Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
1998-05-28
2003-04-08
McKane, Joseph K. (Department: 1676)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
Reexamination Certificate
active
06545173
ABSTRACT:
The present invention relates to an improved process for the preparation of arylcyclobutyl cyanides. 1-(4-Chlorophenyl)cyclobutyl cyanide is an intermediate useful for the preparation of sibutramine, N-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-N,N-dimethylamine. Sibutramine is useful in the treatment of depression, Parkinson's disease, obesity, Non Insulin Dependent Diabetes Mellitus (NIDDM) and epilepsy.
The reaction of phenylacetonitrile with a 1,3-dihalopropane in aqueous sodium hydroxide using benzyltriethylammonium chloride as a catalyst to give 1-phenylcyclobutyl cyanide is reported in Rocz. Chem. 40, 1647, (1966). However, the yield is low (26%) and the amount of monoalkylated uncyclised product formed is significant (20%).
1-(4-Chlorophenyl)cyclobutyl cyanide was prepared by reacting 4-chlorophenylacetonitrile with 1,3-dibromobutane in a mixture of dimethyl sulphoxide and ether at 25-35° C. using sodium hydride as the base (J.Org. Chem. 36 (9), 1308, 1971). It is also disclosed that the process is effective if the mineral oil is removed from the sodium hydride by washing with toluene and then adding a slurry of sodium hydride in toluene to the dimethyl sulphoxide. Similar preparations are also described in U.S. Pat. Nos. 4,235,926, 3,526,656, 4,348,409, 5,405,866 and J.Organomet. Chem. 448, 1-2, p9-14(1993). The yields quoted vary between 43% and 78%.
GB2098602A discloses a process for the preparation of 1-(4-chlorophenyl)cyclobutyl cyanide comprising the reaction of 4-chlorophenylacetonitrile with a 1,3-dibromopropane in the presence of sodium hydride (dispersed in mineral oil). The reaction is described as being carried out in dry dimethyl sulphoxide under nitrogen with stirring initially at room temperature, then at a temperature in the range 30 to 35° C. for 2 hours. This preparation is also reported in EP 191542 and GB 2127819.
The presence of dimethyl sulphoxide in the aqueous waste from these processes renders the waste ineligible for discharge to the chemical effluent drain of chemical production plants. The waste therefore has to be specially disposed of. This leads to high production costs and adverse environmental effects (more resources and energy are required to enable safe disposal of the aqueous waste). It is therefore desirable to find a process which does not require dimethyl sulphoxide.
Initially the reaction was attempted using toluene as the solvent. However, this course of action results in a new problem in that it leads to generation of a significant, delayed exotherm during addition to the reaction mixture of the arylacetonitrile. Such a process is not considered safe. The problem of exotherm generation does not arise when dimethyl sulphoxide is replaced with other water-miscible solvents, such as tetrahydrofuran. However, there is a significant loss of yield which can only be improved by partial distillation of the tetrahydrofuran and addition of a water-immiscible solvent, such as toluene, prior to extraction. Such a procedure has the disadvantages of requiring extra processing (increasing the cost) and of creating a tetrahydrofuran/toluene waste stream, both of which render it unsatisfactory. A similar process is described in WO93/13073 (page 180, Example N10) for producing 1-(4-trifluoromethoxyphenyl)cyclobutyl cyanide. In this process two water-miscible solvents, tetrahydrofuran and dimethylformamide, are used during the reaction, with the water-immiscible solvent ether being used for extraction of the product, to obtain a 61% yield. Again this has the disadvantage of requiring extra processing and producing a tetrahydrofuran/ether waste stream.
WO95/00489 describes a process for producing 1-(2-pyridyl)cyclopropyl cyanide This reaction was carried out in toluene using a 50% aqueous sodium hydroxide solution as the base. The base was added to a stirred mixture of 2-(2-pyridyl)acetonitrile, 1-bromo-2-chloroethane, benzyltriethylammonium chloride and toluene at 25° C. The mixture was then heated at 70-75° C. for 2 hours. The product was extracted into ether and isolated in good yield (~85%). A disadvantage of this process is the presence of water in the initial reaction. This can lead to a rather high level of impurity formation. However, addition of an equivalent amount of a solid base at 25° C. (without the presence of water) would result in a significant delayed exotherm making such a reaction unsafe. Furthermore, it is well known that cyclobutyl rings, as described by the present invention, are considerably less facile to make than the cyclopropyl rings described in the above reference. Therefore it would not be expected that the above procedure would produce as good a yield of cyclobutyl material by using 1-bromo-2-chloropropane instead of 1-bromo-2-chloroethane. Additionally problems can arise from emulsion formation when water is present initially. This may lead to lower yields.
Surprisingly, we have found a process for the preparation of arylcyclobutyl cyanides whereby dimethyl sulphoxide can be excluded, delayed exotherms and mixed solvent waste streams avoided, and impurity formation kept to a minimum whilst still giving the desired product in good yield.
The present invention provides a process for the preparation of compounds of formula I
in which R
1
and R
2
, which may be the same or different, are H, halo, trifluoromethyl, an alkyl group containing 1 to 3 carbon atoms, an alkoxy or alkylthio group containing 1 to 3 carbon atoms, phenyl, or R
1
and R
2
, together with the carbon atoms to which they are attached, form a second benzene ring which may be substituted by one or more substituents selected from halo, an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, or the substituents of the second benzene ring together with the two carbon atoms to which they are attached may form a further benzene ring;
said process comprising the reaction of a 1,3-dihalopropane, a compound of formula II
in which R
1
and R
2
are as defined above, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35° C.
A preferred process according to the present invention provides a process for the preparation of compounds of formula I as defined by formula III
in which R
1
represents halo and R
2
represents hydrogen or halo; comprising the reaction of a 1,3-dihalopropane, a compound of formula II as defined by formula IV
in which R
1
and R
2
are as defined above, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35° C.
A more preferred process according to the present invention provides a process for the preparation of compounds of formula IV in which R
1
represents chloro and R
2
represents hydrogen or chloro comprising the reaction of a 1,3-dihalopropane, a compound of formula IV in which R
1
represents chloro and R
2
represents hydrogen or chloro, respectively, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35° C.
The more preferred processes of the present invention provide a) a process for the preparation of 1-(4-chlorophenyl)cyclobutyl cyanide comprising the reaction of a 1,3-dihalopropane, 4-chlorophenylacetonitrile and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35° C.; and b) a process for the preparation of 1-(3,4-dichlorophenyl)cyclobutyl cyanide and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35° C.
A most preferred process of the present invention provides a process for the preparation of 1-(4-chlorophenyl)cyclobutyl cyanide comprising the reaction of a 1,3-dihalopropane, 4-chlorophenylacetonitrile and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35° C.
Preferably the process comprises the addition of a solution of a 1,3-dihalopropane and a compound of formula II in a substantially dimethyl sulphoxide-free solvent to a
Barker Stephen John
Clark Sharon Michelle
Abbott Laboratories
Keil & Weinkauf
McKane Joseph K.
Murray Joseph
LandOfFree
Process for the preparation of 1-aryl-1-cyanocyclobutane... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of 1-aryl-1-cyanocyclobutane..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of 1-aryl-1-cyanocyclobutane... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3096553