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. a hexyl group, a heptyl group, an octyl group, a nonyl group. a decyl group, etc. are mentioned. Incidentally, these groups contain various kinds of isomers. As the above-mentioned cycloalkyl group, there may be mentioned, for example, a cycloalkyl group having 3 to 10 10 carbon atoms, more specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, which is a compound in which R is a cyano group in the a cycloheptyl group, a cyclooctyl group, etc. are mentioned. above-mentioned formula (4) with hydrogen in the presence As the above-mentioned aralkyl group, there may be of Raney nickel in a solvent containing ammonia. mentioned, for example, an aryl group bonded to a linear or 15 branched alkyl group having 1 to 3 carbon atoms, more BEST MODE FOR CARRYING OUT THE specifically, a benzyl group, a phenethyl group, a phenyl INVENTION propyl group, etc. are mentioned. Incidentally, these groups contain various kinds of isomers. The acetic acid compound or the 4-substituted tetrahy As the above-mentioned aryl group, there may be men dropyran-4-carboxylic acid to be used in the decarboxyla tioned, for example, an aryl group having 6 to 20 carbon tion in the first and the second embodiments of the present atoms, more specifically, a phenyl group, a p-tolyl group, a invention is represented by the above-mentioned formula (1) naphthyl group, an anthryl group, etc. Incidentally, these or (3). In the formula (1) or (3), R represents a cyano group, groups contain various kinds of isomers. a carboxyl group or an ester group. As the ester group, it is As the above-mentioned halogen atom, there may be not specifically limited so long as it is a group which forms 25 mentioned, for example, a fluorine atom, a chlorine atom, a an ester with a carboxyl group, and there may be mentioned, bromine atom, and an iodine atom. for example, a carboxyalkyl ester group, a carboxyaralkyl As the above-mentioned alkoxyl group, there may be ester group, a carboxyaryl ester group, a carboxycycloalkyl mentioned, for example, a linear or branched alkoxyl group ester group, etc. As the carboxyalkyl ester group, there may having 1 to 6 carbon atoms, more specifically, a methoxyl be mentioned those to which a linear or branched alkyl 30 group, an ethoxyl group, a propoxyl group, etc. Incidentally, group having 1 to 6 carbon atoms is bonded, more specifi these groups contain various kinds of isomers. cally, a carboxymethyl ester group, a carboxyethyl ester As the above-mentioned alkylthio group, there may be group, a carboxy-n-propyl ester group, a carboxyisopropyl mentioned, for example, a linear or branched alkylthio group ester group, a carboxy-n-butyl ester group, a carboxyisobu having 1 to 10 carbon atoms, more specifically, a methylthio tyl ester group, a carboxy-t-butyl ester group, etc. As the 35 group, an ethylthio group, a propylthio group, etc. Inciden carboxyaralkyl ester group, there may be mentioned a group tally, these groups contain various kinds of isomers. in which a linear or branched alkyl group having 1 to 3 The above-mentioned alkyl group, cycloalkyl group, carbon atoms bound to an aryl group, more specifically, a aralkyl group, aryl group, alkoxyl group, alkylthio group or carboxybenzyl ester group, a carboxyphenethyl ester group, amino group may have a Substituent(s). As the a carboxyphenylpropyl ester group, etc. As the carboxyaryl 40 Substituent(s), there may be mentioned a Substituent(s) ester group, there may be mentioned a group in which an formed through a carbon atom, a Substituent(s) formed aryl group having 6 to 20 carbon atoms bound, more through an oxygen atom, a Substituent(s) formed through a specifically, a carboxyphenyl ester group, a carboxytolyl nitrogen atom, a Substituent(s) formed through a Sulfur ester group, a carboxyxylyl ester group, a carboxymesityl atom, a halogen atom, etc. ester group, a carboxynaphthyl ester group, etc. As the 45 As the above-mentioned substituent formed through a carboxycycloalkyl ester group, there may be mentioned a carbon atom, there may be mentioned, for example, a linear group in which a cycloalkyl group having 3 to 6 carbon or branched alkyl group having 1 to 10 carbon atoms such atoms bound, more specifically, a carboxycyclopropyl ester as a methyl group, an ethyl group, a propyl group, a butyl group, a carboxycyclobutyl ester group, a carboxycyclopen group, a pentyl group, a hexyl group, etc.; a cycloalkyl group tyl ester group, a carboxycyclohexyl ester group, etc. Of 50 having 3 to 10 carbon atoms such as a cyclopropyl group, a these, preferred is a carboxyalkyl ester group, more pre cyclobutyl group, a cyclopentyl group, a cyclohexyl group, ferred is a carboxymethyl ester group or a carboxyethyl ester etc.; an alkenyl group having 2 to 10 carbon atoms such as group. a Vinyl group, an allyl group, a propenyl group, a cyclopro Also, R' and R in the formula (1) each represent a group penyl group, a cyclobutenyl group, a cyclopentenyl group, which does not participate in the reaction, which may have 55 etc.; a heterocyclic group Such as a pyrrolidyl group, a a Substituent(s), more specifically, for example, a hydrogen pyrrolyl group, a furyl group, a thienyl group, etc.; an aryl atom, an alkyl group, a cycloalkyl group, an aralkyl group. group having 6 to 20 carbon atoms such as a phenyl group, an aryl group, a halogen atom, a hydroxyl group, an alkoxyl a tolyl group, a xylyl group, a biphenylyl group, a naphthyl group, an alkylthio group, a nitro group, a cyano group, a group, an anthryl group, a phenanthryl group, etc.; an acyl carbonyl group or an amino group. Incidentally, R' and R' 60 group (which may be converted into acetal) having 1 to 10 may form a ring by binding to each other. Specific examples carbon atoms such as a formyl group, an acetyl group, a of the compound in which a ring is formed, there may be propionyl group, an acryloyl group, a pivaloyl group, a exemplified by a 4-substituted tetrahydropyran-4-carboxylic cyclohexylcarbonyl group, a benzoyl group, a naphthoyl acid represented by the the above-mentioned formula (3) in group, a toluoyl group, etc.; an alkoxycarbonyl group having which R' and R form a ring through an oxygen atom in the 65 2 to 10 carbon atoms such as a methoxycarbonyl group, an second embodiment of the present invention as a particularly ethoxycarbonyl group, etc.; an aryloxycarbonyl group hav preferred compound. ing 7 to 20 carbon atoms Such as a phenoxycarbonyl group, US 7,300,953 B2 7 8 etc.; a halogenated alkyl group having 1 to 10 carbon atoms chloride, iron(III) chloride, iron(II) bromide, iron(III) bro Such as a trifluoromethyl group, etc.; a cyano group, etc. mide, etc.; a nickel catalyst Such as nickel(II) oxide, nickel Incidentally, these groups contain various kinds of isomers. (III) oxide, nickel(II) chloride, nickel(II) bromide, nickel(II) As the above-mentioned substituent formed through a acetylacetonate, Raney nickel, etc., a Zinc catalyst Such as oxygen atom, there may be mentioned, for example, a 5 Zinc powder, Zinc chloride, Zinc bromide, etc., preferably hydroxyl group; an alkoxyl group having 1 to 10 carbon copper powder, copper(I) oxide, iron, nickel(II) acetylaceto atoms such as a methoxyl