SPECIFICATION
PROCESS F''OH PRODUCING 3-AMINOMETHYLTETRAHYDROFURAN
DERIVATIVE
TECHNICAL FIELD
The present invention relates to a process for producing a 3-ain inometfiyltet rahydrof uran derivative. More specifically, the invention relates to a process for producing a 3-aminomethyltetrahydrofuran derivative reducing a 3-cy a n o t e t r a hydrofuran derivative. The
3-aminomethyLtetrahydrofuran derivative is useful as an intermediate for medicines, agrochemicals, etc.
BACKGROUND ART
A (tetrahydro-3-furanyl)methylamine derivative having a structure represented by the following formula (1) exhibits an extremely high insecticidal activity, and further has low toxicity and an extremely excellent performance as an active ingredient of agrochemicals (see Patent Document 1) . However, a process fo.r producing a 3-aminomethyltetrahydrofuran derivative as raw materials thereof is little known and only the following two methods are known. This is on the ground that the synthesis of a tetrahydrofuran compound having a
subst. i tuer: t: ,-i t the 3-posit ion is extremely difficult, while
a tetrahydroturan compound having a substituent at the
''-''.. -p o s i 1. i o n c a n b e eas i 1. y d e r i v e d from the substitution r e a c t .i o n

(Figure Remove)
i 0 0 0 4 ]
wherein R10, R''1 and RJi represent a hydrogen atom or a lower a i kyi group.
As one process for producing a
3-ami nomethy.l t. et rahydrof uran derivative, a method which inc1u des carrying out a reductive a m i n a t i o n using tetrahydrofuran -3-carboxyaIdehyde as a raw material in an aqueous ammonia solution in the presence of hydrogen, is known (see Patent Document 2). However, this method cannot be said to be an industrially sufficiently advantageous method in that extremely expensive raw materials has to be used, for example, expensive 2-butene-l,4-diol has to be subjected to cyclization and then furtner hydroformylation using an expensive rhodium catalyst in order to obtain tetrahydrofuran-3-carboxyaldehyde b e i n g t; h e r a w m a t: e r i a 1 .
[0005]
Further, as another method, for example, Patent Document 1 discloses a met-hod in which 3 - (tetrahydrof uryl) methylha li de
or 3 - (t e t. r ah vdro f u r;y 1 ) methylsu 1 f ona t e is derived from 3-h yd roxymet 1. y 1 tet rahydrof uran as raw materials and is reacted with potassium phthalimide to carry out hydrolysis or hyd r a z i no.l ys i s. However, this method is also not industrially advantageous in that 2-hydroxyraethyl-1,4-butanediol being raw materials of i-hydroxymethyltetrahydrofuran is expensive, by-products derived from phthalimide are formed in large q 11 a n t i t: i e s and the highly hazardous h y d r a z i n e is used.
[ 0 0 0 6 ]
Fur t-he j more , for a hydrogenat ion method of a 3-cyanotetrahydrofuran derivative, there are not many synthesis examples of effectively obtaining a 3-cyanotetrahydrofuran derivative and thus examples of a process for producing a 3-aminomethyltetrahydrofuran derivative using it as raw materials are not known. A method of obtaining amines by reducing a cyano group is generally known, but the preferred method thereof is largely varied depending on a substrate. For the reduction reaction of a cyano compound h a v i. n g a t e t r a h y d r o f u r a n ring, a 3-cyanotetrahydrofuran derivative and a 2-cyariotetrahydrofuran derivative as its isomer are not completely known and thus the preferred method thereof is a.l.so not completely known.
[ 0 0 0 7 j
Furthe.r, as a process for producing a
3-cyanotetrahydrofuran derivative, only two examples consisting ol a method of ultraviolet irradiation of tetrahydrofuran and chlorocyan in the presence of sodium
bicarbonate ''.see Patent Document 3) and a method of reacting
e thyIe n e ox i < i e a n d acrylonitrile in the presence of a catalyst
(see Patent Document. 4) are known. The former is low in both
yield and selectivity and the latter is high in selectivity
but" no description is given or the yield, and therefore, any
process cannot: be said to be effective as a process for
prod u ci n q a 3 - cyanotetrahydrofuran derivative. A process for
producing a ''3-cyanotetrahydrofuran derivative from a
''3-iia 1 ogenated or 3-al kylsulf onated or 3-arylsulfonated
tet. rahydrofuran derivative, which is a process according to
the present invention, is riot known.
[ 0008]
Furthermore, a p r o c e s s for producing a 3-ha 1o g e n a t e d or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative from a 3-hydroxytetrahydrofuran derivative, which is a process according to the present invention, is also not k n o w n .
(Patent Document 1] Japanese Patent Application Laid-Open (Jp-A) No. 7-179448
[Patent Document 2] JP-A No. 9-110848 Patent Document 3] German Patent No. 1234227 Patent Document 4] JP-A No. 2000-264884
DISCLOSURE OF-1 THE INVENTION [ 0 0 0 9 ]
Accordingly, an industrially sufficiently advantageous process for producing a 3-aminomethyltetrahydrofuran
do i i \/a t: 1 ve has not. been yet found and thus a process for effectively producing the derivative from inexpensive raw materials has been eagerly desired. An object of the present fivent ion is t.o provide a process for producing a }> - a m i n o m e t h y i tetrahydrofuran derivative with high efficiency Lrorn inexpensive industrial materials. | 0 0 1 0 ]
The present inventors have intensively investigated in order, t.o achieve the above object, and as a result, they have found a process for producing a 3-aminomethyltetrahydrofuran derivative by reducing the cyano group of a
3-cyano te t; rahydrof u ran derivative and further a process for producing a i-cyanotet rahydrof uran derivative in a high yield from an inexpensive and industrially easily available malic a c id derivative, a n d t h u s have c omp leted the present invention.
That, is, a first aspect of the present invention provides a process for producing a 3-aminomethyltetrahydrofuran (derivative represented by the formula (2) : (Figure Remove)

wherein R!, P.'' , RJ, R4, R5, R5 and R7 may be the same or different from each other and each represent a hydrogen atom or a
hydroca r:bon a roup having 1 to 4 carbon atoms,
which includes reducing the cyano group of a
V-oyanotetrahydrofuran derivative represented by the formulawhere.! n R1, R"'', P3, R4, R5, R6 and R7 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon crroup having 1 to 4 carbon atoms.
| 0 0 1 6 ]
A second aspect of the present invention provides a process for producing a 3-cyanotetrahydrofuran derivative represented by the formula (1), which includes reacting a 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative represented by the formula (3):
[ 0 0 i 7 ](Figure Remove) R2 R3
X
(3)
wherein RJ , R , RJ, R4, R5, R6 and R7 may be the same or different from each other and each represent a hydrogen atom or a
hydrocarbon group having 1 to 4 carbon atoms; and X represents d halogen atom or an alkylsulfonate group having 1 to 6 carbon atoms or ary1su1fonate group having 6 to 12 carbon atoms, rind an organic or inorganic cyano compound.
[ 0 0 ] 9 ]
A third aspect of the p r e s e n t invention provides a pro c e s s Jo- producing a 3-aminomethyltetrahydrofuran derivative by the process according to the first aspect of the present invent ion, which includes using the 3-cyanotetrahydrofuran derivative obtained by the process according to the second aspect: of the present invention.
[ 0 0 2 0 ]
A fourth aspect of the present invention provides a process for producing a 3-aminomethyItetrahydrofuran derivative by the process according to the third aspect of the present: invention, which includes using a 3-halogenated or 3-a1kylsu1fon ated or 3-arylsulfonated tetrahydrofuran derivative represented by the formula (3a):
| 0 0 2 1 ]
.o.
(3a)

