The method of obtaining substituted n-(aryl)-1,2,4 - triazolopyrimidine-2-sulfonamides

 

(57) Abstract:

Usage: in agriculture as herbicides. The inventive product is N-(aryl)-1,2,4-triazolopyrimidine-2-sulfonamides. Reagent 1; substituted 1,2,4-treatability-2-sulphonylchloride. Reagent 2: arylamine formula N2. Reaction conditions: inert aprotic organic solvent, pyridine base, a catalytic amount of dimethyl sulfoxide. 1 C.p. f-crystals., table 2.

The invention relates to the field of sulfonamides, in particular, to an improved process for the preparation of N-(aryl)- 1,2,4-triazolopyrimidine-3-sulphonamide of the formula I:

< / BR>
where x represents co3or OS2H5;

y represents N, CH3THE CO3or halogen

Z represents H, CH3CH2F, phenyl, CH2OCH3or halogen,

Ar represents a substituted phenyl group of the formula:

< / BR>
in which R1 represents halogen, NO2, CO2-(lower alkyl), lower alkyl, lower alkoxygroup,SCH3, CF3or CH2OCH3, R2represents H OR CH3, R3 represents halogen, NO2, CO2-(lower alkyl), lower alkyl, lower alkoxygroup, SCH3or Ar battle N, NO2or CF3;

R6represents a halogen or CO2-(lower alkyl);

R7represents H or lower alkyl.

Known substituted N - (aryl) 1,2,4 - triazole(1,5-C) pyrimidine-2-sulfonamides of the formula II:

< / BR>
which are valuable herbicides for selective weed control in the fields of cereal crops (1). The connection of this family in the General case was obtained by means of known reactions between aryl-amine (III) and substituted 1,2,4-triazolopyrimidine-3-sulfonyl chloride (IV) in the presence of a tertiary amine base (U.S. patent N 4740233) or an excess of aniline (patent UK N 951652). This procedure in General is satisfactory for obtaining substituted 1,2,4-triazolopyrimidine-2-sulfonanilide when used substituted aniline itself is aniline or substituted aniline derivative, which has a similar chemical activity as a nucleophilic reagent. However, when substituted aniline is significantly lower nucleophilic activity due to the presence of substituents, deriving electrons on the ring, and, in particular, the presence of substituents in positions ORT to amino functions, or when aryl gruska the yields of target products.

This issue of chemical activity is particularly unfortunate, as the most effective herbicide action of substituted 1,2,4-triazolopyrimidine-2-sulfonamides contain such substituents.

In order to overcome this difficulty, related to the problem of chemical activity, instead of a tertiary amine base using a strong base such as an alkyl alkali metal or hydride of an alkali metal capable of transforming a weakly nucleophilic substituted aniline with the corresponding derivative of the metal, as described in U.S. patent N 4740233. Derived metal get in advance, and then give him the opportunity to interact with substituted 1,2,4-triazolopyrimidine-2-sulfonyl a halide. This procedure allows you to brush up on these connections, but requires excessive amounts derived metal substituted aniline, and is carried out at a temperature below 0oWith and, therefore, she is not feasible on an industrial scale.

Alternatively, the nucleophilicity of aniline can be increased by converting it into the corresponding N-trialkylsilyl. In U.S. patent N 5003096 a method of increasing the chemical actinidin-2-sulfonyl guidami; in U.S. patent N 5010195 proposed a similar method of increasing the chemical activity in the case of the corresponding 1,2,4 - triazolo (1,5-C)pyrimidine. Although this procedure allows to obtain a broader scope of products containing deriving the electron group requires additional stages in order to synthesize N-trialkylsilyl and to highlight and recycling valuable, containing silicon, the reagent.

Due to the valuable herbicide properties of sulfonamides (I) and (II), it is highly desirable to have a direct method that can be used for a wide variety of materials in which the aryl groups contain deriving electrons deputies. Ideally, when performing this method, I would like to avoid too much reaction times and the use of strong bases. In addition, when implementing this method, I would like to avoid using unnecessary reaction stages and the selection and recirculatory expensive reagents.