group, an ethoxyl group, a nate, Zinc powder, more preferably copper powder, copper(I) propoxyl group, a butoxyl group, a pentyloxyl group, a oxide, particularly preferably copper(I) oxide is used. Inci hexyloxyl group, a heptyloxyl group, a benzyloxyl group, a dentally, these metal catalysts may be used alone or in piperidyloxyl group, a pyranyloxyl group, etc.; an aryloxyl 10 combination of two or more kinds. group having 6 to 20 carbon atoms such as a phenoxyl An amount of the above-mentioned metal catalyst to be group, a tolyloxyl group, a naphtyloxyl group, etc. Inciden used is preferably 0.001 to 10 mols, more preferably 0.001 tally, these groups contain various kinds of isomers. to 1.0 mol, particularly preferably 0.01 to 0.5 mol in terms As the above-mentioned substituent formed through a of a metal atom based on 1 mol of the acetic acid compound nitrogen atom, there may be mentioned, for example, a 15 or the 4-substituted tetrahydropyran-4-carboxylic acid. primary amino group Such as a methylamino group, an The decarboxylation of the present invention is preferably ethylamino group, a butylamino group, a cyclohexylamino carried out in a solvent. As the solvent to be used, it is not group, a phenylamino group, a naphthylamino group, etc., a specifically limited so long as it does not inhibit the reaction, secondary amino group Such as a dimethylamino group, a and there may be used, for example, water, a secondary diethylamino group, a dibutylamino group, a methylethy amine Such as dibutylamine, piperidine, 2-pipecoline, etc.; a lamino group, a methylbutylamino group, a diphenylamino tertiary amine Such as triethylamine, tributylamine, etc.; a group, etc.; a heterocyclic amino group Such as a mor pyridine Such as pyridine, methylpyridine, dimethylami pholino group, a thiomorpholino group, a piperidino group, nopyridine, etc.; a quinoline such as quinoline, isoquinoline, a piperazinyl group, a pyrazolidinyl group, a pyrrolidino methylduinoline, etc.; an amide Such as N,N-dimethylfor group, an indolyl group, etc.; an imino group, etc. Inciden 25 mamide, N,N-dimethylacetamide, N-methylpyrrolidone, tally, these groups contain various kinds of isomers. etc.; a urea Such as N,N'-dimethylimidazolidinone, etc.; a As the above-mentioned substituent formed through a Sulfoxide such as dimethyl Sulfoxide, Sulfolane, etc.; an Sulfur atom, there may be mentioned, for example, a mer alcohol Such as n-propyl alcohol, n-butyl alcohol, etc.; an capto group; a thioalkoxyl group having 1 to 6 carbon atoms ether such as diisopropylether, dioxane, cyclopropylmeth Such as a thiomethoxyl group, a thioethoxyl group, a thio 30 ylether, etc.; an aromatic hydrocarbon Such as toluene, propoxyl group, etc.; a thioaryloxyl group having 6 to 20 Xylene, etc.; an acetic acid ester Such as ethyl acetate, butyl carbon atoms such as a thiophenoxyl group, a thiotolyloxyl acetate, etc., preferably a tertiary amine, a pyridine, an group, a thionaphtyloxyl group, etc. Incidentally, these amide, a sulfoxide, or a mixed solvent thereof with an groups contain various kinds of isomers. aromatic hydrocarbon or an acetic acid ester, more prefer As the above-mentioned a halogen atom, there may be 35 ably triethylamine, pyridine, N,N-dimethylformamide, N.N- mentioned a fluorine atom, a chlorine atom, a bromine atom, dimethylacetamide, N-methylpyrrolidone, N,N'-dimeth and an iodine atom. ylimidazolidinone, dimethyl sulfoxide, or a mixed solvent As the specific examples of the acetic acid compound thereof with toluene, ethyl acetate or butyl acetate. Inciden represented by the formula (1) in the first embodiment of the tally, these organic solvents may be used alone or in com present invention, there may be mentioned, for example, 40 bination of two or more in admixture. cyanoacetic acid, malonic acid, 2-methylcyanoacetic acid, An amount of the above-mentioned solvent to be used 2,2-dimethylcyanoacetic acid, malonic acid monomethyl may be optionally adjusted depending on a degree of uni ester, 2-methyl malonic acid, 2,2-dimethyl malonic acid, etc. formity or condition of stirring of the reaction mixture, and Specific examples of the 4-substituted tetrahydropyran is preferably 0.1 to 100 ml, more preferably 0.5 to 50 ml, 4-carboxylic acid represented by the formula (3) in the 45 particularly preferably 1 to 10 ml based on 1 g of the acetic second embodiment of the present invention may be men acid compound or the 4-substituted tetrahydropyran-4-car tioned 4-cyanotetrahydropyran-4-carboxylic acid, tetrahy boxylic acid. dropyran-4,4-dicarboxylic acid, tetrahydropyran-4,4-dicar The decarboxylation of the present invention can be boxylic acid monomethyl ester, tetrahydropyran-4.4- carried out, for example, by a method in which an acetic acid dicarboxylic acid monoethyl ester, tetrahydropyran-4.4- 50 compound, a metal catalyst and a solvent are mixed, and dicarboxylic acid mono-n-propyl ester, tetrahydropyran-4, reacted under stirring, etc. A reaction temperature at that 4-dicarboxylic acid mono-isopropyl ester, tetrahydropyran time is preferably 50 to 150° C., more preferably 80 to 130° 4,4-dicarboxylic acid mono-n-butyl ester, tetrahydropyran C., and a reaction pressure is not specifically limited. 4,4-dicarboxylic acid mono-isobutyl ester, tetrahydropyran Incidentally, the nitrile compound or the carboxylic acid 4,4-dicarboxylic acid mono-tert-butyl ester, 55 compound represented by the formula (2) or the 4-substi tetrahydropyran-4,4-dicarboxylic acid monocyclopropyl tuted tetrahydropyran represented by the formula (4) which ester, tetrahydropyran-4.4-dicarboxylic acid monobenzyl are final products can be isolated and purified by a general ester, tetrahydropyran-4.4-dicarboxylic acid monophenyl method, for example, filtration, concentration, distillation, ester, etc. recrystallization, column chromatography, etc., after As the metal catalyst to be used in the decarboxylation of 60 completion of the reaction. the present invention is at least one catalyst of a metal As the specific examples of the nitrile compound, car selected from the group consisting of copper, iron, nickel boxylic acid compound or carboxylic acid ester compound and Zinc, more specifically, there may be mentioned for represented by the formula (2) obtained in the first embodi example, a copper catalyst Such as copper powder, copper(I) ment of the present invention, there may be mentioned, for oxide, copper(II) oxide, copper(I) chloride, copper(II) chlo 65 example, acetonitrile, propionitrile, isobutyronitrile, methyl ride, copper(I) bromide, copper(II) bromide, etc.; an iron acetate, acetic acid, propionic acid, 2-methylpropionic acid, catalyst Such as iron, iron(II) oxide, iron(III) oxide, iron(II) etc. US 7,300,953 B2 9 10 As the specific examples of the 4-substituted tetrahydro An amount of the above-mentioned 2-substituted acetic pyran represented by the formula (4) obtained in the second acid ester to be used is preferably 1.0 to 20 mols, more embodiment of the present invention, there may be men preferably 2.0 to 4.0 mols based on 1 mol of the bis(2- tioned 4-cyanotetrahydropyran, tetrahydropyran-4-carboxy halogenoethyl)ether. lic acid, methyl tetrahydropyran-4-carboxylate, ethyl tet As the base to be used