JPH0249775A - Heterocyclic compound having 6-membered or 7-membered ring and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R is alkyl (substituted with heterocyclic group), aralkyl, cycloalkyl, alkenyl or (substituted) aryl; n is 0, 1 or 2; R<1> is H, cyano, carbamoyl or COOR<3> (R<3> is H, alkyl, aralkyl or aryl); R<2> is alkyl, (substituted) aryl, alkoxycarbonyl or oxo; m is 0 or 1-2; when m is 2, R<2> groups may be the same or different; two R<2> groups may together form a ring; Z is C-C or C-C-C; the bond expressed by the dotted line may be double bond]. EXAMPLE:2-Cyano-5,6-diphenyl-3-phenylthiopyrazine. USE:Useful as a raw material for agricultural chemicals, pharmaceuticals perfumes and polymers. PREPARATION:The compound of formula IV which is one of the compound of formula I can be produced e.g., by reacting a compound of formula II with a compound of formula III (R<4> and R<5> are H, alkyl, etc.).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a 6- and 7-membered heterocyclic compound and a method for producing the same.

[Conventional technology]

To introduce a thio group (R'S group, R' represents any substituent group) into a nitrogen-containing heterocycle, a halogen-substituted heterocycle and R'SH
The main reactions include the alkylation or arylation of a heterocycle having a thioxo group, and the coupling reaction between an azo compound and R'SH. However, in the halogenation of heterocycles, the control conditions are difficult, undesirable reactions occur, and undesirable reaction products are often obtained, and it is often difficult to obtain the desired halogen-substituted heterocycle. Furthermore, when synthesizing thioxo derivatives and diazonium salts, there is no suitable method suitable for each type of heterocycle, and it is not easy to synthesize the thio group-containing heterocycle of the present invention. Moreover, it must be said that it is extremely difficult to synthesize a heterocycle having a cyano group.

[Problem that the invention seeks to solve]

Nitrogen-containing heterocyclic compounds are the #1 raw material for agricultural medicines, fragrances, and polymers.
It is a group of compounds that have a wide range of applications and are used in In particular, cyano-substituted heterocycles are considered to be extremely valuable because they can convert the cyano group into other functional groups. Furthermore, by introducing a thio group and performing a substitution reaction, it becomes possible to replace the thio group with another nucleophile.
It is expected that it will be even more useful.

The present invention provides a method for practically producing a monocyano heterocycle having a thio group.

[Means for solving problems]

[In the formula, R is an alkyl group that may be substituted with a heterocycle, an aralkyl group, a cycloalkyl group, an alkenyl group, or an aryl group that may have a substituent, is O, l, 2
, R' is hydrogen, a cyano group, a carbonyl group S or 2COOR3 (in the formula, R3 represents hydrogen, an alkyl group, an aralkyl group or an aryl group);
R2 is alkylnor, an aryl group which may have a substituent, an alkoxycarbonyl group, or an oxo group, m is 0.1
．． 2 (when m is 2 or more, R2 may be the same or different), and two R2 may be combined with G to form a ring. Z represents C-C or C-C-C,
The connecting lines indicate that each bond can be a double bond. ) and its production method.

In order to simultaneously introduce 6, thio group and cyanogen 5 into the heterocycle in the compound of the present invention, the following method is used: and indicate the meaning.

) with 2,3-diaminoacrylonitrile (hereinafter referred to as DA
Abbreviated as AN. ), N CCN H□ or an organic salt thereof (p-toluenesulfonate, etc.),
Inorganic salts (such as hydrochloride) are used as starting materials.

(]) Method for producing pipyran (III) (IV) In the formula, R has the same meaning as i:I, and R' and rr5 each represent hydrogen, an alkyl group, an aralkyl group, an aryl group, or an alkoxycarbonyl group. show.

Reaction (6 solvents used are alcohols such as ethanol (1), esters such as ethyl acetate, nitriles such as acetonitrile, and hydrocarbons such as toluene,
A mixture of these may also be used.

(2) Method for producing nooxopyrazine <v) [Vl] where, R
(1; has the same meaning as in Section I. R6 represents chlorine or imidazyl group.

For the reaction, ethers such as dioxane, halogenated hydrocarbons such as chloroporm, and aromatic tl such as toluene/yachlorohenzene are used.

(3) Method for producing diazepine In the formula, R indicates the meaning in numerals. R” R1+
represents an alkyl group, an aryl group, or R' Rθ taken together.

As the reaction solvent, alcohols such as ethanol, esters such as ethyl acetate, nitriles such as acetonide, and hydrocarbons such as toluene are used, but mixtures thereof may also be used.

