USOO7300.953B2 (12) United States Patent (10) Patent No.: US 7,300,953 B2 Nishino et al. (45) Date of Patent: Nov. 27, 2007 (54) PROCESS FOR PREPARING NITRILE JP 54-122220 A 9, 1979 COMPOUND, CARBOXYLIC ACID JP 59-51251. A 3, 1984 COMPOUND OR CARBOXYLIC ACID JP 8-5O1299. A 2, 1996 ESTER COMPOUND JP 200O281672 A * 10, 2000 WO WO-94/05639 A1 3, 1994 (75) Inventors: Shigeyoshi Nishino, Ube (JP); Kenji Hirotsu, Ube (JP); Hidetaka Shima, OTHER PUBLICATIONS Ube (JP); Keiji Iwamoto, Ube (JP); Lawerence I. Kruse et al., J. Med. Chem. 1990, vol. 33, No. 2, pp. Takashi Harada, Ube (JP) T81 to 789. Christoph Strassier et al., Helvetica Chimica Acta, vol. 80, pp. 1528 (73) Assignee: Ube Industries, Ltd, Ube-shi (JP) to 1554, 1997. (*) Notice: Subject to any disclaimer, the term of this * cited by examiner patent is extended or adjusted under 35 Primary Examiner Kamal A. Saeed U.S.C. 154(b) by 0 days. Assistant Examiner Shawquia Young (74) Attorney, Agent, or Firm—Birch, Stewart, Kolasch & (21) Appl. No.: 10/572,373 Birch, LLP (22) PCT Filed: Sep. 17, 2004 (57) ABSTRACT PCT/UP2004/O13626 (86). PCT No.: The present invention discloses a process for preparing a S 371 (c)(1), nitrile compound, a carboxylic acid compound or a carboxy (2), (4) Date: Mar. 16, 2006 lic acid ester compound represented by the formula (2): (87) PCT Pub. No.: WO2005/0284.10 (2) PCT Pub. Date: Mar. 31, 2005 R (65) Prior Publication Data R 1. R2 US 2006/0287541 A1 Dec. 21, 2006 wherein R represents a cyano group, a carboxyl group or (30) Foreign Application Priority Data an ester group, R' and Reach represent a group which Sep. 19, 2003 (JP) - - - - - 2003-3285.15 does not participate in the reaction, which may have a Sep. 19, 2003 (JP) - - - - - 2003-328516 substituent, and R' and R may be combined to each - - - - - 2004-12O5O2 other to form a ring, Apr. 15, 2004 (JP) which comprises Subjecting an acetic acid compound rep May 13, 2004 (JP) - - - - - 2004-143637 resented by the formula (1): (51) Int. Cl. A 6LX 3L/075 (2006.01) (1) CO7D 309/08 (2006.01) R COOH (52) U.S. Cl. ....................................... 514/451; 549/426 (58) Field of Classification Search ................ 514/451; R DXR 5497426 See application file for complete search history. wherein R, R' and R have the same meanings as defined (56) References Cited above, to decarboxylation in the presence of a metal catalyst. FOREIGN PATENT DOCUMENTS EP O 659 181 B1 6, 1995 5 Claims, No Drawings US 7,300,953 B2 1. 2 PROCESS FOR PREPARING NITRILE the presence of Raney nickel in anhydrous ethanol (for COMPOUND, CARBOXYLIC ACID example, see International Patent Publication No. COMPOUND OR CARBOXYLIC ACID 94/05639). However, according to this method, yield of the ESTER COMPOUND objective product, 4-aminomethyltetrahydropyran, is low, and a large amount of a by-product (bis(4-tetrahydropyra TECHNICAL FIELD nylmethyl)amine) is produced, etc., so that this is not The present invention relates to a process for preparing a satisfied as an industrial process for preparing 4-aminom nitrile compound, a carboxylic acid compound or a carboxy ethyltetrahydropyran and an acid salt thereof. lic acid ester compound from an acetic acid compound. The present invention also relates to a process for preparing a DISCLOSURE OF THE INVENTION 4-substituted tetrahydropyran from a 4-substituted tetrahy dropyran-4-carboxylic acid or a bis(2-halogenoethyl)ether An object of the present invention is to solve the above and a 2-substituted acetic acid ester. The present invention mentioned problems and to provide an industrially suitable further relates to a process for preparing a 4-aminometh 15 yltetrahydropyran and an acid salt thereof from a 4-cyan process for preparing a nitrile compound, a carboxylic acid otetrahydropyran. The nitrile compound, the carboxylic acid compound or a carboxylic acid ester compound in which a compound or the carboxylic acid ester compound, the 4-Sub nitrile compound, a carboxylic acid compound or a carboxy stituted tetrahydropyran (4-cyanotetrahydropyran, tetrahy lic acid ester compound, in particular, 4-substituted tetrahy dropyran-4-carboxylic acid) and the 4-aminomethyltetrahy dropyran can be prepared from an acetic acid compound, in dropyran and an acid salt thereof are useful compounds as a particular, 4-substituted tetrahydropyran-4-carboxylic acid starting material or a synthetic intermediate of medicines, or bis(2-halogenoethyl)ether and 2-substituted acetic acid agricultural chemicals, etc. ester under mild conditions with a simple and easy process BACKGROUND ART and with high yield. 