Preparation of 2-chloro-3-cyano-quinolines

A process is described for introducing nitrile groups to compounds susceptible to Vilsmeier formylation via two sequential reactions in a single reaction medium. In the first reaction, the susceptible compound is reacted with a Vilsmeier reagent in the presence of phosphorus oxychloride. In the second reaction, a hydroxylamine salt is introduced to the medium in the presence of at least an equivalent amount of phosphorus oxychloride.

BACKGROUND OF THE INVENTION 
This invention relates to a process for introducing nitrile groups to 
compounds susceptible to Vilsmeier formylation. More specifically, a 
process is disclosed for introducing a nitrile group via two sequential 
reactions in a single reaction medium. 
The formylation of aromatic and heterocyclic compounds by reaction with 
dialkylformamides or alkylarylformamides in the presence of phosphorus 
oxychloride is well known in the art. This reaction is commonly referred 
to as the Vilsmeier reaction. 
It is also known that aldehydes can be converted to nitriles by reacting 
them with hydroxylamine hydrochloride in the presence of concentrated HCl 
or a dehydrating agent. J. March, Advanced Organic Chemistry, 2nd Ed., p. 
827 (1977); Findlay et al, Can. J. Chem., 45, 1014 (1967) and VanEs, J. 
Chem. Soc., 1564 (1965). In general, this nucleophilic displacement 
reaction proceeds most readily in base. 
There is no suggestion in the prior art that the conversion of an aldehyde 
to a nitrile using hydroxylamine hydrochloride would proceed readily in 
the presence of such a strong acidic dehydrating agent as phosphorus 
oxychloride. The skilled artisan would expect POCl.sub.3 to react rapidly 
and possibly explosively with the oxime intermediate produced by reaction 
between the hydroxylamine and aldehyde. Also the reaction between the 
hydroxylamine and aldehyde would be predicted to be very slow under such 
acidic conditions. Other undesirable reactions between the hydroxylamine 
and POCl.sub.3 might also be anticipated. 
A convenient method of introducing nitrile groups to aromatic or 
heterocyclic compounds in a single reaction medium without isolation of 
intermediates would be desirable. The subject process is such a method. 
SUMMARY OF THE INVENTION 
The subject invention is a method of introducing a nitrile group to a 
compound susceptible to Vilsmeier formylation. This method consists 
essentially of two steps. In the first step, the compound susceptible to 
Vilsmeier formylation is reacted in a liquid medium with a Vilsmeier 
reagent in the presence of phosphorus oxychloride so as to introduce 
aldehyde or precursors of aldehyde moieties. In the second step, 
hydroxylamine or a strong acid salt thereof is introduced to the liquid 
medium which also contains at least an equivalent amount of phosphorus 
oxychloride, so as to convert a major portion of the iminium salt and 
aldehyde moieties present to nitrile groups. 
DETAILED DESCRIPTION OF THE INVENTION 
Formylation Reaction 
The Vilsmeier reagents referred to herein are well-known compounds. 
Generally, they are reaction products of POCl.sub.3 and disubstituted 
amides. These diamides generally correspond to the formula 
##STR1## 
wherein R.sup.1 is an alkyl group and R.sup.2 is an alkyl or aryl group. 
Preferably R.sup.1 is a C.sub.1 to C.sub.4 alkyl, most preferably methyl. 
Preferably R.sup.2 is phenyl or a C.sub.1 to C.sub.4 alkyl, most 
preferably methyl or phenyl. 
Compounds susceptible to Vilsmeier formylation are likewise well-known. 
These compounds are generally aromatic hydrocarbons or heterocycles which 
have an aromatic system more "electron rich" than benzene. Certain 
unsaturated aliphatic compounds bearing electron-donating substituents are 
also operable, e.g., 1,2-dimethoxyethane. Preferred heterocyclic compounds 
include thiophene or pyrrole, optionally substituted with one or more 
substituents. Preferred aromatic carbocyclic compounds include a benzene 
bearing at least one substituent having more electron donating character 
than hydrogen. 