In accordance with this invention proposes a method of obtaining N-(aryl)-1,2,4-triazolopyrimidine-2-sulfonamides of formula (1), namely, that of substituted 1,2,4 - triazolopyrimidine-2-sulphonylchloride form is2< / BR>
where Ar has the above meanings, in an inert aprotic organic solvent, in the presence of pyridine base and a catalytic amount of dimethyl sulfoxide.

Through the implementation of the reactions in the presence of a pyridine base and a catalytic amount of DMSO has the opportunity to get a variety of N-(aryl)-1,2,4-triazolopyrimidine-2-sulfonamides containing deriving electrons substituents in N-(aryl) group.

As they are used here, the terms "Lower alkyl" and "lower alkoxy" denote linear or branched, saturated group with 1-4 carbon atoms. Where individual members of the family of Halogens are not listed, General terms "halogen", "halide", halos and "Gal", as they are used here, refer to patterns containing only chlorine and bromine.

Under the pyridine base is meant pyridine or methylpyridine such as nichelini or lutidine. The pyridine in the General case is more preferable.

Substituted 1,2,4-triazolopyrimidine-3-sulfonyl halide used according to the method of the present invention, are known compounds and can be obtained in accordance with opisaniya reagents include the following compounds: 8-chloro-7-methoxy-5-methyl-1,2,4 - triazolo(1,5-C)pyrimidine-2-sulfonyl chloride; 8-chloro-5-methoxy, 2,4-triazolo-(1,5-C) pyrimidine-2-sulfonyl chloride; 7-fluoro-5-methoxy-1,2,4-triazolo(1,5-C)pyrimidine-2-sulfonyl chloride; 7-chloro-5,8-dimethoxy-1,2,4-triazolo(1,5-C)pyrimidine-2-sulfonyl chloride; 5-methoxy-1,2,4-triazolo (1,5-C)-pyrimidin-sulfonyl chloride; 7-chloro-5-methoxy-1,2,4-triazolo (1,5-C) pyrimidine-X-sulfonyl chloride; 7-chloro-5-ethoxy - 1,2,4- -triazole (1,5-C) pyrimidine-2-sulfonyl chloride; 5-methoxy-7-methyl-1.2.4-triazolo (1,5-C) pyrimidine-2-sulfonyl chloride; 5-ethoxy-7-methyl-1.2.4-triazolo (1,5-C) pyrimidine-2-sulfonyl chloride; 5-chloro-7-methoxy-1,2,4-triazolo (1,5-C) pyrimidine-2-sulfonyl chloride; 8-bromo-5-chloro-7-methoxy-1,2,4-triazolo (1,5-pyrimidine-2-sulfonyl chloride; 5,7-dimethyl, 2,4-triazolo (1,5-a) pyrimidine-2-sulfonyl chloride; 5-methyl, 2,4-triazolo (1,5-a) pyrimidine-2-sulfonyl chloride; 5-methyl-7-trifluoromethyl-1,2,4-triazolo (1,5-a) pyrimidine-2-sulfonyl bromide; 1,2,4-triazolo (1, 5-a) pyrimidine-2-sulfonyl chloride; 5-methoxy-7-butyl-1,2,4-triazolo (1,5-a) pyrimidine-2-sulfanilamide; 6-chloro-1,2,4-triazolo (1,5-a) pyrimidine-2-sulphonylchloride; 5-methylacyl-7-methylthio-1,2,4-triazolo (1,5-a)- pyrimidine-2-sulphonylchloride; 5,7-dimethyl-6-fluoro-1,2,4-triazolo (1,5-a) pyrimidine-2-sulphonylchloride; and 5,7-dimethoxy-1,2,4-triazolo (1,5-a) pyrimidine-2-sulphonylchloride.