R

R

3

X

[0022]
which produces from a malic acid derivative by three steps [0023] According to the present invention, the

:> -am inomet h y - t. e t r ahyd r of uran derivative can be industrially a d v a n t. a g e o u :-; ! y produced from inexpensive raw ma t e r i a 1 s ( : o in p a r e d t: o <; : o n ventional processes.
BEST MODE FOH CARRYING OUT THE INVENTION
Her e ina r t:. e r , a process for producing a
3 -aminome t hy 1 t e t r a hydrof uran derivative according to the present: invention is specifically explained.
[002 5]
The 3-cyanotetrahydrofuran derivative according to the process of the invention is represented by the formula (1).
I 0 0 2 6 1

R
R'' R

d)

wherein all of R1, FT, R3, R4, R5, R6 and R7 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms. More specific examples of the hydrocarbon group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a 2-butyl group, an isobutyl group and t-butyl group. Specific examples of the 3 - c y a n o t e t. r a \ i y d r o f u r a n derivative include 3-cyanotet rahydrof uran substituted with a hydrocarbon group,

s \ i c h r a s 4 - e t. 11 y.] - i - c y a n o t e t r a h y d r o f u r a n a n d 5 - ir. e t. h y I - 3 - < v'' a n o t. e t: r a h y d r o f u r a n, including 3 -- c y a n o 1: e t r a h y d r o f u r a n .
[0028]
The process for producing a 3-cyanotetrahydrofuran derivative used in the present invention is not limited, but the 3-oyanotetrahydrofurari derivative can be more suitably p i: o d u c e d b y <-:i p r o cess of c y a nation of a 3-halogenated or 3 -a 1 ky I .su 1 f on a t: ed or 3-aryl sulf onated tetrahydrof uran aer 1 vat ive.
[0029]
In the |lesent invention, the
3-aminome thy i t: e t rahydrof uran derivative represented by the formula (2) is produced by reducing the cyano group of the 3--cyanotetrahydrofuran derivative represented by the formula
wherein RJ , R'', R3, R", R'', Rb, R'' are as defined for R1, R2, R3, R''1, Rl;>, Rfl, R in the formula (1).
Specif .ic examples of the 3-aminomethyltet rahydrof uran derivative include a 3-cyanotetrahydrofuran substituted with a hydrocarbon group, such as 4 - e t h y .1 - ''i - a m i. n ome thy 11 e t r a h y d r o f u r a n and
3 -me ihy 1- 3-am i nome t hy .1 te t rahydrof uran , including
i-am inomet hy .1 t.et nahydrof uran . Since the
i - a m 1 n o m e t h y 1 t e t r a h y d r o f u r a ri derivative obtained in t h e process of I he present invention corresponds to the
3 -eyanote t.:rahyd cof u ran derivative used, R1, R'', R3, R4, Rb, Rb and R'' of each substituent in the 3-cyanotetrahydrofuran derivative used, R1, R/, R!, R4, R5, R6 and R'''' of each substituent
in the 3-aminomethyltetrahydrofuran derivative obtained are the same. For example, 3-aminomethyltetrahydrofuran is obtained when 3-cyanotetrahydrofuran is used and 3-me thy 1-3-aminomethy. tetrahydrofuran is obtained when
i -nieth yl- 3-cyanotet rahydrof uran is used . [ 0 0 3 2 ]
Examples of the method of reducing the cyano group of the 3-cyanotetrahydrofuran derivative in the present invention include a method of reducing with a metal hydride and a method of reducing with hydrogen in the presence of a hydrogenation e a t a 1 y s t.
| 0 0 3 3 J
The specific examples of zhe metal hydride when reducing with the metal hydride include an aluminum hydride compound such as lithium aluminum hydride, lithium trimethoxyaluminum hydride, aluminum hydride and diisobutylaluminum hydride, and a boron hydri.de compound such as diborane, lithium borohydride and sodium borohydride. The amount used of the metal hydride when reducinq by the metal hydride is usually in the range of
''/. to 10 mo Ic.-;.;, preferably 3 to 6 moles per mole of a " ''< - c y a n o t e t: r a \ •. y d r o f u ran derivative.
! 0 0 3 4 }
The hyd i. ogenat i on catalyst when reducing with hydrogen .111 the presence of the hydrogenation catalyst may be any compound as long as it catalyzes the reaction in which the cyano g r o u p of the- 3 - c y a n o t e t r a h y d r o f u r a n derivative according to the present, invention is reduced to an aminomethyl group by a molecular hydrogen, but usually at least one metal selected from Groups 7 to 13 of the Periodic Table of the Elements or a metal compound thereof is suitably used. More specifically, it: includes a metal such as manganese, rhenium, iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, gold, zinc and aluminum or metal compounds thereof. These metal or metal compounds may be or may not be dissolved in a reaction liquid. Specific examples of these hydrogenation catalysts include an elemental metal such as rhodium metal powders and palladium metal powders, a Raney metal compound such as Raney nickel, Raney copper and Raney cobalt, a stabi1ized metal compound such as stabilized nickel, a metal-supported catalyst in which a metal such as rhenium, ruthenium, rhodium, palladium is supported on the inorganic support such as carbon black, act ivated carbon, alumina, silica gel, diatom earth, zeolite and magnesia, a metal oxide such as ruthenium oxide, palladium oxide, rhenium oxide and copper oxide, a complex metal-oxide such as copper oxide-chromium oxide, copper oxide-zinc oxide-aluminum oxide, complex
compounds of ruela Is of Groups 8 to 10 of the Periodic Table of the Element.s, such as RuClH ( CO ) ( PPh3) 3, RuClo ( PPh3) ,, PdC 1 ;••( PPh i j ;;. These catalysts may be used alone or in combination of two or more thereof. The amount of the 11 yd r c) qe n at i o n cata 1y s t to be used is in the range of usually 0.1 ppm by weight to lO''t by weight, preferably 1 ppm by weight to 5-,'', by weight relative to the 3-cyanotetrahydrofuran derivative when the catalyst used is dissolved in the reaction Liquid, and is in the range of usually 0.1% by weight to 500% by weight, preferably 1% by weight to 200% by weight relative to the 3-cyanotetrahydrofuran derivative when the catalyst used is not dissolved in the reaction liquid.
[0035]
Of these reduction methods, the method of reducing with hydrogen in the presence of the hydrogenation catalyst is preferred. The hydrogenation catalyst is preferably a metal of Group 9 or 10 of the Periodic Table of the Elements or a metal compound thereof, more preferably a metal such as cobalt or nickel or a metal compound thereof, and most preferably a metal such as cobalt or a metal compound thereof.
[ 0 0 3 6 ]
