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Publication numberUS2742476 A
Publication typeGrant
Publication dateApr 17, 1956
Filing dateOct 26, 1953
Priority dateOct 26, 1953
Publication numberUS 2742476 A, US 2742476A, US-A-2742476, US2742476 A, US2742476A
InventorsBernstein Jack, Kathryn A Losee
Original AssigneeOlin Mathieson
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Derivatives of 2-mercaptopyridine 1-oxide
US 2742476 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

' 2,742,416 DERIVATIVES or Z-XMIEDIECAPTOPYRIDINE Slack Bernstein and Kathryn A. =Losee, New Brunswick,

N. J., assi gnors to Olin Mathieson Chemical Corporationga'corporationof Virginia 'No Drawing. Application October 26, 1953, Serial :No. 388,412,

5 Claims. (Cl. 260-29458) United States Patent wherein each R is a member of the class consisting of. i

is a member of the class consistingof -S-, and


groupsand y and z are each onefof the numbers-Cor 1; and (B) methods of preparing 'thezsame. De'fined other-' wise, the compounds of this invention are members of j:the group consisting f c0mpounds of the general for- -rnulai "of this invention are especially ,active' against a wide group of microorganisms, as indicated by the following in vitro hydrogen, lower alkyl, (lower alkylJ-oxy and halogen, X1

--4,6-dimethyl-2 mercaptopyridine 7 2,742,476 Ratented Apr. 1.7,;1956

TABLE 2 Antifungal activity MIC ug/ml.

Microorganism Derivative 2 Control v (a) r (b) (c) (d) 'klepemilluafumigatus 12:5 0.8 0,-4 0.4 ,Aspergz'llusnigerh. 4.2 0.4 3.1 0.8 1.6 'Canliida albicaflsmn -0.4 1.6- 3.:1 3.1 Microspomm nuliouim. 3. 1{ 0. 74 0.38 -.0.-4 0. 4 Penicillin notatum 12.5 V 0.4, 3.1 0.4 0.8 Rhodotarula-glutinia 31 0.3 "0.8 0.8 0.4 Sa'cchur-Jmycescerevisiae... I 7 "1:6 0.3; g 0.8 0:4. 0;4 Trz'chophyton meutagrophytas 1331 053 10.8 0.4 04 Fusarz'um bulbz'genum 50 0. 4 6. 3 0. 8 1. 6 Ceratosto-mella ulmi 3.1 0.3 0. 8 0.4 0.4

53-hydroxyqulnoline. V 9 (a) 2,2-dithiodlpyridine 1,1-dioxide;

(b) 2,2-dlthio-bis-(4-rnethylpyridine)Li -dioxide;

(c) 2,2-dithiodipyridine 1,1,Strioxide;

(d). 2,2 -dlslllnnyldipyridine l,1-dioxide.

Since the compounds'ofathis invention possess such broad antibacterial and antifungal spectra, they are also utilizable in agriculture to combat plant diseases (for example against 'Peronospora growing on grapevine), and may 'be incorporated into plastics and fabrics in the "conventional manner to increase their resistance to mildew "oro'thenfungus attack.

, The 2,2'-dithiodipyridine LY-dioxides of this invention may be prepared by the'method'comprising reacting compound (I), a Z-mercaptopyridine l-oxide,

a 2 t. I I j V o i with an oxidizing agent of the peroxide type, such as pera'cids (peracetic, performic, perbenzoic, perphthalic) and (especially) hydrogen peroxide in "water, preferably at room temperature, and recovering the reaction prod- -uct, namely a 'Utilizable-reactants Iinclude, inter alia: Zvmercaptopyri- .dine l-oxide,I3-rnethoxy-Z-mercaptopyridine l-oxide, .3- -ethoxy-2-mercaptopyridine l-roxide, 5-bromo-2-mercaptopyridine ll oxide, 4-methyl-2fmercaptopyridine l-oxide, l-oxide, 3-ethyl-6- methyl-Z-mercaptopyridind l-oxide, 3-methyl-2-mercaptopyridine l-oxide, 2mercapto-5,-methylpyridine l-oxide, 2-.mercapto-6-methylpyridine .l-oxide, 2-mercapto-6-propylpyridine 'l-oxide, 4-,ethy1-2-mercaptopyridine 1-oxide (see -for example, I. A. C. S. 72': 4362, and US. applicationSerialfNo. 330,576, filed January 9, 1953 (now Patent No. 2,686,786, issued August 17, 1954),,for the preparation of substituted 2+mercaptopyridine l-oxides).

