Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR PREPARATION OF CYCLOHEXANOL DERIVATIVES
BACKGROUND OF THE INVENTION
Field of the Invention
[01] The present invention relates to a process for preparation of
cyclohexanol
derivatives such as 1-[cyano (4-methoxyphenyl)methyl] cyclohexanol.
Bac k~round of the Related Art
[02] Cyclohexanol derivatives such as 1-[cyano(4-methoxyphenyl)methyl]
cyclohexanol are useful intermediates for making compounds like venlafaxine
which
have anti-depressant effects by inhibiting re-uptake of neurotransmitters,
norepinephrine and serotonin. As disclosed in U.S. Patent No. 4,535,186,
cyclohexanol
derivatives can be produced by reaction of a cycloalkanone or cycloallcenone
with an
appropriately substituted (ortho or para) phenylacetonitrile anion.
[03] The preparation method disclosed in the US '186 patent involves the use
of an organometallic base such as n-butyl lithium in order to induce
phenylacetonitrile
anion in the reaction. The organometallic base is expensive, has to be used in
an
amount of at least one equivalent of the reactant at a low temperature below -
50 C , is
characteristically susceptible to water in air with the risk of fire or
explosion, and
provides a low production yield of less than 50 percent. Therefore,
organometallic
bases are considered impractical for industrial scale synthesis.
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[04] U.S. Patent No. 5,043,466 discloses a process for preparation of
cyclohexanol derivatives which use an organometallic base such as a lithium di-
isopropylamide as illustrated in the following reaction mechanism. The US '466
patent varies the mixed ratio of hydrocarbon solvents in an attempt to improve
reaction
temperature and yield, but there still remains the problem of the base,
lithium di-
isopropylamide being impractical for industrial scale synthesis as it too is
expensive,
hard to handle, and can be a fire or explosion risk.
0
_ ~10H
~~~~H~ '~~ ~~~ BASE R,~_~HM 1 ~ QR~
R?C7
M=Li,Na,I~,IUIgHa( ~~= CN,-G O-N(CW3)2
r~S-Ni ~H ~)~
R~=H,~H~,Proteciive Geouia
[05] Chinese Patent Publication No. 1225356 (CN01225356A) discloses the
use of bases such as sodium methoxide, sodium ethoxide, sodium hydride and
sodium
amide in the preparation of cyclohexanol derivatives to enhance the reaction
temperature in the range of 0 to 5 C . However, the disclosed bases were used
in
amounts of at Ieast one equivalent of the reactant, and are also dangerous as
they too
are prone to combustion or explosion.
[06] The known processes above involve two steps, i.e. reacting
phenylacetonitrile with a base to produce an anion and coupling the anion with
a ketone
compound. In particular, the reaction in the anion-producing step involves
some
difficulties with regard to determination of the end point of the step and
quantitative
analysis of the anion produced. Such problems give rise to variations in yield
in the
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coupling step and therefore they are also difficult for industrial application
for this
reason.
SUMMARY OF THE INVENTION
[07] Accordingly, the present invention is directed to a process for
preparation .
of cyclohexanol derivatives that substantially overcomes problems and
disadvantages
of the conventional art.
[08] An object of the present invention is to provide a process for
preparation
of cyclohexanol derivatives by reaction of phenylacetonitrile with
cyclohexanone to
enable economical and reasonable mass quantity production.
[09] Another object of the present invention is to provide a process for
preparation of cyclohexanol derivatives that is safe and environmentally
friendly
Without the risk of fire or explosion and simpler than conventional syntheses
because
the reactants are all mixed in one reaction.
[10] One aspect of the present invention is a process for preparation of
cyclohexanol derivatives of formula I,
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~f~g
II
~T II r
(I)
wherein R6 and R~ are ortho or para substituents, independently selected from
the group
consisting of hydrogen, hydroxyl, C1-C6 alkyl, C1-C~ alkoxy, C~-C~ aralkoxy,
C~-C~
alkanoyloxy, Cl-C~ alkylmercapto, halo or trifluoromethyl; R8 is hydrogen or
C1-C~
allcyl; p is one of the integers 0, 1, 2, 3 or 4; and R9 is hydrogen or Cl-C6
alkyl;
comprising reacting a compound of formula II with a compound of formula III,
I
i
W ~C I~~P
(n) (nI)
in the presence of non-organometallic base catalysts represented by the
formula IV or V,
in the presence or absence of a reaction solvent,
4
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r
(IV) (V)
wherein A is -(CH2 ) n -where n is an integer from 2 to 4; B is - (CH2)m where
m is an
integer from 2 to 5 ; X is CHZ, O, NH or NR' where R' is a C1-C4 alkyl or
acyl, or an
alkyl supporting polymer ; each of and Rl to R~. is independently hydrogen, an
alkyl, a
cycloalkyl or an alkyl or cycloalkyl supporting polymer, and all of Rl to R4
are not
hydrogen, and RS is an alkyl, a cycloalkyl or an alkyl or cyloalkyl supporting
polymer,
and where R9 is an alkyl, alkyl group is introduced by alkylation.