The method of reducing the 3-cyanotetrahydrofuran derivative of the present invention may be carried out without a solvent., but: is usually carried out in the presence of the soivent. The suitable solvent to be used varies depending on the method of reducing the cyano group.
I 0 0 3 7
When it is reduced by the metal hydride, aliphatic or dMeye lie hydrocarbons having 5 to 20 carbon atoms, such as n-hexane, n-pentane or cyclohexane, aromatic hydrocarbons having 6 to /: 0 carbon atoms such as benzene, toluene ana e I: hy Iben zene, aliphatic or aromatic halides having 1 to 20 carbon atoms such as chloroform, chlorobenzene and d i ch Lo r obenzcMie , and ethers having 2 to 20 carbon atoms such d.s di ethyl el her, diphenyl ether, tetrahydrofuran and ethylene glycoJ dimethyl ether, are suitably used. Further, these solvents may be used in a mixture of two or more thereof. Of these solvents, ethers are particularly used.
[ 0 0 3 8 ]
As the solvent to be used when reducing with hydrogen in the presence of hydrogenat1 on catalyst, for example, water, alcohols havi ng 1 to 20 carbon atoms, such as methanol, ethanol, butanol, aliphatic or alicyclic hydrocarbons having 5 to 20 carbon atoms, such as n-hexane, n-pentane or cyclohexane, benzene, aromatic hydrocarbons having 6 to 20 carbon atoms, such as toluene and ethylbenzene, and ethers having 2 to 20 carbon atoms, such as diethyl ether, diphenyl ether, tetrahydrofuran and ethylene glycol dimethyl ether, are suitably used. Farther, these solvents may be used in a mixture of two or more thereof. Of these solvents, water, alcohols and ethers are preferably used, and water is more p r e f e r a b 1 y 11 s e; d .
[0039]
The amount of the solvent used is not uniform over reaction conditions, but. is in the range of usually 0.01 to 200 parts by weiqht, preferably 0.02 to 50 parts by weight, more preferably 0.05 to 2 parts by weight per part by weight of the 3 •- c y a n o t e t r a h ydrofuran derivative. 0 0 4 0 ]
In the method of reducing the 3-cyanotetrahydrofuran derivative ct the present invention, when reducing the cyano group by hydioqen Jn the presence of the hydrogenation catalyst, Ll is preferable to carry out the reduction reaction in the presence of ammonia. The term "ammonia" as used in the present invention refers to aqueous ammonia, liquid ammonia or ammonia gas, but ammonia is more preferably aqueous ammonia. The a in o u n t. o f a m m o n i a used is not particularly limited, but is in the range of usually 0.01 to 50 mo Is, preferably 0.1 to 20 mo Is, more preferably 0.3 to 5 moles relative to 1 mole of the 3-c y an o tetrahydrofuran derivative.
[0041]
The method of reducing the 3-cyanotetrahydrofuran derivative of the present invention is particularly preferably a method of reducing with hydrogen in the presence of ammonia and also in the presence of a metal of Group 9 or 10 of the Periodic Table of the Elements or a metal compound thereof, as a catalyst: . In this case, the catalyst is more preferably a metal of nickel or cobalt or a metal compound thereof and ammonia is more preferably aqueous ammonia. Further, when the reaction is carried out in the presence of aqueous ammonia,
"it. is prelerabi. y carried out in the presence of 0.05 to 2 parts by weight o1 aqueous ammonia relative to 1 part by weight of t h e 3 - (; y a n o t < t. r a h y d r o f u r a n derivative.
I 0 0/12:]
In t: rie method of reducing the 3-cyanotetrahydrof uran deiivative of the present invention, all of R1, R":, P.3, R4, R5, k'' a n d R'' a r e pr ef e r a b 1 y a hydrogen atom.
[ 0 0 4 3 ]
The temperature and time in the reaction are not uniform over the kinds of the 3-cyanotetrahydrofuran derivative and the reduction method. When reducing with a metal hydride, the i: e a c t. i o n t e in p e r a t u r e is in the range of usually - 1 0 to 15 0 ° C , preferably d to I20°C, more preferably 10 to 100°C. When reducing with hydrogen in the presence of the hydrogenation catalyst, the reaction temperature is in the range of usually 0 to 250°C, preferably 50 to 200°C, more preferably 80 to 150°C. The reaction time is in the range of usually not more than 100 ho u r s, p re f er a b1y 0.01 to 50 hours.
[ 0 0 4 4 ]
The pressure in the reaction may be any of reduced pressure, normal pressure or pressurization, but the preferable mode varies depending on the reduct ion method to be performed. When reducing with the metal hydride, it is preferably carried out at normal pressure. When reducing with hydrogen in the presence of the hydrogenation catalyst, it is preferably carried out under hydrogen pressurization. The hydrogen pressure in pressurization is in the range of usually 0.01 to
>") MPdG, prcierably 0.1 to 20 MPaG, more preferably 1 to 10 IMPaG .
The reaction process of reducing the cyano group is not particularly limited and may be performed in any one of batch, s emi ba tc h a n <: c o nt. i n u o u s flow modes.
When reducing with hydrogen in the presence of the hydrogenation catalyst, the catalyst used may be recovered by the conventional process for recovery of metals after completion of the reaction. E''or example, when the catalyst is dissolved in the reaction liquid, the catalyst can be recovered by contacting with a metal adsorbent such as an ion-exchange t:esin or by extracting with the solvent. When the catalyst is not dissolved in the reaction liquid, the catalyst can be recovered by a solid-liquid separation method such as filtration and centrifugal separation. These recovered catalysts can be repeatedly used as the hydrogenat ion catalyst. In that case, it may be reused after the catalyst deactivated or having reduced activity is subjected to a recycling operation or may be used by adding the fresh catalyst.
[ 0 0 4 7 ]
The 3-aminomethyltetrahydrofuran derivative formed by the method of reducing the 3-cyanotetrahydrofuran derivative of the present invention can be isolated according to the conventional separation method such as distillation.
[ 0 048]
Next., '', he process for producing the
.•i-cyanotetrahydrofu ran derivative of the present invention is explained in detail in the following. The
3 -cyano tet rahydrofu ran derivative represented by the formula (L) is prepared by reacting the 3-halogenated or --5 -a L ky 1 su 1 f onated or 3-arylsulf onated tetrahydrof uran de:t i va L ive it-presented by the formula (3) and an organic or i n o r g a n i o c yr i n o c o m p o u n d . [ 0049]

(3)

