JPH0434547B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a novel iodopropargyl tetrazole compound, a method for producing the same, and an antibacterial agent containing the novel iodopropargyl tetrazole compound as an active ingredient.
This relates to antifungal agents. [Prior art, technical background] As an iodopropargyl nitrogen-containing heterocyclic compound, the antifungal antibiotic pyrolomycin A
-90099) is publicly known. Through research on this substance, the present inventors discovered that an iodopropargyl compound having a substituted pyrrole nucleus (Japanese Patent Application No. 57-6609)
), iodopropargyl compounds with pyrazole, triazole, and tetrazole nuclei (patent application 1983)
-64759), and iodopropargyl tetrazole compounds (Japanese Patent Application No. 191569/1983) in which methyl, phenyl, p-chlorophenyl, p-nitrophenyl, or p-methylphenyl groups are substituted at the 5th position of the tetrazole nucleus are antibacterial. , which was discovered to have antifungal activity and was first filed. [Object of the Invention] The present invention provides a novel compound of a 5-substituted tetrazole iodopropargyl compound with excellent antibacterial and antifungal activity, an antibacterial and antifungal agent containing the compound as an active ingredient, and the advantageous production of these compounds. The purpose is to present a method. [Structure of the invention] The present invention is based on the general formula In the formula, R represents an alkyl group having 2 or more carbon atoms, a benzyl group, or a substituted phenyl group (excluding p-chlorophenyl group, p-nitrophenyl group, p-methylphenyl group) and an iodopropargyl tetrazole compound represented by the general formula R '-SO ₂ -O-CH ₂ C≡CI (2) In the formula, R' represents an alkyl group or an aryl group with or without a substituent. In the formula, R has the same meaning as above, by reacting a compound represented by the general formula In the formula, R has the same meaning as above, and the method for producing the compound represented by the general formula In the formula, R is an antibacterial and antifungal agent containing a compound shown as having the same meaning as above as an active ingredient. General formula of the present invention In the iodopropargyl compound represented by R
represents an alkyl group or substituted phenyl group having 2 or more carbon atoms. Suitable alkyl groups having 2 or more carbon atoms are ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,
These are pentyl, hexyl, and heptyl groups. Suitable substituted phenyl groups include o-
Methoxyphenyl, m-chlorophenyl, o-chlorophenyl, p-trifluoromethyl, p-fluorophenyl, p-cyanophenyl, p-hydroxyphenyl, 3,5-dichlorophenyl, p
-carbamoylphenyl, p-carboxyphenyl, p-dimethylaminophenyl group. Examples of the compound represented by the above general formula (1) of the present invention are as follows. Compound (1) 2-(1'-iodopropyn-3'-yl)
-5-ethyltetrazole compound (2) 1-(1'-iodopropyn-3'-yl)
-5-ethyltetrazole compound (3) 2-(1'-iodopropyn-3'-yl)
-5-n-propyltetrazole compound (4) 1-(1'-iodopropyn-3'-yl)
-5-n-propyltetrazole compound (5) 2-(1'-iodopropyn-3'-yl)
-5-isopropyltetrazole compound (6) 1-(1'-iodopropyn-3'-yl)
-5-isopropyltetrazole compound (7) 2-(1'-iodopropyn-3'-yl)
-5-Butyltetrazole compound (8) 1-(1'-iodopropyn-3'-yl)
-5-Butyltetrazole compound (9) 2-(1'-iodopropyn-3'-yl)
-5-decyltetrazole compound (10) 1-(1'-iodopropyn-3'-yl)
-5-decyltetrazole compound (11) 2-(1'-iodopropyne-3'-
yl)-5-isobutyltetrazole compound (12) 1-(1'-iodopropyne-3'-
yl)-5-isobutyltetrazole compound (13) 2-(1'-iodopropyne-3'-
yl)-5-t-butyltetrazole compound (14) 1-(1'-iodopropyne-3'-
yl)-5-t-butyltetrazole compound (15) 2-(1'-iodopropyne-3'-
yl)-5-pentyltetrazole compound (16) 1-(1'-iodopropyne-3'-
yl)-5-pentyltetrazole compound (17) 2-(1'-iodopropyne-3'-
yl)-5-hexyltetrazole compound (18) 1-(1'-iodopropyne-3'-
yl)-5-hexyltetrazole compound (19) 2-(1'-iodopropyne-3'-
yl)-5-heptyltetrazole compound (20) 1-(1'-iodopropyne-3'-
yl)-5-heptyltetrazole compound (21) 2-(1'-iodopropyne-3'-
yl)-5-benzyltetrazole compound (22) 1-(1'-iodopropyne-3'-
yl)-5-benzyltetrazole compound (23) 2-(1'-iodopropyne-3'-
yl)-5-(p-methoxyphenyl)tetrazole compound (24) 2-(1'-iodopropyne-3'-
yl)-5-(p-chlorophenyl)tetrazole compound (25) 2-(1'-iodopropyne-3'-
yl)-5-(o-chlorophenyl)tetrazole compound (26) 2-(1'-iodopropyne-3'-
yl)-5-(m-trifluoromethylphenyl)tetrazole compound (27) 2-(1'-iodopropyne-3'-