in the cyclization step of the present rahydropyran-4-carboxylate, n-propyl tetrahydropyran-4- invention, there may be mentioned, for example, an alkali carboxylate, isopropyl tetrahydropyran-4-carboxylate, metal hydride Such as Sodium hydride, potassium hydride, n-butyl tetrahydropyran-4-carboxylate, isobutyl tetrahydro etc.; an alkali metal alkoxide such as Sodium methoxide, pyran-4-carboxylate, tert-butyl tetrahydropyran-4-carboxy Sodium ethoxide, Sodium isopropoxide, potassium t-butox late, cyclopropyl tetrahydropyran-4-carboxylate, benzyl tet 10 ide, etc.; an alkali metal carbonate Such as Sodium carbonate, potassium carbonate, etc.; an alkali metal hydrogen carbon rahydropyran-4-carboxylate, phenyl tetrahydropyran-4- ate such as sodium hydrogen carbonate, potassium hydrogen carboxylate, etc. carbonate, etc.; an alkali metal hydroxide Such as sodium Next, a process for preparing a 4-substituted tetrahydro hydroxide, potassium hydroxide, etc., preferably an alkali pyran which is the third embodiment of the present inven 15 metal hydride, an alkali metal alkoxide, and/or an alkali tion will be explained. metal carbonate is/are used. Incidentally, these bases may be used alone or in combination of two or more in admixture. (A) Cyclization Reaction Step An amount of the above-mentioned base to be used is The cyclization step of the present invention is a step of preferably 1.0 to 10.0 mols, more preferably 2.0 to 5.0 mols preparing a mixture of the 4-substituted tetrahydropyran-4- based on 1 mol of the bis(2-halogenoethyl)ether. carboxylic acid ester and the 4-substituted tetrahydropyran As the organic solvent to be used in the cyclization step 4-carboxylic acid by reacting a bis(2-halogenoethyl)ether of the present invention, it is not specifically limited so long and a 2-substituted acetic acid ester in the presence of a base as it does not inhibit the reaction, and there may be men in an organic solvent. tioned, for example, an amide such as N,N-dimethylforma The bis(2-halogenoethyl)ether to be used in the cycliza 25 mide, N,N-dimethylacetamide, N-methyl-pyrrolidone, etc.; tion step of the present invention is represented by the a urea such as N,N'-dimethylimidazolidinone, etc.; a sulfox above-mentioned formula (5). In the formula (5), X is a ide such as dimethyl Sulfoxide, Sulfolane, etc.; a nitrile Such halogen atom Such as a fluorine atom, chlorine atom, bro as acetonitrile, propionitrile, etc.; an alcohol Such as metha mine atom, iodine atom, etc. nol, ethanol, n-butyl alcohol, isopropyl alcohol, n-butyl As the specific examples of the bis(2-halogenoethyl)ether 30 alcohol, t-butyl alcohol, etc.; an ether Such as diisopropy represented by the formula (5) to be used in the cyclization lether, dioxane, cyclopropylmethylether, etc.; an aromatic step of the present invention, there may be mentioned hydrocarbon such as benzene, toluene, xylene, etc.; a ketone bis(2-fluoroethyl)ether, bis(2-chloroethyl)ether, bis(2-bro Such as acetone, methyl ethyl ketone, methyl isobutyl moethyl)ether, bis(2-iodoethyl)ether, etc. ketone, etc., preferably an amide or a sulfoxide is used. 35 Incidentally, these organic solvents may be used alone or in The 2-substituted acetic acid ester to be used in the combination of two or more in admixture. cyclization step of the present invention is shown by the An amount of the above-mentioned organic solvent to be above-mentioned formula (6). In the formula (6), R repre used may be optionally adjusted depending on a degree of sents the above-mentioned groups, and R represents a uniformity or condition of stirring of the reaction mixture, hydrocarbon group. As the above-mentioned hydrocarbon 40 and is preferably 1 to 50 g, more preferably 2 to 20 g based group, there may be mentioned, for example, a linear or on 1 g of the bis(2-halogenoethyl)ether. branched alkyl group having 1 to 6 carbon atoms such as a The cyclization step of the present invention can be methyl group, an ethyl group, a propyl group, a butyl group, carried out by a method in which, for example, the bis(2- a pentyl group, a hexyl group, etc.; a cycloalkyl group halogenoethyl)ether, the 2-substituted acetic acid ester, a having 3 to 10 carbon atoms such as a cyclopropyl group, a 45 base and an organic solvent are mixed, and stirred, etc. A cyclobutyl group, a cyclopentyl group, a cyclohexyl group, reaction temperature at that time is preferably 20 to 150° C. etc.; an aralkyl group in which a linear or branched alkyl more preferably 50 to 130°C., and a reaction pressure is not group having 1 to 3 carbon atoms is bonded to an aryl group, specifically limited. Such as a benzyl group, a phenethyl group, a phenylpropyl According to the cyclization step of the present invention, group, etc.; an aryl group having 6 to 20 carbon atoms Such 50 a solution containing a mixture of the 4-substituted tetrahy as a phenyl group, a tolyl group, a xylyl group, a mesityl dropyran-4-carboxylic acid ester represented by the formula group, a naphthyl group, etc., preferably an alkyl group, (7) and the 4-substituted tetrahydropyran-4-carboxylic acid more preferably a methyl group or an ethyl group. Inciden represented by the formula (3) can be obtained, and in the tally, these groups also contain various kinds of isomers. present invention, the next step is usually carried out by As the specific examples of the 2-substituted acetic acid 55 using the Solution as Such or after concentration thereof. ester represented by the formula (6) to be used in the However, if necessary, the formed 4-substituted tetrahydro cyclization step of the present invention, there may be pyran-4-carboxylic acid ester and the 4-substituted tetrahy mentioned methyl cyanoacetate, ethyl cyanoacetate, n-pro dropyran-4-carboxylic acid may be once separated and pyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoac purified by the usual methods, for example, filtration, crys etate, isobutyl cyanoacetate, tert-butyl cyanoacetate, cyclo 60 tallization, recrystallization, distillation, column chromatog propyl cyanoacetate, cyclobutyl cyanoacetate, cyclopentyl raphy, etc., and then, the next step may be carried out. cyanoacetate, cyclohexyl cyanoacetate, benzyl cyanoac Specific examples of the 4-substituted tetrahydropyran etate, phenyl cyanoacetate, dimethyl malonate, diethyl mal 4-carboxylic acid ester represented by the formula (7) onate, di-n-propyl malonate, diisopropyl malonate, di-n- obtained by the cyclization step of the present invention may butyl malonate, diisobutyl malonate, di-tert-butyl malonate, 65 be mentioned methyl 4-cyanotetrahydropyran-4-carboxy dicyclopropyl malonate, dibenzyl malonate, diphenyl mal late, ethyl 4-cyanotetrahydropyran-4-carboxylate, n-propyl Onate, etc. 4-cyanotetrahydropyran-4-carboxylate, isopropyl 4-cyan US 7,300,953 B2 11 12 otetrahydropyran-4-carboxylate, n-butyl 4-cyanotetrahydro may be used, for example, preferably an alcohol or a mixed pyran-4-carboxylate, isobutyl 4-cyanotetrahydropyran-4- solvent of water and an alcohol. carboxylate, tert-butyl 4-cyanotetrahydropyran-4- An amount of the above-mentioned water to be used is carboxylate, cyclopropyl 4-cyanotetrahydropyran-4- preferably 0.01 to 20 g, more preferably 0.1 to 10 g based carboxylate, benzyl 