R

X

[ 0 0 b 0 ]
wherein R1, R'' , R\ R4, Rb, R6, R7 are as defined for R1, R2, R3, R.''1, R'''', R('', R'' in the formula (1); and X represents a halogen atom or an a.L Icy 1 sul f onate group having 1 to 6 carbon atoms or an arylsulfonate group having 6 to 12 carbon atoms.
Specific, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, specific examples of the alkylsulfonate group having 1 to 6 carbon atoms include a hydrocarbon alkylsulfonate group having 1 to 6 carbon atoms such as a methylsulfonate group, an et. hylsul f.ona L e group, and a halogen group-substituted a ! k y .1 sul f on a t e group having 1 to 6 carbon atoms such as a t r i f .1 u o r o m e t h y .1 s u 1 f o ri a t e group and a ], 1 , 1 -1: .ri fl IK- :r oet hylsul f onate group. Further, examples of
t:he a r y 1 su 1 f c>na te group having 6 to ''..2 carbon atoms include a hydrocarbon arylsu1fonate group having 6 to 12 carbon atoms .such as a benzenesul fonate group and a p-toluenesulf onate group and a halogen group-substituted arylsulfonate group having 6 TO 12 carbon at.cms such as a p-trifluoromethyl benzenesulfonate group. More? specific examples of the 3-halogenated or •: - a J k y 1 s u 1 f o n a t e d or 3 - a r y 1 s u 1 f o n a t e d t e t r a h y d r o f u r a n derivative include 3-halogenated tetrahydrofuran such as 3-chlorotetrahydrofuran and 3-bromotetrahydrofuran, a hyd rocarbon gr. o up-substituted 3-halogenated tetrahydrofuran such as 4-ethyl-3-chlorotetrahydrofuran and
3 -- m e t h y 1-3-io do tetrahydrofuran, 3 - a 1 k y 1 or a r y 1 s u 1 f o n a t e d t. e t. r a h y d r o f u r. a n s u c h as
3-(p-toluenesulfonato)-tetrahydrofuran,
3-1r ifluoromethanesulfonatotetrahydrofuran and a hydrocarbon group-substituted 3-alkyl or arylsulfonated tetrahydrofuran s 11 c h a s 4 - e t h yl-3-benzenesulforiatotetrahydrofuran.
[0051]
The process for producing the 3-halogenated or 3-alkyLsulfonated or 3-arylsulfonated tetrahydrofuran derivative used in the process of the present invention is not limited, but it can be suitably produced by using a malic acid derivative described below as a starting material.
[0052]
The organic or inorganic cyano compound used in the process of the present invention is an organic or inorganic cyano compound capable of converting a halogen group or alkyl
or ary1su 1 fon at e group at the 3-posit ion of the 3-ha 1ogenated or 3-a 1 ky .1 su ! I .onat ed or 3-arylsuL f onated tet rahydrof uran derivative t >... the cyano group. Specific examples of the organic: cyano compound include a hydrogen cyanide adduct of ketone or aJdehycie having 1 to 20 carbon atoms, such as q lyco 1 oni t r j 1. e and acetonecyanhydrin and a cyanated organic ammonium salt such as tetramethylammonium cyanide and i r .1 e t hy 1. ammon J .urn cyanide. Examples of the inorganic cyano compound include ammonium cyanide, an alkali metal cyanide such r.i.s lithium cyanide, sodium cyanide and potassium cyanide, an alkaline earth metal cyanide such as magnesium cyanide, a transition metal cyanide of Groups 3 to 12 of the Periodic Table of: the Elements, such as manganese cyanide, copper cyanide and cyanide ruthenium, including hydrogen cyanide. Of these organic: or inorganic cyano compounds, the hydrogen cyanide adduct: of ket one or aldehyde having 1 to 20 carbon atoms and the alkali metal cyanide are preferred and the alkali metal cyanide is more preferred.
[ 0 0 b 3 ]
The amount of the organic or inorganic cyano compound used is in the range of usually 0.1 to 10 moles, preferably 0.8 to 3 moles per mole of the 3-halogenated or 3-alkylsulfonated or 3-ary1su1fonated tetrahydrofuran derivative.
[0 054]
In the method of cyanation of the compound of the formula ( "'',) of the present invention, a compound accelerating a cyanation can be added to the reaction mixture. Examples of
i I if* compound decelerating a cyanation include a halogena ted
ammon 11.1 m salt such as tetraethylammonium chloride,
i <:.; t r a e I h y 1 a mm o n i. u m b r o m i d e , t riethyla mm o n i u m chloride and
00 t: yipyr i di n j um chloride, a halogenated phosphonium salt such
as te t• rapbenyl .phosphonium chloride and
t e t. r a p h e n y 1 p h o s p h o n i u m bromide, a cyclic ether compound such as 15-erown -b-ether and 18-crown -6-ether, a halogenated phosphazeniun; salt such as phosphazenium chloride, a halogenated a 1 kali metal or alkaline earth metal such as sodium chloride, lithium chloride, potassium bromide, magnesium chloride, sodium iodide and potassium iodide, and amines such a s 1 ,8 -dia z a bic y o1o[5.4.0]u n d e c- 7 -e n e and
1 , 4-diazabi cydo 2.2.2]octane. The amount of these compounds
.is in the range of usually 0.001 to 100 moles, preferably 0.01
to SO moles per mole of the organic or inorganic cyano compound.
[0055]
''The method of cyanation of the compound represented by the formula (3) of the present invention may be carried out in the absence of a solvent, but is usually carried out in the presence of a solvent. Specific examples of the solvent used include mcmohvdric or polyhydric alcohols having 1 to 20 carbon atoms such as methanol, ethanol, butanol and ethylene glycol, aliphatic or al ieye Lie hydrocarbons having 5 to 20 carbon atoms such as n-hexane, n-pentane and cyclohexane, aromatic hydrocarbons having 6 to 20 carbon atoms such as benzene, toluene and et by l.benzene, aliphatic or aromatic halides having 1 to 20 carbon atoms such as chloroform, chlorobenzene and
d ich Loroben:''.---?ne, ethers having 2 to 20 carbon atoms such as di ethyl at hot , diphenyl ether, tet rahydrof uran and ethyl ene qiyco) dimethyl ether, aliphatic or aromatic amides having 2 to 20 carbon atoms such as N, N-dimethyl formami.de and M , N-d .i met hy 1 <) cetamide , aliphatic or aromatic i m:i dazo 1 idinones having 2 to 20 carbon atoms such as 1., i - d i m e t h y 1 - 2-imidazolidinone, aliphatic or aromatic pyr r o.l i done;; having 4 to 20 carbon atoms such as N-methyIpyrrolidone, aliphatic or aromatic esters having 2 to 20 carbon atoms such as ethyl acetate and butyl acetate, aliphatic or aromatic ketones having 3 to 20 carbon atoms such as acetone and methyl ethyl ketone, aliphatic or aromatic nit.riles having 2 to 20 carbon atoms such as acetonitrile and benzonitrile, aliphatic or aromatic sulfoxides having 2 to 20 carbon atoms such as dimethylsulfoxide, and aliphatic or aromatic suliones having 2 to 20 carbon atoms such as sulfolane, incl ud ing wat.er .
[ 0 0 5 6 ]
Of these solvents, it is preferable to use the solvent having permittivity of 20 F-m''1 or more. The term "permittivity" as used in the present invention refers to permittivity at 20 to 30°C. The preferable solvent of the present invention does not have permittivity of 20 F-m''1 or more over the total temperature range, and includes any solvent as long as it has permittivity of 20 F-nT1 or more over a part of ihe temperature range. The permittivity of the solvent can take values described in "Solvent Handbook" (Shozo Asahara,
et a.l . , published by Kodansha Ltd. (1976)) or Handbook of Chemist", ry (Basic Edition), 5th Revised Edition (II) (edited by The Chemical Society of Japan, published by Maruzen Co., Ltd. (2004)). The permittivity is described as specific permittivity in some literatures, but both have the same meanings. Specific examples of the solvent having the permittivity of 20 F • m~ L or more include methanol, ethanol, propanol, ethylene glycol, acetone, acetonitrile, N,N-dimeth y1f o rmamide, N,N-dimethylacetamide, 1,3-dimethy1~2 -imidazolidi none, dimethylsulfoxide and N - m e thy I p y r i o 1 i d o n e , but is not: limited thereto. Of solvents having the permittivity of 20 F-rrf1 or more solvent, it is more preferable to use an aprotic solvent. Further, of these solvents, it i.s most preferable to use aliphatic or aromatic amides, aliphatic or aromatic imidazolidinones, or aliphatic or aromatic su 1. f oxides, each of which has the permittivity of 2 0 F • m'' ! or mo re .
0 0 5 7 ]
These solvents may be used in a mixture of two or more thereof. When the solvent is used, the amount thereof is not uniform over reaction conditions, but is in the range of usually 0.1 to 500 parts by weight, preferably 1 to 200 parts by weight, more preferably 2 to 100 parts by weight relative to 1 part by weight of the 3-halogenated or 3-alkylsulfonated or 3-ary1sulfona t ed tetrahydrofuran derivative.
0 0 5 8 ]
In the method of cyanation of the compound represented by the formula (3) of the present invention, it is particularly preferably to use the alkali metal cyanide as the cyano compound a nd re act if in the presence of the solvent having the permittivity of: 20 F-m"1 or more. In this case, the solvent having the permittivity of 20 F-m"1 or more is more preferably t h e a p r o 1; i c s o 1 v e n t .
(0059]
In the method of cyanation of the compound represented by the formula (3) of the present invention, all of R1, R2, R3, R''1, R'''', R1 and R are preferably a hydrogen atom. Further, X Ls preferably a halogen atom, more preferably a chlorine atom.
[0060]
In the method of cyanation of the compound represented by the formuJa (3) of the present invention, the reaction temperature is in the range of usually 0°C to 250°C, preferably 20 to 200°C, more preferably 50 to 180°C. The reaction time is in the ranqe of usually not more than 100 hours, preferably 0.01 to 50 hours. The pressure in the reaction may be any of reduced pressure, normal pressure or pressurization. The reaction process of the present invention is not particularly limited and may be performed in any one of batch, semibatch an d con t i nu ou s flow modes.
[ 0 061]
After completion of the reaction, the compound accelerating the reaction when used may be also recovered and repeatedly uied in the following reaction.
The 3-cyanot et rahydrof uran derivative formed in t he-process of the present invention can be isolated according to the conventional separation method such as distillation and e x t r a c t; i o n .
In the present invention, it is preferable to produce the 3-cyariotetrahydrofuran derivative and subsequently produce the 3-aminomethy 1 tetrahydrofuran derivative by using the ''•''> - h a 1 o g e n a t e d or 3 - a 1 k y 1 s u 1 f o n a t e d or 3 - a r y 1 s u 1 f o n a t e d tetrahydrofuran derivative represented by the formula (3a), which is prepared from the malic acid derivative by the following first to third steps, according to the process of t. h e p r e s e n t i n v e n t i o n .
[ F i r s t 5] t e p }
A -COOP,''''1 group and a -COOR9 group of the malic acid derivative represented by the formula (4) :
[0064]
R1 OH
R8OOC — C—C—COOR9 (4)
R2 R3
[0065]
wherein R1, R'':, R'', Rb and R9 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms,
are reduced to prepare triols represented by the formula (5): 0066 |