yl)-5-(p-fluorophenyl)tetrazole compound (28) 2-(1'-iodopropyne-3'-
yl)-5-(p-cyanophenyl)tetrazole compound (29) 2-(1'-iodopropyne-3'-
yl)-5-(p-hydroxyphenyl)tetrazole compound (30) 1-(1'-iodopropyne-3'-
yl)-5-(p-hydroxyphenyl)tetrazole compound (31) 2-(1'-iodopropyne-3'-
yl)-5-(3″,5″-dichlorophenyl)tetrazole compound (32) 2-(1′-iodopropyne-3′-
yl)-5-(p-carbamoylphenyl)tetrazole compound (33) 2-(1'-iodopropyne-3'-
yl)-5-(p-carboxyphenyl)tetrazole compound (34) 2-(1'-iodopropyne-3'-
yl)-5-(dimethylaminophenyl)tetrazole The compounds of the present invention have the general formula Reacting a reactive derivative of iodopropargyl alcohol with a 5-substituted tetrazole in which R has the same meaning as defined above, or
Alternatively, a method of producing a propargyl tetrazole compound (4) by reacting a 5-substituted tetrazole with a reactive derivative of propargyl alcohol, followed by iodination to produce the compound of the present invention is preferably carried out.
The reaction formula is as follows. In the formula, R has the same meaning as above, and X represents a halogen atom or a hydroxyl group activated as a sulfonic acid ester. The 5-substituted tetrazole represented by the formula (3), which is a raw material for this method, is, for example, Synthesis, p. 71 (1973
It can be produced by the method described in 2010) and its application. In addition, the reactive derivative of iodopropargyl alcohol (formula (2)) or the reactive derivative of propargyl alcohol [formula (5)] can be obtained by treating iodopropargyl alcohol with a halogenating agent such as thionyl chloride or thionyl bromide, or by Arylsulfonic acids such as alkylsulfonic acids, benzelsulfonic acids, naphthalenesulfonic acids, etc., or substituents containing one or more halogen atoms, alkyl groups, nitro groups, alkoxy groups, carbamoyl groups, alkoxycarbamoyl groups, hydroxyl groups, etc. It is obtained by reacting anhydrides and halides of substituted arylsulfonic acids. Examples of reactive derivatives of iodopropargyl alcohol [formula (2)] used in this reaction include iodopropargyl chloride, iodopropargyl bromide, and iodopropargyl alcohol methane. Sulfonic acid ester, iodopropargyl alcohol butanesulfonic acid ester, iodopropargyl alcohol octane sulfonic acid ester, iodopropargyl alcohol benzenesulfonic acid ester, iodopropargyl alcohol naphthalene sulfonic acid ester, iodopropargyl alcohol p-methoxybenzenesulfonic acid ester, iodopropargyl o -Cyanobenzenesulfonic acid ester, iodopropargyl alcohol Isopropylbenzenesulfonic acid ester, iodopropargyl alcohol p
-Chlorobenzenesulfonic acid ester, iodopropargyl alcohol p-Nitrobenzenesulfonic acid ester, iodopropargyl alcohol p-carbamoylbenzenesulfonic acid ester, iodopropargyl alcohol 2,4,5
-trichlorobenzenesulfonic acid ester, iodopropargyl alcohol 4-chloro-3-nitrobenzenesulfonic acid ester, and the like. In addition, examples of reactive derivatives of propargyl alcohol [formula (5)] include propargyl chloride,
Propargyl Bromide, Propargyl Alcohol Methanesulfonate, Propargyl Alcohol Butanesulfonate, Propargyl Alcohol Octanesulfonate,
Propargyl alcohol benzene sulfonate, propargyl alcohol naphthalene sulfonate, propargyl alcohol p
-Toluenesulfonic acid ester, propargyl alcohol p-methoxybenzenesulfonic acid ester, propargyl alcohol o-cyanobenzenesulfonic acid ester, propargyl alcohol isopropylbenzenesulfonic acid ester,
Propargyl alcohol p-chlorobenzenesulfonic acid ester, propargyl alcohol p
-Nitrobenzenesulfonic acid ester, propargyl alcohol p-carbamoylbenzenesulfonic acid ester, propargyl alcohol 2,
4,5-Trichlorobenzenesulfonic acid ester, propargyl alcohol 4-chloro-3-
Examples include nitrobenzene esters. The above 5-substituted tetrazole [formula (3)] and a reactive derivative of iodopropargyl alcohol [formula (2)] or a reactive derivative of propargyl alcohol [formula
(5)], the reaction with 5-substituted tetrazole [formula (3)]
is dissolved or suspended in an inert solvent to form a base and a reactive derivative of iodopropargyl alcohol [formula
