U.S. patent application number 09/878000 was filed with the patent office on 2002-01-31 for process for the preparation of 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone and an intermediate useful therefore.
Invention is credited to Wong, George S. K..
Application Number | 20020013489 09/878000 |
Document ID | / |
Family ID | 22784187 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013489 |
Kind Code |
A1 |
Wong, George S. K. |
January 31, 2002 |
Process for the preparation of 2,2-dimethyl-5-(4-chlorobenzyl)
cyclopentanone and an intermediate useful therefore
Abstract
There is provided a process for the prepartion of
2,2-dimethyl-5-(4-chloro- benzyl)cyclopentanone 1 a key
intermediate in the production of the antifungal agent metconazole.
Also provided is the intermediate compound,
5-(4-chlorobenzyl)-5-cyano-2,2- -dimethylcyclopentanone. 2
Inventors: |
Wong, George S. K.; (Summit,
NJ) |
Correspondence
Address: |
Intellectual Property Department
BASF Corporation
3000 Continental Drive - North
Mount Olive
NJ
07828-1234
US
|
Family ID: |
22784187 |
Appl. No.: |
09/878000 |
Filed: |
June 8, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60210768 |
Jun 12, 2000 |
|
|
|
Current U.S.
Class: |
558/426 ;
568/325 |
Current CPC
Class: |
C07C 2601/08 20170501;
C07C 49/697 20130101; C07C 45/673 20130101; C07C 255/46 20130101;
C07C 45/673 20130101; C07C 49/697 20130101 |
Class at
Publication: |
558/426 ;
568/325 |
International
Class: |
C07C 049/792; C07C
255/32 |
Claims
What is claimed is:
1. The compound,
5-(4-chlorophenyl)-5-cyano-2,2-dimethylcyclopentanone.
2. A process for the preparation of
5-(4-chlorobenzyl)-2,2-dimethylcyclope- ntanone which comprises the
following steps: (a) reacting isobutyronitrile with
1-bromo-3-chloropropane in the presence of a first base in a
non-polar solvent at a temperature of about 15.degree. to
65.degree. C. to afford 5-chloro-2,2-dimethylpentanenitrile; (b)
treating said 5-chloro-2,2-dimethylpentanenitrile with a
cyanide-delivering reagent in the presence of a phase-transfer
catalyst to form 2,2-dimethyladiponitril- e; c) cyclizing said
2,2-dimethyladiponitrile in the presence of a second base in a
non-polar solvent to afford 3,3-dimethyl-2-amino-1-cyanocyclope-
ntene; (d) hydrolyzing said
3,3-dimethyl-2-amino-1-cyanocyclopentene with acid to give
5-cyano-2,2-dimethylcyclopentanone; (e) treating said
5-cyano-2,2-dimethylcyclopentanone with 4-chlorobenzyl chloride in
the presence of a third base in a polar aprotic solvent to form
5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone; and (f)
hydrolyzing said
5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone in the
presence of an acid to give the desired
5-(4-chlorobenzyl)-2,2-dimeth- ylcyclopentanone compound.
3. The process according to claim 2 wherein said first base is
lithium bis(trimethylsilyl)amide or lithium amide.
4. The process according to claim 2 wherein said non-polar solvent
is hexane, heptane, toluene or ethylbenzene.
5. The process according to claim 2 wherein said second base is
sodium t-butoxide.
6. The process according to claim 2 wherein said cyanide-delivering
reagent is sodium cyanide.
7. The process according to claim 2 wherein said phase-transfer
catalyst is tetrabutylammonium hydrogen sulfate.
8. The process according to claim 2 wherein said third base is
sodium hydride.
9. The process according to claim 2 wherein said polar aprotic
solvent is N,N-dimethylformamide.
10. The process according to claim 2 wherein said acid is sulfuric
acid.
11. The process according to claim 4 wherein the first base is
lithium bis(trimethylsilyl)amide or lithium amide and the
cyanide-delivering agent is sodium cyanide.
12. The process according to claim 11 wherein the second base is
sodium t-butoxide and the polar aprotic solvent is
N,N-dimethylformamide.
13. The process according to claim 12 wherein the third base is
sodium hydride.
14. The process according to claim 13 wherein the acid is sulfuric
acid.
Description
[0001] This application claims the benefit under 35 U.S.C. 119 (e)
of provisional application 60/210,768 filed Jun. 12, 2000.