Similarly, the aryl amine is substituted pyrazol group (PRZ) of the formula:

< / BR>
used according to the method of the present invention are also known compounds and can be obtained using known methods. The corresponding anilines and pyrazoles include, for example: 2,6-dichloroaniline; 2,6-diptiranjan; 2,6-dibromsalan; 2-fluoro-6-Chloroaniline; 2,6-dichloro-3-methylaniline; 2,6-debtor-3-methylaniline; methyl 3-garanterat; methyl 3-parentresult; methyl 3-methylanthranilate; 2-methoxy-6-triptorelin; 2,3-dimethyl-6-nitroaniline; 1-methyl-3-aminopyrazole; 1-methyl-4-bromo-3-aminopyrazole; 1-methyl-4-iodine-3-aminopyrazole; 1-methyl-3-nitro-4-aminopyrazole; 1,5-dimethyl-3-trifluoromethyl-4-aminopyrazole; 1-methyl-4-bromo-5-aminopyrazole; 1-/2-pyridinyl/-4-bromo-5-aminopyrazole; and 1 - phenyl-4-bromo-5-aminopyrazole. When Ar is a substituted phenyl group, preferred compounds are compounds in which R1represents F, Cl or R; R2represents H, or R; R3represents F, Cl, CF3, CO2R or NO2; and R is CH3or CH2CH3, in the most preferred embodiment, CH3. When Ar is a substituted group of the pyrazole, the preferred compounds are 3 - and 5-pyrazolinone compounds in which R4is R; R5and R7represent the nom version of CH3.

This method is generally carried out using the premises of substituted 1,2,4-triazolopyrimidine-2-sulfonyl halide, aryl amine and an inert solvent in the vessel, and then adding the pyridine base and a catalytic amount of dimethyl solitarii. Next, the mixture is allowed the opportunity to respond, generally at ambient temperature. After you have formed a significant amount of product sulfonamida or a significant number of sulfonyl excreted was spent, the target product (V) was isolated using standard techniques. For example, if you used water-soluble solvent, in the General case, it would first replace the water-immiscible solvent. The resulting solution may be washed with dilute acid and water and then dried; the product can be isolated by evaporation of the solvent. The extracted product can be subjected to cleaning, if necessary, by dissolving in dilute aqueous phase, filtration and/or extraction immiscible organic solvent such as diethyl simple ether, and sedimentation of dilute aqueous acid. Alternatively, the target compounds) ravnomernye number of substituted 1,2,4-triazolopyrimidine-2-sulfonyl excreted and aryl amine in General use in the present method, although you can also use a substantial excess of one or the other. It is often convenient, for example, to use up to 2 or 3-fold excess aryl amine relative to sulfonyl chloride. This is especially important when it is desirable to provide a more complete response gene reagent. The pyridine base is in General used in amounts of from 1 to 3 moles per mole 1,2,4-triazolopyrimidine-2-sulfonyl poured. Dimethyl sulphates in General used in amounts of from 0.05 to 0.5 moles per mole 1,2,4-triazolopyrimidine-2-sulfon l excreted; amount greater than about 0.5 moles per mole of sulfonyl excreted, in General, are harmful.

Temperature is not the decisive factor; the reaction in General takes place at temperatures from 0 to 60oAnd in the most preferred embodiment, it is carried out at ambient temperature.

This reaction is in General carried out in a slightly polar aprotic solvent which is inert with respect to both the reagents and the reaction conditions. Appropriate inert aprotic organic solvents include alkyl nitrile such as acetonitrile; ethers, such as, for example, dioxane or tetrahydrofuran; or sophistication of the pits of illustrating the present invention. All temperature melting points are unadjusted.

Example 1. Obtaining N-/2,6-dichlorophenyl/-8-bromo-5 methoxy-1,2,4-triazolo(1,5-C) pyrimidine-2-sulfonamida.

2.6 dichloraniline (1,76 grams (g), 10.9 mmol), 2-chlorosulfonyl-8-bromo-5-methoxy-1, 2,4-triazolo (1,5-C) pyrimidine (1.5 g, 4.6 mmol) and 30 milliliters (ml) of dry acetonitrile were placed in a 100 ml flask equipped with means for supplying gas and a magnetic stirring bar. When mixing and applying nitrogen was added pyridine (0,74 ml, 9.2 mmol) and dimethyl sulphates (of 0.08 ml, 1.2 mmol) and the mixture was allowed to interact for 1.25 hours (h). Volatile materials were then removed by evaporation under reduced pressure, and the residue was dissolved in 100 ml of methylene chloride. The resulting solution was extracted 3 times with 75 ml of 1N HCl solution and once with 100 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure to obtain a yellow solid. This solid was diluted with 100 ml of hexane and after keeping for 1 hour hexane was removed by filtration, and the solids were washed with additional hexane and dried to obtain 1.1 g (yield 52%) of the compound from the header of the example phenyl/-1,2,4-triazolo (1,5-C) pyrimidine-2-sulfonamides.