(2)] or a reactive derivative of propargyl alcohol [formula (5)], and is carried out by an N-alkylation reaction in which an iodopropargyl group or a propargyl group is introduced onto the nitrogen atom of the tetrazole ring. Examples of inert solvents used in this reaction include benzene, dioxane, dichloromethane, and N,N-dimethylformamide. N,N-dimethylformamide is preferred. Examples of bases used in this reaction include inorganic bases such as alkali hydroxide and alkali carbonate, as well as organic bases such as pyridine and triethylamine. This alkylation reaction proceeds rapidly at room temperature when using an alkali hydroxide as a base and reacting it with a sulfonic acid ester, but it may also be carried out under cooling, preferably at -10 to 0°C, in order to prevent side reactions. can. The reaction also proceeds under heating at 40 to 60°C in the presence of a base. When a reactive derivative of iodopropargyl alcohol [formula (3)] is used in this reaction, the iodopropargyl tetrazole compound [formula (1)] of the present invention is obtained by this reaction. When a reactive derivative of propargyl alcohol [formula (5)] is used in this reaction, a propargyl tetrazole compound [formula (4)] is obtained by this reaction. In this case, the iodopropargyl tetrazole compound [formula (1)] of the present invention is obtained by iodination in the presence of a base without separating or separating the propargyl tetrazole compound [formula (4)]. The iodopropargyltetrazole compound [formula (1)] obtained as described above is separated and purified from the reaction mixture. In this method, the product is collected by general separation and purification methods such as precipitation by adding an insoluble solvent such as water, and solvent extraction using an organic solvent such as benzene, ethyl acetate, dichloromethane, etc.
Furthermore, if necessary, well-known purification methods such as column chromatography using silica gel or reconsolidation using an organic solvent can be appropriately applied. Next, the uses of the compounds of the present invention will be described. The compounds of the present invention are useful as antibacterial and antifungal agents,
In particular, it exhibits a strong growth-disturbing effect against a wide range of bacteria and fungi, and is therefore used in the medical field, animal and other livestock medicine, agriculture, and industrial fields to develop various unfavorable symptoms caused by the growth of bacteria and fungi. It is useful for improving various conditions.
In other words, it is used medically as a treatment for external diseases caused by fungi such as Candeida, Aspergillus, Trichophyton, and Cryptococcus, and as an active ingredient in liquids and ointments.
It can be blended in a range of 0.1 to 5%, preferably 0.5 to 2%, and applied to the affected area to achieve the therapeutic purpose. In addition, other medical or pet animals,
It can be used as a sterilizing or disinfecting agent for animals such as livestock to prevent the growth of pathogenic bacteria and fungi, or to treat external diseases caused by their growth. Furthermore, the compounds of the present invention also show utility in agricultural and industrial fields. In particular, these fields include seeds, seedlings, wood, agricultural and horticultural crops, woodwork, pure crafts, leather, fibers, adhesives,
The occurrence of spoilage bacteria and mold in agricultural and industrial products such as paint, pulp, circulating water for cooling, and synthetic resins, as well as in manufacturing environments, causes a serious loss in the value of the product. Since the compound of the present invention exhibits a growth inhibiting effect on harmful bacteria and fungi in these agricultural and industrial fields, it can be used for the purpose of maintaining the quality of products in these fields and preserving the environment. In the agricultural and industrial fields, the compound of the present invention can be used in formulations supported on commonly used carriers, such as oil solvents, emulsions, pastes, powders,
Examples include hydrating powders, aerosols, antifungal paints, and adhesives. Examples of carriers used include inorganic solid carriers such as clay, talc, bentonite, kaolin, silicic anhydride, and calcium carbonate, organic solvent carriers such as kerosene, ligroin, xylene, dimethylformamide, and dimethylsulfonoxide, dimethyl ether, and chlorofluorocarbon gas. Examples of adjuvants to enhance the formulation effect include ionic and nonionic surfactants, and polymeric compounds such as vinyl acetate and methylcellulose. It is also possible to use it in combination with other preservatives and antifungal agents, organophosphorus insecticides, and fungicides. The content of the compound of the invention in the formulation may vary widely depending on the formulation, but generally from 0.01 to 95% by weight, preferably from 0.2 to 95% by weight.