- EIFhese 2,2" ,dithiopyridine 1,1'--dioxides are utilized in "'65 preparing the ;sulfone.:and ,sulfoxide derivatives of this invention. Thus, derivatives of the following general formula:

R- t R H Ni 11 l 0 (wherein R, X and y have the meaning given hereinbefore) may be prepared by interacting a compound of the general formula (II):

with an oxidizing agent, such as peracids (peracetic, performic, perbenzoic, perphthalic acids) and peroxides (especially hydrogen peroxide) in acid solution. Utilizable compounds 11 (prepared as indicated hereinbefore) include, inter alia: 2,2'-dithiodipyridine, 1,1'-dioxide; 2,2'-dithio'bis-[3(4, or 6)methylpyridine] 1,1'-di0xide; 2,2-dithio-bis-(3-chloropyridine) l,1'-dioxide; 2,2-dithiobis-(S-methoxypyridine) 1,1'-dioxide; 2,2'-dithio-bis-(4,6- dimethylpyridine) 1,1-di0xide; 2,2'-dithio-bis-(3-ethyl-6- methylpyridine) 1,1'-dioxide.

Alternatively, the sulfones and sulfoxides of the general formula EXAMPLE 1 Preparation of 2,2'-dithi0dipyridine 1,1'-dioxide 70 cc. 30% hydrogen peroxide solution diluted to 250 cc. with water is added slowly to the suspension of 42.3 g. 2-mercaptopyridine l-oxide in 350 cc. water. The temperature rises to 45 C., and the appearance of the suspended solid changes (although a clear solution does not form at any time). The reaction mixture is stirred for one hour, and the solid then filtered off. The product, 2,2'-dithiodipyridine l,l'-dioxide, weights about 29 g., and melts at about 195-196 C. (dec). After crystallization from one liter of alcohol, the product weighs about 18.5 g. and melts at about 20020l C. (dec).

EXAMPLE 2 Preparation of 2,2 dithio-bis-(4 methylpyridine) 1,1 dioxide 3 g. 2-mercapto-4-methylpyridine l-oxide is suspended in 100 cc. water and cc. 30% H2O: diluted to 50 cc. is added thereto dropwise (gradually, a clear solution forms). The solution is stirred at room temperature for three hours, allowed to stand for 12-16 hours, and then concentrated to cc. under reduced pressure. On cooling, crystals form, and are filtered off. The product, 2,2'-dithio-bis-(4 -methylpyridine) 1,1'- dioxide, weighs about 800 mg. and melts at about 165-175 C. (dec.). After recrystallization from 40 cc. alcohol-ether (1:1), the product weighs about 500 mg. and melts at about 195-196 C. (dec.).

Use of a molar equivalent of 2-mercapto-3-ethoxypyridine l-oxide or Z-mercapto-5-bromopyridine l-oxide in place of 2mercapto-4-methylpyridine l-oxide in Example 4 2 yields 2,2-dithio-bis-(3-ethoxypyridine) l,1-dioxide and 2,2'-dithio-bis-(5 -bromopyridine) 1,l'-dioxide, respectively.

EXAMPLE 3 Preparation of 2,2'-dithiodipyridine 1,1 '-S-trioxide A mixture of 10.08 g. 2,2-dithiodipyridine 1,l'-dioxide (cf. Example 1), cc. acetic acid, and 4.4 g. 30% H202 is allowed to stand at room temperature for three days, and then concentrated to dryness under reduced pressure at 60 C. (bath). The residue is triturated with absolute alcohol to yield about 10.5 g. of a solid, 2,2'-dithiodipyridine 1,1',S-trioxide, melting at about 178-180" C. After recrystallization from 200 cc. alcohol, and then from 200 cc. acetonitrile, the product weighs about 3.5 g. and melts at about l85l86 C. (dec.).

Use of a molar equivalent of 2,2-dithio-bis-(4-methylpyridine) l,l-dioxide (cf. Example 2) in place of 2,2- dithiodipyridine l,l-dioxide in Example 3 yields 2,2- dithio-bis-(4-mcthylpyridine) l,1,S-trioxide.

EXAMPLE 4 Preparation 0] 2,2-disulfinyldipyridine ],1-dioxide Proceeding as in Example 3, but employing 22 g. instead of 4.4 g. 30% H202 yields about 9 g. of 2,2'-disulfinyldipyridine l,l'-dioxide, melting at about 179-180 C. (dec.). After recrystallization from cc. absolute alcohol, the product, 2,2'-disulfinyldipyridine l,1-dioxide, weighs about 5 g. and melts at about 185-186 C. (dec.). It is possible this disulfinyl product may actually be a compound of the following formula:

EXAMPLE 5 Preparation of 2,2'-dithio-bis-(4,6-dimethylpyridine) 1,1

dioxide (a) 2-BROMO-4,6-DIMETHYLPYRIDINE To a solution of 91.5 g. 2-amino-4,6-dimethylpyridine in 850 cc. of 48% HBr is added dropwise 115 cc. bromine at 0-5 C. with vigorous stirring. A thick orange solid forms. After complete addition of the bromine the reaction vmixture is diazotized with a solution of g. sodium nitrite in 200 cc. water at 0 C. The reaction is then allowed to come to room temperature, made strongly alkaline by the addition of approximately one liter 50% NaOH at 10-15 C. and decolorized by the addition of 100 g. sodium sulfite in 500 cc. H2O. The reaction mixture is steam distilled and the distillate extracted with 3 500 cc. ether. The ether is dried over MgSO4 and removed. The residue is fractionated to yield about 64 g. of product, boiling at 9294 C./7 mm.