25 Another object of the present invention is to solve the Heretofore, as a method for preparing a nitrile compound, above-mentioned problems and to provide an industrially a carboxylic acid compound or a carboxylic acid ester Suitable process for preparing 4-aminomethyltetrahydropy compound from an acetic acid compound, it has been ran and an acid salt thereof in which 4-aminomethyltetrahy known, for example, a method in which acetonitrile is 30 dropyran and an acid salt thereof can be prepared from obtained by heating cyanoacetic acid to 160° C. or higher 4-cyanotetrahydropyran with high yield. (for example, see Chem. Ber. 7, 1382 (1874)) or a method in which acetic acid is obtained by heating malonic acid in The first embodiment of the present invention relates to a p-azoxyanisole at 141° C. (for example, see J. Indian Chem. process for preparing a nitrile compound, a carboxylic acid Soc.,58, 868 (1981)). However, in either of the above 35 compound or a carboxylic acid ester compound represented mentioned methods, high reaction temperatures are by the formula (2): required, and yields are low or there is no description about yields, etc., so that these methods are not satisfied as an industrial process for preparing a nitrile compound, a car (2) boxylic acid compound or a carboxylic acid ester com 40 R pound. Also, as a method for preparing 4-substituted tetrahydro R 1. R2 pyran from 4-Substituted tetrahydropyran-4-carboxylic acid, or from bis(2-halogenoethyl)ether and 2-substituted acetic acid ester, it has been known a method, for example, in 45 wherein R represents a cyano group, a carboxyl group or which bis(2-chloroethyl)ether and ethyl cyanoacetate are an ester group, R' and Reach represent a group which reacted to prepare ethyl 4-cyanotetrahydropyran-4-carboxy does not participate in the reaction, each of which may late, then the resulting material is hydrolyzed to prepare have a substituent(s), and R' and R may form a ring by 4-cyanotetrahydropyran-4-carboxylic acid, and further, it is binding to each other, heated at 180 to 200° C. to produce 4-cyanotetrahydropyran 50 with overall yield of 12.2% (for example, see J. Chem. Soc., which comprises Subjecting an acetic acid compound rep 1930, 2525). Also, it has been known a method in which resented by the formula (1): bis(2-chloroethyl)ether and diethyl malonate are reacted to prepare diethyl tetrahydropyran-4.4-dicarboxylate, then, the resulting material is hydrolyzed to prepare tetrahydropyran 55 (1) 4,4-dicarboxylic acid, and then, the resulting material is R COOH heated to 180° C. to prepare tetrahydropyran-4-carboxylic acid with overall yield of 31.8% (for example, see Helv. R Chim. Acta. 80, 1528 (1997)). However, in either of the above-mentioned methods, high reaction temperatures are 60 required, and yields are low, so that these methods are not wherein R, R' and R have the same meanings as defined satisfied as an industrial process for preparing 4-substituted above, tetrahydropyran. Moreover, as a method for preparing 4-aminomethyl to decarboxylation in the presence of a metal catalyst. tetrahydropyran and an acid salt thereof from 4-cyanotet 65 The second embodiment of the present invention relates rahydropyran, it has been known a method, for example, in to a process for preparing a 4-substituted tetrahydropyran which 4-cyanotetrahydropyran and hydrogen are reacted in represented by the formula (4): US 7,300,953 B2 (4) (3) R CO2H 10 wherein R has the same meaning as defined above, which wherein R has the same meaning as defined above, (B) comprises Subjecting a 4-substituted tetrahydropyran-4-car then, a hydrolysis step in which the above-mentioned mix boxylic acid represented by the formula (3): ture is hydrolyzed to prepare a 4-substituted tetrahydropy ran-4-carboxylic acid represented by the formula (3): 15 (3) R COOH (3) R CO2H O wherein R has the same meaning as defined above, to decarboxylation in the presence of a metal catalyst. The third embodiment of the present invention relates to 25 a process for preparing a 4-substituted tetrahydropyran which comprises the steps of (A) a cyclization step in which bis(2-halogenoethyl)ether represented by the formula (5): wherein R has the same meaning as defined above, (C) further, a decarboxylation step in which the 4-substituted 30 tetrahydropyran-4-carboxylic acid is subjected to decar (5) boxylation in the presence of a metal catalyst to prepare a 4-substituted tetrahydropyran represented by the formula (4): ur 35 wherein X represents a halogen atom, and a 2-substituted acetic acid ester represented by the formula (6): (4) 40 (6) COR R 45 wherein R represents a hydrocarbon group, and R has the same meaning as defined above, wherein R has the same meaning as defined above. are reacted in the presence of a base in an organic Solvent to 50 The fourth embodiment of the present invention relates to prepare a mixture of a 4-substituted tetrahydropyran-4- a process for preparing a 4-aminomethyltetrahydropyran carboxylic acid ester represented by the formula (7): represented by the formula (9): 55 (9) (7) NH2 R COR HC 60 O wherein R and R have the same meanings as defined above, and an acid salt thereof 65 and a 4-substituted tetrahydropyran-4-carboxylic acid rep which comprises reacting a 4-cyanotetrahydropyran repre resented by the formula (3): sented by the formula (8): US 7,300,953 B2 6 As the above-mentioned alkyl group, there may be men tioned, for example, a linear or branched alkyl group having (8) 1 to 10 carbon atoms, more specifically, a methyl group, an CN ethyl group, a propyl group, a butyl group, a pentyl group.