BACKGROUND OF THE INVENTION
[0002] A process for the preparation
2,2-dimethyl-5-(4-chlorobenzyl)-cyclo- pentanone, a key
intermediate in the production of the anti-fungal agent metconazole
is described in U.S. Pat. No. 5,028,254 and U.S. Pat. No.
4,938,792. Metconazole is highly effective for the control of a
wide range of foliar diseases caused by phytopathogenic fungi which
damage a number of important agronomic crops. Alternative,
effective methods for the preparation of metconazole contribute to
the enhanced availability of this useful fungicidal agent.
Although, methods such as those mentioned hereinabove are known,
said methods require extreme low temperature conditions for the
prepartion of the intermediate 2,2-dimethyl-5-(4-chlor- obenzyl)
cyclopenanone.
[0003] Therefore, the preparation of
2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone continues to be
studied for new and improved procedures which are more efficient
and environmentally benign.
[0004] It is an object of the present invention to provide an
improved process for the preparation of
2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone.
[0005] It is a further object of the invention to provide a
compound, 5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone,
useful in an improved manufacture of metconazole.
SUMMARY OF THE INVENTION
[0006] There is provided a process for the preparation of
2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (I) 3
[0007] which comprises the following steps:
[0008] (a) reacting isobutyronitrile with 1-bromo-3-chloropropane
in the presence of a first base in a non-polar solvent at a
temperature of about 15.degree. to 65.degree. C. to afford
5-chloro-2,2-dimethylpentanenitrile- ;
[0009] (b) treating said 5-chloro-2,2-dimethylpentanenitrile with a
cyanide-delivering reagent in the presence of a phase-transfer
catalyst to form 2,2-dimethyladiponitrile;
[0010] (c) cyclizing said 2,2-dimethyladiponitrile in the presence
of a second base in a non-polar solvent to afford
3,3-dimethyl-2-amino-1-cyano- cyclopentene;
[0011] (d) hydrolyzing said
3,3-dimethyl-2-amino-1-cyanocyclopentene in the presence of an acid
to give 5-cyano-2,2-dimethylcyclopentanone;
[0012] (e) treating said 5-cyano-2,2-dimethylcyclopentanone with
4-chlorobenzyl chloride in the presence of a third base in a polar
aprotic solvent to form
5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopenta- none; and
[0013] (f) hydrolyzing said
5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclope- ntanone in the
presence of an acid to give the desired compound
5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone.
[0014] The invention further provides the compound,
5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Previously described conditions for effecting the alkylation
of isobutyronitrile with 1-bromo-3-chloropropane require the use of
polar solvents and a reaction temperature of -78.degree. C. (S. S.
Kulp, V. B. Fish and N. R. Easton, Can. J. Chem., 1965, 43,2512; M.
N. Romanelli, F. Gaultiere, R. Mannhold and A. Chiarini, Farmaco,
1989, 44, 449). This temperature requirement is not readily
attainable on a large manufacturing scale. Surprisingly, it has now
been found that the alkylation of isobutyronitrile in a non-polar
solvent,in the presence of a base such as lithium
bis(trimethylsilylamide) or lithium dimethylamide proceeds in high
yield when conducted at temperatures up to 65.degree. C., thus
permitting a more efficient and effective manufacturing
procedure.
[0016] Advantageously, the present invention provides an effective
and practical method for the preparation of
5-(4-chlorobenzyl)-2,2-dimethylcy- clopentanone, a key intermediate
in the production of the antifungal agent metconazole.
[0017] In accordance with the process of the invention
isobutyronitrile (III) is alkylated with at least one molar
equivalent of 1-bromo-3-chloropropane in a non-polar solvent in the
presence of a first base to yield
5-chloro-2,2-dimethylpentanenitrile (IV); said
5-chloro-2,2-dimethylpentanenitrile (IV) is treated with a
cyanide-delivering reagent in the presence of a phase-transfer
catalyst (Ptc) to yield 2,2-dimethyladiponitrile (V); said
2,2-dimethyladiponitril- e (V) is cyclized in the presence of a
second base in a non-polar solvent to form
3,3-dimethyl-2-amino-1-cyanocyclopentene. Advantageously, the
thus-formed 3,3-dimethyl-2-amino-1-cyanocyclopentene (VI) may be
carried on without isolation or purification to acid hydrolysis to
form 5-cyano-2,2-dimethylcyclopentanone (VII). Said cyclopentanone
(VII) is then alkylated with 4-chlorobenzyl chloride in the
presence of a third base in a polar aprotic solvent to give the
intermediate 5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone
(II). Finally, said pentanone is hydrolyzed with acid to provide
5-(4-chlorobenzyl)-2,2-dimet- hylcyclopentanone (I). The process is
depicted in Flow Diagram I. 4
[0018] Non-polar solvents suitable for use in the process of the
invention are essentially water-free solvents such as aromatic
hydrocarbons (e.g. toluene, benzene, xylene, naphthalene or the
like, preferably toluene), halogenated aromatic hydrocarbons (e.g.