4-cyanotetrahydropyran-4-carboxylate, on 1 g of the mixture of the 4-substituted tetrahydropyran phenyl 4-cyanotetrahydropyran-4-carboxylate, dimethyl tet 4-carboxylic acid ester and the 4-substituted tetrahydropy rahydropyran-4.4-dicarboxylate, diethyl tetrahydropyran-4, ran-4-carboxylic acid. 4-dicarboxylate, di-n-propyl tetrahydropyran-4,4-dicar As the above-mentioned alcohol, there may be mentioned, boxylate, diisopropyl tetrahydropyran-4.4-dicarboxylate, for example, methanol, ethanol, n-propyl alcohol, isopropyl di-n-butyl tetrahydropyran-4,4-dicarboxylate, diisobutyl tet 10 alcohol, n-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, rahydropyran-4.4-dicarboxylate, di-tert-butyl tetrahydropy pentyl alcohol, methoxyethanol, ethoxy-ethanol, ethylene ran-4.4-dicarboxylate, dicyclopropyl tetrahydropyran-4.4- glycol, triethylene glycol, etc., preferably methanol, ethanol, dicarboxylate, dibenzyl tetrahydropyran-4.4-dicarboxylate, n-propyl alcohol, isopropyl alcohol, more preferably metha diphenyltetrahydropyran-4,4-dicarboxylate, etc. Also, spe nol, ethanol or isopropyl alcohol is used. Incidentally, these cific examples of the 4-Substituted tetrahydropyran-4-car 15 alcohols may be used alone or in combination of two or boxylic acid represented by the formula (3) may include more in admixture, and may contain water. those as mentioned above. An amount of the above-mentioned alcohol to be used is (B) Hydrolysis Step preferably 0.01 to 20 g, more preferably 0.1 to 10 g based The hydrolysis step of the present invention is a step of on 1 g of the mixture of the 4-substituted tetrahydropyran preparing a 4-substituted tetrahydropyran-4-carboxylic acid 4-carboxylic acid ester and the 4-substituted tetrahydropy represented by the formula (3) by subjecting a mixture of the ran-4-carboxylic acid. 4-substituted tetrahydropyran-4-carboxylic acid ester repre The hydrolysis step of the present invention can be carried sented by the formula (7) and the 4-substituted tetrahydro out by a method in which, for example, a mixture of the pyran-4-carboxylic acid represented by the formula (3) to 4-substituted tetrahydropyran-4-carboxylic acid ester and hydrolysis. 25 the 4-Substituted tetrahydropyran-4-carboxylic acid, an acid or a base, and a water-soluble solvent are mixed, and stirred, The hydrolysis step of the present invention is not spe etc. A reaction temperature at that time is preferably -30 to cifically limited so long as it is a method which can 80° C., more preferably -10 to 40° C., and a reaction hydrolyze a carboxylic acid ester, and preferably carried out pressure is not specifically limited. in the presence of an acid or a base, water, water-soluble 30 solvent or in a mixed solvent of water and a water-soluble According to the hydrolysis step of the present invention, solvent. the 4-substituted tetrahydropyran-4-carboxylic acid can be obtained, and in the present invention, the next step may be As the acid to be used in the hydrolysis step of the present carried out by once carrying out separation and purification invention, there may be mentioned, for example, a mineral after completion of the reaction by a usual method, for acid such as hydrochloric acid, hydrobromic acid, 35 example, filtration, concentration, crystallization, recrystal hydroiodic acid, Sulfuric acid, chlorosulfuric acid, nitric lization, distillation, column chromatography, etc., but the acid, etc.; an organic sulfonic acid Such as methanesulfonic resulting material may be used as such in the next step acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene without carrying out isolation and purification, or may be Sulfonic acid, etc.; a halogenated carboxylic acid Such as used after replacing the solvent to a solvent to be used in the chloroacetic acid, dichloroacetic acid, etc., preferably a 40 mineral acid, an organic Sulfonic acid, more preferably a next step. mineral acid is used. Incidentally, these acids may be used (C) Decarboxylation Step alone or in combination of two or more in admixture. The decarboxylation step of the present invention is a step An amount of the above-mentioned acid to be used is of preparing the 4-substituted tetrahydropyran represented preferably 0.01 to 10 mols, more preferably 2.0 to 5.0 mols 45 by the formula (4) by subjecting the 4-substituted tetrahy based on 1 mol of the mixture of the 4-substituted tetrahy dropyran-4-carboxylic acid represented by the formula (3) to dropyran-4-carboxylic acid ester and the 4-substituted tet decarboxylation in the presence of a metal catalyst, and it rahydropyran-4-carboxylic acid. may be carried out by the same method as in the decarboxy As the base to be used in the hydrolysis step of the present lation of the above-mentioned first and the second embodi invention, there may be mentioned, for example, an alkali 50 ments. Specific examples of the 4-substituted tetrahydropy metal hydroxide Such as sodium hydroxide, potassium ran-4-carboxylic acid represented by the formula (4) may hydroxide, etc.; an alkali metal carbonate such as sodium include those as mentioned above. carbonate, potassium carbonate, etc.; an alkali metal hydro Next, the preparation method of the 4-aminomethyltet gen carbonate such as sodium hydrogen carbonate, potas rahydropyran and an acid salt thereof represented by the sium hydrogen carbonate, etc.; an alkali metal alkoxide Such 55 formula (9) in the fourth embodiment of the present inven as sodium methoxide, potassium methoxide, etc., preferably tion is explained. The preparation process of the 4-aminom an alkali metal hydroxide, an alkali metal carbonate, more ethyltetrahydropyran and an acid salt thereof is a reduction preferably an alkali metal hydroxide is used. Incidentally, of 4-cyanotetrahydropyran represented by the formula (8) in these bases may be used alone or in combination of two or which R is a cyano group in the above-mentioned formula more in admixture. 60 (4) with hydrogen. An amount of the above-mentioned base to be used is The Raney nickel to be used in the reduction of the preferably 0.01 to 10 mols, more preferably 2.0 to 5.0 mols present invention is an alloy comprising nickel and alumi based on 1 mol of the mixture of the 4-substituted tetrahy num as main components, and that preferably with a nickel dropyran-4-carboxylic acid ester and the 4-substituted tet content of 10 to 90% by weight, more preferably 40 to 80% rahydropyran-4-carboxylic acid. 65 by weight is used. In general, developed Raney nickel is As the above-mentioned mixed solvent of the water used, and a pretreated Raney nickel or a stabilized Raney soluble solvent or water and the water-soluble solvent, there nickel, which had been Subjected to according to the various US 7,300,953 B2 13 14 methods, may be also used. Further, that in which a metal ethyltetrahydropyran, a free 4-aminomethyltetrahydropyran Such as cobalt, iron, lead, chromium, titanium, molybde can be prepared by removing carbon dioxide from a by num, Vanadium, manganese, tin, tungsten, etc. is/are con produced carbonic acid salt of the 4-aminomethyltetrahy tained in a Raney nickel may be also used. dropyran, and, contamination of ammonia in the 4-aminom An amount of the above-mentioned Raney nickel to be ethyltetrahydropyran can be prevented. used is preferably 0.01 to 1.0 g, more preferably 0.05 to 0.5 g in terms of a nickel atom based on 1 g of the 4-cyanotet EXAMPLES rahydropyran. A concentration of the ammonia in the solvent containing Next, the present invention will be explained in more ammonia to be used in the reaction of the present invention 10 detail by referring to Examples, but the scope of the present is preferably 0.1 to 50% by weight, more preferably 1 to invention is not limited by these examples. 