A range of 10% by weight is suitable. [Effect of the invention] Table 1 below shows the antibacterial activity of the compounds of the present invention.
Tables 2 and 3 show the antifungal activity of the compounds of the invention.

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〔Example〕

Example 1 2-(1'-iodopropyn-3'-yl)-5-n
-Propyltetrazole [Compound (3)] and 1-
(1'-iodopropyn-3'-yl)-5-n-propyltetrazole [Compound (4)] 5-n-propyltetrazole 1.12 g (10 mmol), triethylamine 1.24 ml, iodopropargyl alcohol p-nitrobenzenesulfonic acid ester Mix 3.30g in 100ml of benzene,
The solution was heated to reflux over water for 20 minutes. Cool the reaction solution,
After adding 50 ml of ethyl acetate and washing twice with water, the mixture was dried over anhydrous sodium sulfate. When the crude crystals obtained by distilling off the organic solvent under reduced pressure were examined by silica gel TLC (solvent system: benzene-ethyl acetate 10:1), Rf
It was a mixture of two substances showing values of 0.57 and 0.20.
When the crude crystals are recrystallized from a mixed solvent of 10 ml of benzene and 10 ml of hexane, they show an Rf value of 0.20. 1-
(1'-Iodopropyn-3'-yl)-5-n-propyltetrazole was preferentially precipitated. Yield 707 mg (28%) mp 95.8-97.8°C Elemental analysis value C, 30.48%; H, 2.83%; _{N, 19.82%, calculated value as C7H9N4I C} , 30.48%; _H , 2.83
%; N, 19.82%, the recrystallization mother liquor was concentrated, the residue was purified by silica gel column chromatography, and 2-(1'-iodopropyne-
3′-yl)-5-n-propyltetrazole 441mg
(18%). mp59.5-62.0℃, elemental analysis value C,
30.3%; H, 2.97%; N, 19.87%. Example 2 2-(1'-iodopropyn-3'-yl)-5-isopropyltetrazole [compound (5)] and 1-
(1'-Iodopropyn-3'-yl)-5-isopropyltetrazole [Compound (6)] 0.56 g (5 mmol) of 5-isopropyltetrazole and 0.20 g (5 mmol) of powdered sodium hydroxide
(mmol) in anhydrous dimethylformamide to form a homogeneous solution. 1.83 g (5 mmol) of iodopropargyl alcohol p-nitrobenzenesulfonic acid ester was added to this solution under water cooling, and the mixture was reacted for 2 hours, and further reacted for 2 hours at 20 to 25°C. The reaction solution was extracted with 100 ml of ethyl acetate and 50 ml of water, and the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.57 g of a crude product. This crude product was further purified by silica gel column chromatography to produce 2-(1'-iodopropyn-3'-yl)-5-isopropyltetrazole and 1-(1'-iodopropyn-3'-yl)-5-
Isopropyltetrazole was obtained as crystals. Yield of compound (5) 534mg (39%) mp52.8 ~
54.3℃, elemental analysis value C, 30.03%; H, 3.24%;
N, 20.59%, calculated value as C ₇ H ₉ N ₄ I, C, 30.45
%; H, 3.29%; N, 20.29%, compound 1-(1'-
Yield of iodopropyn-3'-yl)-5-isopropyltetrazole 650 mg (47%) mp89.0-90.8
°C, elemental analysis value C, 29.77; H, 3.18%; N,
20.28%. Example 3 2-(1'-iodopropyn-3'-yl)-5-t
-butyltetrazole [compound (13)] and 1
-(1'-iodopropyn-3'-yl)-5-t-
