USOO826904.4B2 (12) United States Patent (10) Patent No.: US 8,269,044 B2 Takano et al. (45) Date of Patent: *Sep. 18, 2012 (54) METHOD FOR SELECTIVELY PRODUCING OTHER PUBLICATIONS PRIMARY AMINE COMPOUND M. S. Gibson, et al. The Gabriel Synthesis of Primary Amines, Angew. Chem. Internat. Edit., vol.7. (1968), pp. 919-930. (75) Inventors: Naoyuki Takano, Ibaraki (JP); HanYinglin, et al., A Convenient Synthesis of Primary Amines Using Kazuyuki Tanaka, Oita (JP); Shinzo Sodium Diformylamide as a Modified Gabriel Reagent, Synthesis, Seko, Toyonaka (JP) 1990, pp. 122-124. Nikola Blazevic, et al., Hexamethylenetetramine, A Versatile (73) Assignee: Sumitomo Chemical Company, Reagent in Organic Synthesis, Synthesis, 1979, pp. 161-176. Limited, Tokyo (JP) Chrisey et al., “Tris-N,N',N" (3', 4', 5'-Trimethoxyphenethyl)-1, 3, 5-Hexahydrotriazine, a Methylenemescaline Trimer: Characteriza (*) Notice: Subject to any disclaimer, the term of this tion and Selective Cyclization to Anhalinine Under Non-Aqueous patent is extended or adjusted under 35 Conditions.” Heterocycles, vol. 29, No. 6, 1989, pp. 1179-1183. Chinese Office Action issued in the corresponding Chinese Patent U.S.C. 154(b) by 1046 days. Application No. 200680052617.1 on Aug. 18, 2011 (with English This patent is Subject to a terminal dis translation). claimer. Japanese Office Action for Application No. 2006-336654 datedMar. 13, 2012 (with English translation). (21) Appl. No.: 12/097,234 * cited by examiner Primary Examiner — Venkataraman Balasubramanian (22) PCT Filed: Dec. 14, 2006 (74) Attorney, Agent, or Firm — Birch, Stewart, Kolasch & Birch, LLP (86). PCT No.: PCT/UP2OO6/324938 (57) ABSTRACT S371 (c)(1), Disclosed is a method for producing a primary amine com (2), (4) Date: Jun. 12, 2008 pound represented by the formula (3): (87) PCT Pub. No.: WO2007/069685 PCT Pub. Date: Jun. 21, 2007 (3) Air 1n NH2 (65) Prior Publication Data US 2009/O281325A1 Nov. 12, 2009 wherein, Aris as defined below, which is characterized in that a halogen compound represented by the formula (1): (30) Foreign Application Priority Data (1) Dec. 15, 2005 (JP) ................................. 2005-361489 Air 1N X (51) Int. Cl. wherein, Ar represents an unsubstituted aromatic group Such CO7D 213/38 (2006.01) as a phenyl group, a naphthyl group, a pyridyl group, a furyl CO7D 2.5L/04 (2006.01) group, a thienyl group, a pyrrolyl group, an oxazolyl group. C07C 209/08 (2006.01) an isoxazolyl group or a pyrimidinyl group, or an aromatic (52) U.S. Cl. ......................... 564/386; 544/193: 564/376 group obtained by Substituting Such an unsubstituted aro (58) Field of Classification Search .................. 544/193; matic group with 1-3 Substituents; and X represents a halogen 564/386, 376 atom, ammonia and formaldehyde are reacted with each See application file for complete search history. other, thereby obtaining a hexahydrotriazine compound rep resented by the formula (2): (56) References Cited (2) Air U.S. PATENT DOCUMENTS 2,608,584 A 8/1952 Sprules et al. 5,210.303 A 5/1993 Sugiyama ( 7,439,357 B2 * 10/2008 Takano et al. ................. 544, 193 7.977,490 B2 * 7/2011 Tanaka et al. ................. 548,202 r 2007/O1978O3 A1 8, 2007 Takano et al. ^n-1 NS-N FOREIGN PATENT DOCUMENTS JP 32-6256 B 8, 1957 JP 63-198654 A 8, 1988 wherein, Ar is as defined above, and then the thus-obtained JP 2.908510 B2 6, 1999 hexahydrotriazine compound is decomposed. By this JP 34O7082 B2 5, 2003 method, a primary amine compound can be commercially JP 2006-290758 A 1, 2006 JP 2006-290758 A 10, 2006 advantageously produced by using a low-cost ammonia while SU T98102 A1 1, 1981 Suppressing production of a secondary amine as a by-product. WO WO-2005/123704 A1 12/2005 WO WO-2006,109811 A1 10, 2006 5 Claims, No Drawings US 8,269,044 B2 1. METHOD FOR SELECTIVELY PRODUCING PRIMARY AMINE COMPOUND (1) Air 1n X TECHNICAL FIELD wherein Ar represents an aromatic group selected from the The present invention relates to a method for selectively group consisting of a phenyl group, a naphthyl group, a producing a primary amine compound. pyridyl group, a furyl group, a thienyl group, apyrrolyl group, BACKGROUND ART an oxazolyl group, an isoxazolyl group, an isothiazolyl group, 10 an imidazolyl group, a pyrazolyl group, a pyridazinyl group, Hitherto, many selective synthesis methods for primary a pyrimidinyl group, a pyrazinyl group, a quinolinyl group, a amine compounds have been reported, and examples thereof quinoxalinyl group and a benzimidazolyl group, and said Ar may have 1 to 3 substituents which may be the same or include a Gabriel reaction using phthalimide (for example, different and are independently a halogenatom, a lower alkyl Non-Patent document 1) and a related reaction thereof (for 15 group, a lower alkoxy group, a lower alkylenedioxy group, a example, Non-Patent document 2), a Delepine reaction using nitro group, a cyano group or a di(lower alkyl)amino group, hexamethylene