35% by weight. As the solvent to be used in the reaction of the present Example 1 invention, it is not specifically limited so long as it does not inhibit the reaction, and there may be mentioned, for 15 Synthesis of Acetonitrile example, water, an alcohol Such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec In a flask made of glass equipped with a stirring device, butyl alcohol, t-butyl alcohol, etc.; an aromatic hydrocarbon a thermometer and a reflux condenser and having an inner Such as benzene, toluene, Xylene, mesitylene, etc.; a halo volume of 50 ml were charged 200 mg (1.40 mmol) of genated aliphatic hydrocarbon Such as chloroform, dichlo copper(I) oxide, 25 ml of dimethylsulfoxide and 5.0 g (55.8 roethane, etc.; an ether such as diethyl ether, tetrahydrofu mmol) of cyanoacetic acid with a purity of 95%, and under ran, diisopropylether, etc., preferably water, an alcohol, nitrogen atmosphere, the mixture was reacted at 110 to 120° more preferably water, methanol, ethanol or isopropyl alco C. for 30 minutes with stirring. After completion of the hol is used. Incidentally, these organic solvents may be used reaction, the reaction mixture was cooled to room tempera alone or in combination of two or more in admixture. 25 ture, and when the reaction mixture was analyzed by gas An amount of the above-mentioned solvent to be used chromatography (Internal standard method), 2.17 g (Reac may be optionally adjusted depending on a degree of uni tion yield: 95.0%) of acetonitrile was found to be formed. formity or condition of stirring of the reaction mixture, and is preferably 0.1 to 100 ml, more preferably 1.0 to 10 ml Example 2 based on 1 g of the 4-cyanotetrahydropyran. 30 An amount of the hydrogen to be usd in the reaction of the Synthesis of Acetonitrile present invention is preferably 0.1 to 20 mols, more pref erably 0.2 to 10 mols based on 1 mol of the 4-cyanotetrahy The reaction was carried out in the same manner as in dropyran. Example 1 except for changing the solvent to N,N-dimeth The reaction of the present invention can be carried out, 35 ylformamide in Example 1. As a result, 2.25 g (Reaction for example, by a method that a solvent containing 4-cyan yield: 98.3%) of acetonitrile was found to be formed. otetrahydropyran, Raney nickel and ammonia is mixed, and reacted with hydrogen under stirring, etc. A reaction tem Example 3 perature at this time is preferably 0 to 150° C., more preferably 5 to 120° C., particularly preferably 5 to 80°C., 40 Synthesis of Acetonitrile and a reaction pressure is preferably 0.1 to 10 MPa, more preferably 0.1 to 1 MPa. Incidentally, after completion of the The reaction was carried out in the same manner as in reaction, an appropriate acid is reacted with the 4-aminom Example 2 except for changing copper(I) oxide to 91 mg ethyltetrahydropyran to prepare an acid salt of the 4-ami (1.40 mmol) of Zinc powder and changing the reaction time nomethyltetrahydropyran. As the above-mentioned acid salt 45 to 3 hours in Example 2. As a result, 2.13 g (Reaction yield: to be used in the present invention, there may be mentioned 93.1%) of acetonitrile was found to be formed. a salt of an inorganic acid Such as hydrogen chloride, hydrogen bromide, hydrogen iodide, hydrogen fluoride, Example 4 Sulfuric acid, hydrogen nitrate, etc., a salt of an organic acid Such as formic acid, acetic acid, propionic acid, oxalic acid, 50 Synthesis of Acetonitrile Succinic acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, The reaction was carried out in the same manner as in benzenesulfonic acid, p-toluenesulfonic acid, p-chloroben Example 2 except for changing copper(I) oxide to 226 mg Zenesulfonic acid, p-bromobenzenesulfonic acid, phthalic (1.40 mmol) of iron(III) chloride and changing the reaction acid, isophthalic acid, benzoic acid, etc. 55 time to 5 hours in Example 2. As a result, 2.12 g (Reaction Incidentally, 4-aminomethyltetrahydropyran which is a yield: 92.7%) of acetonitrile was found to be formed. final product represented by the formula (9) and an acid salt thereof may be isolated and purified by, for example, after Example 5 completion of the reaction, a general method Such as filtra tion, concentration, distillation, recrystallization, colunm 60 Synthesis of Acetonitrile chromatography, etc. Also, after completion of the reaction, it is desired to carry out a post-treatment of the reaction The reaction was carried out in the same manner as in mixture by using an amine Such as triethylamine, tetraeth Example 2 except for changing copper(I) oxide to 125 mg ylenepentamine, pentaethylene hexamine, etc. By using (0.025 g was used based on 1 g of the cyanoacetic acid) of these amines, there are merits that, for example, Solidifica 65 Raney nickel, and changing the reaction time to 3 hours in tion of the liquid in a reactor due to aggregation of Raney Example 2. As a result, 2.06 g (Reaction yield: 89.8%) of nickel can be prevented during distillation of the 4-aminom acetonitrile was found to be formed. US 7,300,953 B2 15 16 Example 6 successively added in this order to the mixture under stir ring. After separating the aqueous layer and the organic layer Synthesis of Acetic Acid (the toluene layer), the aqueous layer was extracted three times with each 500 ml of toluene, then, the said organic In a flask made of glass equipped with a stirring device, 5 layer and these toluene extracts were combined and the a thermometer and a reflux condenser and having an inner mixture was concentrated under reduced pressure. The volume of SO ml were charged 170 mg (1.19 mmol) of obtained concentrate was distilled under reduced pressure copper(I) oxide, 25 ml of dimethylsulfoxide and 5.0 g (47.6 (100 to 120° C., 2.0 to 2.7 kPa) to give 133.5 g (Isolation mmol) of malonic acid with purity of 99%, under nitrogen yield: 93%) of 4-cyanotetrahydropyran with purity of 99% atmosphere, and the mixture was reacted at 110 to 120° C. 10 (areal percentage according to gas chromatography) as col for 1.5 hours under stirring. After completion of the reaction, orless liquid. the reaction mixture was cooled to room temperature, and Physical properties of the 4-cyanotetrahydropyran are as when the reaction mixture was analyzed by gas chromatog follows. raphy (Internal standard method), 2.86 g (Reaction yield: CI-MS (m/e); 112 (M+1) 100%) of acetic acid was found to be formed. 