[11] The non-organometallic base used in the present invention comprises
amidines or guanidines represented by formula IV or V More specifically,
examples
of non- organometallic bases of the present invention include amidines, e.g.
1,8-
diazabicyclo [5,4,0]undec-7-ene (DBU) and 1,5-diazabicyclo[4,3,0]non-5-ene
(DBN);
cyclic guanidines, e.g. 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD) and 7-methyl-
1,5,7-
triazabicyclo[4,4,0]dec-5-ene (MTBD); alkyl guanidines, e.g. tetra methyl
guanidine
(TMG), tetra butyl guanidine, penta methyl guanidine, penta butyl guanidine
and N'-
butyl-N",N"-dicyclohexylguanidine. The base catalyst of the present invention
may
be a homogeneous catalyst or may be a catalyst containing an amidine- or
guanidine-
based organic amine base immobilized on a polymer support (e.g. polystyrene)
or an
inorganic support (e.g. silica). The non-organometallic base of the present
invention
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is at least one selected from the group consisting of the above-mentioned
bases.
[12] The amount of the non-organometallic base used is not specifically
limited
and may be in the range from about 0.0001 to about 2 equivalents, and more
preferably,
from about 0.005 to 0.5 equivalents relative to one equivalent of the compound
of
formula II. The reaction of the present invention can be successfully
accomplished
with the base catalysts used only in a catalytic amount, which is
advantageous.
[13] The present invention may optionally not use an organic solvent
comprising hydrocarbons or ethers that are required in conventional synthesis.
Whether to use an organic solvent or not is optimally decided by those skilled
in the art,
but it is generally preferred not to use an organic solvent.
[14] In preparation of the cyclohexanol derivatives such as 1-[cyano(4-
methoxyphenyl)methyl]cyclohexanol represented by formula I according to the
present
invention, the reaction temperature is preferably in the range of about -20 to
80 C ,
more preferably about 10 to 30 C . The process of the present invention can
be'
conducted even at room temperature, which is advantageous.
[15] The present invention presents a process for preparation of cyclohexanol
derivatives by reaction of an appropriately substituted, para-
phenylacetonitrile with a
cyclohexanone in the presence of a non-organometallic amine base (e.g. DBU,
DBN,
TBN, MTBD, TMG or N'-butyl-N",N"-dicyclohexylguanidine) in accordance with
reaction mechanism T.
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4
Catalyst
J
c~~~a
(I)
[16] In the above reaction, R6 to R9, and p are the same as defined above, and
where R9 is an alkyl, it is introduced by alkylation.
[I7] In the preparation of the cyclohexanol derivatives such as 1-[cyano(4-
methoxyphenyl)methyl]cyclohexanol represented formula I, a non-organo metallic
base
such as DBU, DBN, TBD, MTBD, TMG or N'-butyl-N",N"-dicyclohexylguanidine
that is an amine base is used instead of an organometallic base such as n-
butyl lithium
or lithium diisopropyl amide used in conventional processes to induce a
phenylacetontirile anion. The use of a non-organometallic base, in a
relatively small
amount that is relatively inexpensive, less susceptible to hydration, operable
at room
temperature, with no risk of fire or explosion, enables mass quantity
production
through a safe and relatively simple industrial process. Only catalytic
amounts of
non-organometallic base are needed in the present invention, which produces
highly
pure, high yield cyclohexanol derivatives.
[18] The present process is also more simplified and environment-friendly
without production of organometallic byproducts as use of organic solvents is
avoided.
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[19] The present invention will now be described in detail with reference to
the
following examples, which are not intended to limit the scope of the present
invention.
