Process for preparing isothiazolones

The process involves the cofeeding of an acrylonitrile with an appropriate alcohol or its equivalent and a strong acid to form an acrylamide which is thiolated to form a mercapto-propionamide which is halogenated to afford the desired biocidally active isothiazolones. This invention relates to a novel process for preparing N-substituted 3-mercaptopropionamides, an intermediate in the preparation of isothiazolones.

Procedures are already known on how to prepare N-substituted 
3-mercaptopropionamides. One procedure involving two steps is Bauer, 
Ludmig and Welsh, Thomas L., Addition of Thiourea to Acrylonitriles and 
Acrylamides, J. Org. Chem 26, p. 1443, 1444, 1445. 
This invention, while still proceeding in two steps, is carried out in a 
single pot. The first step of the instant invention involves treating an 
acrylonitrile with an alcohol (or its equivalent) and a strong inorganic 
acid optionally a solvent may also be employed. When solvents are 
employed, they may be selected from inert or substantially inert organic 
solvents including halobenzenes, glacial acetic acid or primary alcohols. 
The mole ratio of nitrile to alcohol is in the range of from about 0.8 to 
about 1.2 and the mole ratio of strong inorganic acid to unsaturated 
nitrile is in the range of from about 1.5 to about 3.0. The reaction is 
conducted at a temperature in the range of from above the freezing point 
of the reaction mixture to below the boiling point of the lowest boiling 
component for a period of time of from about 1 to about 24 hours to yield 
a compound of the formula: 
##STR1## 
wherein R is an unsubstituted or substituted secondary or tertiary alkyl 
or aralkyl and X is hydrogen, alkyl, such as C.sub.1 -C.sub.5 alkyl and 
the like, alkenyl such as C.sub.2 -C.sub.6 alkenyl and the like, or aryl 
such as phenyl, phenylalkyl and the like. The second step of the invention 
comprising treating the acrylamide (I, supra) with a thiolating agent in 
the presence of a substantially inert organic solvent and an acid catalyst 
for from about 0.5 to about 3 hours at a temperature in the range of from 
about 0.degree. to about 70.degree. C. wherein the mole ratio of the 
thiolating agent to acrylamide is in the range of from about 0.9 to about 
1.2 followed by treating the reaction mixture with a neutralizing amount 
of strong or weak base at a temperature in the range of from about 
0.degree. to about 70.degree. C. for from about 0.5 to about 3 hours to 
afford N-substituted 3-mercaptopropionamide (II, infra) of the formula: 
##STR2## 
mwherein X and R are as defined above, which may be isolated or 
halogenated to afford the desired biocidally active isothiazolone of the 
formula: 
##STR3## 
wherein X and R are as defined above and X.sup.1 is hydrogen or halo. 
The present invention resulted from the fact that 
N-cyclohexyl-3-mercaptopropionamide could not be prepared by presently 
employed procedures for preparing commercial biocides. 
The preparation of two commercial isothiazolone biocides procedes through 
an appropriately substituted mercaptopropionamides. However, all attempts 
to use a similar procedure to prepare a cycloalkyl substituted 
mercaptopropionamide were unsuccessful. 
The procesure has the following advantages: 
Low raw material cost; 
Low operating cost; 
An all liquid process; and 
Nitrosoamine precursor free. 
The key to the process is in cofeeding sulfuric acid and a premixed 
acrylonitrile/alcohol.

DETAILED DESCRIPTION 
The first two steps, which are the center of this invention, are described 
here. 
STEP 1 
##STR4## 
wherein X and R are as defined above. 
Nitriles that are suitable for this preparation are those wherein X is 
hydrogen, alkyl(acylcic or cyclic) such as methyl, ethyl, propyl, butyl, 
pentyl, cyclopentyl, cyclohexyl and the like, or unsubstituted or 
substituted aryl for example phenyl or phenyl substituted with one or more 
dialkyl, halo, nitro, alkoxycarbonyl, alkoxy and the like, and R is 
secondary or tertiary alkyl such as isopropyl, cyclopentyl, cyclohexyl, 
tert-butyl, 2-methyl-2-butyl, or substituted or unsubstituted benzyl 
wherein the substitutent is one or more alkyl, halo, nitro, 
alkoxycarbonyl, alkoxy and the like. (Any olefins corresponding to 
dehydration of ROH, for example the dehydration of cyclohexanol to form 
cyclohexene or otherwise able to form a stable carbonium ion may also be 
used.) Inorganic acids which may be employed include sulfuric, p-toluic, 
hydrochloric, phosphic and the like. Sulfuric acid is the preferred 
inorganic acid. The acid which may be used should have a concentration in 
the range of from 50 to 100% and, preferably in the range of from about 96 
to about 99.5%. The reaction can be carried out neat or in a solvent such 
as inert organic solvents including halobenzene and the like, or glacial 
acetic acid or primary alcohols such as methanol, ethanol and the like. 