[ 0 0 6 7 1
wlierein R1, FT" and R3 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms, corresponding to the malic acid derivative used.
t S e c on d Step]
The triols represented by the formula (5) obtained from the first step is subjected to an intramolecular dehydration reaction in the presence of an acid catalyst to prepare a 3-hydroxytetrahydrofuran derivative represented by the f ormula f 6) :
[00681

R1

R" RJ

OH

(6)

[ 0069]
wherein RJ, R'''' and RJ may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms, corresponding to the triols used.
[Third Step]
The 3-hydroxytetrahydrofuran derivative represented by the formula (6) obtained from the second step and a halogenating
agent or a 1 k y .1 or ary1sulfony1 at ing agent are reacted to ha''iogenate or. alky] or arylsulf onate a hydroxyl group thus to prepare the -;~ha 1 ogenated or 3-alkylsulfonated or ''i-ar yl su 1 f oiirited tetrahydrofuran derivative represented by t he to rmu la ( 3a ) :
I co 70] XX
(3a)

R

X

[0071]
wherein KJ, R" and R'''' may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms; and X represents a halogen atom, or an a 1kylsuJfonate group having 1 to 6 carbon atoms or an ary]suLionate group having 6 to 12 carbon atoms.
[ 0 0 7 2 ]
Hereinafter, the process for producing the compound represented by the formula (3a) is explained in detail.
[ 0 0 7 3 }
In the preferable process of the present invention, the malic acid derivative represented by the formula (4) is used a s raw mater i a 1s .
R1 OH R8OOC — C —C—COOR9 (4)
wherein H1, K and R; are as defined for R1, R2 and R": in the i 01 mu. a ( 1 ) ; R!'' and R>;) each represent a hydrogen atom or a 11 y a rooa rhon q ro up having 1 to 4 carbon atoms.
More-- specific examples of the malic acid derivative include malic acid substituted by a hydrocarbon group at the 2-pos.i t" on and/or 3-position, such as citramalic acid ( y - me 1: h y .1 m a 1 i c acid) , 3-ethylmalic acid and 3, 3-d i methyl ma lie acid, malic monoester or diester such as monoisopropyl malate, dimethyl malate and diethyl malate, and monoester or diester .substituted by a hydrocarbon group at the 2-positon and/or 3-posit: ion, such as dimethyl citramalate, monobutyl citramalate and dimethyl 3-ethylmalate, including malic acid. These malic acid derivatives have an asymmetric carbon, but the malic acid derivative used, in the present invention may be an optically active substance or racemate. Of these malic acid derivatives, it is preferable to use malic acid, or malic monoester or diester, more preferably malic acid.
[ 0 0 7 6 ]
In the f i rst step of the preferable process of the present invent ion, the -COOR8 group and -COOR9 group of the malic acid derivative represented by the formula (4) are reduced to prepare the t riols represented by the formula (5):
10077]
R1 OH
HO—CH2-C—C R2 R3