[20] Example 1
[21] 100 g (0.68 mole) of p-methoxyphenylacetonitrile, 100 g (1.02 mole) of
cyclohexanone and 32 g (0.21 mole) of 1,8-diazabicyclo [5,4,0] undec-7-ene
(DBU)
were added to a flask and kept at 15 to 20 °C with stirring fox 48
hours. 1N HC1 was
then added to the resulting solution to regulate the pH to acid level. After
one hour of
stirring at room temperature, the formed precipitate was separated by
filtration and
washed with purified water and then with ethyl acetate and n-hexane, to yield
140 g of
a white solid as,the target compound, 1-[cyano(4-
methoxyphenyl)methyl]cyclohexanol
(yield 84%, melting point 123.7 °C).
[22] 1H NMR Analysis (DMSO-d6) : S 7.27-6.93 (4H, q, aromatic). 4.85 (1H,
s, OH), 4.05 (3H, s, OCH3), 3.76 (1H, s, CHCN), 1.69-1.08 (10H, m, cyclohexyl)
[23] 1H NMR Analysis (CDC13) : s 7.23-6.89 (4H, q, aromatic). 3.82 (3H, s,
OCH3), 3.73 (1H, s, CHCN), 1.72-1.16 (10H, m, cyclohexyl)
[24] 13C NMR Analysis (DMSO-d6) : s 159.4, 131.3, 125.8, 121.4, 114.1,
72.2, 55.8, 48.8, 36.0, 34.7, 25.9, 22.0, 21.9
[25] Mass Spectral Analysis: Molecular weight 245 [M+ by C.LM.S.]
8
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[26] 11Z (KBr pallet) : 3408 cm 1 (-OH), 2249 cm 1 (-CN)
[27] Example 2
[28] 52.7 g (0.36 mole) of p-methoxyphenylacetonitrile, 35.8 g (0.36 mole) of
cyclohexanone and 28.6 g (0.19 mole) of 1,8-diazabicyclo[5,4,0]undec-7-ene
were
added to a flask and kept at 15 to 20 °C with stirring for 90 hours. 1N
HC1 was then
added to the resulting solution to regulate the pH to acid level. After one
hour of
stirring at room temperature, the formed precipitate was separated by
filtration and
washed with purified water and then with ethyl acetate and n-hexane to yield
62 g of a
white solid as the target compound, 1-[cyano(4-
methoxyphenyl)methyl]cyclohexanol
(yield 70%).
[29] Example 3
[30] The procedures were performed in the same manner as described in
Example I, except that 0.5 equivalent of 1,8-diazabicyclo[5,4,0]undec-7-ene
was used
in the 6-day reaction to yield 67 g of a white solid as the target compound, I-
[cyano(4-
methoxyphenyl)methyl]cyclohexanol (yield 80%).
[31] Example 4
[32] 100 g (0.68 mole) of p-methoxyphenylacetonitrile, 167 g (1.70 mole) of
cyclohexanone and 52 g (0.34 mole) of 1,8-diazabicyclo[5,4,0]undec-7-ene were
added
to a flask and kept at 0 °C with stirring for 60 hours. 1N HCl was then
added to the
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resulting solution to regulate the pH to acid level. After one hour of
stirring at room
temperature, the precipitate produced was separated by filtration and washed
with
purified water and then with ethyl acetate and n-hexane to yield 147 g of a
white solid
as the target compound, 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield
88%).
[33] Example 5
[34] The procedures were performed in the same manner as described in
Example l, except that 0.5 equivalent of 1,8-diazabicyclo[5,4,0]undec-7-ene
was used,
in the 8-hour reaction to yield 116 g of a white solid as the target compound,
1-
[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 70%).
[35] Example 6
[36] 25.4 g (0.17 mole) of p-methoxyphenylacetonitrile, 41.8 g (0.42 mole) of
cyclohexanone and 13.2 g (0.087 mole) of 1,8-diazabicycle[5,4,0]undec-7-ene
were
added to a flask and kept at 25 °C with stirring for 24 hours. 1N HCl
was then added
to the resulting solution to regulate pH to acid level. After adding 50m1 of
methyl
alcohol and one hour of stirring at room temperature, the precipitate produced
was
separated by filtration and washed with purified water and then with ethyl
acetate and
n-hexane to yield 23.7 g of a white solid as the target compound, 1-[cyano(4-
methoxyphenyl)methyl]cyclohexanol (yield 56.1%).
[37] Example 7
[38] 50.3 g (0.34 mole) of p-methoxyphenylacetonitrile, 34.8 g (0.35 mole) of
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cyclohexanone and 43.38 (0.35 mole) of 1,5-diazabicyclo[4,3,0]none-5-ene (DBN)
were added to a flask and kept at 20 to 25 C with stirring for 90 hours. To
the
resulting solution were added 50 ml of methyl alcohol and 200 ml of purified
water.