Preferably, a premixed solution of nitrile and alcohol (or olefin) and 
concentration sulfuric acid are added concurrently to a heel of solvent or 
sulfuric acid at temperature ranging from about 0.degree. to about 
65.degree. C. The mole ratio of nitril to alcohol is in the range of from 
about 0.8 to about 1.2 and preferably 1.0. The mole ratio of sulfuric acid 
to nitrile (or alcohol) is in the range of from about 1.5 to about 3.0 
and, preferably, 2.0. The temperature at which the reactants are mixed is 
dependent on the substrate nature, and is preferably above the freezing 
point of the reaction mixture and below the boiling point of the lowest 
boiling component. The whole mixture is then held at room temperature or 
some elevated temperature for from 1 to 24 hours. The organic solvent used 
for the entire process is then added to the above mixture followed by slow 
addition of water to produce the desired amide in the organic solvent. 
This mixture is ready for the second step (thiolation) without any further 
isolation or purification. 
The only detected by-products from this procedure are hydrolyzed forms of 
the nitrile such as the amide and acid in about 0.2% weight of the total 
product mixture. Their existence at such small levels has not interfered 
with the thiolation step. 
STEP 2 
##STR5## 
The acrylamide, (I) produced in the previous step is directly treated with 
a thiolating agent selected from thiourea, carbon disulfide/sodium 
sulfide, hydrogen sulfide and the like in the same pot and the mixture is 
allowed to react at a temperature in the range of from about 0.degree. to 
about 70.degree. C. for about 30 minutes to about 3 hours. The mole ratio 
of thiourea to the starting alcohol or nitrile is generally in the range 
of from about 0.9 to about 1.2 and, is preferably 1.05. The thiolation is 
catalyzed by a strong acid such as hydrochloric, sulfuric, perchloric, 
p-toluenesulfonic acids and the like. Hydrochloric and sulfuric acids are 
preferable because they are cheaper and afford better yields. The above 
mixture is then treated with enough base to completely neutralize the 
mixture at a temperature in the range of from about 0.degree. to about 
70.degree. C. for from 30 minutes to 3 hours. (Excess base should be 
avoided as it destroys the mercaptoamide.) Bases that can be employed 
includes sodium hydroxide, ammonium hydroxide, sodium carbonate, sodium 
bicarbonate, alkaline earth oxides, ammonia and the like. Hydrolysis with 
base can be done at lower temperature and brought to higher temperaturer 
for hold. Or it can be done and held at certain chosen temperature. After 
hydrolysis, the mercaptoamide solution in the specified organic solvent is 
dried, preferably by azeotropic removal of water employing those solvents 
which can form azeotropes with water for example chloroform, heptane, 
toluene and the like. Drying of the mercaptoamide solution is necessary as 
a small quantity of water can substantially lower the yield of the 
subsequent halogenation reaction. Other thiolating agents such as sodium 
sulfide, sodium hydrosulfide with combination of carbon disulfide are 
suitable for thiolating acrylamide (I). Typically, carbon disulfide is 
added to a solution of sodium sulfide at a molar ratio of 1.5 to 1.0 in 
methanol and water at temperatures ranging from 0.degree. C. to 30.degree. 
C. Acrylamide or its solution in an inert solvent as defined earlier is 
added to the above mixture at 20.degree.-50.degree. C. The resulting 
mixture is then hydrolyzed with mineral acid preferably hydrochloric or 
sulfuric acid. Upon layer separation and solvent removal, the 
mercaptoamide obtained is thus formulated into an appropriate solvent for 
the subsequent chlorination. The halogenation reaction has been previously 
described in U.S. Pat. No. 4,105,431 which is hereby incorporated by 
reference. 
The following examples illustrate this invention; however, it is to be 
understood that the invention is not limited to the specific examples but 
is as described by the specification and appended claims. 
EXAMPLE 1 
N-Cyclohexyl-3-mercaptopropionamide 
Step A--N-Cyclohexylacrylamide 
Sulfuric acid (46.0 g) was placed in a 3-liter 3-neck flask and heated to 
45.degree. C. A mixture of acrylonitrile (94.5g) and cyclohexanol (180.2g) 
was prepared and added to the flask simultaneously with additional 
sulfuric acid (95.8%, 322.3 g) keeping the temperature at 
45.degree.-55.degree. C. At the end of the addition, the brown solution 
was heated to 60.degree. C. for 3 hours. The mixture was then poured into 
3 liters of ice water with constant stirring. The white precipitate formed 
was filtered, washed with water until filtrate is no longer acidic and 
dried in a vacuum oven at 55.degree. C. to yield N-cyclohexylacrylamide 
(242.4 g, 88%); m.p. 109.degree.-110.degree. C. 