tetramine (for example, Non-Patent docu and X represents a halogen atom, with ammonia and formal ment 3), and the like. However, these methods are not exactly dehyde to obtain a hexahydrotriazine compound represented satisfactory from the industrial viewpoint because they require an expensive aminating agent or a complicated by the formula (2): decomposition process. Although a synthesis method com prising use of ammonia, which is inexpensive, as an aminat (2) ing agent is industrially useful, the method has difficulty in Air Suppressing production of a secondary amine and requires 20 mol times or more of ammonia for selectively obtaining a 25 ( primary amine (Patent document 1). Under the circum stances, a method of Suppressing production of a secondary r amine using coexistence of aromatic aldehyde has been pro "N-1 NS-N posed (Patent document 2). However, the method requires separation and recovery of aromatic aldehyde and therefore, 30 is not satisfactory. Non-Patent document 1: Angew. Chem. Int. Ed. Engl. Vol. 7, wherein Ar is as defined above, and subjecting the hexahy 919 (1968) drotriazine compound represented by the formula (2) to a Non-Patent document 2: Synthesis 122 (1990) decomposition treatment. Non-Patent document 3: Synthesis 161 (1979) 35 Patent document 1: U.S. Pat. No. 2,608,584, JP-B 32-6256 Effect of the Invention Patent document 2: Japanese Patent No. 2908510 According to the present invention, it is possible to selec DISCLOSURE OF THE INVENTION tively and industrially advantageously produce a primary 40 amine compound from a halogen compound and ammonia. Problems to be Solved by the Invention BEST MODE FOR CARRYING OUT THE Under the above-described situation, inventors of the INVENTION present invention studied for development of a method for industrially advantageously producing a primary amine com 45 First, a step of reacting the halogen compound represented pound which comprises usinginexpensive ammonia and Sup by the formula (1) with ammonia and formaldehyde to obtain pressing production of a secondary amine as a by-product. As the hexahydrotriazine compound represented by the formula a result, they found that the desired primary amine compound (2) (hereinafter referred to as the hexahydrotriazine com could be produced by reacting a halogen compound with pound (2)) is explained. ammonia and formaldehyde, which is inexpensive and easily 50 In the formula of the halogen compound (1), the aromatic available, to convert the halogen compound into a hexahy group represented by Ar may have 1 to 3 Substituents. drotriazine compound, and then Subjecting the hexahydrotri Examples of the Substituent include a halogen atom, a lower azine compound to a decomposition treatment. Thus the alkyl group, a lower alkoxy group, a lower alkylenedioxy present invention has been completed. group, a nitro group, a cyano group, and a di(lower alkyl) 55 amino group. Examples of the halogen atom include a fluo Means for Solving the Problems rine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the lower alkyl moiety of the lower alkyl The present invention provides a method for producing a group, the lower alkoxy group and the di(lower alkyl)amino primary amine compound represented by the formula (3): group include a C1-6 alkyl grou Such as methyl, ethyl, propyl. 60 butyl, pentyl, hexyl or the like. Examples of the lower alky lenedioxy group include a methylenedioxy group, an ethyl (3) enedioxy group, and the like. Examples of the halogen atom 1n represented by Xinclude a chlorine atom, a bromine atom, an Air NH2 iodine atom, and the like. 65 Examples of the halogen compound (1) include benzyl wherein Ar is as defined below, which comprises reacting a chloride, 2-chlorobenzyl chloride, 3-chlorobenzyl chloride, halogen compound represented by the formula (1): 4-chlorobenzyl chloride, 2-fluorobenzyl chloride, 3-fluo US 8,269,044 B2 3 4 robenzyl chloride, 4-fluorobenzyl chloride, 2,4-dichloroben or the like; a halogenated hydrocarbon Solvent Such as chlo Zyl chloride, 3,4-dichlorobenzyl chloride, 2,6-dichloroben robenzene, dichlorobenzene or the like; an aliphatic hydro Zyl chloride, 2,4-difluorobenzyl chloride, 3,4-difluorobenzyl carbon solvent Such as hexane, heptane, cyclohexane or the chloride, 2,6-difluorobenzyl chloride, 4-methylbenzyl chlo like: an ether solvent such as diethyl ether, tetrahydrofuran, ride, 4-ethylbenzyl chloride, 2,4-dimethylbenzyl chloride, dioxane or the like; an aprotic polar solvent such as acetoni 4-t-butylbenzyl chloride, 3-methoxybenzyl chloride, 4-meth trile, propionitrile, dimethylsulfoxide, N,N-dimethylaceta oxybenzyl chloride, 4-cyanobenzyl chloride, 3-nitro-benzyl mide or the like, and water, which may be a single solvent or chloride, 4-N,N-dimethylamino-3-fluoro-benzyl chloride, a mixture of Solvents. Among them, preferred are an alcohol benzyl bromide, 2-chlorobenzyl bromide, 3-chlorobenzyl Solvent and water, and more preferred is an alcohol solvent.