The catalyst used is an organic acid such as oxalic acid or ρ-toluenesulfonic acid, or an inorganic acid such as sulfuric acid or phosphorus pentoxide.

(4) Method for producing dihydro "J diazepine In the formula, R has the same meaning as in 1j11. R9RlG represents an alkyl group or an aryl group.

As the reaction solvent and catalyst, those described in the section (3) Method for producing diazepine are used.

The sulfide of the compound of the present invention can be converted to m-
The corresponding sulfoxides and sulfonyl compounds can be obtained using organic and inorganic oxidizing agents such as chloroperbenzoic acid and hydrogen peroxide. Further, an appropriate catalyst can be used to smoothly proceed the reaction.

In addition, by hydrolyzing and decarboxylating the cyano group, cal-
It can be converted to hydrogen via an h-mo-yl group or a carboxyl group.

After the reaction is completed, the desired product can be obtained by carrying out usual post-treatments.

The structure of the compound of the present invention was determined from [R, NMR, MasS, etc.

〔Example〕

Next, the compounds of the present invention will be further explained with reference to Examples.

Example 1 2-cyano-56-diphenyl-3-phenylthiopyrazine (compound number 1) Recrystallized from n-hexane to give 7.6 g (yield 70%)
crystals were obtained. m, p, 137-138'CNM
The R,lR,Mass spectrum results supported the structure of the target product, which was further confirmed by incorporation into known compounds. That is, the product obtained by the reaction of the target substance and methylate is J, lleterocyclicChe.
It is exactly the same as 2-cyano-3-methoxy-56-diphenylpyrazine, which is a known substance described in J. M., +7455 (1980).

(Ph: indicates a phenyl group.) 2.3-diamino-3-phenylthioacrylonitrile (hereinafter abbreviated as Ph5-DAAN) 5.7 g (
0,0298 mol) was dissolved in 100 mN ethanol, Hensyl 6, Ig (0,029 mol) was added,
Stirred at room temperature for 2 hours. The precipitated crystals were filtered and added to Hensen's Example 2 2-cyano-5,6-dimethyl-3-phenylthiopyrazine (Compound No. 2) PhS-DAANI9. 3 g of anhydrous magnesium sulfate was added to a C6 solution prepared by dissolving I g (0.1 mol) in 400 IIIβ ethyl acetate, and while stirring, 8.6 g (0
, 1 mol) of diacetyl was added dropwise, and the mixture was stirred at room temperature for 1 hour. 1 g of activated carbon was added to the reaction mixture, and the filtrate was distilled off under reduced pressure. 23 g of yellow crystals remained, so they were recrystallized from benzene-n-hexane (1:1).
White crystals of 51T were obtained. Yield 85% m, p, +09-110°C Example 3 2-cyano-3-methylthiopyrazine (compound number 3) CIl mountain DAAN ・++ s O3-< Σ mountain 6
g (0.02 mol) and 40% glyochidyl 2.9
g (0.02 mol) was stirred in 100 ml of ethanol at 50-60°C for 2 hours. After distilling off the ethanol, 100 ml of ethyl acetate was added, the insoluble matter was filtered, and the solution was washed with dilute hydrochloric acid. , dried over anhydrous magnesium sulfate. After distilling off the ethyl acetate, the residue was recrystallized from n-hexane to obtain 1.5 g (yield: 50%) of crystals.

m, p, 81.5-82.5°C Example 4 Cyano-5-methylmethylthiopyrazine (Compound No. 4) N M RlI R1Mass spectrum results support the structure of the target product.

The desoanated product of the target product is JOC29415 (+964
) is exactly the same as 2-methylthio-6-methylpyrazine, which is obtained by chlorinating 2-hydroxy-6-methylpyrazine to produce 2-chloro-6-methylpyrazine and reacting it with methylmercaptide (C1l, 5Na). It was a servant.

was suspended in 200 m 12 of acetonitrile, and 3.1 g (0.03 mol) of triethylamine was added. Uniform? 40% pyruvic aldehyde 5,4 after turning into w liquid
g (0.03 mol) and stirred at room temperature for 2 hours. Benzene was added to the residue left after acetonitrile was distilled off, and the residue was filtered, washed with saturated saline, and dried over anhydrous magnesium sulfate. When the benzene is distilled off, 5 g of the nephrogenic residue remains, so it is subjected to solica gel chromatography (
The effluent solvent was benzene). 3.6g (yield 7
3%) of yellow oblique crystals were obtained. m, p, 83-8
4.5°C Example 5 5 G-dimethyl-3-phenylthiopyrazine 2-carboxamide (compound number 31) 2-cyano-5,6-dimethyl-3=phenylthiopyrazine log was dissolved in concentrated sulfuric acid 60
ml and stirred for 1 day.The reaction mixture was
1. Pour the precipitated crystals of β into ice water. Wash thoroughly with water and dry.