Some of these preferred reactants can be represented by the following 
formulae: 
##STR2## 
wherein R at each occurrence is independently --SC.sub.n H.sub.2n+1, 
--OC.sub.n H.sub.2n+1, --C.sub.n H.sub.2n+1 or 
##STR3## 
p is an integer from 0 to 3, q is an integer from 1 to 5, and n is an 
integer from 1 to 10, preferably 1. R can also be selected from --Br, 
--Cl, --CN, --C.sub.n H.sub.2n CN or other electron withdrawing groups 
provided the compound remains more electron-rich than benzene. Preferably, 
p is an integer from 0 to 2, more preferably 0 or 1. Preferably q is 1 or 
2. 
In one preferred embodiment of the instant process the compound susceptible 
to Vilsmeier formylation corresponds to the formula 
##STR4## 
wherein R.sup.3 is independently at each occurrence --OC.sub.n H.sub.2n+1, 
--SC.sub.n H.sub.2n+1 or --C.sub.n H.sub.2n+1, m is an integer from 0 to 4 
and n is as described hereinbefore. This compound may bear one or more 
--Cl or --Br moieties, so long as there are sufficient electron donating 
substituents to make the aromatic ring more electron-rich than benzene. 
The formylation of this compound in the presence of excess POCl.sub.3 can 
produce in good yield a quinoline corresponding to the formula 
##STR5## 
This reaction is described in some detail by Meth-Cohn et al in J. Chem. 
Soc., Perkin Trans. I, pp. 1520-1543 (1981). 
The compound susceptible to Vilsmeier formylation and the Vilsmeier reagent 
are brought together at conditions known in the art to promote 
formylation. Conveniently, the Vilsmeier reagent and the susceptible 
compound are brought together in a stoichiometric ratio. A slight excess 
of the Vilsmeier reagent is preferred. The reactants are desirably 
combined slowly so as to avoid an excessive exotherm. 
The temperature during the formylation is desirably maintained so that the 
desired reaction is not unduly slow. The reaction temperature should not 
be so high as to initiate an uncontrolled exothermic reaction or produce 
other deleterious effects. A reaction temperature in the range from about 
70.degree. to about 110.degree. C. is generally preferred. Agitation of 
the medium to promote mass and heat transfer is advantageous. 
The reaction medium desirably contains an excess of POCl.sub.3 over that 
required to form the Vilsmeier reagent. An excess of at least 25 percent 
over the quantity of POCl.sub.3 reacted with the diamide to form the 
Vilsmeier reagent is generally preferred. The POCl.sub.3 can be employed 
in such excess as to be the major component in the reaction medium. 
However, generally it is preferred that the POCl.sub.3 constitute no more 
than about 75 weight percent of the reaction medium. 
The formylation reaction can be conducted in the presence of diluents inert 
in the reaction, such as 1,2-dichloroethane. However, recovery of the 
final product from the reaction medium is generally facilitated by 
conducting the reactions without inert diluents, i.e., neat. 
The product of the formylation reaction is an iminium salt, i.e., 
##STR6## 
wherein "V" is derived from the compound susceptible to formylation and 
R.sup.1 and R.sup.2 are as defined hereinbefore. The iminium salt in the 
presence of water hydrolyzes spontaneously to an aldehyde and an amine. 
However, it is advantageous to conduct the instant reaction at anhydrous 
conditions. Consequently, the iminium salt is not generally hydrolyzed in 
the subject process. 
Conversion to Nitrile 
The product of the formylation reaction can be reacted with hydroxylamine 
or a strong acid salt thereof in the same reaction medium to convert the 
aldehyde or iminium salt moiety to a nitrile group. The formylation 
reaction product is not isolated. No additional POCl.sub.3 need be added 
to the reaction mixture, if the excess POCl.sub.3 stated to be 
advantageous was employed in the formylation reaction. Generally, it is 
desirable that the POCl.sub.3 relative to the hydroxylamine be present in 
a molar ratio in the range from about 2:1 to about 6:1. An approximately 
stoichiometric amount or slight excess of NH.sub.2 OH relative to the 
aldehydes or aldehyde precursors present is desirable. 
