent, and then optionally treating the and reduced yield. Accordingly, Said method is inefficient resulting product with an acid, for the purpose of industrial production. 0013 (2) The method according to the above (1), DISCLOSURE OF THE INVENTION wherein the hydrocarbon group is an alkyl group, an 0006 An object of the present invention is to improve aromatic group or an aralkyl group, problems relating to the known methods of introducing a 0014) (3) The method according to the above (1) or Substituent by halogen-metal-exchange reaction and to pro (2), wherein the halide which has a group containing vide an industrially Superior method of introducing a Sub an acidic proton and in which one or more halogen Stituent by halogen-metal eXchange reaction. atom(s) is/are substituted with the carbon atom of the 0007. The present inventors conducted intensive studies carbon-carbon double bond is a compound repre on a method of introducing a Substituent by halogen-metal sented by the formula (IV): US 2005/0104233 A1 May 19, 2005 pyl magnesium chloride, isopropyl magnesium bro mide, n-butyl magnesium chloride, n-butyl IV magnesium bromide, isobutyl magnesium chloride, X2 phenyl magnesium chloride or phenyl magnesium bromide, and the magnesium compound represented by the formula (II) is dimethylmagnesium, diethyl o-O 3 magnesium, di-n-propylmagnesium, diisopropyl magnesium, di-n-butylmagnesium, diisobutylmag nesium, di-Sec-butylmagnesium, n-butyl(Sec 0015 wherein butyl)magnesium or diphenylmagnesium, 0016 X is a halogen atom; 0025 (7) The method according to any one of the above (1) to (6), wherein the lithium compound 0017 X is a hydrogen atom or a halogen atom; represented by the formula (III) is methyllithium, 0018 n is an integer of 1 to 4; n-butyllithium, sec-butyllithium, tert-butyllithium or 0019 Y is a carboxyl group, a hydroxymethyl phenylithium, group, a hydroxy group, a Sulfamoyl group, a group 0026 (8) The method according to any one of the of the formula: -SOH, a phosphono group, a group above (1) to (7), wherein the electrophilic reagent is of the formula: -NH-Y (wherein Y is a hydro benzaldehyde, methyl iodide, N,N-dimethylforma gen atom, a hydroxy group, an alkyl group, a car mide, 1-benzyl-4-piperidone, 1-tert-butoxycarbonyl boxyl group, an aromatic group, a benzyloxycarbo 4-piperidone, allyl bromide, cyclohexanone, n-hep nyl group, an alkoxycarbonyl group or a tanal, n-hexanal, acetone or methyl ethyl ketone, phenyloxycarbonyl group), a group of the formula: -CO-NH-Y (Y is a hydrogen atom, an alkyl 0027 (9) The method according to the above (1), group or an aromatic group) or a group of the which comprises reacting 2-bromobenzoic acid rep formula: -NH-SO-Y (wherein Y is a hydro resented by the formula: gen atom, an alkyl group or an aromatic group), and 0020 the group represented by the formula: Br COOH 0028 with di-n-butylmagnesium, di-sec-butylmagne sium, n-butyl(Sec-butyl)magnesium, isopropyl magnesium chloride, n-butyl magnesium bromide, or a mixture thereof, 0021 is a divalent homocyclic or heterocyclic group, and followed by Successive reactions with n-butyllithium, and when n is more than 1, each Y may be the same or different, then with a piperidone derivative represented by the for 0022 (4) The method according to the above (2) or mula: (3), wherein the alkyl group is a linear or branched C-C alkyl group, and the aromatic group is phenyl, 1-naphthyl, 2-naphthyl or benzyl, 0023 (5) The method according to any one of the above (1) to (4), wherein the homocyclic or hetero cyclic ring is a benzene ring, a naphthalene ring, an indene ring, an indane ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a 0029 and then treating the product with an acid to give thiophen ring, a furan ring, a pyran ring, an isoben a Spiro compound represented by the formula: Zofuran ring, a pyrrole ring, an imidazole ring, a pyrazole ring, an isothiazole ring, a thiazole ring, an Oxazole ring, an isoxazole ring, aquinoline ring, an isoquinoline ring, a benzofuran ring, an indole ring, an isolindole ring, a phthalazine ring, a quinoxaline ring, a benzimidazole ring, a 1,8-naphthyridine ring, a benzoxazole ring, a benzothiazole ring, a ben Zothiophen ring, a cinnoline ring or a quinazoline ring, 0024 (6) The method according to any one of the above (1) to (5), wherein the magnesium halide represented by the formula (I) is methyl magnesium bromide, methyl magnesium chloride, ethyl magne sium chloride, n-propyl magnesium chloride, isopro US 2005/0104233 A1 May 19, 2005 0030) and 0041.