B" rind R'' are as defined for R , R'': and R ir. the f orrm; id ( 1! .
More spec!tic examples of the triols include
1 ,,->., 4-bur.anet r i ol substituted by a hydrocarbon group at the 2-positon and/cr 3-position, such as
2-methy 1 - .1., ,-'', A -butanet r iol and 3-butyl- 1, 2 , 4-butanet r iol , Including 1, 2 , ''I -butanet riol . The triols obtained in the first step of l;he present Invention corresponds to the malic acid derivative and a hydrogen atom or hydrocarbon group at the 2-position and the 3-position of the malic acid derivative used is the same as a hydrogen atom or hydrocarbon group of the 2-position arid the 3-position of the triols obtained. For example, when malic monoester or diester, citramalic acid (2-methylma": i c acid) and dimethyl 3-ethylmalate are used as the malic acid derivative, respectively, 1,2,4-butanetriol, 2-methyl-1., 2, 4-butanet riol and 3-ethyl-l, 2 , 4-butanet riol are obt.a ined, respectively .
[ G 0 7 9 ]
In the first step of the preferable process of the present invention, examples of the method of reducing the -COORd group and -COOR^ group of the malic acid derivative represented by the formula (4) include a method of electrolytic reduction, a method of reducing with the metal hydride, a method of reducing with hydrogen in the presence of the hydrogenation
i''peo i f J o exarnpl es of the method of electrolytic reduction ..-.neJude a mot. hod of electrolytic reduction using a lead electrode in an aqueous sulfuric acid solution. I 0 0 K : ]
When reducing with the metal hydride, specific examples of: the metal hydride include the aluminum hydride compound such ay lithium aluminum hydride, lithium trimethoxyaluminum tiyclri.de, aluminum hydride and diisobutyla luminum hydride and the boron hydride compound such as diborane, lithium borohydride and sodium borohydride. The amount of the metal hi ydride when reducing with the metal hydride is in the range oi usually 2 to 10 moles, preferably 3 to 6 moles per mole of t he ma 1 i c a o :i d de r i va t i ve .
The) hydrogenation catalyst when reducing with hydrogen in the presence of the hydrogenation catalyst may be also any compound as long as it catalyzes the reaction in which the carboxyl group or ester group of the malic acid derivative according to the present invention is reduced to a hydroxyl group by a molecular hydrogen, but usually at least one metal selected from Groups 7 to 13 of the Periodic Table of the Elements or a metal compound thereof is suitably used. Specific examples of the hydrogenation catalyst and the amount used thereof may be exemplified by the same as those exemplified in the method of reducing the cyano groups of the 3-cyanotetrahydrofuran derivative represented by the formula
i i
Of tbesf reduct Jon methods, the method of reducing with hydroqen in the presence of the hydrogenation catalyst is preferred. The hydrogenation catalyst is preferably a metal such as ruthenium, rhodium, palladium, copper or rhenium or a metal compound thereof, more preferably a metal such as ruthenium 01 rhodium or metal compound thereof, and most preferably a metaJ such as ruthenium or metal compound thereof.
[0084]
The first step of the preferable process of the present invention may be carried out without a solvent, but is usually carried out in the presence of the solvent. When the solvent is used, the solvent may be any solvent as long as it does not i 11 h i bi t. t he r e duc t i o n r e a c t ion.
f 0085]
As the solvent used in the method of electrolytic reduction, water and alcohols having 1 to 20 carbon atoms, methanol, ethanol and butanol, are suitably used. Further, these solvents may be used in a mixture of two or more thereof.
[0086]
When reducing with the metal hydride, aliphatic or alicyclic hydrocarbons having 5 to 20 carbon atoms such as n-hexane, n-pentane and cyclohexane, aromatic hydrocarbons having 6 to /: 0 carbon atoms such as benzene, toluene and ethylbenzene, aliphatic or aromatic halide havings 1 to 20 carbon atoms such as chloroform, chlorobenzene and d:i chlorobenzene, and ethers having 2 to 20 carbon atoms such
•-is diet. hyJ ei:n i t: a t. e d a f t e r c omp let ion of the reaction was
1: i !. t o r e d o f i a n d the f i 11 r a 1: e was analyzed by gas
ohroina t: oqraphy . The yield of the 3-cyanotet rahydrof uran was
H 7 , 1 v.. Further, 10.1° of 2 , 5 -dihydro f uran as a major
by-product w^s formed. 21.1 g (217 mmol) of
3-cyariotet: r a)1 yd r of uran formed was distilled under reduced
pressure to isolate as a transparent liquid being a fraction
of 12.r''C/]O.H kPa.
(Table Remove) Kxamp.lt. s 17 to 22]
Reaction and after-treatment were carried out in the same manner as in Example 16, except that the type of the solvent, the react.ion temperature and the reaction time were replaced a r; shown in Table 2. The results are shown in Table 2 together with those of E]xample 16. Further, permittivity of each solvent: was also shown in Table 2.
10127]
(*) The figures in parentheses indicate the measured temperature of permittivity, (#) 2,5-DHF: 2,5-dihydrofuran
[Example; 23]
Reaction and after-treatment were carried out in the same manner as in Example 16, except that the solvent was not used. The results are shown in Table 2.
f Example 2 4]
Reaction arid after-treatment were carried out in the same marine t: as in Example 16, except that, in Example 16 wherein DMFwas used as a solvent, the reaction temperature was adjusted to 170°0 and the reaction time was adjusted to 4 hours. The conversion rate was 100% and the yield of 3 ~ c y a n o t e t; r a h y d r o f u r a n was 74.6%.
[ 0 1 3 0 ]
[ Example- 2 5 ]
Reaction and after-treatment were carried out in the same manner as in Example 16, except that, in Example 16 wherein DMF was used as a solvent, the amount of the solvent was adjusted to 130 rnL. The conversion rate was 100% and the yield of 3-c y a n o t e t r a h y d r o f u r a n was 87.0%.
[ 0 131 ]
[Example 26]
Reaction and after-treatment were carried out in the same manner as in Example 25, except that 24.4 g (375 mmol) of KCN was used instead of NaCN. The conversion rate was 80.8% and the y i e 1 ci o f "•• - c; y a n o t e t r a h y d r o f u r a n was 54.8%.
[0132J
[ Example 2 7 j
Reaction and after-treatment were carried out in the same mariner as in Example 25, except that 31.9 g (375 minol) of acetonecyanhydr in was used instead of NaCN and 41. 9 g (275 mmol) of I, 8-diazabicyclo[5.4.0]undec-7-ene was used. The c:onver s i on rale was 8 1 . 7 % and the yield of 3-cyanotetrahydrofuran was 54.5%.
f 0 1 3 3 ]
fEx ample 23 j
Reaction and after-treatment were carried out in the same manner as in Example 17, except that, in Example 17 wherein dimethy.lsulfoxi.de (hereinafter abbreviated to "DMSO") was used as a solvent, the reaction temperature was adjusted to 120°C. The conversion rate was 98.1% and the yield of 3-cyanotetrahydrofuran was 89.3%.
[ 0 1 3 4 ]
[Example2 9]
Reaction and after-treatment were carried out in the same manner as in Example 17, except that, in Example 17 wherein DMSO was used as a solvent, the reaction temperature was adjusted to 110 °C and the reaction time was adjusted to 8 hours. The conversion rate was 94.3% and the yield of 3-cyanotetrahydrofuran was 86.3%.
[ 0135]
[ Example 3 0]
React i.on and after-treatment were carried out in the same manner as in Example 17, except: that, in Example 17 wherein
DM SO was used as a solvent, the amount used of NaCN was adjusted to 13.5 g (275 rnmol). The conversion rate was 99.7% and the yield of 3-cyanotetrahydrofuran was 87.0%.
[0136]
[Example 31]
Reaction and after-treatment were carried out in the same manner as in Example 25, except that 60.6 g (250 mmol) of 3~(p-toluenesu1fonato)-tetrahydrofuran was used instead of 3-chlorotetrahydrofuran. The yield o f 3-oyanotetrahydrofuran was 71.3% . 0 1 3 7 ]
[Example 32]
Reaction and after-treatment were carried out in the same mariner as in Example 25, except that 55.0 g (250 mmol) of 3-(trif1uoromethanesulfonato)-tetrahydrofuran was used instead of 3-chlorotetrahydrofuran. The yield of 3-cyanotetrahydrofuran was 68.0%.
[ 0 1 3 8 ]
[Preparative Example of 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative from malic acid derivative]
[ 0139]
[Example 33]
[First; Step (step of reducing malic acid)]
56.0 g (-118 mmol) of malic acid, 400 mL of water and 40 g of 5% ruthenium-carbon powders were charged into a 1L a u t o c1 a ve. After purging the inside of a reactor with nitrogen,