Butyltetrazole [Compound (14)] Example except that 504 mg (4 mmol) of 5-t-butyltetrazole and an equivalent amount of the reaction reagent were reacted in 15 ml of dimethylformamide for 2 hours under ice cooling and for 2 hours at room temperature. A mixture of 2-(1'-iodopropyn-3'-yl)-5-t-butyltetrazole and 1-(1'-iodopropyn-3'-yl)-5-t-butyltetrazole was obtained in the same manner as in 2. ,
Further, they were purified by silica gel chromatography (solvent: toluene-ethyl acetate 10:1) and separated. 2-(1'-iodopropyn-3'-yl)
- Yield of 5-t-butyltetrazole 624 mg (54
%) mp85.8-87.7℃, elemental analysis value C, 33.17%;
H, 3.71%; N, 19.31%, calculated value as C ₈ H ₁₁ N ₄ I C, 33.12%; H, 3.82%; N, 19.31%, 1
- Yield of 399 mg (34%) of (1'-iodopropyn-3'-yl)-5-t-butyltetrazole oil;
Elemental analysis value C, 32.18%; H, 3.56%; N, 18.33
%. Example 4 2-(1'-iodopropyn-3'-yl)-5-pentyltetrazole [compound (15)] and 1-
(1'-Iodopropyn-3'-yl)-5-pentyltetrazole [Compound (16)] Using 0.70 g (5 mmol) of 5-pentyltetrazole, iodopropargyl alcohol p was substituted for p-nitrobenzenesulfonic acid ester.
-2-(1'-
obtaining a mixture of iodopropyn-3′-yl)-5-pentyltetrazole and 1-(1′-iodopropyn-3′-yl)-5-pentyltetrazole;
They were mutually separated using silica gel chromatography.
Yield of 2-(1'-iodopropyn-3'-yl)-5-pentyltetrazole 588 mg (36%) oil;
Mass spectrum (EI), 304 (M ⁺ ), yield of 1-(1'-iodopropyn-3'-yl)-5-pentyltetrazole 867 mg (57%) oil, mass spectrum (EI), 304 (M ⁺ ). Example 5 2-(1'-iodopropyn-3'-yl)-5-heptyltetrazole [compound (19)] and 1-
(1'-Iodopropyn-3'-yl)-5-heptyltetrazole [Compound (20)] Using 0.51 g (3 mmol) of 5-heptyltetrazole and equimolar amounts of reaction reagents, in 20 ml of dimethylamide under ice cooling. 2-(1'-iodopropyne-
3′-yl)-5-heptyltetrazole and 1-
1.20 g of a mixture of (1'-iodopropyn-3'-yl)-5-heptyltetrazole was obtained and separated from each other by silica gel chromatography. 2-
Yield of (1'-iodopropyn-3'-yl)-5-heptyltetrazole 341 mg (34%) Oil, mass spectrum (EI), 332 (M ⁺ ), 1-(1'-iodopropyn-3'-yl) )-5-heptyltetrazole yield 595 mg (60%) oil, mass spectrum (EI), 332 (M ⁺ ). Example 6 2-(1'-iodopropyn-3'-yl)-5-ethyltetrazole [compound (1)] and 1-(1'-
Iodopropyn-3'-yl)-5-ethyltetrazole [Compound (2)] 5-butyltetrazole 490 mg (5 mmol)
and equimolar amounts of sodium hydroxide and iodopropargyl-p-nitrobenzenesulfonic acid ester were reacted in 15 ml of dimethylformamide under ice cooling overnight to obtain a crude mixture in the same manner as in Example 2. Yield 1.15g (crude yield 88%) This mixture was subjected to silica gel chromatography (solvent: benzene-
They were purified with ethyl acetate (10:1 to 4:1) and separated from each other. 2-(1'-iodopropyn-3'-yl)-
Yield of 5-ethyltetrazole 367 mg (28%) Mass spectrum (EI), 262 (M ⁺ ), elemental analysis value C,
26.90%; H, 2.60%; N, 21.00%, calculated value as C ₆ H ₇ N ₄ I C, 27.50%; H, 2.69%; N,
21.38%, 1-(1'-iodopropyn-3'-yl)-
Yield of 5-ethyltetrazole 693 mg (53%) Mass spectrum (EI), 262 (M ⁺ ), elemental analysis value C,