chlorobenzene, dichlorobenzene or the like), hydrocarbons (e.g.
pentane, hexane or the like), halogenated hydrocarbons (e.g.
chloroform, methylene chloride, dichlorethane, or the like, or any
of the conventional, preferably water immiscible, organic non-polar
solvents.
[0019] Preferred non-polar solvents suitable for use in the process
of the invention are hydrocarbons and aromatic hydrocarbons such as
hexane, heptane, toluene, ethylbenzene or the like.
[0020] Polar aprotic solvents suitable for use in the inventive
process are dimethyl formamide, dimethylsulfoxide, tetrahydrofuran,
diethyl ether, or the like.
[0021] Preferred polar aprotic solvents suitable for use in the
process of the invention are dimethylformamide and
dimethylsulfoxide.
[0022] Bases suitable for use as the first base in the inventive
process are alkali metal amides, such as lithium amide, lithium
dimethylamide, sodium bis(trimethylsilyl)amide,
magnesiochlorodiethylamide (Et.sub.2NMgCl), preferably lithium
bis(trimethylsilyl)amide or lithium amide.
[0023] Bases suitable for use as the second base in the inventive
process are alkali metal alkoxides, such as sodium or potassium
C.sub.1-C.sub.4alkoxide, preferably sodium t-butoxide.
[0024] Bases suitable for use as the third base in the inventive
process are alkali metal hydrides, such as sodium, potassium or
lithium hydride, preferably sodium hydride.
[0025] Bases may be present in amounts ranging from catalytic to
excess amounts such as 10 mole % to 4.0 molar excess.
[0026] Acids suitable for use in the process of the invention
include strong mineral acids such as HCl, HBr or H.sub.2SO.sub.4,
preferably H.sub.2SO.sub.4.
[0027] The term catalysis refers to the enhancement of the rate of
a reaction by the presence of a base when the base is left
unchanged by the overall reaction. A phase transfer catalyst is a
compound which facilitates the transfer of reactants across the
interface of a two-phase organic-water system thereby enhancing the
rate of reaction in said systems.
[0028] Phase-transfer catalysts suitable for use in the process of
this invention are tetrabutylammonium hydrogen sulfate,
tetrabutylammonium bromide, benzyltriethylammonium chloride, or the
like, preferably tetrabutylammonium hydrogen sulfate.
[0029] In actual practice, isobutyronitrile (III) is alkylated with
at least one molar equivalent of 1-bromo-3-chloropropane in a
non-polar solvent, preferably a hydrocarbon, more preferably
hexane, in the presence of a first base, preferably an alkali metal
amide, more preferably lithium bis(trimethylsilylamide) or lithium
dimethylamide, to yield 5-chloro-2,2-dimethylpentanenitrile (IV);
said 5-chloro-2,2-dimethylpentanenitrile (IV) is treated with a
cyanide-delivering reagent, preferably an alkali metal cyanide,
more preferably sodium cyanide, in the presence of a phase-transfer
catalyst, preferably tetrabutylammonium hydrogen sulfate, to yield
2,2-dimethyladiponitrile (V); said 2,2-dimethyladiponitrile (V) is
cyclized in the presence of a second base, preferably an alkali
metal alkoxide, more preferably sodium t-butoxide, in a non-polar
solvent, preferably an aromatic hydrocarbon, more preferably
toluene; the thus formed 3,3-dimethyl-2-amino-1-cyanocyclopentene
(VI) advantageously may be carried on without isolation or
purification to acid hydrolysis, preferably with a strong mineral
acid, more preferably with sulfuric acid, to form
5-cyano-2,2-dimethylcyclopentanone (VII); said cyclopentanone (VII)
is alkylated with 4-chlorobenzyl chloride in the presence of a
third base, preferably an alkali metal hydride, more preferably
sodium hydride, in a polar aprotic solvent, preferably
N,N-dimethylformamide, to give the intermediate compound
5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone (II); said
compound is hydrolyzed with acid, preferably strong mineral acid,
more preferably sulfuric acid, to provide the desired product
5-(4-chlorobenzyl)-2,2-dime- thylcyclopentanone (I).