the inside of trie reaction system was pressurized with hydrogen of ] MPaG. Tl«e:'' reaction solution was heated to 100 °C and then reacted at hydrogen pressure of 12 MPaG for 24 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was distilled under reduced pressure to obtain 34.2 g (322 mmol) of 1, 2,4-butanetriol as a fraction of 185 to 190°C/2.4 kPa. The yield was 77%.
1 01 4 0 ]
[Second Step (step of cyclizing trio1) ]
31.8 g (300 mmol) of 1,2,4-butanetriol obtained in the f i rst step and 0 . 3 g of p-toluenesulf onic acid monohydrate were placed into a 75 mL three-necked flask equipped with a cooling extraction pipe. The inside of the reaction system was adjusted to a reduced pressure of 6.6 kPa and the inside of the reactor was heated to 140°C, and then the cyclization reaction of 1,2,4-butanetriol was carried out. The reaction was carried out i ri the form of reactive distillation and 3-hydroxytetrahydrofuran as a cyclization product was extracted through the cooling extraction pipe out of the reaction system, together with the formed water. The moisture was removed from the moisture-containing
3-hydroxytetrahydrofuran obtained by means of distillation to obtain 25.6 g (291 mmol) of 3-hydroxytetrahydrofuran. The yieId was 97%.
[0141]
Third Step (step of halogenating 3 - h y ci i'' o x y t e t r a h y d r o f u r a n) ]
/A.I g (280 mrnol) of 3-hydroxytetrahydrofuran obtained in the second step and 85 mL of DMF were placed into a 200 mL three-necked f iask. After immersing the flask in an ice bath, 36.7 g (308 mnioJ) of thionyl chloride was added dropwise over 30 minutes to the N,N-dimethylformamide solution. After completion of. dropwise addition, the reaction was continued for further 6 hours. After completion of the reaction, the sulfur dioxide and hydrogen chloride formed were ejected by nitrogen bubbling and then the resulting product was distilled under normal pressure to obtain 27.1 g (254 mmol) of 3-ohlorotetrahydrofuran as a fraction of 125 to 130°C. The y i (-• Id wa s 91%.
(0142]
Hereinafter, an example of each step of preparing the 3-ha logenated or 3-alkyIsulfonated or 3-arylsulfonated tet. rahycirof uran derivative from the malic acid derivat ive will be separately and specifically explained. The 3-halogenated or 3-alkyIsuli onated or 3-arylsulfonated tetrahydrofuran derivative can be synthesized from the malic acid derivative by any suitable combination of each step of Example 33, and Example 34 and the subsequent Examples.
i 0 1 4 3 1
[Example 34 i F''i r s t St ep j
Reaction and distillation were carried out in the same manner as in the lirst step of Example 33, except that, in the fjist step of Example 33, 40 g of 5% rhodium-carbon powders
was used instead of 40 g of 5% ruthenium-carbon powders and hydrogen pressure was adjusted to 16 MPaG. The yield of 1,2,4-butanetriol was 56%.
(0144]
[Example 35]
[First Si ep 1
Reaction and distillation were carried out in the same manner as in the first step of Example 33, except that, in the first step of Example 33, the reaction temperature was changed to 120 °C and t: he reaction time was changed to 6 hours. The yield of 1,2,4 -butanetriol was 63%.
f 0 1 4 5 ]
[Example 36]
[First Step]
Reaction and distillation were carried out in the same manner as in the first step of Example 33, except that, in the first, step of Example 33, 400 mL of ethanol was used instead of 400 ml, of water as a solvent, hydrogen pressure was changed to 16 MPaG and the reaction time was changed to 90 hours. The yield of 1,2,4-butanetriol was 90%.
I 0146]
[Example 37
[First Step]
Reaction and distillation were carried out in the same manner as in the first step of Example 33, except that, in the first step of Example 33, 400 mL of ethanol was used instead of 400 rn L of wafer as a solvent, hydrogen pressure was changed
to 16 MPaG, the reaction temperature was changed to 120°C and the reaction time was changed to 70 hours. The yield of 1,2,4 -bu t a ne t) i o1 was 90%.
[ 0 1 4 7 ]
[Example 38| F i- r s t S t e p |
50.0 g (308 mrnol) of dimethyl malate, 200 mL of tetrahydrofuran and 25 g of CuO/ZnO/Al203 (CuO/ZnO/Al203 were 52. 815 by weight, 28.1% by weight and 19.1% by weight, respectively) were charged into a 500 mL autoclave. After purging the inside of a reactor with nitrogen, the inside of t h e r e a c t i o n s ystern was pressurized with hydrogen of 1 MPaG. The reaction solution was heated to 180°C and then reacted at hydrogen pressure of 10 MPa for 4 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was distilled under reduced pressure. The yield of 1,2,4-b u t a n e11io I was 80%.
| 0148]
[ toxample 39]
(Second Step]
Reaction and distillation were carried out completely in the same manner as in the second step of Example 33, except that, in the second step of Example 33, 0.3 g of sulfuric acid was used instead of p-toluenesulfonic acid monohydrate. The y i e 1 d o f 3 - h y (i r oxytetrahydrofuran was 98%. 0 .149]
[ F.xamp 1 e 4 0 [
Reaction .and distillation were carried out in the same manner as in rho second step of Example 33, except that, in the second stop of Example 33, 0.5 g of samarium t. r i f 1 uor ome t ha nesu J f ona t e was used instead of p-toluenesulionic acid monohydrate. The yield of 3 - h y d r o x y t e t r a n y ci r o f u r a n was 9 7 % .
[ 0 1 5 0 |
I Example 41 |
[ S e c o n d 81 e p ]
Reaction rind distillation were carried out completely in the same manner as in the second step of Example 33, except that, in the second step of Example 33, 1 . 0 g of H-type mordenite was used instead of p-toluenesulfonic acid monohydrate. The yield of 3-hydroxytetrahydrofuran was 95%.
[01511
[Example 42 j
[Second Step]
Reaction and distillation were carried out completely in the same mariner as in the second step of Example 33, except that, in the second step of Example 33, the pressure during the reaction was changed to 13.2 k P a. The yield of 3-hydroxytetrahydrofuran was 95%.
[ 0 1 5 2 J
[Example 43]
[Third Step]
Reaction was carried out. in the same manner as in the third step of L''xanipl*- 33, except that, in the third step of Example 33, 22.1 g (2HU mmol) of pyridine and 50 mL of toluene were used instead or DME''. After completion of the reaction, the sulfur dioxide and hydrogen chloride formed were ejected by nitrogen bubbling, the precipitated pyridiniuiu salt was filtered off, and then the resulting product was distilled under normal pressure to obtain 3-chlorotetrahydrofuran. The y i e 1 d w a s 9 3 % .
[01S3j
[ Example 4 4 ]
[Third Step!
50 mL of concentrated hydrochloric acid and 76.4 g (560 mmol ) of. zinc chloride were mixed in a 250 mL three-necked flask and then 2 4 . ''/'' g (280 mmol) of 3-hydroxytetrahydrofuran was added dropwiso to the resulting solution. The solution was refluxed for 2 hours, and the upper layer was separated and heated under reflux with concentrated hydrochloric acid. The p r c > cl uct w a s d i s tilled to obtain 3-chlorotetrahydrofuran. The yi eld was 78 I.
[0154]
[Example- 45]
[Third ^t.ep]
24.7 c (280 mmol) of 3-hydroxytetrahydrofuran and 53.5 a (280 mnio''l.) of tosyl chloride were dissolved in 150 mL of ether and a solution of 44.3 g (560 mmol) of pyridine dissolved in 50 mL of ether was added dropwise at 0°C to the resulting
s o 1 a i i o n . A f t c; r: c amp 1 e t i o n of the reaction, p y r i d i n e hydrochJ or ide was separated by filtration, the solvent was distilled off and the residue was recrysta Hi zed with ether to obtain 40.0 g (165 mmol) of 3- ( p- toluenesu 1 tonato ) -tetrahydrofuran . The yield was 59%.
[Example 46]
[ Th i rd Step |
3.6 g (l''i() mmol) of sodium hydride was suspended in 200 ml, of ether, and thereto was slowly added dropwise at 0°C a solution of 1 2 . 4 g (140 mmol) 3-hydroxyt etrahydrof uran dissolved in SO mL of ether. 33.7 g (200 mmol) of t r i f luo rometha nesul f onyl chloride was added dropwise the resulting solution and refluxed for 3 hours. After cooling, water was added to the resulting solution and an ether layer was separated. The ether was distilled off and the residue was distilled under reduced pressure to obtain 26.2 g (119 mmol) of 3- (ti if iuo t: omethanesul f onato ) -tetrahydrofuran. The yield was 85%.
[0156]
According to the present invention, a
3-aminomet hyl t et. rahydrof uran derivative, which is useful as an intermediate for medicines and agrochemicals , can be obtained and provided in the synthesis of the medicines and ag rocherni ca Is .