27.11; H, 2.73%; N, 20.83%. Example 7 2-(1'-iodopropyn-3'-yl)-5-
(p-methoxyphenyl)tetrazole [Compound (23)] 5-(p-methoxyphenyl)tetrazole
1.86 g (1.0 mmol) and 420 mg (10 mmol) of powdered sodium hydroxide were mixed well in anhydrous dimethylformamide to form a homogeneous solution. Add 3.67 g (10 mmol) of iodopropargyl alcohol p-nitrobenzenesulfonic acid ester under ice cooling and allow to react for 4 hours. The reaction solution was extracted with 200 ml of ethyl acetate and 100 ml of water, and the ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure. The solid residue obtained was recrystallized twice from methanol to give 2-(1'-iodopropyne-3' -yl)-5-(p-methoxyphenyl)tetrazole was obtained. Yield 2.06g (60
%) mp146.7-149.8℃, elemental analysis value C, 37.57
%; H, 2.58%; N, 16.06%, calculated value as C ₁₁ H ₉ ON ₄ I C, 38.84%; H,
2.67%; N, 16.47%. Example 8 2-(1'-iodopropyn-3'-yl)-5-
(m-chlorophenyl)tetrazole [Compound (24)] 5-(m-chlorophenyl)tetrazole 3.61
Crude crystals were obtained in the same manner as in Example 7, except that the reaction was carried out in 40 ml of dimethylformamide using g (20 mmol) and an equimolar amount of the reaction reagent. Iodopropyne-3'-
4.74 g (69%) of purified crystals of (chlorophenyl)-5-(m-chlorophenyl)tetrazole were obtained. mp91.5~93.2
°C, elemental analysis value C, 34.83%; H, 1.70%; N,
16.22%, calculated value C as C ₁₀ H ₆ N ₄ ClI, 34.86
%; H, 1.76%; N, 16.26%. Example 9 2-(1'-iodopropyn-3'-yl)-5-
(o-chlorophenyl)tetrazole [Compound (25)] 5-(o-chlorophenyl)tetrazole 3.61
A crude reaction product (oil) was prepared in the same manner as in Example 7, except that the reaction was carried out in 40 ml of dimethylformamide using g (20 mmol) and equimolar amounts of reaction reagents.
5.8g was obtained. The crude product was purified by silica gel chromatography (solvent system: toluene) and further recrystallized from isopropyl ether to purify 2-(1'-iodopropyn-3'-yl)-5-(o-chlorophenyl)tetrazole. 3.03 g of crystals were obtained (yield 44%). mp92.5-93.8℃, elemental analysis value C, 34.97
%; H, 1.77%; N, 16.46%; Calculated value as C ₁₀ H ₆ N ₄ ClI C, 34.86%; H,
1.76%; N, 16.26%. Example 10 2-(1'-iodopropyn-3'-yl)-5-
(m-Trifluoromethyl)tetrazole [Compound (26)] 3.44 g of crude reaction product was obtained in the same manner as in Example 7, except that 2.14 g (10 mmol) of 5-(m-trifluoromethylphenyl)tetrazole was used. (91%). The crude crystals were recrystallized twice from a methanol-water mixed solvent to give 2-(1'-iodopropyn-3'-yl)-
2.23 g of purified crystals of 5-(m-trifluoromethyl)tetrazole were obtained (59%). mp70.0~72.0℃. Example 11 2-(1'-iodopropyn-3'-yl)-5-
(p-fluorophenyl)tetrazole [Compound (27)] 5-(p-fluorophenyl)tetrazole
2.71 g of a crude reaction product was obtained in the same manner as in Example 7 except that 1.64 g (10 mmol) was used. Purified by silica gel chromatography and further purified with 4ml of benzene.