10 g (yield 93%) of the target product was obtained.

m, p, 208-209.5 °C (recrystallized from ethyl acetate).

Example 6 56-Thmethyl-,3-phenylthiopyrazine-2-carboxylic acid (Compound No. 33) 5g of phenylthiopyrazine-2=carboxamide was added to [5%
The mixture was heated and refluxed in 80 m2 of hydrochloric acid for 3 hours.

After extracting the reaction mixture with ethyl acetate, the solvent is distilled off under reduced pressure, and the remaining residue is made alkaline with caustic soda. Crystals precipitate, so they are filtered out. When these crystals are treated with 0=hydrochloric acid, they dissolve once and are easily drained. White crystals precipitated. It was thoroughly washed with water and dried. 1.2 g (yield 24%) of the target product was obtained.

m, p, 12=L5-126'C.

Example 7 5,6-dimethyl-3-phenylthiopyrazine 2-car71eethyl ester (Compound No. 34) 5,6-dimethyl-3-phenylthio-2-pyrazinecarboxylic acid obtained in Example 6 50ml using 1g of concentrated sulfuric acid as a catalyst 1. The mixture was heated to reflux in ethanol for 5 hours. When the alcohol was distilled off, crystals remained, so recrystallization was performed from n-hexane to obtain 1 g of the desired product, 5,6-nomethyl-3-f (90%) obtained in Example 5.

m, p, 79-80°C Example 8 2-cyano-3-phenylsulfonylpyrazine (Compound No. 22) Example 9 23-Tmethyl5-phenylthiopyrazine (Compound Layer 5-37) 10g of 2 -Cyano-3-phenylthiopyrazine 20
The mixture was dissolved in 0 mff1 of chloroform and cooled to below 10°C, and then 17 g of m-chloroperbenzoic acid was added in small portions and the temperature was kept below 10°C. After the addition was complete, the mixture was returned to room temperature and stirred for 3 hours. The precipitated crystals (m
-chlorobenzoic acid) was filtered, and the solution a was washed three times with thorium carbonate water and then with saturated saline. After separating the precipitate layer, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Recrystallized from ethanol or chloroform-〇-hexane, 9.1 g of white crystals were obtained. (yield 7
9%) m, p, 120.5-121.5°C5,6
-Simethyl-3-phenylthiopyrazine-2-calphoky4nomide 1.3 g in 50 ml of 15% hydrochloric acid CZ?
, Q, and heated under reflux for 3 hours. During that time, the solution changed from uncontained to a homogeneous solution. Transfer the reaction mixture to a separatory funnel;
If you add saturated saline, it will become cloudy, so add 100% ethyl acetate.
Extraction was performed by adding mE.

0.4 g of the target product was obtained. Yield 40% no: 1.
6192 Other product was 5,6-notty-3-phenylthiopyrazine-2-carboxylic acid.

Example 10 Ph of 0.96 g of ethyl 5-noano-6-phenylthio-23-virazinenocarboxylate (Compound No. 35)
1.01 g of diethyl dioxotartrate was added dropwise to a solution of 5-DAAN in 20 ml of ethanol at room temperature. After stirring at room temperature for 1 hour, the mixture was heated under reflux for 2 hours.

Ethanol was distilled off under reduced pressure, and the residue was poured into water to extract ethyl acetate. After drying over anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure. 1.3 by column preparation (chloroform)
4 g of yellow crystals were obtained. (Yield 75%) m, p, 83-84°C Example 11 5-cyano-2,3-dioxo-6-phenylthio-1
, 2,3,4-tetrahydropyrazine (compound number 36
) 1.3 g of oxalyl chloride in 7 volumes of 20 ml of dioxane, Ph5-DA at 12-15°C at night.
AN 1.9 g of dioxane? 8iff12On/
! was dripped. After dropping, stir at room temperature for 30 minutes, and then stir for 50 minutes.
Heated at °C for 90 minutes (removes generated HCI)
TLCT: After confirming the disappearance of DAAN, dioxane was distilled off from the reaction solution under reduced pressure using a rotary evaporator. A ladle of 1.79 g of crude product was obtained. After dissolving this crude product in saturated sodium carbonate water and filtering off the insoluble matter,
Neutralization with Hc+ gave 1 g of product.