(1)) 2-BROMO-4,6-DIMETHYLPYRIDINE l-OXIDE HYDRO- CHLORIDE 64 g. 2-bromo-4,6-dimethyl pyridine is dissolved in 200 cc. acetic acid and 100 g. 40% peracetic acid is added keeping the temperature below 15 C. After complete addition, the reaction is allowed to come to room temperature and then heated at 45 C. for 12 hours. The acetic acid is removed under reduced pressure and the residue poured onto cracked ice and made strongly alkaline with 40% KOH. The oil which precipitates is extracted with 3x200 cc. chloroform. The chloroform is dried over MgSO4 and then dry HCl gas added until acid to Congo. This solution is concentrated to 250 cc. under reduced pressure to yield about 62 g. product, which melts at about 157-158 C. (dec.). After recrystallization from absolute alcohol, the product melts at about l57-158 C. (dec.).

() 2-MERCAPTO-4,6-DIMETHYLPYRIDINE l-OXIDE A solution of 2.38 g. 2-bromo-4,6-dimethylpyridine loxide HCl in 20 cc. absolute alcoholis added to a solution of 0.76 g. thiourea in 20 cc. absolute alcohol. The solution is refluxed for minutes and then concentrated under reduced pressure. The resulting oil is dissolved in 100 cc. H and solid NazCOa added until the solution is alkaline. After standing 15 minutes, the solution is filtered and acidified with 10% HCl. The crystalline solid is filtered and melts at 105-107 C. After recrystallization from cc. aqueous alcohol, the compound melts at about 108-109 C.

Alternatively, 2-bromo-4,6-dimethylpyridine l-hydrochloride in water is neturalized with sodium hydroxide solution; and to this solution is added a solution of sodium hydrosulfide in water and the procedure continues as in Example 2b of Patent No. 2,686,786 to yield 2 mercapto-4,6-dimethylpyridine l-oxide.

(d) 2,2-DITHIO-BIS-(4,6-DIMETHYLPYRIDYL) 1,1- DIOXIDE To a suspension of 0.775 g. 2-mercapto-4,6-dimethylpyridine loxide in 50 cc. H2O is added 2.3 g. H202 in 50 cc. H2O at room temperature. The reaction is warmed on a steam bath for a few minutes to cause solution. After cooling, a crystalline solid precipitates and is filtered. The product weighs about 310 mg. and melts at about 192-194 C. After recrystallization from aqueous alcohol, the product melts at about 228-229 "C.

wherein each R is a member of the class consisting of hydrogen, lower alkyl, (lower alkyD-oxy, and halogen, X is a member of the class consisting of -S and groups, and y and z are each one of the numbers 0 and l.

2. Compounds of the general formula:

i l 3. 2,2'-dithiopyridine 1,1'-dioxide. 4. 2,2'-dithiopyridine 1,1, S-trioxide. 5. 2,2'-disulfinyldipyridine 1,l'-dioxide.

(lower alkyl)- (lower alkyl)- (lower alkyl) (lower alkyl) References Cited in the file of this patent UNITED STATES PATENTS Ladd et a1 Oct. 14, 1947 Shaw et a1 Aug. 17, 1954 OTHER REFERENCES Itai: Chem. Abst., vol. 44, cols. 4473-4 (1950).

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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3027371 *May 4, 1959Mar 27, 1962Olin MathiesonMolybdenum-containing derivatives of 1-hydroxy-2-pyridinethiones and method of preparing same
US3027372 *May 4, 1959Mar 27, 1962Olin MathiesonStannous chloride bis-(2-pyridyl-1-oxide) disulfide and method of preparing same
US3121725 *Jul 18, 1960Feb 18, 1964Phillips Petroleum CoN-heterocyclic sulfides, sulfoxides, sulfones, and n-oxides of said sulfoxides and sulfones
US3207760 *Apr 10, 1962Sep 21, 1965S B Penick & CompanyS-(2-pyridyl-1-oxide)-thioarylates
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US3517018 *Jul 3, 1968Jun 23, 1970Olin MathiesonFormaldehyde adducts of 2-mercaptopyridine-n-oxide
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CN102875463A *Aug 29, 2012Jan 16, 2013滨海明鸿精细化工有限公司Synthesis method for high-quality and low-cost bispyrithione
CN102875463BAug 29, 2012Jun 25, 2014滨海明鸿精细化工有限公司Synthesis method for high-quality and low-cost bispyrithione
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U.S. Classification546/261
International ClassificationA01N43/40, C11D1/00, C10L1/22, C07D213/89
Cooperative ClassificationC07D213/89, C10L1/22, C11D1/00, A01N43/40
European ClassificationA01N43/40, C10L1/22, C11D1/00, C07D213/89