The compounds listed in Table 1, were obtained from the corresponding starting materials in accordance with the procedure described in example 1.

Example 3. Obtaining N-(4-bromo-1-methylpyrazole-3-yl)-7-chloro-5-methoxy-1,2,4-triazolo(1,5-C) pyrimidine-2-sulfonamida

Pyridine (1.08 g, 8 mmol) and dimethyl sulphates (0.2 g) was added to a solution of 7-chloro-5-methoxy-1,2,4-triazolo (1,5-C) pyrimidine-2-sulfonyl chloride (1.0 g, 4.0 mmol) and 3-amino-4-bromo-1-methylpyrazole (0.7 g, 4.0 mmol) in 10 ml of acetonitrile under stirring at ambient temperature, and then the mixture was allowed to interact during the night. Next, the mixture was concentrated by evaporation under reduced pressure, and the residue was transferred into methylene chloride. The resulting R the target was extracted with water and dried over magnesium sulfate. Volatile materials were then removed by evaporation under reduced pressure and the solid residue was extracted with diethyl simple ether and water were isolated by filtration and dried under reduced pressure to obtain 0,38 g (yield 25%) of the compound from header example in the form of a white solid, which melts at a temperature 230-232oC.

Example 4. Obtaining N-(pyrazolyl)-1,2,4-triazolo-(1,5-C) pyrimidine-2 - print materials in accordance with the procedure described in example 3.

Example 5. Obtaining N-(2,6-dichlorophenyl)-6-bromo-5-methoxy-1,2,4-triazolo (1,5-C) pyrimidine-2-sulfonamida.

2,6-dichloroaniline (0,49 g, 3.1 mmol), 2-chlorosulfonyl-8-bromo-5-methoxy-1, 2,4-triazolo (1,5-C) pyrimidine (1.0 g, 3.1 mmol) and 20 ml of dry acetonitrile were placed in a 100 ml flask equipped with means for supplying gas and magnetic stirring bar Under stirring in nitrogen atmosphere was added pyridine (0,50 ml, 6.2 mmol) and dimethyl sulphates (0.06 ml, 0.8 mmol) and the mixture was allowed to interact for 1 hour. Volatile materials were then removed by evaporation under reduced pressure, and the residue was dissolved in 180 ml of methylene chloride. The resulting solution was extracted 2 times with 100 ml of 1N HCl solution and once with 100 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure to obtain a yellow solid. This solid was stirred with 200 ml of hexane and filtered to obtain 0,38 g (27% yield) of the compound from header example in the form of a yellow solid, melting at 198-200oC (Razlog.).

Example 6. Obtaining N-(2,6-dichlorophenyl)-8-bromo-methoxy-1,2,4-triazolo (1,5-C) pyrimidine-2-sulfones is 3.1 mmol) and 20 ml of dry acetonitrile were placed in a 100 ml flask, provided with a means for supplying gas and a magnetic stirring bar. The solution was cooled to 0oC. With stirring in an atmosphere of nitrogen was added pyridine (0,50 ml, 6.2 mmole) and dimethyl sulphates (0.06 ml, 0.8 mmol) and the mixture was allowed to interact for 1 hour at 0oC. Volatile materials were then removed by evaporation under reduced pressure, and the residue was dissolved in 150 ml of methylene chloride. The resulting solution was extracted 2 times with 100 ml of 1N HCl solution and once with 100 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure to obtain a yellow solid. Then, this solid was stirred with 200 ml of hexane and filtered to obtain and 0.37 g (yield 26%) of the compound from header example in the form of a yellow solid, melting at 196-198oWith (Razlog.).