15 'H-NMR (CDC1, 8 (ppm)); 1.63 to 1.74 (2H, m), 1.80 to Example 7 1.89 (2H, m), 3.04 to 3.11 (1H, m), 3.43 to 3.50 (2H, m), 3.67 to 3.75 (2H, m) Synthesis of Acetic Acid Example 9 The reaction was carried out in the same manner as in Example 6 except for changing a solvent to N,N-dimethyl Synthesis of 4-cyanotetrahydropyran formamide in Example 6. As a result, 2.86 g (Reaction yield: 100%) of acetic acid was found to be formed. In a flask made of glass equipped with a stirring device, 25 a thermometer and a reflux condenser and having an inner Example 8 Volume of 30 ml were charged, under nitrogen atmosphere, 2.0 g (12.76 mmol) of 4-cyanotetrahydropyran-4-carboxylic Synthesis of 4-cyanotetrahydropyran acid with purity of 98%, 46 mg (0.319 mmol) of copper(I) oxide and 6.0 ml of N,N-dimethylformamide, and the mix In a flask made of glass equipped with a stirring device, 30 ture was reacted at 110 to 120° C. for 1 hour under stirring. a thermometer, a dropping funnel and a reflux condenser and After completion of the reaction, the reaction mixture was having an inner volume of 2 L were charged, under nitrogen cooled to room temperature and analyzed by gas chroma atmosphere, 4.6 g (31.9 mmol) of copper(I) oxide and 200 tography (Internal standard method), 1.41 g (Reaction yield: g of pyridine, and a temperature of the mixture was raised 100%) of 4-cyanotetrahydropyran was found to be formed. to 100° C. under stirring. Then, a solution of 200 g (1.28 35 mol) of the 4-cyanotetrahydropyran-4-carboxylic acid with Examples 10 to 38 purity of 99% dissolved in 400 g of pyridine was gradually added dropwise to the above mixture while a temperature of Synthesis of 4-cyanotetrahydropyran the reaction mixture is maintained to 100 to 110°C., and the mixture was reacted at 100 to 110° C. for 1 hour. After 40 In the same manner as in Example 9 except for changing completion of the reaction, the reaction mixture was cooled the catalyst, the solvent and/or the reaction time, the reaction to room temperature, and 500 ml of water, 650 ml (7.80 mol) was carried out as in Example 9. The results are shown in of conc. hydrochloric acid and 500 ml of toluene were Table 1.

TABLE 1. Reaction time Reaction yield Example Catalyst Solvent (h) (%) 10 Copper(I) oxide Triethylamine 98 11 Copper(I) oxide Tributylamine 98 12 Copper(I) oxide N-methylpyrrollidone 96 13 Copper(I) oxide N,N-dimethylacetamide 100 14 Copper(I) oxide N,N'-dimethylimidazolidinone 100 15 Copper(I) oxide Dimethyl sulfoxide 98 16 Copper(I) oxide 2-Picoline 98 17 Copper(I) oxide Quinoline 100 18 Copper(I) oxide n-Butyl alcohol 84 19 Copper(I) oxide Cyclopropyl methyl ether 92 2O Copper(I) oxide Toluene?triethylamine(=5/1) 99 21 Copper(I) oxide Toluene? N,N-dimethylformamide(=5/1) 98 22 Copper(I) oxide Toluene? N,N-dimethylacetamide(=5/l) 100 23 Copper(I) oxide Toluene? dimethyl sulfoxide(=5/1) 100 24 Copper(I) oxide Water N,N-dimethylformamide(=1/1) 93 25 Copper(I) oxide Ethyl acetate? N,N-dimethylformamide(=1/5) 100 26 Copper(I) oxide Ethyl acetate? N,N-dimethylacetamide(=1/5) 100 27 Copper(I) oxide Ethyl acetate? dimethyl sulfoxide(=1/5) 100 28 Copper(I) oxide Butyl acetate? N,N-dimethylformamide(=5/1) 100 29 Copper(I) oxide Butyl acetate? N,N-dimethylacetamide(=5/1) 100 30 Copper(I) oxide Butyl acetate? dimethyl sulfoxide(=3/2) 100 US 7,300,953 B2 17 18

TABLE 1-continued Reaction time Reaction yield Example Catalyst Solvent (h) (%) 31 Copper powder Pyridine 90 32 Copper powder N,N-dimethylformamide 95 33 Iron) N,N-dimethylformamide 97 34 Iron(III) chloride N,N-dimethylformamide 96 35 Nickel(II) acetylacetonate Pyridine 5 97 36 Raney nickel N,N-dimethylformamide 83 37 Zinc powder N,N-dimethylformamide 1OO 38 Zinc chloride N,N-dimethylformamide 1OO 0.1 mol was used based on 1 mol of 4-cyanotetrahydropyran-4-carboxylic acid. 0.025 g was used based on 1 g of 4-cyanotetrahydropyran-4-carboxylic acid. In the parentheses are a volume ratio of these solvents.

Example 39 bined and concentrated under reduced pressure to give 548 mg (Isolation yield: 73%) of tetrahydropyran-4-carboxylic Synthesis of Tetrahydropyran-4-carboxylic Acid acid with purity of 100% (analytical value by differential refractometry) as white crystals. In a flask made of glass equipped with a stirring device, a thermometer and a reflux condenser and having an inner Example 41 volume of 50 ml were charged 1.0 g (5.74 mmol) of tetrahydropyran-4,4-dicarboxylic acid with purity of 100%, Synthesis of 4-cyanotetrahydropyran 21 mg (0.14 mmol) of copper(I) oxide and 3.0 ml of pyridine under nitrogen atmosphere, and the mixture was reacted at In a flask made of glass equipped with a stirring device, 110 to 120° C. for 1 hour under stirring. After completion of a thermometer and a dropping funnel and having an inner the reaction, the reaction mixture was cooled to room Volume of 10 L were charged, under argon atmosphere, 4.72 temperature, 5 ml of water, 5 ml (60 mmol) of conc. L of N,N-dimethylformamide and 1486 g (27.5 mol) of hydrochloric acid and 10 ml of ethyl acetate were succes 30 Sodium methoxide, an inner temperature was cooled to 0° sively added in this order to the reaction mixture. The C., then 2753 g (27.5 mol) of cyanomethyl acetate with aqueous layer and the organic layer (the ethyl acetate layer) purity of 99% was gradually added dropwise to the above were separated, the aqueous layer was extracted three times mixture under stirring. After completion of the dropwise with each 10 ml of ethyl acetate, then, the organic layer and addition, the mixture was stirred at room temperature for 3 the ethyl acetate extracts were combined and the mixture 35 hours to prepare a solution containing a sodium salt of was concentrated under reduced pressure to give 534 mg cyanomethyl acetate. (Isolation yield: 72%) of tetrahydropyran-4-carboxylic acid In a flask made of glass equipped with a stirring device, with purity of 100% (analytical value by differential refrac a thermometer, a reflux condenser and a dropping funnel and tometry) as white crystals. having an inner volume of 20 L was charged 1589 g (11.0 40 mol) of bis(2-chloroethyl)ether with purity of 99%, and after Physical properties of the tetrahydropyran-4-carboxylic raising a temperature of the mixture to 64° C., the above acid are as follows. mentioned solution containing the Sodium salt of cyanom Melting point: 83 to 84° C. ethyl acetate was gradually added dropwise thereto. After CI-MS (m/e); 131 (M+1) completion of the dropwise addition, the mixture was sub 45 jected to cyclization under nitrogen atmosphere at 80°C. for H-NMR (DMSO-de, 6 (ppm)); 1.45 to 1.60 (2H, m), 1.68 9 hours. to 1.76 (2H, m), 2.40 to 2.52 (1H, m), 3.28 to 3.37 (2H, m), After completion of the reaction, the reaction mixture was 3.77 to 3.83 (2H, m), 12.19 (1H, brs) cooled to 0°C., and 1760 g (22.0 mol) of a 50% sodium hydroxide aqueous solution was gradually added dropwise Example 40 50 thereto. After completion of the dropwise addition, the mixture was Subjected to hydrolysis at room temperature for Synthesis of Tetrahydropyran-4-carboxylic Acid 1 hour. After completion of the reaction, the reaction mixture was cooled to 0° C., and 2.21 L (26.5 mol) of 35% In a flask made of glass equipped with a stirring device, hydrochloric acid was gradually added dropwise thereto. a thermometer and a reflux condenser and having an inner 55 After completion of the dropwise addition, the mixture was Volume of 50 ml were charged, under nitrogen atmosphere, stirred at room temperature for 30 minutes. 