1. A process for producing a 3-aminomethyIterrahydrofuran derivative represented by the
i o r m u 1. a ( 2 ) :
(Figure Remove) wherein R1, R'', R'', R4, R''J, R" and R7 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms,
compr i s j. rig :
reducing Che cyano group of a 3-cyanotetrahydrofuran derivative represented by the formula (1):
whereJn R] , R'''', R3, R4, R5, R6,and R7 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms.
2. The process for producing a
3-aminomethy1tetrahydrofuran derivative as set forth in claim 1, wherein the cyano group of the 3-cyanotetrahydrofuran derivative :i s reduced with hydrogen in the presence of ammonia
arid j n t h(:• pr •:•se11ce ot a metal of Group 9 or 10 of the Periodic Table of the Hlements or a metal compound thereof, as a
catal ys t .
3. The process as set: forth in claim 2, wherein the catalyst
is a metal such as cobalt; or nickel or a metal compound thereof.
4. The process as set forth in claim 2 or 3, wherein the
a mm o n i a i s a q u e o u s a mm o n i a .
5. The process as set forth in claim 4, wherein the reaction
is carried out i.n the presence of 0.05 to 2 parts by weight
of water relative to 1 part by weight of the
3 -c y a no t e tr a 1: y d r o f uran d e r i v a t i v e.
6. A process for producing a 3-cyanotetrahydrofurari derivative represented by the formula (1), comprising:
r ea c t i n q a 3-halogenated or 3-alkylsulfonated or 3-ary1sulfonated tetrahydrofuran derivative represented by t. he f ormu 1 a i. 3 ) :
wherein RL, R , P.''1, R4, Rb, R6 and R7 may be the same or different from each o1her and each represent a hydrogen atom or a
hydrocarbon q.t»up having I to 4 carbon atoms; and X represents a h a 1 (i a e n a t c > n i o r a n a J. k y 1 s u 1 f o n a t e group having 1 to 6 carbon a t: o rn s o r a r y 1 s u i. f o n a t e group h a v i n g 6 to 12 carbon atoms, and an organic or inorganic cyano compound.
7. The process as set forth in claim 6, wherein the organic
or inorganic cyt-mo compound is alkali metal cyanide and,
the reaction is carried out using in the presence of the solvent having t''.he permittivity of 20 F-rtT1 or more.
8. The process as set forth in claim 7, wherein the solvent
having the permittivity of 20 F-m"1 or more is an aprotic
s c ,1 v e n t .
9 . T he process as set forth in any one of claims 1 to 5,
wherein the 3 cyanotetrahydrofuran derivative is obtained by
the process as set forth in any one of claims 6 to 8.
10 . ''].'' h e pro c e s s as set forth in claim 9, wherein the
3-haloqenated or 3-alkyIsulfonated or 3-arylsulfonated
t; et rahydr c>f ur an derivative represented by the formula (3a) is prepared from the malic acid derivative by the following first t o third steps:
[First Step]
A -COOK" group arid a -COOR9 group of the malic acid derivative represented by the formula (4):
R1 OH
R8OOC —C—C—COOR9 (4)
R2 R3
wherein R'', R , k'', Rb and Ry may be the same or different from
each other and each represent a hydrogen atom or a hydrocarbon
qro u p ha vi ng 1 to 4 carbon at o m s,
are reduced to prepare triols represented by the formula (b) :
R1 OH
HO—CH2-C—C-CH2-OH (5) R2 R3
wherein R1, R'' and R'' may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms, corresponding to the malic acid derivative used.
| Second Step]
The triols represented by the formula (5) obtained from the first step is subjected to an intramolecular dehydration reaction in the presence of an acid catalyst to prepare a 3-hydroxytefrahydrofuran derivative represented by the formula (6):
(Figure Remove)wherein R1, R'': and R3 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group naving 1 to 4 carbon atoms,
corresponding Lo the triols used.
f Th i rd :.i t: ep ]
The .:i -I "i yd roxy te t rahydrof uran derivative represented by the formula (6) obtained from the second step and a halogenating aqont; or a Iky.I. or a ryl sul f ony lat ing agent are reacted to halogena t: e or a.lkyi or arylsul f onate a hydroxyl group thus to p r e p a r. e the .•--halogenated or 3-alkylsulfonated or .1-a ry 1 sul f ona (• ed tet rahydrof uran derivative represented by the fo rmula (Ja) :

(3a)
^\ ^ 1.
R
''X
3
R R"
wherein R1, R" and R* may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms; and X represents a halogen atom, or an aikylsuIfonate group having 1 to 6 carbon atoms or an arylsulfonatt? group having 6 to 12 carbon atoms.