Example 7. Obtaining N-(2,6-dichlorophenyl)-8-bromo-5-methoxy-1, 2,4-triazolo (1,5-C) pyrimidine-2 - sulfonamida.

2,6-dichloroaniline (1.0 g, 6.2 mmol), 2-chlorosulfonyl-8-bromo-5-methoxy-1, 2,4-triazolo (1,5-C) pyrimidine (1.0 g, 3.1 mmol) and 20 ml of dry acetonitrile were placed in a 100 ml flask equipped with means for supplying gas and magnetic stirring plancii), and the mixture was allowed to interact for 3.5 hours. Then volatile materials were removed by evaporation under reduced pressure, and the residue was dissolved in 150 ml of methylene chloride. The resulting solution was extracted 2 times with 100 ml of 1N HCl solution and once with 100 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure to obtain a yellow solid. This solid was stirred with 200 ml of hexane and filtered to obtain and 0.46 g (yield 34%) of the compound from header example in the form of a yellow solid, melting at 196-198C (Razlog.).

Example 8. Obtaining N-(2,6-dichlorophenyl)-5-methyl-1,2,4-triazolo (1,5-a) pyrimidine-2-sulfonamida.

2.6 dichloraniline (2,78 g, 17.2 mmol), 2-chlorosulfonyl-5-methyl-1,2,4-triazolo (1,5-a) pyrimidine (2.0 g, 8.6 mmol) and 30 ml of dry acetonitrile were placed in a 100 ml flask equipped with means for supplying gas and a magnetic stirring bar. Under stirring in nitrogen atmosphere was added pyridine ( 1.39 ml, 17.2 mmol) and dimethyl sulphates (0.15 ml, 2.2 mmol) and the mixture was allowed to interact for 1.0 hour. Volatile materials, then, was removed by evaporation under reduced pressure the measures 100 ml of 1N solution of HC once with 100 ml of water, was dried over magnesium sulfate, filtered and concentrated by evaporation and reduced pressure to obtain white solid. This solid was stirred with 200 ml of hexane and filtered to obtain of 1.62 g (yield 52%) of the compound from header example in the form of a white solid, melting p and temperature 126-129oC (Razlog.). TTT TTT TTT

1. The method of obtaining substituted N-(aryl)-1,2,4-triazolopyrimidine-2-sulfonamides of the formula

< / BR>
where X OCH3or OS2H5,

Y N, SN3, OCH3or halogen,

Z N, SN3CH2F, phenyl, CH2OCH3or halogen,

Ar is a substituted phenyl group of the formula

< / BR>
where R1halogen, O2, CO2(lower alkyl), lower alkyl, lower alkoxy group, SOH3, CF3or CH2OCH3,

R2H or CH3,

R3halogen, NO2, CO2(lower alkyl), lower alkyl, lower alkoxygroup, SCH3or Ar substituted pyrazol group (PRZ) formula

< / BR>
in which R5H, NO2or CF3,

R6halogen for CO2(lower alkyl),

R7H or lower alkyl,

wherein said substituted 1,2,4-triazoline with arylamino formula

ArNH2,

where Ar has the abovementioned meaning,

in an inert aprotic organic solvent in the presence of pyridine base and a catalytic amount of dimethyl sulfoxide.

2. The method according to p. 1, wherein each of Y and Z is independently H, CH3, F, or Cl or Y-OCH3.

3. The method according to p. 1, wherein Ar is substituted phenyl, in which R1F, Cl or CH3, R2H or CH3, R3F, Cl, CO2CH3or NO2.

4. The method according to p. 1, wherein Ar is 5-pyrazolyl or 3-pyrazolyl, where R6H, F, Cl or I, R5and R7H.

5. The method according to p. 1, characterized in that as pyridine pyridine bases use.

 

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The invention relates to new derivatives of arylsulfonamides, which can be used in agriculture as a herbicide for weed control in soybean crops, in particular in a mixture with other compounds

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

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EFFECT: possibility to use in agriculture as herbicidal means or in herbicidal compositions.

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