Step B--N-Cyclohexyl-3-mercaptopropionamide 
A mixture of N-cyclohexylacrylamide (15.3 g), concentrated hydrochloric 
acid (19.4 g, 37.6%), thiourea (7.6 g) and water (10 g) was heated to 
60.degree. C. for 2 hours, cooled to 20.degree. C. and sodium hydroxide 
(50%, 16 g) was slowly added under nitrogen keeping the temperature below 
30.degree. C. The resulting mixture was heated to 60.degree. C. for 1 hour 
and extracted with methylene chloride (2.times.50 ml). Removal of the 
solvent afforded N-cyclohexyl-3-mercaptopropionamide (16.9 g) which was 
purified by vacuum distillation at 0.05 mm and 130.degree. C. to yield 
13.7 g of N-cyclohexyl-3-mercaptopropionamide; m.p. 
73.5.degree.-75.5.degree. C. 
EXAMPLE 2 
N-Cyclohexyl-3-mercaptopropionamide 
A pre-mix of acrylonitrile/cyclohexanol (13.3 g/25.1 g) and concentrated 
sulfuric acid (51.1 g) were added through two addition funnels into a 
flask containing chlorobenzene (60 g) at 45.degree.-55.degree. C. The 
mixture was then heated to 60.degree.-70.degree. C. for 3-5 hours and 
cooled to 20.degree. C. when water (150 g) was added slowly. After 30 
minutes stirring, thiourea (19 g) was added and the mixture brought to 
60.degree. C. for 1 hour. On cooling to 20.degree. C., caustic (50%, 80 g) 
was added between 20b 60.degree. C. C under nitrogen and held at 
60.degree. C. for 1 hour. The organic layer was separated and washed with 
warm water to yield 33.9 of N-cyclohexyl-3-mercaptopropionamide in 
chlorobenzene (72.4% yield). 
EXAMPLE 3 
(N-Cyclohexyl-3-mercatopropionamide 
Carbon disulfide (76 g) was added to a mixture of sodium sulfide (55 g) in 
methanol (80 g) and water (80 g) and kept at 20.degree. C. To this was 
slowly added N-cyclohexylacrylamide (100 g) maintaining the pot 
temperature at 20.degree.-30.degree. C. The resulting solution was stirred 
for an additional 2-3 hour and neutralized with concentrated hydrochloric 
acid. The organic layer was separated, washed with water and evaporated to 
dryness to afford 122.6 g of N-cyclohexyl-3-mercaptopropionamide (90.5% 
yield). 
PREATION OF OTHER AMIDES 
EXAMPLE 4 
N-Tert-butylacrylamide 
To a solution of acrylonitrile (5.3 g), tert-butyl alcohol (7.4 g) and 
acetic acid (50 ml), cooled in an ice-bath, was added dropwise 
concentrated sulfuric acid (10.1 g, 97%) at a temperature below 40.degree. 
C. The mixture was held at 40.degree. C. for 1 hour and then poured into 
200 g of ice water with constant stirring. The precipitate was filtered, 
washed with water and dried to afford N-tert-butylacrylamide (10.3 g, 
82.4%); m.p. 124.degree.-6.degree. C. 
EXAMPLE 5 
N-(2-Methyl-2-butyl)methacrylamide 
2-Methyl-2-butene (7.0 g) was added to a stirred mixture of 
methacrylonitrile (6.7 g) in acetic acid (50 ml) and concentrated sulfuric 
acid (10 g) at 10.degree. to 20.degree. C. The mixture was allowed to 
stand overnight at room temperature, and then poured into 200 g of water 
and extracted with methylene chloride (2.times.100 ml). The methylene 
chloride solution was dried over sodium sulfate, the solid filtered off 
and the methylene chloride evaporated to afford an oily product. 
Distillation of the product at 10 mm yielded 
N-(2-methyl-2-butyl)methacrylamide (10.1 g, 65%); bp 84.degree. C. 
PREATION OF ISOTHIAZOLES 
EXAMPLE 6 4,5 
Dichloro-N-cyclohexylisothiazolone 
A 45% solution (100 g) of N-cyclohexyl-3-mercaptopropionamide in 
chlorobenzene was fed into a reactor containing a small heel of the same 
solvent concurrently with chlorine. (The molar feed ratio of chlorine to 
propionamide ranges from 3.0 to 3.6.) The temperature was kept at 
40.degree.-70.degree. C. during the chlorination. After the end of 
propionamide fed, the remaining chlorine to make up to 4.0 equivalents was 
charged at the same temperature. The mixture was held for 30 minutes, 
washed with water, 80 to 85% solvent of the solvent removed and the crude 
material was recrystallized from acetone/water to afford 36.0 of white 
crystals of 4,5-dichloro-N-cyclohexylisothiazolone (59.5% yield); m.p. 
115.degree.-116.degree. C.