The hydroxylamine reactant is desirably used in the form of a salt of a 
strong mineral acid, e.g., HCl, H.sub.2 SO.sub.4 or HBr. The hydrochloride 
salt of hydroxylamine is particularly preferred. Although the order in 
which the reactants are combined is not critical, preferably the 
hydroxylamine is added to the product of the formylation reaction at a 
rate which results in a controllable exotherm and gas evolving at a rate 
which avoids excessive foaming of the medium. An inert gas, such as 
nitrogen, can be blown over the medium to moderate foaming. 
The temperature during conversion to the nitrile can generally be in the 
same range as employed during the formylation reaction. Temperatures in 
the range from about 60.degree. to about 110.degree. C. are preferred for 
reasons of convenience. 
Recovery of Product 
The product bearing the nitrile group can be readily recovered by 
conventional methods known in the art. Typically, sufficient water is 
added to the reaction mixture to react with any remaining POCl.sub.3 
before attempting to recover the product. 
The desired product often precipitates from the reaction mixture and can be 
recovered by filtration. The precipitate can be recrystallized in CH.sub.2 
Cl.sub.2 or other similar organic solvents to increase purity. 
Alternatively, the reaction medium after quenching with H.sub.2 O can be 
contacted with an organic solvent such as CH.sub.2 Cl.sub.2 to extract the 
product. The organic solvent can then be separated and evaporated from the 
product. 
Other methods for recovering the desired product are known in the art. The 
subject invention is not limited to any specific method for recovery of 
this product. 
The resulting products are useful as intermediates for a variety of 
pharmaceutical or other compositions. See, e.g., U.S. patent application 
Ser. No. 478,964, filed Mar. 25, 1983, U.S. Pat. No. 4,496,569 issued 
11/29/85. 
The following examples are presented to illustrate the invention but are 
not otherwise intended to limit the invention.

EXAMPLE 1 
To a reaction vessel containing 25 grams (0.18 mole) of acetanilide were 
added concurrently 41 grams (0.54 mole) of dimethylformamide (DMF) and 118 
milliliters (1.26 moles) of POCl.sub.3 over a period of 15 minutes. During 
addition the reaction mixture was stirred, purged with nitrogen gas and 
maintained at a temperature of 60.degree. to 75.degree. C. After addition, 
the stirred mixture was maintained at 75.degree. C. for 20 hours. 
The mixture was allowed to cool to 62.degree. C. and then 14 grams (0.2 
mole) of NH.sub.2 OH HCl was added all at one time to the stirred mixture. 
(Slower addition of NH.sub.2 OH HCl is recommended when larger quantities 
are involved.) Gas evolution was observed after about 2 minutes. The 
temperature of the reaction medium increased due to the exothermic 
reaction to 77.degree. C. over a period of 15 minutes. The mixture was 
allowed to cool to ambient temperature (about 20.degree. C.). A yellow, 
dense, solid precipitate was observed. 
To the resulting mixture was added with vigorous stirring 100 milliliters 
(ml) of distilled water. The mixture was filtered to recover 24.3 grams 
(g) of a yellow solid having a melting point of 145.degree.-160.degree. C. 
This crude product was recrystallized in CH.sub.2 Cl.sub.2 to recover 15.5 
grams of light yellow crystals having a melting point of 165.degree. C. 
The product was identified by infrared spectroscopy, proton magnetic 
resonance analysis and other conventional techniques to correspond to the 
formula 
##STR7## 
The isolated yield of this product was 44%. 
EXAMPLE 2 
In a manner and mole ratios otherwise generally similar to Example 1, 
dimethylaniline (instead of acetanilide) was reacted with 
dimethylformamide and POCl.sub.3 for two hours at reflux. The mixture was 
cooled to 70.degree. C. and hydroxylamine.HCl was added. The exothermic 
reaction raised the temperature of the medium to 90.degree. C. 