After one hour stirring at room temperature, the precipitate produced was
separated by
filtration and washed with purified water and then with ethyl acetate and n-
hexane to
yield 116 g of a white solid as the target compound, 1-[cyano(4-methoxyphenyl)
methyl]cyclohexanol (yield 70%).
[39] Example 8
[40] 20 g (0.14 mole) of p-methoxyphenylacetonitrile, 13.7 g (0.14 mole) of
cyclohexanone and 21.2 g (0.14 mole) of 1,8-diazabicyclo[5,4,0]undec-7-ene
were
added to a flask, diluted with 100 ml of methyl alcohol and kept at 15 to 20
°C with
stirring for 20 hours. To the resulting solution were added 20 ml of methyl
alcohol
and 150 ml of purified water. After one hour of stirring at room temperature,
the
precipitate produced was separated by filtration and washed with purified
water and
then ethyl acetate and n-hexane to yield 17.4 g of a white solid as the target
compound,
1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 52%).
[41] Example 9
[42] The procedures were performed in the same manner as described in
Example 1, except that 0.1 equivalent of 1,8-diazabicyclo[5,4,0]undec-7-ene
was used
in the 6-day reaction to yield 76.1 g of a white solid as the target compound,
1-
[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 90.5%).
m
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[43] Example 10
[44] 25.4 g (0.17 mole) of p-methoxyphenylacetonitrile, 83.6 g (0.85 mole) of
cyclohexanone and 26.7 g (0.17 mole) of 1,8-diazabicyclo[5,4,0] undec-7-ene
were
added to a flask and kept at 20 to 25 °C with stirring for 24 hours. To
the resulting
solution were added 50 ml of methyl alcohol and 200 ml of purified water.
After one
hour of stirring at room temperature, the precipitate produced was separated
by
filtration and washed with purified water and then ethyl acetate and n-hexane
to yield
18.0 g of a white solid as the target compound, 1-[cyano(4-methoxyphenyl)
methyl]cyclohexanol (yield 42.6%).
[45] Exam 1p a 11
[46] The procedures were performed in the same manner as described in
Example 1, except that the reaction temperature was kept in the range from 35
to 40 °C
to yield 30.6 g of a white solid as the target compound, 1-[cyano(4-methoxy-
phenyl)methyl]cyclohexanol (yield 36.8%).
[47] Example 12
[48] 100 g (0.68 mole) of p-methoxyphenylacetonitrile, 100 g (1.02 mole) of
cyclohexanone and 0.47 g (0.0034 mole) of 1,5,7-triazabicyclo[4,4,0] dec-5-ene
(TBD)
were added to a flask and kept at 20 to 25 °C with stirring for 10 to
12 hours. 1N HCl
was then added to the resulting solution to regulate the pH to acid level.
After one hour
of stirring at room temperature, the precipitate produced was separated by
filtration and
washed with purified water and then ethyl acetate and n-hexane to yield 128 g
of a
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white target compound, 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield
77%).
[49] Example I3
[50] The procedures were performed in the same manner as described in
Example 1, except that 0.03 equivalent of 7- methyl-1, 5, 7-triazabicyclo [4,
4, 0] dec-
5-ene (MTBD) was used in the 20 to 22-hour reaction to yield 128 g of a white
solid as
the target compound, 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol(yield 77%).
[51] Exam 1p a 14
[52] 50 g (0.34 mole) of p-methoxyphenylacetonitrile, 50 g (0.51 mole) of
cyclohexanone and 0.24 g (0.0017 mole) of 1, 5, 7-triazabicyclo[4, 4, 0] dec-5-
ene
(TBD) were added to a flask and kept at 20 to 25°C with stirnng for 19
hours. The
reaction mixture was dissolved in 500 ml of ethyl acetate and, after addition
of 200 ml
of purified water, was neutralized with 6N HC1. Following phase separation at
30 to
35 °C, the organic solvent was removed under vacuum and 500 ml of ethyl
acetate and
200 ml of purified water were added to the filtrate. After one hour of
stirring at room
temperature, the precipitate produced was separated by filtration and washed
with
purified water and then with ethyl acetate and n-hexane to yield 74g of a
white solid as
the target compound, 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 89%).