1.0 g (5.74 mmol) of tetrahydropyran-4,4-dicarboxylic acid, Then, 4.72 Loftoluene was added to the reaction mixture, 32 mg (0.57 mmol) of iron and 3.0 ml of pyridine, and the the mixture was azeotropically dehydrated at 50° C. under mixture was reacted at 110 to 120° C. for 1 hour under reduced pressure (4.67 kPa). Thereafter, toluene was added stirring. After completion of the reaction, the reaction mix 60 so that an amount of the toluene remained in the reaction ture was cooled to room temperature, and 5 ml of water, 5 mixture was made 4.72 L, and then, the mixture was heated ml (60 mmol) of conc. hydrochloric acid and 10 ml of ethyl to 50° C. and filtered. The filtrated material was washed with acetate were successively added in this order to the reaction 3.15 L of toluene, and the washed solution was combined mixture. The aqueous layer and the organic layer (the ethyl with the filtrate to obtain an organic solution containing acetate layer) were separated, and the aqueous layer was 65 4-cyanotetrahydropyran-4-carboxylic acid. washed three times with each 10 ml of ethyl acetate. Then, In a flask made of glass equipped with a stirring device, the organic layer and the ethyl acetate extracts were com Dean-Stark device, a thermometer and a dropping funnel US 7,300,953 B2 19 20 and having an inner Volume of 20 L were charged the methyl isobutyl ketone, and the mixture was filtered to give organic Solution containing the above-mentioned 4-cyan crystals of tetrahydropyran-4,4-dicarboxylic acid. otetrahydropyran-4-carboxylic acid, 1.57 L of toluene and In a flask made of glass equipped with a stirring device, 39.5 g (275 mmol) of copper(I) oxide, and decarboxylation a thermometer and a dropping funnel and having an inner was carried out under argon atmosphere at 115° C. for 1.5 volume of 50 ml were charged the above-mentioned tet hours while removing low-boiling point compounds. rahydropyran-4.4-dicarboxylic acid, 17.6 ml of pyridine and After completion of the reaction, the reaction mixture was 123.1 mg (0.86 mmol) of copper(I) oxide, and the mixture cooled to room temperature, and filtered, and the filtrated was Subjected to decarboxylation under nitrogen atmosphere material was washed with 1.57 L of toluene. Also, to the at 110 to 120 C. for 1 hour. After completion of the reaction, filtrate were added 1.57 L of water and 64 ml of 35% 10 the mixture was cooled to room temperature, 30 ml of water, hydrochloric acid to make a pH of the reaction mixture 1.8, 30 ml (360 mmol) of conc. hydrochloric acid and 60 ml of then, the aqueous layer was separated and extracted with ethyl acetate were successively added in this order, and the 3.15 L of toluene. The above-mentioned filtrate and the aqueous layer and the organic layer were separated. After the extract were combined, and concentrated at 60° C. under aqueous layer was washed three times with each 60 ml of reduced pressure (10.67 kPa). To the concentrate was added 15 2650 ml of ethyl acetate, the mixture was washed with 660 ethyl acetate, these extracts and the organic layer were ml of a Saturated Sodium chloride aqueous solution, and the combined and concentrated under reduced pressure to give organic layer was concentrated. The concentrate was dis 3.15 g (Isolation yield: 24.2%) of tetrahydropyran-4-car tilled under reduced pressure (120° C., 1.33 kPa) to give boxylic acid with purity of 100% (analytical value by 529.3 g (Isolation yield: 42.9%) of 4-cyanotetrahydropyran differential refractometry) as white crystals. with purity of 99% (areal percentage according to gas chromatography). Example 43 Example 42 Synthesis of 4-aminomethyltetrahydropyran 25 Synthesis of Tetrahydropyran-4-carboxylic Acid In an autoclave made of stainless equipped with a stirring device, a thermometer and a pressure gauge and having an In a flask made of glass equipped with a stirring device, inner volume of 200 ml were charged 10.0 g (90.0 mmol) of a thermometer and a dropping funnel and having an inner 4-cyanotetrahydropyran, 50.0 g of 22% by weight ammonia Volume of 200 ml were charged, under nitrogen atmosphere, 30 methanol solution and 2.0 g (17.0 mmol in terms of a nickel 115.6 ml of N,N-dimethylformamide and 13.51 g (0.25 mol) atom) of developed Raney nickel (available from Nikki of sodium methoxide, an inner temperature was cooled to 5° Chemical Co., Ltd.; sponge nickel N154D), and the mixture C., then 33.02 g (0.25 mol) of dimethyl malonate was was reacted under hydrogen atmosphere (0.51 to 0.61 MPa) gradually added dropwise thereto under stirring. After at 45 to 55° C. for 17 hours under stirring. After completion completion of the dropwise addition, the mixture was stirred 35 of the reaction, insoluble materials were filtered, and the at room temperature for 3 hours to prepare a solution filtrated material was washed with 30 ml of methanol. The containing a sodium salt of dimethyl malonate. filtrate and the washed solution were combined and concen In a flask made of glass equipped with a stirring device, trated under reduced pressure, and then, the concentrate was a thermometer, a reflux condenser and a dropping funnel and distilled under reduced pressure (73 to 74° C., 2.67 kPa) to having an inner volume of 200 ml was charged 14.45 g (0.10 40 tive 7.94 g (Isolation yield; 76.6%) of 4-aminomethyltet mol) of bis(2-chloroethyl)ether with purity of 99%, and after rahydropyran as colorless liquid. raising a temperature of the mixture to 80°C., the above Physical properties of the 4-aminomethyltetrahydropyran mentioned solution containing the Sodium salt of dimethyl are as follows. malonate was gradually added dropwise thereto. After H-NMR (DMSO-de, 6 (ppm)); 1.02 to 1.16 (2H, m), 1.10 completion of the dropwise addition, the mixture was sub 45 to 1.50 (2H, brs), 1.34 to 1.45 (1H, m), 1.56 to 1.61 (2H, m), jected to cyclization under nitrogen atmosphere at 85°C. for 2.39 (2H, d, J=6.3 Hz), 3.20 to 3.29 (2H, m), 3.81 to 3.86 20 hours. (2H, m) After completion of the reaction, the reaction mixture was filtered, and the filtrated material was washed with 30 ml of CI-MS (m/e); 116 (M+1), 99 N,N-dimethylformamide. The filtrate and the washed solu 50 tion were combined, the temperature of the mixture was Example 44 cooled to 5° C., and 36.0 g (0.45 mol) of a 50% sodium hydroxide aqueous solution was gradually added dropwise Synthesis of 4-aminomethyltetrahydropyran thereto. After completion of the dropwise addition, 52 ml of Hydrochloride water was added to the mixture, and the resulting mixture 55 was subjected to hydrolysis at room temperature for 3 hours. In an autoclave made of stainless equipped with a stirring After completion of the reaction, the reaction mixture was device, a thermometer and a pressure gauge and having an cooled to 5°C., 44 ml (0.45 mol) of 35% hydrochloric acid inner volume of 25 L were charged 1685.8 g (containing was gradually added dropwise thereto. After completion of 15.2 mol of 4-cyanotetrahydropyran) of 65.9% by weight the dropwise addition, the mixture was stirred at room 60 4-cyanotetrahydropyran-toluene solution, 8.8 kg of 5.86% temperature for 30 minutes, and then, the reaction mixture by weight ammonia-methanol solution, 337.2 g (2.86 mmol was concentrated under reduced pressure. To the concentrate in terms of a nickel atom) of developed Raney nickel were added 200 ml