Recrystallized from a mixed solvent of 46ml of hexane and 2-
1.04 g of purified crystals of (1'-iodopropyn-3'-yl)-5-(p-fluorophenyl)tetrazole
I got it. mp104.6~106.2℃, elemental analysis value C,
36.67%; H, 1.78%; N, 17.42%, C ₁₀ H ₆ N ₄ IF
Calculated value as C, 36.61%; H, 1.84%; N,
17.08%. Example 12 2-(1'-iodopropyn-3'-yl)-5-
(p-cyanophenyl)tetrazole [Compound (28)] 5-(p-cyanophenyl)tetrazole 1.71
3.05 g (95%) of a crude reaction product was obtained in the same manner as in Example 7, except that 3.05 g (10 mmol) of the crude reaction product was used. Recrystallization from 16 ml of acetone gave 1.41 g (42%) of crystals of 2-(1'-iodopropyn-3'-yl)-5-(p-cyanophenyl)tetrazole. mp174～
184.6℃, elemental analysis value C, 39.74%; H, 1.80%;
Calculated value as N, 21.16%, I, 36.87%, C ₁₁ H ₆ N ₅ I, C, 39.43%; H, 1.80
%; N, 20.90%; I, 37.87% Example 13 2-(1'-iodopropyn-3'-yl)-5-
(p-hydroxyphenyl)tetrazole [compound (29)] and 1-(1'-iodopropyne-
3′-yl)-5-(p-hydroxyphenyl)tetrazole [Compound (30)] 5-(p-hydroxyphenyl)tetrazole
0.81g (5 mmol) and sodium hydroxide powder
Dissolve 200 mg in dimethylformamide. 1.84 (5 mmol) of iodopropargyl alcohol p-nitrobenzenesulfonic acid ester was added under ice cooling, and the reaction solution was stirred for 4 hours. 100 ml of ethyl acetate and 50 ml of water were added to the reaction solution for extraction, and the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 1.23 g (75%) of a crude product. Column chromatography of the crude product using 65 g of silica gel (solvent system: hexane-ethyl acetate 1:1)
Upon separation, the following two substances were sequentially eluted. 2
-(1'-iodopropyn-3'-yl)-5-(p-
Hydroxyphenyl)tetrazole yield 643mg
(39%), mp187-188℃ (recrystallized from IpA), 1-
(1'-iodopropyn-3'-yl)-5-(p-hydroxyphenyl)tetrazole yield 500 mg,
mp179-180℃ (recrystallized from IpA). Example 14 2-(1'-iodopropyn-3'-yl)-5-
(3″,5″-dichlorophenyl)tetrazole [Compound (31)] Stir 645 mg (3 mmol) of 5-(3′,5′-dichlorophenyl)tetrazole and 120 mg of sodium hydroxide powder with 15 ml of dimethylformamide. ,
Make a homogeneous solution. Propargyl bromide 357mg
was added and the reaction solution was left at room temperature for 16 hours. Extract the reaction solution with 50 ml of benzene, wash the benzene layer with water,
Dry with anhydrous magnesium sulfate. 0.78g of the residue obtained by concentrating the benzene solution was added to 100% of benzene again.
Morpholine-iodine complex dissolved in ml
Add 1.02 g (3 mmol) and allow to react for 2 days while stirring vigorously. The reaction solution was washed with sodium thiosulfate solution and water, dried, and concentrated to obtain 948 mg of crude iodide. This crude product was purified by column chromatography using 50 g of silica gel (solvent system: toluene), and 2-
(1′-iodopropyn-3′-yl)-5-(3″, 5″
−
626mg of crude crystals of dichlorophenyl)tetrazole
I got it. Pure crystals when recrystallized from 20ml of hexane
527 mg was obtained (yield 46%). mp102.0~103.5
°C, elemental analysis value C, 31.88%; H, 1.31%; N,
14.91%, total halogens 52.04%, calculated as C ₁₀ H ₅ N ₄ Cl ₂ I C, 31.69%; H, 1.33%; N, 14.78
%, Cl: 18.71%, I, 33.48%. Example 15 2-(1'-iodopropyn-3'-yl)-5-
(p-Carbamoylphenyl)tetrazole [Compound (32)] A crude product was prepared in the same manner as in Example 7, except that 1.89 g (10 mmol) of 5-(p-carbamoylphenyl)tetrazole and an equimolar amount of the reaction reagent were used. obtain crystals,
Recrystallization was performed twice from acetone to obtain 1.66 g (60%) of purified crystals of 2-(1'-iodopropyn-3'-yl)-5-(p-carbamoylphenyl)tetrazole. mp192.4-193.7℃, elemental analysis value C, 37.10
%; H, 2.36%; N, 19.56%; Calculated value as C ₁₁ H ₈ N ₅ I C, 37.41%; H, 2.28
%; N, 19.83%. Example 16 2-(1'-iodopropyn-3'-yl)-5-
(p-carboxyphenyl)tetrazole [Compound (33)] 5-(p-carboxyphenyl)tetrazole
1.15 g (65 mmol) of crude crystals were prepared in the same manner as in Example 7, except that the reaction was carried out in 5 ml dimethylformamide using 0.92 g (5 mmol) and an equimolar amount of the reaction reagent.