Yield 41% m, p, 250°C or higher.

Example 12 2-cyano-57-dimethyl-3-phenylthio-1'
, 4,6H-diazepine (compound number 40) ρhs, D
AAN1.91g 20m f! 1.1 g of acedelacetone and 0.03 g of phosphoric acid were added, and the mixture was reacted for 3 hours while water was distilled off by azeotropic dehydration under heating. After the reaction was completed, the reaction solution was cooled and filtered (old materials were removed), and then the solvent was distilled off. The residue was subjected to silica gel force column chromatography θF+'t'14.
] Target 1i 1.2 g <: f5 ta. If! 1LI
7.1% m, p, lll-111,5'C real
Example 13 2-Noano5,6-sihydro7-methyl2]-phenyl-3-phenylthio-1,4,4F+Diazepine (Compound No. 43) PhS-DAAN 1.91 g of ethanol? Add 1.46 g of Handel acetonate to the solution, then add 0.0 g of concentrated sulfuric acid.
．． 05 g was added and reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was analyzed by silica gel column chromatography to obtain 2.7 g of the desired product.

Yield: 85% No.: 1.658 (including the compounds of Examples 1-1-) Representative examples of the compounds of the present invention are shown in Table 1.
Table 2 shows Q.

Table 1 [Effects of the Invention] The compounds of the present invention can be used as raw materials or intermediates for agricultural medicines, fragrances, dyes, millimers, etc., and can be advantageously produced industrially using DAAN as a starting material.

Representative (430) Nippon Soda Co., Ltd. (7125) Yoshi Yokoyama Mika Continued from page 1 ■Int, C1,' Identification code Internal reference number "[Ai] From [Ai] Inventor Hiroshi Hata Tasakino 4/7 days Miji 345 Yanagimachi, Takada, Odawara City, Kanagawa Prefecture Odawara Research Institute, Nippon Soda Co., Ltd. 2767-12 Niihama, Kojima Shio, Kurashiki City, Okayama Prefecture Inside the Mizushima Factory of Nippon Soda Co., Ltd.

Claims (5)

[Claims] (1) General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R is an alkyl group, an aralkyl group, a cycloalkyl group, an alkenyl group, which may be substituted with a heterocycle, or a substituted an aryl group which may have a group, n is 0, 1, 2
, R^1 is hydrogen, cyano group, carbamoyl group or formula C
A group represented by OOR^3 (wherein R^3 represents hydrogen, an alkyl group, an aralkyl group, or an aryl group), R
^2 is an alkyl group, an aryl group which may have a substituent,
an alkoxycarbonyl group or an oxo group, m is 0, 1,
2 (when m is 2 or more, R^2 may be the same or different), and two R^2 may be combined to form a ring. Z represents C-C or C-C-C,
The dotted line indicates that each bond can be a double bond. ] A compound represented by (2) General formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (In the formula, R has the same meaning as above.) Compounds represented by the general formula [III] ▲ Numerical formulas, chemical formulas, There are tables, etc. ▼ (In the formula, R^4 and R^5 are each hydrogen, an alkyl group, an aralkyl group, an aryl group, an alkoxycarbonyl group, or R^4 and R^5 together represent a ring.) General formula [IV] characterized by reacting with a compound represented by
▲There are mathematical formulas, chemical formulas, tables, etc.▼ [IV] (In the formula, R, R^4 and R^5 have the same meanings as above.) A method for producing a compound represented by the formula. (3) General formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (In the formula, R has the same meaning as above.) Compounds represented by the general formula [V] ▲ Numerical formulas, chemical formulas, There are tables etc.▼
(In the formula, R^6 represents chlorine or imidazole group.) General formula [VI] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[VI] (In the formula , R has the same meaning as above). (4) General formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (In the formula, R has the same meaning as above.) Compounds represented by the general formula [VII] ▲ Numerical formulas, chemical formulas, There are tables etc. ▼ (In the formula, R^7 and R^8 are an alkyl group, an aryl group, or R^7 and R^8 together represent a ring.) Featured general formula [VII
I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[VIII] (In the formula, R, R^7 and R^8 have the same meanings as above.) A method for producing a compound represented by the formula. (5) General formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (In the formula, R has the same meaning as above.) Compounds represented by the general formula [IX] ▲ Numerical formulas, chemical formulas, There are tables etc. ▼ [IX] General formula [X] characterized by reacting with a compound represented by (wherein R^9 and R^1^0 represent an alkyl group or an aryl group) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [X] (In the formula, R, R^9 and R^1^0 have the same meanings as above.) A method for producing a compound represented by.