Water was added to the reaction mixture after the reaction appeared 
complete. The mixture was extracted with CH.sub.2 Cl.sub.2. The CH.sub.2 
Cl.sub.2 was separated and then evaporated to yield a dark brown oil. This 
oil was determined by conventional analytical techniques to consist 
predominantly of dimethylaminobenzonitrile, 
##STR8## 
EXAMPLE 3 
3,4-Dimethoxyacetanilide (25 g, 0.13 mole) was added to a 300 ml 
round-bottom flask containing phosphoryl chloride (119 ml, 1.3 mole). DMF 
(24 g, 0.32 mole) was added dropwise to the stirred solution at a rate 
such that the temperature of the reaction mixture remained below 
80.degree.-90.degree. C. After the addition was complete, the reaction 
mixture was heated to reflux (.about.105.degree. C.) for 2.5 hours. 
Hydroxylamine.HCl (13.3 g, 0.19 mole) was added to the reaction mixture in 
small portions over a period of about 20 minutes. Vigorous foaming (HCl 
evolution) occurred a few seconds after addition of each portion of 
NH.sub.2 OH HCl, and sufficient time for the foam layer to form and 
subside was allowed between portions. 
After addition of hydroxylamine was complete, the mixture was heated to 
reflux for an additional 10-15 minutes, and the hot reaction mixture was 
quenched in water (.about.600 ml). The mixture was filtered, yielding 21.8 
g of a brown solid. The solid was analyzed via proton magnetic resonance 
analysis and confirmed to correspond to predominantly 
2-chloro-6,7-dimethyoxy-3-quinolinecarbonitrile. The crude product was 
dissolved in 300 ml of hot chloroform, treated with charcoal and filtered. 
The filtrate was combined with ethanol and the resulting solution refluxed 
until crystallization was observed. The solution was cooled and filtered 
to recover 15.7 g of light yellow product. 
EXAMPLE 4 
4-Methylthioacetanilide (63 g, 0.35 mole) was added to a reaction flask 
containing phosphoryl chloride (2.24 ml, 2.45 mole). Dimethylformamide (77 
g, 1.05 mole) was added dropwise to the stirred solution at a rate such 
that the temperature of the reaction mixture remained below 75.degree. C. 
After the addition was completed, the reaction mixture was heated to 
75.degree. C. for 16 hours. 
Hydroxylamine hydrochloride (34.7 g, 0.5 mole) was added to the reaction 
mixture in small portions over a period of about 15 minutes. The 
temperature of the reaction mixture rose to 95.degree. C. over the course 
of addition. After an additional 15 minutes at 95.degree. C., the reaction 
was quenched with water (1500 ml). The resulting precipitate was collected 
and dried to recover 42.7 g (52% yield) of crude product. The product was 
analyzed by conventional methods and determined to correspond to the 
formula: 
##STR9## 
A sample was recrystallized from methylene chloride/hexane to yield yellow 
needles melting at 227.degree.-228.degree. C. 
EXAMPLE 5 
N-(thien-3-yl)-acetamide (3.0 g, 0.02 mole) was added to a solution of 
phosphoryl chloride (23 g, 0.15 mole) and dimethylformamide (4.3 g, 0.059 
mole) at ambient temperatures. The resulting solution was heated to reflux 
for 1.5 hours, and then NH.sub.2 OH HCl (2 g, 0.03 mole) was added slowly 
over a period of 10 minutes. After the reaction subsided, the mixture was 
cooled to 25.degree. C. and filtered. The collected solid was washed with 
water and dried to yield 2.1 g (51%) of product. The light yellow solid 
melted at 222.degree.-224.degree. C. 
The product was confirmed by conventional analytical methods to correspond 
to the formula: 
##STR10## 
EXAMPLE 6 
A stirred mixture of 3-thienylacetonitrile (25 g, 0.21 mole), phosphoryl 
chloride (135 ml, 1.47 mole), and DMF (46 g, 0.63 mole) was heated to 
reflux for 2.5 hours. Hydroxylamine hydrochloride (29.2 g, 0.4 mole) was 
added in portions over a period of 20 minutes. After the addition was 
complete, the mixture was cooled and filtered to yield 26 g of product as 
a yellow solid. A sample was recrystallized from acetone to give fluffy 
white needles, m.p. 208.degree.-209.degree. C. 
The product was confirmed by conventional analytical methods to correspond 
to the formula: