US 4,939,266 AGrant
Nitrosamine-Free 3-Isothiazolone
Issue Date:1990-07-03
•2 Claims
Abstract
Nitrosamine-free 3-isothiazolone biocidal compositions suitable for applications where substantial human or animal contact is anticipated, their method of use and process of preparation are disclosed.
Metadata
Assignee
- Rohm and Haas Company
Inventors
- Horst O. Bayer
- Barry C. Lange
- Ramesh B. Petigara
Application Information
Application Number:US 3761991
Filing Date:1989-07-03
Priority Date:1982-06-01
Art Unit:122
Classifications
IPC:
C07D27502
Field of Search:
56451454874392;184213;101
Patent Drawings
This patent does not have any drawings.
Description
EXAMPLE 1 (Comparative example - illustrates state of the art)
Step 1: Amidation Preparation of N,N'-dimethyl-3,3'-dithiodipropionamide Intermediate
Charged to a vapor-tight reaction kettle was dimethyl-3,3'-dithiodipropionate (101 lb, 0.424 mol), laktane (131 lb.) and methanol (5.06 lb). The mixture was cooled to 15.degree.-20.degree. C. with agitation. Monomethylamine (32.8 lb, 1.06 mol) was added beneath the surface of the reaction mixture with agitation at 15.degree.-20.degree. C. and 5-10 psi over 2 hr. After completing the monomethylamine addition, the mixture was stirred at 15.degree.-20.degree. C. for 10 hr. A thick, pale-yellow slurry was obtained. At this time the unreacted monomethylamine and methanol by-product were distilled from the mixture at .about.100 mmHg. After the distillation period, the yellow slurry was rotary vacuum dried and isolated without washing to provide crude, dry N,N'-dimethyl-3,3'-dithiodipropionamide (100 lb, 100% yield), containing 5,000 ppm N-methyl-3-(N'-methyl) aminopropionamide.
Step 2: Chlorination (oxidation cyclization)
Preparation of a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one hydrochloride and 2-methyl-4-isothiazolin-3-one hydrochloride
A slurry of the crude N,N'-dimethyl-3,3'-dithiodipropionamide reaction product of Step 1 was diluted with toluene and chlorinated to yield a slurry containing 5-chloro-2-methyl-4-isothiazolin-3-one hydrochloride and 2-methyl-4-isothiazolin-3-one hydrochloride and mother liquor.
Step 3: Filtration and Neutralization
The chlorinated slurry from Step 2 was filtered and neutralized with a magnesium oxide slurry to form the tech grade product.
Step 4: Formulation and Heat Treatment (Stabilization)
The Tech product made in Step 3 was formulated by adding magnesium nitrate hexahydrate, and transferring the mixture to a heat treatment kettle equipped with an agitator and a reflux condenser.
The product was heat treated for 4 hours and then allowed to cool to room temperature. The batch was filtered to remove small amounts of suspended solids. This gave a product with the following AI analysis:
EXAMPLE 2
(Comparative Example/Illustrates State of the Art and Removal by Filtration
Step 1: Amidation
Into a three-liter, 4-necked flask equipped with a mechanical stirrer, thermometer, gas dispersion tube and dry ice condenser with nitrogen inlet adapter, was placed dimethyl-3,3' dithiodipropionate (1,062.5 g, 4.46 mol), toluene (535.0 g) and methanol (55.0 g). The apparatus was purged with nitrogen and the mixture was cooled to 10.degree. C. Monomethylamine (346.0 g, 11.14 mol) was added through the gas dispersion tube with stirring at 10.degree.-20.degree. C. over 2 hrs. After completing the monomethylamine addition, the mixture was stirred at 20.degree. C. for 20 hrs. to complete the reaction. A thick, pale yellow slurry was obtained. At this time the unreacted monomethylamine and methanol by-product were distilled from the mixture at .about.100 mmHg. The crude dry N,N'-dimethyl-3,3'-dithiodipropionamide intermediate (1,022.4 g, 97% yield) contained 11,000 ppm N-methyl-3-(N'-methyl)aminopropionamide.
A portion of the intermediate slurry was filtered, washed with toluene and dried. The dry intermediate contained 8,000 ppm of N-methyl-3-(N'-methyl)aminopropionamide.
Step 2: Chlorination
Preparation of a mixture of 5-chloro-2-methyl-4-isothiazoline-3-one hydrochloride and 2-methyl-4-isothiazolin-3-one hydrochloride.
A one-liter 3-necked round bottom flask was equipped with an overhead agitator, a feed line (outlet) and a condenser with a drying tube. Into this flask, 635.8 g of a slurry of N,N'-dimethyl-3,3'-dithiodipropionamide (with 8,000 ppm precursor) in toluene was placed and agitated.
A one-liter, 5-necked resin kettle (i.e., a chlorinator) was equipped with an agitator, a fritted glass gas dispersion tube for Cl.sub.2 inlet, a thermometer, a condenser attached to an off-gas scrubber, and a feed line-inlet for intermediate slurry. The kettle was jacketed for ice-water circulation. The cooling system maintained the chlorination batch at 25.degree.-30.degree. C. The chlorinator was charged with a 108 g of toluene as a heel, and the agitator was started.
The slurry and Cl.sub.2 were fed concurrently at a molar feed ratio of 5.2. Thus, 453 g of the slurry was charged over a 55-minute period at a rate of about 8.2 g/min., while 227 g of Cl.sub.2 (gas) was fed at a rate of about 4.1 g/min., using a calibrated flowmeter.
Step 3: Filtration and Neutralization
To the agitated chlorination slurry 20 g of water was added gradually. After 10 min. of agitation, the batch was allowed to settle, and the mother liquor was siphoned out using a dipstick. An additional 45 g of water was added, and additional mother liquor was removed.
To the hydrochloride wet cake was added 116 g of water. The mixture was neutralized to a pH 4.5 by gradually adding an aqueous MgO slurry. The neutralized material was transferred to a separatory funnel and a 469 g of an aqueous Tech grade was separated from the organic layer:
Step 4: Formulation and Heat Treatment
(Stabilization)
The pH of the above Tech was adjusted to 2.9, and 46.5 g of magnesium nitrate hexahydrate and 7.24 g of water were added to 100 g of the AI with agitation to give a solution with the following composition:
The above formulated product was transferred to a 500 ml 3-necked round bottom flask equipped with an overhead agitator, a water-cooled condenser and a thermometer attached to a themo-watch and pneumatic pot lifter assembly supporting a heating mantle.
The formulated product was heat-treated at 95.degree. C. for 4 hrs. The product, 153.7 g, was filtered to remove any trace amounts of solids, and analyzed.
Analysis:
EXAMPLE 3
Recrystallization of Crude N,N'-Dimethyl-3,3'-dithiodipropionamide (Removal of Nitrosamine Precursor)
Crude amide intermediate (disulfide produced/see Example 1, above), 1400 g, was dissolved in 1750 g of boiling 2-propanol and the solution was filtered rapidly through a pre-heated Buchner funnel. The filtrate was kept overnight at 5.degree.-10.degree. C. in a refrigerator. The crystalline product was collected by filtration on a Buchner funnel, washed with a 560 g portion of cool methanol and dried on a rotary evaporator (35.degree. C./20 mm of Hg/2 hours) to give 995 g of 99.1% pure intermediate m.p. 113.degree.-115.degree. C.
Next, 789.2 g of the crystallized amide intermediate was recrystallized from 2300 g of boiling 2-propanol to give 685.6 g of 99.9.sup.+ % w/w amide intermediate, m.p. 113.degree.-115.degree. C.
Anal. calcd. for C.sub.8 H.sub.16 N.sub.2 O.sub.2 S.sub.2 : C,40.65; H,6.82; N,11.85; O,13.54; S,27.13. Found: C,40.29; H,6.83; N,11.61; O,13.57: S,27.38.
The N-methyl-3-(N'-methyl)aminopropionamide content was 0 ppm.
Nitrosamine-Free Product, Using Pure Amide Intermediate
Following the chlorination procedure described in Example 2, 152.6 g of recrystallized pure amide was chlorinated; the chlorination slurry was filtered and neutralized to give 537.9 g of Tech product, with a total AI of 21.5%.
A 350 g portion of this Tech product was formulated by dissolving 145.5 g magnesium nitrate hexahydrate in the product. The formulated product was heat-treated at 95.degree. C. for 4 hours to give 495 g of 3-isothiazolone composition with the following ingredients:
Nitrosamine-free Products, from Pure Active Ingredient Isothiazolones
Alternatively, pure 2-methyl-4-isothiazolin-3-one, and pure 5-chloro-2-methyl-4-isothiazolin-3-one, can be obtained and formulated as above to give pure product. This material, with or without 95.degree. C./4 hour heat treatment, was found to be nitrosamine-free.
EXAMPLE 4
(Precursor Removal by Solvent Extraction)
Into a three-liter, 4-necked flask equipped with a mechanical stirrer, thermometer, gas dispersion tube and dry ice condenser with nitrogen inlet adapter, was placed dimethyl-3,3'-dithiodipropionate (1062.5 g, 4.45 mol) toluene (295.0 g) and methanol (295.0 g). The apparatus was purged with nitrogen and the mixture was cooled to 10.degree. C. Monomethylamine (304.7 g, 9.81 mol) was added through the gas dispersion tube with stirring at 10.degree.-20.degree. C. over 2 hrs. After completing the monomethylamine addition, the mixture was stirred at 20.degree. C. for 20 hrs. to complete the reaction. A thick, pale yellow slurry was obtained. At this time, the unreacted monomethylamine, methanol and some toluene were distilled from the mixture at 100 mmHg over 8 hrs. The resulting slurry was rotary evaporated to give crude N,N'-dimethyl-3,3'-dithiodipropionamide (1058.9 g, 100% yield), containing 5,000 ppm N-methyl-3-(N'-methyl)aminopropionamide. A portion of the crude product (353.0 g was slurried in 784.5 g toluene) and vacuum filtered through a 2,000 ml course sintered glass funnel to give a toluene wet cake (419.1 g). The toluene wet cake was washed with cold (0.degree. C.) methanol (352.4 g) to give the methanol wet cake (315.2 g). The methanol wet cake was dried in a vacuum desiccator at ambient temperature to give the washed, dried amide intermediate (251.1 g), 71% recovery), containing 400 ppm N-methyl-3-(N'-methyl)aminopropionamide.
Following the process steps 2, 3 and 4 described in Example 2, above, the dry N,N'-dimethyl-3,3'-dithiodipropionamide was converted to give 260 g of 3-isothiazolone product (pH 2.1) with the following composition:
EXAMPLE 5
(Precursor Removal by Ion Exchange)
Unfiltered laktane (Example 1, above) process N,N'-dimethyl-3,3'-dithiodipropionamide was rotary evaporated in the laboratory to constant weight. The dried intermediate contained 10,000 ppm N-methyl-3-(N'-methyl)aminopropionamide.
Conditioned Amberlyst 15 sulfonic acid ion exchange resin (22.2 g of 45.1% w/w material in water, 10.0 g of dry resin) was washed into a 50 ml buret (1 cm diameter) with methanol (25 ml). The resin was rinsed on the column with methanol (500 ml) to give a resin bed volume of 28 ml.
The dry intermediate was dissolved in methanol to give a 19.9% w/w solution. This solution was passed through the resin column at ambient temperature and atmospheric pressure at a flow rate of 9.21 bed volumes per minute. The resin became saturated with N-methyl-3-(N'-methyl)aminopropionamide and break-through occurred after collecting 34 bed volumes. The total quantity of methanolic solution treated up to the break-through point was 737.2 g. Rotary evaporation of the eluent allowed recovery of the crude N,N'-dimethyl-3,3'-dithiodipropionamide (146.5 g, 99.9% recovery), containing 380 ppm N-methyl-3-(N'-methyl)aminopropionamide.
EXAMPLE 6
(Precursor Removal by Ion Exchange)
Into a one-liter, 4-necked flask equipped with a mechanical stirrer, thermometer, gas dispersion tube and dry ice condenser with nitrogen inlet adapter, was placed dimethyl-3,3'-dithiodipropionate (215.5 g, 0.904 mol) and methanol (118.0 g). The apparatus was purged with nitrogen and the mixture was cooled to .about.10.degree. C. Monomethylamine (70.0 g, 2.25 mol) was added through the gas dispersion tube with stirring at 10.degree.-20.degree. C. over 2 hrs. After completing the addition, the mixture was stirred at 20.degree. C. for 20 hrs. to complete the reaction. A thick, pale yellow slurry was obtained. At this time the unreacted monomethylamine and some methanol were distilled from the mixture at .about.100 mmHg. After distillation, a portion of the slurry (17.2 g) was rotary evaporated to constant weight (8.0 g), giving the concentration of crude product in the slurry at 47% w/w. The 47% w/w slurry was 436.0 g, corresponding to 204.9 g of crude N,N'-dimethyl- 3,3'-dithiodipropionamide (96% yield). The dry, crude product contained 9,000 ppm N-methyl-3-(N'-methyl)aminopropionamide.
Conditioned Amberlyst 15 sulfonic acid ion exchange resin (22.2 g of 45.1% w/w material in water, 10.0 g of dry resin) was washed into a 50 ml buret (1 cm diameter) with methanol (25 ml). The resin was rinsed on the column with methanol (500 ml) to give a resin bed volume of 28 ml.
The 47% w/w slurry in methanol was further diluted with methanol to provide a 20.0% w/w solution. This solution was passed through the resin column at ambient temperature and atmospheric pressure at a flow rate of 0.21 bed volumes per minute. The resin became saturated with N-methyl-3-(N'-methyl)aminopropionamide and break-through occurred after collecting 18 bed volumes of eluent. The total quantity of methanolic N,N'-dimethyl-3,3'-dithiodipropionamide solution treated up to the break-through point was 315.0 g (63.0 of AI). Rotary evaporation of the eluent allowed recovery of the crude N,N'-methyl-3,3'-dithiodipropionamide (63.0 g, 100% recovery), containing 300 ppm N-methyl-3-(N'-methyl)aminopropionamide.
Following the procedure described in Example 2, 73.3 g of the above-mentioned intermediate was chlorinated, filtered and neutralized to give 217.5 g of Tech grade product.
A 60 g sample of this Tech grade product was formulated with 29.4 g of Mg(NO.sub.3).sub.2.6H.sub.2 O and 7.8 g of water. The formulated product was heat-treated at 95.degree. C. for 4 hours, cooled and filtered to give about 97 g of 3-isothiazolone with the following composition:
EXAMPLE 7
(Inhibition of Precursor by Nucleophilic Scavenger)
Following the procedure of Example 2, Step 1, dimethyl-3,3'-dithiodipropionate (212.5 g, 0.982 mol), methyl-3-mercaptopropionate (18.4 g, 0.153 mol) and monomethylamine (69.0 g, 2.22 mol) were reacted. The intermediate slurry was rotary evaporated to give crude N,N'-dimethyl-3,3'-dithiodipropionamide (224.1 g, 98% crude yield), containing 1,000 ppm N-methyl-3-(N'-methyl)aminopropionamide.
This Example has been repeated using higher levels of a nucleophilic scavenger. The results of these experiments have established an essentially proportional reduction of nitrosamine precursor as higher concentrations of nucleophilic scavenger were used.
EXAMPLE 8
(Inhibition of Precursor by Mercaptan Reactant Route)
Step 1: Preparation of N-methyl-3-mercaptopropionamide (MMPA)
Into a one-liter, 4-necked flask equipped with a mechanical stirrer, thermometer, gas dispersion tube, and dry ice condenser with nitrogen inlet adapter, was placed methyl-3-mercaptopropionate (MMP, 504.7 g, 4.20 mol). The vessel was purged with nitrogen and the liquid was cooled to 10.degree. C. Monomethylamine (163.0 g, 5.25 mol) was added through the gas dispersion tube with stirring at 10.degree.-20.degree. C. over 1 hr. After completing the addition, the mixture was stirred at 20.degree. C. for 20 hrs. to complete the reaction. At this time the methanol by-product and unreacted monomethylamine were distilled from the mixture at .about.100 mmHg. The resulting mixture was rotary evaporated to give crude N-methyl-3-mercaptopropionamide (500.8 g, 100% yield), containing <30 ppm N-methyl-3-(N'-methyl)aminopropionamide.
Step 2: Chlorination
The procedure described in Example 2 was modified in that N-methyl-3-mercaptopropionamide (MMPA) was used in place of N-N'-dimethyl-3,3'-dithiodipropionamide. Thus, a 31% solution of N-methyl-3-mercaptopropionamide in toluene and Cl.sub.2 were fed concurrently at a molar feed ratio of about 3.2.
To 59.5 g of a toluene heel, 398.9 g of 31% MMPA solution was charged over a period of 55 minutes at a rate of 7.1 g per minute, while a 220 g of Cl.sub.2 was fed concurrently at a feed rate of 4.0 g per minute.
Step 3: Filtration and Neutralization
Following the procedure described in Example 2, the chlorination slurry made above was worked-up and neutralized to give 355 g of Tech grade 3-isothiazolone with the following composition:
Step 4: Formulation and Heat Treatment (Stabilization)
Following the procedure described in Example 2, a 200 g portion of the Tech grade material made above was formulated by adding 87.7 g Mg(NO.sub.3).sub.2.6H.sub.2 O and 2.1 g water. The formulated product was heat-treated, cooled and filtered to give 289 g of 3-isothiazolone product with the following composition:
EXAMPLE 9
(Preparation of N-(n-octyl)-3-mercaptopropionamide by Mercaptan Reactant Route)
In a small multi-necked reaction vessel equipped with a magnetic stirrer and gas inlet was placed isopropanol (2 ml), methyl-3-mercaptopropionate (2.0 g, 16.64 mmol), and n-octylamine (2.19 g, 16.94 mmol). The reaction vessel was connected to a trap containing bleach to trap mercaptan vapors, and the reaction was stirred for 19.5 hours while the reaction temperature was held at 30.degree.-35.degree. C. Methylene dichloride was added and the crude product was transferred to a round bottom flask. Evaporation of the solvent under reduced pressure yielded crude N-(n-octyl)-3-mercaptopropionamide as an oily white solid in essentially quantitative yield.
The N-(n-octyl)-3-mercaptopropionamide of Example 9 may be converted to the corresponding 2-n-octyl-isothiazolin-3-one substantially free of nitrosamine and nitrosamine precursor.
EXAMPLE 10
(Preparation of N-propyl-3-mercaptopropionamide by Mercaptan Reaction Route)
In a small multi-necked reaction vessel equipped with a magnetic stirrer, reflux condenser, and gas inlet was placed isopropanol (2 ml), n-propylamine (1.00 g, 16.92 mmol), and methyl-3-mercaptopropionate (2.0 g, 16.64 mmol). The reaction vessel was connected to a trap containing bleach, and the reaction was stirred at 30.degree.-35.degree. C. for 19.5 hours. The crude reaction mixture was concentrated under reduced pressure to remove excess amine, solvent and methanol. A light yellow liquid was obtained, with essentially all N-propyl-3-mercaptopropionamide.
The N-propyl-3-mercaptopropionamide of Example 10 may be converted to the corresponding N-propyl-isothiazolin-3-one substantially free of nitrosamine and nitrosamine precursor.
EXAMPLE 11
(Combinations of Inhibition and Removal of Precursor)
Following the procedure of Examples 1-8 above, combined use of the illustrated techniques has been employed to produce isothiazolone products having drastically reduced or no nitrosamines or precursors whatsoever.
Claims
We claim:
1. A process for preparing a biologically active, metal nitrate salt-stabilized, 3-isothiazolone composition substantially free of nitrosamine impurities and precursors thereof which comprises: (a) preparing a biologically active 3-isothiazolone substantially free of a by-product compound containing an amine moiety capable of being nitrosated to a nitrosamine, or a nitrosamine compound derived therefrom, which 3-isothiazolone may be represented by the formula: ##STR12## wherein R and R' are independently selected from hydrogen, halogen or an alkyl group of 1 to 4 carbon atoms; Y is an alkyl group of 1 to 8 carbon atoms, a cycloalkyl group of 5 or 6 carbon atoms, an aralkyl group of up to 8 carbon atoms, or an aryl or substituted aryl group of 6 carbon atoms, wherein said 3-isothiazolone is prepared by a process comprising amidation of dimethyl dithiopropionate to form a dithioamide intermediate wherein formation of undesirable N-methyl-3-(N'-methylamino) propionamide by- product compound is inhibited by use of a nucleophilic scavenger selected from the group consisting of methyl mercaptan, ethyl mercaptan, propyl mercaptan, phenyl mercaptan. HS--CH.sub.2 CH.sub.2 COO--(alkyl) and H.sub.2 S--CH.sub.2 CH.sub.2 CONH--(alkyl) in said amidation process; (b) adding to said 3-isothiazolone a ring-stabilizing metal nitrate salt in an amount sufficient to stabilize the ring of the 3-isothiazolone.
2. A method according to claim 1 wherein said mercaptan is methyl-3-mercaptopropionate (MMP).
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