[0030] In order to present a clear understanding of the invention,
the following examples are set forth below. These examples are
merely illustrative, and are not to be understood as limiting the
scope and underlying principles of the invention in any way.
EXAMPLE 1
Preparation of 5-Chloro-2,2-dimethylpentanenitrile
[0031] 5
[0032] a) Lithium bis(trimethylsilylamide) Procedure
[0033] Isobutyronitrile (13.8 g, 0.20 mole), and
1-bromo-3-chloropropane (34.5 g, 0.22) are added sequentially to a
stirred 1 M solution of lithium bis(trimethylsilylamide) (200 ml,
0.20 mole) in hexanes, stirred for two hours at 69.degree. C. and
quenched with water. The phases are separated and the organic phase
is concentrated in vacuo to afford the title product as an oil,
38.9 g (64% pure, 85.7% yield), identified via gas
chromatography.
[0034] b) Lithium dimethylamide Procedure
[0035] Isobutyronitrile (9.9 g, 0.143 mole) is added dropwise to a
suspension of lithium dimethylamide (7.3 g, 0.143 mole) in hexanes.
The resultant anion solution is added to a solution of
1-bromo-3-chloropropane (24.8 g, 0.16 mole) in hexane at 5.degree.
to 10.degree. C., warmed to room temperature, and quenched with
water. The phases are separated and the organic phase is
concentrated in vacuo to afford the title product as a yellow oil,
19.0 g(80% pure, 90.9% yield), identified via gas
chromatography.
EXAMPLE 2
Preparation of 2,2-Dimethyladiponitrile
[0036] 6
[0037] A mixture of 5-chloro-2,2-dimethylpentanenitrile (145.6 g, 1
mole), sodium cyanide (98.0 g, 2 mole), and tetrabutylammonium
hydrogen sulfate (10.2 g, 0.03 mole) in water is stirred for 2
hours at 100.degree. C., cooled to room temperature and extracted
with ethyl acetate. The extracts are combined, washed with water,
and concentrated in vacuo to give a brown oil. The oil is distilled
(0.2 torr, 90.degree. C.) to afford the title product as a
colorless oil, 123.7 g (94.9% pure, 91% yield) identified by gas
chromatography.
EXAMPLE 3
Preparation of 5-Cyano-2,2-dimethylcyclopentanone
[0038] 7
[0039] A suspension of potassium t-butoxide (60.2 g, 0.54 mole) in
toluene is treated with 2,2-dimethyladiponitrile (120.7 g, 0.87
mole) at 80.degree. C., stirred for 2 hours, cooled to less than
30.degree. C., and quenched with water. The phases are separated,
the organic phase is stirred with 3N hydrochloric acid and
filtered. The filtrate is concentrated in vacuo to give an oil
which is distilled (2 torr, 150.degree. C.) twice to afford the
title product as a colorless oil, 65.7 g (98.5% pure, 55% yield),
identified by gas chromatography.
EXAMPLE 4
Preparation of
5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone
[0040] 8
[0041] A 60% mineral oil suspension of sodium hydride (12.7 g, 0.31
mole) in dimethylformamide under nitrogen, is treated with
cyano-2,2-dimethylcyclopentanone over a 50 minute period at
ice-bath temperatures, then with a solution of 4-chloro-benzyl
chloride (50.2 g, 0.31 mole) over a 30 minute period, stirred for 5
hours and quenched with water. The resultant mixture is extracted
with ethyl acetate. The extracts are combined, washed with water
and concentrated in vacuo to afford a solid residue. The residue is
titurated with hexane to afford the title product as white
crystals, 59.3 g (72.6% yield), mp 101.degree.-103.degree. C.,
identified by gas chromatography.
EXAMPLE 5
Preparation of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone
[0042] 9
[0043] A suspension of
5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentano- ne (5.0 g,
0.02 mole) in water is treated with sulfuric acid (50%, 25 ml),
stirred for 5 hours at 140.degree. C., cooled to room temperature,
and extracted with toluene. The extracts are combined, washed with
water, filtered through celite and concentrated in vacuo to afford
the title product as a dark oil, 5.5 g (76.5% pure, 93.1% yield),
identified by gas chromatography.
* * * * *