[53] Example 15
[54] 25 g (0.17 mole) p-methoxyphenylacetonitrile, 25 g (0.25 mole) cyclo-
hexanone and 2.5g (0.0090 mole) N'-butyl-N",N"-dicyclohexylguanidine were
added
13
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to a flask and kept at 20 to 25°C with stirring for 24 hours. 1N HCl
was then added to
the resulting solution to regulate the pH to acid levels. After one hour of
stirring at
room temperature, the precipitate produced was separated by filtration and
washed with
purified water and then with ethyl acetate and n-hexane to yield 30 g of a
white solid as
the target compound, 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 72%).
[55] Comparative Example 1
[56] 50g (0.34 mole) of p-methoxyphenylacetonitrile was diluted with 250m1
of dry tetrahydrofuran (THF) and cooled to -70°C under a nitrogen
atmosphere.
210m1 (0.34 mole) of n-butyl lithium (n-BuLi) was dropped into the resulting
solution
while maintaining the temperature of the solution below -50°C. The
solution was
then stirred for 30 minutes and, after addition of 50 g (0.51 mole) of
cyclohexanone,
was stirred for 45 minutes more, while the temperature of the solution was
kept at less
than -50°C. Thereafter, the temperature of the reaction solution was
raised to 0°C,
and a saturated ammonium chloride solution was added to cause phase
separation.
The aqueous layer was extracted with diethyl ether and combined with the
organic layer.
The organic solvent was then removed under reduced pressure to yield 25.2 g of
the
target compound, 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 34.2%).
[57] Melting point: 123 to 126 °C.
[58] Mass Spectral Analysis: Molecular weight 245 [M+ by C.LM.S.]
14
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[59] 1H NMR Analysis (DMSO-d6): s 7.32, 6.95 (4H, q, p-substituted
aromatic), 3.8 (3H, s, O-CH3), 3.76 (1H, s, CH-CN), 1.56 (10H, m, aliphatic
cyclohexyl)
[60] Comparative Example 2
[61] While maintaining internal temperature below 10°C, 76.5 g of p-
methoxyphenylacetonitrile diluted with 75 ml of toluene was slowly added to
lithium
diisopropylamide solution made by adding 73 ml of diisopropylamine to 325 ml
of 6M
BuLi and 300 ml of toluene under a nitrogen atmosphere. After 30 minutes of
stirring,
46.0g of cyclohexanone diluted with 50m1 of toluene was slowly added with the
internal temperature kept below 10°C, and stirred for more than about
30 minutes.
The resulting solution was then added to 100m1 of 12N HCl aqueous solution and
1 L
of cold purified water. After filtration, the filtrate was diluted with
dichloromethane
and washed with purified water. With the dichloromethane replaced with
diisopropyl
ether, the solvent was removed under reduced pressure and the filtrate was
cooled down
and filtered to yield 91.0g of a white solid as the target compound, 1-
[cyano(4-
methoxyphenyl)methyl]methyl]cyclohexanol (yield 79%).
[62] Reference Example
[63] 12 g (0.05 mole) of 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol
prepared in Example 1 was dissolved in 250m1 of a mixture of ammonia and
ethanol,
with the mixing ratio of 2:8 (vlv), and 2.8g of 5% rhodium on alumina was
added to
cause a hydrogenation reaction. The catalyst was filtered out and washed with
ethanol
and the filtrate was concentrated under reduced pressure to provide a compound
in the
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form of oil, which was then diluted with 100m1 of toluene and acidified to pH
2.
After filtration, 9 g of a white solid was obtained as the target compound, 1-
[2-amino-
1-(4-methoxyphenyl)ethyl]cyclohexanol (yield 57%).
[64] Melting point: 168 to 172 °C.
[65] Mass Spectral Analysis: Molecular weight 250 [M+ by C.LM.S.]
[66] 1H NMR Analysis (DMSO-d6): s 7.85 (3H, s, NH3+), 3.75(3H, s, O-
CH3), 3.20 (3H, m, CHCHZ), 1.35 (10H, m, aliphatic cyclohexyl)
[67] As described above, the present invention provides a safe and relatively
simple process for industrial scale mass quantity production of cyclohexanol
derivatives such as 1-[cyano4-methoxyphenyl]methyl]cyclohexanol represented by
formula I. The present invention uses a relatively inexpensive, non-metallic
base in
small amounts, which is environment-friendly and avoids organic solvents, to
produce
highly pure 1-[cyano4-methoxyphenyl] methyl]cyclohexanol in high yield.
16