of ethyl acetate and 100 ml of water and (available from Nikki Chemical Co., Ltd.; sponge nickel the resulting mixture was separated, then, the obtained N154D) and 2.1 L of methanol, and the mixture was reacted organic layer was washed with 20 ml of a saturated aqueous 65 under hydrogen atmosphere (0.51 to 0.61 MPa) at 50 to 60° Sodium chloride Solution and concentrated under reduced C. for 7 hours under stirring. After completion of the pressure. To the obtained concentrate was added 30 ml of reaction, insoluble materials were filtered, the filtrated mate US 7,300,953 B2 21 22 rial was washed with 2.0 L of methanol, and the filt-rate and 4-cyanotetrahydropyran, 100 ml of methanol and 2.0 g (17.0 the washed solution were combined and concentrated under mmol in terms of a nickel atom) of developed Raney nickel reduced pressure. (available from Nikki Chemical Co., Ltd.; sponge nickel To a reaction vessel made of glass equipped with a stirring N154D), and the mixture was reacted under hydrogen atmo device and a thermometer and having an inner Volume of 3 L were charged said concentrate and 833 ml of tetraethyl sphere (0.51 to 0.61 MPa) at 50 to 60° C. for 5 hours under enepentamine, the mixture was stirred at 105 to 115° C. for stirring. After completion of the reaction, insoluble materials 2 hours. After completion of the stirring, said solution was were filtered, the filtered material was washed with 30 ml of distilled under reduced pressure (70 to 80° C., 1.73 to 4.67 methanol, and the filtrate and the washed solution were kPa) to obtain 1430.2 g of the distilled solution containing 10 combined. When this solution was analyzed by gas chro 4-aminomethyltetrahydropyran. matography (Internal standard method), 7.19 g (Reaction To a reaction vessel made of glass equipped with a stirring yield: 52.7%) of the 4-aminomethyltetrahydropyran was device, a thermometer and a dropping funnel and having an found to be formed. Incidentally, 4.28 g of bis(4-tetrahy inner volume of 20 L were charged 8.3 L of n-butanol and dropyranylmethyl)amine which is a by-product was formed. 1232 ml (15.0 mol) of 37% by weight hydrochloric acid, and 15 in a salt-ice bath, said distulled solution was gradually added Utilizable Field in Industry dropwise to the mixture while maintaining a temperature of According to the present invention, an industrially Suit the mixture to 0°C. or therearound, and after completion of able process for preparing a nitrile compound or a carboxy dropwise addition, the mixture was stirred at room tempera ture for 30 minutes. An operation that the resulting solution lic acid compound or a 4-substituted tetrahydropyran can be was concentrated under reduced pressure, and 5.0 L of provided which can prepare a nitrile compound or a car n-butanol was added to the concentrate and further concen boxylic acid compound or a 4-substituted tetrahydropyran trated was repeated twice. Then, in a salt-ice bath, when the from an acetic acid compound or a 4-substituted tetrahy concentrate was stirred for 50 minutes, a solid was precipi dropyran-4-carboxylic acid with high yield under mild con tated and filtered. The filtered material was washed with 1.7 25 ditions with a simple and easy process. L of toluene, and then, it was dried under reduced pressure Also, according to the present invention, an industrially at 60° C. to give 1692.9 g (Isolation yield: 73.6%) of Suitable process for preparing a 4-substituted tetrahydropy 4-aminomethyltetrahydropyran hydrochloride as white crys ran which can prepare a 4-substituted tetrahydropyran with tals. high yield from a bis(2-halogenoethyl)ether and a 2-substi Physical properties of 4-aminomethyltetrahydropyran 30 hydrochloride are as follows. tuted acetic acid ester can be provided under mild conditions Melting point: 190 to 1939 C. with a simple and easy process. The nitrile compound or the carboxylic acid compound or H-NMR (DMSO-de, 6 (ppm)); 1.13 to 1.26 (2H, m), 1.63 the 4-substituted tetrahydropyran obtaind by the the present to 1.68 (2H, m), 1.78 to 1.92 (1H, m), 2.67 (2H, d. J–7.1 Hz), 35 invention is a useful compound as a starting material or a 3.22 to 3.30 (2H, m), 3.82 to 3.87 (2H, m), 8.21 (3H, brs) synthetic intermediate for medicine, agricultural chemicals, CI-MS (m/e); 116 (M+1-HCl), 99 etc. Moreover, according to the present invention, an indus Example 45 trially Suitable process for preparing a 4-aminomethyltet 40 rahydropyran and an acid salt thereof which can prepare a Synthesis of 4-aminomethyltetrahydropyran 4-aminomethyltetrahydropyran and an acid salt thereof from In an autoclave made of stainless equipped with a stirring a 4-cyanotetrahydropyran with high yield can be provided. device, a thermometer and a pressure gauge and having an The 4-aminomethyltetrahydropyran and an acid salt inner volume of 200 ml were charged 10.0 g (90.0 mmol) of 45 thereof obtained by the present invention is a useful com 4-cyanotetrahydropyran, 100 ml of 22% by weight ammonia pound as a starting material or a synthetic intermediate for methanol solution and 2.0 g (17.0 mmol in terms of a nickel medicine, agricultural chemicals, etc. atom) of developed Raney nickel (available from Nikki Chemical Co., Ltd.; sponge nickel N154D), and the mixture was reacted under hydrogen atmosphere (0.51 to 0.61 MPa) 50 The invention claimed is: at 50 to 60° C. for 5 hours under stirring. After completion of the reaction, insoluble materials were filtered, the filtered 1. A process for preparing a 4-substituted tetrahydropyran material was washed with 30 ml of methanol, and the filtrate represented by the formula (4): and the washed solution were combined. When this solution was analyzed by gas chromatography (Internal standard 55 method), 8.84 g (Reaction yield: 85.3%) of 4-aminometh (4) yltetrahydropyran was found to be formed. Incidentally, bis(4-tetrahydropyranylmethyl)amine which is a by-product was not formed. 60 Comparative Example 1 Synthesis of 4-aminomethyltetrahydropyran wherein R represents a cyano group, a carboxyl group or In an autoclave made of stainless equipped with a stirring 65 an ester group, device, a thermometer and a pressure gauge and having an which comprises subjecting a 4-substituted tetrahydropyran inner volume of 200 ml were charged 10.0 g (90.0 mmol) of 4-carboxylic acid represented by the formula (3): US 7,300,953 B2 23 24 3. The process for preparing a 4-substituted tetrahydro pyran according to claim 2, wherein the decarboxylation is (3) R COOH carried out in a solvent. 4. The process for preparing a 4-substituted tetrahydro pyran according to claim 3, wherein the solvent is a tertiary amine, a pyridine, an amide, a Sulfoxide, or a mixed solvent O of any one of the above solvents and an aromatic hydrocar bon or an acetic acid ester. wherein R has the same meaning as defined above, 10 5. The process for preparing a 4-substituted tetrahydro to decarboxylation in the presence of a metal catalyst. pyran according to claim 1, wherein a temperature of the 2. The process for preparing a 4-substituted tetrahydro decarboxylation is 50 to 150° C. pyran according to claim 1, wherein the metal catalyst is a catalyst containing at least one metal selected from the group consisting of copper, iron, nickel and zinc.