%) was obtained. The crude product was purified by silica gel column chromatography (solvent system: ethyl acetate), and Rf
Only the substance showing a value of 0.66 (silica gel TLC/ethyl acetate) was isolated, yield 438 mg (yield 25%). Recrystallization from 10 ml of methanol gave 269 mg of pure crystals of 2-(1'-iodopropyn-3'-yl)-5-(p-carboxyphenyl)tetrazole.
mp210.8~211.5℃. Example 17 2-(1'-iodopropyn-3'-yl)-5-
(p-Dimethylaminophenyl)tetrazole [Compound (34)] 420 mg (12.2 mmol) of 5-(p-dimethylaminophenyl)tetrazole and 84 mg of sodium hydroxide powder are dissolved in 5 ml of dimethylformamide. Iodopropargyl alcohol p- under water cooling.
Toluene sulfonic acid ester 672 mg (2 mmol)
was added, and the reaction solution was allowed to react for 5 hours while returning to room temperature. Add 20 ml of ice water to the reaction solution. A candy-like substance precipitated. Remove the supernatant and add 5 ml of methanol to
-(1'-iodopropyn-3'-yl)-5-(p-
Crystals of dimethylaminophenyl)tetrazole precipitated. Yield 300mg (43%), mp164.5~166℃,
Elemental analysis value C, 40.18%; H, 3.24%; N, 19.03
%, calculated value as C ₁₂ H ₁₂ N ₅ I C, 40.89%; H,
3.43%; N, 19.83%. Next, examples of formulations of the present invention will be shown. Formulation example 1 Wettable powder 2-(1'-iodopropyn-3'-yl)-5-n
-40 parts by weight of propyltetrazole [compound (3)] and 5 parts by weight of polyoxyethylene alkylaryl ether
Parts by weight 3 parts by weight of ligninsulfonic acid and diatomaceous earth
By uniformly pulverizing and mixing 52 parts by weight, a wettable powder containing 40% of the active ingredient can be obtained. Formulation example 2 Granules 2-(1'-iodopropyn-3'-yl)-5-n
-12 parts by weight of propyltetrazole [compound (3)],
By uniformly pulverizing and mixing 1 part by weight of calcium lignosulfonate and 30 parts by weight of bentonite, adding an appropriate amount of water and kneading, the mixture is granulated and dried to obtain granules containing 12% of the active ingredient. Formulation Example 3 Emulsion 2-(1'-iodopropyn-3'-yl)-5-isopropyltetrazole [compound (5)] 20 parts by weight,
By uniformly mixing 30 parts by weight of dimethylformamide, 35 parts by weight of xylene, and 15 parts by weight of polyoxyethylene alkylaryl ether, an emulsion containing 20% of the active ingredient is obtained. Formulation example 4 Powder 2-(1'-iodopropyn-3'-yl)-5-isopropyltetrazole [compound (5)] 3 parts by weight,
0.5 parts by weight of silicic anhydride fine powder, 0.5 parts by weight of calcium stearate, 50 parts by weight of clay, and 46 parts by weight of talc
By uniformly pulverizing and mixing parts by weight, a powder containing 3% of the active ingredient is obtained.

Claims (1)

[Claims] 1. General formula An iodopropargyl tetrazole compound represented by the formula in which R represents an alkyl group, benzyl group, or substituted phenyl group having 2 or more carbon atoms (excluding p-chlorophenyl group, p-nitrophenyl group, and p-methylphenyl group). 2 General formula R'-SO ₂ -O-CH ₂ C≡CI In the formula, R' represents an alkyl group or an aryl group with or without a substituent. In the formula, R represents an alkyl group having 2 or more carbon atoms, a benzyl group, or a substituted phenyl group (excluding p-chlorophenyl group, p-nitrophenyl group, p-methylphenyl group). General formula for A method for producing an iodopropargyltetrazole compound represented by the formula in which R has the same meaning as defined above. 3 General formula In the formula, R is an alkyl group having 2 or more carbon atoms, a benzyl group, or a substituted phenyl group (excluding p-chlorophenyl group, p-nitrophenyl group, p-methylphenyl group) Contains an iodopropargyl tetrazole compound as an active ingredient An antibacterial and antifungal agent.